The Biology And Practice Of Current Nutritional Support 2nd Edition (Vademecum)

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Table of contents

7. Protein Metabolism in Liver and Intestine During Sepsis: Mediators, Molecular Regulation, and Clinical Implications

2. Current Nutrient Substrates

8. Biochemical Assessment and Monitoring of Nutritional Status

4. Acute Phase Proteins in Critically Ill Patients 5. Arginine Metabolism in Critical Care and Sepsis 6. Wound Healing and the Role of Nutrient Substrates

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(excerpt)

1. Clinical Implications of Carbohydrate, Proteins, Lipids, Vitamins and Trace Elements in Nutrition Support

3. Biochemistry of Amino Acids: Clinical Implications

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9. Optimizing Drug Therapy and Enteral Nutrition: Detecting Drug-Nutrient Interactions

The Biology and Practice of Current Nutritional Support 2nd edition

10. Techniques and Monitoring of Total Parenteral Nutrition 11. Radiologic Assessment of Nutritional and Metabolic Status 12. Enteral Nutrition: Indications, Monitoring and Complications

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Rifat Latifi Stanley J. Dudrick

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The Biology and Practice of Current Nutritional Support 2nd Edition Rifat Latifi, M.D. Department of Surgery University of Arizona Tucson, Arizona, U.S.A.

Stanley J. Dudrick, M.D. Yale University School of Medicine St. Mary’s Hospital/Yale Affiliate Waterbury, Connecticut, U.S.A.

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GEORGETOWN, TEXAS U.S.A.

VADEMECUM The Biology and Practice of Current Nutritional Support, 2nd Edition LANDES BIOSCIENCE Georgetown, Texas U.S.A. Copyright ©2003 Landes Bioscience All rights reserved. No part of this book may be reproduced or transmitted in any form or by any means, electronic or mechanical, including photocopy, recording, or any information storage and retrieval system, without permission in writing from the publisher. Printed in the U.S.A. Please address all inquiries to the Publisher: Landes Bioscience, 810 S. Church Street, Georgetown, Texas, U.S.A. 78626 Phone: 512/ 863 7762; FAX: 512/ 863 0081 ISBN: 1-57059-595-X

Library of Congress Cataloging-in-Publication Data CIP applied for, but not received at time of printing.

While the authors, editors, sponsor and publisher believe that drug selection and dosage and the specifications and usage of equipment and devices, as set forth in this book, are in accord with current recommendations and practice at the time of publication, they make no warranty, expressed or implied, with respect to material described in this book. In view of the ongoing research, equipment development, changes in governmental regulations and the rapid accumulation of information relating to the biomedical sciences, the reader is urged to carefully review and evaluate the information provided herein.

Dedication Jonathan Evans Rhoads, M.D. 1907-2002 Dedicated to the surgeon of the century, whose extraordinary personal attributes and countless professional, educational and scientific contributions serve as the quintessential model that has greatly influenced and inspired the editors and will continue to endure for future generations. Rifat Latifi, M.D. and Stanley J. Dudrick, M.D.

Contents Foreword ....................................................................... xvii 1. Clinical Implications of Carbohydrate, Proteins, Lipids, Vitamins and Trace Elements in Nutrition Support ......................................................... 1 Larry H. Bernstein Overview .................................................................................................... 1 Stress Hypermetabolism and the Nutritionally-Dependent Adaptive Dichotomy .............................................................................. 2 Energy Requirements of Injured Man ......................................................... 3 Nutritional Requirements ........................................................................... 6 Clinical vs. Laboratory Information ............................................................ 8 Information Model ................................................................................... 10 Length of Stay (LOS) ................................................................................ 11 Improving Correction of Malnutrition ...................................................... 11 Nutrition Support Monitoring .................................................................. 12 Quality Management ................................................................................ 13

2. Current Nutrient Substrates ............................................ 17 Wendy Swails Bollinger, Timothy J. Babineau and George L. Blackburn Introduction ............................................................................................. 17 Hepatic Disease and Stress: Branched-Chain Amino Acid Enriched Diets ..................................................................................... 17 Arginine .................................................................................................... 24 Glutamine ................................................................................................ 27 Nucleotides ............................................................................................... 33 Lipids ....................................................................................................... 35 Conclusion ............................................................................................... 43

3. Biochemistry of Amino Acids: Clinical Implications ....................................................... 52 Rifat Latifi, Khawaja Aizimuddin Introduction ............................................................................................. 52 Structure of Amino Acid and Proteins ....................................................... 52 Amino Acid and Protein Synthesis ............................................................ 53 Post-Synthetic Modification ...................................................................... 54 Protein Function ....................................................................................... 54 Classification of Amino Acids ................................................................... 55 Amino Acids in Critical Illness and Injury ................................................ 58 Amino Acids in Circulation ...................................................................... 59 Digestion of Amino Acids ......................................................................... 59 Absorption of Amino Acids ....................................................................... 60 Biochemical Transformation of Amino Acids ............................................ 61

4. Acute Phase Proteins in Critically Ill Patients ................. 63 Khawaja Azimuddin, Rifat Latifi and Rao R. Ivatury Role of the Acute Phase Response ............................................................. 63 Physiology ................................................................................................ 63 Sequence of Events During Acute Phase Response .................................... 65 Modulation of the Acute Phase Response .................................................. 65 The Acute Phase Proteins .......................................................................... 65 Albumin ................................................................................................... 66 Prealbumin ............................................................................................... 67 Retinol-Binding Protein ............................................................................ 67 Transferrin ................................................................................................ 67 C-Reactive Protein .................................................................................... 67 Ceruloplasmin .......................................................................................... 68 Fibrinogen ................................................................................................ 68 Complement ............................................................................................. 68 Amyloid .................................................................................................... 68 Alpha 1 Acid Glycoprotein ....................................................................... 68 Alpha-1 Protease Inhibitor ........................................................................ 68 Monitoring Nutrition in the Critically Ill Patient ...................................... 69

5. Arginine Metabolism in Critical Care and Sepsis ............ 72 Rima I. Kandalaft, V. Bruce Grossie, Jr. Pathways of Arginine and Ornithine Metabolism ...................................... 72 Fate of Exogenous Arginine ...................................................................... 80 Nitric Oxide in Critical Care .................................................................... 81 Conclusion ............................................................................................... 83

6. Wound Healing and the Role of Nutrient Substrates ...... 88 David A. Lanning, Rifat Latifi Basic Principles of Wound Healing ........................................................... 88 Malnutrition and Wound Healing ............................................................ 89 Nutritional Supplementation and Wound Healing ................................... 91 Specific Nutrients, Vitamins, and Trace Elements ..................................... 92 Conclusion ............................................................................................... 98

7. Protein Metabolism in Liver and Intestine During Sepsis: Mediators, Molecular Regulation, and Clinical Implications .............................................. 103 Timothy A. Pritts, Eric Hungness and Per-Olof Hasselgren Introduction ........................................................................................... 103 Liver ....................................................................................................... 103 Intestine .................................................................................................. 113

8. Biochemical Assessment and Monitoring of Nutritional Status ..................................................... 126 Robert S. DeChicco, Laura E. Matarese, Douglas Seidner and Ezra Steiger The Incidence of Malnutrition ............................................................... 126 Methods of Nutrition Assessment ........................................................... 126

9. Optimizing Drug Therapy and Enteral Nutrition: Detecting Drug-Nutrient Interactions .......................... 145 Marcia L. Brackbill, Gretchen M. Brophy Introduction ........................................................................................... 145 Avoiding Tube Occlusions ...................................................................... 145 Pharmacokinetic Interactions .................................................................. 148 Pharmacodynamic Interactions ............................................................... 150 Influence of Tube Placement on Drug Efficacy ....................................... 151 Optimizing Tolerance to Enteral Nutrition and Drug Therapy ............... 152 Summary ................................................................................................ 153

10. Techniques and Monitoring of Total Parenteral Nutrition ...................................................... 158 Renee Piazza-Barnett, Laura E. Matarese, Douglas L. Seidner and Ezra Steiger Introduction ........................................................................................... 158 Macronutrients ....................................................................................... 158 Micronutrients/Additives ........................................................................ 159 Access/Delivery ....................................................................................... 162 Monitoring Parameters ........................................................................... 163 Complications of Parenteral Nutrition Therapy ...................................... 165 Cycling Total Parenteral Nutrition .......................................................... 177 Conclusion ............................................................................................. 177

11. Radiologic Assessment of Nutritional and Metabolic Status ..................................................... 181 Diane R. Horowitz, Rifat Latifi Introduction ........................................................................................... 181 Ultrasound Use in Assessing Body Composition ..................................... 181 Conclusion ............................................................................................. 190

12. Enteral Nutrition: Indications, Monitoring and Complications ........................................................ 192 Gayle Minard Introduction ........................................................................................... 192 Indications .............................................................................................. 192 Contraindications ................................................................................... 194 Monitoring ............................................................................................. 194 Complications ........................................................................................ 195 Conclusion ............................................................................................. 198

13. Enteral Access: Open, Endoscopic & Laparoscopic Techniques .......................................... 199 Keith Zuccala, John M. Porter Gastrostomy ........................................................................................... 199 Jejunostomy ............................................................................................ 203 Conclusion ............................................................................................. 206

14. Total Parenteral Nutrition: Current Concepts and Indications ............................................................. 208 Rifat Latifi, Stanley J. Dudrick Introduction ........................................................................................... 208 General Indications for Use of TPN ........................................................ 209 Specific Indications for Total Parenteral Nutrition .................................. 210 Short Bowel Syndrome ........................................................................... 210 Enterocutaneous Fistula .......................................................................... 211 Inflammatory Bowel Disease ................................................................... 212 Liver Failure ............................................................................................ 212 Acute Pancreatitis .................................................................................... 214 Cancer and TPN: To Feed or Not to Feed? ............................................. 215

15. Intestinal Adaptation: New Insights .............................. 219 Jon S. Thompson Introduction ........................................................................................... 219 Structural Changes .................................................................................. 219 Functional Adaptation ............................................................................ 220 Summary ................................................................................................ 230 Systemic Factors ...................................................................................... 230 Clinical Implications ............................................................................... 235

16. Intestinal Regeneration and Nutrition .......................... 250 Jon S. Thompson, Shailendra K. Saxena and John G. Sharp Introduction ........................................................................................... 250 Mechanism ............................................................................................. 250 Clinical Implications ............................................................................... 253

17. Nutritional and Metabolic Management of Short Bowel Syndrome ............................................. 261 Stanley J. Dudrick, Frizan Abdullah and Rifat Latifi Introduction ........................................................................................... 261 Pathophysiology ...................................................................................... 263 Nutritional and Metabolic Management ................................................. 265 Immediate Postoperative Period .............................................................. 265 Bowel Adaptation Period ........................................................................ 268 Long-Term Management Period ............................................................. 270 Growth Hormone, Glutamine, and Hormone Modified Diet ................. 270 Surgical Considerations ........................................................................... 271

18. Pharmacologic Aspects of Short Bowel Syndrome ........ 275 Patricia Pecora Fulco, Donald F. Kirby Physiologic Considerations ..................................................................... 275 Site Specific Contributions ..................................................................... 276 Adaptation .............................................................................................. 278 Intravenous Access in SBS Patients ......................................................... 278 Conclusion ............................................................................................. 296

19. Nutritional Support in Inflammatory Bowel Disease .... 306 John H. Seashore, Melissa F. Perkal Introduction ........................................................................................... 306 Malnutrition in Inflammatory Bowel Disease ......................................... 306 Nutritional Support in Inflammatory Bowel Disease ............................... 309 Summary ................................................................................................ 314

20. Nutrition Support of Acute Pancreatitis........................ 320 Rifat Latifi, Stanley J. Dudrick Introduction ........................................................................................... 320 Pathophysiology of Acute Pancreatitis ..................................................... 320 Alcohol and Biliary Disease ..................................................................... 322 Oxygen-Derived Free Radicals ................................................................ 322 Pancreatic Ischemia in Experimental Acute Pancreatitis .......................... 323 Metabolic Changes and Other Complications in Acute Pancreatitis ........................................................................... 323 Biochemical Abnormalities ..................................................................... 325 Lung Injury ............................................................................................ 326 Nutritional Management in Acute Pancreatitis ....................................... 326 The Effects Of Nutrient Substrates ......................................................... 327 Inhibition of Pancreatic Secretion ........................................................... 328 Rationale for TPN in Acute Pancreatitis ................................................. 329 Dextrose and Amino Acids ..................................................................... 329 Lipids ..................................................................................................... 330 Administration and Monitoring of TPN ................................................. 330

21. Nutritional Management of Chronic Pancreatitis: Current Concepts .......................................................... 334 Rifat Latifi, Paul G. Perch and Stanley J. Dudrick Introduction ........................................................................................... 334 Etiologic and Risk Factors of Chronic Pancreatitis .................................. 335 Nutritional Deficiencies in Chronic Pancreatitis ..................................... 335 Pancreatic Diabetes ................................................................................. 336 Diagnosis of Malabsorption in Chronic Pancreatitis ................................ 336 Principles of Clinical Management of Chronic Pancreatitis ..................... 337 Enteral Feeding ....................................................................................... 338 Total Parenteral Nutrition ....................................................................... 339 Nutrient Substrates in Chronic Pancreatitis ............................................ 339 Enzyme Treatment of Exocrine Pancreatic Insufficiency .......................... 340 The Role of Exogenous Pancreatic Enzymes in Pain Management .......... 341 The Effect of Exogenous Enzymes in Gastrointestinal Hormones ........... 342 Conclusion ............................................................................................. 342

22. Nutritional Support in Liver Failure and Liver Transplantation ............................................. 346 Rifat Latifi Introduction ........................................................................................... 346 Malnutrition in Patients with Chronic Liver Disease .............................. 347 Hepatic Encephalopathy ......................................................................... 347

Amino Acids in Hepatic Encephalopathy ................................................ 349 Nutritional Assessment ........................................................................... 350 Peritransplant Nutrition: Support ........................................................... 352 Metabolic Changes ................................................................................. 353 Nutrition Status of Donors ..................................................................... 353 How to Feed Liver Transplant Patients .................................................... 354 Conclusion ............................................................................................. 356

23. Nutritional Support in Renal Transplantation .............. 360 Susan T. Crowley, Richard Formica and Antonio Cayco Introduction ........................................................................................... 360 Protein Malnutrition and Nitrogen Balance ............................................ 360 Dyslipidemia .......................................................................................... 362 Vitamin Supplementation ....................................................................... 364 Bone Metabolism .................................................................................... 365 Summary ................................................................................................ 366

24. Biology of Nutrition Support in the Critically Ill Patient ............................................ 369 Rifat Latifi, Selman Uranües Introduction ........................................................................................... 369 Protein and Nitrogen Metabolism in Critically Ill Patients ...................... 370 Amino Acid Metabolism ......................................................................... 370 Branched-Chain Amino Acids (BCAA) ................................................... 372 Nucleotides and Nucleic Acids in Nutritional Support ............................ 372 Omega 3-Fatty Acids .............................................................................. 375 Growth Hormone ................................................................................... 375 Immune-Enhancing Enteral Nutrition: Clinical Evidence ....................... 376 Summary ................................................................................................ 378 Selected References ................................................................................. 379

25. Nutrition Support in Patients with Pulmonary Failure and ARDS ......................................................... 384 Vanessa Fuchs, A.K. Malhotra and Rifat Latifi Malnutrition and Lung Functions ........................................................... 384 Anatomy of Respiratory Failure .............................................................. 384 Acute Respiratory Distress Syndrome (ARDS) ........................................ 385 Nutritional Assessment ........................................................................... 387 Molecular Basis Nutritional Management ............................................... 389 Summary ................................................................................................ 392

26. Nutritional Support for the Burned Patient .................. 395 G.J.P Williams, Michael J. Muller and David N. Herndon Introduction ........................................................................................... 395 Hypermetabolism in Burns ..................................................................... 395 Physiologic Responses to Burn Injury ..................................................... 397 Nutritional Support ................................................................................ 399 Hormonal Manipulation of Burn Hypermetabolism ............................... 406 Summary ................................................................................................ 409

27. Nutritional Support after Small Bowel Transplantation ............................................................. 418 S. Janes, S.V. Beath Introduction ........................................................................................... 418 Recovery from Ischemia and Preservation ............................................... 419 Weaning off Parenteral Nutrition ............................................................ 420 Establishment of Normal Diet ................................................................ 424 Monitoring ............................................................................................. 424 Complications after Intestinal Transplant and Implications for Nutritional Support ...................................................................... 425 Conclusion ............................................................................................. 426

28. Nutritional Support in Patients with Head and Neck Cancer ........................................................... 430 Matthew E. Cohen, Rosemarie L. Fisher Introduction ........................................................................................... 430 Risk Factors for Malnutrition .................................................................. 430 Malnutrition and Clinical Outcome ....................................................... 432 Surgery, Nutritional Support and Clinical Outcome ............................... 434 Radiotherapy, Nutritional Support and Clinical Outcome ...................... 439 Chemotherapy, Nutritional Support and Clinical Outcome .................... 440 Enteral Nutrition Delivery ...................................................................... 441 Surgical Gastrostomy or Jejunostomy ...................................................... 444 Conclusion ............................................................................................. 445

29. Nutritional Support in Patients with Gastrointestinal, Pancreatic and Liver Cancer .......................................... 449 Matthew E. Cohen Esophageal Cancer .................................................................................. 453 Gastric Cancer ........................................................................................ 455 Colon Cancer ......................................................................................... 456 Pancreatic Cancer ................................................................................... 459 Liver Cancer ........................................................................................... 460 Cost Effectiveness ................................................................................... 463 Conclusion ............................................................................................. 464

30. The Treatment of Obesity ............................................. 473 Souheil Abou-Assi, Rifat Latifi and Stephen J.D. O’Keefe Epidemiology .......................................................................................... 473 Measurements of Obesity ........................................................................ 473 Health Risks Associated with Obesity ..................................................... 474 Can Obesity and Its Co-Morbid Diseases Be Reversed? .......................... 475 Summary of Interventions, and Results of Randomized Controlled Trials ................................................................................ 475 Bariatric Surgery ..................................................................................... 481 Current Operations ................................................................................ 481 Nutritional Complications Following Bariatric Surgery ........................... 484

Index ............................................................................. 489

Editors Rifat Latifi, M.D. Associate Professor of Clinical Surgery Department of Surgery University of Arizona Tucson, Arizona, U.S.A. Chapters 3, 6, 11, 17, 20, 24, 25, 30

Stanley J. Dudrick, M.D. Professor of Surgery Yale University School of Medicine St. Mary’s Hospital/Yale Affiliate Waterbury, Connecticut, U.S.A. Chapters 14, 17, 20, 21

Contributors Frizan Abdullah Department of Surgery Yale University New Haven, Connecticut, U.S.A. Chapter 17

S. V. Beath The Birmingham Children's Hospital and University of Birmingham Birmingham, U.K. Chapter 27

Souheil Abou-Assi Section of Nutrition Division of Gastroenterology Department of Internal Medicine Richmond, Virginia, U.S.A.

Larry H. Bernstein Yale University Pathology Bridgeport, Connecticut, U.S.A. Chapter 1

Chapter 30

Khawaja Azimuddin University of New Mexico Espanola Hospital Espanola, New Mexico, U.S.A. Chapters 3, 4

George L. Blackburn Division of Nutrition Beth Israel Deaconess Medical Center Harvard Medical School Boston, Massachusetts, U.S.A. Chapter 2

Timothy J. Babineau Minimally Invasive Surgery Boston Medical Center Boston University School of Medicine Boston, Massachusetts, U.S.A. Chapter 2

Wendy Swails Bollinger Department of Health Matters Pennsylvania State University University Park, Pennsylvania, U.S.A. Chapter 2

Marcia Brackbill Department of Pharmacy Shenandoah University Winchester, Virginia, U.S.A.

Rosemarie L. Fisher Section of Digestive Diseases Yale University School of Medicine New Haven, Connecticut, U.S.A.

Chapter 9

Chapter 28

Gretchen M. Brophy Department of Pharmacy and Neurosurgery Virginia Commonwealth University Medical College of Virginia Richmond, Virginia, U.S.A.

Richard Formica Section of Nephrology Yale University School of Medicine New Haven, Conneticut, U.S.A.

Chapter 9

Vanessa Fuchs Hospital General de México The American British Cowdray Medical Center México DF, Mexico

Antonio Cayco Section of Nephrology Yale University School of Medicine New Haven, Connecticut, U.S.A.

Chapter 23

Chapter 25

Chapter 23

Matthew E. Cohen Section of Digestive Diseases Yale University School of Medicine New Haven, Connecticut, U.S.A.

Bruce Grossie Department of Nutrition and Food Sciences Texas Woman's University Denton, Texas, U.S.A.

Chapters 28, 29

Chapter 5

Susan T. Crowley Section of Nephrology Yale University School of Medicine New Haven, Conneticut, U.S.A.

Per-Olof Hasselgren Department of Surgery Beth Israel Medical Center Harvard Medical School Boston, Massachusetts, U.S.A.

Chapter 23

Chapter 7

John M. Daly Department of Surgery Weill Medical College of Cornell University New York, New York, U.S.A.

David N. Herndon Galveston Shriners Hospital Blocker Burn Unit Galveston, Texas, U.S.A.

Forward

Chapter 26

Robert S. Dechicco The Cleveland Clinic Foundation Cleveland, Ohio, U.S.A.

Diane R. Horowitz Radiologist Private Practice Orlando, Florida, U.S.A.

Chapter 8

Chapter 11

Eric Hungnness Department of Surgery University of Cincinnati Cincinnati, Ohio, U.S.A. Chapter 7

Rao R. Ivatury Virginia Commonwealth University Department of Surgery Medical College of Virginia Hospitals and Physicians Richmond, Virginia, U.S.A.

A. K. Malhotra Virginia Commonwealth University Department of Surgery Medical College of Virginia Hospitals and Physicians Richmond, Virginia, U.S.A. Chapter 25

Laura E. Matarese The Cleveland Clinic Foundation Cleveland, Ohio, U.S.A. Chapters 8, 10

Chapter 4

S. Janes The Birmingham Children's Hospital and University of Birmingham Birmingham, U.K. Chapter 27

Rima I. Kandalaft Department of Nutrition and Food Sciences Texas Woman's University Denton, Texas, U.S.A. Chapter 5

Donald F. Kirby Section of Nutrition Medical College of Virginia Hospitals Richmond, Virginia, U.S.A. Chapter 18

David A. Lanning Children’s Hospital of Michigan Wayne State University Detroit, Michigan, U.S.A. Chapter 6

Gayle Minard Department of Surgery The University of Tennessee Memphis, Tennessee, U.S.A. Chapter 12

Michael M. J. Muller Department of Surgery South Auckland Burn Service Middlemore Hospital Otahuhu, Auckland, New Zealand Chapter 26

Stephen J. D. O'Keefe Section of Nutrition Division of Gastroenterology Department of Internal Medicine Richmond, Virginia, U.S.A. Chapter 30

Patricia Pecora Fulco Medical College of Virginia Hospitals Virginia Commonwealth University Richmond, Virginia, U.S.A. Chapter 18

Paul G. Perch Department of Surgery Virginia Commonwealth University Medical College of Virginia Hospitals and Physicans Richmond, Virginia, U.S.A. Chapter 21

Melissa F. Perkal Department of Surgery Yale University School of Medicine New Haven, Connecticut, U.S.A. Chapter 19

Renee Piazza-Barnett The Cleveland Clinic Foundation Cleveland, Ohio, U.S.A. Chapter 10

John M. Porter Department of Surgery University of Arizonia Tucson, Arizona

John G. Sharp Department of Anatomy University of Nebraska Medical Center Surgical Services at the Omaha VA Medical Center Omaha, Nebraska, U.S.A. Chapters 15, 16

Jon S. Thompson Department of Surgery University of Nebraska Medical Center Omaha, Nebraska, U.S.A. Chapter 15, 16

Chapter 13

Timothy A. Pritts Department of Surgery University of Cincinnati Cincinnati, Ohio, U.S.A.

Selman Uranues Department of Surgery AustriaGraz University Graz, Austria Chapter 24

Chapter 7

Shailendra K. Sazena Department of Surgery University of Nebraska Medical Center Omaha, Nebraska, U.S.A. Chapters 15, 16

John H. Seashore Yale University School of Medicine New Haven, Connecticut, U.S.A. Chapter 19

Douglas L Seidner The Cleveland Clinic Foundation Cleveland, Ohio, U.S.A. Chapters 8, 10

Ezra Steiger Cleveland Clinic Hospital Cleveland, Ohio, U.S.A. Chapter 8

G.J.P. Williams Clinical Burns Fellow Shriners Burns Hospital Galveston, Texas, U.S.A. Chapter 26

Abdulmasih Zarif St. Mary's Hospital Waterberry, Connecticut, U.S.A. Chapter 17

Keith Zuccala Danbury Hospital Danbury, Connecticut, U.S.A. Chapter 13

Foreword It has been over 35 years since Dudrick et al described the growth of beagle puppies fed intravenously demonstrating normal weight gain and normal growth compared to their orally fed counterparts. This major achievement is worthy of all the accolades that have been heaped on Drs. Dudrick, Rhoades and Vars for this work done at the University of Pennsylvania. These studies demonstrated for the very first time that one could grow an animal from a young age by administration of all nutrients by vein. This study in animals was followed shortly thereafter in 1967 by the birth of a young child with intestinal atresia. She was treated for well over a year with intravenous nutrition demonstrating normal growth. Studies such as these were replicated in a whole variety of clinical situations such as trauma, cancer, inflammatory bowel disease, radiation enteritis, G-I fistula and poor wound healing. Major achievements by Dr. Dudrick were not only to initiate a new therapy and bring it from the laboratory to the clinical bedside but also to refine the technique such that it could be applied with low morbidity. The development of nutrition support teams and the development of the American Society of Parenteral and Enteral Nutrition were created by the concept of teaching proper nutritional support throughout the world. Teams of doctors, nurses, dietitians and pharmacists as well as others came together in hospitals to administer parenteral and enteral nutrition. Utilization of teams minimized complications and maximized effectiveness. The decade of the 1970’s was marked by the ever-increasing use of parenteral nutrition demonstrating its metabolic efficacy in terms of weight gain, serum protein metabolism, wound healing and improvement in outcome. Prospective randomized trials were then begun and carried through into the 1980’s evaluating the use of parenteral nutrition compared with other modalities in situations of cancer treatment. The use of crystalline amino acids replaced protein hydrolysates. Fat emulsions were refined and brought into general use. Multi-vitamin preparations were better defined along with micronutrient requirements. These studies were painstaking occurring in both animal models and in humans, but they

were necessary as new nutrient administration techniques gave rise to vitamin and mineral deficiencies. Early recognition of these problems led to their solution. The decades of the 1980’s and 1990’s demonstrated efficacy of certain specific amino acids that would provide either metabolic fuels such as glutamine for the intestinal track and for muscle as well as specific amino acids such as arginine that might enhance immune effector cell function. Omega-3 fatty acids, use of RNA and use of specific vitamins and minerals were demonstrated to enhance immunological cell function. We entered an age of nutrient pharmacology as noted by Dr. J. Wesley Alexander. Prospective randomized trials of enteral and parenteral nutrition were carried out in elective surgery patients as well as critically ill patients in the intensive care unit. These studies focused not only on clinical outcome measures but also focused on cost efficiencies. Again, use of nutritional support teams in hospitals minimized morbidity using nutritional support. Drs. Latifi and Dudrick have superbly put this text, “The Biology and Practice of Current Nutrition Support”, together. The chapters vary from methods of assessing and monitoring nutritional status to those of the use of intravenous and enteral nutritional support. Practical chapters define laparoscopic placement of feeding tubes as well as the use of a variety of nutritional substrates, which can be administered in different clinical scenarios. Of particular importance, is the chapter on nutritional metabolic management of the short bowel syndrome. Dr. Dudrick was the first to propose the use of long-term intravenous nutritional support for patients with short gut syndrome and defined quite well the metabolic needs of these patients. Many were kept alive for long periods of time by their intestinal tract to adapt and finally giving way to combinations of enteral and parenteral nutrition. There is no question that the discovery, implementation and utilization of total parenteral nutritional support have made enormous benefits to our patients; saving lives and improving clinical outcome. The recent death of Dr. Jonathan E. Rhoads, former Chairman of the Department of Surgery at the University of Pennsylvania and mentor to Dr. Stanley J. Dudrick exemplifies the value of an inquisitive mind and the strength of working in partnership with many others to achieve beneficial outcomes. John M. Daly, M.D. Lewis Atterbury Stimson Professor Chairman, Department of Surgery Weill Medical College of Cornell University Surgeon-in-Chief New York Presbyterian Hospital-Weill Cornell Center

CHAPTER 1 CHAPTER 1

Clinical Implications of Carbohydrate, Proteins, Lipids, Vitamins and Trace Elements in Nutrition Support Larry H. Bernstein

Overview Malnutrition occurs in 30-50% of hospitalized patients admitted to acute care hospitals.1 Patients who are malnourished or are at malnutrition risk usually have risk factors or disease co-morbidities, any and all of which, unattended, may adversely affect the outcomes of the surgical patient. Severe malnutrition is usually easily recognized merely by extreme or significant weight loss, loss of strength, and loss of function. Identifying severe malnutrition in a timely manner, then, should lead to appropriate intervention.1,2 Nevertheless, that is not always the case, and malnutrition of moderate degree is often unnoticed at the time of admission. It is especially important for surgeons to be aware of the risk of malnutrition, particularly in the geriatric patient, because of the very strong association between malnutrition and postoperative complications.3,4 Malnutrition occurs with co-morbidities and is a significant co-morbidity. The surgeon also has to be concerned with the effects of the metabolic requirements for acute injury independent of and interacting with a malnourished state.

The Malnutrition Risk The problem of unrecognized patient risk is tied to our conception and definition of the malnutrition risk. Increasingly, the risk of malnutrition is viewed in terms of unexpected complications, such as, pneumonia, urinary infection, sepsis, systemic inflammatory response syndrome (SIRS), which lends itself to expression in statistical terms. That has not always been the case.

Definitions of Malnutrition We traditionally make a distinction between marasmus, or chronic inanition and kwashiorkor. Marasmus is starvation with loss of fat stores and skeletal muscle, but sparing of circulating transport proteins produced by the liver. Kwashiorkor is defined by the decrease in circulating plasma proteins. These concepts fit neatly into measurement criteria using anthropometrics and the laboratory, but they don’t embody the dynamic changes of the critically-ill patient. We refine our concept of the high risk surgical patient, in particular, by reviewing the metabolic response to stress injury.

The Biology and Practice of Current Nutritional Support, 2nd Edition, edited by Rifat Latifi and Stanley J. Dudrick. ©2003 Landes Bioscience.

2

The Biology and Practice of Current Nutritional Support

Imperative for Nutritional Intervention

1

The identification of geriatric surgical patients at high risk for malnutrition and initiating their timely nutritional support is a critical standard of care issue used by the Joint Commission for Accreditation of Healthcare Organizations. This can be achieved by a systematized program for identifying patients who might need either nutritional supplements or aggressive nutritional support. The program has to identify chronic losses and an acute stress state by both clinical and laboratory characteristics and allow for timely correction of deficits.5,6

Stress Hypermetabolism and the Nutritionally-Dependent Adaptive Dichotomy Stress Injury Stress injury is described in three stages: the ebb phase, the catabolic flow phase, and the anabolic flow phase.7,8 The ebb phase is dominated by circulatory changes that requires fluid resuscitation over a period of 8-24 hours. The catabolic flow phase is dominated by catabolism with initial liver glycogenolysis over the first 24 hours concomitant with skeletal muscle proteolysis to provide gluconeogenic substrates, and lipolysis to provide fatty acid fuel for energy after enzyme induction. This phase lasts for three to 10 days, but may be extended. The anabolic flow phase emerges as metabolism shifts to synthetic activities and reparative processes.

Cytokine and Hormonal Events It is essential to control the hormonal and metabolic balances in these phases for the metabolic management of the stressed patient. The catabolic flow phase is driven by cytokine mediators released by lymphocytes and macrophages in the cellular immune reaction, dominated by interleukin-6 (IL-6).9 The release of these mediators is proportionate to the amount of the injury. The release of cytokines is linked to upregulation of hormonal and humoral events.9 The hormonal events include the release of glucagon and catecholamines, thyroid hormone, growth hormone, and cortisol, and their effects—hyperglycemia, metabolic rate, release of free fatty acids and associated ketosis, insulin growth factor 1 (IGF1), and negative nitrogen balance from gluconeogenesis.

Catabolic Reactions The principal action of glucagon is on the conversion of hepatic glycogen to glucose, thereby, raising the plasma glucose level. Thyroid hormone (T4) has an effect on target organs through the free hormone (FT4). The catabolic effect of growth hormone on lipid metabolism is reciprocal to an anabolic effect through IGF1. An adrenal cortisol secretory response opposes the action of insulin and promotes a diabetogenic response. Hypercortisolemia results in muscle proteolysis. Amino acids, especially branch chains amino acids from skeletal muscle, provide the gluconeogenic precursors through alanine. These hormones are released by the stress response and drive the metabolic pathways necessary for the use of carbohydrate and fatty acid fuels, and necessary to support the repair of damaged tissue. The humoral events include the changes in and interactions between serum proteins in the inflammatory response. The systemic effects of fever, tachycardia, increased energy expenditure, muscle weakness and wasting are associated with the elevations of acute phase reactants (APRs) (C-reactive protein, tumor necrosis factor-alpha, alpha-1 acid glycoprotein) and hormonal changes.7,8

Clinical Implications of Nutrition Elements

3

Suppressed Syntheses The stress response immediately suppresses synthetic activity by the liver,9 an organ that has a sole synthetic function with NADP dominated pathways. The serum cholesterol decreases as does the production of essential transport proteins, such as, albumin, transferrin, cortisol-binding globulin (CBG), thyroxine-binding globulin (TBG), transthyretin or thyroxine-binding prealbumin (TTR), insulin growth-factor 1 (IGF1).9 While the transport proteins decline abruptly by as much as 40%, the synthesis of APRs is unaffected. Their essentially controlling and adaptive role they exert through their binding to and effects on active ligands.

Nutritionally-Dependent Adaptive Dichotomy (NDAD) The above relationship, under the influence of cytokines, Ingenbleek refers to as the nutritionally-dependent adaptive dichotomy (NDAD).9 One has to also consider that this adaptive relationship in stress injury is affected by protein malnutrition prior to the injurious state. Why? Because the basal level of binding proteins is set low and the adaptive response is blunted.

Free Ligands and the Adaptive State The metabolic effect of stress injury in the catabolic phase increases the flow of fuel substrates for energy using processes by its effect on the liver. The decrease in CBG, TBG, TTR and RBP increases the hypermetabolic effect. The free hormone hypothesis states that hormonal effect on target tissue is a result of the free hormone. The adrenal gland is releasing increased cortisol which has an amplified effect with it’s binding to a lower plasma concentration of CBG. The liver is the repository for extrathyroidal T4. The extrathyroidal T4 is released with a decreased circulating TBG and TTR.9 The result is an increased thyroidal activity measured by an increased free T4 (FT4). This is actually what is referred to as the sick euthyroid syndrome. The TSH is not affected or slightly decreased, but not in the hyperthyroid range. Vitamin A is stored in the liver, and it is transported in the circulation in a complex with TTR and RBP. The vitamin A and RBP are dependent on the level of TTR.

Effect of Stress Injury on Liver Syntheses The metabolic effect of stress injury on the liver is coupled with the reciprocal effect of GSH.9 The decreased synthesis of GSH dependent IGF1 occurs with a high level of GSH. The IGF1 promotes anabolism and protein retention. The result is an increase of lipid utilization with a breakdown of lean body mass to support gluconeogenesis. The IGF1 is bound to IGF1 binding protein-3 (IGFBP-3), which is unaffected by stress. The decreased level of IGF1, which has a short halflife of 8 hours, results in a decrease in the free and active protein, supporting the increased catabolism.

Energy Requirements of Injured Man Proteolysis and Nitrogen Loss The hypermetabolism as it affects protein metabolism is measured by the breakdown of skeletal muscle and the oxidation of amino acids through alanine to alpha-ketoglutarate in the Krebs cycle.7,8 This results in the release of the amino group and the production of urea nitrogen through the urea cycle. The somatic protein loss is also associated with the release of 3-methyl histidine, an amino acid specific for skeletal muscle that is excreted into the urine with urea nitrogen.

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Cuthbertson described the catabolic loss of nitrogen that cccurs with severe injury and is associated with skeletal muscle wasting, loss of strength, and attributed to extensive breakdown of muscle.7,8 The increased rate of metabolism in stress injury is measured by the rate of protein oxidation and by the rate of CO2 production. The rate of protein oxidation is measured by the rate of nitrogen appearance in the urine. There is normally 4 grams of unmeasured nitrogen to be accounted for in 24 hours, so the total nitrogen is calculated from urinary urea nitrogen by adding 4 grams, assuming that the nonurea nitrogen is negligible.

Nitrogen Loss and Gluconeogenesis The rate of gluconeogenesis is decreased in normal man, a nitrogen sparing effect, when 6-10 grams of carbohydrate is provided. The rate of gluconeogenesis is not increased in starvation as the body economy relies on lipolysis and fatty acid fuels associated with ketogenesis. These patients have a normal or decreased urinary nitrogen. The rate of gluconeogenesis is accelerated during the acute catabolic state, even when glucose is provided. This is unabated, though, by providing exogenous glucose.10 The loss of nitrogen with trauma or sepsis is related to the extent of the injury.7,8 Nitrogen balance studies measure nitrogen equilibrium, which is the net loss or gain of protein from the body.11 The nitrogen loss after severe injury is proportional to the severity and extent of trauma, and it tapers off in days. Indeed, the nitrogen loss is greatest with severe trauma and delayed refeeding. The net accretion of body protein in the reparative phase is slow in the post-injury phase and has been measured by Hill and associates using whole body neutron activation analysis.12 Anabolism with refeeding occurs at a constant rate of 3 gm of nitrogen (20 gm protein) per 70 kg body weight per day, but muscle activity is required for rebuilding the loss.12

Stress Metabolism of Carbohydrate and Fat Stress injury results in alterations in carbohydrate and fat utilization. Adipose tissue is converted to fatty acids and glycerol as described above. Fatty acids are oxidized by non glucose-dependent tissues. The glycerol is and unoxidized ketones are used as a glucose fuel. As the concentration of plasma glucose rises in severe injury, the hyperglycemia is related to crude muscle losses with increased urinary nitrogen loss. The site of injury is supported by the breakdown of whole body protein to support the immune response. This is not associated with a lack of insulin, but with increased activities of counterregulatory hormones opposing the insulin action.9 Fat is not utilized as the primary fuel in the extensively injured extremity because of the shift to glycolytic metabolism in the injured tissue associated with increased production of lactate.7-9 A significant amount of glucose production by the liver is from lactate and pytuvate as the wound metabolizes glucose.

Measuring Energy Expenditure Indirect calorimetry and tracer techniques are used to study substrate oxidation in vivo.10,13,14 The latter requires blood sampling and is only used in the research setting. CO2 production is used to measure substrate oxidation and energy expenditure by indirect calorimetry from measurement of respiratory gas exchange rates. The method assumes the CO2 expired is proportional to the rate of respiration. The assumption depends on the O2 disappearing from the inspired air being used exclusively for biological oxidations so that all the CO2 expired is derived from

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combustion of substrates. It is also assumed that all of the nonprotein nitrogen excreted into the urine is derived only from the oxidation of free amino acids, which is 16% of the nitrogen content. Indirect calorimetry measures the net loss of substrate by oxidation, regardless of cycling that may occur along the way. The method of indirect calorimetry and the Fick principle both measure the oxygen consumption (VO2) and the carbon dioxide production (VCO2). Indirect calorimetry measures the oxygen consumption (VO2) and the transpulmonary O2 gradient from the respiratory gas exchange. Fick proposed to measure the VO2 and VCO2 from gas exchange and the transpulmonary O2 and CO2 gradient by heart catheterization. In this idealized model, the O2 input and CO2 output is measured, and the cardiac output (CO) provides the flow rate. The result is: VO2 = CO (arterial O2 – mixed venous O2) VCO2 = CO (arterial CO2 – mixed venous CO2) Assuming that ambient air is the only source for O2 and the only sink for metabolic CO2, the VO2 and the VCO2 are measured from the fractional concentrations of O2 and CO2 concentrations in the inspired (FI) and the expired (FE) air flows. The calculation is: VO2 = (FIO2 – FEO2)Ve VCO2 = (FICO2 – FECO2)Ve, where Ve is the ventilatory rate. The only significant difference between these is that the measures of VCO2 are 12% lower and less accurate with Fick than with indirect calorimetry.13

Energy of Fuels The respiratory quotient (RQ), defined as VCO 2/VO2, is the measure of efficiency of respiration.10 The calorimetric RQ is between 0.69 and 1.00. The energy expenditure being measured by the VO2, a value of less than 1.0 is incomplete combustion. RQ is important for calculating the nutritional requirements in providing assisted nutritional support. The RQ for fat is 0.7, whereas the RQ for carbohydrate is 1.0. We have to weigh the advantage of the administration of fat versus carbohydrate energy sources. Fat has an advantage over carbohydrate because it is a dense calorie source and it is efficiently oxidized based on it’s low RQ. The effect of excessive carbohydrate calories is excessive CO2 production, which drives a hyperpnea, detrimental to the pulmonary compromized patient. Lipid has a rate of administration that is rate limited by it’s clearance. Excessive fat administration is immunosuppressive.

Harris-Benedict Equation The use of indirect calorimetry is limited in most clinical settings, except for intensive care units, because of cost requirements for the technology and for the staffing. The Harris-Benedict equation is most commonly used to calculate the estimated calorie and protein needs with reasonable agreement with actual needs. Males BEE = 66.47 + 13.75 W + 5.0 H—6.76 A Females BEE = 655.10 + 9.56 W + 1.85 H—4.68 A, where W is weight in kg, H is height in cm and A is age in years. Consideration must be given to existing energy needs that go beyond basal or resting needs. This basic estimate of energy needs (BEE/REE) is often increased to reflect the energy required for physical activity and any anticipated hypermetabolic response to injury or illness. BEE x (activity factor) x (injury factory) = TEE (total energy expenditure)

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Nutritional Requirements

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Energy Requirements Under Stress The calorie and protein requirements for stressed patients are shown in Table 1.1. For normal energy needs 100-150 g of CHO must be furnished daily. Glucose oxidation under normal conditions is at approximately 2-4 mg/kg/min, and in severe stress is only slightly greater at 3-5 mg/kg/min. Catabolism of peripheral muscle and lipolysis release carbohydrate and lipid substrates in severe stress (14). An excess of 400-500 g of glucose per day is not used. However, administration of carbohydrate as a sole energy source has a calorigenic effect, increasing the utilization of fuel by about 20% over REE. Protein sparing by glucose is abrogated by severe stress.

Protein Requirements Protein is required for growth, maintenance and repair of tissue. 6.25 grams of protein has one gram of nitrogen. Nitrogen balance occurs when protein synthesis and breakdown are in equilibrium. Dietary protein contains 20 common amino acids of which nine are essential. The recommended dietary allowance of protein for an adult (non pregnant or lactating) is 0.8 g/kg/day. In the catabolic phase of acute stress or trauma, protein requirements are increased at 1.5 to 2.0 g/kg/day or more for wound repair, or to replace protein lost in drainage of exudate. The provision of adequate calories and protein is mandatory.

Fat Requirements 35% of diet intake as fat is required for energy and for essential fatty acids. EFAD occurs at a ratio of 0.4 or greater. Linolenic acid deficiency is characterized by: growth retardation, scaly dermatitis, and alteration of the normal triene:tetrene ratio. Linoleic acid is derived from linoleic and may be derived exogenously. Oils as corn, soy and safflower contain 50-70% of their fat as linolenic. Linoleic acid is a precursor of arachidonic acid, which is needed for prostaglandin and thromboxane synthesis. Most lipid emulsions presently available are composed for the most part of long chain triglycerides (LCT). Complications from use of LCTs include compromised immune function, hyperlipidemia, impaired alveolar diffusion capacity, and reduced function of the reticulo-endothelial system.

Minerals and Trace Elements The macronutrients, water and electrolytes constitute the major part of nutrient intake, regardless of the route of administration. The major minerals—calcium, phosphorus, and magnesium, and electrolytes—sodium, potassium and chloride must be provided. They are essential for neuromuscular, cardiac, endocrine and skeletal function. Potassium is the main intracellular cation and it is in equilibrium with sodium, divalent cations, and anions. Its intracellular concentration is 140 mmol/L. The total body potassium is 71 mmol/kg. The total body potassium is depleted in malnourished surgical patients, and it is disproportionately reduced compared with nitrogen. It is increased with short term TPN without increasing the total body nitrogen, but long term feeding also increases nitrogen.11 It is important to keep in mind the following: 1. glucose infusions increase the need for K+; 2. there is a retention of 3 meq K+ per gm of nitrogen;

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Table 1.1. Stress 0 1 2 3

Calorie and protein needs in stress Clinical Setting Simple starvation Elective Surgery Polytrauma Sepsis

CHO% 28 32 40 50

NPC:N 150:1 100:1 100:1 180:1

Stress 1.0 1.5 2.0 2.5

3. infusion of about 80-120 meq K+ per day is required to replenish stores in patients receiving TPN. The most important divalent cation is magnesium, important for membrane, mitochondrial, and nuclear metabolic functions. The extracellular magnesium accounts for only 3% of the total body magnesium. Magnesium becomes depleted with protein-energy malnutrition, and it has to be increased to about 15 mmol per day to improve nitrogen balance. Phosphate is the main intracellular anion. It is critical for buffering systems, energy linked nucleotide reactions, membrane function, oxygen transfer systems, and neuromuscular function. The majority of phosphorus is in bone matrix with calcium. The serum phosphorus falls rapidly during TPN, and it is extremely sensitive to the administration of glucose and insulin and less sensitive to use of a mixed substrate. As with magnesium and potassium, phosphorus promotes nitrogen retention. The importance of monitoring for adequate blood levels of magnesium and phosphate is covered later.

Vitamins Beyond maintenance requirements, little of a definitive nature is known regarding the needs for vitamins and minerals in critical illness or injury, except for the nutrients involved in wound repair, as Vit A, Vit C and Zinc.11 The most important trace elements for our consideration include iron, zinc, chromium, copper, manganese, iodide, selenium and molybdenum, and cobalt. These are required for metabolic function and their deficiency is associated with specific biochemical change and functional abnormality that is relieved by giving these nutrients. Of these, cobalt is associated with vitamin B12. These are absorbed in bound and elemental forms, and they circulate as protein-bound complexes or ligands that are not in free equilibrium with tissue stores. These are usually incorporated as cofactors of enzymes or proteins in tissue. In relationship to this dissociation of plasma level and tissue stores, the plasma concentration is not a measure the total body stores. For example, zinc plasma concentration is normal in the hypercatabolic state as zinc is being lost and the patient is in negative zinc balance. The plasma zinc is maintained by a net outflow from tissue stores. A positive zinc balance occurs with provision of nutritional support as there is a net inflow of zinc into tissue with anabolism, and the plasma level falls unless exogenous zinc is given. Vitamins are active in minute quantities and have to be provided in any regimen of TPN to avoid deficiency. Patients with steatorrhea, short bowel, and pancreatic insufficiency require increased fat soluble vitamins, including 10,000-30,000 IU per day of vitamin A. Patients with chronic liver disease will have reduced vitamin A stores. Those receiving TPN may need 3300 IU per day.

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Clinical vs. Laboratory Information

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Clinical and Functional Status The importance of clinical indicators is correlation with functional status and identification of prior co-morbidities, i.e., cancer, sepsis, major surgical procedure, prolonged vomiting or diarrhea, fistula, inability to take in or utilize nutrients.15 These are associated with depletion from hypo- and/or hypermetabolism. Clinical indicators are excellent categorical criteria for risk assessment, but they can by themselves, contribute to over- and underutilization (malutilization) of nutritional support. Table 1.2 lists clinical risk factors for malnutrition.

Laboratory Evaluation Laboratory indicators are objective and may be used for measuring calorie and protein needs, for identifying serious clinical risk of malnutrition, for documenting agreement between clinical criteria and actual deficits, for documenting anabolic response from nutrient repletion, and for assessing prognosis.5,6 These are shown in Table 1.3. The finding that the laboratory is no better than subjective global assessment is expected concordance between two types of observations. The sensitivity and one—specificity of a test is actually fitted to a receiver-operator characteristic curve to remove, as much as possible, the effect of decision value selection, but it is affected by the choice of the dependent variable that is used to define the outcome. We have to put into context additional value provided by the laboratory. Agreement between SGA and severe losses for at least two laboratory measures confirms correlation between clinical and laboratory tests. On the other hand, there are unique patient (sub)groups (syndromic classes) that have incongruously depressed serum proteins either because of early protein depletion or repletion that may or may not agree with clinical assessment.16

Redundant Laboratory Abnormals Syndromic classes is treated in the information-based definition of decision-values proposed by Spiekerman, Rudolph and Bernstein.16 A simple example of this concept is the observation that a patient has an albumin of 2.7 g/dl AND and lymphocyte count of 1,080. In a more formal way, one takes the tests and scales them for intervals, assigning values in the assigned ranges from 1 to k. The test combinations form pattern classes, which group into the malnourished and nonmalnourished groups with frequencies related to risk. The existence of three groups (non-disease, moderate, severe) requires a multivalued logic with at two decision-values for a laboratory test. In the absence of a gold standard test to use as a supervisory variable, it would be possible to determine the correct assignment of laboratory data to each group only if sufficient variables are used to form a classification.

Tests to Monitor Test selection has a basis in pathophysiology. Hypermetabolism increases proteolysis and gluconeogenesis with loss of muscle mass and amino acid oxidation resulting in urinary loss of nitrogen as 3-methyl histidine, creatinine, and urea. Nitrogen loss is a primary measure of stress. The greatest nitrogen losses in trauma occur in the first few days, at a time when total urinary nitrogen reflects the catabolic phase more accurately than urinary urea nitrogen.

Clinical Implications of Nutrition Elements

Table 1.2.

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Clinical risk factors

• inadequate nutrient intake for 5 days or more • recent unexplained weight loss • surgery or disease of the gastrointestinal tract • unwillingness or inability to eat or eat enough

Table 1.3.

Laboratory risk factors

Total lymphocyte count < 1200/mm2 Pre-Albumin < 11 mg/dl Transferrin < 150 mg/dl Albumin < 3.0 g/dl

Liver transport proteins are characterized by different rates of production and degradation, and short halflife is a useful characteristic for following catabolism and anabolic response. The acute phase proteins, C-reactive protein (CRP) and alpha-1 antitrypsin are elevated with the inflammatory response (ceruloplasmin and transferrin are also) even when other proteins are severely depressed. CRP is a particularly good indicator of bacterial infection. CRP and TNF-α are increased associated with the cytokine mediated response, particularly interleukin-6. Table 1.4 is a comparison of the plasma proteins that are used to assess protein energy malnutrition (PEM). The phenomenon of protein depletion is referred to as an inverted acute phase response. Serum albumin, with a halflife of 21 days, is insensitive for measuring anabolism, and its volume distribution makes it a population rather than an individual measure of nutrition. It is unsuitable for the dynamic evaluation of nutritional repletion. Albumin increases by only 0.2 g/dl a week with aggressive nutrition support. Transferrin, with a halflife of 8 days, is somewhat better than albumin, but it is affected by iron balance. Table 1.5 shows the features of an ideal nutritional marker.

Rapid Turnover Proteins Proteins with short halflifes less than 2 days, such as transthyretin (prealbumin, thyroxine-binding prealbumin, TBPA, TTR), are needed to measure the anabolic response. TTR increases at an expected rate of 1 g/dl a day, or doubles in a week with nutrition support.5,16 It may be halved after a week to 10 days NPO. It may be elevated by corticosteroid therapy after a few days. Retinol-binding protein (RBP), which has a half-life of 36 hours, circulates bound with vitamin A to TTR in a 1:1:1 molar ratio. The complex is elevated in patients with renal failure on dialysis and RBP is excreted in the urine. RBP and TTR are both measured easily by nephelometry. Insulin growth-factor 1 (IGF1) or somatomedin C is the best measure of anabolic response because it has the insulin effect without the lipolytic effect of growth hormone. It is bound to the IGFBP3 receptor and it is difficult to measure because of an extraction and long incubation time. The method has been improved by an automated column methodology (Nichols). Arguments have been made for measuring fibronectin, which may have a role in wound healing. Fibronectin is decreased in burn patients and appears to be a predictor of sepsis. The most easily measured of this class of tests is TTR. A TTR of less than 8.5 mg/dl is a critical

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Table 1.4.

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Plasma protein used in nutrition assessment

Albumin:

limited value for detecting acute changes in nutritional status. 3.0-3.5 g/dl Mild depletion 2.5-2.9 g/dl Moderate depletion 2.4 or less Severe depletion

Transferrin:

half-life of 8 days Affected by iron metabolism

TTR:

half-life is 1.9 days Early predictor of protein malnutrition Measures response to nutritional support A serum TTR < 11 mg/dl is protein malnutrition

TTR decreases at a rate of 0.8 to 1.5 mg/dl per day, depending on the level of stress with no oral feeding. It doubles in a week with nutritional support.

Table 1.5.

Features of an ideal marker

• Identify clinically significant depletion • Reflects severity of deficits • Indicator of current status and change in status • Sensitive to decline • Sensitive to improvement • Minimal interference

finding for a burn patient because the patient can’t hold a graft. A TTR of less than 5 mg/dl is severe protein depletion. A case study illustrates its advantage.

Case Example An 88-year old woman with lower GI bleeding associated with perforated diverticulitis had a surgical resection and proximal diverting colostomy with a somewhat complicated recovery. She was maintained on PPN initially and changed to central TPN day 13 when she had an obstruction that resolved by day 20 after the small bowel was decompressed. Postoperative Day Test 1 13 16 26 Reference range ALB, g/L 27 25 25 27 35-55 TTR, mg/L 72 121 160 205 160-350

Information Model Getting the Most Out of Information I previously referred to the concept of syndromic classes.16,17 Even though it is a formal idea that is measurable, it is not important for surgeons to feel a deficiency of knowledge with unfamiliarity with this. The truth of the matter is that you use it often in practice. Clinical decisions are made by observing data from laboratory and clinical findings together. The evaluation of nutritional status is somewhat refined by an information model. The model is derived from the fundamental theory of communication, which uses

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redundancy to minimize the effects of noise in message transmission. We use an information model for medical decision-making by treating disease as a symptom complex that is a coded-message (each coded-message is a syndromic class). The message transmission can be interpreted from the redundant information (correlation) in the message. Regression is the most common approach to continuous data. It is a smoothing function and carries a risk of loosing information. It does not reveal the structure of the data. There are approaches that learn and classify data (clinical and laboratory) based on analysis of the information content of the data, such as, recursive partitioning and amalgamation, Rypka’s truth table comprehension,17 Rudolph’s group-based reference,16 and neural networks. These are based on classification matrices that are formed by similarities and differences of features that define data sets. Normal-reference is defined by Rudolph and Bernstein18 as the set having no information. That is a departure from distance from the center.

Length of Stay (LOS) Association between Malnutrition and Length of Hospital Stay Clinical and laboratory indicators of nutritional status are associated with excess LOS.19 The best predictor of nutritional class is a combination of tests.20 Use of the chemistry profile can take into account the information in: albumin, total protein, cholesterol. TTR (prealbumin, transthyretin, thyroxine-binding prealbumin), with its short halflife (1.9 days), is sensitive to changes in nutrititional status and is an indication of severity of deficits. It is not affected by hydration status in the way that albumin is. Serum TTR can be combined with the chemistry panel. These tests may be scored and used to predict LOS. Although the information model can be used to examine the relationship between malnutrition and LOS, it can be used to examine the effects of an implementation program, which includes early feeding, but may include other measures. In this case LOS becomes an outcome variable and interventions become inputs.

Improving Correction of Malnutrition Identify Malnutrition Risk and Intervene The ability to identify malnourished patients and to implement early intervention has implications for continuous quality improvement.1 Using laboratory as well as clinical indicators of malnutrition should allow identification of all patients at risk within 24 hours of admission. Laboratory tests can be triggered by admission criteria, such as weight loss, decreased food intake, or medical condition, or they can be added to a standard admission profile. Advanced age over 65 years or serum albumin concentration below 3.2 g/dl can be used as automatic criteria for obtaining TTR.

Monitoring Effectiveness of Feeding The greatest value of TTR is its measure of current nutritional status.5,6,21 Thereby, it allows determination of adequacy of feeding, and it should reduce the discharge of wasted patients who are at risk of readmission. Its physiological range is 16-35 mg/ dl. Serious malnutrition is reflected by a serum concentration < 11 mg/dl, severe at < 7 mg/dl. It increases at a rate of 1 mg/dl per day with adequate nutritional support. A TTR concentration of less than 11 mg/dl after a week of nutrition support or a daily increase of less than 0.5 mg/dl is a reasonable indication that the feeding is

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inadequate or that the patient is unresponsive. Serum TTR concentration is a prognostic indicator.

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Clinical Processes Incorporating Transthyretin (Prealbumin) A profile including TTR can be incorporated into a clinical practice guideline implemented through a critical pathway. Although TTR acts as an acute phase reactant, it can be used to establish a baseline for nutritional support. Urinary nitrogen excretion is often used to assess the amount of protein deficit prior to feeding. Failure to increase TTR is an indication of inability to provide adequate nutrients by method of feeding. Systematic identification of patients at risk, appropriate timing and mode of feeding, and monitoring effectiveness are essential elements for such a guideline.

Nutrition Support Monitoring TTR a Measure of NDAD We have seen how the use of a short halflife protein, such as TTR can be used alone, or in combination with serum albumin and clinical indicators for identifying serious risk. TTR is a measure of the NDAD, so the decrease in TTR is associated with changes in CRP, TNFalpha, RBP and IGF1.9 In some patients who have recieved high dose corticosteroids, the TTR is elevated, but it is possible to trend patients as they receive nutritional support. In these patients it might be argued that urinary nitrogen excretion is done weekly.

Nitrogen Loss Nitrogen balance is daily intake of nitrogen minus the excretion. The intake represents nutritional nitrogen and the excretion consists of measured urinary nitrogen plus a factor for unmeasured gastrointestinal and cutaneous losses, usually 2 to 4 grams. Nitrogen balance is calculated as: N intake—(urinary N + change BUN + 4) change in BUN (g) = (0.6 weight) (SUNf—SUNi), where i and f are the initial and final values in the measurement period, SUN is serum urea nitrogen (g/l), and weight is body weight in kilograms. A positive balance indicates an anabolic state with an overall gain in body protein for the day. A negative nitrogen balance indicates a catabolic state with a net loss of protein. Urinary nitrogen excretion may rise to 30-50 g/day with severe stress, which is the equivalent of 1 to 1.5 kg of lean body mass.

Overfeeding and Monitors We have already considered the consequence of lipids versus carbohydrate as an energy source. The effects of excess carbohydrate are hyperglycemia and on driving pCO2 production with CO2 retention. Carbohydrate also leads to fatty liver. This necessitates the close monitoring of pCO2 measurement for patients on nutritional support and less frequent evaluation of liver function, such as the alkaline phosphatase. Table 1.6 lists the complications of overfeeding. The electrolytes have to be monitored because of losses from fluid loss. The fluid associated electrolyte losses are listed in Table 1.7. We have to add to the complications the serious effect of hypophosphatemia. Hypophosphatemia and hypokalemia can both occur as a result of the refeeding syndrome. They have to be watched as closely as the pCO2, the glucose, and the

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TTR. The K+, Mg2+ and H2PO32- are intracellular cations and anion, respectively. They move into the cell and out of the circulation with refeeding. They are critical for excitation-contraction coupling, and failure to monitor these can result in sudden death. In the case of magnesium, the serum level is not an accurate measure of the total body load. A patient with tetany may have low calcium concentration, but if the calcium fails to resolve this, than administration of magnesium is the best test. Table 1.8 lists the requirements for monitoring phosphate levels. The lowering of serum phosphorus levels leads to a decrease in ATP and other phosphorylated compounds in the tissues and blood. When the serum level falls to 1.0 mg/dl or lower, leukocyte dysfunction and a potential for sepsis occurs. In addition, reduced nucleotide production due to hypophosphatemia can result in hemolytic anemia, neuromuscular dysfunction, myocardial depression and respiratory failure. Adequate treatment of the severely malnourished patient requires adequate nutritional support with careful monitoring. Repletion must be initiated slowly while monitoring serum phosphorus, along with serum electrolytes, glucose, and magnesium levels.

Quality Management Excess LOS variation is a global outcome variable. It is dependent on extended period after surgery without oral intake (Meguid’s IONIP), initial condition, unexpected complication (wound site infection, pneumonia), and malnutrition. The effect of nutritional status is independent and interacts with the other factors. The laboratory tests predict outcome by forming severity classes. Mozes et al22 recently classified surgical and nonsurgical major diagnostic categories into groups homogeneous with respect to LOS from seven laboratory values (wbc, Na, K, CO2, BUN, HCT, ALB) for 73,117 admissions at UCSF and Stanford. Studies have shown that Hb, cholesterol23 and insulin-like growth factor 1 (IGF1)24 are predictors of mortality. Nutritional markers are important tests in any analysis. Quality Management has to focus on medical outcomes of alternative strategies, i.e., feeding, not feeding, delayed intervention, and the costs of interventions. Policy considerations are the organizational purview of a Nutrition Committee and the Nutrition Support Team. The cost of data collection can be significant. The cost of prevention, with an effect on under- and over-utilization, can be less than the cost of failure to develop a system. The use of the laboratory has a low cost in supporting a system of quality management. The information model has been used to determine optimum decision-values for tests, and has been used to examine the relationship between tests, malnutrition and LOS. It can be used to examine differences in the effects of interventions. Not all interventions can be assumed to be equivalent. Preoperative feeding for five days before a major procedure assumes utilization costs that have a different significance for marginally than severely at risk patients. Perioperative interventions, intravenous and enteral, are uniquely identified input variables. In addition to the assignment of treatment effects, it is necessary to identify the initial pretreatment condition as distinguished from the treatment effects. Therefore, laboratory data need to be adequate to examine post-treatment status. These can be described in the form of a truth table with each defining variable as a column and each patient as a row. It is important to recognize that a quality improvement model for nutritional interventions has to take into account the expectations of costs to do nothing, the expected costs of alternative interventions, and the costs reduced by failure avoidance. Traditional cost accounting models are not adequate for the complexity of the issues.

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Table 1.6.

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The Biology and Practice of Current Nutritional Support

Problems of overfeeding

• excess CO2 production • fat deposition • hyperglycemia • pulmonary edema • worsening of existing congestive heart failure • hepatic complications

Table 1.7. Electrolyte

Etiology of common electrolyte deficiencies Cause of Deficiency

Sodium

Loss of skin, GI tract, lungs or kidney Kidney—diuretic use, renal damage, adrenal insuffic

Potassium

Starvation, loss from skin, bile, lower GI tract or fistula. Renal: diuretics, alkalosis, Amphotericin

Bicarbonate

Diarrhea, pancreas or small bowel loss, renal tubular acidosis, mineralcorticoid deficiency

Chloride

Diuretics, gastric loss, intestinal loss, secretory loss, renal reabsorption due to drug therapy-carbenicillin, sulfate, phosphate

Magnesium

starvation, intestinal loss, malabsorption, diarrhea, laxative abuse, diuretics, cyclosporin

Phosphorus

starvation, alkalosis, glucose administration, diabetic keto acidosis, GI tract losses, aluminum containing antacids.

Table 1.8.

Clinical conditions for which phosphorus levels should be monitored during treatment

• Refeeding phase for the malnourished patient • Alcohol withdrawal and nutritional support • Insulin therapy with diabetic keto-acidosis • Phosphate binding antacid therapy • Recovery diuretic phase after severe burns • Severe respiratory alkalosis

The ability to identify malnourished patients and to implement early intervention has implications for continous quality improvement (1). Using laboratory as well as clinical indicators of malnutrition should allow identification of all patients at risk within 24 hours of admission. Laboratory tests can be triggered by admission criteria, such as weight loss, decreased food intake, or medical condition, or they can be in a standard admission profile. Transthyretin (prealbumin, thyroxine-binding prealbumin, TBPA, TTR) is a transport protein with a short halflife (1.9 days) that is sensitive to changes in nutrititional status and is an indication of severity of deficits. It allows determination of adequacy of feeding, and it should reduce the discharge of wasted patients who are at risk of readmission. It has a physiological range of 16-35 mg/dl. Serious

Clinical Implications of Nutrition Elements

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malnutrition is reflected by a serum concentration < 11 mg/dl, severe at < 7 mg/dl. It increases at a rate of 1 mg/dl per day with adequate nutritional support. The table of ranges shows the effect of nutrition support on TBPA. Moderately malnourished patients with low ALB have increased TBPA with nutrition support. A profile including TTR can be incorporated into a clinical practice guideline implemented through a critical pathway. Although TTR acts as a acute phase reactant, it can be used to establish a baseline for nutritional support. Urinary nitrogen excretion is often used to assess the amount of protein deficit prior to feeding. Failure to increase TTR is an indication of inability to provide adequate nutrients by method of feeding. Systematic identification of patients at risk, appropriate timing and mode of feeding, and monitoring effectiveness are essential elements for such a guideline.

Selected References 1. 2. 3. 4. 5. 6. 7. 8. 9. 10. 11. 12. 13. 14.

Brugler L, DiPrinzio MJ, Bernstein L. The five-year evolution of a malnutrition treatment program in a community hospital. J Qual Imp. 1999; 25:191-206. Bernstein LH, Shaw-Stiffel TA, Schorow M et al. Financial implications of malnutrition. In: Labbe R, ed. Clinics in laboratory medicine. Nutition support. Vol 13. Philadelphia: Saunders, June 1993:491-506. Meguid MM, Mughal MM, Meguid V et al. Risk-benefit analysis of malnutrition and preoperative nutrition support: a review. Nutr Int 1987; 3:25-34. Meguid MM, Campos ACL, Meguid V et al. IONIP: a criterion of surgical outcome and patient selection for preoperative nutritional support. Br J Clin Pract 1988; 42(suppl 63):8-14. Bernstein LH, Leukhardt-Fairfield CJ, Pleban W et al. Usefulness of data on albumin and prealbumin concentrations in determining effectiveness of nutritional support. Clin Chem 1989; 35:271-274. Bernstein LH. Utilizing laboratory parameters to monitor effectiveness of nutritional support. Nutr Int 1994; 10:58-60. Kinney JM. Metabolic Responses to Injury. Chapter 2. In: Winters RW, Greene HL, eds. Nutritional Support of the Seriously Ill Patient. New York: Academic Press, 1983:5-12. Wilmore DW, Black PR, Muhlbacher F. Injured Man: Trauma and Sepsis. Chapter 4. In: Winters RW, Greene HL, eds. Nutritional Support of the Seriously Ill Patient. New York: Academic Press, 1983:33-52. Ingenbleek Y, Bernstein L. The stressful condition as a nutritionally dependent adaptive dichotomy. Nutrition 1999; 15:305-320. Kinney JM. Energy Metabolism: Heat, Fuel and Life. Chapter 1. In: Kinney JM, Jeejeebhoy KN, Hill GL et al, eds. Nutrition and Metabolism in Patient Care. Philadelphia: W.B. Saunders, Harcourt Brace Jovanovich, 1988:3-34. Jeejeebhoy KN. Nutrient Metabolism. Chapter 3. In: Kinney JM, Jeejeebhoy KN, Hill GL et al, eds. Nutrition and Metabolism in Patient Care. Philadelphia: W.B. Saunders, Harcourt Brace Jovanovich, 1988:60-88. Hill GL, King RFGJ, Smith RC et al. Multi-element analysis of the living body by neutron activaion analysis—application to critically ill patients receiving intravenous nutrition. Br J Surg 1979; 66:868-72. Ferrannini E. Equations and Assumptions of Indirect Calorimetry: Some Special Problems. In: Kinney JM, Tucker HN, eds. Energy Metabolism: Tissue Determinants and Cellular Corollaries. New York: Raven Press, 1992:1-17. Young VR, Yong-Ming Y, Fukagawa NK. Whole Body Energy and Nitrogen (Protein) Relationships. In: Kinney JM, Tucker HN, eds. Energy Metabolism: Tissue Determinants and Cellular Corollaries. New York: Raven Press, 1992:139-161.

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1

16. 17.

18. 19. 20. 21. 22. 23. 24.

Jeejeebhoy KN, Baker JP, Wolman SL et al. Critical evaluation of the role of clinical assessment and body composition studies in patients with malnutrition after total parenteral nutrition. Am J Clin Nutr 1982;35:1117-27. Spiekerman AM, Rudolph RA, Bernstein LH. Determination of malnutrition in hospitalized patients with the use of group-based reference. Arch Path Lab Med 1993; 117:184. Rypka EW. Methods to evaluate and develop the decision process in the selection of tests. In: McPherson RA, Nakamura RM, eds. Clinics in laboratory medicine. Laboratory immunology II. Strategies for clinical laboratory management. Vol 12. Philadelphia: Saunders, June 1992:351. Rudolph RA, Bernstein LH, Babb J. Information-Induction for the diagnosis of myocardial infarction. Clin Chem 1988; 34:2031-2038. Shaw-Stiffel TA, Zarny LA, Pleban WE et al. Effect of nutrition status and other factors on length of hospital stay after major gastrointestinal surgery. Nutr Int 1993; 9:140-145. Bernstein LH, Shaw-Stiffel T, Zarny L et al. An information approach to likelihood of malnutrition. Nutrition 1996; 12(9/10):772-776. Bernstein LH (Chairman). Prealbumin in Nutritional Care Consensus Group. Measurement of visceral protein status in assessing protein and energy malnutrition: Standard of care. Nutrition 1995; 11:169-171. Mozes B, Easterling MJ, Sheiner LB et al. Case-mix adjustment using objective measures of severity: The case for laboratory data. Health Services Research 1994; 28[6]:689-712. Verdery RB, Goldberg AP. Hypocholesterolemia as a predictor of death: a prospective study of 224 nursing home residents. J Gerontol:Med Sci 1991; 46:M84-M90. Sullivan DH. The role of nutrition in increased morbidity and mortality. (Review) Clin Geriatric Med 1995; 11:661-74.

CHAPTER 1 CHAPTER 2

Current Nutrient Substrates Wendy Swails Bollinger, Timothy J. Babineau and George L. Blackburn

Introduction Traditionally, nutrition support was simply the provision of calories and protein. More recently, however, we have discovered that manipulation of certain nutrients may significantly alter the response to illness and facilitate the healing process. These findings suggest that patient-specific feeding with nutrient-specific formulas may hold promise for improved patient outcome. This chapter discusses some of the advantages and disadvantages of administering certain nutrient substrates, specifically branched-chain amino acids, arginine, glutamine, nucleotides, and lipids.

Hepatic Disease and Stress: Branched-Chain Amino Acid Enriched Diets Hepatic Disease The discovery of altered plasma amino acid concentrations (low branched-chain amino acids and high aromatic and sulfur- containing amino acids) in patients with hepatic encephalopathy prompted the development of branched-chain enriched parenteral and enteral formulas. These formulas differ from conventional amino acid formulas in that they contain a greater concentration of the branched-chain amino acids (BCAA) leucine, valine, isoleucine and a lower amount (or none) of the aromatic amino acids (AAA) phenylalanine, tyrosine, tryptophan and the sulfur-containing amino acid methionine. The modified amino acid profile in these solutions is thought to counterbalance the altered plasma amino acid concentrations seen in patients with hepatic encephalopathy. These plasma amino acid alterations are a result of an increased utilization of BCAA by the peripheral muscles and a decreased metabolism of the AAA by the failing liver. The use of BCAA-enriched formulas in patients with encephalopathy is based predominantly upon the AAA/false neurotransmitter theory.1 Fischer postulated that the decrease in BCAA and increase AAA plasma concentrations seen in patients with hepatic dysfunction allows a disproportionate amount of AAA to cross the blood brain barrier. As a result, there is an increase in serum levels of “false neurotransmitters” (octopamine and phenyethylanine) and a concomitant decrease in the levels of normal neurotransmitters (dopamine and norepinephrine). In addition, there is an increased serum serotonin concentration (physiologic neuroinhibitor) due to excess tryptophan. This altered ratio of BCAA to AAA is believed to contribute, in part, to the development of encephalopathy. It was Fisher and colleagues who first noted that the administration of BCAA-enriched, low AAA solutions to animals The Biology and Practice of Current Nutritional Support, 2nd Edition, edited by Rifat Latifi and Stanley J. Dudrick. ©2003 Landes Bioscience.

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and humans with hepatic encephalopathy resulted in more normal patterns of plasma amino acid concentrations and an improvement in encephalopathy.2,3 A number of prospective, randomized clinical trials have investigated the use of parenteral BCAA solutions when hepatic encephalopathy is present.3,4-6 Most of these trials have shown no significant change in mental status. It is important to note, however, that many of the early trials used solutions containing only BCAA as opposed to the BCAA-enriched, low AAA formulas typically used today. In an early multicenter, prospective, randomized trial, 34 patients with cirrhosis of the liver (predominantly cryptogenic) and grade III to IV hepatic encephalopathy received either an intravenous solution containing 60 g of BCAA only in 20% dextrose or lactulose (30-40 g every 4 hours via a nasogastric tube or 200-300 g/day via intermittent rectal enemas) plus 20% dextrose.4 Seventy percent of the patients receiving the BCAA solution regained consciousness (defined as grade 0 hepatic encephalopathy) within 48 hours compared to only 47% in the lactulose group. Although this difference was not statistically significant, the authors concluded that parenteral administration of BCAA is at least as effective as lactulose in ameliorating the symptoms of hepatic encephalopathy. Interestingly, these authors found no correlation between the modifications in plasma amino acid levels and an improvement in the patient’s mental status. Instead, they noted a significant decrease in plasma ammonia levels in both groups at the time of mental recovery. Since lactulose is believed to work by binding excess ammonia, these results suggest that BCAA may favorably impact on hepatic encephalopathy, at least in part, by decreasing free plasma ammonia levels. Wahran, et al5 also noted a slight improvement in responsiveness in patients with hepatic encephalopathy who received a BCAA parenteral solution. In this prospective, double-blind trial, 50 cirrhotic patients with acute hepatic encephalopathy (grade II to IV) were randomized to receive either an amino acid free parenteral solution consisting of dextrose and lipids or the same solution with the addition of 40 g of a 100% BCAA solution. The carbohydrate and fat portions of each parenteral solution were isocaloric and provided 30 kcal/kg. In addition, all patients were prohibited from taking any food by mouth. Although the patients in the BCAA-treated group showed a statistically significant improvement in their plasma BCAA to AAA ratios (1.10 ± 0.08 to 1.96 ± 0.22), this ratio never returned to a normal ratio of 3.0 to 3.5. Fifty-six percent of the patients receiving the BCAA solution demonstrated an improvement in encephalopathy compared to 48% in the control group. This difference, however, was not statistically significant. As the authors readily pointed out, this study had two major shortcomings. First, patients with active gastrointestinal bleeds were not excluded from the study; a complication that may worsen encephalopathy. Second, twice as many patients in the control group received systemic antibiotics which would theoretically decrease the amount of enteric bacteria and their byproducts and subsequently ameliorate hepatic encephalopathy. The largest and most complete prospective, double-blind trial was a multicenter study done by Cerra and colleagues.6 Seventy-five patients with acute hepatic encephalopathy (grade II or higher; average grade 2.65) due to chronic hepatic disease (85% alcoholic cirrhosis) were randomized to receive either oral neomycin or a branched-chain enriched (36%) parenteral solution low in AAA and methionine. Patients with acute viral hepatitis, acute fulminant hepatitis, hepatorenal syndrome, significant gastrointestinal bleeding, nonhepatic coma and patients requiring

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severe fluid restriction were excluded from the study. The control group received 25% dextrose intravenously plus oral neomycin (4 g daily divided into 4 doses) whereas the treatment group received a daily infusion of the branched-chain enriched parenteral solution plus placebo tablets. Oral intake was restricted in both groups until the encephalopathy had resolved. A maximum daily protein intake of 1.1 g/kg was reached by day 3 and was well tolerated in the group receiving the BCAA-enriched solution. Despite receiving what some clinicians would consider a high protein load for this patient population, 53% of the patients in the BCAA group demonstrated complete resolution of their encephalopathy compared to only 17% of the patients in the control group (p<0.05). Not suprisingly, net protein catabolism was decreased in the group being fed as evidenced by a positive nitrogen balance by day 4. The group not being fed protein remained in negative nitrogen balance throughout the study. Moreover, 55% of the patients in the control group died whereas only 17% of the patients receiving the BCAA-enriched solution died (p<0.01). These results suggest that administration of BCAA-enriched parenteral solutions in amounts that provide at least 1 g protein/kg/day is well tolerated in cirrhotic patients with hepatic encephalopathy, and may improve mental status and survival. There are, however, some researchers who contend that the improved survival may have been a result of providing nutritional support in these critically ill patients rather than due to the BCAA-enriched solution itself.7 The disparity between the results of these clinical trials may be partially due to differences in experimental design, patient population, type and amount of BCAA solution administered, as well as diversity of the control group (Table 2.1). It has been suggested that because Cerra and collegues6 excluded patients with serious complications (i.e., fulminant hepatitis, hepatorenal syndrome, etc.) that would not be expected to improve by changing the serum BCAA to AAA ratio that this may explain why the results of their study differed from others.8 Interestingly, none of the studies shown in Table 2.1 compared a BCAA solution to a conventional parenteral amino acid solution. There are, however, several enteral studies that have addressed this issue. Eriksson and collegues9 were among the first to investigate the use of a BCAA formula delivered orally. Seven patients with liver cirrhosis and chronic hepatic encephalopathy (grade I to II) participated in a 28 day study with a cross-over design. Patients received each of the following oral supplements, in addition to their regular diet, for a 14 day period: a BCAA solution containing BCAA only (30 g protein/ day) or a placebo solution devoid of amino acids. The results failed to demonstrate a significant improvement in mental status when patients consumed the BCAA solution instead of the placebo (43% vs 29%, respectively). These findings have been substantiated by several other small, prospective cross-over studies.10,11 In contrast, Horst, et al12 noted a significant worsening of mental status in cirrhotic patients with encephalopathy receiving a standard oral diet containing a maximum of 80 g protein/day compared to those receiving a standard oral diet, restricted to 20 g protein/day, supplemented with an oral BCAA-enriched (35% BCAA) solution, low in AAA that provided up to a maximum of 60 g protein/day. Most of the clinical trials using oral BCAA examined the efficacy of using these formulas over a short time period (i.e. less than one month). Thus, in an attempt to evaluate the long-term effects of using BCAA during hepatic encephalopathy, Marchesini, et al13 conducted a multicenter prospective, randomized, double-blind trial in which patients were followed for a three-month period. Sixty-four cirrhotic

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Parenteral BCAA clinical trials

Author Rossi-Fanelli, et al4

Patients 34 patients with liver cirrhosis/grade III to IV encephalopathy

Experimental Group 100% BCAA (57 g protein/day) + 20% dextrose

Control Group Lactulose + 20% dextrose

Results/Conclusions No significant change in encephalopathy. BCAA are as effective as lactulose in reversing hepatic encephalopathy.

Wahran, et al5

50 patients with liver cirrhosis/grade II to IV encephalopathy

100% BCAA (40 g protein/day) + dextrose + lipid

Dextrose + lipid

No significant change in encephalopathy.

Cerra, et al6

75 patients with liver cirrhosis/grade II to IV encephalopathy

35% BCAA-enriched (maximum of 85 g protein/day) + placebo tablets

25% dextrose + oral neomycin

Significant improvement in encephalopathy and survival in BCAA-enriched group.

The Biology and Practice of Current Nutritional Support

Table 2.1.

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patients (66% alcoholic) with hepatic encephalopathy were randomized to receive either a 100% BCAA oral supplement or a casein-based oral supplement in addition to an oral diet containing 45-65 g protein daily. Patients were randomized to receive either one packet of BCAA/kg body weight (0.24 g 100% BCAA/packet) or one packet of casein/kg body weight (0.17 g casein/packet: 22% BCAA). Since all patients weighed between 60 and 80 kg, the oral supplements provided between 14 to 19 g BCAA or 10 to 14 g casein daily. After three months, twice as many patients receiving the BCAA supplement demonstrated an improvement in mental status (defined by the portal-systemic encephalopathy index) when compared to those patients receiving the casein-based supplement (p<0.01). In addition, when the ten casein-treated patients who showed no improvement in mental status were given the BCAA supplement, eight of them demonstrated a rapid improvement in their neuropsychologic function. These results suggest that long-term supplementation (i.e., 3 months or more) of oral BCAA is superior to casein in terms of improving mental status in cirrhotic patients with chronic encephalopathy. The results of these enteral BCAA studies are summarized in Table 2.2. As was the case with the parenteral BCAA studies, there are several factors which may account for the different results seen in the enteral studies. First, of the studies reported here, those which failed to demonstrate any difference between BCAA and standard amino acid solutions had a sample size of less than ten patients. Thus, they may have been unable to detect any significant differences due to a Type II error. Second, not all of the studies used the same experimental design (i.e., cross-over design versus parrallel group comparison) nor did they administer the diets in the same fashion. Several of the studies gradually increased the daily protein intake until encephalopathy developed, whereas others adminstered a constant amount of protein throughout the study. Finally, all of the diets differed in regard to the total percentage of BCAA, as well as the ratio of each BCAA. Taken together, therefore, it is difficult to compare the studies or to draw any definite conclusion. The primary goal of nutrition support during hepatic dysfunction is to provide sufficient protein in order to support protein synthesis and to promote regeneration of liver cells. In view of this, perhaps the most important finding of these clinical trials is that BCAA formulas can be safely administered to this patient population in amounts that provide 1.0 to 1.5 g protein/kg/day without exacerbating preexisting encephalopathy. Thus, encephalopathic, cirrhotic patients who are unable to tolerate low to moderate intakes of standard protein sources may benefit from receiving BCAA-enriched solutions. In 1997 the European Society for Parenteral and enteral nutrition published guidelines recommending the aforementioned.14 In addition, there is evidence to suggest that administration of BCAA-enriched solutions are better utilized by cirrhotic patients and can improve hepatic protein synthesis.15

Stress The metabolic response to injury is characterized, in part, by an increase in lean body mass catabolism, a reduction in total body protein synthesis, and an increase in the use of BCAA by the skeletal muscle. The result is an obligatory negative nitrogen balance. In view of this, numerous investigators have examined the protein-sparing effects of administering BCAA-enriched formulas in the setting of stress, sepsis or trauma. The results of these clinical trials suggest that administration of BCAA-enriched solutions can reduce nitrogen loss and support protein synthesis better than standard amino acid solutions in critically ill patients.

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Table 2.2.

Enteral BCAA clinical trials Patients

Experimental Group

Control Group

7 patients with liver cirrhosis/grade I to II encephalopathy

100% BCAA oral supplement (30 g protein/day) + oral diet

Oral supplement No significant improvement devoid of amino acids) in mental status. + oral diet

McGhee, et al10

4 patients with liver cirrhosis/grade II to IV encephalopathy

35% BCAA oral supplement + casein based protein module

Oral casein modular supplement (50 g protein)

No significant improvement in mental status.

Christie, et al11

8 patients with liver cirrhosis/grade 0 to II encephalopathy

50% BCAA oral supplement + 40 g protein oral diet

Casein-based oral supplement (18% BCAA) + 40 g protein oral diet

No significant improvement in mental status.

Horst, et al12

37 patients with liver cirrhosis/grade 0 to I encephalopathy

35% BCAA oral supplement (maximum of 60 g protein/day) + 20 g protein oral diet

80 g (maximum) protein oral diet

Mental status worsened in patients receiving oral diet alone.

Results/Conclusions

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Author Ericksson, et al9

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Most of the studies in this area have used 24-hour urinary urea nitrogen excretion to assess protein catabolism and nitrogen balance. Clinically, this test is an inexpensive and quick tool for assessing the degree of catabolism a patient is experiencing. The disadvantage, however, is that it does not allow one to determine whether nitrogen balance fluctuations are due to changes in the rate of protein synthesis or the rate of protein breakdown.16 While being able to make this distinction is not critical in the clinical setting, it is important in the setting of a clinical trial that is comparing differences in the protein-sparing effects of various amino acid solutions. Thus, several researchers have used isotopic kinetic studies in order to determine whole body protein turnover. Using this technique, Echenique, et al17 assessed the value of administering BCAA-enriched solutions in five critically ill patients, in the intensive care unit, who had catabolic indexes ranging from 0 to 3 (indicative of moderate stress). Two different parenteral solutions were compared in each patient: a BCAA-enriched parenteral solution (50% BCAA) and a standard parenteral solution containing 15.6% BCAA. Both solutions were isocaloric and isonitrogenous and were administered over two consecutive 24-hour periods. During the last ten hours of each infusion, an isotopic tracer (L-[1-14C] Leucine) was added in order to estimate protein kinetics (i.e., total body leucine oxidation, incorporation of leucine during protein synthesis, and release of leucine during protein breakdown). Results showed a significant increase in plasma leucine, isoleucine, and valine concentrations, as well as an increase in leucine oxidation and net balance (i.e., the difference between the rate of leucine incorporation into protein and the rate of release from protein). These results suggest that administration of a BCAA-enriched solution containing 50% BCAA may result in a significant improvement in amino acid utilization in critically ill patients. Similarly, Bonau and collegues18 used an isotopic tracer (15N glycine) to determine whole body protein turnover in surgical patients receiving BCAA-enriched solutions. Twenty-five patients undergoing elective radical cystectomies for bladder cancer received one of four parenteral infusions: 5% dextrose alone (n=4); dextrose plus a standard amino acid mixture containing 7% amino acids (n=9); dextrose and a low-leucine, BCAA-enriched solution (45% BCAA; 22 mmol leucine/L) (n=6); or dextrose and a high-leucine, BCAA-enriched solution (45% BCAA; 120 mmol leucine/L) (n=6). All dextrose and amino acid solutions provided 30 kcal/kg/day and 1.5 g protein/kg/day. Administration of the low leucine, BCAA-enriched solution resulted in a significant decrease in mean cumulative nitrogen balance (1.67 ± 0.74 g nitrogen/day versus 3.80 ± 1.01 for the high leucine, BCAA-enriched group and 4.38 ± 0.99 for the standard amino acid group) and an increased rate of mean whole body protein catabolism compared to the other two amino acid groups. The authors concluded that the optimal dose of leucine required by this patient population in order to achieve protein sparing effects was 0.13 g/kg/day. In comparison, normal, healthy subjects only require 11 mg of leucine/kg/day.19 These results suggest that the ability of BCAA-enriched solutions to reduce postsurgical muscle catabolism is related more to the amount of leucine in the solution than to the total percentage of BCAA.

Renal Failure Another controversial area in the use of BCAA-enriched solutions is in the setting of renal failure. The use of BCAA-enriched solutions in renal failure patients with severe azotemia (i.e., blood urea nitrogen greater than 100 mg percent) may aid in

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reducing urea and acid production from proteolysis since BCAA are preferentially used by the body for protein synthesis.20,21 The ability of BCAA to affect overall patient outcome remains controversial. However, it is clear that the administration of BCAA does not exacerbate preexisting encephalopathy. Moreover, BCAA are more efficiently used, promote better nitrogen retention, and are less ureagenetic than conventional amino acid formulas. Thus, when protein intake must be restricted due to encephalopathy or uremia, then BCAA-enriched solutions may potentially offer certain neurologic and metabolic advantages over conventional amino acid solutions.21

Arginine Traditionally, arginine has been considered to be a “semi-essential” amino acid.22 In normal, unstressed adult subjects, arginine requirements can be met through tissue synthesis. Early animal studies established that arginine was not an essential amino acid for maintaining nitrogen balance in healthy adult rats. In contrast, it was noted that immature growing rats required arginine for optimal nitrogen balance. 23 Most conventional adult parenteral and enteral formulas contain only a small amount of arginine (<0.5% of total calories). However, some researchers suggest that arginine requirements are increased during periods of injury or stress.24 This suggestion has been substantiated by a number of animal and human studies demonstrating that supplemental dietary arginine improves nitrogen retention, and enhances wound healing and immune response following injury.25-32 These findings suggest that supplemental arginine may have a potential theurepeutic role in the clinical setting.

Laboratory Studies Barbul and collegues conducted many of the early studies that evaluated the effects of arginine supplementation. In a series of animal studies, supplemental arginine resulted in increased thymic weight, increased thymocyte response to mitogens, and improved wound healing and nitrogen retention.29,33-35 These experiments prompted other investigators to further explore the relationship between supplemental arginine and immune response following injury. Saito and colleges30 studied the effect of supplemental arginine on immunity in burned guinea pigs. After receiving a 30% total body surface area burn, animals were intragastrically fed one of four diets containing either 0%, 1%, 2%, or 4% arginine. Animals receiving the 2% arginine supplementation demonstrated the most significant improvement in their cell-mediated immunity and ability to clear staphylococcus aureus from intradermal injection sites. In addition, those animals receiving the 1% and 2% arginine supplemented diets had a lower mortality rate than those receiving the 0% and 4% arginine supplemented diets, although this difference was not statistically significant. Interestingly, these investigators noted that 4% arginine supplementation did not result in any beneficial effects which suggests that administration of excess arginine may, in fact, be detrimental. Thus, the authors concluded that arginine supplementation in the amount of 2% of total calories may help to prevent sepsis after burn injury. Since burn injury is responsible for increased gut permeability to enteric bacteria, Gianotti, et al36 conducted a series of experiments to investigate the effects of an arginine enriched diet on resistance of gut-origin sepsis (i.e., bacterial translocation)

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and survival after peritonitis in the burned animal model. In one experiment, animals were randomized to receive one of the following diets: rat chow, semipurified diet, semipurified diet plus 2% arginine, or semipurified diet plus 4% glycine. After 14 days of feeding, the animals were subjected to an injection of E. coli followed by a 20% burn injury. Animals fed with the semipurified diet demonstrated significantly more bacterial translocation to the mesenteric lymph nodes (as measured by radionuclide counts) compared to all of the other diets. Moreover, analysis of the number and percentage of viable translocated bacteria in the mesenteric lymph nodes and spleen showed that the arginine enriched diet significantly improved the animals’ ability to kill translocated organisms compared to the other three diets. In another experiment, animals were fed either the arginine enriched diet, the semipurified diet, or rat chow for 15 days prior to being subjected to cecal ligation and puncture followed by a 20% burn injury. Following this, all animals were allowed to feed on their designated diets ad libitum. Although the arginine enriched group showed a 45% improvement in survival when compared to the animals receiving the semipurified diet and the rat chow, this difference was not statistically significant. However, when this experiment was repeated and the animals were transfused with allogenic blood five days prior to the injury, there was a significant improvement in survival in the group receiving the arginine enriched diet. Fifty-six percent of the arginine supplemented animals survived compared to 28% in the semipurified diet group and 20% in the chow fed group (p<0.02). These experiments suggest that diets supplemented with arginine may favorably affect survival when provided prior to the onset of infection. In order to better define the mechanism by which arginine alters immune function, Reynolds, et al31 examined the effects of supplemental arginine on specific components of the immune response. In this study, mice received an oral diet containing either 1% arginine supplementation or an isonitrogenous glycine supplemented diet for at least 10 days. Arginine supplementation was noted to significantly enhance cytotoxic T-lymphocyte development, increase endotoxin-induced natural killer cell activity, and augment interleukin-2 (IL-2) receptor activity on T-lymphcytes stimulated with the mitogen, conconavalin A. However, basal- and endotoxin-induced macrophage IL-1 and superoxide production were not significantly influenced by supplemental arginine. These results suggest that arginine supplementation directly modulates T-lymphocyte activation which may result in an enhanced production of cytotoxic T-lymphocytes. More recently, investigators have explored the ability of arginine to alter the mRNA expression of inflammatory cytokines in organs. In this study, animals receiving an enteral diet supplemented with arginine (2.3% of total energy intake) for seven days after receiving a 30% burn injury demonstrated a significant decrease in mRNA expression for TNF-α in the spleen and lung, IFN-γ in the lung, IL-1β in the spleen, and IL-6 in the thymus and liver compared to those animals receiving no supplemental arginine. In addition, the arginine supplemented animals showed a significant improvement in survival rate after thermal injury compared to the control group (100% versus 66.6%;p<.05).37 Another aspect of arginine’s ability to modulate immune function relates to its effects on tumor development. Over the past few decades, there have been numerous studies demonstrating the anti-tumor properties of arginine in animals with either chemically induced or transplanted tumors.38-40 In addition to decreasing tumor growth in these animal models, arginine supplementation has also been noted to

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prolong survival. These findings, coupled with the fact that cancer patients are frequently immunosuppressed, prompted several investigators to examine the potential clinical applicability of administering arginine in this patient population.

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Clinical Trials In 1988, Daly and collegues32 conducted the first clinical trial to evaluate the immunologic effects of arginine supplementation in the surgically stressed patient. Thirty adults with gastrointestinal malignancies undergoing major surgery were randomized to receive either an enteral diet supplemented with 25 g arginine daily (7% of maximum caloric intake) or the same enteral diet supplemented with an isonitrogenous amount of glycine. Mean daily nitrogen balance was not significantly different between the two groups, however, a positive nitrogen balance was only achieved in the arginine supplemented group. There was, however, a statistically significant improvement in immune function in those patients receiving the arginine supplementation as compared to the glycine group. Specifically, the arginine supplemented group demonstrated a significantly enhanced T-lymphocyte response to the mitogens, conconavalin A (ConA) and phytohemagglutinin (ConA), as well as an increase in CD4 (helper T-cells) levels from postoperative day 1 to postoperative day 7 when compared to the glycine supplemented group. Encouraged by these results but unsure whether the administration of arginine alone would still cause the increase in peripheral blood monocyte mitogenesis, the investigators conducted another clinical trial in an attempt to answer this question. Thirty adult patients undergoing surgery for lower gastrointestinal malignancy were randomized to receive intravenously either 20 g arginine hydrochloride in 5% dextrose and water or one liter of a standard 10% amino acid solution (3.7 g arginine hydrochloride) daily for 7 days postoperatively. Additional dextrose containing solutions were administered as clinically indicated. Postoperative mean daily nitrogen balance was similar between the two groups (-8.8 g/day for arginine group versus -9.2 g/day for mixed amino acid group). There was no significant difference between the two groups in terms of peripheral blood mononuclear cell proliferative responses to ConA. In the arginine group, mitogen-stimulated lymphocyte response levels returned to preoperative levels by postoperative day 7 while the standard amino acid group’s levels were actually below their preoperative levels by postoperative day 7. In contrast, when peripheral monocytes were stimulated with ConA, the mixed amino acid group demonstrated a significantly higher stimulation level on postoperative day 4 than the arginine group. These results suggest that when arginine is administered parenterally as the sole nitrogen source with minimal additional calories, there is no significant enhancement of mitogen-stimulated lymphocyte proliferation. Thus, arginine may require supplemental protein and calories in order to exert its maximum effect.41 While it appears that delivery of some arginine may be beneficial in the clinical setting, Sigal, et al41 have suggested that the immunostimulatory effects of arginine may be due to an interaction between arginine and other dietary substrates rather than the arginine itself. This point is exemplified in a study by Van Buren, et al42 in which mice who were fed a nucloetide-free casein-based diet containing 4% arginine showed no improvement in allogeneically stimulated lymphocytes responses. In contrast, those animals receiving the arginine diet supplemented with RNA or fish oil demonstrated a significant improvement in lymphocyte proliferative responses. Whether or not these same findings are applicable to humans remains unanswered.

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Moreover, it is not clear if enhanced stimulation of lymphocytes translates into improved clinical outcome. To date, there have been no clinical trials examining the effects of an arginine supplemented diet versus an arginine supplemented diet that also contains one or more of the so-called “immuno-stimulatory” nutrients (i.e., RNA, fish oil, or glutamine). There are however, a number of clinical trials comparing an enteral formula that is enriched with arginine in addition to one or more of these “immuno-stimulatory” nutrients to a standard enteral formula that is devoid of supplemental arginine, RNA, fish oil, or glutamine.43-51 Although arginine is not an essential amino acid in unstressed adult animals and humans, it appears to become a “conditionally essential” amino acid during periods of injury or stress. Supplementation with arginine has been shown to promote wound healing, enhance immune function, and improve nitrogen retention in both animals and humans. In addition, animal studies have shown that supplemental arginine retards growth in animals with chemically induced or transplanted tumors, and improves survival by modulating bacterial clearance in animals with gut-derived sepsis and peritonitis. While the animal studies appear to suggest that a diet containing 2% of total calories as arginine provides the most beneficial effects, the optimal dose in stressed humans remains unclear. The clinical trials discussed here have administered doses ranging from approximately 10 to 25 grams per day. This dose would be the equivalent of 2 to 6 % of total calories for a 70 kg man receiving 25 kcal/kg. It is quite possible that the optimal dose will vary depending on the severity of illness, type of injury, or surgery. One potential complication of arginine administration is its competition with the essential amino acid lysine for tubular reabsorption.52 Large doses of arginine may, therefore, theoretically induce lysine deficiency by increasing its renal excretion.53 Thus, additional clinical trials are clearly needed in order to determine the optimal dose of arginine for a variety of clinical settings. Moreover, investigators need to pursue the question of whether or not the immunostimulatory effects of arginine are due to the arginine itself or whether they are a result of interactions with other dietary substrates.

Glutamine Glutamine is currently classified as a nonessential amino acid because sufficient quantities can be synthesized by the body in healthy subjects.19 However, during periods of stress, the body’s requirement for glutamine exceeds its production.54-56 Animal studies suggest that provision of glutamine-enriched parenteral and enteral nutrition maintains gut epithelial structure and integrity, enhances nitrogen retention and intestinal mucosal immune function, decreases the incidence of bacterial translocation and improves survival following injury.57-59 Furthermore, glutamine-enriched nutrition administered to surgical and bone marrow transplant patients has been shown to reduce losses of free glutamine in skeletal muscle tissue,60,61 reduce infectious complications,62,63 decrease length of hospital stay62,64 and improve six month survival in critically ill patients.65 Thus, glutamine, like arginine, may be regarded as a “conditionally essential” amino acid.66 Traditionally, it was thought that glucose was the main source of fuel for the enterocytes, however, there is now evidence that glutamine is actually the preferred fuel of the enterocytes, as well as the colonocytes.67,68 This finding coupled with the observation of intestinal atrophy in animals receiving parenteral nutrition,69 prompted investigators to examine the effects of glutamine supplementation on intestinal mucosal structure and function.

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O’Dwyer, et al57 performed a series of animal experiments to examine the effects of glutamine supplementation on the intestine. In the first experiment, rats were intravenously fed a standard 10% amino acid solution that was enriched with either gutamine or glycine in amounts of either 1 or 2 g/100 mL. Animals receiving 2 g glutamine/100 mL demonstrated a significant increase in intestinal weight, DNA and protein content, and villus height when compared to the group receiving 2 g glycine/100 mL (p<0.01). No increase in intestinal parameters was noted in the group receiving 1 g glutamine/100 mL. The authors then investigated the dose-response effects of glutamine by feeding the animals an isonitrogenous, isocaloric solution containing either 0, 2, or 3 g glutamine/100 mL. Increasing the glutamine intake from 0 to 3 g/100 mL led to a significant increase in intestinal mucosal weight, DNA and protein content, and villus height. Interestingly, the animals receiving 2 g glutamine/100 mL demonstrated a significantly greater nitrogen retention compared to the animals receiving 0 or 3 g glutamine/100 mL. These results suggest that glutamine, an amino acid that is not currently contained in commercially available parenteral amino acid solutions, may be important for maintaining intestinal integrity. In addition, there is evidence to suggest that glutamine may also be essential for maintaining intestinal function following mucosal injury. Fox and collegues58 investigated the effects of a 2% glutamine supplemented elemental diet on nutritional status, intestinal morphology, bacterial translocation, and survival in rats with methotrexate-induced enterocolitis. Rats receiving the glutamine supplemented diet exhibited significantly less intestinal damage, less weight loss, a lower incidence of bacterial translocation, and an improved nitrogen balance and survival compared to the animals receiving the control diet (2% glycine supplemented elemental diet). Similar benefits have been reported by O’Dwyer, et al70 and Jacobs, et al71 who demonstrated that both enteral and parenteral glutamine supplementation resulted in a rapid regeneration of enterocytes in rats receiving the chemotherapeutic agent 5-fluoruracil. In addition, provision of oral glutamine has been shown to accelerate healing of the small intestine and improve outcome in animals undergoing whole abdominal radiation.72 However, since glutamine is the principle fuel used by most rapidly proliferating tumors,73 it raises the question of whether or not providing exogenous glutamine during chemo- or radiation therapy might present more of a risk (promote tumor growth) rather than a benefit (intestinal preservation). In an attempt to answer this question, Austgen, et al74 studied the effects of administering glutamine supplemented TPN in tumor-bearing rats. The addition of glutamine to the TPN did not appear to increase tumor size, DNA content, or glutamine metabolism. Glutamine supplementation did, however, cause a significant increase in the intratumor ratio of aneuploid cells to diploid cells suggesting a more aggressive cell variant. Thus, the authors speculated that glutamine supplemented TPN caused an increase in the number of differentiated tumor cells within a specified amount of tumor mass without yielding a measurable increase in tumor size. However, Klimberg and collegues75,76 have demonstrated in two separate animal studies that supplemental glutamine does not stimulate tumor growth. In fact, enteral glutamine supplementation was actually noted to increase the effectiveness of methotrexate while reducing its morbidity and mortality in cachectic tumor-bearing animals.76

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The ability of glutamine supplemented nutrition to attenuate intestinal atrophy and decrease the incidence of bacterial tranlocation may be, in part, due to changes in intestinal immune function. Alverdy, et al59 randomized rats to receive one of three diets: rat chow, a standard parenteral solution, or a standard parenteral solution supplemented with 2% glutamine. After one week of feeding, the animals receiving the standard parenteral solution demonstrated a significant decrease in biliary secretory immunoglobulin A (S-IgA) levels and intestinal lamina propria IgA-synthesizing plasma cell (IgA+) levels compared to the chow fed animals. This finding is of particular importance because S-IgA prevents bacteria from adhering to the intestinal mucosa which may, in turn, help to decrease the incidence of bacterial translocation. In addition, there was a significant decrease in CD4 (helper T-cells) and CD8 (suppressor T-cells) levels in the standard parenteral diet group compared to the chow group. In contrast, animals receiving the glutamine supplemented solution had CD4 and CD8 levels comparable to those of the chow fed animals. These findings suggest that glutamine may be an essential amino acid for the maintenance of intestinal immune function during parenteral feeding. Taken together, these animal studies suggest that the provision of glutamine either enterally or parenterally may increase the function of various immune cells and therefore potentially lead to enhanced resistance to infection.

Clinical Trials Over the past decade, the potential therapeutic use of glutamine supplementation in humans has been an area of intense research. Ziegler and collegues77 were the first to evaluate the safety of administering the free amino acid glutamine to humans. In a series of dose-response studies, these investigators demonstrated that glutamine administration in healthy volunteers at daily doses of 0.3 g/kg enterally and 0.57 g/kg parenterally was well tolerated. The safety of glutamine administration was subsequently confirmed in the clinical setting when eight patients undergoing bone marrow transplantation recieved glutamine-enriched TPN solution without evidence of adverse clinical or metabolic effects. Moreover, nitrogen retention was enhanced in this patient population when glutamine was administered at a dose of 0.57 g/kg/day compared to a lower dose (0.285 g/kg/day). These findings subsequently spurred researchers to investigate the efficacy of parenteral glutamine supplementation in patients undergoing elective surgery. In a randomized, prospective trial conducted by Stehle, et al,60 twelve patients undergoing surgical resection for colonic or rectal carcinoma received either standard TPN or glutamine enriched TPN. The addition of approximately 12 g of glutamine per day, provided as the dipeptide L-alanyl-L-glutamine, resulted in a diminished loss of free glutamine in skeletal muscle tissue and improved nitrogen retention. Similar benefits were reported by Hammarqvist and collegues61 who administered TPN supplemented with approximately 20 g of free glutamine daily to patients undergoing cholecystectomies. More recently, investigators have examined the effects of administering glutamine supplemented TPN in bone marrow transplant patients. Ziegler, et al62 conducted a prospective, randomized, double-blind trial in which 45 patients undergoing allogeneic bone marrow transplantation for hematologic malignancies were randomized to receive either standard TPN or TPN supplemented with 0.57 g of free glutamine/kg body weight per day. Based on a mean body weight of 67.2 kg, patients in the glutamine supplemented TPN group received approximately 38 g glutamine per day for an average of 26 days. The mean duration of parenteral

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feeding was comparable for patients in the standard TPN group (28 days). Despite an equivalent caloric and nitrogen intake in both groups, the glutamine supplemented patients demonstrated a significant improvement in their mean daily nitrogen balance in comparison to the standard TPN group (-1.4 ± 0.5 g/d versus -4.2 ± 1.2 g/d, respectively; p=0.002). In addition, fewer patients receiving the glutamine supplemented TPN developed infections (13% versus 43% in the standard TPN group; p=0.041) even though antibiotic administration was similar in both groups. Moreover, the average length of hospital stay following transplantation was 29 ± 1 days in the glutamine supplemented group compared to 36 ± 2 days in the standard TPN group (p=0.017). This study demonstrated that the administration of glutamine supplemented TPN in this patient population resulted in improved nitrogen balance, decreased incidence of infectious complications, and shortened length of hospital stay compared to patients receiving standard TPN. A subsequent study by this group showed that bone marrow transplant patients receiving glutamine- supplemented TPN had greater numbers of circulating total lymphocytes, T lymphocytes, and CD4+ lymphocytes after discharge than patients receiving standard TPN.78 Schloerb and Amare64 published results of clinical trial with a protocol similar to that of Ziegler, et al.62 Twenty-nine patients undergoing either allogeneic or autologous bone marrow transplantations were randomized to receive either standard TPN solution or TPN supplemented with approximately 40 g of free glutamine per day for approximately one month. One of the parameters that was assessed in the current trial that was not investigated by Ziegler, et al62 was the effect of glutamine on total body water and extracellular water. Total body water, as measured by deuterium oxide dilution and bioimpedance, was significantly decreased from baseline (before TPN) to end of study (after TPN) in patients receiving the glutamine supplemented TPN (p<0.05). This finding suggests that the provision of glutamine may help to maintain vascular endothelial integrity and prevent the extreme fluid shifts frequently seen during critical illness. In contrast, patients receiving standard TPN showed a significant increase in the change in their total body water. In terms of infectious complications, the researchers did not note any significant difference between the two feeding groups; thirty-eight percent of the patients in each group developed clinical infections. Patients were then subdivided into those with hematologic malignancies versus those with solid tumors. In patients with hematologic malignancies, clinical infections occured in only 20% of those patients receiving the glutamine supplemented TPN compared to 50% of those receiving the standard TPN. This difference, however, was not statistically significant. Although this observation is in contrast to that of Ziegler, et al59 the authors do not dispute Ziegler and collegues’ conclusion that glutamine supplemented TPN decreased the incidence of clinical infections in patients with hematologic malignancies. Instead, the authors suggest that differences in patient population may have precluded them from observing all of the same benefits as Ziegler, et al.62 In particular, the authors suggest that they had a patient population with a higher severity of illness than Ziegler, et al62 as demonstrated by a higher mortality rate (14% versus 0%, respectively). Schloerb and Amare64 were, however, able to confirm the finding of Ziegler, et al62 that patients receiving the glutamine supplemented TPN had a significant reduction in length of hospital stay following transplantation compared to patients receiving standard TPN. The use of glutamine-enriched TPN has also been investigated in critically ill patients. Griffiths, et al65 reported improved six-month survival in critically ill patients

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receiving glutamine-enriched TPN (an average intake of 21 g glutamine/day) compared to those patients receiving conventional TPN (24/42 patients versus 14/42 patients; p=.049) The aforementioned studies have yielded promising results with respect to providing glutamine-enriched parenteral nutrition in select patient populations. However, some researchers have speculated that in order to meet the glutamine requirements of the enterocytes and gut-associated lymphoid tissue it might be more beneficial to provide glutamine enterally rather than parenterally. Gottschlich, et al79 were among the first to study the effects of providing glutamine enterally rather than parenterally in a clinical setting. In a study of 90 burn patients who were randomized to receive an enteral formula supplemented with either 2, 4, or 6 g free glutamine/L, serial measurements of plasma glutamine were obtained during the first four weeks post burn. Results showed that plasma glutamine levels remained depressed (i.e., < 400 nmol/mL) throughout the four week period in all feeding regimens. These findings suggest that plasma glutamine levels may be marginal in burn patients and that enteral glutamine supplementation in excess of 6 g/ L of enteral formula may be warranted in this patient population. Jensen, et al80 conducted a prospective, double-blind trial in which 28 critically ill patients were randomized to receive one of two isocaloric, isonitrogenous enteral fromulas differing only in glutamine concentration (i.e., six-fold difference). Data was analyzed for all patients receiving at least 50 cc/hr by day 5 (n=19). Results demonstrated that the plasma phenylalanine to tryrosine ratio, an indicator of catabolism, was significantly decreased by day 5 in patients receiving the glutamine enriched enteral formula. Moreover, immune function, as assessed by CD4/CD8 ratios, was significantly improved in the glutamine enriched group compared to the standard feeding. A subsequent study by these investigators compared glutamine-enriched parenteral nutrition with glutamine-enriched enteral nutrition (isocaloric, isonitrogenous formulas that provided 0.3 g glutamine/kg body weight) in 17 patients undergoing surgery for gastric or pancreatic carcinomas. Results showed that both types of feeding resulted in similar amino acid profiles although there was a trend for serum glutamine levels to recover more slowly in the enterally fed group compared to the parenterally fed group.81 More recently, Houdijk and colleagues63 have investigated the effects of glutamine-enriched enteral nutrition on the incidence of infectious complications. In a study of 60 multiple trauma patients, those patients who received the enteral formula supplemented with glutamine (30.5 g glutamine/100 g protein) within 48 hours of trauma showed a significant reduction in pneumonia (17% versus 45% for the control group; p<.02), bacteremia (7% versus 42%; p<.005), and sepsis (4% -check this versus 25%; p<.02) compared to the patients receiving an isocaloric, isonitrogenous control formula containing 3.5 g glutamine/100 g protein. The patients receiving the glutamine-enriched enteral formula (an average intake of 31 g glutamine/day by study day 7) also demonstrated a decrease in TNF-soluble receptors compared to the patients receiving the control formula. Whether the decrease in TNF-soluble receptor suggests a modulation of the immune response to the trauma or is the result of a decrease in the number of infections remains unanswered. A later study by this same group of investigators82 suggested that the reduction in infectious morbidity seen in the glutamine-supplemented trauma patients could not be explained by a modulation of the humoral stress response and its metabolic consequences. A study by Aosasa, et al83 in fifteen patients with colorectal cancer demonstrated that oral glutamine supplementation (30 g L-glutamine/day) in patients receiving

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TPN significantly suppressed cytokine production from LPS-stimulated mesenteric blood mononuclear cells (M-MNC) compared to patients receiving conventional glutamine-free TPN. There were, however, no significant differences in cytokine production from LPS-stimulated M-MNC between patients receiving the oral glutamine supplementation and TPN and those patients consuming a regular diet.

Administration Although it is too early to define the optimal dose or route of glutamine, these clinical trials have prompted much discussion regarding the different routes (i.e., enteral versus parenteral) and types (i.e., free glutamine versus glutamine as a dipeptide) of glutamine supplementation. Currently, commercially available parenteral amino acid solutions do not contain the free amino acid glutamine for several reasons. First, glutamine was traditionally considered to be a nonessential amino acid. Second, the free amino acid glutamine has a shorter “shelf-life” than the amino acids commonly used in commercially available parenteral amino acid solutions. However, glutamine’s stability in parenteral formulas appears to be better than previously thought. Schloerb and Amare61 recently reported that their free glutamine supplemented parenteral solution was able to be stored at 5˚C for up to six weeks without loss of more than 5% of the glutamine. In terms of enteral formulas, almost all commercially available enteral formulas contain glutamine. The exceptions are a few free amino acid based diets which contain the amino acid glutamate rather than glutamine, and several products specifically designed for hepatic and renal failure which contain neither glutamate nor glutamine. Glutamine in enteral products can exist in two forms: protein bound (in whole proteins or in peptides) or as the free amino acid. Manufacturers of formulas containing the free amino acid glutamine list the glutamine content of the formulas on the product label. In comparison, the glutamine content of enteral formulas containing whole or partially hydrolyzed protein (peptides) can only be estimated. Thus, the glutamine content of these formulas is not listed on the product label. The amount of glutamine present in whole protein or peptide based enteral formulas depends upon the protein source and amount of protein, as well as the processing conditions. Whole protein based formulas contain glutamine in amounts characteristic of their original protein source (casein, whey, soy, etc.) because protein bound glutamine is stable and will not degrade during processing or storage. In contrast, enteral formulas containing partially hydrolyzed proteins (so-called peptide based diets) contain less glutamine than was present in their original intact protein because hydrolysis of the intact protein to peptides leads to the degradation of a portion of the glutamine originally present in the intact protein to glutamate (glutamic acid) and ammonia. The greater the degree of protein hydrolysis of a peptide based diet, the less peptide bound glutamine remains. In view of this, it is difficult to estimate the amount of glutamine in peptide based formulas. Although, it has been reported that more than half of the original glutamine in these formulas may be converted to glutamate and ammonia during processing and storage.84 The amount of protein-bound glutamine in selected commercially available whole protein formulas has been estimated to range from 2.80 to 7.99 g/1000 kcal.85 In comparison, there are several commercially available enteral formulas enriched with free glutamine in amounts that range from 4.9 to 14.2 g/1000 kcal (Table 2.3).

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Table 2.3.

Commercially available enteral formulas containing free glutamine

Product Vivonex Immun-Aid Vivonex Plus Alitraq

Manufacturer Novartis Nutrition B. Braun/McGaw Novartis Nutrition Ross Laboratories

g Free Glutamine/1000 kcal 4.9 9.0 10.0 14.2

The animal and human data presented herein strongly suggest that glutamine should be classified as a “conditionally essential” amino acid rather than as a nonessential amino acid. Plasma and skeletal muscle concentrations of free glutamine which have been shown to be markedly diminished during periods of stress, infection, and injury can be restored with parenteral and enteral glutamine supplementation. In addition, there is increasing evidence that glutamine has beneficial effects on nitrogen balance, lean tissue mass, gut integrity, and immune function. To date, clinical trials suggest that glutamine supplementation has been shown to have some beneficial effects after major surgery, after bone marrow transplantation, in critically ill patients, and in patients with multiple traumas.

Nucleotides Nucleotides are an important component of a wide variety of biochemical processes. These molecules which consist of three main components: a nitrogenous base (either purine or pyrimidine), a pentose sugar (either ribose or 2-deoxyribose), and one or more phosphate groups, are perhaps best known for their role in deoxyribonucleic acid (DNA) and ribonucleic acid (RNA) synthesis. However, nucleotides are also present in adenine triphosphate (ATP), as well as a number of coenzymes which participate in carbohydrate, protein, and lipid synthesis. In addition, nucleotides are required by T-lymphocytes in order to maintain normal cellular immune responses. Various tissues in the body, such as the liver, are capable of synthesizing nucleotides from other substrates. However, certain rapidly dividing cells, such as intestinal epithelial cells and T-lymphocytes, appear to be unable to produce nucleotides. Moreover, during severe metabolic stress, such as sepsis, trauma, and burns, de novo nucleotide synthesis is not sufficient to meet the needs of these rapidly dividing cells. Some investigators have subsequently suggested that this is the mechanism for the immune dysfunction which is often present in stressed patients. This theory coupled with the fact that standard parenteral and enteral diets, except those made from blenderized protein-containing food sources, do not contain nucleotides has prompted some investigators to suggest that the provision of exogenous nucleotides to stressed, immunocompromised patients may be beneficial.

Laboratory Studies The role of dietary nucleotides on immune function, specifically lymphocyte metabolism, has been the focus of intense research. Van Buren and collegues have pioneered much of the work in this area, and were among the first to demonstrate that helper/inducer T-lymphocytes require exogenous nucleotides in order to respond normally following immune stimulation.86 In addition, there have been numerous studies demonstrating that a nucleotide-free diet suppresses a variety of T-cell

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mediated immune responses, such as delayed cutaneous hypersensitivity,87 cardiac allograft rejection,88 in vitro response to T-cell mitogens,89 and production of interleukin-2.86 Furthermore, animals receiving a nucleotide-free diet demonstrated a significantly higher mortality rate following intravenous injections of staphylococcus aureus or candida albicans compared to animals fed diets supplemented with either 0.25% RNA (a nucleotide) or 0.06% uracil (a pyrimidine nucleotide base).89-92 However, it is worth mentioning that in all three of these studies there was also a fourth group of animals who received a diet supplemented with 0.06% adenine (a purine nucleotide base). Interestingly, in all instances, the adenine supplementation had no beneficial effect in terms of survival following bacterial or fungal infection. Thus, it appears that RNA or pyrimidine bases are the key substrates for maintaining normal cellular immunity. Numerous investigators have demonstrated that malnutrition can profoundly suppress immune function. In view of this relationship, Pizzini and co-workers93 designed several studies to examine the effect of dietary nucleotide deprivation in both the protein malnourished, as well as the starved animal model. Animals were randomized to receive one of four diets: standard rodent chow, protein-free, nucleotide-free, or nucleotide-free supplemented with 0.25% yeast RNA. The provision of dietary nucleotides in the form of yeast RNA resulted in the reversal of immunosuppression in both protein malnourished and starved animals. These results suggest that nucleotides are required to maintain cellular immune function during times of nutritional stress.

Clincal Studies The idea that dietary nucleotides could be used to modulate cellular immunity in humans initally arose from the observation that renal allograft patients supported by conventional intravenous nutrition, which is devoid of nucleotides, displayed a suppressed immune response even when traditional pharmacologic immuno- suppressive agents (i.e. cyclosporin) had been reduced.94 Despite this observation, there are no prospective, randomized clinical trials that have examined the singular effect of nucleotides. Instead, the clinical trials have compared an enteral formula that contains nucleotides (1.2 g yeast RNA/1000 kcal), in addition to other “immunostimulatory” substrates (i.e., fish oil, arginine, glutamine) to a standard commercially available enteral formula.44-51 Thus, clinicians are left wondering whether the addition of nucleotides alone would produce the same results. Dietary sources of nucleotides appear to be important for maintaining optimal growth and function of metabolically active cells such as lymphocytes, macrophages, and intestinal cells. The daily requirement for purines and pyrimidines combined is estimated to be 450-700 mg/day in healthy adults.95,96 However, this requirement may be increased during periods of stress. Moreover, animal studies have demonstrated that the use of a nucleotide-free diet results in a decrease in cellular immune function and a diminished resistance to infection. These effects were able to be reversed with the provision of a diet containing 0.25% yeast RNA, and subsequently lead to the incorporation of yeast RNA into several commercially available enteral formulas. Although preliminary animal data suggests that the provision of exogenous nucleotides is necessary to support optimum immune function, the clinical data is less definative. Clearly, further prospective, randomized clinical trials are warrented to determine whether or not nucleotides require the presense of other immunostimulatory substrates in order to be of benefit in the

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clinical setting. It is quite possible that the additional nutrients cause a further improvement in immunocompetence (synergism) that translate into fewer infectious complications and, ultimately, a shorter length of hospital stay. However, to be sure, one would need to conduct a trial using an enteral formula that differed only with respect to the immunostimulatory nutrients; that is, both formulas would be isonitrogenous and isocaloric but one formula would contain just nucleotides where as the other would contain nucleotides as well as to one or more additional immunostimulatory nutrients (i.e. fish oil, arginine, glutamine).

Lipids Lipids are an essential component in enteral and parenteral formulas because they provide energy and essential fatty acids, as well as function as carriers of fat-soluble vitamins and precursors of hormones. For years, long-chain triglycerides were the standard source of fat in enteral formulas, and, in fact, they are still the sole source of fat in commercially available intravenous lipid emulsions. In the past two decades, the role of fat in the diet has been elucidated. There is now compelling evidence to suggest that manipulation of dietary nutrients such as lipids can have a profound effect upon serum and cell membrane lipid concentration, immune function, as well as critical endpoints such as survival.97-102 Based on these findings, the current recommendations for fat intake focus not only on the percent of total calories coming from fat, but also on the composition of the fat.103,104 Thus, there has been a surge of investigations in the area of alternative lipid sources such as γ-linolenic acid, monounsaturated fatty acids, ω-3 polyunsaturated fatty acids (particularly fish oil), medium-chain triglycerides, and structured lipids.

ω-6 Polyunsaturated Fatty Acids In the past, naturally occuring vegetable oils consisting of long-chain triglycerides (LCT) of the ω-6 family were the conventional fat source because they were readily available and relatively inexpensive. In addition, these oils are a rich source of the major essential fatty acid, linoleic acid. Since linoleic acid can not be synthesized by the body, it must be provided by the diet. Adult requirements for essential fatty acids are usually met by providing 3 to 4% of total calories as ω-6 fatty acids.102 Thus, corn, safflower, soybean, and sunflower oil serve as important sources of linoleic acid in nutritional formulations. The amount of linoleic acid provided in the formula will vary depending upon the type and amount of LCT used. As shown in Table 2.1, safflower oil contains the highest percentage of linoleic acid and the lowest percentage of saturated fatty acids when compared to the other ω-6 fatty acids typically used in enteral formulas.106,107 There are a number of commercially available enteral formulas which contain ω-6 fatty acids as their sole source of lipids, and, as previously mentioned, all commercially available intravenous lipid emulsions are comprised solely of ω-6 fatty acids. Yet, controversy exists over whether ω-6 fatty acids should be the primary source of lipids in critically ill patients because of their potentially detrimental effect on immune function. Clearly, provision of a small amount of linoleic acid in the diet is necessary for normal immune function.108 However, provision of larger amounts of linoleic acid leads to an increased production of arachidonic acid and its metabolites, prostaglandin E2 (PGE2) and leukotriene B4 (LTB4). These eicosanoids are known to enhance vasocontriction, platelet aggregation, neutrophil migration, immunosuppression,

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cytokine depression, and free radical formation, all of which may predispose patients to secondary inflammation and sepsis.109 Although most of the work in this area has been done in animals,110,111 at least one prospective clinical trial suggests that reticulendothelial system (RES) function is impaired when lipid emulsions are infused in the standard intermittent fashion (over 10 hours) for 3 consecutive days.112 Seidner, et al112 provided 18 patients receiving parenteral nutrition (amino acids and dextrose) with a 20% soybean oil emulsion administered over ten hours as a piggyback infusion. Patients received the intermittent infusion for either 1 or 3 days at a rate that provided 0.13 g lipid/kg/hr or approximately 85 g lipid/day. Patients receiving the lipid emulsion over 10 hours for 1 day showed no impairment in RES function based on the clearance rate of intravenous technetium-99 sulfur colloid (TSC). However, patients receiving 3 days of intermittent lipid infusion exhibited a statistically significant reduction in TSC. These findings prompted the researchers to then determine whether administering the same amount of lipids continuously as a three-in one admixture would have the same effect upon RES function. In contrast to the intermittent lipid infusion, the continuous administration did not impair TSC clearance by the RES.113 Thus, provision of standard LCT lipid emulsions in a continuous manner may be preferable in critically ill or septic patients. In addition, these authors recommend a modest lipid intake of 30 to 60 g daily in this already immunocompromised patient population. These findings, coupled with current recommendations regarding the optimal dietary fat intake (i.e., < 30% of total calories), have prompted a search for alternative lipid sources.

γ-Linolenic Acid Interest in the potential metabolic benefits of dietary γ-linolenic acid (GLA), a plant seed oil found in borage oil and evening primrose oil, has grown as of late. Dietary supplementation of γ-linolenic acid, a metabolite of the omega-6 essential fatty acid, linoleic acid, has been shown to suppress both acute and chronic inflammation in animals, as well as lower plasma cholesterol and triglycerides, and inhibit platelet aggregation in diabetics.114,115 More recent studies have demonstrated that the addition of γ-linolenic acid to an eicosapentaenoic acid (EPA)-enriched diet provides additional benefits with regard to lung function during endotoxemia.116,118 The conversion of linoleic acid to γ-linolenic acid requires the presence of the enzyme, ∆-6 desaturase. However, under normal conditions, this enzyme has a low activity, therefore, only a small portion of the linoleic acid is actually converted to γ-linolenic acid which is, in turn, further metabolized to dihomo-γ-linolenic acid (DGLA). Dihomo-γ-linolenic acid is a precursor of the anti-inflammatory eicosanoids, prostaglandin E1 (PGE1) and thromboxane A1 (TXA1), as well as a precursor for arachidonic acid. The conversion of dihomo-γ-linolenic acid to arachidonic acid requires the presence of ∆-5 desaturase, an enzyme that is rate limiting in some macrophages.119 Thus, the desaturation of dihomo-γ-linolenic acid to arachidonic acid is relatively slow, particularly in the presense of EPA, an inhibitor of ∆-5 desaturase.120 It has been shown in animals that the addition of γ-linolenic acid (5.0 mole %) to a diet containing EPA modulates the fatty acid composition of alveolar macrophage phospholipids, thereby promoting a shift toward formation of less inflammatory eicosanoids by stimulated macrophages without causing an impairment in macrophage bactericidal functions.121 These changes in immune function observed in animals receiving a diet containing γ-linolenic acid and EPA are undoubtably

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responsible for the improvements in clinical outcomes seen in patients with acute respiratory distress syndrome (ARDS) who received a similar diet.122 In a multicenter trial, 98 patients with ARDS caused by sepsis/pneumonia, trauma, or aspiration were randomized to receive an enteral formula containing both EPA and γ-linolenic acid, as well as antioxidants (vitamins E and C, and beta-carotene) or an isonitrogenous, isocaloric standard diet. By study day 7, patients receiving the EPA and γ-linolenic acid-enriched formula exhibited significant improvements in pulmonary neutrophil recruitment and inflammation, gas exchange, requirement for mechanical ventilation, length of intensive care unit stay, and a reduction in new organ failures.122

ω-3 Polyunsaturated Fatty Acids There is a plethora of research to suggest that ω-3 fatty acids may have beneficial effects on plasma cholesterol and triglyceride levels.123,125 More recently, research in this area has centered around the ablility of ω-3 fatty acids to favorably effect immune function through their ability to alter ecoisanoid formation and metabolism. Eicosapentaenoic acid (EPA) has been shown to be the metabolically active ω-3 fatty acid because of its structural similarity to the ω-6 fatty acid that is the usual ecoisanoid precursor, arachidonic acid. In contrast to the ω-6 fatty acids, the omega-3 fatty acids favor production of prostaglandins of the “3” series (PGE3) and leukotrienes of the “5” series (LTB5), which have significantly different biological activities than the eicosanoids produced by the omega-6 fatty acids.108 Thromboxane A3, one of the prostanoids formed from EPA, is a moderate vasoconstrictor yet it does not aggregate platelets. In comparison, thromboxane A2, synthesized from arachidonic acid, is a very potent platelet aggregator and vaso-constrictor. Leukotriene B5, also derived from EPA, is a much less chemotactic and aggregatory agent than the leukotriene B4 that is formed from arachidonic acid. However, both prostacyclin I3, derived from EPA, and prostacyclin I2, synthesized from arachidonic acid, are potent vasodilators and platelet antiaggregators.109 In addition to synthesizing different eicosanoids than ω-6 fatty acids, EPA competes with arachidonic acid as a substrate for the enzymes cyclooxygenase and 5-lipoxygenase, further reducing the formation of proinflammatory ecosanoids. Furthermore, EPA and docosahexaenoic acid (DHA) have been shown to displace linoleic acid and arachidonic acid in cell membranes and to reduce arachidonic acid production through inhibition of the enzyme ∆-6 desaturase.108 These alterations in eicosanoid metabolism suggest that provision of lipids rich in EPA may be advantageous in critically ill patients suffering from systemic inflammation and infection. A number of animal studies appear to support the aforementioned hypothesis. In one set of experiments, administration of both short-term parenteral (i.e., 3 days) and long-term enteral (i.e., 6 weeks) diets enriched with ω-3 fatty acids improved survival in animals receiving an endotoxin infusion.126 A similar set of experiments showed that animals receiving short-term parenteral nutrition (TPN) containing soybean oil developed significant metabolic and lactic acidosis after being infused with endotoxin compared to animals receiving TPN enriched with ω-3 fatty acids from fish oil.127 In addition to having improved lactate levels, the animals receiving the ω-3 fatty acid containing TPN also demonstrated a significantly higher mixed venous oxygen than the animals given the TPN containing soybean oil. Administration of ω-3 fatty acids found in fish oil appears to attenuate tissue hypoxia and

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improve survival in animals during endotoxemia, presumably through alterations in prostaglandin metabolism. Another area of intense research is the ability of ω-3 fatty acids to alter cytokine production. The synthesis of several cytokines, specifically tumor necrosis factor (TNF) and interleukin-1 (IL-1), is related to the production of prostaglandin E2 (PGE2). The presence of stress or sepsis causes an increased production of PGE2 from monocytes and macrophages, which, in turn, results in an increased production of cytokines. It has been suggested that prolonged cytokine exposure results in increased muscle degradation,128 increased hepatic lipogenesis, 129 and hypertriglyceridemia.130 These findings have prompted some investigators to suggest that administration of fish oil may help to suppress the deleterious effects of excessive cytokine production. However, because certain cytokines help to control the body’s defense system, a substantial reduction in their production may result in impairment of normal immune response. Thus, researchers continue to search for the optimal dose of ω-3 fatty acids with respect to cytokine production. Hardardottir, et al131 fed mice diets containing varying amounts of ω-3 fatty acids, ranging from 0.15% to 1.5% by weight, for five weeks and noted an increased production of TNF from peritoneal macrophages in animals receiving the 1.5% ω-3 fatty acid diet compared to those receiving lower amounts of ω-3 fatty acids. Simlarly, other investivators have noted increased TNF132,133 and IL-1133 production in animals receiving ω-3 fatty acids compared to those fed corm oil. While other researchers have found contrasting results,134 Drs. Meydani and Dinarello135 attribute these discrepancies to the amount of EPA and DHA in the diet and/or the duration of feeding. With respect to human trials, several studies have examined the effects of fish oil supplementation on eicosanoid and cytokine production in healthy volunteers.136,137 These studies have consistantly shown a decrease in the production of proinflammatory cytokines in volunteers receiving the fish oil supplemented diets. However, one study also noted an impairment of the body’s ability to mount an immune response in healthy individuals who ate a low-fat (< 30% of total calories), high-fish (1.23 g EPA plus DHA/day or 121-188 g fish/day) diet for 6 weeks.138 These individuals demonstrated a significant reduction in percentage of helper T cells, mitogenic response to T-cell mitogen, delayed-type hypersensitivity skin response, as well as production of TNF, IL-1, and IL-6 compared to those people receving a low-fat, low-fish (0.27 g EPA plus DHA/day or 33 g fish/day) diet. Several undesirable changes in immune function (i.e. increased IL-6 release and decreased CD4 cell counts) have also been observed in patients with HIV infection who consumed five food bars daily that provided a total of 1.96 ω-fatty acids/day for 6 weeks.139 Chlebowski, et al,140 however, demonstrated a significant reduction in hospitalizations in patients with HIV infection who drank 500 mL/day of a commercially available oral supplement that provided a mere 1.1 g fish oil/day (475 mg EPA plus DHA) for a 6-month period. These findings suggest that for long-term (i.e., > 6 weeks) feeding of fish oil to be of benefit in immunocompromised individuals, it must be provided in modest amounts. With respect to the short-term (i.e., 1-2 weeks) use of enteral formulas containing fish oil, a number of studies have shown that feeding fish oil in amounts that provide 1.2-5.0 g ω-3 fatty acids/1000 kcal in select populations is safe with respect to immune function. A number of prospective, randomized trials have demonstrated improved immune function,44-46,50 fewer infectious complications,43,45-49,51 and decreased length

Current Nutrient Substrates

39

of stay43,45,47,49 in patients receiving enteral formulas enriched with fish oil, in addition to other immunostimulatory nutrients, compared to those receiving standard diets rich in ω-6 fatty acids (Tables 2.4 and 2.5). Only two studies have compared the effects of ω-3 fatty acids alone.141,142 Taken together, these studies suggest that short term administration of enteral formulas containing 7 to 11 g fish oil/L (~ 1.4 to 1.7 g EPA plus DHA/L) may be beneficial in certain hospitalized patient populations. However, further studies are needed to examine the immunological and clinical effects of feeding such diets for an extended period of time. As a result of these findings, an ever growing number of enteral formula manufacturers have begun to incorporate ω-3 fatty acids in to their products either in the form of α-linolenic acid from vegetable oils (particularly canola or soybean oil) or from the eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) in fish oil. However, a great deal of controversy exists with regard to the difference between vegetable and animal sources of ω-3 fatty acids. The main difference between these two sources of ω-3 fatty acids is that fish oil contains the preformed EPA and DHA, whereas, the α-linolenic acid in the vegetable oil must be converted in the body to EPA. This conversion process, however, yields a relatively low amount of EPA when compared to the amount of EPA obtained from consuming fish oil.143 Thus, plant sources, although useful, may not be an adequate substitute for the preformed EPA and DHA found in fish oil.

Medium Chain Triglycerides In addition to the naturally occurring and processed ω-6 and ω-3 fatty acids currently used in enteral formulas, medium chain triglycerides (MCT) are a novel lipid alternative frequently found in many of today’s enteral formulas. Although the incorporation of MCT into intravenous fat emulsions has been studied extensively, these products are not yet commercially available. Medium chain triglycerides are principally prepared by hydrolyzing and re-esterifying coconut oil, however, they can also be derived from palm kernal oil. These lipids are significantly different from the conventional fats (i.e., LCT) used in enteral formulas and intravenous lipid emulsions. LCT are absorbed via the lymphatic system and are carnitine-dependent for chylomicron formation and transport. In contrast, MCT are directly absorbed via the portal system, are not carnitine-dependent, and do not require chylomicron formation.144 Thus, MCT are absorbed and metabolized as rapidly as glucose. Severely catabolic patients may therefore benefit from this rapidly available, high energy fuel because MCT are less likely to be deposited and more likely to be oxidized in tissues.145 Furthermore, animal studies suggest that MCT do not depress RES function.110 MCT, however, have their greatest clinical impact in patients with impaired fat absorption due to pancreatic, biliary, or intestinal dysfunction. In principle, replacing LCT in the diet with MCT in the setting of impaired fat absorption should help to decrease stool frequency and volume while concommitantly improving nutrient absorption. One important point about MCT is that they are devoid of essential fatty acids. Thus, the provision of some LCT is necessary in order to meet essential fatty acid requirements.144 Most MCT-containing enteral products consist of a physical mixture of LCT and MCT. However, there is now a new generation of fats known as structured lipids which combine both MCT and LCT on the same glycerol backbone.

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Table 2.4.

Summary of studies assessing efficacy of immune-enhancing enteral formulas Patients 50 burn patients

Diets* Modular diet (containing supplemental arginine and fish oil) vs. Osmolite with Promix vs.Traumacal

Results Significant reduction in length of hospital stay (LOS) and incidence of wound infections in modular group

Cerra, et al44

20 surgical ICU patients with sepsis syndrome

Impact vs Osmolite HN

Significant improvement in T-lymphocyte proliferation in Impact group

Daly, et al45

85 patients undergoing surgery for upper GI malignancies

Impact vs. Osmolite HN

Significant reduction in LOS and infectious/wound complications in Impact group

Moore, et al46

98 trauma patients

Immun-Aid vs. Vivonex TEN

Significant increases in total lymphocytes, T lymphocytes and T-helper lymphocytes; significantly fewer intraabdominal abscesses, and less multiple organ failure in Immun-Aid group

Daly, et al47

60 patients undergoing surgery for upper GI malignancies

Impact vs. Traumacal

Significant decrease in peripheral WBC PGE2 production, LOS, and infectious/wound complications in Impact group

Bower, et al48

326 ICU patients with an APACHE score ≥10

Impact vs. Osmolite HN

Significant reduction in LOS and frequency of infectious complications in septic patients receiving Impact

Kudsk, et al49

35 trauma patients

Immun-Aid vs. Promote with Casec

Significantly fewer major infectious complications and shorter LOS in Immun-Aid group continued on next page

The Biology and Practice of Current Nutritional Support

Author Gottschlich, et al43

Summary of studies assessing efficacy of immune-enhancing enteral formulas (continued)

Author Kenler, et al141

Patients 50 patients undergoing surgery for upper GI malignancies

Diets* Osmolite HN vs. isocaloric, isonitrogenous fish oil structured lipid-based diet

Results Significant incorporation of EPA into plasma and erythrocyte phospholipids, and 50% decline in gastrointestinal complications and infections in FOSL-HN group

Kemen, et al50

42 patients undergoing surgery for GI malignancies

Impact vs isocaloric, isonitrogenous diet

Significant increase in total T lymphocytes, helper T cells, activated T cells, B-lymphocyte indices, immunoglobin M & G concentrations in Impact group

Swails, et al142

20 patients undergoing surgery for upper GI malignancies

Osmolite HN vs isocaloric, isonitrogenous fish oil structured lipid-based diet (FOSL-HN)

Significant reduction in PGE2 and 6-keto prostaglandin PGF1a production from PBMC with endotoxin stimulation in FOSL-HN group

Galban, et al51

176 septic ICU patients with an APACHE II score > 10

Impact vs. Precitene Hiperproteico

Significant reduction in mortality rate, number of bacteremias, and number of patients with more than one nosocomial infection in Impact group

Gadek, et al122

98 patients with ARDS

High fat, low carbohydrate formula vs. isocaloric, isonitrogenous EPA + GLA** lipid-based diet

Significant improvements in pulmonary netrophil recruitment and inflammation, gas exchange, requirement for mechanical ventilation, length of unit stay, and a reduction in organ failures

Current Nutrient Substrates

Table 2.4.

*Manufacturers of diets and protein modules: Ross Laboratories: Osmolite, Osmolite HN. Novartis Nutrition: Impact, Vivonex T.E.N. B Braun.: Immune-Aid. Mead Johnson Nutritionals: Traumacal, Casec. Clintec: Promote. Navaco Laboratories: Promix. **EPA=eicosapentaenoic acid; GLA=γ-linolenic acid

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Table 2.5.

2

Commercially available immune-enhancing enteral formulas used in studies shown in Table 2.4

Per 1000 kcal

Impact

Immun-Aid

Kcal/mL

1.0

1.0

Carbohydrate (g/% total kcal)

132 (53%)

120 (48%)

Carbohydrate source

Hydrolyzed cornstarch

Maltodextrins

Protein (g/% total kcal)

56 (22%)

80 (32%)

Protein source

Sodium and calcium caseinates L-arginine (12.3 g) Yeast RNA (1.2 g)

Lactalbumin L-arginine (14.0 g) L-glutamine (9.0 g) BCAA (20.0 g) Yeast extract (1.0 g)

Fat (g/% total kcal) Fat source

28 (25%) Structured lipid from palm kernal oil and sunflower oil; refined menhaden oil

22 (20%) MCT; canola oil

ω-3 fatty acids (g)

1.68

1.10

Structured Lipids Another alternative to LCT are structured triglycerides. These triglycerides are the product of MCT and LCT that have been hydrolyzed and then re-esterified after a random distribution of the MCT and LCT has occurred. Depending on the proportions of oils used, the resulting “structured lipid” may consist of one MCT and two LCT or two MCT and one LCT on the same glycerol backbone. This MCT/LCT mixture provides both rapidly and slowly metabolized fuels, as well as essential fatty acids.144,145 Preliminary animal studies suggest that structured lipids result in significantly better nitrogen balance and weight gain, and increased protein synthetic rates in both the skeletal muscle and liver when compared to either LCT, MCT, or a physical mixture of MCT and LCT.146,147 These results were particularly evident when the structured lipid contained a mixture of either 60% MCT and 40% LCT or 75% MCT and 25% LCT. In contrast, a 50:50 MCT/LCT mixture yielded no improvement in the protein-sparing effect. The 75% MCT/25% LCT structured lipid emulsion was then intravenously infused over a 19-hour period in 9 hospitalized patients, and no significant impairment in RES function was observed.101 Additional clinical trials have shown that provision of parenteral structural lipid emulsions (40% MCT/60% LCT by weight) are well tolerated148 and cause a significantly higher whole body fat oxidation, without promotion of ketogenesis, in postoperative patients when compared with the provision of standard parenteral LCT emulsions.149 More recently, a parenteral structured lipid emulsion (64% MCT/ 36% LCT by weight) was compared to a parenteral MCT/LCT physical mixture (50% MCT/50% LCT by weight) in forty patients undergoing abdominal surgery. Liver function tests (ASAT and ALAT) and plasma triacylglycerol levels were sig-

Current Nutrient Substrates

43

nificantly increased in the patients receiving the parenteral MCT/LCT physical mixture compared to those patients receiving the parenteral structured lipid.150 Presently, in the United States, intravenous structured lipids are still in the experimental phase. They are, however, present in several commercially available enteral formulas as a mixture of palm kernal oil (MCT) and sunflower oil or fish oil (LCT). More recently, a prospective, randomized clinical trial was conducted in patients undergoing surgery for upper gastrointestinal malignancies using an enteral formula that incorporated ω-3 fatty acids from fish oil directly into the structured lipid.141,142 Patients receiving the experimental formula demonstrated significant improvements in renal function, presumably due to changes in eicosanoid metabolism, and liver function, as well as a decrease in the number of patients with multiple infections compared to patients receiving a commercially available enteral formula differing only with respect to its lipid composition. There is good evidence that lipid mixtures designed for special medical purposes play an important role in the nutritional support of a wide variety of patient populations. It is clear from both animal and human studies that modulation of the composition of lipid emulsions can significantly affect the response to disease, injury, and infection. Based on these studies, several recommendations regarding fat administration in hospitalized patients can be made. First, lipid intake should ideally be limited to providing no more than 30% of total calories. Second, the type of lipid administered should be based upon the patient’s disease state. There is convincing evidence that critically ill patients may benefit from the administration of a lipid mixture that contains ω-3 fatty acids and MCT in addition to LCT. Patients undergoing surgery for upper gastrointestinal cancers may also benefit from receiving such a lipid mixture in the early postoperative period. However, more research is needed in this area to further define the optimal dose and mixture of lipids that is best suited for each specific patient population.

Conclusion Recent evidence suggets that specific nutrients may favorably affect certain aspects of organ and immune function independent of their general nutrition effects. The administration of branched-chain amino acids may be advantageous in patients with significant renal failure due to the fact that BCAA are preferentially used by the body for protein synthesis thereby decreasing the rate of urea production. In addition, the provision of glutamine-enriched nutrition may be efficacious in specific patient populations. Finally, the addition of such nutrients as arginine, glutamine, nucleotides, ω-3 fatty acids from fish oil and γ-linolenic acid to enteral formulas administered to critically ill, burn, and trauma patients, as well as those with ARDS and those undergoing surgical resections for upper gastointestinal malignancies has been shown to decrease infectious complications and length of hospital stay. Despite this exciting promise with respect to nutritional immune moduation and patient outcome, broad application of the enteral and parenteral products shown to be effective in specific populations is premature. Additional randomized, prospective trials are required to evaluate the efficacy of using these products in other patient populations. As we forge ahead in the field of bionutrition, we can look forward to the continual development and refinement of specialized “functional formulas”-parenteral and enteral formulas that provide health benefits beyond basic nutrition. In addition, we can expect to see further advances in the use of ligand-binding proteins, probiotics and prebiotics, and other natural phytonutrients.151

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62.

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Current Nutrient Substrates 65. 66. 67. 68. 69. 70. 71. 72. 73. 74. 75. 76. 77. 78. 79. 80. 81. 82. 83. 84. 85. 86.

47

Griffiths R, Jones C, Palmer A. Six-month outcome of critically ill patients given glutamine-supplemented parenteral nutrition. Nutr 1997; 13:295-302. Lacey JM, Wilmore DW. Is glutamine a conditionally essential amino acid? Nutr Rev 1990; 48:297-309. Windmueller HG, Spaeth AE. Uptake and metabolism of plasma glutamine by the small intestine. J Biol Chem 1974; 249:5070-5079. Ardawi MSM, Newsholme EA. Utilization in colonocytes of the rat. Biochem J 1985; 231:713-719. Johnson LR, Copeland EM, Dudrick SJ et al. Structural and hormonal alterations in the gastrointestinal tract of parenterally fed rats. Gastro 1975; 68:1177-1183. O’Dwyer ST, Scott T, Smith RJ et al. 5-fluorouracil toxicity on small intestinal mucosa but not white blood cells is decreased by glutamine (abstract). Clin Res 1987; 35:369A. Jacobs DO, Evans DA, O’Dwyer ST et al. Disparate effects of 5-FU on the ileum and colon of enterally fed rats with protection by dietary glutamine. Surg Forum 1987; 38:45-49. Klimberg VS, Salloum RM, Kasper M et al. Oral glutamine accelerates healing of the small intestine and improves outcome after whole abdominal radiation. Arch Surg 1990; 125:1040-1045. Kovacevic Z, Morris HP. The role of glutamine in the oxidative metabolism of malignant cells. Cancer Res 1972; 32:326-333. Austgen TR, Dudrick PS, Sitren H et al. The effects of glutamine-enriched total parenteral nutrition on tumor growth and host tissues. Ann Surg 1992; 215:107-113. Klimberg VS, Souba WW, Salloum RM et al. Glutamine-enriched diets support muscle glutamine metabolism without stimulating tumor growth. J Surg Res 1990; 48:319-323. Klimberg VS, Nworkedi E, Hutchins LF et al. Glutamine facilitates chemotherapy while reducing toxicity. JPEN 1992(supplement); 16:83s-87s. Ziegler TR, Benfell K, Smith RJ et al. Safety and metabolic effects of L-glutamine administration in humans. JPEN 1990; 14:1375-1465. Ziegler TR, Bye RL, Persinger RL et al. Effects of glutamine supplementation on circulating lymphocytes after bone marrow transplantation: A pilot study. Am J Med Sci 1998; 315:4-10. Gottschlich M, Powers C, Khoury J et al. Incidence and effects of glutamine depletion in burn patients (abstract). JPEN 1993(supplement); 17:23s. Jensen GL, Miller RH, Talabiska DO et al. A double-blind prospective, randomized study of glutamine-enriched compared with standard peptide-based feeding in critically ill patients. Am J Clin Nutr 1996; 64:615-621. Fish J, Sporay G, Beyer K et al. A prospective, randomized study of glutamineenriched parenteral compared with enteral feeding in postoperative patients. Am J Clin Nutr 1997; 65:977-983. Houdijk AP, Nijveldt RJ, van Leeuwen PAM. Glutamine-enriched enteral feeding in trauma patients: Reduced infectious morbidity is not related to changes in endocrine and metabolic responses. JPEN 1999; 23:S52-S58. Aosasa S, Mochizuki H, Yamamoto T et al. A clinical study of the effectiveness of oral glutamine supplementation during total parenteral nutrition: Influence on mesenteric mononuclear cells. JPEN 1999; 23:S41-S44. Kaproth PL, Konstantinides FN, Cerra FB. Free glutamine is available to the intestinal mucosa from intact protein based enteral diets (abstract 77). ASPEN:San Francisco, 1991:413. Swails WS, Bell SJ, Borlase BC et al. Glutamine content of whole proteins: Implications for enteral formulas. Nutr Clin Prac 1992; 7:77-80. Van Buren CT, Kulkarni AD, Fanslow WC et al. Dietary nucleotides, a requirement for helper/inducer T lymphocytes. Transplantation 1985; 40:694-698.

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The Biology and Practice of Current Nutritional Support 87. 88.

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89. 90. 91. 92. 93. 94. 95. 96. 97. 98. 99.

100. 101. 102. 103. 104. 105. 106. 107. 108.

Kulkarni AD, Schandle VB, Rudolph RF et al. Suppression of delayed type hypersensitivity (DTH) to SRBC in mice fed nucleotide-free diet. Fed Proc 1982; 41:589. Van Buren CT, Kulkarni AD, Rudolph FB. Synergistic effect of a nucleotide-free diet and cyclosporin on allograft survival. Transplant Proc 1983; 15:2967-2968. Van Buren CT, Kulkarni AD, Schandle VB et al. The influence of dietary nucleotides on cell-mediated immunity. Transplantation 1983; 36:350-352. Kulkarni AD, Fanslow WC, Rudolph FB et al. Effect of dietary nucleotides on response to bacterial infections. JPEN 1986; 10:169-171. Kulkarni AD, Fanslow WC, Drath DB et al. Influence of dietary nucleotide restriction on bacterial sepsis and phagocytic cell function in mice. Arch Surg 1986; 121:169-172. Fanslow WC, Kulkarni AD, Van Buren CT et al. Effect of nucleotide restriction and supplementation on resistance to experimental murine candidiases. JPEN 1988; 12:49-52. Pizzini RP, Kumar S, Kulkarni AD et al. Dietary nucleotides reverse malnutrition and starvation-induced immunosuppression. Arch Surg 1990; 125:86-90. Van Buren CT, Kulkarni AD, Rudolph F. Synergistic effect of a nucleotide-free diet and cyclosporin on allograft survival. Transplant Proc 1983; Supple 1-2:2967-2968. Bono VH Jr, Weissman SM, Frei E III. The effect of 6-azauridine administration on de novo pyrimidine production in chronic myelogenous leukemia. J Clin Inves 1964; 43:1486-1494. Smith JL Jr. Pyrimidine metabolish in man. N Engl J Med 1973; 288:764-771. Lee JG, Ikeda I, Sugano M. Effects of dietary n-6/n-3 polyunsaturated fatty acid balance on tissue lipid levels, fatty acid patterns, and eicosanoid production in rats. Nutr 1992; 8:162-166. Wardlaw GM, Snook JT, Lin MC et al. Serum lipid and apolipoprotein concentrations in healthy men on diets enriched in either canola oil or safflower oil. Am J Clin Nutr 1991; 54:104-110. Kwon JS, Snook JT, Wardlaw GM et al. Effects of diets high in saturated fatty acids, canola oil, or safflower oil on platelet function, thromboxane B2 formation, and fatty acid composition of platelet phospholipids. Am J Clin Nutr 1991; 54:351-358. Pomposelli JJ, Mascioli EA, Bistrian BR et al. Attenuation of the febrile response in guinea pigs by fish oil enriched diets. JPEN 1989; 13:136-140. Mascioli E, Leader L, Flores E et al. Enhanced survival to endotoxin in guinea pigs fed IV fish oil emulsion. Lipids 1988; 23:623-625. Peck MD, Ogle CK, Alexander JW. Composition of fat in enteral diets can influence outcome in experimental peritonitis. Ann Surg 1991; 214:74-82. Dietary guidelines for healthy American adults. A statement for physicians and health professionals by the Nutrition Committee, American Heart Association. Circulation 1988; 77:721A-724A. National Cholesterol Education Program Expert Panel. Detection, evaluation, and treatment of high blood cholesterol in adults. Arch Intern Med 1988; 148:36-69. James P, Norum K, Rosenberg I. Meeting Summary. Nutr Rev 1992; 50:68-70. Dupont J, White PJ, Johnston KM et al. Food safety and health effects of canola oil. J Am Coll Nutr 1989; 8:360-375. Typical fatty acid compositions of selected edible fats and oils. Columbus: Capital City Products Company, 1987. Kinsella JE, Lokesh B, Broughton S et al. Dietary polyunsaturated fatty acids and eicosanoids: Potential effects on the modulation of inflammatory and immune cells: An overview. Nutr 1990; 6:24-45.

Current Nutrient Substrates 109. 110. 111. 112. 113. 114. 115. 116. 117. 118. 119. 120. 121. 122. 123. 124. 125. 126. 127. 128. 129.

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Babineau TJ, Pomposelli J, Forse RA et al. Lipids. Zaloga GP, ed. Nutrition in Critical Care. St. Louis: Mosby Year Book, Inc, 1994:191-204. Sobrado J, Moldawer LL, Pomposelli JJ et al. Lipid emulsions and reticuloendothelial system function in healthy and burned guinea pigs. Am J Clin Nutr 1985; 42:855-863. Hamawy KJ, Moldawer LL, Georgiff M et al. The effect of lipid emulsion on reticuloendothelial system function in the injured animal. JPEN 1985; 9:559-565. Seider DL, Mascioli EA, Istfan NW et al. Effects of long-chain triglyceride emulsions on reticuloendothelial system function in humans. JPEN 1989; 13:614-619. Jensen GL, Mascioli EA, Seidner DL. Parenteral infusion of long- and medium-chain triglycerids and reticuloendothelial system function in man. JPEN 19909; 14:467-471. Tate G, Mandell BF, LaPosata M et al. Suppression of acute and chronic inflammation by dietary gamma linolenic acid. J Rheumatol 1989; 16:729-733. Chaintreuil J, Monnier L, Colette B et al. Effects of dietary gamma-linolenate supplementation on serum lipids and platelet function in insulin-dependent diabetic patients. Hum Nutr-Clin Nutr 1984; 38:121-130. Mancuso P, Whelan J, DeMichele SJ et al. Effects of eicosapentaenoic and γ-linolenic acid on lung permeability and alveolar macrophage eicosanoid synthesis in endotoxic rats. Crit Care Med 1997; 25:523-532. Mancuso P, Whelan J, DeMichele SJ et al. Dietary fish oil and borage oil suppress intrapulmonary pro-inglammatory eicosanoid biosynthesis and attenuate pulmonary neutroph accumulation in endotoxic rats. Crit Care Med 1997; 25:1198-1206. Murray MJ, Kumar M, Gregory TJ et al. Select dietary fatty acids attenuate cardiopulmonary dysfunction during acute lung injury in pigs. Am J Physiol 1995; 269:H2090-2099. Fan Y-Y, Ramos KS, Chapkin RS:Dietary γ-linolenic acid enhances mouse macrophage-derived prostaglandin E1 which inhibits vascular smooth muscle cell proliferation. J Nutr 1997; 127:1765-1771. Kinsella JE, Broughton KS, Whelan. Dietary unsaturated fatty acids: Interactions and possible needs in relation to eicosanoid synthesis. J Nutr Biochem 1990; 1:123-141. Palombo JD, DeMichele SJ, Boyce PJ et al. Effect of short-term enteral feeding with eicosapentaenoic and γ-linolenic acids on alveolar macrophage eicosanoid synthesis and bactericidal function in rats. Crit Care Med 1999; 27:1908-1915. Gadek JE, DeMichele SJ, Karlstad MD et al. Effect of enteral feeding with eicosapentaenoic acid, γ-linolenic acid, and antioxidants in patients with acute respiratory distress syndrome. Crit Care Med 1999; 27:1409-1420. Phillipson BE, Rothrock DW, Connor WE et al. Reduction of plasma lipids, lipoproteins, and apoproteins by dietary fish oils in patients with hypertriglyceridemia. N Engl J Med 1985; 312:1210-1216. Thorngren M, Gustafson A. Effects of 11-week increase in dietary eicosapentaenoic acid on bleeding time, lipids, and platelet aggregation. Lancet 1981; 2:1190-1193. Simopoulos AP. Omega-3 fatty acids in health and disease and in growth and development. Am J Clin Nutr 1991; 54:438-463. Mascioli EA, Leader L, Flores E et al. Enhanced survival to endotoxin in guinea pigs fed IV fish oil emulsion. Lipids 1988; 23:623-625. Pomposelli JJ, Flores E, Hirschberg Y et al. Short-term TPN containing ω-3 fatty acids ameliorate lactic acidosis induced by endotoxin in guinea pigs. Am J Clin Nutr 1990; 52:548-552. Flores EA, Bistrian BR, Pomposelli JJ et al. Infusion of tumore necrosis factor/ cachectin promotes muscle catabolism in the rat. J Clin Invest 1989; 83:1614-1622. Hellerstein MK, Grunfeld C, Wu K et al. Increased de novo hepatic lipogenesis in human immunodeficiency virus infection. J Clin Endocrinol Metab 1993; 76:559-565.

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The Biology and Practice of Current Nutritional Support 130. 131.

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133. 134. 135. 136. 137. 138. 139. 140.

141. 142. 143. 144. 145. 146. 147.

Hirschberg Y, Pomposelli JJ, Blackburn GI et al. The effects of chronic fish oil feeding in rats on protein catabolism induced by recombinant mediators. Metabolism 1990; 39:397-402. Hardardottir I, Kinsella JE. Tumor necrosis factor production by murine resident peritoneal macrophages is enhanced by dietary ω-3 polyunsaturated fatty acids. Biochem Biophys Acta 1991; 1095:187-195. Turek JJ, Schoenlein IA, Bottoms GD. The effect of dietary ω-3 and ω-6 fatty acids on tumor necrosis factor-productin and leucine aminopeptidase levels in rat peritoneal macrophages. Prostaglandins Leukotrines Essent Fatty acids 1991; 43:141-149. Lokesh BR, Sayers TJ, Kinsella JE. Interleukin-1 and tumor necrosis factor synthesis by mouse peritoneal macrophages is enhaved by dietary ω-3 polyunsaturated fatty acids. Immunol Lett 1990; 23:281-286. Billar TR, Bankey PE, Svingen BA. Fatty acid intake and Kupffer cell function: Fish oil alters eicosanoid and monokine production to endotoxin stimulation. Surgery 1988; 104:343-349. Meydani SN, Dinarello CA. Influence of dietary fatty acids on cytokine production and its clinical implications. Nutr Clin Prac 1993; 8:65-72. Meydani SN Endres S, Woods MN et al. Oral (ω-3) fatty acid supplementation suppresses cytokine production and lymphocyte proliferation:comparison between young and older women. J Nutr 1991; 121:547-555. Endres S, Ghorbani R, Kelley VE et al. The effect of dietary supplementation with (ω-3) polyunsaturated fatty acids on the synthesis of interleukin-1 and tumor necrosis factor by mononuclear cells. New Engl J Med 1989; 320:265-271. Meydani SN, Lichtenstein AH, Cornwall S et al. Immunologic effects of national cholesterol education panel step-2 diets with and without fish-derived ω-3 fatty acid enrichment. J Clin Invest 1993; 92:105-113. Bell SJ, Chavali S, Bistrian BR et al. Dietary fish oil and cytokine and eicosanoid production during human immunodeficiency virus infection. JPEN 1996; 20:43-49. Chlebowski RT, Beall G, Grosvenor M et al. Long-term effects of early nutritional support with new enterotropic peptide-based formula vs. standard enteral formula in HIV-infected patients: Randomized prospective trial. Nutrition 1993; 9:507-512. Kenler A, Swails W, Driscoll D et al. Early enteral feeding in postsurgical cancer patients: Fish oil structured lipid-based polymeric diet versus a standard polymeric formula. Ann Surg 1996; 223:316-333. Swails WS, Kenler AS, Driscoll DF et al. Effect of a fish oil structured lipid-based diet on protaglandin release from mononuclear cells in cancer patients after surgery. JPEN 1997; 21:266-274. Nettleton JA. ω-3 fatty acids: Comparison of plant and seafood sources in human nutrition. J Am Dietet Assoc 1991; 91:331-337. Babayan VK. Medium chain triglycerides and structured lipids. Nutr Supp Serv 1986; 6:26-29. Mascioli EA, Bistrian BR, Babayan VK et al. Medium chain triglycerides and structured lipds as unique nonglucose energy sources in hyperalimentation. Lipids 1987; 22:421-423. DeMichele SJ, Karstad MD, Babayan VK et al. Enhanced skeletal muscle and liver protein synthesis with structured lipid in enterally fed burned rats. Metab 1988; 37:787-795. Mok KT, Maiz A, Yamazaki K et al. Structured medium-chain and long-chain triglyceride emulsions are superior to physical mixtures in sparing body protein in the burned rat. Metab 1984; 33:910-915.

Current Nutrient Substrates 148. 149. 150. 151.

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Sandstrom R, Hyltander A, Korner U et al. Structured triglycerides to postoperaive patients:a safety and tolerance study. JPEN 1993; 17:153-157. Sandstrom R, Hyltander A, Korner U et al. Structured triglycerides were well tolerated and induced increased whole body fat oxidation compared with long-chain triglyceride in postoperative patients. JPEN 1995; 19:381-386. Chambrier C, Guiraud M, Gibault JP et al. Medium- and long-chain triacylglycerols in postoperative patients: Structured lipids versus a physical mixture. Nutrition 1999; 15:274-277. Blackburn GL. Pasteur’s Quadrant and malnutrition. Nature 2001; Jan 18(409 supl):397-401.

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CHAPTER 3

Biochemistry of Amino Acids: Clinical Implications Rifat Latifi, Khawaja Aizimuddin

Introduction Amino acids, as organic compounds, containing both an amino group and a carboxylic acid group, are the monomeric and basic constituents of all proteins. Amino acids occurring in protein are known as alpha-amino acids and have one or two empirical formulae RCH (NH+)COOH- or R-CH-(NH3)COO-. Beta-amino acids and gamma-amino acids also occur in nature but are not components of proteins, and their significance is not known. This chapter reviews the basic biochemistry and physiology of amino acids and their functions as fundamental units of proteins. Their increasingly recognized and valued role in the metabolic and nutritional management of critically ill patients will be discussed through out this volume.

Structure of Amino Acid and Proteins A protein molecule consists of amino acids held together by peptide bonds, which form a long polypeptide chain. The exact sequence of amino acids in the chain, referred to as the primary structure of the protein, is determined genetically and defines how the chain is folded into more complex conformations or shapes. A polypeptide, which is folded into a helical or pleated sheet configuration, is referred to as a secondary structure. If the sequence of amino acids is then folded into a three-dimensional configuration, a tertiary structure is created. Some proteins have a higher level of molecular architecture known as the quaternary structure, in which several chains aggregate and function as a unit. The amino acid sequence and protein structure determine the nature and function of protein molecules upon which virtually every process of life depends. The folding of polypeptide chains into alpha helix and beta pleated sheets has clinical implications. The alpha helix is a rod-like structure and contains a tightly coiled polypeptide main chain. Two or more such alpha helices can entwine to form a cable, which serves as a mechanical support by forming stiff bundles of fibers. Such alpha-helical coils are found in the keratin of a hair, myosin and tropomyosin in muscle, epidermis in skin and fibrin in blood clots. In contrast to the coiled alpha helix, beta-pleated sheets are fully extended sheets of polypeptide chains. Another type of periodic structure is the collagen helix. Collagen is triple-stranded helical rod which is tightly held together by the amino acid glycine. By virtue of its very small size, glycine fits into the inner aspect of the tightly packed helical cable and thereby allows the different polypeptide chains to come together. It is easy to see that mutation of a single glycine in collagen can lead to weak collagen as occurs in osteogenesis imperfecta. The Biology and Practice of Current Nutritional Support, 2nd Edition, edited by Rifat Latifi and Stanley J. Dudrick. ©2003 Landes Bioscience.

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Although more than 100 different amino acids have been identified in nature, only 20 amino acids are used to build the enormous number of biologically active peptides and proteins that comprise most of the dry weight of the human body. When one realizes that muscle, bone, blood, brain, genes, and other tissues are all composed of amino acids, it is not difficult to understand the importance of acquiring knowledge of amino acid biochemistry and metabolism, not only for biochemists and basic scientists, but also for surgeons and other physicians.

Amino Acid and Protein Synthesis Amino acids are building blocks for protein. All proteins are initially synthesized from 20 amino acids known as common or primary amino acids. Primary amino acids are defined as amino acids for which a specific codon exists in the DNA genetic code. The genetic code is a directory that provides the correspondence between a sequence of nucleotide bases and a sequence of amino acids. The codons represent genetic words in a code composed of three nucleotide bases which are transcribed from DNA into the messenger RNA (mRNA), and their sequence is always read from its 5’-end (amino-terminal end) to its 3’-end (carboxyl-terminal end). Codons exist for all 20 of the amino acids in the human body. Genetic information is transmitted from the DNA sequence by mRNA translation into the amino acid sequence of a protein. The genetic code is thought to be specific, usually universal, redundant or degenerate, non-overlapping and commaless. Conventionally, the code is read from a fixed starting point as a continuous sequence of bases, taken three at a time. Protein synthesis is a highly complex biochemical process that requires 1. an amino acid sequence information, as coded by mRNA, 2. activated amino acids assembled as aminoacyl transfer RNA (tRNA) complex 3. energy in the form of guanosine triphosphate (GTP), and 4. various protein initiation or release factors. Protein synthesis occurs on the surface of ribosome, or multiprotein, multi-RNA complexes that provide the enzyme, peptidyl-transferase. This enzyme is one of many proteins of the larger ribosomal subunit and is imbedded in the surface of the subunit. It catalyzes peptide bond formation and covalent linkage of one amino acid residue to another. The process of protein synthesis itself is called “translation,” because the “language” of the nucleotide sequence on the mRNA is translated into the language of an amino acid sequence. The mRNA is translated from its 5’-end to its 3’-end producing a protein synthesized from its amino-terminal end to its carboxyl-terminal end. The direction of translation is precisely defined, with the amino terminal of the evolving protein being synthesized first and the carboxyl terminal synthesized last. The polypeptide chains produced by translation may be modified further after translation. Protein synthesis has three steps: initiation, elongation, and termination.

Initiation Initiation involves assembly of the components of the translational system before the peptide bonds are formed. Components of the translational system include two ribosomal subunits, the mRNA to be translated, the specified aminoacyl tRNA along with GTP and the initiation factors. Eukaryotic initiation, which requires ribosomal subunits 40S and 60S, mRNA, GTP, initiation factors (IF-1, IF-2, and

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IF-3) and ATP, first involves the formation of a complex outer 40S ribosomal subunit, and secondly, the addition of the 60S ribosomal subunit to give an 80S initiation complex.

Elongation

3

The second step in protein synthesis is elongation of the polypeptide chain. The necessary components for this process are the 80S initiation complex, aminoacyl-tRNA, GTP and eukaryotic elongation factors eEF-l alpha, eEF-1 beta and eEF-2. During elongation, the ribosome moves from the 5’-end to the 3’-end of the mRNA that is being translated. At one time, a single mRNA molecule may be translated by many ribosomes, thereby markedly increasing the efficiency of the utilization of the mRNA. The group of ribosomes bound to a mRNA molecule is called a polyribosome. The concluding event of elongation is translocation. Translocation is a process in which the ribosome advances three nucleotide segments toward the 3-end of the mRNA following formation of the peptide bond. It causes the release of the uncharged tRNA and movement of peptidyl tRNA into the P site.

Termination The final step of protein synthesis, occurs in response to termination signals, after the final amino acid residue is placed at the carboxyl terminal of the newly synthesized protein. This process occurs when one of the three termination codons (UAA, UAG and UGA) moves into the A site. These codons are recognized by release factors (RF): RF-1, RF-2, and RF-3 and cause the newly generated protein molecule to be released from the ribosomal complex, and also effect the dissociation of ribosomes from the mRNA.

Post-Synthetic Modification The basic set of 20 amino acids can be modified after synthesis of a polypeptide chain to enhance their capabilities. For example, the amino acid terminals of many proteins can be acetylated to make them more resistant to degradation. Similarly, the proline residues in collagen may be hydroxylated to form hydroxyproline, which stabilizes the collagen fiber. Carboxylation of glutamate is another important step in the synthesis of coagulation factor.

Protein Function Protein function may be classified into two categories: dynamic and structural (static). Dynamic functions include enzymatic catalysis of biochemical reactions, transport and storage, contraction, generation and transmission of nerve impulses and immune protection. Structurally, proteins provide the matrix for bone and connective tissue, which give structure and form to the body. Some of these important functions are discussed in detail below.

Enzymatic Catalysis Specific enzymes catalyze chemical reactions in living organisms. Several thousand enzymes have been recognized and many of them are essential for the function and survival of the organism. Nearly all enzymes in biological systems are proteins. It is easy to see that a defect in the amino acid constitution of an enzyme may lead to abnormal functioning of that enzyme system.

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Transport and Storage Many small molecules and ions are transported or stored by proteins. Oxygen is transported in blood by hemoglobin and stored in muscles in combination with myoglobin. Similarly iron is carried in plasma by transferrin and stored in liver as a complex with ferritin. Thyroxine, cortisol, sex hormone, calcium and copper are examples of some of the large array of hormones and ions transported by proteins.

Coordinated Motion Proteins provide the contractile element for the cytoskeleton. Movement of chromosomes during mitosis, movement of organelles within the cell and the propulsion of sperms by flagella is produced by coordinated actions of contractile assemblies consisting of proteins. Most importantly, muscle contraction is accomplished by sliding motion of two proteins, actin and myosin.

Mechanical Support Proteins provide the framework for the living organism. Collagen, a fibrous protein, provides tensile strength to skin and bone.

Immune Protection Antibodies consist of highly specific amino acid chains, which protect the body from viruses, bacteria and other exogenous or endogenous antigens. Nutrient substrate deficits may therefore lead to suppressed humoral and delayed type hypersensitivity immune responses

Tissue Repair Proteins not only play a pivotal role in the inflammatory response but also provide building blocks for the process of repair after tissue injury.

Generation and Transmission of Impulses The synaptic receptors at nerve terminals consist of small proteins which are in turn stimulated by other protein molecules such as acetyl choline. Furthermore, most membrane functions such as transport of ions or molecules, intercellular communications and energy transduction are mediated by specific proteins that traverse the cell membrane.

Control of Growth and Differentiation Many hormones such as growth hormone, insulin and thyroid stimulating hormones are proteins. Further more many of the growth factors such as nerve growth factor, platelet derived growth factor are also proteins.

Specialized Functions Some amino acids have specialized functions. For example, glutamine serves as energy source for lymphocytes and macrophages. It is also required for the maintenance of the intestinal mucosa. Similarly arginine is important for cell mediated immunity.

Classification of Amino Acids Amino acids occurring in biologic proteins are known as alpha-amino acids and have one of two empirical formulae: R-CH-(NH2)-COOH or R-CH-(NH3+)-COO-. Beta amino acids and gamma-amino acids also occur in nature but are not

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components of proteins, and their significance is not known. The core of an α-amino acid is the α-carbon atom next to the carboxylic acid (COOH) group. All α-amino acids, except glycine, are asymmetric, with four different groups bonded to the a-carbon: a hydrogen atom, a carboxyl group, an amino group (NH2), and a distinctive R-group. The characteristic acid-base properties of each amino acid and the variety of possible R-group configurations and interactions make peptides and proteins versatile in structure and function. Although the primary amino acids can be polymerized to form proteins, each of the 20 primary amino acids is a unique compound with its own individual biological and metabolic functions. Many amino acids of biological significance, such as thyroxine, triiodothyronine and beta-alanine, are not numbered among the 20 primary amino acids. Other amino acids, such as ornithine and citrulline, are intermediates of the urea cycle and have major roles in the body economy. Some proteins, such as collagen, elastin, and prothrombin, incorporate special amino acids. For example, collagen contains 4-hydroxyproline and 5-hydroxylysine; elastin contains desmosine; myosin has n-methyllysine; and prothrombin contains γ-carboxyglutamic acid. Primary amino acids are classified in several ways. Because the nature of the side chains ultimately dictates the role of an amino acid in a protein, one useful classification of amino acids is based on the polarity of the side chain. This classification identifies and categorizes amino acids as nonpolar (hydrophobic), uncharged polar (hydrophilic), negatively charged (acidic), and positively charged (basic) (Table 3.1). Amino acids with non-polar side chains typically do not bind or release protons, or participate in hydrogen or ionic bonding. Proline is unique in this group in that it contains an amino group rather than an alpha-amino group. Amino acids with uncharged polar side chains have zero net charge at neutral pH, although the side chains (R-groups) of cysteine and tyrosine can lose a proton in alkaline conditions. Amino acids with acidic side chains (aspartic acid and glutamic acid) are negatively charged and are proton donors; amino acids with basic side chains bind protons (arginine, lysine and histidine). The side chains of arginine and lysine are fully ionized and positively charged at neutral pH. Histidine, on the other hand, is a weak basic amino acid because as a free amino acid it is largely uncharged at physiologic pH. As a component of proteins, however, the histidine side chain can have a positive or neutral charge, depending on the ionic environment. In addition to basic and acidic amino acids, a large number of amino acids are classified as neutral. The neutral amino acids are monoamino-monocarboxylic acids and are characterized by their side chains. This group includes glycine, alanine, valine, leucine, isoleucine, serine, threonine, phenylalanine, tyrosine, tryptophan, and the sulfur-containing amino acids (cysteine, methionine, and cystine). Another useful classification is based on whether amino acids are glycogenic, glucogenic and ketogenic, or only ketogenic. Amino acids are classified as ketogenic or glucogenic according to their metabolic end products. Amino acids that yield either acetoacetate or one of its precursors, acetyl CoA or acetoacetyl CoA, are ketogenic. The only amino acids that are exclusively ketogenic are leucine and lysine because they cannot function as carbon sources for the net synthesis of glucose. On the other hand, amino acids whose catabolism yields pytuvate or one of the intermediates of the citric acid cycle (such as oxaloacetate) are glucogenic amino acids (Table 3.2). However, as depicted in Table 3.2, some amino acids have both ketogenic and glucogenic functions.

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Table 3.1.

Classification of the 20 amino acids found in proteins according to the charge and polarity of the side chains (R-groups)

Nonpolar (Hydrophobic) Side Chains Alanine Glycine Leucine Valine Isoleucine Phenylalanine Tryptophan Methionine Proline Acidic Side Chains Aspartic acid Glutamic acid

Table 3.2.

Uncharged Polar (Hydrophilic) Side Chains Asparagine Glutamine Cysteine Serine Threonine Tyrosine

Basic Side Chains Histidine Lysine Arginine

Classification of primary amino acids according to metabolic end products

Glycogenic or Glucogenic Glycine Serine Valine Histidine Arginine Cysteine Proline Alanine Glutamate Glutamine Aspartate Asparagine Methionine

Ketogenic

Both

Leucine Lysine

Threonine Isoleucine Phenylalanine Tyrosine Tryptophan

Amino acids may also be classified as essential or non-essential. Whether amino acids are nutritionally essential (indispensable) or non-essential (dispensable) depends on whether they can be synthesized endogenously and are not necessarily required in the diet (non-essential), or those that cannot be synthesized endogenously and, therefore, must be provided in the diet (essential) (Table 3.3). A new category of amino acids termed “conditionally essential” is emerging and includes arginine, taurine, and others. An amino acid falls into this class when its production is either limited by immature synthetic mechanisms or its requirements are increased under certain stressful conditions.

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Table 3.3.

3

Classification of primary amino acids based on dietary requirements

Essential (Indispensable) Arginine* Histidine Methionine Threonine Valine Isoleucine Lysine Phenylalanine Tryptophan Leucine Nonessential (Dispensable) Alanine Aspargine Aspartate Cysteine Glutamine* Glutamate Glycine* Proline Serine Tyrosine*

* These amino acids plus cystine, proline and taurine are considered to be conditionally indespensable.

Amino Acids in Critical Illness and Injury Arginine is a semi or conditionally essential amino acid, and its requirements are increased during sepsis and tissue injury. Through its role in the urea cycle, arginine takes part in the synthesis of other amino acids, urea and nitric oxide. Arginine is important for cell mediated immunity. It is required for the growth and function of T lymphocytes in cultures. In vivo, arginine retards thymic involution by encouraging production of thymic hormones and thymocyte proliferation. Arginine also promotes leukocyte-mediated cytotoxicity. Growth hormone receptors are widely distributed in the immune system, and by releasing growth hormone, arginine may increase the cytotoxic activity of macrophages, neutrophils, NK cells and cytotoxic T cells. Furthermore, nitric oxide, a product of arginine metabolism, has important tumoricidal, anti-microbial and inflammatory activities. Glutamine is the most abundant amino acid in blood and in the body’s free amino acid pool. Lymphocytes and macrophages use glutamine as a source of energy. After entering the cell, glutamine is converted to glutamate and ammonia by the action of glutaminase in the inner mitochondrial membrane. Further processing results in production of aspartate and oxidation of about 25% of glutamine to carbondioxide. This “glutaminolysis” pathway works in conjunction with the glycolytic pathway to allow the combined use of glucose and glutamine as an energy source for macrophages and lymphocytes. Thus, a relative deficiency of glutamine stores that occurs during critical illness, is likely to lead to poor immune responses.

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Glutamine also plays an important role in maintaining the integrity of the intestinal mucosa. In animal studies it has been shown that addition of glutamine to parenteral nutrition inhibits gut mucosa atrophy, reduces bacterial translocation across the gut epithelium and increases the production of secretory IgA. Glutamine and arginine are mobilized from the skeletal muscles during critical illness to provide substrate for production of glucose by the liver, to provide energy substrate for rapidly dividing cells and to take part in the acid base balance. The concentration of skeletal muscle glutathione also falls during critical illness. Since glutathione is a scavenger of free oxygen radicals, the reduced levels may predispose skeletal muscles to free radical injury. The plasma levels of phenylalanine rise after critical illness and the ratio of phenylalanine to tyrosine has been used as an indicator of the severity of muscle protein catabolism. The excretion of carnitine and 3-methyl histidine in urine is increased in critically ill patients, indicating muscle breakdown and catabolism of proteins. The rate of excretion of pyridinium cross-liked breakdown products of collagen is also increased.

Amino Acids in Circulation Serum levels of free amino acids are generally low. The normal concentration of total amino acids in the blood is between 35 and 65 mg/dL. Although some amino acids circulate in higher concentrations than others, serum concentration averages about 2 mg/dL for each of the 20 amino acids. Although the distribution of amino acids in the blood can depend on the type of dietary protein ingested, the concentrations of some amino acids are regulated by selective synthesis in different types of cells. The concentration of free amino acids in the intracellular compartment is considerably higher than the concentration in the extracellular compartment. The total amount of free amino acids in the body is about 100 g, of which 50% consists of glutamate plus glutamine, and 10% consists of essential amino acids. Furthermore, because immediately after entering a cell, amino acids form peptide bonds to create proteins, storage of large quantities of amino acids as such does not occur in most cells. However, the cells of some tissues such as the liver, kidney, and the intestinal mucosa can store large quantities of amino acids. The plasma concentration of each amino acid is relatively constant although various hormones secreted by the endocrine glands affect the balance between tissue proteins and free amino acids.

Digestion of Amino Acids During digestion, proteins are degraded into peptides and amino acids. Protein digestion begins during the gastric phase and is influenced by both hormonal and neural factors. Pepsinogen, which is secreted by gastric chief cells in response to ingested foods and low gastric pH, is converted by hydrochloric acid to pepsin, the major gastric protease. Pepsin is an endopeptidase that is specific for disruption of peptide bonds involving aromatic primary amino acids. Although important for breaking down dietary proteins, pepsin is not essential for normal protein digestion and absorption unless pancreatic function is impaired. For example, patients who have had a total gastrectomy and those with pernicious anemia absorb protein efficiently and can maintain positive nitrogen balance if adequate amounts of protein are ingested. The hydrolysis of proteins to free amino acids and their absorption into the circulation is a stepwise process. Gastric hydrolysis of protein yields peptides that, when entering the intestine, stimulate intestinal endocrine cells to release cholecystokinin and secretin which, in turn, stimulate the pancreas to secrete enzymes and

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bicarbonate into the intestinal lumen. When the gastric contents mix with the alkaline pancreatic juice in the duodenum, pepsin activity is terminated, and digestion by pancreatic proteases is initiated. The pancreatic endopetidases (trypsin, chymotrypsin, and elastase) cleave the proteins at specific interior peptide bonds. These pancreatic proteases are secreted in inactive forms and are converted to active enzymes by the combined action of enterokinase, a brush border mucosal cell enzyme, and trypsin. The end products of the additive action of endopeptidases and exopeptidases are free amino acids and oligopeptides. Subsequently, proteases in the brush border cells contribute to the enzymatic digestion of the oligopeptides (a peptide chain several peptides long). The brush border oligopeptidases generally cleave the N-terminus amino acids from their substrate to yield smaller peptides.

Absorption of Amino Acids The final products of protein digestion, amino acids and small peptides (dipeptides and tripeptides) are absorbed by distinct transport systems. Whereas, proteins are absorbed mainly in the form of small peptides and amino acids, the final measurable amino nitrogen in postprandial portal-vein blood is primarily in the form of amino acids. Nevertheless, a few small peptides, usually dipeptides and tripeptides, do appear in portal blood after protein ingestion. Several mechanisms have been identified for amino acid transport from the gut lumen into the intestinal epithelial cells, but some amino acids (such as the amino acids—glycine, proline, and hydroxyproline) may be transported by more than one mechanism. Separate transport mechanisms exist for neutral amino acids (alanine, valine, leucine, isoleucine, methionine, phenylalanine, tyrosine, and tryptophan); basic amino acids (lysine, arginine, and histidine); acidic amino acids (aspartic acid and glutamic acid); and for beta-amino acids (beta-alanine and taurine). The transport of amino acids across the special membrane of enterocytes is carrier mediated, sodium-dependent, and characteristically energy-dependent. The transport is associated with the entry of sodium into the cell and is fueled by the energy derived from the electrochemical sodium gradient. In other words, the “downhill” entry of sodium can bring about the “uphill” concentration of amino acids in the brush border cells. Once inside the liver cells, amino acids may be catabolized, with the conversion of their nitrogen to ammonia and urea. Because this process occurs in the mitochondria, transport mechanisms may exist in the mitochondrial membrane. Although little is known concerning the intracellular transport of amino acids across the mitochondrial membrane, the transcellular transport of amino acids in the kidneys appears to occur by a special mechanism in which amino acids are covalently linked to gamma-glutamyl residues of the tripeptide glutathione. During absorption, peptides and amino acids are taken up by the mucosal cells by independent processes. While oligopeptides, apparently, can be absorbed by the intestine without first being broken down into individual amino acids, dipeptides and tripeptides are actively transported against a concentration gradient by a carrier mechanism separate from that for amino acids. The propensity for a dipeptide to be transported is influenced by the dipeptide structure including the specific amino acid residues, the position relative to the carboxyl and amino terminals, the length of the side chains, and stereoisomerism. The majority of oligopeptides that are absorbed undergo additional intracellular hydrolysis.

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The absorption of small peptides may represent a major mechanism for absorption of dietary protein and has important physiologic and clinical implications. For example, consideration of oligopeptide absorption is essential in designing formulas for optimal enteral nutrition. Absorption of oligopeptides across the brush border occurs more rapidly than the transport of free amino acids. Whereas free amino acids are absorbed more rapidly in the proximal intestine, the peptides appear to be absorbed well in both the proximal and distal gut. Resection of long segments of the small bowel, or jejunoileal bypass in patients undergoing treatment for morbid obesity may result in protein calorie malnutrition. This malnutrition is related to a reduced rate of amino acid absorption in the residual functioning jejunum. On the other hand, dipeptide absorption is not affected significantly by jejunoileal bypass.

Biochemical Transformation of Amino Acids The process by which an amino group at least in different amino acids (alanine, arginine, aspartic acid, asparagine, cysteine, glutamic acid, glutamine, isoleucine, phenylalanine, tryptophan, tyrosine, and valine) is transferred from one carbon chain to another to form a new amino or keto acid is called “transamination”. The enzymes that catalyze this process, the transaminases (aminotransferases), are widely distributed and are responsible for an active redistribution of amino groups among amino acids in vivo. Furthermore, the transfer of the amino group from one carbon chain to another helps to maintain appropriate ratios of the various amino acids while individual compounds are undergoing synthesis or degradation. An essential cofactor for all transaminases, and for many other reactions involving amino acids, is pyridoxal phosphate. The most important transaminases are aspartate aminotransferase (AST), also known as glutamine-oxaloacetic transaminase (GOT); alanine aminotransferase (ALT), also known as glutamic-pyruvic transaminase (GPT); a-amino acid-a-ketoglutarate aminotransferase and amino acid-pytuvate aminotransferase. Because transaminases are present in high concentrations in the heart muscle and liver, damage to either or both of these organs leads to transaminase leakage into the plasma or serum. Transamination is of great importance in the metabolism of amino acids and is the process, which allows a-keto acids to be used as substitutes for many amino acids in nutrition regimens, especially in the management of renal failure or insufficiency. Before oxidation of the carbon group of the amino acid molecule can take place, the amino group must be detached. Detachment is accomplished by oxidative deamination, a process that occurs mainly in the liver and which, in contrast to transamination, produces free ammonia. The main mechanism for net use or production of amino acids is a reaction catalyzed by glutamate dehydrogenase. This enzyme catalyzes the following reaction: Glutamate + NAD (or NADP+) + H2O ↔ α-ketoglutarate + NADH (or NADP+) + H+ + NH4+. The reaction direction depends on the relative concentrations of glutamate, a-ketoglutarate, and ammonia and the ratio of oxidized to reduced cofactors. After ingestion of a meal containing protein, glutamate levels in the liver are elevated, and the reaction proceeds in the direction of amino acid degradation and ammonia formation. Glutamate dehydrogenase is located in the mitochondrial matrix space, is polymorphic, and in vitro uses either NAD or NADP.

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Glutamate is the only amino acid that undergoes rapid oxidative deamination, which results in the liberation of the a21mino group as free ammonia. The sequential action of transamination that results in production of glutamate and its subsequent oxidative deamination provides a route by which the amino groups of most amino acids can be released as free ammonia. Glutamate dehydrogenase therefore plays a major role in the transport of nitrogen from muscle to liver, although the major transporters are glutamine and alanine. Glutamine is also the main mode of transporting NH3 from the brain. The removal of the a-amino group from an amino acid is the first step in amino acid catabolism. Once released, the nitrogen molecule can be incorporated into other compounds or excreted. Urea is the major disposal form of amino groups derived from amino acids and accounts for 80% to 90% of the nitrogen-containing components of urine. Urea nitrogen is produced during the urea cycle. Liver is the exclusive site of urea synthesis, although the enzymes for producing arginine, the precursor of urea, are present in the brain, kidney, and skin. Urea nitrogen is derived from glutamate, which is present in both the mitochondrial matrix and the cytosol. While in the cytosol, aspartate is formed by transamination of glutamate with cytosolic oxaloacetate in the mitochondrial matrix; nitrogen can arise from glutamate via glutamate dehydrogenase and from glutamine via mitochondrial glutaminase. Urea cycle enzyme levels depend on nutritional patterns; with a high-protein diet or during starvation (during which glucogenesis from amino acids is increased), the levels of urea-cycle enzymes increase several-fold. Additionally, the provision of carbamoyl phosphate to the urea cycle is regulated by acetylglutamate synthetase, an enzyme whose activity is markedly increased by amino acids, especially arginine. After removal of nitrogen, the carbon skeletons of amino acids can be oxidized, providing a source of energy. Based on their use as an energy source, amino acids may be grouped into a nonfat-like (histidine and all nonessential amino acids) category and a fat-like category that consists of tyrosine and all the essential amino acids except histidine. All of the amino acids of the nonfat-like group are glucogenic because they either form pytuvate or enter the tricarboxylic acid cycle. On the other hand, the fat-like group of amino acids consists of some amino acids that are glucogenic, glycogenic, or both.

Selected References 1. 2. 3. 4. 5. 6. 7.

Devlin MT. Textbook of Biochemistry with Clinical Correlations. Fourth edition. New York: John Wiley & Sons, 1997. Halberston IDK. Biochemistry. Second edition. New York: John Wiley & Sons, 1988. Champe PC, Harvey RA. Biochemistry. Lippincott’s Illustrated Reviews. Second edition. Philadelphia: J.B. Lippincott Company, 1994. Guyton AC, Hall JE. Textbook of Physiology. Ninth edition. Philadelphia: Harcourt Brace & Company, 1994. Latifi R. Amino Acids in Critical Care and Cancer. Austin: R.L. Landes Company, 1994. Stryer L. Biochemistry. Fourth Edition. W H Freeman and Company, 1995. Shils, ME, Olson JA, Shike M et al. Modern nutrition in health and disease. Ninth edition. Baltimore: Williams and Wilkins 1997.

CHAPTER 1 CHAPTER 4

Acute Phase Proteins in Critically Ill Patients Khawaja Azimuddin, Rifat Latifi and Rao R. Ivatury Tissue injury initiates a complex series of rapid homeostatic events.1-3. The host to prevent ongoing tissue damage and to activate the repair process initiates these events. Classically, inflammation has been recognized as the hallmark of this response. More recently, attention has been focused on defining these events at the cellular, metabolic and molecular level. The physiologic changes that develop after a traumatic insult occur irrespective of the type of injurious agent and result in a predictable increase in the level of cortisol, catecholamines, insulin, glucagon, vasopressin and growth factor. An early non-specific component of this response to systemic tissue injury takes place in the liver and is termed the Acute Phase Response (APR). It is characterized by reprioritization of protein synthesis in the liver. While the production of some proteins is exponentially increased (positive acute phase proteins), the production of others (negative acute phase protein) is cut down (negative acute phase proteins). The magnitude of the response is varied and depends upon the severity of the injury.

Role of the Acute Phase Response The shift in the hepatic production of proteins from constitutive proteins to acute phase reactants, after major injury or trauma, is aimed at fulfilling the needs of the immune, coagulation and wound healing process. The most important part of this protective response is to serve as a check on the injury-induced inflammatory reaction and to limit further tissue damage by inhibition of serine proteases and transport of proteins with antioxidant activity. Elimination of microbes, cleanup of tissue debris and the initiation of the reparative process are other important aspects of this rapid response system. These functions are further discussed under the individual proteins. The decrease in negative acute phase reactants may serve to reprioritize the body to conserve nitrogen loss by shifting protein synthesis to those proteins that are absolutely necessary for survival. Furthermore, the negative acute phase proteins (albumin, prealbumin and transferrin) can be used to evaluate and monitor the nutritional status of critically ill patients.

Physiology Tissue injury or infection leads to a local inflammatory response. Cytokines released at the site of inflammation gain access to the circulation and are carried to the liver where they act upon the hepatocytes. Quantitatively, liver is the major pool for cytokines that circulate in the blood stream because it has the largest number of cells The Biology and Practice of Current Nutritional Support, 2nd Edition, edited by Rifat Latifi and Stanley J. Dudrick. ©2003 Landes Bioscience.

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with cytokine receptors and a high density of receptors per cell. The liver responds to the cytokine signal by a burst of acute phase protein synthesis. These proteins reach a maximum concentration within few days after the onset of tissue damage and return to their normal concentrations within a week. Initially it was thought that cytokines released from locally occurring mononuclear cells (Kupffer cells) in liver initiate the APR but it is now agreed that circulating cytokines can initiate this reaction.4 A variety of cytokines have been implicated in the production of acute phase proteins from the liver, including interleukin (IL-1, IL-6) and Tumor necrosis factor-alpha (TNF). IL-6 is the most potent of these stimuli and has been termed the hepatocytes-stimulating factor. It is thought to be responsible for the induction of a variety of APP in vivo and in vitro.4 Although IL-6 may act on the hepatocytes after being produced locally by the Kuppfer cells, it mainly acts as a long-distance alarm signal that alerts the hepatocytes to the presence of tissue damage in peripheral tissues. It is secreted by monocytes, fibroblasts and several other cells at the site of inflammation. The serum levels of IL-6 increase dramatically after injury. The pattern of appearance of various cytokines has been studied in animals. TNF level peaks at about 90 minutes, while IL-1 peaks around three hours. IL-6 levels continue to rise up to eight hours after injury. It has been suggested that IL-6 act by binding with a specific receptor on the surface of hepatocytes.4 This interaction leads to a series of events, which result in the re-orchestration of the pattern of gene expression for secretory proteins in the hepatocytes.5 This results in an increase in the expression of mRNA of various APP.6 It has been shown that IL-6 transcriptional regulation of the acute phase response is mediated through activation of transacting transcription factors of the C/EBP family which bind to IL-6 response elements identified in the promoter regions of acute phase response genes.7,8 IL-6 can also downregulate one isoform of the C/EBP family, C/EBP alpha, which binds to the albumin gene promoter.9 This can explain the mechanism of how cytokines induce a positive and negative acute phase response.8 Other metabolic changes associated with injury may also be involved in regulating the acute phase response. Glucocorticoids have a permissive role, enhancing IL-6 stimulation of acute phase protein synthesis.7,8 However the presence of glucorticoids is not an absolute requirement for induction of acute phase protein synthesis by IL-6 in human hepatocytes.4 In vitro, insulin is a nonspecific inhibitor of the cytokine stimulation of acute phase protein secretion.10 Insulin inhibition of acute phase protein gene expression appears independent of C/EBP-mediated transactivation, although other upstream promoter elements may be involved. Unlike insulin, glucagon, catecholamines, growth hormone and triiodothyronine have no effect. Both IL-1 and TNF secreted by monocytes and macrophages at the site of inflammation are also responsible for the induction of acute phase response. However these cytokines tend to produce a limited spectrum of acute phase proteins only. Unlike IL-6, these cytokines, once produced by Kupffer cells in the liver, act in a local or paracrine fashion only. In addition to its direct effects on the APR, TNF may also indirectly increase the levels of IL-1 and IL-6.4,11

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Sequence of Events During Acute Phase Response Immediately after tissue injury or sepsis, there is a predictable pattern in the alteration of the acute phase proteins. First, there is a decrease in the serum concentration of most of the acute phase proteins, both for positive and negative reactants. Redistribution of the body protein pool from intravascular to extravascular space occurs immediately following injury as a result of increased microvascular permeability and vascular stasis and accounts for part of the initial decline in acute phase proteins. Later there is a decrease in the hepatic synthesis of negative acute phase proteins and the concentration of serum albumin remains depressed for days to weeks after injury. Albumin reaches a nadir by the fifth post-injury day. Whether nutritional support in the immediate post-injury phase can alter this response has not been adequately studied. In one study,2 prealbumin concentrations increased within the first week of injury, although lagging behind increased protein-calorie intake and nitrogen balance, while serum albumin levels slowly declined over the same time and were still decreased 18 days after injury. The positive acute phase protein concentrations begin to rise after a lag period of six hours.12 C-reactive protein (CRP) is the earliest acute phase reactant to respond and its serum concentration peaks at 48 hours. The serum protein concentrations of the positive acute phase reactants in minor injury returns to normal by the end of the first week. Failure of return indicates ongoing tissue injury. It has been shown that in patients who survive thermal injury, the APR quickly returns to normal.13 Continued and prolonged production of acute phase reactants in the critically ill patients may be an indicator of ongoing sepsis and tissue damage and it has been shown that prolonged expression of alpha-1 acid glycoprotein in burned animals is associated with higher mortality rates.14 Measurements of the acute phase response can therefore be used to detect the presence of ongoing inflammation or sepsis following injury.15

Modulation of the Acute Phase Response The modulation of protease/antiprotease activity at the focus of injury is delicately balanced to enhance efficient tissue repair without prolonged inflammation. It has been suggested that the least intense APR and its timely recovery are most beneficial in terms of survival after burn injury.13 Pharmacological manipulation of certain aspects of the APR is possible and may provide new modes of therapy in patients with major trauma. Adjuvant recombinant human growth hormone (rhGH), which improves whole body protein synthesis in severely injured trauma patients, can modulate the APR to the benefit of the patient. It has been shown that rhGH therapy exerts an inhibitory effect on the positive acute phase proteins and an additive effect on the constitutive proteins.13,16,17 It has been shown that serum levels of most of the positive acute phase proteins, except CRP, increase during the administration of total parenteral nutrition (TPN). The entire negative APP also increase during administration of TPN.18

The Acute Phase Proteins As mentioned above, the acute phase response is bidirectional. The concentration of (CRP), Alpha-1 Acid Glycoprotien, alpha-l-antitrypsin, serum amyloid A, fibrinogen, haptoglobulin, ceruloplasmin and complement factor C-3 is increased during the response. The positive acute phase response seems to be a protective response to tissue injury and appears to serve as a check on the injury-induced

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inflammatory response. These reactants have diverse functions such as antioxidants, proteolytic inhibitors, and mediators of coagulation, which may in part prevent excessive tissue damage and hemorrhage from injury. The negative acute phase reactants include the serum transport proteins: albumin, prealbumin (PA), retinol-binding protein and transferrin. The serum concentrations of these proteins fall immediately and in proportion to the severity of the injury. These negative acute phase proteins are used to monitor the nutritional status of acutely ill patients. Following the trends in the serum concentration of these proteins may give valuable information to the clinician about the improving or deteriorating nutritional status of these patients.

Albumin Albumin is a negative acute-phase reactant. Levels of albumin may drop up to 30-50% after severe injury. Inflammation reduces the hepatic mRNA level of albumin, which leads to decreased production of this protein. Also albumin is lost in the interstitial space as a result of increased vascular permeability during periods of acute stress and third spacing. Since albumin is a major transport protein, the reduced levels seen during inflammation and infection may play a role in minimizing the delivery of nutrients to microbes during infection. Albumin is frequently used to assess and monitor nutritional status in the critically ill patients. However the use of albumin as a nutritional index has several drawbacks. The half-life of albumin is approximately 21 days, and changes in the serum concentration of albumin, in response to increased or decreased protein-calorie intake, takes weeks and not days to manifest. Therefore, albumin is a poor marker of protein-calorie malnutrition. Even in severe malnutrition states like marasmus, the serum albumin concentration may be normal. Albumin also has a large body pool, with an extravascular-to-intravascular distribution ratio of 1:5.3 Redistribution from one space to the other can potentially mask a concurrent change in albumin synthesis rate. The serum concentration of albumin can also be affected by non-nutritional entities including liver disease, renal dysfunction and total body water composition. Additionally, post-injury, critically ill patients may require albumin infusions, which will alter its serum concentration irrespective of the nutritional status of the patient. Despite these disadvantages albumin is widely used as a marker of nutrition status perhaps because of the its widespread availability and low cost. Serum albumin levels obtained at the time of admission re reasonably accurate markers of nutrition status, and low levels have been shown to correlate with prolonged hospital stay and mortality.19,20 Serum hepatic secretory proteins with a shorter half-life are preferable indicators of short-term changes in protein-calorie intake and correlate better with the nitrogen balance.2,3 Several studies have evaluated the longitudinal response of short half-life proteins to injury. However, few have evaluated their usefulness in monitoring effects of nutritional support.2,21 Boosalis et al2 serially measured protein-calorie intake, nitrogen balance, and serum albumin and prealbumin levels in trauma patients from the time of admission until 18 days post-injury. In the short-term, prealbumin was a better indicator of nutritional intervention than albumin. Within one week of increasing protein-calorie intake and improved nitrogen balance, the prealbumin concentration increased while the serum albumin level continued to decline during the first two weeks after injury.2

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Prealbumin Prealbumin (transthyretin) is a serum transport protein for thyroid hormone and the vitamin A-retinol binding protein complex.12,22 It has a short half-life of 18-24 hours. Compared with albumin, prealbumin has a smaller body pool with a greater intravascular-to-extravascular distribution. Numerous studies in non-trauma patients have demonstrated a consistent correlation between the serum prealbumin concentration and parallel increases or decreases in protein-calorie intake or nitrogen balance.2,22,23 The response time is usually within the order of several days. Non-nutritional factors including cirrhosis and hepatitis can lower prealbumin level whereas increased levels of prealbumin occur with chronic renal failure.

Retinol-Binding Protein Retinol-binding protein (RBP) has an even shorter half-life of 12 hours, though clinically this does not improve its sensitivity as a nutritional marker over prealbumin.12 RBP transports vitamin A from the liver to peripheral tissues. Serum RBP concentration is dependent on vitamin A stores which regulate hepatic release of RBP. Aside from vitamin A deficiency, RBP concentration is decreased in chronic liver diseases, cystic fibrosis, zinc deficiency and hyperthyroidism. Increased RBP levels occur with chronic renal failure. Both prealbumin and retinol-binding protein are accurate markers of nutrition, and their serum concentrations are highly correlated.24 However because prealbumin can be easily monitored and its assay is subject to few interfaces, it is the preferred biochemical index of follow the nutritional status of the critically ill patient.

Transferrin Transferrin is also commonly used as a nutritional marker. Its mainly intravascular distribution and shorter half-life are advantageous. As the primary function of transferrin is to transport iron, its serum concentration is dependent on the iron stores of the individual. Another shortcoming of transferrin is its serum half-life of 7-10 days which, like albumin, significantly delays its response to changes in nutritional repletion. An increasing concentration of transferrin is a good indicator of positive nitrogen balance. However, a decreasing transferrin level is a poor indicator of nitrogen loss.3 Transferrin is also an unreliable index of nutritional status when patients are receiving high doses of certain antibiotics.25 Levels of serum transferrin decrease 30-50% after injury. The decrease in circulating transferrin along with a concomitant increase in intrahepatic transferrin helps to decrease the availability of iron to peripheral sites of infection.

C-Reactive Protein During the acute-phase response, there is almost a 1000-fold increase in the circulating levels of CRP. Since the level of this pentameric protein is very low in the non-stressed resting period, it has been suggested that the sharp rise in serum levels indicates a central role for this protein during periods of stress. It has therefore been suggested that CRP levels can be used for detecting and following septic complications and intra-abdominal infections.26,27 CRP participates in complement activation and opsonization. It attaches to the phosphorylcholine containing membranes of certain microorganisms including pneumococcus thereby activating the complement cascade. Digestion of CRP by neutrophil protease releases chemotactic peptides including tuftsin and a component of the Fc segment of immunoglobulin (Ig)

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heavy chains. In addition, the binding of CRP to necrotic host tissues may protect against autoimmune responses by promoting the rapid removal of self-molecules from circulation.28 The serum levels of CRP are closely liked to changes in plasma levels of IL-6 and it has therefore been suggested that this cytokine is the major mediator of CRP production in liver during periods of stress.

Ceruloplasmin Ceruloplasmin is a major copper binding protein. It also removes iron from the sites of inflammation and may act as an oxygen radical scavenger.

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Fibrinogen Fibrinogen is the major protein involved in the coagulation process. It causes bacterial clumping thereby preventing the dissemination of bacteria. It also creates a fibrin scaffold, which helps the macrophages and neutrophil in the phagocytosis of bacteria. In addition, by-products of fibrin formation (fibrinopeptides) can increase vascular permeability and induce chemotaxis. The plasma level of fibrinogen increases 2- to 2.5-fold after an inflammatory stimulus and the elevation persists for several weeks.

Complement During the acute phase response the levels of two important components of complement, C3 and properdin are increased. Both are involved in bacterial opsonization and their increase represents a state of readiness of the human body to fight infection.

Amyloid The level of serum amyloid increases drastically during the acute phase response. Though the increase is almost as high as the 1000 fold increase in CRP level, the exact role of amyloid in acute phase response is not well understood. A rising level of serum amyloid A may be used as an indicator of transplant rejection. Amyloid, A which binds to the extracellular matrix, is also a major component of the deposits seen in secondary amyloidosis and thus may play a role in chronic inflammation.

Alpha 1 Acid Glycoprotein The levels of alpha-1 acid glycoprotein (AAG) also increase 2-5 fold during the acute phase response. It may play a role as inhibitor of platelet activation and as a modulator of T-lymphocyte function. AAG has a short half-life of 12-18 hours and is therefore a useful nutritional marker for the acutely ill patient.

Alpha-1 Protease Inhibitor Proteinases released by dead or dying cells at the site of injury can further propagate tissue destruction. Alpha-1 protease inhibitor is a major inhibitor of neutrophil proteases, especially elastase. It is synthesized in liver as well as in the periphery by monocytes and macrophages. The elastase released from neutrophil regulates the synthesis of alpha-1 protease inhibitor, thereby providing an auto feedback mechanism for preventing excessive tissue destruction at the sites of inflammation.

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Monitoring Nutrition in the Critically Ill Patient Following tissue injury a hypermetabolic, catabolic state exists. Energy requirements, depending on the nature of injury, can range from 1.5 to twice the basal metabolic rate. Protein needs are also very high and increased amounts of protein are required to yield a non-protein calorie to nitrogen ratio in the range of 150:1. Once nutritional therapy is instituted the question is how to best monitor the response to treatment. Over-feeding a patient can be as deleterious as under-nutrition. An ideal monitor should respond quickly to changes in nutritional status, remain uninfluenced by physiologic changes induced by trauma and pharmacological support of patients or sepsis and by pharmacological support of patients and should provide easy and reproducible measurements. The physical consequences of surgery can limit the use of traditional nutritional parameters. Postoperatively, anthropometric measurements can be difficult to ascertain and may be unreliable as nutritional indices. Fluid resuscitation or the application of large dressings, casts, splints and so forth may alter body weight. Daily weights are not always feasible in a critically ill patient. Skinfold thickness is often unattainable, for example in burn patients, and is not a reliable measurement in an edematous patient. Skinfold thickness also responds to changes in nutritional intervention in terms of weeks and not days. Arm muscle circumference or area has similar limitations. Biochemical indices such as nitrogen balance have their own restrictions, which can be accentuated by the result of tissue injury.21 The multiple trauma or burn patient may have increased extraurinary nitrogen losses from fistulas, wounds, diarrhea or the burn surface area which, if unaccounted for, will lead to an overestimation of nitrogen balance. Generally, nitrogen equilibrium is not attained until 2-12 days after a change in protein intake. Often nutritional support in critically ill patients needs to be intermittently interrupted to perform diagnostic tests or in preparation for surgery, making it difficult to sustain a consistent day-to-day protein-calorie intake necessary to obtain nitrogen equilibrium for correct interpretation of nitrogen balance studies. Other biochemical parameters, especially visceral serum proteins, have been utilized as monitors of nutritional repletion in critically ill patients.1,2 Ideally, to be a clinically useful marker of nutritional repletion, a change in the concentration of a serum protein should reflect only its synthetic rate, which in turn is dependent on the provision of sufficient calories and proteins during the hypermetabolic state. The serum protein should also have a short serum half-life, a small body pool, rapid rate of synthesis and a constant catabolic rate.3 A number of visceral proteins are used to measure the nutritional status of the surgical patient. None of these meet all of the above requirements and have one or more shortcomings. In practice therefore, a number of proteins are measured simultaneously in conjunction with weekly anthropometric measurements. By serially measuring the serum concentrations of several proteins with different half-lives together, we can better monitor the short and long-term response to nutritional support. For example, in a patient with deteriorating weight, skinfold thickness and mid-arm muscle circumference, the benefit of increasing the daily caloric intake should in several days be reflected by an increase in AAG and pre-albumin, levels, later followed by an increase in transferrin. Hopefully, albumin levels will rise and finally even later anthropometric measurements will improve. Conversely, with nutritional depletion, AAG and prealbumin

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levels will decrease first without a change in transferrin. Finally, albumin levels will rise, and eventually anthropometric measurements will improve. Conversely, with nutritional depletion, AAG and pre-albumin levels will decrease at first without a change in transferrin, albumin or anthropometric measurements. Measuring several proteins with similar half-lives eliminates some of the problems in misinterpreting changes in their serum levels due to non-nutritional factors since each protein is affected differently. These proteins are measured by nephelometry so results are available in less than 24 hours, and only 100 microliters of serum is required for the entire panel. Following tissue injury a hypermetabolic, catabolic response occurs which, left unabated, will lead to depletion of somatic and visceral protein stores, delayed wound healing and impaired immune response. Despite increased protein synthesis post-injury, the magnitude of protein breakdown is so great that a state of negative nitrogen balance exists. Adequate calorie (based on indirect calorimetric studies) and protein supplementation during this time period will improve nitrogen retention but not sufficiently to achieve positive nitrogen balance.29 Nutritional support improves nitrogen retention by enhancing protein synthesis. However, it may not effect whole body protein breakdown.30 Post-injury there also appears to be less efficient recycling of nitrogen.11 Furthermore the mobilized protein may be reprioritized from nitrogen recycling to provide carbon substrates for energy production. Possibly, mediators of the inflammatory response dually regulate the enhanced post-injury protein catabolism and the negative acute phase response. In the future nutritional support may involve selectively antagonizing the metabolic effects of cytokines and other mediators of the acute-phase response to preserve body protein stores.

Selected References 1. 2. 3. 4. 5. 6. 7. 8. 9.

Kudlackova M, Andel M, Hajkova H et al. Acute phase proteins and prognostic inflammatory and nutritional index (PINI) in moderately burned children aged up to three years. Burns 1990; 16:53-56. Boosalis MG, Ott L, Levine AS et al. Relationship of visceral proteins to nutritional status in chronic and acute stress. Crit Care Med 1989; 17:741-774. Church JM, Hill GL. Assessing the efficacy of intravenous nutrition in general surgical patients: Dynamic nutritional assessment with plasma proteins. JPEN 1987; 11:135-139. Castell JV, Gomez-Lechon MJ, David M et al. Acute-phase response of human hepatocytes: Regulation of acute-phase protein synthesis by interleukin-6. Hepatology 1990; 12:1179-1186. Fey GH, Gauldie J. The acute phase response to the liver in inflammation. Prog Liver Dis 1990; 9:89-116. Wu JZ, Ogle CK, Fischer JE et al. The m-RNA expression and in vitro production of cytokines and other proteins by hepatocytes and Kuppfer cells following thermal injury. Shock 1995; 3:268-273. Baumann H, Morella KK, Campos SP et al. Role of CAAT-enhancer binding protein isoform in the cyrokinc regulation of acute phase protein genes. J Biol Chem 1992; 627:19744-19751. Ramji DP, Vitelli A, Tranche F et al. The two C/EBP isoforms, IL-6DBP/NFIL6 and C/EBP8/NF-IL6p are mediated by IL-6 to promote acute phase gene transcription via different mechanism. Nuc Acid Res 1993; 21:289-294. Issihiki H, Akira S, Sugita T et al. Receprocal expression of NF-IL6 and C/EBP in hepatocytes: possible involvement of NF-IL6 in acute phase protein gene expression. New Biol 1991; 3(1):63-70.

Acute Phase Proteins in Critically Ill Patients 10. 11. 12. 13. 14. 15. 16. 17. 18.

19. 20. 21. 22. 23. 24. 25. 26. 27. 28. 29. 30.

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Campos SP, Baumann H. Insulin is a prominent modulator of the cytokine stimulated expression of acute phase plasma protein genes. Mol Cell Biol 1992; 12:1789-1792. Bankey PE, Mazuski JE, Ortiz M et al. Hepatic acute phase protein synthesis is indirectly regulated by tumor necrosis factor. J Trauma 1990; 30:1181-1187. Fleck A, Colley CM, Myers MA. Liver export proteins and trauma. Brit Med Bull 1985; 41:265-273. Jarrar D, Wolf SE, Jeschke MG et al. Growth hormone attenuates the acute-phase response to thermal injury. Arch Surg 1997; 132:1171-1176. Sevaljevic L, Glibetic M, Poznanovic M et al. Thermal injury-induced expression of acute phase proteins in rat liver. Burns. 1988; 14:250-256. Kudsk KA, Minard G, Wojtysiak SL et al. Visceral protein response to enteral versus partenteral nutrition and sepsis in patients with trauma. Surgery 1994; 116:516-523 Jeschke MG, Wolf SE, DebRoy MA et al. The combination of growth hormone with hepatocyte growth factor alters the acute phase response. Shock 1999; 12:181-187. Jeschke MG, Wolf SE, DebRoy MA et al. Recombinant human growth factor (rhGH) downregulates hepatocyte growth factor (HGF) in burns. J Sur Res 1998; 76:11-16. Peterson SR, Jeevanandam M, Shahbazian LM et al. Reprioritization of liver protein synthesis resulting from recombinant human growth supplementation in parenterally fed trauma patients: The effect of growth hormone on the acute-phase response. J Trauma 1997; 42:987-996. McEllistrum MC, Collins JC, Powers JS. Admission serum albumin level as a predictor of outcome among geriatric patients. South Med J 1993; 86:1360-1. D’Erasmo E, Pisani D, Ragno A et al. Serum albumin level at admission: mortality and clinical outcome in geriatric patients. Am J Med Sci 1997; 314:17-20. Mattox TW, Brown RO, Boucher BA et al. Use of fibronectin and somatomedinC as markers of enteral nutrition support in traumatized patients using a modified amino acid formula. JPEN 1988; 12:592-596. Winkler MF, Gerrior SA, Pomp A et al. Use of retinol-binding protein and prealbumin as indicators of the response to nutrition therapy. J Amer Diet Assoc 1989; 89:684-687. Tuten MB, Wogt S, Dasse F et al. Utilization of prealbumin as a nutritional parameter. JPEN 1985; 9:709-711. Sachs E, Bernstein LH. Protein markers of nutrition status as related to sex and age. Clin Chem 1986; 32:339-41. Spickerman AM. Proteins used in nutritional assessment. Clin Lab Med. 1993; 13:353-396. Mustard RA, Bohnen JMA, Haseeb S et al. C-reactive protein levels predict postoperative septic complications. Arch Surg 1987; 122:69-73. McCartney AC, Grange GV, Pringle SD et al.. Serum C-reactive protein in infective endocarditis. J Clin Path 1988; 41:44-48. Volanakis JE. Complement activation of C-reactive protein complexes. Ann NY Acad Sci 1982; 389:235-242. Jeevanadam M, Young DH, Schiller WR. Endogenous protein-synthesis efficiency in trauma victims. Metabolism 1989; 38:967-973. Shaw JHF, Wolfe RR. An integrated analysis of glucose, far, and protein metabolism in severely traumatized patients. Ann Surg 1989; 209:63-72.

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CHAPTER 5

Arginine Metabolism in Critical Care and Sepsis Rima I. Kandalaft, V. Bruce Grossie, Jr. Arginine and ornithine are naturally occurring amino acids that exist in close metabolic relationship in the urea cycle. These amino acids differ significantly, however, in their metabolism and their nutritional significance. Arginine is considered to be an essential amino acid for growth, but the requirements of the adult man, rat, and other species for arginine appear to be met by endogenous synthesis. Although of considerable biological significance, ornithine is not considered a dietary essential amino acid and all of its cellular requirements are apparently supplied via the urea cycle. The concept of essential amino acids has changed over the past few years. The classic definition used by Rogers et al1 stated that an amino acid was essential if it was required for growth. Recently 2,3 it has been suggested that certain amino acids that are classified as nonessential under normal conditions may be essential under certain disease conditions such as cancer, trauma, or sepsis. These are called conditionally essential amino acids. The results of numerous studies in man and experimental animals have shown that supplementation of arginine to otherwise balanced diets 4,5 is beneficial during stress suggesting that arginine should be considered as a conditionally essential amino acid. This has not been a universal conclusion, however. 6-8

Pathways of Arginine and Ornithine Metabolism Urea Cycle Arginine, a major component of the urea cycle (Fig. 5.1), is converted to ornithine and urea by arginase. Results from our laboratory8 as well as others,9,10 demonstrate that ornithine can be substituted for arginine in its role of maintaining appropriate ammonia levels but appears unable to replace arginine for cell growth. As shown in Figure 5.1, ornithine is a precursor for several biologically active compounds such as polyamines, proline and glutamate, that are significant cofactors for cell growth.11 Ornithine and it metabolites, therefore, may be the biological mechanism that is responsible for the changes that occur when arginine is added to parenteral and enteral regimens. In studies that evaluated amino acid concentrations, the concentration of ornithine in plasma13,14 and liver15,16 was altered in the same manner as arginine, suggesting that a major part of the response seen when arginine is supplemented may be associated with an increase in ornithine concentrations. A mechanism for this hypothesis, however, has not been critically evaluated. Our results8,12

The Biology and Practice of Current Nutritional Support, 2nd Edition, edited by Rifat Latifi and Stanley J. Dudrick. ©2003 Landes Bioscience.

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Fig. 5.1. Metabolism of arginine through the urea cycle—ornithine metabolites. ODC, ornithine decarboxylase; OAT, ornithine amino transferase; OCT, ornithine carbamyl transferase.

suggest that the tissue content of arginine is rate limiting to the TPN-associate enhanced growth of a Ward colon tumor. Tumor growth was enhanced during TPN with arginine as part of the regimen but not when ornithine was substituted. The polyamine content of the tumors was not changed when ornithine was substituted while the arginine content was significantly decreased.12 This may reflect a differing requirement for arginine by normal and tumor cells.

Nitric Oxide Synthesis A pathway of arginine metabolism that has become of major importance in the past decade is that of nitric oxide synthesis. As is shown in Figure 5.2, arginine is converted directly to citrulline with the release of nitric oxide. This conversion is controlled by the enzyme nitric oxide synthase (NOS). The activity of NOS is tightly regulated and exists as three isoforms which are structurally similar17 but have different cofactor requirements. Normal tissue requirements utilize a small amount of nitric oxide at any one time. Epithelial and neuronal isoforms of NOS (eNOS and nNOS, respectively) control these levels of nitric oxide and are normally present at low activities in most tissues.18 Another isoform is inducible (iNOS) by a number of exogenous agents, such as those associated with sepsis, and can be induced to synthesize a large amount of nitric oxide in a brief period of time. One measure of nitric oxide synthesis by the host, used extensively to measure acute changes in activity, is the plasma or urine concentration of nitrate/nitrites (NOx). Nitric oxide is a stable gas that diffuses readily through cell membranes. NOx are stable end products of nitric oxide that can be measured in biological fluids, tissues, and cell culture media. Although not a stoichiometric reaction, an increase in plasma NOx is correlated with an enhanced nitric oxide synthesis.7

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Fig. 5.2. Pathway of nitric oxide synthesis and its relationship with the urea cycle.

Arginine Availability for Nitric Oxide Synthesis The cell has many mechanisms to insure that the arginine supply for NOS and other essential metabolic pathways is maximal. Competition for arginine is mainly through the urea cycle (argininearginase >ornithine) (Fig. 5.1), which would in-turn support the many diverse pathways of ornithine. The conversion of citrulline ASS > ASL> arginine (Fig. 5.1) has been reported to be the major urea cycle enzyme pathway in kidneys, making host arginine synthesis possible. As will be reviewed later in this chapter, this pathway may be induced during times of increased arginine requirements. Thus, a change in the activity of arginase, ASS, or ASL will affect the cellular supply of arginine. The requirement for an exogenous source of arginine to support the synthesis of nitric oxide has not been adequately defined but may be of importance to the determination of what may be expected from administration of exogenous arginine or ornithine. Schott et al19 demonstrated that the infusion of LPS at 10 mg/kg/hr for 50 min resulted in no change in the arginine content of plasma or aortic rings. These authors concluded that circulating L-arginine was sufficient to maximally activate the synthesis of nitric oxide in the aorta of endotoxemic rats. Pastor et al20 demonstrated that for livers isolated from rats treated with LPS and perfused for 20 min with Krebs-Henseleit-bicarbonate buffer, the intracellular arginine was not sufficient to support maximal nitric oxide synthesis. Although livers expressing iNOS released high levels of NOx, this release could be enhanced by adding arginine to the perfusate. Adding ornithine to the perfusate did not affect the NOx output. A study to evaluate the requirements of specific organs under differing levels of stress is needed to further define the arginine requirement of the host.

Absorption and Cellular Uptake of Arginine The circulating levels of arginine can be significantly affected by trauma, sepsis or injury. The absorption of arginine by the rat intestine using everted sacs in vitro

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was decreased by experimental sepsis induced by cecal legation and puncture or after administration of endotoxin,21 presenting some potential problems with the oral administration of arginine. A role for the gut in absorption/synthesis was also suggested from observations of a patient with short bowel syndrome and renal failure .22 The arginine, ornithine, and citrulline concentrations of the plasma from this patient was significantly reduced which resulted in hyperammonemia. An I.V. supplement of arginine normalized the arginine, ornithine, and citrulline levels and decreased plasma ammonia concentrations. It is of importance to this discussion that during the arginine infusion (10.8 mg/kg/day) the patient developed hypotension and fell into shock during hemodialysis. After this episode, the arginine supplementation was decreased to every other day and the patient survived for an additional 5 months. Although no data was presented, the possibility of an increased nitric oxide synthesis during arginine infusion was suggested. Data to support this possibility will be presented later in this chapter. It has also been demonstrated that the plasma levels of arginine, ornithine and citrulline were decreased in patients within 2-18 hours after gun shot injury.14 The results suggested that the changes in plasma concentrations of arginine, ornithine, and citrulline were of systemic origin and not related to the type of injured tissues. The results of other studies,23-25 however, show that the uptake of arginine by individual cells in vitro is enhanced by endotoxin. Our results (Fig. 5.3) show that the plasma concentration of arginine in the rat is decreased as early as two hours after a nonlethal dose of endotoxin (5 mg/kg, ip). The plasma concentration of citrulline, but not ornithine, was increased at 5 hours after endotoxin. In addition, the plasma concentration of NOx (Fig. 5.4) and liver iNOS protein content (Fig. 5.5) was increased at 5 hours but not at 2 hours. Subsequent results 26 demonstrate that the plasma NOx begins to increase significantly between 120 and 180 minutes after this dose of endotoxin. The early decline in plasma arginine concentration, accompanied by a constant concentration of ornithine and citrulline (2 hours), suggest an increase in arginine uptake by tissues. This would be significant since the iNOS protein content of the liver (Fig. 5.5), intestine,26 and spleen (data not shown) does not differ from the control at 120 min.

Arginase An increase in NOS activity would significantly increase the cellular requirement for arginine. Since ornithine is a direct metabolite of arginine (Fig. 5.1), arginase activity would also be expected to have a significant effect. With arginine being the only substrate for the synthesis of nitric oxide, a depletion of the available arginine might serve to reduce the nitric oxide related effects. Hey et al27 presented results demonstrating that LPS shifted the available arginine away from the synthesis of ornithine to nitric oxide synthesis for rat macrophages in vitro. Sonoki et al28 reported that the mRNA for iNOS and arginase I in rat peritoneal macrophages were induced in a dose-dependent manner. Bacterial LPS treatment of rats in vivo resulted in a rapid increase of iNOS mRNA for lung and spleen reaching a peak at 2-6 hrs after LPS while the arginase I mRNA was increased rapidly but did not reach a peak until 12 hours after LPS. Shearer et al29, however, demonstrated that when nitric oxide synthesis was increased with Interferon (IFN-γ and LPS, the arginase activity in mouse peritoneal exudate cells was decreased. These authors also demonstrated that the products of nitric oxide synthase—nitric oxide and citrulline—inhibited arginase activity. Benninghoff et al30 demonstrated that in mouse peritoneal macrophages, combining IFN-γ with TNF or LPS treatment in vitro resulted in a

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Fig. 5.3. Plasma arginine, ornithine, and citrulline concentration of endotoxemic rats. Fischer 344 male rats (3-4/group) were given endotoxin (5 mg/kg, ip), anesthesized with Ketamine/xylazine at 2 or 5 hours and blood and tissues removed. The controls received 0.85% NaCl ip. The data is presented as the mean ± sd. Means were compared using a one-way ANOVA analysis using StatView version 4.0 (Abacus Concepts, Inc., Berkley, CA) with P<0.05 being considered significant. Significance is shown on the graph vs the results of rats that receive saline—*,P=0.0031; **, P=0.0004.

shift from increasing ornithine synthesis to increased citrulline synthesis. In these studies, however, no further metabolism of ornithine to citrulline was evaluated. Gotoh et al31 reported that the mRNA for arginase II and NOS was coinduced by LPS for RAW 264.7 cells. Since arginase I is located predominantly in the liver and arginase II in extrahepatic tissues, any alteration in the activity of either of the isoforms of arginase could have a significant impact on the arginine available for nitric oxide synthesis in all tissues. Boucher et al,32 Buga et al,33 and Daghigh et al34 reported that an intermediate in the arginine to nitric oxide pathway, N δ-hydroxy-L-arginine, will inhibit arginase I activity of rat liver and murine macrophages. Nitric oxide has been reported by Hrabak et al35 to inhibit arginase. Although the enzyme arginase may be have a role in down-regulating nitric oxide synthesis, direct impact of its metabolic product, ornithine, has not been demonstrated. Recent results (Grossie unpublished observations) show that adding ornithine to a parenteral regimen containing arginine will not significantly alter the plasma NOx concentration 5 hours after an endotoxin challenge, suggesting that ornithine does not have an effect on nitric oxide synthesis. A treatment strategy may be to reduce the available arginine for nitric oxide synthase. Bune et al36 reported that reduction of arginine by arginase treatment significantly decreased the synthesis of nitric oxide by the liver, kidney, lung, and spleen and reduced the blood NOx concentration. Results from my laboratory show that the endotoxin-induced increase in NOx from rats given a parenteral diet with ornithine substituted for arginine was significantly decreased (Fig. 5.6) as compared with that of isonitrogenous arginine. The plasma arginine concentration was also significantly decreased (Fig. 5.7).

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Fig. 5.4. Plasma nitrate/nitrite (NOx) concentration of rats 2 and 5 hours after endotoxin treatment. The treatment and data analysis is described in Figure 5.3.

Fig. 5.5. Inducible nitric oxide synthase (iNOS) content of the liver of endotoxemic rats. The treatment and data analysis is described in Figure 5.3.

Arginine Synthesis from Citrulline The enzymes, ASS and ASL, which catalyze the reactions responsible for this conversion (Fig. 5.2) are normally at low activities and are present in different tissues depending on their metabolic function. When endotoxin is administered, the activities of ASS and ASL were reported to be significantly increased, 37-40 thus

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Fig. 5.6. Effect of substituting ornithine (TPN-Orn) for arginine (TPN-Arg) on the plasma nitrate/nitrite (NOx) concentration. The TPN solutions7 were isocaloric and isonitrogenous and were administered for 48 hours. At this time, endotoxin (5 mg/kg, ip) was administered ip and the blood and tissues collect at 2 and 5 hours. Data analysis is described in Figure 5.3.

increasing the availability of substrate for the continued synthesis of nitric oxide. Ellis and Conanan41 reported that L-citrulline was both more potent and efficacious than L-arginine in reversing an L-NNA nitric oxide synthesis inhibition in the guinea pig trachea and human bronchus. Grossie42 showed that a continuous IV infusion of TPN with citrulline substituted for arginine on an isonitrogenous basis resulted in a greater elevation in the plasma arginine than was observed after a TPN with arginine. Xie and Gross43 reported on studies using vascular smooth muscle cells (VSMC) that were transfected with human ASS cDNA. The LPS/IFN-γ induced nitric oxide production of these cells was 3-4 fold greater than untransfected VSMC. For untransfected cells, a citrulline concentration 3-4 fold higher than arginine was needed for comparative nitric oxide synthesis while in transfected cells citrulline and arginine were equally efficient. The iNOS immunoreactivity from both cell lines was equivalent, supporting an increased substrate as the mechanism for the increased nitric oxide concentration.

Potential Effect of Glutamine Glutamine is a nonessential amino acid that can be synthesized by virtually all tissues in the body. It becomes conditionally essential during stress and critical illness, when endogenous supply fails to meet increased demands. Houdijk et al44 showed that glutamine-enriched nasoduodenal feedings (30.5 g of glutamine per 100 g of protein) significantly reduced the number of infections in critically injured patients. Plasma glutamine, as well as plasma arginine and citrulline, were increased, suggesting that renal production of arginine was stimulated by glutamine supplementation. Arginine increases the rate of wound healing and stimulates lymphocyte immune responses. In rats, glutamine has been demonstrated to stimulate renal production of arginine by raising plasma concentrations of the precursor citrulline.45

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Fig. 5.7. Plasma arginine (Panel A), ornithine (Panel B), and citrulline (Panel C) concentrations of rats receiving a parenteral nutrition regimen with ornithine (TPN-Orn) substituted for arginine (TPN-Arg) for 48 hours followed by endotoxin (5 mg/kg, ip) or 0.85% NaCl. Rats were anesthesized at 2 or 5 hours and blood and tissues collected. Data analysis is described in Figure 5.3. Significance is shown on the graph is a comparison with the results of TPN-Arg vs TPN-Orn—*, P<0.0005; NS, not significant. The LPS-associated reduction in plasma arginine concentration for TPN-Arg rats was significant at 2 and 5 hours after LPS compared with the concentration at the previous time point.

The pathway from arginine to glutamine involves several steps including hydrolysis of arginine to ornithine by arginase. Yoshida et al46 investigated the flux of arginine to glutamine in tumor-bearing rats (TB) receiving a six-hour infusion of U-14C-arginine (2.0 µ Ci/h). Glutamine production derived from the carbon skeleton of arginine via ornithine was significantly greater in TB rats than in control rats. We have reported that the plasma glutamine concentration was increased when ornithine was added to a complete regimen (unpublished data), and when ornithine was substituted for arginine in TPN.42

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Arginine is a precursor of nitric oxide (NO), which is known to mediate the vascular effects of endotoxin and reduce bacterial growth.47 Citrulline produced by NO synthase can be recycled into arginine in endothelial cells (EC). Glutamine inhibits the conversion of citrulline into arginine, and decreases NO synthesis from arginine. Meininger and Wu48 showed that NO synthesis in cultured bovine EC was reduced by 22% to 44% by glutamine (0.5-2.0 mM) with or without the receptor-mediated vasodilators bradykinin and substance P. A decreased biosynthesis of nitric oxide was observed in rabbits receiving glutamine at 205 nmols/hr (IV) for 24 hours prior to ischemic/reperfusion (I/R). I/R resulted in an increase in serum nitric oxide concentration that was diminished when glutamine was administered.49 On the other hand, Murphy and Newsholme50 demonstrated the existence of a pathway for arginine synthesis from glutamine in macrophages and monocytes. The addition of 10 mM of glutamine to Bacillus Calmette-Guerin (BCG)-activated macrophages caused an approximate 6-fold elevation in nitrite production compared with incubation in standard tissue culture. The authors suggest that glutamine can be converted to arginine, allowing NO production in the absence of extracellular arginine. In contrast, glutamine has been demonstrated to inhibit the conversion of citrulline to arginine51-53 in cultured endothelial cells. The protective effects of glutamine may be in part due to the enhanced conversion to arginine through citrulline, and consequently to increased NO synthesis. This is of importance to determining the precise mechanism for improvements with glutamine-supplemented nutritional support regimens.54,55

Fate of Exogenous Arginine Several investigators have demonstrated that the amino acid pool in plasma and tissues of rats8,12 and man16 can be significantly altered by relatively short term administration of parenteral amino acid solutions. Beamier et al15 found that the nitric oxide synthesis—as measured by plasma NO3, total daily output of NO3, and conversion of [15N]-arginine to labeled NO3— was not increased in normal man during administration of an isonitrogenous diet supplemented to administer 561.3 mg arginine/kg/d as compared with a diet formulated to administer 56.1 mg/kg/d. The plasma free arginine and ornithine, but not citrulline concentration, was significantly increased. This might be expected, however, since only the cNOS isoform would be expected to be active in these normal volunteers. Nakabi et al56 and Hishikawa et al57 demonstrated that an arginine infusion (500 mg/kg x 30 min)57 resulted in a significant hypotension accompanied by a significant increase in the plasma concentration of L-arginine, L-citrulline, and cGMP and the urine concentration of nitrate. Castillo et al58 measured urinary 15N-NO3 from [guanidino15N-5,5-2H ] arginine and estimated that approximately 16% of dietary arginine is 3 converted to nitrate & nitrites during “first pass” in the splanchnic region of normal adult males. Castillo et al59 demonstrated that the arginine flux when tracer arginine was given intragastrically was significantly higher than when the same tracer was given intravenously. This suggests that there is a first pass disappearance of tracer (and dietary) arginine in the splanchnic area after uptake from the gastrointestinal tract. Kanno et al60 reported that an iv infusion of L-arginine to adult healthy male volunteers at 30 mg/30 min resulted in no change in plasma NOx or cGMP concentration. The urine output of nitrate and nitrites (µmol/mg creatinine) and cGMP (mmol/mg creatinine), however, was significantly increased. Adding arginine to parenteral and enteral nutritional support regimens, may therefore, increase the basal

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nitric oxide production by the host. Arginine is a major component of most commercially available parenteral amino acid solutions and is present at various concentrations in all enteral diets given orally or by controlled administration. In addition, arginine has been added to existing parenteral and enteral formulations alone or in combination with other substrates.

Nitric Oxide in Critical Care Endotoxin-Induced Sepsis The activity of iNOS, and therefore the concentration of nitric oxide, may be increased to damaging concentrations when sepsis is induced by factors such as endotoxin.18,61-64 An increase in the peripheral blood levels of NOx7 was correlated with an increase in LPS-induced lethality to tumor bearing rats. Further results from the author’s laboratory demonstrates that an enhanced liver and spleen iNOS86,87 protein content is associated with the increased toxicity and elevated plasma NOx concentration after an endotoxin challenge to tumor-bearing rats. This was interpreted as more evidence of the relationship of increased nitric oxide synthesis and the toxicity of endotoxin. The phrases “double-edged sword” and “Jekell and Hyde”, however, adequately describe the many, diverse, biological roles of nitric oxide. Results from experiments using non-specific nitric oxide inhibitors suggest that a complete inhibition of nitric oxide synthesis increases the toxicity of endotoxin.65,66 Tracy et al67 presented results using a specific inhibitor for iNOS, (dexamethasone) suggesting that the inhibition of the endothelial and neuronal isoforms increased LPS toxicity to the rat and mouse. When only iNOS was inhibited, the toxicity of LPS was not altered. Nava et al68 suggested that the degree of NOS inhibition by NG -monomethyl-L-arginine (L-NMMA) was dependent on the dose of the drug administered. The lethality to rats given 4 mg/kg of endotoxin (7/19) was decreased when 10 mg/kg L-NMMA was administered with endotoxin (0/5). The lethality was not affected, however, when 300 mg/kg of L-NMMA was given (7/10). The differential in survival with the higher dose of L-NMMA was accompanied by a drop in blood pressure and an increase in blood levels of alanine aminotransferase (ALT) for these rats. The inhibition of iNOS by dexamethasone completely eliminated deaths from endotoxin, normalized blood pressure, and blood ALT, suggesting that the critical factor determining the difference between a beneficial and an adverse effect of L-NMMA is the degree of inhibition of nitric oxide synthesis. Park et al69 reported that L-NNA increased the mortality rates and damage to the lung, liver, and kidney of mice treated with LPS. The LPS-induced increase in NOx of the major tissues examined, however, was reduced to normal when L-NNA was administered with LPS.

Ischemia/Reperfusion Injury Arginine, as a nitric oxide donor, has also been implicated in tissue damage after ischemia/reperfusion (I/R). Reperfusion injury after ischemia of the intestine often results in significant damage at sites such as liver and lung that are remote from the original insult.70,71 The role of nitric oxide in the process is becoming more evident. Seekamp et al72 reported that hind limb ischemia in rats resulted in limb and lung damage that was ameliorated by systemic treatment (10 min prior to reperfusion) with L-NNA and L-NAME. Belenky et al73 showed that nitric oxide synthase inhibitors attenuate LPS-stimulated chemotaxis in vitro. Nitric oxide inhibitors were shown by Seth et al74 to inhibit free radical generation by rat PMN.

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Many studies, however, suggest a protective role for arginine and/or nitric oxide. Villarreal et al 75 reported that the nitric oxide donors (Spermine-NO and 3-morpholinosydonimine-N-ethyl-carbamide [SIN1]) attenuated the hyperthermic ischemia-induced increase in mucosal permeability and the depressed net water absorption of the distal ileum of cats. The protective effects of nitric oxide on the mucosal epithelium appeared to be unrelated to actions on the microvasculature. Kanwar et al76 demonstrated that L-arginine (2.5 µmole/min x 4 hours) during reperfusion of small intestine of cats attenuated the epithelial barrier dysfunction for the first 120 min but not at 180 or 240 min. Epithelial permeability, quantitated as blood-to-lumen clearance of the 51Cr-EDTA from the intestine was increased during reperfusion. Administration of a nitric oxide donor (CAS 754) at 60 min after the start of reperfusion, however, attenuated the dysfunction throughout the time and attenuated the intestinal dysfunction at 240 min. The constitutive NOS of the small intestine was not affected by the 60 min of ischemia, but was significantly lower at 180 and 240 min after reperfusion. The iNOS activity, however, was detectable in the control, undetectable immediately after ischemia, but was increasing by 240 min after ischemia. Niu et al77 reported that prolonged inhibition of nitric oxide synthesis by L-NAME of human umbilical vein epithelial cells (HUVEC) caused an oxidant- and platelet activating factor (PAF)-associated rise in adhesion of neutrophils in a dose dependent manner. This was prevented when L-arginine or nitric oxide donors were added to the culture media but not when an analogue of cGMP was added. An arginine infusion in man (17 mg/kg/min x 30 min) was found to inhibit basal and FMLP-stimulated superoxide anion release from peripheral blood polymorphonuclear cells (PMN).78 This inhibition was also seen when PMN were pretreated with a 1mM arginine solution in vitro. Andrews et al79 reported that the mechanism for protection of the rat stomach by arginine from ischemia/reperfusion damage was a reduction in PMN infiltration to the mucosa. Whittle et al80 demonstrated that when coadministered with capsaicin (to deplete sensory neuropeptides) or indomethacin (to inhibit prostaglandin synthesis), L-NMMA resulted in a dose dependent-induction of acute gastric mucosal damage in rats. The injury was inhibited by L-arginine. Shoskes et al81 compared the effect of ischemia followed by reperfusion in the rat kidney. They found that the total NOS activity of the ischemic kidney increased during the first six hours of reperfusion then decreased below the control from day 3 to day 14. The “L-NAME sensitive NOS activity” was similar between groups and only the total NOS was reported. The eNOS protein was consistently higher in the ischemic kidney at all times between 2 hours and 14 days of reperfusion. The ischemia-reperfusion related increase in serum creatinine at 7 days was decreased when arginine was given at 1.25 g/L or 5 g/L in the drinking water 24 hours before ischemia and continued during the 14 days of reperfusion. Schleiffer and Raul82 demonstrated that gavage pretreatment of rats with L-arginine (0.8 g/kg) or molsidomine (a nitric oxide donor) at 19, 16, and 1.5 hours before a 90 min gut ischemia (superior mesenteric artery occlusion) increased survival of rats, increased blood flow, and improved the barrier function of the gut to 14C-PEG. L-arginine, but not molsidomine, increased the cGMP content of the intestinal mucosa. Raul et al83 demonstrated that pretreatment of rats with arginine or ornithine, by gavage, 17 and 2 hours before ischemia accelerated the morphologic repair at the intestine 4 hours after reperfusion. Arginine was significantly more effective than orninthine. Intestinal sucrase and aminopeptidase were also improved. The polyamine

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content of the mucosa was increased by arginine and ornithine to the same degree, suggesting that this is not a likely mechanism. Formation of cGMP was increased by arginine suggesting that nitric oxide was involved. The epithelial cell proliferation (3H-tritium uptake) in this study was enhanced both in the arginine and ornithine pretreatment groups. Kurose et al84 demonstrated that the nitric oxide donors sodium nitroprusside, spermine – NO, and SIN-1, 5 min before reperfusion after 20 min ischemia by SMA occlusion, significantly reduced the leukocyte adherence/ emigration and albumin leaks from the mesenteric venules. Plasma NOx concentration was significantly reduced 30 min after reperfusion suggesting a decrease in endogenous nitric oxide synthesis. DiLorenzo et al85 reported the efficacy of L-arginine in a model of necrotizing entercolitis. They demonstrated that L-arginine, given by peripheral IV infusion (600 mg/kg/hr x 3 hrs), attenuated the acidified casein-induced damage to isolated intestinal loops in the terminal ileum and distal colon of the neonatal pig. It is of importance that the arginine infusion was started after the injection of the acidified casein. The role of nitric oxide in critical care, therefore, and a potential challenge to nutritional supplementation with arginine, is whether nitric oxide will be beneficial or harmful in a specific circumstance.

Conclusion The results reviewed in this chapter clearly show that nitric oxide is a biologically active double-edged sword in the management of the critically ill and/or septic patient. The ability of nitric oxide synthase to respond to a change in the concentration of endotoxin or cytokines such as tumor necrosis factor is a great challenge to the researchers and clinicians trying to improve the outcome of the critically ill patient. The appropriate use of existing, and future, nutritional support regimens can greatly improve the outcome for these patients if properly administered. Although combining nutrients such as arginine, nucleotides, glutamine, and/or different lipids has proven somewhat successful in the clinic for a subset of patients, improving the outcome of all critically ill patients will depend on our knowledge of the specific mechanism by which molecules such as nitric oxide function under normal and pathological conditions.

Acknowledgments The author wishes to thank Yerga Keflemariam for her assistance in preparing this manuscript and Norman W. Weisbrodt, Ph.D. for his review and critique.

Selected References 1. 2. 3. 4. 5. 6.

Rogers QR, Chen M-Y, Harper AE. The importance of dispensable amino acids for maximal growth in the rat. Proc Soc Expt Biol Med 1970; 134:517-22. Laidlaw SA, Kopple JD. Newer concepts of the indispensable amino acids. Am J Clin Nutr 1987; 46:593-605. Jackson AA. Amino acids: essential and nonessential. The Lancet 1983; 1:1034-37. Adjei AA, Yamauchi K, Nakasone Y et al. Arginine-supplemented diets inhibit endotoxin-induced bacterial translocation in mice. Nutrition 1995; 11:371-374. Kirk SJ, Hurson M, Regan MC et al. Arginine stimulates wound healing and immune function in elderly human being. Surgery 1993; 114:155-160. Torre PM, Ronnenberg AG, Hartman WJ et al. Supplemental arginine and ornithine do not affect splenocyte proliferation in surgically treated rats. J Parent Enter Nutr 1993; 17:532-536.

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24. 25. 26. 27.

Grossie VB Jr, Mailman D. Influence of the Ward colon tumor on the host response to endotoxin. J Cancer Res Clin Oncol 1997; 123:189-194. Grossie VB Jr, Nishioka K, Ajani JA et al. Substituting ornithine for arginine in total parenteral nutrition eliminates enhanced tumor growth. J Surg Oncol 1992; 50:161-170. Tytell AA, Neuman RE. Growth response of stable and primary cell cultures to L-ornithine, L-citrulline, and L-arginine. Exp Cell Res 1960; 20:84-91. Edmonds MS, Lowry KR, Baker DH. Urea cycle metabolism: Effects of supplemental ornithine or citrulline on performance, tissue amino acid concentrations and enzymatic activity in young pigs fed arginine-deficient diets. J Animal Sci 1987; 65:706-16. Gray RGF, Hill SE, Pollitt. Studies on the pathway from ornithine to proline in cultured skin fibroblasts with reference to the defect in hyperornithinaemia with hyperammonemia and homocitrullinuria. J Inherit Metab Dis 1983; 6:143-148. Grossie VB Jr, Nishioka K. A parenteral nutrition regimen with ornithine substituted for arginine alters the amino acid, but not polyamine, content of the Ward colon tumor. Nutr Cancer 1997; 27:102-106. Hurson M, Regan MC, Kirk SJ et al. Metabolic effects of arginine in a healthy elderly population. J Parent Enter Nutr 1993; 19:227-230. Zunic G, Savic J, Ignjatovic D et al. Early plasma amino acid pool alterations in patients with military gunshot/missile wounds. J Trauma 1996; 40:S152-S156. Beaumier L, Castillo L, Ajami AM et al. Urea cycle intermediate kinetics and nitate excretion at normal and “therapeutic” intakes of arginine in humans. Am J Physiol 1995; 269(Endocrinol Metab. 32):E884-896. Barle H, Nyberg B, Andersson K et al. The efects of short-term parenteral nutrition on human liver protein and amino acid metabolism during lararoscopic surgery. J Parent Enter Nutr 1997; 21:330-335. Griffith OW, Stuehr DJ. Nitric oxide synthases:Properties and catalytic mechanism. Ann Rev Physiol 1995; 5707-736. Salter M, Knowles RG, Moncada S. Widespread tissue distribution, species distribution, and changes in activity of Ca2+dependent and Ca2+-independent nitric oxide synthases. FEBS 1991; 291:145-149. Schott CA, Gray GA, Stoclet J-C. Dependence of endotoxin-induced vascular hyporeactivity on extracellular L-arginine. Br J Pharmacol 1993; 108:38-43. Pastor CM, Morris SM Jr, Billiar TR. Sources of arginine for induced nitric oxide synthesis in the isolated perfused liver. Am J Physiol 1995; 269:G861-866. Gardiner KR, Gardiner RE, Barbul A. Reduced intestinal absorption of arginine during sepsis 1995; 23:1227-1232. Yokoyama K, Ogura Y, Kawabata M et al. Hyperammonia in a patient with short bowel syndrome and chronic renal failure. Nephron 1996; 72:693-695. Wileman SM, Mann GE, Baydoun AR. Induction of L-arginine transport and nitric oxide synthase in vascular smooth muscle cells:synergistic actions of pro-inflammatory cytokines and bacterial lipopolysaccharide. Brit J Pharm 1995; 116:3243-3250. Cendan JC, Souba WW, Copeland EM 3rd et al. Cytokines regulate endotoxin stimulation of endothelial cell arginine transport. Surgery 1995; 117:213-219. Inoue Y, Bode BP, Souba WW. Hepatic NA(+)-independent amino acid transport in endotoxemic rats: evidence for selective stimulation of arginine transport. Shock 1994; 2:164-172. Arya R, Grossie VB Jr, Weisbrodt NW et al. Temporal expression of tumor necrosis factor-α and nitric oxide synthase 2 in the rat small intestine after endotoxin. Dig Dis Sci 2000; 45(4):744-749. Hey C, Boucher J-L, Vadon-Le Goff S et al. Inhibition of arginase in rat and rabbit alveolar macrophages by N-hydroxy-D,L-indospicine, effects on L-arginine utilization by nitric oxide synthase. Brit J Pharmacol 1997; 121:395-400.

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Sonoki T, Nagasake A, Gotoh T et al. Conduction of nitric-oxide synthase and arginase I in cultured rat peritoneal macrophages and rat tissues in vivo by lipopolysaccharide. J Biol Chem 1997; 272:3689-3693. Shearer JD, Richards Jr, Mills CD. Differential regulation of macrophage arginine: a proposed in wound healing. Amer J Physiology 1997; 272(2Pt 1):E181-190. Benninghoff B, Lehmann V, Eck H-P et al. Production of citrulline and ornithine by interferon-γ treated macrophages. Inter J Immunol 1990; 3:413-417. Gotoh T, Sonoki T, Nagasaki A et al. Molecular cloning of cDNA for nonhepatic mitochondrial arginase (arginase II) and comparison of its induction with nitric oxide synthase in a murine macrophage-like cell line. FEBS Letters 1996; 395:119-122. Boucher J-L, Custot J, Vadon S et al. Nω-hydroxyl-L-arginine, an intermediate in the L-arginine to nitric oxide pathway, is a strong inhibitor of liver and macrophage arginase. Biochem Biophys Res Comm 1994; 203:1616-1621. Buga GM, Singh R, Pervin S et al. Arginase activity in endothelial cells: inhibition by Ng-hydroxyl-L-arginine during high -output NO production. Am J Physio1 1996; 271(Heart Circ, Physiol)40:H1988-1998. Daghigh F, Fukuto JM, Ash DE. Inhibition of rat liver arginase by an intermediate in NO biosynthesis, Ng-hydroxyl-L-arginine: implications for the regulation of nitric oxide biosynthesis by arginase. Biochem Biophys Res Comm 1994; 202:174-180. Hrabak A, Bajor T, Temesi A et al. The inhibitory effect of nitrite, a stable product of nitric oxide (NO) formation, on arginase. FEBS Letters 1996; 390:203-206. Bune AJ, Shergill JK, Cammack R et al. L-arginine depletion by arginase reduces nitric oxide production in endotoxic shock: an electron paramagnetic resonance study. REBS Letters 1995; 366:127-130. Nussler AK, Billar TR, A-A Liu et al. Coinduction of nitric oxide synthase and argininosuccinate synthetase in a murine macrophage cell line Implications for the regulation of nitric oxide production. J Biol Chem 1994; 269:1257-1261. Nagasaki A, Gotoh T, Takeya M et al. Coinduction of nitric oxide synthase, argininosuccinate synthetase, and argininosuccinate lyase in lipopolysaccharidetreated rats RNA blot, immunoblot, and immunohistochemical analysis. J Biol Chem 1996; 271:2658-2662. Hattori Y, Shimoda S-I, and Gross SS. Effect of lipopolysaccharide treatment in vivo on tissue expression of arginosuccinate synthetase and argininosuccinate lyase nRNAs: Relationship to nitric oxide synthase. Biochem Biophys Res Comm 1995; 215:148-153. Wang WW, Jenkinson CP, Griscavage JM et al. Co-induction of arginase and nitric oxide synthase in murine macrophages activated by lipopolysaccharide. Biochem Biophys Res Comm 1995; 210:1009-1016. Ellis JL, Conanan N. L-citrulline reverses the inhibition of nonadrenergic, noncholinergic relaxations produced by nitric oxide synthase inhibitors in guinea pig trachea and human bronchus. J Pharm Exp Therap 1993; 269:1073-1078. Grossie VB Jr. Citrulline and arginine increase the growth of the Ward colon tumor in parenterally fed rats. Nutr Cancer 1996; 26:91-97. Xie L, Gross SS. Argininosuccinate synthetase overexpression in vascular smooth muscle cells potentiates immunostimulant-induced NO production. J Biol Chem 1997; 272:16624-16630. Houdijk A, Rijnsburger E, Jansen J et al. Randomized trial of glutamine- enriched enteral nutrition on infectious morbidity in patients with multiple trauma. Lancet 1998; 352:772-776. Houdijk A, van Leeuwen P, Teerlink T et al. Glutamine-enriched enteral diet increase renal arginine production. JPEN J Parent Enteral Nutr 1994; 18: 422-426. Yoshida S, Ishibashi N, Noake T et al. Glutamine and arginine metabolism in tumor-bearing rats receiving total parenteral nutrition. Metabolism 1997; 46:370-373.

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Newsholme E, Hardy G. Supplementation of diets with nutritional Pharmaceuticals. Nutrition 1997; 13:837-839. Meininger C, Wu G. L-glutamine inhibits nitric oxide synthesis in bovine venular endothelial cells. J Pharmac Exper Therap 1997; 281:448-453. Basoglu M, Yildirgan I, Alcay F et al. Glutathione and nitric oxide concentrations in glutamine-infused rabbits with intestinal ischaemia/reperfusion. Eur J Clin Chem Clin Biochem 1997; 35:415-419. Murphy C, Newsholme P. Importance of glutamine metabolism in murine macrophages and human monocytes to L-arginine biosynthesis and rates of nitrite or urea production. Clinical Science 1998; 95: 397-407. Hecker M, Sessa WC, Harris HJ et al. The metabolism of L-arginine and its significance for the biosynthesis of endothelium-derived relaxing factor: cultured cells recycle L- citrulline to L-arginine. Proc Natl Acad Sci 1990; 87:8612-8616. Sessa WC, Hecker M, Mitchell JA et al. The metabolism of L-arginine and it significance for the biosynthesis of endothelium-derived relaxing factor: L-glutamine inhibits the generation of L-arginine by cultured endothelial cells. Proc Natl Acad Sci 1990; 87:8607-8611. Wu G, Meinger CJ. Regulation of L-arginine synthesis from L-citrulline by L-glutamine in endothelial cells. Am J Physiol 1993; 265(Heart Circ Physiol 34):H1965-H1971. Khogali SE, Harper EE, Lyall JA et al. Effects of L-glutamine on post-ischemic cardiac function: protection and rescue. J Mol Cell Cardiol. 1998; 30:819-827. Griffiths RD, Jones C, Palmer TEA. Six month outcome of critically ill patients given glutamine-supplemented parenteral or enteral nutrition. Nutrition 1997; 13:295. Nakaki T, Hishikawa K, Suzuki H et al. L-arginine-induced hypotension. Lancet 1990; 336:696. Hishikawa K, Nakaki T, Suzuki H et al. L-arginine-induced hypotension. Lancet 1991; 337:683-684. Castillo L, DeRojas TC, Chapman TE et al. Splanchnic metabolism of dietary arginine in relation to nitric oxide synthesis in normal adult man. Proc Natl Acad Sci 1993; 90:193-197. Castillo L, Chapman TE, Yu Y-M et al. Dietary arginine uptake by the splanchnic region in adult humans. Am J Physiol 1993; (Endocrinol Metabol 28):E532-E539. Kanno K, Hirata Y, Emori T et al. L-arginine infusion induces hypotension and diuresis/natriuresis with concomitant increased urinary excretion of nitrite/nitrate and cyclic GMP in humans. Clin Exp Pharmacol Physiol 1992; 19:619-625. Weisbrodt NW, Pressley TA, Li YF et al. Decreased ileal muscle contractility and increased NOSII expression induced by lipopolysaccharide. Amer J Physiol 1996; 371:G454-60. Koga K, Sata T, Nanri H et al. Role of nitric oxide during carrageenan-sensitized endotoxin shock in mice. Life Sciences 1995; 57(25):2309-2316. Chamulitrat W, Blazka ME, Jordan SJ et al. Tumor necrosis factor- and nitric oxide production in endotoxin-primed rats administered carbon tetrachloride. Life Sciences 1995; 57(24):2273-2280. Downs TR, Dage RC, French JF. Reduction in endotoxin-induced organ dysfunction and cytokine secretion by a cyclic nitrone antioxidant. Int J Immunopharmac 1995; 17(7):571-580. Robertson FM, Offner PJ Cireri DP et al. Detrimental hemodynamic effects of nitric oxide synthase inhibition in septic shock. Arch Surg 1994; 129:149-156. Minnard EA, Shou J, Naama H et al. Inhibition of nitric oxide synthesis is detrimental during endotoxemia. Arch Surg 1994; 129:142-148.59. Tracey WR, Tse J, Carter G. Lipopolysaccharide-induced changes in plasma nitrite and nitrate concentrations in rats and mice: Pharmacological evaluation of nitric oxide synthase inhibitors. J Pharmacol Exp Therap 1995; 272:1011-1015.

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Nava E, Palmer MJ, Moncada S. The role of nitric oxide in endotoxic septic shock: Effects of NG-Monomethyl-L-arginine. J Cardiovasc Pharmaco 1992; 20(Suppl 12):S132-S134. Park J-H, Chang S-H, Lee K-M et al. Protective effect of nitric oxide in an endotoxin-induced septic shock. Am J Surg 1996; 171:340-345. Brooks EC, Mahr NN, Radisavljevic Z et al. Nitric oxide attenuates and xanthine oxidase exaggerates lung damage-induced gut damage. Amer J Physiol-Gastro Liver Physiol 1997; 35:G845-852. Terada LS, Mahr NN, Jacobson ED. Nitric oxide decreases lung injury after intestinal ischemia. J Applied Physiol 1996; 81:2456-2460. Seekamp A, Mulligan MS, Till GO. Requirements for neutrophil products and L-Arginine in ischemia-reperfusion injury. Amer J Pathol 1993; 142:1217-1226. Belenky SN, Robbins RA, Rennard SI et al. Inhibitors of nitric oxide synthase attenuate human neutrophil chemotaxis in vitro. J Lab Clin Med 1993; 122:388-394. Seth P, Diksht M, Srimal RC. Modulation of rat peripheral polymorphonuclear leukocyte response by nitric oxide and arginine. Blood 1994; 84:2741-2748. Villarreal D, Grishan MB, Granger DN: Nitric oxide donors improve gut function after prolonged hypothermic ischemia. Transplantation 1995; 59:685-689. Kanwar S, Tepperman BL, Payne D et al. Time course of nitric oxide production and epithelial dysfunctin during ischemia/reperfusio of the feline small intestine. Circ Shock 1994; 42:135-140. Niu X-fC, Smith W, Kubes P. Intracellular oxidative stress induced by nitric oxide synthesis inhibition increases endothelial cell adhesion to neutrophils. Circ Res 1994; 74:1133-1140. Wiedermann CJ, Sitte B, Zilian U et al. Inhibition of superoxide anion release from circulating neutrophils by L-arginine in man. Clin Investigation 1993; 71:985-989. Andrews FJ, Malcontenti-Wilson C, O’Brien PE. Protection against gastric ischemia-reperfusiion injury by nitric oxide generators. Dig Dis Sci 1994; 39:366-373. Whittle BJR, Lopez-Belmonte J, and Moncada S. Regulation of gastric mucosal integrity by endogenous nitric oxide: interactions with protaoids and sensory neuropeptides in the rat. Br J Pharmacol 1990; 99:607-611. Shoskes DA, Xie Y, Gonzalez-Cadavid NF. Nitric oxide synthase activity in renal ischemia-reperfusion injury in the rat. Transplantation 1997; 63:495-500. Schleiffer R, Raul F. Prophylactic administration of arginine improves the intestinal barrier function after mesenteric ischemia. Gut 1996; 39:194-198. Raul F, Galluser M, Schleiffer R et al. Beneficial effects of L-arginine on intestinal epithelial restitution after ischemic damage in rats. Digestion 1995; 56:400-405. Kurose I, Wolf R, Grisham MB et al. Modulation of ischemia/reperfusion-induced microvascular dysfunction by nitric oxide. Circ Res 1994; 74:376-382. Di Lorenzo M, Bass J, and Krantis A. Use of L-arginine in the treatment of experimental necrotizing enterocolitis. J Ped Surg 1995; 30:235-241. Grossie VB Jr, Mailman D. Influence of the Ward Colon tumor on the host response to endotoxin. J Cancer Res Clin Oncol 1997; 123(4):189-194. Gossie VB Jr. Influence of the Ward Colon tumor on the innate and endotoxininduced inflammatory response of the rat. Cancer Invest 2001; 19(7):698-705.

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Wound Healing and the Role of Nutrient Substrates David A. Lanning, Rifat Latifi

Basic Principles of Wound Healing The details of the wound healing process vary depending upon the location and type of wound. However, there are basic principles of the wound healing process that are essentially common to all sites of healing wounds. Since more is known and published in regards to cutaneous wound healing, the principles of wound healing as they occur in the skin will be described below. Normal wound healing occurs by a sequence of events in which cellular, soluble factors, and matrix components act in concert to repair a wound. The healing response can be described in four broad, overlapping phases—hemostasis, inflammation, proliferation, and remodeling.1 The disruption in the integrity of the vascular endothelium activates the coagulation cascade, which results in the formation of a clot consisting of fibrin, platelets, and erythrocytes. The initial wound matrix of fibrin acts as a scaffold upon which inflammatory cells enter the wound.2 The injury also stimulates the release of various mediators of cell-cell and cell-matrix interactions, such as eicosanoids and cytokines. Eicosanoids are metabolites of cell membrane essential fatty acids and function mainly as messengers in the wound and initiate the signs and symptoms of inflammation, such as redness, swelling, and pain. Included in this group are prostaglandins and thromboxanes, which are formed via the cyclooxygenase pathway, and leukotrienes, which are formed via the lipoxygenase pathway. Cytokines, such as platelet derived growth factor (PDGF) and transforming growth factor-β (TGF-β), are polypeptides that mediate the early inflammatory response but also modulate this and the immune response. Furthermore, cytokines are chemoattractants, mitogens and stimulators of extracellular matrix (ECM) deposition for cells that enter the wound.3-5 Initially, neutrophils are present in increased numbers and are important in phagocytosis of foreign material and bacteria. Shortly thereafter, monocytes migrate into the tissue, transform into macrophages, and become the predominant inflammatory cell type. Similar to the neutrophils, macrophages continue to phagocytose foreign material and release various cytokines.6 Lymphocytes also appear in increased numbers in the wound at a delayed point and secret cytokines but are not able to phagocytose material. Studies have demonstrated that only the macrophage is critical for normal healing. However, all of the cells contribute to the organized repair of a wound by cleaning the wound site and releasing mediators of cell-cell and cell-matrix interactions, such as eicosanoids and cytokines. In addition to that seen from the inflammatory cells, platelet aggregation and degranulation result in the release of cytokines. The ECM The Biology and Practice of Current Nutritional Support, 2nd Edition, edited by Rifat Latifi and Stanley J. Dudrick. ©2003 Landes Bioscience.

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contains various proteins, glycosaminoglycans (GAG), glycoproteins, and proteoglycans. For example, the glycoprotein fibronectin, which is synthesized by fibroblasts and epithelial cells, facilitates cellular attachment and migration.7 The GAG hyaluronan (HA) is also thought to be important in cell motility in the immediate post-wounding period. Type IαI and III collagen are the predominant ECM proteins deposited at the wound site resulting in a scar, which continues to be remodeled for years.8 Approximately 10% to 20% of the collagen seen in the skin are Type III, with increased levels seen prenatally and in the early wound. Studies have suggested that it is deposited in a more organized pattern and can by remodeled more easily. Fibroblasts interact with the ECM and other cells through heterodimeric, transmembrane receptors called integrins. These cell-surface receptors are composed of two subunits, one α and one β and are important in cell-cell and cell-ECM interactions.9 More specifically, the integrins α2β1 and α1β1 are thought to be the receptors associated with wound contraction.10,11 Despite extensive investigation, the mechanisms responsible for wound contraction remain unknown. There is continued controversy over this aspect of wound healing, primarily amongst those investigators that believe that the myofibroblast vs. the fibroblast is the effector cell in this process. The myofibroblast is characterized histologically by large cable-like actin-rich stress fibers.12 Alpha-smooth muscle (SM) actin is the actin isoform typical of contractile vascular SM cells and is also expressed by practically all myofibroblastic populations in vivo.12 Increased numbers of this cell type are seen in contracting wounds and primarily at the wound edge, which suggested that they contribute to closure of the wound. Furthermore, studies have demonstrated that if the peripheral wound edge was excised, contraction wound be prevented. However, additional studies by other investigators using in vitro and in vivo models suggest that the fibroblast is in fact responsible for contraction. The final phase of normal adult wound healing consists of continued remodeling of the wound site with ongoing collagen deposition and resorption. The small amount of collagen Type III, as well as Type IαI collagen are broken down and replaced with Type IαI collagen. At approximately 21 days after wounding, the net accumulation of collagen becomes stable.13 The strength of the scar gradually increases as it is remodeled up to its peak strength at 6 months after injury at which point it remains about 80% of that seen in normal skin. The complex mechanisms involved in wound healing on a molecular and cellular level remain poorly understood. In addition, the genes that regulate the mechanisms seen in wound healing have not been determined. As a result, the implication of malnutrition and the role of supplemental nutrition on wound healing are only now beginning to be appreciated.

Malnutrition and Wound Healing Even despite poor nutritional status and/or post injury starvation, the body is able to heal most wounds. Reallocation of nutritional resources through the mobilization of lean body mass occurs in order to provide substrates to the wound. The body’s ability to mobilize substrates for healing is not unlimited as demonstrated in studies of animals with multiple injuries. Those with femur fractures have reduced tensile strength in incisional wounds compared to control animals without fractures.14 Also, wound implants placed in patients with concurrent major trauma were found to contain lower hydroxyproline levels than in normal volunteers.15 The causal relationship between poor nutritional status and poor wound healing has been

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suspected for many years yet the details of how nutrition affects the biology of the healing wound continue to be investigated. The healing of incisional wounds in mice that had restricted diets was performed by Greenhalgh et al.16 The authors demonstrated that the strength-to-disruption of incisional cutaneous wounds in the group that underwent cecal ligation and puncture (CLP) was less than that of wounds in sham-operated control animals up to 14 days after wounding. However, there was no difference in wound breaking strength between the groups 3 to 5 weeks after wounding. In review of the groups, the rodents in the CLP-wounded group lost weight and consumed 40% less food during the first post-operative week than the control wounded group. A subsequent experiment used pair feeding of animals with incisional skin wounds with and without CLP and revealed a similar reduction in tensile strength of the incisional wounds in those with CLP as those in the sham-operated group. These data supported the conclusion that decreased food intake led to weaker wounds and not the concurrent sepsis in the CLP group. Another study looked at the effect of seven weeks of a protein-free diet on the healing of colonic anastomoses in rats.17 The investigators demonstrated that colonic-bursting pressure and colonic-bursting wall tension was diminished in the protein-starved group compared to the control group. Furthermore, there was a 34% weight loss in the protein-deprived group again implicating severe malnutrition as a contributing factor to the altered anastomotic healing. A number of studies have implicated the importance of nutrition in wound healing by demonstrating poor healing or high wound complication rates in patients with hypoalbuminemia.18 Other researchers have studied hydroxyproline levels in subcutaneously-placed implants such as polytetrafluoroethylene (PTFE) tubing as a wound-healing model.19 One group utilized weight history, anthropometric measurements, and recent dietary-recall history to determine nutritional status and found decreased hydroxyproline levels in those that were malnourished by a weight loss history of 10% ± 5% of original body weight.20 One group using fasting guinea pigs investigated the cause of reduced hydroxyproline levels in subcutaneously-placed implants.21 These authors found that the level of collagen synthesis was significantly lower in the group starved for four days than the control group. However, the level of collagen synthesis was restored within four days of restarting feeds. Furthermore, there was no evidence of collagen degradation and low levels of messenger RNA levels were confirmed in the fasting group. Alterations in the level of various hormones were implicated in the reduced level of collagen synthesis. A reduction of insulin and somatomedin levels but an increase in glucocorticoids were some of the changes in fasting-induced hormones cited by the authors. The importance of these hormones in wound healing were noted in that somatomedin C, or insulin-like growth factor-1, is a competence growth factor and promotes angiogenesis and collagen synthesis. In addition, glucocorticoids are known to have anti-inflammatory and antihealing effects in wounds. Many of these animal studies need to be reviewed in a critical manner in that wounds in rodents heal differently than in humans and their response to protein-free diets or complete starvation vary from the human. Furthermore, many of these studies may show a reduced level of collagen in an implant or wound site but this is at one time-point and the level of collagen does not necessarily correlate with the quality of healing. Furthermore, the wounds in many of these studies were not evaluated clinically using measurements such as tensile strength.

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A number of human studies have been performed to address wound healing and overall outcome after surgical intervention with and without associated malnutrition. In a prospective study of female patients with femoral neck fractures that underwent surgery, outcomes were determined in relation to nutritional status.22 Those that were greater than two standard deviations below the mean body weight had a more prolonged period of rehabilitation and a higher overall mortality. Another prospective study in over 200 non-cancer patients determined pre-operative nutritional status as measured by percent ideal body weight, percent weight loss, serum albumin levels, and arm muscle circumference and correlated these findings with surgical outcome.23 The group of patients that had one of the above indicators of poor nutritional status were found to have a significant increase in overall complications, major complications, and in length of stay compared to the control group.

Nutritional Supplementation and Wound Healing As a result of the numerous studies that have demonstrated that poor nutritional status correlates with poor wound healing, much investigation has ensued in an attempt to identify the ideal amount, timing, and content of nutritional supplementation in patients undergoing surgery or after traumatic injury. One study examined hydroxyproline content in subcutaneous PTFE grafts in patients that received total parenteral nutrition (TPN).24 Researchers found that lower levels were found in patients that were considered to be malnourished when compared to normal controls. However, levels were increased after patients had received TPN for variable periods of time before wounding. Furthermore, patients that received TPN pre- and postoperatively had greater hydroxyproline levels in experimental wounds than those that received TPN only after surgery. Enteral feeding has also been demonstrated to affect hydroxyproline levels in implants.25 Patients that received four days of enteral nutrition post-operatively had elevated levels in PTFE implants inserted at the time of surgery and harvested one week later. A large study that addressed the relationship of perioperative TPN with surgical outcome and wound healing was the Veterans Affairs Cooperative Study.26 It enrolled 395 malnourished patients that had abdominal or thoracic surgical procedures. Suprisingly, the TPN group had a higher rate of infectious complications compared with the unfed control group. While the patients that were borderline or mildly malnourished had no demonstrable benefit from TPN, those patients that were severely malnourished had fewer wound complications such as anastomotic leaks and bronchopleural fistulas. The role of preoperative enteral hyperalimentation in malnourished surgical patients was assessed in a study by Shukla et al.27 Patients that were randomized to receive nasogastric feeds had significant improvement in body weight, serum protein levels, and multiple anthropometric measures compared with the patients in the control group. These parameters have routinely been correlated with nutritional status and the quality of wound healing and, in this study, the enteral hyperalimentation group had significantly lower rates of mortality and wound infection rates. As previously mentioned, Bastow et al performed a randomized control trial to determine the effect of nocturnal feeds in patients that were undergoing surgery for femoral neck fractures.22 Over 700 patients were grouped at the time of surgery according to anthropometric measurements. Patients were either categorized as well-nourished, thin (between 1 and 2 standard deviations below the mean), or very

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thin (greater than two standard deviations below the mean). Patients in the thin and very thin groups were then randomized to receive noctural tube feeds in addition to a standard diet or just standard diet alone. In both the thin and very thin groups, the patients that received the nocturnal feeds in addition to the standard diet had significant reductions in their rehabilitation times compared to their matched control groups that had standard diets only. Kiyama et al recently investigated the effect of enteral vs. parenteral nutrition on gastrointestinal anastomotic healing.28 Using 20 male Sprague-Dawley rats, a distal colonic anastomosis was performed in an inverted, single-layer manner. Identical nutrient infusates of amino acids, dextrose, and vitamins were either given via a parenteral or enteral route. While there was no difference in nutritional parameters at five days, colonic anastomotic bursting pressures were significantly higher in the enterally fed group and the measured insoluble collagen and total protein content in anastomotic tissue was enhanced. The authors conclude that the preservation of colonic structural collagen in the enteral group may improve the ability of the gut to hold sutures and thus improve anastomotic healing. In a similar study by another group of investigators, rat colonic anastomotic bursting pressures were tested after the intravenous infusion of n-butyrate.29 Total collagen content was not altered but the bursting pressures were significantly increased compared to control rats that received TPN without additional n-butyrate. The role of enteral and parenteral supplementation in improving the strength of anastomotic healing is yet to be determined. A group of orthopedic surgeons from Sweden assessed whether supplemental nutrition would improve healing and decrease mortality in patients that underwent transtibial amputation for occlusive arterial disease.30 In a prospective study, 28 malnourished patients were given pre and postoperative supplemental nutrition to an average intake of 2098 kcal/day for a total of at least 16 days. A group of 32, well-matched patients served as the controls and did not receive supplemental nutrition. Healing occurred in 26 of the nutrition group compared with 13 in the control group, which was statistically significant. While mortality was not altered in this study, supplemental nutrition did improve healing of transtibial amputation wounds.

Specific Nutrients, Vitamins, and Trace Elements Arginine Arginine is a nonessential amino acid that can become an essential dietary nutrient with severe stress. It has multiple pharmacologic and biologic effects including stimulation of various immune parameters, acting as a pituitary and pancreatic secretagogue, and increasing angiogenesis in response to ischemic injury. In addition, arginine may also serve as a local precursor for collagen-bound proline. More importantly, the amino acid is the unique precursor of the highly reactive radical nitric oxide (NO).31 Various studies suggest that NO plays a critical role in wound healing. It is known to act as a messenger molecule for different physiological actions.32 After injury, NO synthesis occurs for prolonged periods and macrophages appear to be a major cellular source for it.33 Schaffer et al investigated the role of NO in acutely malnourished rats that had subcutaneously implanted polyvinyl alcohol (PVA) sponges.33 The authors postulated that wound NO production plays a regulatory role in wound collagen synthesis in normal and impaired healing and that levels would be altered in the malnourished group. The rats that had a 50% reduction of food intake lost 10% of their weight while control animals gained 18% of their original body weight. Wound

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collagen accumulation and Types I and III collagen gene expression were measured in the subcutaneously placed sponges. Nitric oxide synthesis was also determined in wound fluid and from wound cell culture supernatants. Collagen content as measured by hydroxyproline levels in the sponges from the protein-calorie malnourished animals was significantly less than compared to the control group. The gene expression of Type III collagen, but not Type I collagen, was also reduced in the malnourished group. The concentration of nitrite, nitrate, and citrulline, which are stable end products of NO were also reduced in the wound fluid and wound cell supernatants of the malnourished rats, indicating a net decrease in NO production. The investigators concluded that impaired wound collagen accumulation caused by protein-calorie malnutrition may be a reflection of reduced NO synthesis within the wound. To further investigate the mechanism by which NO affects wound healing, a group of investigators utilized iNOS knockout (KO) mice to determine if arginine acts through this enzyme in producing its vulnerary effects. 34 Twenty wild type and 20 iNOS knockout mice were randomized to receive either normal food and water or food and water supplemented with 0.5% arginine. A 2.5-cm dorsal skin incision was then made through which four PVA sponges were implanted into subcutaneous pockets. The animals were sacrificed on post-operative day 14 and the dorsal wound was tested for breaking strength and the sponges were assayed for hydroxyproline content and total wound fluid nitrite and nitrate concentration. Wound breaking strength and collagen deposition was increased in the wild type group but not in the iNOS-KO group with dietary arginine supplementation. Also, wound fluid nitrite and nitrate levels were higher in the wild type group compared to the iNOS-KO group but were not significantly influenced by additional arginine. These data supported previous studies that demonstrated that supplemental dietary arginine enhances wound healing in normal mice. However, the loss of a functional iNOS gene abrogates the beneficial effect of arginine in wound healing. The authors concluded that the iNOS pathway is at least partially responsible for the enhancement of wound healing by arginine and that exogenous arginine and its associated NO production via iNOS most likely enhance wound healing through multiple physiologic mechanisms. While arginine has been demonstrated to increase collagen deposition and breaking strength of cutaneous wounds, its role in altering the healing of intestinal anastomoses is unclear. In an effort to determine if supplemental arginine improved colonic anastomoses, a group of researchers fed 42 Sprague-Dawley rats either 0, 1, or 3% arginine diets for three preoperative and three postoperative days prior to transection and reanastomosis of the transverse colon.35 Animals were harvested on either postoperative day 6, 10, or 14 and the bursting pressure, histologic inflammation, and collagen content of the hand-sewn anastomoses were determined. Rats that were fed a 0% arginine diet showed a significantly lower bursting anastomotic pressure on postoperative day 6 than those fed 1 and 3% arginine diets, but no bursting pressure differences by diets were noted by days 10 or 14. There were no differences in the degree of inflammation in stained anastomotic tissue upon histologic evaluation nor was there any difference in collagen content between the various groups. Perioperative arginine deficiency resulted in reduced bursting pressures in this model of rat colon anastomoses suggesting impaired healing. However, supranormal levels of dietary arginine did not increase the bursting pressure of anastomoses above the normal level of arginine. This study reinforces the importance of adequate nutrition in the surgical patient, especially those with gastrointestinal anastomoses.

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In an attempt to further define the mechanisms responsible for collagen biosynthesis and the role of NO, Shukla et al. studied the effect of topical arginine and the NO releaser, sodium nitroprusside (SNP) in full thickness excisional wounds in rats.36 Interestingly, the SNP decreased the collagen content of the wounds at all doses as demonstrated by reduced hydroxyproline levels and confirmed histologically, yet L-arginine decreased collagen content. Various doses of N-nitro-L-arginine methyl ester (L-NAME), a competitive inhibitor of NOS, significantly increased wound collagen when administered intraperitoneally and compared to untreated and SNP treated animals. In addition, thick collagen bundles, proliferation of fibroblasts, and increased angiogenesis were seen on review of the wound histology from the L-NAME treated group. An inactive isomer of the inhibitor, N-nitro-D-arginine methyl ester did not affect wound collagen levels. Administering L-arginine to L-NAME pretreated rats resulted in significantly elevated wound collagen content. The authors postulate that NO could decrease collagen by inhibiting prolyl hydroxylase, which is an oxygenase type of enzyme. Also, they point out that the reduced collagen content may be as a result of the route of administration since arginine given intraperitoneally resulted in a trend towards increased collagen content and other studies have shown that systemically given arginine increases the level of wound collagen. The authors conclude that NO plays a pivotal role in regulating the biosynthesis of collagen. Also, NOS inhibitors administered systemically may help to lower NO concentration at the injury site as well as in whole body so as to enhance collagen synthesis and to lower the inflammatory response for better healing. Barbul et al investigated the effect of oral arginine supplementation on human collagen synthesis and T-cell function in 36 healthy human volunteers.37 After a 5 cm segment of PTFE tubing was inserted into a subcutaneous pocket in the deltoid region, the volunteers where then randomly assigned to receive daily oral supplements of either arginine hydrochloride (25 gm free arginine), arginine aspartate (17 gm free arginine), or a placebo for two weeks. Mitogenic responses of peripheral blood lymphocytes to phytohemaglutinin and concanavalin A were determined at 0, 1, and 2 weeks after supplementation. The catheters were removed after two weeks and the amount of hydroxyproline was determined. Both arginine-supplemented groups had increased amounts of hydroxyproline deposited in the grafts as well as increased lymphocyte mitogenesis in response to phytohemaglutinin and concanavalin A. These data suggested that arginine may be of clinical benefit in improving wound healing and immune responses. Another study by the same group of investigators addressed the affect of arginine on wound healing and immune function in elderly patients.38 In this double-blind, randomized study, 15 patients received either arginine aspartate (17 gm free arginine) while another 15 patients received a placebo syrup. PTFE catheters were placed in a subcutaneous position in the deltoid region and a 2 x 2 cm split thickness wound was created on the lateral aspect of the upper thigh. The catheters were analyzed for α-amino nitrogen to determine total protein accumulation, hydroxyproline content, and DNA accumulation. The mitogenic response of peripheral blood lymphocytes to concanavalin A, phytohemaglutinin, pokeweed mitogen, and allogeneic stimuli was determined at the beginning and end of the experiment. The catheters were removed at two weeks and found to contain significantly more hydroxyproline in the arginine supplemented group. There was no difference in cellularity of the catheter as assessed by DNA content nor was there any difference in time to complete epithelialization of the skin defect. However, the blastogenic

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response of peripheral blood mononuclear cells to all the mitogens as well as to allogeneic stimulation was significantly greater in the arginine supplemented group compared to the control group. Furthermore, insulin-like growth factor-1 levels were significantly elevated in the arginine group. These findings support previous studies that demonstrated arginine supplementation increases protein and collagen deposition and T-cell activity in experimental wounds. Barbul and his colleagues have continued to study arginine and NO and, in a series of papers over the last several years, they have provided additional convincing evidence that inducible NO plays a critical role in the wound healing process. Using Balb/C mice that had cutaneous incisional wounds and had PVA sponges implanted, they demonstrated decreased wound breaking strength and wound collagen accumulation when NO synthesis was inhibited by S-methyl isothiouronium, a competitive inhibitor of NO synthase.39 Furthermore, rat colon anastomoses were found to have increased, localized expression of inducible NO synthase that, when blocked with S-methyl isothiouronium, had lower bursting pressures than control anastomoses.40 The investigators also demonstrated that impaired diabetic wound healing was associated with decreased wound NO synthesis in Sprague-Dawley rats rendered diabetic after streptozotocin administration.41 Lastly, Barbul was able to successfully transfect male rats with plasmid DNA that contained murine iNOS gene driven by a CMV promoter and demonstrated that increased production of iNOS was associated with a localized increase in collagen production.42 These studies have strengthened the link between arginine, NO, and wound healing but further investigation is necessary to understand the mechanisms by which they participate in this process.

Glutamine Glutamine is an amino acid that is considered to be a conditionally essential amino acid during serious injury or illness but is nonessential in healthy adults.43 It is the most abundant amino acid in plasma and skeletal muscle, but levels in blood and tissues fall acutely after injury, infection, or surgery.44 This amino acid is a precursor for synthesis of nucleotides and may be a regulator of protein turnover.45 More importantly, it has been recognized as a major oxidative substrate for enterocytes, colonocytes, and cells for the immune system.46,47 In the gastrointestinal tract, glutamine has trophic actions that may decrease bacterial translocation and in animal studies it has been shown to improve growth and repair of small bowel and colonic mucosa after injury.48 However, limited studies have looked at its direct effect on wound healing. Demetriades et al examined the effect of early postoperative enteral administration of glutamine on the healing of gastrointestinal anastomoses in rats.49 Four groups of 15 rats were randomly assigned to receive 1 of 4 diets, one of which included glutamine, after undergoing a colonic anastomosis. After seven days, the rats were sacrificed and the anastomotic bursting pressure was determined for each animal as well as histologic examination of each anastomosis. The rats fed with enteral diets that contained glutamine had significantly higher bursting pressures and decreased inflammation. The authors concluded that early postoperative enteral feeding with glutamine improves healing of experimental colonic anastomoses in rats.

Vitamin C L-ascorbic acid functions as a biologic cofactor in many diverse biochemical reactions and as a nonspecific antioxidant.50 Numerous studies have demonstrated

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that Vitamin C facilitates collagen synthesis in the posttranslational hydroxylation stage but also by influencing collagen messenger RNA levels.51 Vitamin C deficiency or scurvy results in scorbutic wounds that are characterized by decreased accumulation of ECM, abnormal angiogenesis with hemorrhage, very little collagen deposition, and markedly retarded gain in tensile strength.52 In addition, there is an increased susceptibility to wound and more severe infections secondary to reduced production of neutrophil superoxide, complement components, and various gamma globulins.52 Interestingly, plasma concentration and urinary excretion of ascorbate are markedly decreased in injured humans, and tissue saturation for ascorbate is remarkably reduced in the early hours after injury.53 Some postulate that this aspect of ascorbate metabolism may contribute to the alterations in wound healing seen in polytraumatized patients. The effects of Vitamin C deficiency on wound healing are generally seen only after a prolonged period of ascorbate deprivation. Crandon et al demonstrated that clinical scurvy and impaired healing was present only after patients were deprived of Vitamin C for 180 days.54 Cutaneous wounds at 90 days healed without difficulty. Another study showed that patients that were deprived of Vitamin C for seven months had reduced tensile strength of cutaneous wounds compared to those on an ascorbate-supplemented diet, but only for the first ten days after injury.55 These studies demonstrate that while Vitamin C is important in wound healing, this process is fairly resilient to simple ascorbate deficiency in animals and humans. Pharmacologic doses of Vitamin C have been proposed to improve wound healing in a handful of studies. However, many elderly patients, as well as smokers and cancer patients, have low plasma and leukocyte ascorbate concentrations and levels can be depressed in the acute injury setting. Therefore, improved wound healing is most likely as a result of injury or surgery in patients that have marginal ascorbate levels initially. As a result, dietary supplementation with Vitamin C may be beneficial.

Vitamin B The B vitamins are coenzymes that function interdependently as coenzymes in a wide variety of reactions involving carbohydrate, fat, and protein metabolism, as well as being important in DNA synthesis.56 Deficiencies of some of the B vitamins can alter wound healing by impairing the relatively rapid turnover rate of cells that is required for tissue repair and the immune response.56 Vitamin B deficiency is usually associated with poor food choices as a result of poverty, ignorance, illness, or poor health habits such as alcohol abuse.

Vitamin A The mechanisms responsible for the vulnerary effects of Vitamin A are not completely known. However, it is well known that Vitamin A counteracts the deleterious effects of glucocorticoids on wound healing in both animals and humans.57 Supplementation with Vitamin A increases collagen content and breaking strength of experimental cutaneous wounds and colonic anastomoses in normal rats.58 In addition, alterations in wound healing as a result of femoral fractures, whole body irradiation, or streptozotocin-induced diabetes, were reversed with administration of Vitamin A.59-61 One of the theories for how Vitamin A exerts its effect is by inducing fibroblast differentiation and collagen secretion.62 In fact, topical application of Vitamin A accelerated healing of cutaneous wounds that were healing poorly secondary to steroids.62 Alternatively, Vitamin A may exert its effects systemically by

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upregulating overall immune responses as demonstrated by its prevention of thymic involution after trauma.63 It also increases cell-mediated reactivity as demonstrated by skin graft rejection in animals consuming supplemental Vitamin A.63 Despite concerns about the increased incidence of intra-abdominal adhesions found in animals given Vitamin A, patients with severe injuries and those receiving steroids should receive diets supplemented with standard doses of Vitamin A every day.58

Vitamin E Vitamin E is an antioxidant and free-radical scavenger that helps prevent the oxidation of cell membrane polyunsaturated phospholipids.64 Supplemental vitamin E has been shown to increase the healing strength of wounds that are slow to heal after radiotherapy.65 However, excess dietary vitamin E has been found to delay wound healing, slow allograft rejection, lessen postoperative adhesion formation, and interfere with the beneficial effects of vitamin A.58 Interestingly, serum concentrations of this vitamin are reduced in burn patients due to consumption by oxygen radical release and subsequent systemic inflammation.66

Vitamin D Vitamin D is not only required for normal calcium metabolism and bone formation, but it also appears to be required for normal collagen production.67 However, deficiency states are uncommon in that Vitamin D can be synthesized by the body with adequate exposure to sunlight. Supplementation may be necessary in selected patients.

Vitamin K While vitamin K is synthesized by intestinal bacteria, dietary sources are necessary to meet the body’s total need. This vitamin is involved in the formation of at least four protein-clotting factors and also a calcium-binding protein required for bone metabolism. 68 A vitamin K deficiency can lead to impaired healing and infection.68

Copper Copper is involved in the maturation of collagen by lysyl oxidase, a copper metalloenzyme that catalyzes the oxidation of lysyl residues on collagen.69 Hydroxylysyl groups add to the strength of the scar through cross-linking of extracellular collagen. Copper deficiency results in anemia, neutropenia, leukopenia, and skeletal demineralization.50,70

Zinc Zinc is an essential component of multiple metalloenzymes, including RNAand DNA-polymerases.71 The physiologic functions of zinc include tissue growth by nucleic acid metabolism, protein synthesis, bone formation, skin integrity, and the maintenance of host defense mechanisms.50,58 Zinc deficiency in animals results in alterations in the immune system including thymic atrophy, lymphopenia, T-cell impairment, and decreased granulocyte function.72 The role of zinc in wound healing was investigated in patients with pilonidal sinuses.73 Oral administration of zinc resulted in a more rapid rate of reepithelialization. Another study demonstrated that zinc supplementation accelerated the healing of chronic venous leg ulcers but only in those patients with a low pretreatment serum zinc level.74 Since a significant portion of hospitalized patients have been shown to have low serum zinc levels,

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especially those that have poor food intake, diarrhea, a gastrointestinal fistula, or malabsorption, supplementation of patients’ diets with zinc is recommended.

Other Trace Elements Manganese, selenium, and silicon are a few of the additional trace elements that participate in the wound healing process. Manganese is necessary for the function of O-lysyl galactosyltransferase, the enzyme responsible for the glycosylation of procollagen fibers.75 This element is also involved in the production of HA, chondroitin sulfate, heparin, and other mucopolysaccharides that are important components of the ground substance in healing wounds.76 Selenium-dependent glutathione peroxidase is an enzyme that protects the cell from oxidative damage by catalyzing the reduction of hydrogen peroxide.76 Altered macrophage and polymorphonuclear cell function may result with selenium deficiency.76 Lastly, silicon may stimulate the production of collagen and mucopolysaccharides and deficiency of this trace element has been linked to altered connective tissue matrix formation.77

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Fatty Acids Several studies have shown that ω-3 fatty acids, which are abundant in fish oils, have significant anti-inflammatory effects that appear to be mediated through the inhibition of proinflammatory eicosanoid production.78 Tumor necrosis factor-α, interleukin-1, and platelet-activating factor production are also decreased in patients with diets high in these compounds.79,80 The anti-inflammatory effect produced has been shown to alter cutaneous wound healing in a study by Albina et al.81 Animals that were fed diets rich in ω-3 fatty acids had weaker wounds when compared to wounds in the control animals. These differences were attributed to altered collagen spacing or cross-linking and not collagen production.

Conclusion The quality and rate of the wound healing process is intricately dependent upon the availability of a number of nutritional substrates. Reduced levels of one or more of these substrates results in delayed or inadequate wound healing. Furthermore, supplementation of various substrates to correct deficiencies or to produce supranormal levels can increase the rate and/or quality of the healing process following wounding and reduce the number of complications. Further research into the mechanisms of wound healing and role of nutrient substrates will continue to reveal new biological and chemical pathways that can be altered to reduce the morbidity and mortality associated with injury, disease, and surgery in all patients.

Selected References 1. 2. 3. 4. 5.

Schilling JA. Wound healing. Surg Clin North Am 1976; 56:869-874. Weigel PH, Fuller GM, LeBoeuf RD. A model for the role of hyaluronic acid and fibrin in the early events during inflammatory response and wound healing. J Theor Biol 1986; 119:219-234. Seppa HEJ, Grotendorst GR, Seppa SI. The platelet derived growth factor is a chemoattractant for fibroblasts. J Cell Biol 1982; 92:584-588. Grotendorst GR, Chang T, Seppa HEJ. Platelet-derived growth factor is a chemoattractant for vascular smooth muscle cells. J Cell Physiol 1983; 113:261-266. Roberts AB, Sporn MR, Assoian RK. Transforming growth factor type β: Rapid induction of fibrosis and angiogenesis in vivo and stimulation of collagen formation in vitro. Proc Natl Acad Sci USA 1986; 83:4167-4171.

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11. 12. 13. 14. 15. 16. 17. 18. 19. 20. 21. 22. 23. 24. 25. 26. 27. 28. 29.

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Leibovich DS and Ross R. The role of the macrophage in wound repair. A study with hydrocortisone and antimacrophage serum. Am J Pathol 1975; 78:71-100. Ali U, Hynes RO. Effectof LETS glycoprotein on cell motility. Cell 1978; 14:439-446. Cohen IK, Diegelmann RF, Crossland MC. Wound Care and Wound Healing, Chapter 8. In: Schwartz, ed. Wound Care and Wound Healing, Principles of Surgery, 6th edition. New York: McGraw-Hill Co., 1990:279-303. Hynes RO. Integrins: versatility, modulation, and signaling in cell adhesion. Cell 1992; 69:11-25. Zambruno G, Marchisio PC. Transforming growth factor-beta 1 modulates beta 1 and beta 5 integrin receptors and induces the de novo expression of the alpha v beta 6 heterodimer in normal human keratinocytes: Implications for wound healing. J Cell Biol 1995; 129:853-865. Enenstein J. Waleh NS et al. Basic FGF and TGF-beta differentially modulate integrin expression of human microvascular endothelial cells. Exp Cell Res 1992; 203:499-503. Gabbiani G, Schmid E, Winter S et al. Vascular smooth muscle cells differ from other smooth muscle cells: Predominance of vimentin filaments and a specific α-type actin. Proc Natl Acad Sci USA 1981; 78:298-302. Madden JW, Peacock EE Jr. Studies on the biology of collagen during wound healing. I. Rate of collagen synthesis and deposition in cutaneous wounds of the rat. Surgery 1968; 64:288. Crowley LV, Seifter E, Kriss P. Effects of environmental temperature and femoral fracture on wound healing in rats. J Trauma 1977; 17:436-445. Diegelmann RF, Lindblad WJ, Cohen IK. A subcutaneous implant for wound healing studies in humans. J Surg Res 1986; 40:229-237. Greenhalgh DG, Gamelli RL. Is impaired wound healing caused by infection or nutritional depletion? Surgery 1987; 102:306-312. Irvin TT, Hunt TK. Effect of malnutrition on colonic healing. Ann Surg 1974; 180:765-772. Dickhaut SC, DeLee JC, Page CP. Nutritional status: Importance in predicting wound-healing after amputation. J Bone Joint Surg 1984; 66:71-75. Goodson WH III, Hunt TK. Development of a new miniature method for the study of wound healing in human subjects. J Surg Res 1982; 33:394-401. Haydock DA, Hill GL. Impaired wound healing in surgical patients with varying degrees of malnutrition. JPEN 1986; 10:550-554. Spanheimer RG, Peterkofsky B. A specific decrease in collagen synthesis in acutely fasted, Vitamin C-supplemented, guinea pigs. J Biol Chem 1985; 260:3955-3962. Bastow MD, Rawlings J, Allison SP. Benefits of supplementary tube feeding after fractured neck of femur: a randomized controlled trial. BMJ 1983; 287:1589-1592. Warnold I, Lundholm K. Clinical significance of preoperative nutritional status in 215 non-cancer patients. Ann Surg 1984; 199:299-305. Haydock DA, Hill GL. Improved wound healing response in surgical patients receiving intravenous nutrition. Br J Surg 1987; 74:320-323. Schroeder D, Gillanders L, Mahr K et al. Effects of immediate postoperative enteral nutrition on body composition, muscle function, and wound healing. JPEN 1991; 15:376-383. Veterans Affairs Total parenteral nutrition Cooperative Study Group. Perioperative total parenteral nutrition in surgical patients. N Engl J Med 1991; 325:525-532. Shukla HS, Rao RR, Banu N et al. Enteral hyperalimentation in malnourished surgical patients. Indian J Med Res 1984; 80:339-346. Kiyama T, Efron DT, Tantry U et al. Effect of nutritional route on colonic anastomotic healing in the rat. J Gastrointest Surg 1999; 3:441-446. Rolandelli RH, Buckmire MA, Bernstein KA. Intravenous butyrate and healing of colonic anastomoses in the rat. Dis Colon Rectum 1997; 40:67-70.

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The Biology and Practice of Current Nutritional Support 30. 31. 32. 33. 34. 35. 36.

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37. 38. 39. 40. 41. 42. 43. 44. 45. 46. 47. 48. 49. 50. 51. 52.

Eneroth M, Apelqvist J, Larsson J et al. Improved wound healing in transtibial amputees receiving supplementary nutrition. Int Orthop 1997; 21:104-8. Albina JE, Mills CD, Barbul A. Arginine metabolism in wounds. Am J Physiol 1988; 254:E459-E467. Albina JE, Mills CD, Henry WL Jr et al. Temporal expression of different pathways of L -arginine metabolism in healing wounds. J Immunol 1990; 144:3877-3880. Schaffer MR, TantryU, van Wesep RA et al. Nitric oxide metabolism in wounds. J Surg Res 1997; 71:25-31. Shi HP, Efron DT, Most D et al. Supplemental dietary arginine enhances wound healing in normal but not inducible nitric oxide synthase knockout mice. Surgery 2000; 128:374-8. Shashidharan M, Lin KM, Ternent CA et al. Influence of arginine dietary supplementation on healing colonic anastomosis in the rat. Dis Colon Rectum 1999; 42:1613-1617. Shukla A, Rasik AM, Shankar R. Nitric oxide inhibits wound collagen synthesis. Mol Cell Biochem 1999; 200:27-33. Barbul A, Lazarou SA, Efron DT et al. Arginine enhances wound healing and lymphocyte immune responses in humans. Surgery 1990; 108:331-337. Kirk SJ, Hurson M, Regan MC et al. Arginine stimulates wound healing and immune function in elderly human beings. Surgery 1993; 114:155-160. Schaffer MR, TantryU, Gross SS et al. A. Nitric oxide regulates wound healing. J Surg Res 1996; 63:237-240. Efron DT, Thornton FJ, Steulten C et al. Expression and function of inducible nitric oxide synthase during rat colon anastomotic healing. J Gastrointest Surg 1999; 3:592-601. Schaffer MR, TantryU, Efron PA et al. Diabetes-impaired healing and reduced wound nitric oxide synthesis: A possible pathophysiologic correlation. Surgery 1997; 121:513-519. Thornton FJ, Schaffer MR, Witte MB et al. Enhanced collagen accumulation following direct transfection of the inducible nitric oxide synthase gene in cutaneous wounds. Biochem Biophys Res Commun 1998; 246:654-659. Lacey JM, Wilmore DW. Is glutamine a conditionally essential amino acid? Nutr Rev 1990; 48:297-309. Askanazi J, Carpentier YA, Michelsen CB. Muscle and plasma amino acids following injury. Ann Surg 1990; 192:78-85. Jepson MM, Bates PC, Broadbent P. Relationship between glutamine concentration and protein synthesis in rat skeletal muscle. Am J Physiol 1988; 18:E166-172. Windmueller HG. Glutamine utilization by the small intestine. Adv Enzymol 1982; 53: 201-237. Ardawi MSM, Newsholme EA. Glutamine metabolism in lymphocytes of the rat. Biochem J 1983; 212:835-842. Klimberg VS, Salloum RM, Kasper M. Oral glutamine accelerates healing of the small intestine and improves outcome following whole abdominal radiation. Arch Surg 1990; 125:1040-1045. Demetriades H, Botsios D, Kazantzidou D et al. Effect of early postoperative feeding on the healing of colonic anastomoses in rats. Comparison of three different enteral diets. Eur Surg Res 1999; 31:57-63. Hunt SLM, Groff JL. Advanced Nutrition and Human Metabolism. St. Paul: West Publishing Co., 1990:170-183. England S, Seifter S. The biological functions of ascorbic acid. Annual Rev of Nutr 1986; 6:365-406. Anderson TW. Vitamin C. Nutr Today 1977; 12:6-13.

Wound Healing and the Role of Nutrient Substrates 53. 54. 55. 56. 57. 58. 59. 60. 61. 62. 63. 64. 65. 66. 67. 68. 69. 70. 71. 72. 73. 74. 75. 76. 77. 78.

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Levenson SM, Green RW, Taylor FHL. Ascorbic acid, riboflavin, thiamine, and nicotinic acid in relation to severe injury, hemorrhage, and infection in the human. Ann Surg 1946; 124:840-856. Crandon JH, Lund CC, Dill DB. Experimental human scurvy. N Engl J Med 1940; 223:353-369. Wolfer JA, Farmer CJ, Carroll WW. An experimental study in wound healing in Vitamin C depleted human subjects. Surg Gynecol Obstet 1947; 84:1-15. Lakshmi R, Lakshmi AV, Bamji MS. Skin wound healing in riboflavin deficiency. Biochem Med Metab Biol 1989; 42:185-191. Ehrlich HP, Hunt TK. Effect of cortisone and vitamin A on wound healing. Ann Surg 1968; 167:324-328. Levenson SM, Demetriou AA. Metabolic factors. In: Cohen IK, Diegelmann RF, Lindblad WJ, eds. Wound Healing: Biochemical and Clinical Aspects, Philadelphia: WB Saunders Co, 1992:248-273. Seifter E, Crowley LV, Rettura G. Influence of vitamin A on wound healing in rats with femoral fractures. Ann Surg 1975; 181:836-841. Levenson SM, Gruber CA, Rettura G. Supplemental vitamin A prevents the acute radiation-induced defect in wound healing. Ann Surg 1984; 200:494-512. Seifter E, Rettura G, Padawer J. Impaired wound healing in streptozotocin diabetes: Prevention by supplemental vitamin A. Ann Surg 1981; 194:421-450. Demetriou AA, Levenson SM, Rettura G. Vitamin A and retinoic acid: Induced fibroblast differentiation in vitro. Surgery 1985; 98:931-934. Rettura G, Levenson SM, Shcittek A. Vitamin A: Actions in oncogenesis and skin graft rejection. Surg Forum 1975; 26:301-303. Hinder RA, Stein HJ. Oxygen-derived free radicals. Arch Surg 1991; 126:104-105. Ehrlichman RJ, Seckel BR, Bryan DJ. Common complications of wound healing: Prevention and management. Surg Clin North Am 1991; 71:1323-1351. Drost AC, Burleson DG, Cioffi WG. Plasma cytokines following thermal injury and their relationship with patient mortality, burn size, and time postburn. J Trauma 1993; 35:335-339. Berg RA. Nutritional aspects of collagen metabolism. Annual Review of Nutrition 1992; 12:369-383. Whitney EN, Rolfes SR. Understanding nutrition. St. Paul: West Publishing Co., 1993:132-142. van Rij AM, Pories WJ. Zinc and copper in surgery. In: Karcioglu ZA, Sarper RM, eds. Zinc and Copper in Medicine. Springfield: 1980:535-578. Boykin JV Jr, Molnar JA. Burn scar and skin equivalents. In: Cohen IK, Diegelmann RF, Lindblad WJ, eds. Wound Healing: Biochemical and Clinical Aspects. Philadelphia: WB Saunders Co, 1992;527-528. Vallee BL, Falchuk KH. The biochemical basis of zinc physiology. Physiol Rev 1993; 73:79-118. Prasad AS. Zinc deficiency in human subjects. Prog Clin Biol Rev 1983; 129:1-33. Pories WJ, Henzel JH, Rob CG. Acceleration of wound healing in man with zinc sulphate given by mouth. Lancet 1967; 1:121-124. Hallböök T, Lanner E. Serum-zinc and healing of venous leg ulcers. Lancet 1972; 1:780-782. Ruberg RL. Role of nutrition in wound healing. Surg Clin North Am 1984; 64:705-714. Lindner MC. Nutrition and metabolism of the trace elements. In: Lindner MC, ed. Nutrional Biochemistry and Metabolism. Second edition. New York: Elsevier 1991:215-276. Carlisle EM. The nutritional essentiality of silicon. Nutr Rev 1982; 40:193-198. Simopoulos AP. Omega-3 fatty acids in health and disease and in growth and development. Am J Clin Nutr 1991; 54:438-463.

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102 79. 80. 81.

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The Biology and Practice of Current Nutritional Support Sperling RI, Robin JL, Kylander KA. The effects of N-3 polyunsaturated fatty acids on the generation of platelet-activating factor by human monocytes. J Immunol 1987; 139:4186-4191. Endres S, Ghorbani R, Kelley V. The effect of dietary supplementation with n-3 polyunsaturated fatty acids on the synthesis of interleukin-1 and tumor necrosis factor by mononuclear cells. N Engl J Med 1989; 320:265-271. Albina JE, Gladden P, Walsh WR. Detrimental effects of an ω-3 fatty acid-enriched diet on wound healing. JPEN 1993; 17:519-521.

CHAPTER 1 CHAPTER 7

Protein Metabolism in Liver and Intestine During Sepsis: Mediators, Molecular Regulation, and Clinical Implications Timothy A. Pritts, Eric Hungness and Per-Olof Hasselgren

Introduction Sepsis is associated with pronounced metabolic alterations in various organs and tissues. In particular, changes in protein metabolism are prominent in muscle, lungs, liver and intestine.1 Whereas the response to sepsis and severe injury, including burn injury, is that of catabolism in muscle and lungs,2-4 sepsis results in increased protein synthesis in liver and intestine.5,6 One of the consequences of protein breakdown in peripheral tissues is net release of glutamine and other amino acids. A large portion of these amino acids is taken up by the liver to serve as precursors for gluconeogenesis and acute phase protein synthesis, and by the small intestine where they serve as an important energy source (Fig. 7.1). Glutamine is also taken up by cells in the immune system and is important for maintained function of these cells.7 Increased production of acute phase proteins in the liver5 and stimulated protein synthesis in the mucosa of the small intestine6 support the concept of an anabolic response to sepsis in these tissues. The metabolic response to sepsis in the liver and intestine is important from a clinical standpoint for a number of reasons. Several of the acute phase proteins serve as immunomodulators or participate in tissue repair. In previous studies, survival in septic patients was dependent on a well-maintained protein synthesis in the liver. Recent studies provided evidence that acute phase proteins are synthesized not only by the hepatocyte but by the enterocyte as well,8-10 and the intestine may be an additional source of acute phase proteins during sepsis and other critical illness. Part of the sepsis-induced increase in intestinal protein synthesis reflects increased production in the enterocyte of gut peptides, including vasoactive intestinal peptide (VIP) and peptide YY (PYY).11 Some of the gut peptides may be involved in sepsisinduced hemodynamic changes and in altered gastrointestinal motility. In this Chapter, sepsis-induced changes in protein metabolism in liver and intestine are reviewed together with mediators and molecular regulation. In addition, clinical implications of the metabolic changes are discussed.

Liver The Acute Phase Response Acute phase proteins have been defined as plasma proteins whose concentrations in blood are increased 25 % or more by various stimuli, including inflammation, The Biology and Practice of Current Nutritional Support, 2nd Edition, edited by Rifat Latifi and Stanley J. Dudrick. ©2003 Landes Bioscience.

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Fig. 7.1. Sepsis is associated with a catabolic response in skeletal muscle and lungs, resulting in release of glutamine and other amino acids. The function of cells in the immune system and in the gut and the synthesis of acute phase proteins in the liver are supported by changes in protein turnover in muscle and lungs. Reprinted with permission from Hasselgren PO, Protein Metabolism in Sepsis, Austin: RG Landes, 1993.

injury and sepsis. More recently, it has been suggested that the term should be limited to proteins that are induced by cytokines derived from an inflammatory focus.12. In contrast to these proteins, certain plasma proteins, most notably albumin, are reduced during sepsis and critical illness, and these proteins are usually referred to as “negative” acute phase reactants. Thus, during sepsis and following severe injury, the synthesis and release of certain proteins are reprioritized. The acute phase proteins can be divided into different groups depending on the degree of reactivity; some acute phase proteins show an increase of up to 1,000-fold, whereas other proteins show a more moderate (2- to 10-fold) increase following stimulus.13 The acute phase response is species specific. In man, for example, C-reactive protein (CRP) is a particularly strong reactant, showing increased levels even after moderate trauma (Fig. 7.2),14 whereas in rats, α2-macroglobulin and α1-acid glycoprotein show pronounced increases in plasma concentrations during the acute phase response.13 The biological functions of different acute phase proteins have been reviewed elsewhere.12 In general, the acute phase proteins serve a number of important functions in the inflammatory response and in restoring homeostasis following injury and sepsis. Considering the wide range of biological functions of the acute phase proteins, it is not surprising that they are essential for the outcome in sepsis and injury. Several authors have found evidence that survival in septic patients is dependent on a well-maintained protein synthesis in the liver.

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Fig. 7.2. Changes in plasma levels of acute phase proteins following uncomplicated open cholecystectomy. C-reactive protein (CRP) is a particularly strong acute phase reactant in man. Reprinted with permission from Aronson KF et al, Scand J Clin Lab Invest 1972; 29:127-136.

Most clinical evidence for increased acute phase protein synthesis during sepsis and other critical illness has been derived from elevated plasma levels of the proteins. Direct evidence for stimulated protein synthesis in the liver during sepsis has been reported in animal experiments using various experimental models and different techniques to measure protein synthesis. Results from those experiments suggest that sepsis stimulates the synthesis not only of secreted plasma proteins but of endogenous (non-secreted) proteins as well, such as intracellular enzymes and structural proteins, and this is one of the reasons why liver weight and protein content are typically increased during sepsis and inflammation.5,15 Increased hepatic protein

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synthesis is not unique to sepsis, but occurs in a number of inflammatory conditions, including endotoxemia, bacteremia, surgical trauma, and burn injury.5,15 In addition to changes in the synthesis rates, plasma levels of the acute phase proteins can also be influenced by changes in the secretion of the proteins. Plasma proteins usually reach the cell surface of the hepatocyte within 20-25 min after their synthesis. There is evidence that this time is shortened for some proteins during the acute phase response. Thus, both synthesis and secretion of acute phase proteins may be upregulated during sepsis. A more detailed discussion of mechanisms involved in the production and secretion of secretary proteins is given below.

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The cellular mechanisms of the acute phase response are to a certain extent influenced by the unique microanatomy of the liver. Sepsis and inflammation do not affect all hepatocytes in a homogeneous fashion. Thus, at least during the early phase of the acute phase response, protein synthesis is stimulated mainly in the periportal hepatocytes. The inhibition of albumin synthesis also affects hepatocytes in a heterogeneous fashion, with the most pronounced changes occurring in the periportal hepatocytes.16 This heterogeneous response in hepatocytes located in different regions of the liver lobule probably reflects gradients in oxygen, nutrients, and inflammatory mediators with falling concentrations from the periportal area towards the central vein. Although not all hepatocytes are recruited for the acute phase response, at least not initially, each individual hepatocyte that participates in the acute phase response is capable of exhibiting a complete response, i.e., simultaneously increasing the synthesis of multiple acute phase proteins and decreasing the production of albumin. The liver contains several different cell types (hepatocytes, endothelial cells, Kupffer cells, Ito cells, pit cells and neutrophils), most of them arranged in wellorganized, repeating units. The anatomic and functional organization of the hepatic architecture was reviewed recently by Clemens et al (Fig. 7.3).17 Because the microanatomy of the liver is important for the understanding of the metabolic response to sepsis and inflammation, it is briefly reviewed here with special emphasis on the functional organization and the communication between different cell types. The parenchymal cells of the liver, the hepatocytes, are arranged in cords with sinusoids surrounding them. In addition to the heterogeneous function of the hepatocytes caused by gradients in oxygen, nutrients and inflammatory mediators from the terminal portal vein branches to the central vein, the hepatocytes exhibit differences in metabolic activity in different regions because of variations in enzymatic activities. One example of this is the high activity of glutamine synthase in perivenous hepatocytes by which NH3 generated by upstream hepatocytes is cleared. This interaction between periportal and perivenous hepatocytes has led to the concept of a “perivenous scavenger” system18 in which substances left behind by periportal cells are removed by perivenous hepatocytes. The sinusoids are lined by endothelial cells which are characterized by large fenestrae, spaces between the cells, and lack of a well-developed basement membrane. This arrangement allows for an easy exchange of large molecules, including acute phase proteins secreted by the hepatocytes, between the sinusoidal and perisinusoidal (Disse’s) spaces. Similar to other vascular beds, the endothelial cells in the liver are metabolically active and may exhibit phagocytosis, in particular when the capacity of the Kupffer cells has been saturated.

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Fig. 7.3. Three-dimensional view of the microanatomy of the liver. The hepatocytes (H) are arranged in cords surrounded by sinusoids. The sinusoids are lined by a discontinuous endothelium, allowing for communication between the vascular and perisinusoidal (Disse’s space) spaces. The Kupffer cells (K) are present in the sinusoidal lumen. The Ito cells are located in Disse’s space where they wrap around the sinuoid. Reprinted with permission from Clemens MG et al, Shock 1994; 2:1-9.

The Kupffer cells are located within the sinusoids (Fig. 7.3) and constitute the majority of the fixed macrophages in the body. They are most numerous in the periportal sinusoids and are also most active in this location. Following stimulation with endotoxin, the Kupffer cells release a number of inflammatory mediators, including cytokines, prostaglandins, oxygen radicals, and nitric oxide.19,20 The interaction between Kupffer cells and the hepatocytes is of particular significance in the regulation of the acute phase response (see below). The Ito cells are specialized fat and vitamin A storing cells located in Disse’s space where they encircle the sinusoids and also make contact with adjacent Ito cells by long stellate processes; the Ito cells are also known as stellate cells.21 In addition to being a primary site of vitamin A storage in the body, activated Ito cells are contractile in response to mediators such as endothelin, prostaglandin F2α (PGF2α) or thromboxane A2 and may act as postsinusoidal sphincters. The Ito cells may, therefore, be important in mediating changes in the distribution of sinusoidal blood flow in various pathophysiological conditions, such as sepsis and endotoxemia. The pit cells are mononuclear cells located within the sinusoidal space and probably originate from infiltrating lymphocytes. They may be important for the host defense response. Neutrophils infiltrate the liver in large numbers during inflammatory states and accumulate primarily in the sinusoids and hepatic venules.22 Accumulation of neutrophils in the sinusoids may be particularly important since substances released

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from the neutrophils in this position may influence the activity in other nonparenchymal liver cells as well as in the hepatocytes. Recent studies suggest that substances released from neutrophils are more important for reduced blood flow in the postischemic liver than the mechanical blockade caused by accumulated neutrophils.23 The morphological arrangement of the different types of liver cells is important for the intercellular communication during sepsis, shock and inflammation. Communication within the liver can be paracrine, juxtacrine, autocrine or gap junctional. The acute phase response is probably influenced by all these mechanisms. In this respect, the interaction between Kupffer cells and hepatocytes is the most important example of paracrine regulation of protein synthesis during sepsis and inflammation. The communication between Kupffer cells and hepatocytes is probably bidirectional, with Kupffer cells talking to the hepatocytes and the hepatocytes talking back to the Kupffer cells. Juxtacrine communication can take place when cells are in close apposition. For example, activation of neutrophils by platelet-activating factor bound to the plasma membrane of endothelial cells occurs through juxtacrine communication. Autocrine regulation of protein synthesis and cytokine release occurs in both Kupffer cells and hepatocytes. The production of nitric oxide (NO) and cytokines in Kupffer cells is regulated by cytokines and prostaglandins produced in the same Kupffer cells.24 In addition to Kupffer cells, the hepatocytes release NO. Recent studies suggest that acute phase proteins may down-regulate the production of cytokines, possibly by an autocrine mechanism.25 Gap junctions are large channels that connect the cytoplasms of adjacent cells.26 The channels are formed by specific proteins (connexins) in each cell membrane that align to form a pore between the cells. Connexins with different molecular weights have been described; in the liver, connexins with a molecular weight of 26 and 32 kDa (Cx 26 and Cx 32) form gap junctions between hepatocytes; Cx 43 forms gap junctions between Ito cells.26 Gap junctions allow for the passage of small molecular weight substances (less than 1,000 daltons) such as cAMP, cGMP and inositol triphosphate, as well as ions such as Ca2+, and electrical current. The nature of the substances that can pass through the gap junctions supports the significance of this intercellular communication for metabolic regulation. The speed of intercellular communication by gap junctions is regulated by endotoxin. The function of the gap junctions is regulated at the molecular level. For example, the 26 and 32 connexin genes are differentially regulated during inflammation.

Molecular Regulation of Acute Phase Proteins Most acute phase protein genes have been cloned, making it possible to study the acute phase response at the molecular level. Previous studies provided evidence that the acute phase response is regulated at the transcriptional level, and this is probably true for both positive and negative acute phase reactants. In rats, fibrinogen mRNA levels in liver tissue were increased and albumin mRNA levels were reduced following induction of inflammation with turpentine injection.27 Increased mRNA levels for acute phase proteins were also noticed in isolated and cultured hepatocytes following stimulus, further supporting the concept of upregulated gene activity during the acute phase response. This increase in gene activity reflects the activation of transcription factors which are cellular proteins that bind to responsive elements in the gene promoter. By doing so, these proteins interact with the basal

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transcription machinery and modulate mRNA production. Of the many transcription factors involved in the inflammatory response, nuclear factor kappa B (NFκB), activating protein-1 (AP-1), CCATT/enhancer-binding proteins (C/EBP), and cAMP responsive element binding protein (CREB) are particularly important. It should be noted that although transcriptional regulation is important for acute phase protein synthesis, regulation probably occurs at the post-transcriptional level as well. Because the acute phase proteins are secretory proteins, regulation of the intracellular sorting and processing of these proteins may be as important as the regulation of the synthesis itself. The sorting and processing of secretory proteins and the molecular regulation of these events were reviewed recently.28 Secretory proteins are synthesized in the rough endoplasmic reticulum from where they are transported to the Golgi complex. Typically, proteins are secreted via a regulated or a constitutive pathway, both of which involve transfer of vesicles or granules to the plasma membrane followed by the secretary process itself, i.e., exocytic discharge of the vesicle or granule contents. Most secretary proteins are synthesized as precursors carrying a signal peptide. This peptide is cleared from the protein rapidly after the complex enters the Golgi apparatus. Recent evidence suggests that an alternative pathway exists in which proteins may be secreted directly from the cytosol via membrane transporters or translocators or as a result of localized evagination of the plasma membrane. Interestingly, this novel pathway is involved in the secretion of certain cytokines, including interleukin-l. The Golgi complex consists of the cis-Golgi network (CGN), the Golgi stacks and the trans-Golgi network (TGN). It is in the TGN that proteins destined for the regulated secretary pathway are sorted from those to be secreted via the constitutive pathway (Fig. 7.4). In addition, proteins are diverted to lysosomes or to be retained within the Golgi compartments. Regulation of secretion via the regulated pathway occurs at the level of exocytosis itself, the most distal step in the pathway, and may allow for the rapid release of large quantities of proteins stored in granules following the appropriate stimulus. In contrast, exocytosis from the constitutive pathway is a continuous process limited by the availability of product. The molecular events involved in the intracellular sorting and processing of secretary proteins are complex, and several important features involving both the sorting mechanisms and the post-translational modification of proproteins to proteins by conversion endoproteases remain unknown. The influence of sepsis and inflammation on these cellular processes are also largely unknown and will be an important field for future studies, in particular in liver and intestine, where inflammatory stimuli have a significant impact on the synthesis of secretary proteins.

Mediators of the Acute Phase Response The regulation of acute phase protein synthesis in the liver is complex, with a number of substances influencing protein synthesis in the hepatocyte, either by acting alone or as cofactors to other mediators. The three groups of substances that are particularly important for regulation of the acute phase response are cytokines, glucocorticoids, and nitric oxide (NO). Cytokines Among the cytokines, interleukin-6 (IL-6) is the most important regulator of the acute phase response in the liver. The role of IL-6 in the acute phase response has been reviewed in greater detail elsewhere.13,29

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Fig. 7.4. Sorting of secretory proteins in the Golgi complex. Proteins received from the rough endoplasmic reticulum are transferred from the cis-Golgi network (CGN) to the trans-Golgi network (TGN) via the Golgi stacks in non-clathrin-coated vesicles (NCV). In the TGN, lysosomal proteins and regulated secretory proteins are actively sorted to corresponding clathrin-coated regions. Delivery to the constitutive release takes place by default. Reprinted with permission from Halban PA et al, Biochem J 1994; 299:1-18.

There are several lines of evidence that support a role of IL-6 in the acute phase response. Circulating levels of IL-6 are increased in patients with sepsis and following infusion of endotoxin in healthy volunteers. In a group of patients with severe sepsis, high IL-6 levels were associated with high serum concentrations of CRP,30 consistent with the concept that IL-6 is a mediator of acute phase protein synthesis in man. In other studies, correlations were found between IL-6 levels and severity score and outcome, indicating that serum IL-6 levels may be useful as a marker of severity of sepsis and as a predictor of survival.31 When IL-6 was administered in vivo to rats, mRNA levels in liver tissue for α2macroglobulin, α-fibrinogen, cysteine protease inhibitor and α1-acid glycoprotein increased and albumin mRNA levels decreased, indicating that an almost complete acute phase response can be induced by this cytokine. Also in mice, administration of IL-6 resulted in an acute phase response. Evidence for a direct effect of IL-6 was found in in vitro experiments in which acute phase protein synthesis was stimulated in human hepatocytes, cultured in the presence of IL-6.32 The predominant source of IL-6 during sepsis and inflammation is the Kupffer cell, although other cell types, including the hepatocyte itself, have been found to secrete IL-6. Recent studies in our laboratory suggest that the enterocyte may be an

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additional source of IL-6 during sepsis and endotoxemia.33,35 Thus, it is possible that acute phase protein synthesis in the hepatocyte is regulated by IL-6 both in an autocrine (IL-6 produced in the hepatocyte), paracrine (IL-6 produced in Kupffer cells) and endocrine fashion (IL-6 produced in the intestine and reaching the liver through the portal vein). The molecular regulation of IL-6-induced acute phase protein synthesis has been extensively studied in recent years. When IL-6 binds to its receptor on the hepatocyte, a number of different transcription factors are activated to stimulate acute phase protein genes. The induction of the acute phase protein expression is a fast process with increased mRNA levels noticed already 1-2 h after stimulus. In addition to IL-6, other cytokines as well are involved in the regulation of the acute phase response, although these cytokines usually do not induce a complete acute phase response. In experiments in our laboratory, administration of rIL-1_ to rats during three days resulted in increased synthesis in perfused liver of total secreted proteins, complement component C3 and α1-acid glycoprotein, whereas the synthesis of albumin was unchanged and not reduced as expected.36 There is evidence that TNF as well regulates the acute phase response. The liver is an important source of TNF following injury and during sepsis and endotoxemia. Treatment of cultured rat hepatoma cells with TNF in vitro stimulated the synthesis of α1-acid glycoprotein and inhibited the production of albumin, and these effects of TNF were probably regulated at the transcriptional level since mRNA levels for α1-acid glycoprotein were increased and those for albumin were decreased.37 In the same report, TNF had no effect on fibrinogen mRNA, consistent with a partial acute phase response induced by TNF. Recent studies suggest that the effect of TNF on hepatocyte protein synthesis is influenced by insulin and glucose substrate availability.38 Thus, exposure of cultured rat hepatocytes to TNF did not affect albumin synthesis in glycogen-depleted cells, whereas TNF inhibited albumin synthesis by 10-25% in cells exposed to insulin or in cells that were not glycogen-depleted. The results are important because they imply that the acute phase response may be influenced by an interaction between cytokines and nutritional and/or hormonal factors. In addition to IL-6, IL-1 and TNF, other cytokines as well may be involved in the regulation of acute phase protein synthesis. Those cytokines include interferon (IFN)-γ, transforming growth factor β, leukemia inhibiting factor, IL-11 and oncostatin M. The large number of substances that regulate the acute phase response illustrates the complexity of the system. Glucocorticoids Acute phase protein synthesis is under hormonal regulation and is influenced by both catecholamines, glucocorticoids, and glucagon.39 Most evidence suggests that glucocorticoids act as an important or perhaps essential cofactor to IL-6 and other cytokines in the induction of the acute phase response, and this interaction is regulated at the molecular level.40 The activated glucocorticoid receptor, i.e., the receptor with bound hormone, may influence acute phase protein genes through a direct activation of a glucocorticoid receptor element in the promoter or through a protein-protein interaction with other transcription factors or with nuclear coactivating factors.41 Treatment of isolated rat hepatocytes with cytokines induce an acute phase response only in the presence of dexamethasone. In other studies, dexamethasone potentiated several-fold the effects of IL-1 and IL-6 on the synthesis of plasma proteins in cultured human hepatoma cells. In contrast, dexamethasone alone did not

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influence the expression of plasma proteins. Evidence for a permissive role of glucocorticoids was found in vivo as well. Administration of IL-6 to rats stimulated the acute phase protein expression in the liver, but glucocorticoids were needed to achieve a maximal response to the cytokine. An interaction between glucocorticoids and cytokines is important not only at the cellular level for induction of the acute phase response, but also more “proximally.” Thus, a number of cytokines, including IL-1, IL-6 and TNF, stimulate the hypothalamic-pituitary-adrenal axis to secrete ACTH and glucocorticoids. Glucocorticoids, in turn, inhibit the release of cytokines from macrophages in a negative feedback manner. The complexity of the regulation of acute phase proteins is further illustrated by the fact that different classes of the proteins are individually regulated at the molecular level. The acute phase genes have been divided into two major classes: class I genes (including the rat haptoglobin, C3, α1-acid glycoprotein and the human CRP gene) are regulated by IL-1, combinations of IL-1 and IL-6, and combinations of these two cytokines with glucocorticoids;42 class 2 genes (including the α1-antitrypsin, α1-antichymorrypsin, fibrinogen, and α2- macroglobulin genes) are mainly regulated by IL-6 and leukemia inhibitory factor and by combinations of these cytokines with glucocorticoids. In studies using cultured human hepatoma cells, IL-6 activated two different classes of acute phase genes and this activation, which was strongly potentiated by glucocorticoids, was mediated by different transcription factors.40 Nitric Oxide (NO) NO is an important biological mediator released by a number of different cell types, including endothelial cells, Kupffer cells and other macrophages, hepatocytes, cerebellar neurons and neutrophils. The biological functions of NO as well as the molecular regulation of NO production by constitutive and inducible NO synthase have been extensively reviewed elsewhere.43 The possible role of NO in the regulation of liver protein synthesis was initially described in in vitro experiments in which rat Kupffer cells or peritoneal macrophages were co-cultured with isolated hepatocytes. When this co-culture system was treated with endotoxin, hepatocyte protein synthesis was inhibited. Subsequent studies provided evidence that the inhibition of protein synthesis was mediated by NO, mainly released from the Kupffer cells and acting on the hepatocytes in a paracrine fashion, but also released by the hepatocytes themselves and acting in an autocrine fashion. The production of NO in the hepatocytes is probably regulated by cytokines released from stimulated Kupffer cells. Thus, when supernatant from cultured Kupffer cells that had been stimulated by endotoxin and IFN-γ was added to cultured hepatocytes, the hepatocytes produced increased amounts of NO.44 At the same time, hepatocyte protein synthesis was reduced. The endotoxin-induced release from Kupffer cells of substances that stimulated NO release from the hepatocytes was regulated by cytokines and was maximal when a mixture of IL-1, TNF and IFN-γ was added to the endotoxin-stimulated Kupffer cells.45 Although most of the experiments described above were performed in hepatocytes from rats, other studies suggest that similar regulatory mechanisms are present in humans as well. Plasma concentrations of nitrite/nitrate (NO2/NO3), the stable end- products of NO, are increased in patients after trauma and during sepsis, and NO production can be induced in human hepatocytes by a mixture of TNF, IL-1, IFN-γ and endotoxin.

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It should be noted that although in vitro experiments suggest that NO inhibits hepatic protein synthesis, the role of NO for the regulation of hepatic protein synthesis in vivo is not clearly understood. Several studies suggest that NO may be protective in vivo and even increase hepatic protein synthesis. In studies in our laboratory, treatment of endotoxemic rats with the NO synthase inhibitor NG-nitro-Larginine effectively blocked the increase in plasma levels of NO2/NO3 and significantly reduced the endotoxin-induced increase in in vivo hepatic protein synthesis.46 The results suggest that NO may participate in the stimulation of hepatic protein synthesis in vivo during sepsis and endotoxemia. The mechanism of this effect of NO is not known, but may be improved hemodynamics, perhaps at the microcirculatory level, secondary to the vasodilatory effect of the substance or to prevention of platelet aggregation and adhesion.

Intestine It is only relatively recently that the influence of sepsis and systemic inflammation on intestinal protein synthesis has been studied.1,6 Changes in intestinal protein synthesis are important from a clinical standpoint for several reasons. The intestine has one of the highest protein turnover rates in the body, accounting for 10-15% of total body protein production under normal conditions. Consequently, changes in intestinal protein synthesis rates may have a significant impact on whole body protein economy. The intestine is the production site for a number of proteins with important biological functions, such as digestive enzymes, gastrointestinal hormones, mucin and immunoreactive protein. In addition, recent studies, including studies in our laboratory, suggest that the intestine is an important source of cytokines during sepsis, endotoxemia and shock.33-35,47-49 The potential importance of the gut during sepsis and endotoxemia is underscored by the fact that proteins (including cytokines) synthesized in the intestinal mucosa can reach the liver directly via the portal vein and may therefore be able to influence metabolic processes in the liver. This concept is referred to as the “gut-liver axis” (Fig. 7.5) and is supported by a recent report from our laboratory in which levels of several gut hormones were elevated in the portal, but not systemic, circulation following induction of sepsis.50 Finally, changes in the production of IgA, mucin, and perhaps other proteins as well, may be essential for bacterial translocation across the gut mucosa.

Sepsis Stimulates Intestinal Protein Synthesis Initial studies concerning the potential role of the intestinal mucosa in the metabolic response to sepsis examined the effect of sepsis on mucosal protein synthesis. When sepsis was induced by cecal ligation and puncture (CLP) in rats, the protein synthesis rate was increased by approximately 15% in jejunal mucosa after 8 h and by 50-60% in jejunal and ileal mucosa after 16 h.6 This increase was greatest in jejunal mucosa, but also involved ileal mucosa and jejunal and ileal seromuscular layers. Parenteral administration of the pro-inflammatory cytokines TNF-α or IL-1α was also associated with increased mucosal protein synthesis, suggesting that the response to sepsis may be mediated, at least in part, by these cytokines. Interestingly, increases in mucosal protein synthesis rates during sepsis varied among different regions of the gastrointestinal tract. Sepsis stimulated protein synthesis in different regions of the small and large bowel, from the duodenum to the anus.51 In sharp contrast, protein synthesis in gastric mucosa was significantly reduced during sepsis (Table 7.1). The mechanism of this differential effect of sepsis

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Fig. 7.5. The “gut-liver axis”. Substances synthesized by the gut may reach (and influence) the liver directly via the portal circulation. Reprinted with permission from Hasselgren PO, in Cytokines and Abdominal Surgery, Schein M, Wise L, eds., Austin: RG Landes, 1998:197-213.

on protein synthesis in the stomach and the rest of the gastrointestinal tract is not known, but may be differences in blood flow; gastric perfusion is reduced whereas intestinal blood flow is unchanged or even increased during sepsis.52 It may be speculated that reduced protein synthesis in gastric mucosa during sepsis in part reflects reduced production of mucin and other substances important for the protection of the gastric mucosa. The finding, therefore, may be important for the understanding of the pathogenesis of gastric stress ulcers, commonly observed in patients with sepsis or other critical illness. Further studies are necessary to elucidate the implications of reduced protein synthesis in gastric mucosa during sepsis. Studies in other laboratories confirmed our results of increased intestinal protein synthesis during sepsis.53 They found that protein synthesis in mucosa of small intestine was increased 20 h after the intravenous injection of live E. coli bacteria and the increase in protein synthesis was more pronounced in the jejunum than in ileum, similar to our findings.6 Interestingly, in those studies,53 mucosal protein synthesis was further stimulated in septic rats that were treated with glutamine-enriched total parenteral nutrition. In our previous experiments,6 mucosal protein synthesis rates were measured by using a flooding dose technique. Because that method measures total mucosal protein synthesis, it was not possible to delineate with cell type(s) were involved. In addition to enterocytes, a number of other cell types are present in the intestinal

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Table 7.1.

Specific radioactivity of protein bound (SB) and tissue free (SA) leucine and protein synthesis rate (KS) in mucosa of different parts of the gastrointestinal tract of sham-operated and septic rats

SB Stomach 0.43±0.03 Duodenum 0.56±0.03 Jejunum 0.52±0.03 Ileum 0.40±0.05 Ascending Colon 0.26±0.03 Descending Colon 0.29±0.04 Rectum 0.41±0.04

Sham SA 98±6 87±3 86±5 87±3 103±14 91±4 95±14

KS 65±5 94±4 89±7 67±6 40±5 45±6 66±8

SB 0.22±0.03* 0.76±0.04* 0.64±0.07* 0.53±0.05* 0.56±0.07* 0.65±0.05* 1.10±0.20*

CLP SA 77±5 80±3 81±4 87±6 139±13* 130±19* 131±16*

KS 41±4* 139±5* 115±9* 91±7* 61±6* 74±8* 123±15*

SB and SA are given as dpm/nmol; KS is given as %/day Protein synthesis rates in mucosa of different parts of the gastrointestinal tract were determined following a flooding dose of 14C-leucine. The studies were performed 16 h after sham-operation or CLP. Results are means ± SEM. The number of rats in each group was eight. *p<0.05 vs sham. Reprinted with permission from Higashiguchi T et al, Clin Sci 1994; 87:207-211.

mucosa, including endothelial cells, smooth muscle cells, lymphocytes, macrophages and pericryptal myofibroblasts. To examine this issue, we measured protein synthesis rates in enterocytes isolated from the jejunum of control and septic rats.54 Results from those experiments suggest that sepsis stimulates protein synthesis in enterocytes and that the effect of sepsis is particularly pronounced in crypt cell. In other experiments in the same report, the subcutaneous injection of endotoxin in rats gave rise to an almost identical metabolic response in jejunal enterocytes, indicating that that findings in septic rats were not caused by the local effects of septic peritonitis (induced by CLP), but that increased enterocyte protein synthesis is part of the systemic response to sepsis.

Synthesis and Release of Secretory Proteins, Including Certain Gut Peptides When endogenous and secreted proteins were separately measured in enterocytes isolated from the jejunum of control and septic rats, results showed that sepsis stimulates the synthesis of both these classes of proteins (Fig. 7.6).11 One important group of proteins synthesized and released from the intestine are gastrointestinal hormones. In previous studies, circulating levels of vasoactive intestinal peptide (VIP) were increased during sepsis or endotoxemia. More recently, we found that plasma concentrations of VIP, peptide YY (PYY) and secretin were increased in septic rats. Plasma levels of VIP and PYY were higher in portal than in peripheral blood, consistent with a gut origin of these peptides. To further elucidate the origin of gut peptides during sepsis, we measured the release of PYY and VIP in isolated jejunal enterocytes .11 The amount of VIP released into the incubation medium (determined by radioimmunoassay) was increased 10- to 15-fold in enterocytes from septic rats as compared with non-septic control rats. Sepsis stimulated VIP release in enterocytes from different regions of the villi, but the effect of sepsis was particularly pronounced in cells from the tips of the villi.

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Fig. 7.6. Effect of sepsis, induced by cecal ligation and puncture (CLP), on synthesis of non-secreted (left panel) and secreted (right panel) proteins in jejunum of rats. Control animals were sham-operated. *p<0.05 vs. corresponding sham-operated group. Based on data in Higashiguchi T et al, Am J Surg 1994; 168:251-256.

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The release of PYY from incubated enterocytes was also increased during sepsis, but the changes were less pronounced than those for VIP. Studies using the protein synthesis blocker cycloheximide suggested that the increased release of VIP and PYY by enterocytes from septic rats reflected both stimulated de novo synthesis and release of preformed intracellular stores of the peptides. Thus, sepsis seems to stimulate both the synthesis and release of certain gut peptides. Increased synthesis and release of gut peptides may have several important clinical implications. Certain gut peptides may delay gastric emptying and impair intestinal motility and may therefore play a role in the pathogenesis of abnormal gastrointestinal motility during sepsis. VIP may stimulate glycogenolysis and lipolysis during sepsis, and may also influence the hemodynamic changes induced by sepsis through its vasodilatory and positive inotropic effects. In vitro experiments have provided evidence that gut peptides may have a direct effect on enterocyte metabolism. Other studies suggest that PYY may stimulate cellular proliferation in the intestinal epithelium. Finally, because secreted gut peptides reach the liver at high concentrations through the portal vein, it may be speculated that the peptides influence hepatocellular functions. Thus, changes in intestinal protein synthesis during sepsis may be important for the regulation of metabolic activity in the liver, consistent with a functional “gut-liver axis.”

Sepsis and Mucosal Cytokine Production Several lines of evidence suggest that the proteins secreted by the intestinal mucosa during sepsis may include a wide variety of cytokines. In recent years, the gut has been increasingly recognized as an important source of cytokines, during both local and systemic inflammation.33-35,47-49 There is evidence that enterocytes as well as mononuclear cells in the lamina propria can produce cytokines.34,35,49 In a previous report, endotoxemia in mice was associated with increased tissue levels of IL-1α in mucosa of small intestine and this increase in IL-1 production was regulated at the transcriptional level.47 Other studies have provided evidence that mucosal production of TNF may also be increased during sepsis and endotoxemia. Recent studies in our laboratory focused on the influence of sepsis and endotoxemia on mucosal production of IL-6. Release of IL-6 from intestinal mucosa may be of even greater significance than TNF and IL-1 considering the important role of IL-6 in the regulation of acute phase protein synthesis, both in the liver13 and locally in the intestinal mucosa.8-10 Endotoxemia in mice resulted in increased tissue levels of IL-6 in jejunal mucosa consistent with stimulated local production of the cytokine (Fig 7.7, upper panel). Reverse transcriptase PCR analysis of RNA extracted from jejunal mucosa demonstrated that the elevated mucosal IL-6 levels were associated with increased IL-6 mRNA levels (Fig. 7.7, lower panel), consistent with the concept that sepsis and endotoxemia may stimulate mucosal IL-6 production at the transcriptional level.33 The studies described above did not define in which cell type IL-6 production was increased. In studies using cultured intestinal epithelial cells, we found evidence that the enterocyte may be an important source of IL-6 during sepsis and endotoxemia. Endotoxin treatment resulted in IL-6 protein and mRNA production in IEC-6 cells (a rat intestinal epithelial cell line) in a time- and dose-dependent fashion.49 In Caco-2 cells, a human intestinal epithelial cell line, the pro-inflammatory cytokine IL-1α stimulated IL-6 secretion into the culture medium (Fig. 7.8, upper panel). 34 IL-6 mRNA levels were likewise increased, suggesting that

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Fig. 7.7 Effect of endotoxin (LPS) on IL-6 protein (upper panel) and mRNA levels (lower panel) in jejunal mucosa as determined by ELISA and RT-PCR, respectively. *p<0.05 vs. saline. β-actin was used to control for equal mRNA loading. Reprinted with permission from Meyer TA et al, Surgery 1995; 118:336-342.

IL-1α-induced IL-6 production is regulated at the transcriptional level (Fig. 7.8, lower panel). In more recent studies utilizing examination of jejunal mucosa by immunohistochemistry, we found that enterocytes, in addition to cells present in the lamina propria, produced IL-6 in vivo during endotoxemia.35 Thus, studies from our and other laboratories suggest that sepsis and endotoxemia result in increased production in intestinal mucosa of TNF, IL-1, and IL-6 and that the enterocyte may be an important source of cytokines in these conditions. Mucosal production of cytokines is significant because they may influence enterocyte metabolism locally in an autocrine or paracrine fashion. In addition, they may reach the liver through the portal vein and may therefore influence the metabolic response to sepsis in the liver.

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Fig. 7.8. Effect of IL-1β on IL-6 protein (upper panel) and mRNA levels (lower panel) in Caco-2 cells as determined by ELISA and RT-PCR, respectively. *p<0.05 vs. respective control group. β-actin was used to control for equal mRNA loading. Reprinted with permission from Parikh AA et al, Shock 1997; 8:249-255.

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Recent studies have examined the regulation of cytokine production in the enterocyte and intestinal mucosa. Early experiments indicated that IL-6 production in cultured intestinal epithelial cells was augmented by addition of other inflammatory mediators to the culture medium. For example, prostaglandin E2 interacted synergistically with endotoxin to increase IL-6 production in IEC-6 cells55 and interferon-α treatment augmented IL-1α-induced IL-6 production in Caco-2 cells.34 More recently, our and other laboratories have begun to explore the potential role of transcription factors in cytokine and acute phase protein production in the enterocyte and intestinal mucosa. Transcription factors are proteins that act to regulate gene transcription rates, leading to either increased or decreased transcription of the target gene. A given transcription factor may influence the transcription of multiple genes, making these proteins attractive potential targets through which the inflammatory response may be manipulated in a therapeutic fashion. One transcription factor that my play an important role in the inflammatory response of the intestinal mucosa to sepsis and endotoxemia is nuclear factor-kappa B (NF-κB). NF-κB is a dimer consisting of various subunits, most commonly p50 and p65, and is normally sequestered in the cytoplasm in an inactive form by the inhibitory protein IκB (for review see ref. 56). Multiple proinflammatory mediators, including IL-1β, LPS, and TNF-α, can activate NF-κB in different cell types. Through various signaling pathways, these stimuli lead to phosphorylation of IκB. After phosphorylation, IκB is ubiquitinated and degraded by the proteasome, freeing NF-κB to translocate to the nucleus and bind to its target sequences. NF-κB activation is usually rapid, transient, and self-limited. In addition to other target genes, NF-κB also encourages transcription of the IκB proteins, which then serve to terminate NF-κB activation and re-sequester NF-κB in the cytoplasm. A simplified diagram of the NF-κB activation pathway is presented in Fig. 7.9. Recent studies have examined NF-κB activation in the enterocyte and intestinal mucosa. Initial reports from this57 and another58 laboratory demonstrated that IκB-α degradation and increased NF-κB DNA binding activity occurred in cultured human intestinal epithelial cells after treatment with IL-1β, concurrent with increased expression of the NF-κB-associated genes for IL-6 and IL-8. Subsequent studies indicated that IκB degradation and NF-κB activation also occurred in cultured intestinal epithelial cells in response to TNF-α, LPS, bacterial adhesion, and bacterial invasion. Recent studies have begun to examine NF-κB activation in the gastrointestinal tract in vivo. In a report from our laboratory, the effect of endotoxin on IκB-α protein levels and NF-κB DNA binding activity was examined in jejunal mucosa.59 We found that endotoxin injection resulted in rapid decrease in IκB-α levels, with a concomitant increase in NF-κB DNA binding activity, consistent with NF-κB activation in this tissue (Fig. 7.10). Additional experiments have indicated that NF-κB activation varied in different regions of the gastrointestinal mucosa during endotoxemia.60 Interestingly, the jejunum was the region most sensitive to endotoxemia, similar to our findings with mucosal protein synthesis,6 IL-6,61 and complement C3 production.62 In addition to NF-κB, several other transcription factors likely play important roles in regulating protein metabolism in intestinal mucosa during sepsis. We recently found evidence that activating protein-1 (AP-1) and members of the C/EBP transcription factor family, including CEBP-β and CEBP-δ, are activated in cultured

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Fig. 7.9. Schematic diagram showing the pathway leading to IκB-α degradation and NF-κB activation in response to pro-inflammatory stimuli. Reprinted with permission from Perkins ND, Int J Biochem Cell Biol 1997; 29:1433-1448.

intestinal epithelial cells in response to IL-1α.63,64 Further studies are needed to determine the relative role of the different transcription factors in increased cytokine and acute phase protein production in the enterocyte and intestinal mucosa during acute inflammation. The identification and characterization of the transcription factors activated in the enterocyte and intestinal mucosa during sepsis may enable therapeutic modification of the metabolic and inflammatory responses in gut mucosa. For example, inhibition of NF-κB activation by proteasome inhibitors resulted in decreased IL-8 production in cultured enterocytes. In other studies, treatment of cells with various NF-κB inhibitors decreased IL-1α-induced IL-6 and complement component C3

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Fig. 7.10. NF-κB DNA binding activity determined by electrophoretic mobility shift assay (lower panel) and IκB-α levels determined by Western blotting (upper panel) in jejunal mucosa at various timepoints after injection of saline (left panel) or LPS (right panel) in mice. Reprinted with permission from Pritts TA et al, Arch Surg 1998; 133:1311-1315.

production.65,66 The further modification of sepsis-induced changes in protein production and metabolism will be an important goal for future work in this field.

Cytokines Induce a Sepsis-Like Response in Intestinal Mucosa Several of the metabolic changes induced by sepsis and endotoxemia in intestinal mucosa can be duplicated by cytokines. For example, administration of rIL-lα or rTNF-α to rats resulted in increased protein synthesis in jejunal and ileal mucosa, similar to the response seen during sepsis.6 In other experiments, administration of TNF in rats gave rise to increased portal plasma levels of PYY.50 In contrast, no changes in circulating gut peptide concentrations were noted following the administration of IL-1, suggesting a differential role of the two cytokines in the regulation of gut peptide release. For the interpretation of results seen following the administration of cytokines, it is important to remember that cytokines interact with each other and with glucocorticoids. It is possible that metabolic changes observed following the administration of TNF are caused by IL-1, IL-6 and/or glucocorticoids since TNF induces the release of other cytokines as well as glucocorticoids. Several of the in vitro studies described above lend strong support to the concept that proinflammatory cytokines are important mediators of metabolic changes in the enterocyte and that these changes are caused by direct effects of the cytokines on the enterocyte.

Selected References 1. 2. 3.

Hasselgren PO. Protein Metabolism in Sepsis. Austin: RG Landes, 1993. Hasselgren PO, James JH, Benson DW et al. Total and myofibrillar protein breakdown in different types of rat skeletal muscle: effects of sepsis and regulation by insulin. Metabolism 1989; 38:634-640. Fang CH, James JH, Ogle CK et al. Influence of burn injury on protein metabolism in different types of skeletal muscle and the role of glucocorticoids. J Am Coll Surg 1995; 180:33-42.

Protein Metabolism in Liver and Intestine During Sepsis 4. 5. 6. 7. 8. 9. 10. 11. 12. 13. 14. 15. 16. 17. 18. 19. 20. 21. 22. 23. 24.

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Plumley DA, Souba WW, Hautamaki RD et al. Accelerated lung amino acid release in hyperdynamic septic surgical patients. Arch Surg 1990; 125:57-61. Pedersen P, Säljö A, Hasselgren PO. Protein and energy metabolism in liver tissue following intravenous infusion of live E. coli bacteria in rats. Circ Shock 1987; 21:59-64. von Allmen D, Hasselgren PO, Higashiguchi T et al. Increased intestinal protein synthesis during sepsis and following the administration of tumor necrosis factor α or interleukin-1α. Biochem J 1992; 286:585-589. Newsholme EA, Parry-Billings M. Properties of glutamine release from muscle and its importance for the immune system. JPEN 1990; 14:63S-67S. Molmenti EP, Ziambaras T, Pearlmutter DH. Evidence for an acute phase response in human intestinal epithelial cells. J Biol Chem 1993; 268:14116-14124. Moon MR, Parikh AA, Szabo C et al. Complement C3 production in human intestinal epithelial cells is regulated by IL-1α and TNF-α. Arch Surg 1997; 132:1289-1293. Wang Q, Meyer TA, Boyce S et al. Endotoxemia in mice stimulates the production of complement component C3 and serum amyloid in mucosa of small intestine. Am J Physiol 1998; 275:R1584-R1592. Higashiguchi T, Noguchi Y, Noffsinger A et al. Sepsis increases production of total secreted proteins, vasoactive intestinal peptide, and peptide YY in isolated rat enterocytes. Am J Surg 1994; 168:251-256. Thompson D, Milford-Ward A, Whicher JT. The value of acute phase protein measurements in clinical practice. Ann Clin Biochem 1992; 29:123-131. Heinrich PC, Castell JV, Andus T. Interleukin-6 and the acute phase response. Biochem J 1990; 265:621-636. Aronsen KF, Ekelund G, Kindmark CO et al. Sequential changes of plasma proteins after surgical trauma. Scand J Clin Lab Invest 1972; 29:127-136. Vary TC, Kimball SR. Regulation of hepatic protein synthesis in chronic inflammation and sepsis. Am J Physiol 1992; 262:C445-C452. Ballmer PE, Ballmer-Hofer K, Repond F et al. Acute suppression of albumin synthesis in systemic inflammatory disease: an individually graded response of rat hepatocytes. J Histochem Cytochem 1992; 40:201-206. Clemens MG, Bauer M, Gingalewski C et al. Hepatic intercellular communication in shock and inflammation. Shock 1994; 2:1-9. Haussinger D, Stehle T. Hepatocyte heterogenity in response to icosanoids. The perivenous scavenger hypothesis. Eur J Biochem 1988; 175:395-403. Winwood P, Arthur MPJ. Kupffer cells: their activation and role in animal models of liver injury and human liver disease. Semin Liver Dis 1993; 13:50-59. Spitzer JA. Cytokine stimulation of nitric oxide formation and differential regulation in hepatocytes and nonparenchymal cells of endotoxemic rats. Hepatology 1994; 19:217-228. Ramadori G. The stellate cell (Ito-cell, fat-storing cell, lipocyte, perisinusoidal cell) of the liver: new insights into pathophysiology of an intriguing cell. Virchows Arch B Cell Pathot 1991; 61:147-158. Ferguson D, McDonagh PF, Biewer J et al. Spatial relationship between leukocyte accumulation and microvascular injury during reperfusion following hepatic ischemia. Int J Microcirc Clin Exp 1993; 12:45-60. Zhang JX, Jones DV, Clemens MG. Effect of activation on neurrophil-induced hepatic microvascular injury in isolated rat liver. Shock 1994; 1:273-278. Stadler J, Harbrecht BG, Di Silvio M et al. Endogenous nitric oxide inhibits the synthesis of cyclooxygenase products and interleukin-6 by rat Kupffer cells. J Leuko Biol 1993; 53:165-172.

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124 25.

26. 27. 28. 29. 30. 31. 32.

7 33. 34. 35. 36. 37. 38. 39. 40. 41. 42. 43. 44. 45.

The Biology and Practice of Current Nutritional Support Tilg H, Vannier E, Vachino G et al. Antiinflammatory properties of hepatic acute phase proteins: preferential induction of interleukin-I (IL-1) receptor antagonist over IL-1α synthesis by human peripheral blood mononuclear cells. J Exp Med 1993; 178:1629-1636. Dermietzel R, Hwang TK, Spray DC. The gap junction family: structure, function and chemistry. Anat Embryol 1990; 182:517-528. Princen JMG, Nieuwenhuizen W, Mol-Back GPBM et al. Direct evidence of transcriptional control of fibrinogen and albumin synthesis in rat liver during the acute phase response. Biochem Biophys Res Commun 1981; 102:717-723. Halban PA, Irminger JC. Sorting and processing of secretary proteins. Biochem J 1994; 299:1-18. Papanicolaou DA, Wilder RL, Manolagas SC et al. The pathophysiological roles of interleukin-6 in human disease. Ann Intern Med 1998; 128:127-137. Damas P, Ledoux D, Nys M et al. Cytokine serum levels during severe sepsis in human: IL-6 as a market of severity. Ann Surg 1992; 215:356-362. Calandra T, Gerain J, Heumann D et al. High circulating levels of interleukin-6 in patients with septic shock: Evolution during sepsis, prognostic value, and interplay with other cytokines. Am J Med 1991; 91:23-29. Castell JV, Gomez-Lechon MJ, David M et al. Interleukin-6 is the major regulator of acute-phase protein synthesis in adult human hepatocytes. FEBS Lett 1989; 242:237-239. Meyer TA, Wang JJ, Tiao G et al. Sepsis and endotoxemia stimulate intestinal IL-6 production. Surgery 1995; 118:336-342. Parikh A, Salzman AL, Fischer JE et al. Interleukin-1α and interferon-γ regulated interleukin-6 production in human intestinal epithelial cells. Shock 1997; 8:249-255. Wang Q, Wang JJ, Boyce S et al. Endotoxemia and IL-1α stimulate mucosal IL-6 production in different parts of the gastrointestinal tract. J Surg Res 1998; 76:27-31. Pedersen P, Hasselgren PO, Li S et al. Synthesis of acute phase proteins in perfused liver following administration of recombinant interleukin-1α to normal or adrenalectomized rats. J Surg Res 1988; 45:333-341. Andus T, Geiger T, Hirano T et al. Regulation of synthesis and secretion of major rat acute phase proteins by recombinant human interieukin-6 (BSF-2/IL-6) in hepatocyte primary cultures. Eur J Biochem 1988; 173:287-293. Dahn MS, Hsu CJ, Lang MP et al. Effects of tumor necrosis factor-α on glucose and albumin production in primary cultures of rat hepatocytes. Metabolism 1994; 43:476-480. van Gool J, Boers W, Sala M et al. Glucocorticoids and catecholamines as mediators of acute-phase proteins, especially rat α-macrofetoprotein. Biochem J 1984; 220:125-132. Hocke GM, Barry D, Fey GH. Synergistic action of interieukin-6 and glucocorticoids is mediated by the interleukin-6 response element of the rat α2 macroglobulin gene. Mol Cell Biol 1992; 12:2282-2294. Pfahl M. Nuclear receptor/AP-1 interaction. Endocr Rev 1993; 14:651-658. Baumann H, Gauldic J. Regulation of hepatic acute phase plasma protein genes by hepatocyte stimulating factors and other mediators of inflammation. Mol Biol Med 1990; 7:147-160. Zamora R, Vodovotz Y, Billiar TR. Inducible nitric oxide synthase and inflammatory diseases. Mol Med 2000; 6:347-373. Curran RD, Billiar TR, Stuehr DJ et al. Hepatocytes produce nitrogen oxide from L-arginine in response to inflammatory products of Kupffer cells. J Exp Med 1989; 170:1769-1774. Curran RD, Billiar TR, Stuehr DJ et al. Multiple cytokines are required to induce hepatocyte nitric oxide production and inhibit total protein synthesis. Ann Surg 1990; 212:462-471.

Protein Metabolism in Liver and Intestine During Sepsis 46. 47. 48. 49. 50. 51. 52. 53. 54. 55. 56. 57. 58. 59. 60. 61. 62. 63. 64. 65. 66.

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Frederick JA, Hasselgren PO, Davis S et al. Nitric oxide may upregulate in vivo hepatic protein synthesis during endotoxemia. Arch Surg 1993; 128:152-157. Mester M, Tompkins RG, Gelfand JA et al. Intestinal production of interleukin1α during endotoxemia in the mouse. J Surg Res 1993; 54:584-591. Deitch EA, Xu D, Franko L et al. Evidence favoring the role of the gut as a cytokinegenerating organ in rats subjected to hemorrhagic shock. Shock 1994; 1:141-146. Meyer TA, Noguchi Y, Ogle C et al. Endotoxin stimulates IL-6 production in intestinal epithelial cells: A synergistic effect with PGE2. Arch Surg 1994; 129:1290-1295. Zamir O, Hasselgren PO, Higashiguchi T et al. Effect of sepsis or cytokine administration on release of gut peptides. Am J Surg 1992; 163:181-185. Higashiguchi T, Noguchi Y, O’Brien W et al. Effect of sepsis on mucosal protein synthesis in different parts of the gastrointestinal tract in rats. Clin Sci 1994; 87:207-211. Lang CH, Bagby Gj, Ferguson JL et al. Cardiac output and redistribution of organ blood flow in hypermetabolic sepsis. Am J Physiol 1984; 246:R331-R337. Yoshida S, Leskiw MJ, Schluter MD et al. Effect of total parenteral nutrition, systemic sepsis, and glutamine on gut mucosa in rats. Am J Physiol 1992; 263:E368-E373. Higashiguchi T, Noguchi Y, Meyer T et al. Protein synthesis in isolated enterocytes from septic or endotoxemic rats: regulation by glutamine. Clin Sci 1995; 89:316-319. Meyer TA, Noguchi Y, Ogle C et al. Endotoxin stimulates IL-6 production in intestinal epithelial cells: a synergistic effect with PGE2. Arch Surg 1994; 129:1290-1295. Ghosh S, May MJ, Kopp EB. NF-κB and Rel proteins: Evolutionarily conserved mediators of immune response. Annu Rev Immunol 1998; 16:225-260. Parikh A, Salzman A, Kane CD et al. IL-6 production in human intestinal epithelial cells following stimulation with IL-1α is associated with activation of the transcription factor NF-κB. J Surg Res 1997; 69:139-144. Jobin C, Haskill S. Mayer L et al. Evidence for altered regulation of IκBα degradation in human colonic epithelial cells. J Immunol 1997; 158:226-234. Pritts TA, Moon MR, Fischer JE et al. Nuclear factor-κB is activated in intestinal mucosa during endotoxemia. Arch Surg 1998; 133:1311-1315. Pritts TA, Moon MR, Wang Q et al. Activation of NF-κB varies in different regions of the gastrointestinal tract during endotoxemia. Shock 2000; 14:118-122. Wang Q, Wang JJ, Boyce S et al. Endotoxemia and IL-1α stimulate mucosal IL-6 production in different parts of the gastrointestinal tract. J Surg Res 1998; 76:27-31. Wang Q, Wang JJ, Fischer JE et al. Mucosal production of complement C3 and serum amyloid A is differentially regulated in different parts of the gastrointestinal tract during endotoxemia in mice. J Gastrointest Surg 1998; 2:537-546. Hungness ES, Pritts TA, Luo GJ et al. The transcription factor AP-1 is activated and IL-6 production is increased in IL-1α-stimulated human enterocytes. Shock 2000; 14:386-391. Hungness ES, Pritts TA, Luo G, Hasselgren PO. IL-1α activates C/EBP-β and C/ EBP-δ in human enterocytes through a mitogen activated protein kinase (MAPK) signaling pathway. Surg Forum 2000; 51:207-209. Parikh, AA, Moon MR, Pritts TA et al. IL-1α induction of NF-κB activation in human intestinal epithelial cells is independent of oxyradical signaling. Shock 2000; 13:8-13. Moon MR, Parikh AA, Pritts TA et al. Complement component C3 production in IL-1α-stimulated human intestinal epithelial cells is blocked by NF-κB inhibitors and by transfection with Ser 32/36 mutant IκBα. J Surg Res 1999; 82:48-55.

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CHAPTER 8

Biochemical Assessment and Monitoring of Nutritional Status Robert S. DeChicco, Laura E. Matarese, Douglas Seidner and Ezra Steiger

The Incidence of Malnutrition The prevalence of malnutrition in hospitalized patients ranges from 30 to 50% (Table 8.1).1-11 The incidence of malnutrition actually increases if patients are hospitalized for two or more weeks. 7 Although the criteria used to define malnutrition and the types of patients and hospitals varies, the prevalence has remained relatively constant throughout the years. Malnutrition in the hospital setting has far-reaching implications. Malnutrition has been associated with longer hospital stays,7,13-17 delayed wound healing,18-21 increased morbidity and mortality, 1,7,11,13,17, 22-32 and ultimately, higher health care costs.15-17, 33-35 There is no clinical situation which benefits from malnutrition.

Methods of Nutrition Assessment Changes in nutritional status, particularly in the critically ill patient, are often subtle and influenced by many factors. It is important to have an objective assessment tool to identify patients who are at nutritional risk and to document the efficacy of therapy. Unfortunately, there is no single tool which can be used to identify malnutrition. Thus, a variety of methods are used including patient history, physical examination, anthropometric measurements, biochemical indices, and tests of immune function.

History The history comprises the basis of any assessment. For the purposes of determining nutritional status, the history can be divided into medical and nutrition. The history should include an investigation of unexplained weight loss, abnormal or inadequate nutrient intake, recent surgery or illness, chronic illness, and hypermetabolic states (Table 8.2). Malnutrition is classified as primary or secondary. Primary malnutrition results from inadequate diet or excessive intake of certain nutrients (e.g., vitamins, calories). This type of malnutrition is generally a socioeconomic phenomenon but also involves age, sex, and race. Secondary, or conditional malnutrition occurs when nutrients are not absorbed or utilized appropriately, generally as a consequence of a disease process. Causes of secondary malnutrition include the impaired ability to ingest foods (e.g., esophageal cancer), the impaired ability to digest, absorb, or utilize nutrients (e.g., Crohn’s disease, ulcerative colitis), and increased nutritional

The Biology and Practice of Current Nutritional Support, 2nd Edition, edited by Rifat Latifi and Stanley J. Dudrick. ©2003 Landes Bioscience.

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Table 8.1.

The prevalence of malnutrition*

Investigator Bistrian et al3 Bistrian et al4 Hill et al5 Mullen et al6 Weisner et al7

Date 1974 1976 1977 1979 1979

Patient Type General Surgical General Medical Surgical Elective Surgical General Medical

Hospital Type Urban Teaching Urban Teaching General Teaching Urban VA Teaching

1980

% Malnourished 50 44 or more 50 35 48 on admission 69 after 2 weeks 31.5

Willard et al8

General Med/Surg

Bastow et al9

1983

53

Sullivan et al10

1989

39

Coates et al11

1993

38 on admission 48 after 2 weeks

Elderly Female Orthopedic Elderly General Medical/Surgical General Medical

Private Community University VA University Affiliated Teaching

* Adapted from: Mosner M and Bader S.12

requirements (e.g., sepsis, trauma). Nutritional deficiencies can also develop as a result of drug-nutrient interactions. The nutrition history should provide detailed information about the patient’s general health, eating patterns, and nutrient intake. There are several methods available to assess nutrient intake including a 24-hour diet recall and a food frequency questionnaire. The adequacy of the diet should be evaluated, usually by comparing nutrient intake with estimated energy and protein requirements adjusted for disease state, if necessary.

Physical Examination Along with a medical and nutrition history, a physical examination is an essential component of a comprehensive nutrition assessment. A physical examination consists of observing physical signs or symptoms that may be associated with nutritional deficiencies (Tables 8.3 and 8.4). The appearance of symptoms of a nutritional deficiency depends upon the specific nutrient in question. However, single nutrient deficiencies are rare. An individual with symptoms of a single nutrient deficiency is likely to have multiple deficiencies. Some fat soluble vitamins and minerals have body stores which require long periods, up to a year or longer, to become depleted. 36 Conversely, some of the water soluble vitamins have more labile body pools which result in physical manifestations of deficiencies after a much shorter period, less than one month in some cases.37 Recognizing signs of nutritional deficiencies requires experience and skill because the symptoms can vary in time of appearance and severity, and interpretation of these symptoms can be affected by examiner and subject bias. Since most symptoms are non-specific and the criteria are not well-defined, there may be a lack of consistency between observers.

Clinical Anthropometry and Body Composition Analysis Anthropometry is the science in which the body is described by a series of measurements of the external morphology. Anthropometry is used to assess nutritional

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Table 8.2.

8

Medical and nutrition history

Medical History * Medication profile * Diagnostic procedures * Chronic illnesses * Surgical procedures * Weight history Nutrition History * Nausea/vomiting * Anorexia * Early satiety * Dysgeusia * Psychosocial history * Previous dietary modifications and compliance * Living conditions * Ability to purchase and prepare food * Food preferences * Food allergies * Use of vitamin/mineral supplements * Alcohol intake * Elimination habits * Activity level * Cultural/religious observances

status and monitor the efficacy of therapy. Height, weight, skinfold and circumference measurements are the most common anthropometric measurements used in the clinical setting.

Height Height (stature) can be obtained via recall from the patient of from the medical archives but should be measured if possible because it is often misreported.38 Accurate assessment of stature is important because it is compared to weight to determine degree of adiposity and used in formulas to estimate energy and protein requirements and to calculate creatinine height index and body mass index. There are several methods available to measure height in nonambulatory patients.39, 40

Frame Size Frame size is useful in assessing body weight because it can affect weight independent of stature and percent body fat. Frame size includes body width, muscularity, bone thickness, and truncal length relative to weight.41 There are several techniques to estimate frame size including measurements of wrist circumference and elbow breadth42-44 although no consensus has been reached regarding the ideal method.

Weight Weight can be used a gross estimate of muscle and adipose tissue stores. This relationship is more meaningful when weight is corrected for height and frame size. Serial measurements are also useful in monitoring the efficacy of nutrition therapy. However, weight must be interpreted with caution since it may not accurately reflect an individual’s body composition due to altered fluid status or tumor growth. Weight is generally interpreted based on comparison with two parameters:

Biochemical Assessment and Monitoring of Nutritional Status

Table 8.3.

Organ function alteration secondary to nutrient deficiencies

Cardiovascular

Cutaneous Gastrointestinal

Hepatic

Pulmonary

Renal

129

Decreased RBC production Decreased blood volume Decreased cardiac output, stroke volume, and contractility Decreased blood pressure Decreased heart muscle mass Decreased venous return Bradycardia Postural hypotension Hemodilution Anemia Cheilosis, glossitis, ecchymosis, dermatosis, follicular hyperkeratosis, petechiae Decreased brush border enzymes Maldigestion and malabsorption Decreased mucosal cell integrity Decreased bile production Intestinal villus atrophy Decreased liver weight Decreased visceral protein synthesis Hepatic insufficiency Fatty infiltration Respiratory infections Decreased functional, vital and maximum breathing capacities Decreased response to hypoxia Decreased plasma flow Reduced glomerular filtration rate Decreased tubular function Polyuria Metabolic acidosis

Summarized from: Keys, A. Biology of Human Starvation and Torum B and Viteri FE: Protein-calorie malnutrition. In: Shils M and Young V (eds). Modern Nutrition in Health and Disease. Lea and Fibiger, 1988;746-773, and Baker JP, Detsky AS, Wesson DE et al, N Engl J Med 1982;306(16):969.

1. The individual’s usual or pre-morbid weight; and, 2. Ideal or desirable weight of a healthy population (Table 8.5). The use of the term “ideal” or “Adesirable” in reference to weight is misleading because there is no consensus regarding what set of values are truly ideal and these values may change according to the population under study. In clinical practice, ideal body weight is usually based on a set of established standards such as the Metropolitan Life Insurance Company Height-Weight Tables47 or calculated using the following formula:47 Males: allow 106 pounds for the first five feet of height and six pounds for every additional inch Females: allow 100 pounds for the first five feet of height and five pounds for every additional inch Ideal body weight should be adjusted for frame size by adding 10% for a large frame and subtracting 10% for a small frame. Ideal body weight should also be

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Table 8.4. Body Part or System Hair

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Physical signs of malnutrition Symptoms/Signs

Lackluster, thinness, sparseness, dryness, dyspigmentation, easy pluckability, texture change Face Paleness, moon face (swollen), greasy, scaling around nostrils (nasolabial seborrhea) Eyes Pale whites of eyes and eyelid lining (pale conjuctivae), redness and fissuring of eyelid corners, dullness and dryness (corneal or conjuctivae (Bitot’s spots) Mouth Angular redness, lesions or scars at corners of mouth (stomatitis), swelling and redness of lips and mouth (cheilosis) Tongue Smoothness, slickness (filiform papillary atrophy), beefiness, redness, pain (glossitis), swollen, magenta color Gums Swelling, sponginess, bleeding, receding Skin Dryness;scaling;lightening of skin color often centrally on the face (diffuse pigmentation); rough, “goose-flesh” skin (follicular hyperkeratosis); small skin hemmorrhages (petechiae); excessive bruising; hyperpigmented patches that may peel off, leaving superficial ulcers of hypopigmented skin (flaky paint dermatosis); edema, delayed wound healing Nails Spoon-shape (koilonychia), pale, brittle, ridged Glands Enlarged thyroid or parotid MusculoBowlegs, knock knees, enlarged skeletal joints, hemorrhages, muscle and fat wasting Neurological Mental confusion, irritability, psychomotor changes, motor weakness, sensory loss

Possible Deficiency Protein, protein-calorie, zinc, copper, biotin Riboflavin,niacin,pyridoxine, iron Iron, vitamins A, C, and B12, riboflavin,pyridoxine, folate

Riboflavin,niacin,pyridoxine, iron

Niacin, pyridoxine,riboflavin, vitamin B12, folate, iron

Vitamin C Vitamins A, C, and K, zinc, essential fatty acids, protein.

Iron Protein, iodine Protein-calorie, vitamins C and D, calcium Thiamin, vitamin B12

Nutrition Assessment. In: Manual of Clinical Dietetics, American Dietetic Association, 1992:3-30.

adjusted for persons with amputations by subtracting the weight of the missing body part as a percentage of the total weight.48 Weight loss over time is another useful tool in assessing nutritional status because it reflects gross changes in energy and nitrogen balance and has a prognostic

Biochemical Assessment and Monitoring of Nutritional Status

Table 8.5.

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Evaluation of weight

A. Percent usual body weight Formula: Percent usual body weight = actual body weight x 100 usual body weight Interpretation: 45 85-90% Mild nutritional depletion 75-84% Moderate nutritional depletion < 75% Severe nutritional depletion B. Percent ideal body weight Formula: Percent ideal body weight = actual body weight x 100 ideal body weight Interpretation:45 200% Morbidly obese 130% Obese 110-120% Overweight 80-90% Mild malnutrition 70-79% Moderate malnutrition 69% Severe malnutrition

value. An unintentional weight loss of 10% or greater within a period of six months or less is considered severe.49 Percent weight loss can be determined using the following formula: Percent weight loss = usual body weight—actual body weight x 100 usual body weight

Skinfold and Circumference Measurements Skinfold and circumference measurements are indirect methods of estimating body composition. These measurements are commonly used in the clinical setting because they are simple, noninvasive, inexpensive, and require limited technical skill from the observer or cooperation from the patient. Skinfold measurements provide a gross estimate of body fat. The triceps skinfold (TSF) is the most common site measured in the clinical setting. Circumference measurements are used in estimating somatic protein stores. Results are compared to sex and age standards, usually based on data from the National Health and Nutrition Examination Survey. Results between the 15th and 85th percentiles are considered within the normal range. Patients with measurements below the 15th percentile are at risk for nutritional depletion and above the 85th percentile are at risk for obesity.43 Alternatively, skinfolds can be compared with standards based on average measurements for age and sex. A measurement 60-90% of the standard is considered a moderate nutritional deficit while less than 60% is considered severe.45 Anthropometry is specific but lacks sensitivity since skinfold and circumference measurements change more slowly than other nutritional indices, making it difficult to detect short term changes.

Body Mass Index Body mass index (BMI) is a method of evaluating body weight corrected for height based on the assumption that it is correlated to degree of adiposity and corresponding health risks associated with obesity50, 51 (Table 8.6). The higher the BMI, the greater the degree of body fat as a percentage of body weight.53 BMI is not valid in extremely muscular individuals or in cases in which weight is altered by fluid status or pregnancy.

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Table 8.6.

Body mass index (BMI)

Formula:

BMI = weight (kg) height2 (m)

Interpretation:50,52 Lean Normal Excess weight Obese

Males <18.5 18.5 - 23.5 >23.5 - 29.5 >29.5

Females <19.5 19.5 - 24.5 >24.5 - 29.5 > 29.5

Direct Measurements of Body Composition

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Body composition can be measured directly by a variety of methods such as neutron activation and whole body conductivity but these tests usually require expensive equipment that is not widely available. These methods can be extremely accurate compared with more traditional techniques of assessing body composition in the clinical setting such as anthropometry. However, many of these methods have been tested only in healthy individuals and their applicability to an ill population remains in question. Radiographic techniques including ultrasound, computed tomography and magnetic resonance imaging have also been use to study body composition 54,55 and can provide cross-sectional images which clearly define muscle, fat, and visceral organs. Since the images are cross-sections, these techniques are more useful in determining regional fat distribution than overall body composition Dual energy x-ray absorptiometry (DEXA) is emerging as an important technology in the area of nutrition support and body composition analysis. It uses a low-energy x-ray tube coupled to a filter that results in two energies of about 40 and 70 keV. DEXA provides independent assessments of bone mass, fat mass, and lean body mass.57

Biochemical Assessment and Monitoring of Nutritional Status Creatinine Height Index (CHI) Somatic protein stores can be estimated based on the amount of creatinine excreted in the urine over a 24-hour period since creatinine is a byproduct of protein metabolism and is excreted proportional to muscle mass. The actual amount of creatinine excreted is compared to the amount of creatinine expected for sex and height (Table 8.7). One method to determine expected creatinine is to use 23 mg/ kg for males and 18 mg/kg for females. There are several limitations of CHI which prohibit its widespread use as a nutrition assessment tool. CHI requires an accurate urine collection and can be affected by a number of non-nutritional factors such as emotional stress, fever, and trauma.

Urinary 3-Methylhistidine Measuring urinary 3-methylhistidine (3MH) is another biochemical method of estimating somatic protein stores since 3MH is a nonrecyclable component of muscle breakdown and excreted proportional to muscle mass. Similar to CHI, a valid test requires adequate renal function and an accurate urine collection. Urinary 3MH is not commonly used in clinical practice because it requires an amino acid analyzer which is not widely available and no universally accepted standards exist for interpreting the results.

Biochemical Assessment and Monitoring of Nutritional Status

Table 8.7. Formula: Interpretation: 49

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Creatinine height index (CHI) % CHI = 24 hr urinary creatinine ideal urinary creatinine 90-100% Normal 60-80% Moderate malnutrition < 60% Severe malnutrition

Serum Proteins Nutrition assessment parameters may be classified into “somatic” and “visceral” compartments of the body. The somatic portion comprises primarily skeletal muscle and adipose tissue; whereas, the visceral portion refers to the enzymatic and structural components of the remaining organ systems. Serum proteins such as albumin, transferrin, prealbumin, and retinol binding protein, are commonly used to assess the visceral protein compartment of the body, and recently other proteins such as fibronectin and somatomedin-C have been studied in this capacity. Normal values may vary slightly among laboratories but the results can help assess the degree of malnutrition (Table 8.8). Albumin Serum albumin, produced by the liver, is the most abundant plasma protein, representing approximately 60% of total body proteins. Albumin is necessary for maintenance of oncotic pressure and functions as a carrier protein for zinc, magnesium, calcium, fatty acids and many drugs. Due to its large body pool and relatively long half-life of 20 days, albumin is insensitive to acute changes in nutritional status and is more reflective of chronic rather than acute protein depletion. Serum albumin concentration is commonly used as a screening indicator of nutritional status in hospitalized patients since its measurement is routinely ordered, and it has been shown to correlate with clinical outcome.58,59 Caution should be exercised when evaluating albumin levels in stressed hospitalized patients because serum concentrations of albumin and other acute phase proteins will decrease after trauma, surgery, or stress, primarily due to a redistribution of albumin into extravascular compartments and through external losses of albumin as in ascites, draining wounds, and burns. It is sometimes difficult to determine whether a reduction in a patient’s serum albumin reflects protein-calorie malnutrition or the metabolic response to trauma and stress. Plasma albumin levels will generally not increase in stressed patients until the cause of the stress is removed. Other non-nutritional causes of hypoalbuminemia include fluid overload, liver disease, infection, multiple myeloma, acute or chronic inflammation, hypervitaminosis A, and rheumatoid arthritis. Increased losses of albumin are seen in nephrotic syndrome, protein-losing enteropathy, burns, and open wounds.64 Exogenous albumin is sometimes used in critically ill patients to maintain fluid within the vascular space. This results in a transient increase in the serum albumin level, thereby limiting the use of serum albumin as a nutritional marker. Transferrin Transferrin is a beta globulin synthesized in the liver. Transferrin functions to transport iron and prevents binding of gram negative bacteria with free iron. The half-life of transferrin ranges from eight to ten days. Serum transferrin is thought to

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Table 8.8.

The Biology and Practice of Current Nutritional Support

Standards for laboratory studies 57

Albumin (g/dL) Transferrin (g/dL) Prealbumin (g/dL)

Normal 3.5-5.0 176-315 18-45

Mildly Depleted 3.0-3.4 134-175 10-17

Moderately Depleted 2.1-2.9 117-133 5-9

Severely Depleted < 2.1 <117 <5

be a more sensitive indicator of acute changes in nutritional status compared with albumin due to its shorter half-life and more rapid equilibration with the extravascular compartment. Non-nutritional factors that can affect serum transferrin include pregnancy, iron deficiency anemia, blood transfusions, acute hepatitis, and oral contraceptives.42 Transferrin appears to be as effective as other visceral proteins with shorter half-lives in assessing nutritional status. Levels of serum transferrin can be obtained directly by radial immunodiffusion, or indirectly by measurement of total iron-binding capacity as suggested by the following formula: serum transferrin level = (0.8 x TIBC) - 43

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Thyroxine-Binding Prealbumin As a plasma transport protein, thyroxine-binding prealbumin (TBPA) carries thyroxine and assists in the transport of retinol-binding protein (RBP). With a half-life of 2.5 to 3.0 days, prealbumin responds rapidly to protein deprivation and rises quickly with resumption of adequate intake. Since TBPA is synthesized in the liver and degraded in the kidney, it is not valid in patients with severe hepatic or renal insufficiency. Retinol-Binding Protein (RBP) Retinol-binding protein (RBP) is another plasma protein synthesized in the liver and used as an indicator of visceral protein status. In addition to TBPA, RBP functions to transport retinol, the alcohol form of vitamin A. With a half-life of 12 hours, RBP reflects acute changes in nutritional status. Plasma RBP is very sensitive to calorie and protein restriction, however, measurement of RBP is reserved for research purposes because it is difficult to obtain and is not practical for routine clinical use. Fibronectin (Fn) Fibronectin (Fn) is a glycoprotein which functions in cell-to-cell adherence, cell and tissue differentiation, wound healing, microvascular integrity, and the opsonization of particulate. Endothelial cells, peritoneal macrophage, hepatocytes, and fibroblasts are considered sites for synthesis of Fn. The half-life of Fn is 12 hours. Fn is considered a sensitive indicator of nutrition support and a potential marker of visceral protein status because it increases regardless of the presence or absence of inflammation. Fibronectin concentrations decline during starvation and increase in response to refeeding in healthy subjects and hospitalized subjects receiving nutrition support.61,62 Somatomedin-C Somatomedin-C (SM-C), also called insulin-like growth factor-I (IGF-I), is a peptide growth factor synthesized in the liver. SM-C is postulated to mediate the growth promoting effects of growth hormone. Normal plasma concentrations of

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SM-C range from 1.0 to 1.7 U/mL. SM-C levels are low in chronically malnourished as well as acutely starved patients and rapidly rise with refeeding. 63-65 Although measurement of SM-C offers potential as a useful means of documenting the efficacy of nutrition therapy, laboratory testing of this peptide is not routinely available.

Immunocompetence Immunocompetence results from the interaction of three complex systems: 1. Cell-mediated immunity; 2. Humoral antibody response; and 3. Nonspecific immune response. Protein-calorie malnutrition can compromise immune function and is the most common cause of anergy in hospitalized patients.66,67 Nutrition intervention has been reported to reverse immunosuppression.68,69 Total Lymphocyte Count (TLC) The blood lymphocyte count has been recognized as one of the most simple and reliable immunologic measurements of nutritional status. With protein malnutrition, the TLC is reduced.70 A reduced TLC has been associated with increased morbidity and mortality in hospitalized patients.28,70,71 Preoperative lymphocytopenia has been identified as a risk factor in post-operative sepsis72 and septic episodes in thermally injured patients.71 Factors other than malnutrition may cause or contribute to lymphocytopenia including pneumonia, sepsis, administration of glucocorticosteroids and chemotherapeutic agents, as well as diseases of the immune system.60 TLC is obtained from a routine complete blood count with a differential using the following formula: TLC (mm3) = percent lymphocytes x white blood cell count 100 Delayed Cutaneous Hypersensitivity Skin Testing Delayed cutaneous hypersensitivity skin testing (DHST) is an inexpensive, convenient, and widely available measure of cell-mediated immunity. Testing involves an intradermal injection of an antigen to which the individual has been previously exposed. Antigens generally utilized include: purified protein derivative (PPD), trichophyton, candida albicans, and mumps. A positive reaction is considered an induration of 5 mm or greater at 24 to 72 hours post-injection. Anergy is the absence of a reaction to an antigen that normally would elicit a response. Immunocompetence is generally classified as anergy, relative anergy, or normal. Although higher rates of sepsis and mortality have been documented in anergic patients compared with patients with a normal skin test response,67,68 the utility of skin testing in nutrition assessment remains unproven.73 Many non-nutritional influences, such as administration technique, age of the patient, drugs, surgery, anesthesia, and presence of disease may affect DHST and must be considered when evaluating an individual’s response.73

Prognostic Indices Attempts to determine the value of various nutrition assessment parameters in predicting clinical outcome has led to the development of prognostic indices. The prognostic nutrition index (PNI) is a linear predictive model that relates the risk of operative morbidity and mortality to nutrition status (Table 8.9).23 The risk of complications and death increase with increasing PNI. The PNI model has been validated in

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surgical patients; however, clinical usefulness in other patient groups is limited. The Hospital Prognostic Index (HPI)74 and Nutritional Risk Index (NRI)75 are other prognostic indices.

Assessment of Energy Requirements Energy requirements are based on the age, sex, body build, activity level, and disease state of an individual. Basal energy expenditure (BEE) is the energy required to perform essential body functions such as respiration, cardiac function, and maintenance of body temperature. Resting energy expenditure (REE) is defined as the energy expended at rest in a supine position and included physical and psychological stress, and variations in ambient or body temperature. Measured REE is approximately 10% higher than BEE. Total energy expenditure (TEE) is comprised of REE, diet-induced thermogenesis, shivering and non shivering thermogenesis, and physical activity. REE represents the major portion (i.e., 75-100%) of TEE in hospitalized patients. Energy needs may be assessed by direct and indirect calorimetry or through use of predictive equations and nomograms.

Calorimetry

8

Direct calorimetry is the process of measuring heat production as the temperature change of a medium (e.g., water) and is reserved for research purposes because it is expensive and time-consuming. Indirect calorimetry is the determination of energy requirements by measuring oxygen consumption and carbon dioxide production during respiratory gas exchange. Indirect calorimetry provides the clinician with a measurement of energy expenditure and an assessment of substrate utilization in the respiratory quotient (RQ). In hospitalized patients, REE is usually derived from a 20 minute gas exchange measurement. Measurement of REE should be done more than two hours post prandially in a thermoneutral environment. The thermic effect of continuous enteral or parenteral nutrition is stable but should be considered in interpreting the test. Measurements of O2 consumption and CO2 production are translated into REE by the Weir formula.76 To account for other activities during the day such as sitting in a chair, dressing changes, physical therapy, and diurnal variations, REE is multiplied by 1.1 to 1.3 to determine TEE.77 The RQ is the ratio of carbon dioxide produced to oxygen consumed (VCO2/ VO2). The physiologic range for RQ is 0.67 to 1.30 (Table 8.10).78 Possible causes for an RQ less than 0.71 include oxidation of ethanol or ketone bodies, lipolysis, underfeeding, and hypoventilation. Reasons for an RQ greater than 1.0 include hyperventilation, excess CO2 production, hydrogen ion buffering by bicarbonate generating carbon dioxide, lipogenesis, and overfeeding. If the RQ is equal to or greater than 1.0, the total calories and/or carbohydrate should be decreased. If the RQ is less than 0.8, total calories should be increased.

Predictive Equations Over 190 equations to predict energy expenditure exist based on some combination of height, weight, age, and sex.79 The Harris-Benedict equation 80 is frequently used in clinical practice to estimate basal energy requirements (Table 8.11). The Harris-Benedict is more reflective of REE than BEE and is usually multiplied by activity and injury factors to determine TEE. The advantage of predictive equations is that they are quick and easy to use without the need of expensive equipment. However, they offer an estimate rather than a measurement of energy needs and can be affected by the weight used in the calculation. Current or dry body weight should

Biochemical Assessment and Monitoring of Nutritional Status

Table 8.9. Formula:

Interpretation

137

Prognostic nutritional index (PNI) PNI % = 158 - 16.6 (ALB) - 0.78 (TSF) - 0.20 (TFN) - 5.8 (DH) where ALB = serum albumin (g/dL) TSF = triceps skinfold (mm) TFN = serum transferrin (mg/dL) DH = cutaneous delayed hypersensitivity reactivity to any of the four recall antigens graded as 0 (nonreactive), 1 (< 5 mm induration), or 2 (> 5 mm induration). > 50 % = high risk 40 - 49 % = intermediate risk <40% = low risk

Table 8.10. Respiratory quotient (RQ) Substrate Alcohol Fat Protein Mixed Carbohydrate

RQ 0.67 0.71 0.82 0.85 1.00

be used unless the patient is considered obese (i.e., BMI 30 to 50). In obese patients, an adjusted body weight (AdjBW) should be used in calculating energy expenditure using the following formula:82 AdjBW = [ (actual body weight—ideal body weight) 0.5] + ideal body weight REE can also be estimated in patients with a pulmonary artery catheter by using the Fick equation and the known caloric value of oxygen.83 This requires the measurement of cardiac output and arterial and mixed venous oxygen (Table 8.12). The Fick equation has been correlated with indirect calorimetry83 but requires an accurate measurement of cardiac output and oxygen saturation and only provides a “snapshot” of energy expenditure at the moment the blood samples were drawn.

Assessment of Protein Requirements Predictive Equations There are several methods to estimate protein requirements. The requirement for protein can be viewed as it relates to calorie needs. The nonprotein calorie to nitrogen ratio (NPC:N) refers to the amount of nonprotein calories per gram of nitrogen. In a typical oral diet, the NPC:N is 300:1. The greater the stress, the higher the requirement for protein. Patients receiving parenteral nutrition may require 80 to 150 NPC/g N for tissue synthesis.78 Protein may also be administered based on body weight and stress level (Table 8.13).42 Adjustments in protein load should be made according to the patient’s clinical response, and through monitoring laboratory and nitrogen balance techniques.

Nitrogen Balance Nitrogen balance studies are utilized to assess protein requirements, stress level, and efficacy of nutrition support therapy. Nitrogen lost in the urine measured from

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Table 8.11. Estimating energy requirements Basal Energy Expenditure (BEE) Harris-Benedict Equation: 80 Men BEE (kcals/d) = 66.47 + (13.75 x W) + (5.0 x H) - (6.76 x A) Women BEE (kcals/d) = 655.10 + (9.56 x W) + (1.75 x H) - (4.68 x A) where W = weight in kg H = height in cm A = age in years Activity and Injury Factors 81 Activity Factor: Confined to bed 1.2 Out of bed 1.3 Injury Factor: Minor surgery 1.2 Skeletal trauma 1.3 Major sepsis 1.6 Severe burns 2.1

8

a 24 hour urine urea nitrogen (UUN) is added to an estimate of nitrogen lost from the skin, hair, nails, and GI tract and subtracted from nitrogen intake using the following formula: Nitrogen balance = Protein intake (g) (UUN + 2 to 4) 6.25 Additional nitrogen losses from draining wounds or burns must also be measured or estimated. The goal of nitrogen balance is to be positive 2 to 4 g/d which is indicative of an anabolic state and suggests accumulation of lean body mass (LBM). However, this may be difficult to obtain in the critically ill patient. In these patients it may be more realistic to strive for neutral balance or equilibrium which implies adequate energy and protein support for preservation of LBM. A negative nitrogen balance suggests a state of catabolism with progressive loss of LBM. Losses of 5 to 10 g/d have been suggestive of mild catabolism, 10 to 15 g/d of moderate catabolism, and more than 15 g/d of severe catabolism.84 Determination of a valid nitrogen balance is dependent primarily on an accurate urine collection and stable renal function.

Urea Kinetic Modeling Urea kinetics is a pharmacokinetic model initially developed for use in hemodialysis patients to assess protein balance and is based on the premise that the patient’s protein catabolic rate is directly proportional to the rate of urea nitrogen generation.85 Unlike the traditional nitrogen balance study in which urea measurements become less accurate under conditions of renal insufficiency and changes in urea pool, urea kinetic modeling accounts for the changing urea pool and allows for changes in BUN and extrarenal losses or urea.

Urinary Nitrogen Appearance Urinary nitrogen appearance (UNA) attempts to quantify changes in BUN and is useful in clinical situations in which increased BUN levels and variations in weight secondary to renal function exist.86 This formula is applicable to measurements done over one to three days and in dialysis patients during interdialytic interval. In stable patients nitrogen balance may be estimated from the difference between nitrogen

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Table 8.12. Fick equation CO = Hgb (SaO2 - SvO2) x 95.18 where CO = cardiac output (L/min) Hgb = hemoglobin SaO2 = arterial oxygen saturation SvO2 = mixed venous oxygen saturation

Table 8.13. Estimating protein requirements No stress Mild stress Moderate stress Severe stress

0.7 to 0.8 g/kg/d 0.8 to 1.0 g/kg/d 1.0 to 1.5 g/kg/d 1.5 to 2.0 g/kg/d

intake and UNA. UNA is not an accurate reflection of total nitrogen output in patients on peritoneal dialysis due to protein lost in the dialysate.

Determining an Endpoint of Nutrition Therapy The purpose of the nutrition assessment is two-fold: 1. To determine the degree and type of malnutrition, and 2. To document the efficacy of therapy. In resolving nutritional deficiencies, it is important to ensure that nutrients are delivered safely and accurately in the amounts prescribed to meet the patient’s requirements. This type of monitoring becomes integrated into the comprehensive nutrition assessment. The amount of time required to improve nutritional status will depend on the degree and type of malnutrition, surgical risk, medical treatments and overall clinical course. The follow-up assessment should occur at regular intervals (Fig. 8.3). The frequency will depend on the depth of the assessment. For example, a daily assessment of fluid and electrolyte status may be necessary for the patient receiving parenteral nutrition; whereas an assessment of visceral protein status or lean muscle mass may occur less frequently. Monitoring the results of nutrition support requires the use of many nutrition assessment parameters. The usefulness of each parameter will depend on the length of time the patient is on nutrition support, the disease process and prior nutritional status. Body weight is measured to monitor fluid status and effectiveness of nutrition therapy. Although many patients gain weight during nutrition therapy, this weight gain generally represents an increase in body water and adipose tissue rather than lean body mass. Weight gain greater than a half pound per day probably represents fluid accumulation and not tissue synthesis. The composition of weight change can be estimated if a nitrogen balance study is available using the following formula: FFM = ( + g N balance x 6.25 g dry protein/g nitrogen) x 4.6 g FFM/g dry protein FM = ( + g body weight change) - ( + g FFM) where FFM = fat free mass FM = fat mass Α+@ = gain or loss of that compartment

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8

Fig. 8.1. Reassessment of Nutritional Status. Adapted from Matarese LE. Reassessment and determining an endpoint of therapy. Adapted from Dynamics of Nutrition Support. Appleton-Century-Crofts, 1986.

This is an estimate and will be influenced by fluid balance and accuracy of the nitrogen balance study. Anthropometric measurements, although very specific, lack the sensitivity to assess short-term changes in adipose tissue or lean body mass and are more useful for monitoring long-term patients. Energy and proteins requirements need to be reevaluated periodically to ensure the patient is receiving adequate nutrition. The patient’s energy expenditure may change during the course of nutrition therapy as clinical status changes. Protein requirements can be assessed by performing a nitrogen balance study. For those patients who do not have normal renal function, urea kinetics can be employed. Changes in visceral proteins depend on their half-life, and total body pool. Serum albumin, due to its relatively long half-life, may not return to normal levels until well after nutrition support has been discontinued. Transferrin and thyroxine-binding prealbumin are considered more sensitive nutritional markers since each has a shorter half-life and smaller body pool than albumin. Total

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lymphocyte count and delayed hypersensitivity skin testing has been correlated with morbidity and mortality but both can be affected by a number of non-nutritional factors. Mineral and electrolyte imbalances can occur rapidly, especially in critical ill patients receiving nonvolitional feeding. Clinical signs of vitamin and mineral deficiencies as well as biochemical aberrations will reverse with therapeutic doses of the limiting vitamin or mineral. However, the patient’s stores may take weeks to months to replenish. It is important to note that many patients will not return to “normal” or even premorbid nutritional status until well after discharge. Because nutrition assessment parameters are so nonspecific, one can not look for a single laboratory value or parameter to determine the endpoint of therapy. While all of the parameters must be evaluated within the context of the patient’s clinical condition, it is probably more useful to look for trends in improving nutritional status.

Selected References 1. 2. 3. 4. 5. 6. 7. 8. 9. 10. 11. 12. 13. 14. 15. 16.

Rhoads JE, Alexander CE. Nutritional problems of surgical patients. Ann NY Acad Sci 1955; 63:268-275. Butterworth CE. The skeleton in the hospital closet. Nutr Today 1974; 9:4-8. Bistrian BR, Blackburn GL, Hallowell E et al. Protein status of general surgical patients. JAMA 1974; 230:858-860. Bistrian BR, Blackburn GL, Vitale J et al. Prevalence of malnutrition in general medical patients. JAMA 1976; 235:1567-1570. Hill GL, Pickford I, Young GA et al. Malnutrition in surgical patients: An unrecognized problem. Lancet 1977; 1:689-692. Mullen JL, Gertner MH, Buzby GP et al. Implications of malnutrition in the surgical patient. Arch Surg 1979; 114:121-125. Weisner RL, Hunker EM, Krumdieck CL et al. Hospital malnutrition: A prospective evaluation of general medical patients during the course of hospitalization. Am J Clin Nutr 1979; 32:418-426. Willard Md, Gilsdorf RB, Price RA. Protein-calorie malnutrition in a community hospital. JAMA 1980; 243(17):1720-1722. Bastow MD, Rawlings J, Allison SP. Benefits of supplementary tube feeding after fractured neck of femur: A randomized controlled trial. Br Med J 1983; 287:1589-1592. Sullivan DH, Moriarty MS, Chernoff R et al. Patterns of care: An analysis of the quality of nutritional care routinely provided to elderly hospitalized veterans. JPEN 1989; 13:249-254. Coates KG, Morgan SL, Bartolucci AA et al. Hospital-associated malnutrition: A re-evaluation 12 years later. J Am Diet Assoc 1993; 93:27-33. Mosner M, Bader S. Rationale for nutrition support. In: Krey SH, Murray RL, eds. Dynamics of Nutrition Support. Norwalk: Appleton-Century-Crofts, 1986:3-15. Walesby RK, Goode AW, Spinks TJ et al. Nutritional status of patients requiring cardiac surgery. J Thorac Cardiovasc Surg 1979; 77:570-576. Weinsier RL, Heimburger DC, Samples CM et al. Cost containment: A contribution of aggressive nutritional support in burn patients (abstract). Am J Clin Nutr 1984;39:673. Christensen KS. Hospital-wide screening increases revenue under prospective payment system. J Am Diet Assoc 1986; 86:1234-1235. Epstein AM, Read JL, Hoefer M. The relation of body weight to length of stay and charges for hospital services for patients undergoing elective surgery: A study of two procedures. Am J Public Health 1987; 77:993-997.

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28. 29. 30. 31. 32. 33. 34. 35. 36. 37. 38. 39. 40. 41. 42.

Reilly JJ, Hull SF, Albert N et al. Economic impact of malnutrition: A model system for hospitalized patients. JPEN 1988; 12:371-376. Dickhaut SC, DeLee JC, Page CP. Nutritional status: Importance in predicting wound-healing after amputation. J Bone Joint Surg 1974; 66-A:71-75. Haydock DA, Hill GL. Impaired wound healing in surgical patients with varying degrees of malnutrition JPEN 1986; 10:550-554. Kay SP, Moreland JR, Schmitter E. Nutritional status and wound healing in lower extremity amputations. Clin Orthop 1987; 217:253-256. Myers SA, Takiguchi S, Slavish S et al. Consistent wound care and nutritional support in treatment. Decubitis 1990; 3(3):16-28. Studley HO. Percentage of weight loss: A basic indicator of surgical risk in patients with chronic peptic ulcer. JAMA 1936; 106:458-460. Cannon PR, Wissler RW, Woolridge RL et al. The relationship of protein deficiency to surgical infection. Ann Surg 1944; 120:514-525. Buzby GP, Mullen JL, Matthews DC et al. Prognostic nutritional index in gastrointestinal surgery. Am J Surg 1980;139:160-167. Hickman DM, Miller RA, Rombeau JL et al. Serum albumin and body weight as predictors of postoperative course in colorectal cancer. JPEN 1980; 4:314-316. Klidjian AM, Archer TJ, Foster KJ et al. Detection of dangerous malnutrition. JPEN 1982;6:119-121. Pinchcofsky-Devin GD, Kaminski MV. Correlation of pressure sores and nutritional status. J Am Geriatr Soc 1986; 34:435-440. Seltzer MH, Bastidas JA, Cooper DM et al. Instant nutritional assissment. JPEN 1979; 3:157-159. Seltzer MH, Fletcher HS, Slocum BA et al. Instant nutritional assessment in the intensive care unit. JPEN 1981; 5(1):70-72. Seltzer MH, Slocum BA, Cataldi-Betcher EL et al. Instant nutritional assessment: Absolute weight loss and surgical mortality. JPEN 1982; 6:218-221. Meguid MM, Mughal MM, Debonis D et al. Influence of nutritional status on the resumption of adequate food intake in patients recovering from colorectal cancer operations. Surg Clin North Am 1986; 66:1167-1176. Mughal MM, Meguid MM. The effect of nutritional status on morbidity after elective surgery for benign gastrointestinal disease. JPEN 1987; 11:140-143. Christensen KS, Gstundtner KM. Hospital-wide screening improves basis for nutrition intervention. J Am Diet Assoc 1985; 85:704-706. Riffer J. Malnourished patients feed rising costs: Study. Hospitals 1986; March 5:86. Robinson G, Goldstein M, Levine GM. Impact of nutritional status on DRG length of stay. JPEN 1987; 11:49-51. Sauberlich HE, Hodges RE, Wallace DL et al. Bitamin A metabolism and requirements in the human studied with the use of labeled retinol. Vit Hormones 1974; 32:251-275. Sauberlich HE, Kretsch MJ, Taylor PC et al. Ascorbic acid and erythorbic acid metabolism in nonpregnant women. Am J Clin Nutr 1989; 50:1039-1049. Rowland ML. Self-reported weight and height. Am J Clin Nutr 1990; 52:1125-1133. Dequeker JV, Baeyens JP, Claessens J. The significance of stature as a clinical measurement in ageing. J Am Geriatr Soc 1969; 17:169-179. Chumlea WC, Roche AF, Steinbaugh ML. Estimating stature from knee height for persons 60 to 90 years of age. J Am Geriatr Soc 1985; 33:116-120. Frisancho AR, Flegel PN. Elbow breadth as a measure of frame size for U.S. males and females. Am J Clin Nutr 1983; 37:311-314. Grant JP. Handbook of Total parenteral nutrition. 2nd ed. Philadelphia: W.B. Saunders Co., 1992.

Biochemical Assessment and Monitoring of Nutritional Status 43. 44. 45. 46. 47. 48. 49. 50. 51. 52. 53. 54. 55. 56. 57. 58. 59. 60. 61. 62. 63. 64. 65. 66.

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Frisancho AR. New standards of weight and body composition by frame size and height for assessment of nutritional status of adults and the elderly. Am J Clin Nutr 1984; 40:808-819. Nowak RK, Schulz LO. A comparison of two methods for the determination of body frame size. J Am Dietet Assoc 1987; 87:339-341. Hopkins B. Assessment of Nutritional Status. In: Gottschlich MM, Matarese LE, Shronts EP, eds. Nutrition Support Dietetics Core Curriculum. ASPEN, 1993:15-70. Build Study, 1979. Society of Actuaries and Association of Life Insurance Medical Directors of America. Philadelphia, Recording and Statistical Corporation, 1980. Hamwi GJ. Changing Dietary Concepts. In: Dankowski TS, ed. Diabetes Mellitus: Diagnosis and Treatment. American Diabetes Association: New York: 1964:73-78. Brunnstrom S. Clinical Kinesiology, 2nd ed. Philadelphia: FA Davis, 1966. Blackburn GL, Bistrian BR, Maini BS et al. Nutritional and metabolic assessment of the hospitalized patient. JPEN 1977; 1:11-22. Roche AF, Siervogel RM, Chumlea WC et al. Grading body fatness from limited anthropometric data. Am J Clin Nutr 1981; 34:2831-2838. Garrow JS, Webster J. Quetlet’s index (W/H2) as a measure of fatness. Int J Obesity 1985; 9:147-153. Bray GA. Definition, measurement, and classification of the syndromes of obesity. Int J Obesity 1978; 2:99-112. Cronk CE, Roche AF. Race- and sex-specific reference data for triceps and subscapular skinfolds and weight/stature2. Am J Clin Nutr 1982; 35:347-354. Heymsfield SB, Olafson RP, Kutner MH et al. A radiographic method of quantifying protein-calorie undernutrition. Am J Clin Nutr 1979; 32:693-702. Lewis DS, Rollwitz WL, Bertrand HA et al. Use of NMR for measurement of total body water and estimation of body fat. J Appl Physiol 1986; 60:836-840. Heymsfield SB, Wang J, Heshka S et al. Dual-photon absorptiometry: Comparison of bone mineral and soft tissue mass measurements in vivo with established methods. Am J Clin Nutr 1988; 49:1283-1289. Matarese LE, ed. The Cleveland Clinic Foundation Nutrition Support Handbook. 1997:21. Reinhardt GF, Myscofski JW, Wilkens DB et al. Incidence and mortality of hypoalbuminemic patients in hospitalized veterans. JPEN 1980; 4:357-359. Tayek JA. Albumin synthesis and nutritional assessment. NCP 1988; 3:219-221. Stone Williams C. Laboratory values and their interpretation. In: Krey SH, Murray RL, eds. Dynamics of Nutrition. Support. Norwalk: Appleton-Century-Crofts, 1986:83-97. Buonpane EA, Brown RO, Boncher BA et al. Use of fibronectin and somatomedin-C as nutritional markers in the enteral nutrition support of traumatized patients. Crit Car Med 1989; 17:126-132. Kirby DF, Marder RJ, Craig RM et al. The clinical evaluation of plasma fibronectin as a marker for nutritional depletion and repletion and as a measure of nitrogen balance. JPEN 1985; 9:705-708. Minuto F, Barreca A, Adami GF et al. Insulin-like growth factor-I in human malnutrition: Relationship with some body composition and nutritional parameters. JPEN 1989; 13:392-396. Unterman TG, Vazguez RM, Slas AJ et al. Nutrition and somatomedin. Usefulness of Somatomedin-C in nutritional assessment. Am J Med 1985; 78:228-234. Clemmons DR, Klibanski A, Underwood LE et al. Reduction of plasma immunoreactive somatomedin-C during fasting un humans. J Clin Endocrinol Metab 1981; 53:1247-1250. Bistrian BR. Nutritional assessment and therapy of protein-calorie malnutrition in the hospital. J Am Diet Assoc 1977; 71:393-397.

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76.

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77. 78. 79. 80. 81. 82. 83. 84. 85. 86.

MacLean L. Host resistance in surgical patients. J Trauma 1979; 19:296-304. Meakins JL, Pietsch JB, Bubenick O et al. Delayed hypersensitivity: Indicator of acquried failure of host defenses in sepsis and trauma. Ann Surg 1977; 186:241-250. Law DK, Dudrick SJ, Abdou NI. Immunocompetence of patients with protein-calorie malnutrition. The effects of nutritional repletion. Ann Int Med 1973; 79:545-550. Bistrian BR, Blackburn GL, Scrimshaw NS et al. Cellular immunity in semi-starved states in hospitalized adults. Am J Clin Nutr 1975; 28:1148-1155. Morath MA, Miller SF, Finley RF. Nutritional indicators of postburn bacteremic sepsis. JPEN 1981; 5:488-491. Lewis RT, Klein H. Risk factors in postoperative sepsis: Significance of preoperative lymphocytopenia. J Surg Res 1975; 26:365-371. Twomey P, Ziegler D, Rombeau J. Utility of skin testing in nutritional assessment: A critical review. JPEN 1982; 6:50-58. Harvey KB, Moldawer LL, Bistrian B et al. Biological measures for the formulation of a hospital prognostic index. Am J Clin Nutr 1981; 34:2013-2022. Buzby GP, Williford WO, Peterson OL et al. A randomized clinical trial of total parenteral nutrition in malnourished surgical patients: The rationale and impact of previous clinical trials and pilot study on protocol design. Am J Clin Nutr 1988; 47:357-365. DeWeir J. New methods for calculating metabolic rate with special reference to protein metabolism. J Physiol 1949; 109:1-9. Goran MI, Peters EJ, Herndon DN et al. Total energy expenditure in burned children using the doubly labeled water technique. Am Physiol Society 1990; 259:E576-585. Cerra FB, Shronts EP, Raup FD et al. Enteral nutrition in hypermetabolic surgical patients. Crit Care Med 1989; 17:619-622. Foster GD, Know LS, Dempsey DT et al. Caloric requirements in total parenteral nutrition. J Am Col Nutr 1987; 6:231-253. Harris JA, Benedict FG. A biometric study of basas metabolism in man. Washington, DC: Carnegie Institute, 1919. Publication No. 179. Long CL, Schaffel N, Geiger JW et al. Metabolic response to injury and illness: Estimation of energy and protein needs from indirect calorimetry and nitrogen balance. JPEN 1979; 3:452-456. Glynn CC, Greene GW, Winkler MF et al. Predicted versus measured energy expenditure using limits of agreement analysis in hospitalized obese patients. JPEN 1999; 23:147-154. Liggett SB, St. John RE, Lefrak SS. Determination of resting energy expenditure utilizing the thermodilution pulmonary artery catheter. Chest 1987; 91:562-566. Rutten P, Blackburn GL, Flatt JP et al. Determination of optimal hyperalimentation infusion rate. J Surg Research 1975; 18:477-483. Murray RL. Protein and energy requirements. In: Krey SH, Murray RL, eds. Dynamics of Nutrition Support. Norwalk: Appleton-Century-Crofts, 1986:188-192. Renal Failure. In: Bernard MA, Jacobs DO, Rombeau JR, eds. Nutritional and Metabolic Support of Hospitalized Patients. Philadelphia: W.B. Saunders Co, 1986:233.

CHAPTER 1 CHAPTER 9

Optimizing Drug Therapy and Enteral Nutrition: Detecting Drug-Nutrient Interactions Marcia L. Brackbill, Gretchen M. Brophy

Introduction Recent clinical studies in surgical, trauma, and burn patients have demonstrated the benefits of early initiation of enteral feedings over delayed enteral nutrition or total parenteral nutrition (TPN).1-7 Benefits include preservation of gut mucosa, reduction of bacterial translocation, enhancement of immune function, improved control of hypercatabolic state, reduction of septic complications, and improved patient outcomes.1-7 Surgical and endoscopic advancements allow health care practitioners to place tubes for feeding access earlier in the hospital stay, with subsequent initiation of enteral nutrition. Although advantageous, enteral nutrition may be problematic. Critically ill patients receive numerous drugs that may directly effect the delivery of enteral formulas. Conversely, enteral formulas may alter the absorption of a drug, resulting in clinically significant drug-nutrient interactions. Information regarding drug-enteral nutrition interactions is sparse. Most of the literature consists of small pharmacokinetic studies and anecdotal case reports. A basic understanding of drug-nutrient interactions and proper administration techniques will optimize drug therapy and improve delivery of enteral feeds. This chapter will address clinically significant drug-nutrient interactions in patients receiving enteral nutrition and provide suggestions for avoiding these interactions. Specific guidelines for administering medications via feeding tubes are also provided.

Avoiding Tube Occlusions Physical Incompatibilities Physical incompatibilities between medications and enteral formulas may manifest as a change in formula flow rate, texture, or viscosity; or cause separation or precipitation of the formulation. One study evaluated the physical compatibility of 52 medications with Ensure, Ensure Plus, and Osmolite.8 Most suspensions, elixirs, and emulsions were physically compatible with the enteral formulas. Medications known to be incompatible with enteral formulas are listed in Table 9.1. Acidic syrups or those buffered to a pH below 4 were responsible for most physical incompatibilities, which included gel formation and granulation of the enteral formula. These incompatibilities resulted in consistent clogging of the feeding tube The Biology and Practice of Current Nutritional Support, 2nd Edition, edited by Rifat Latifi and Stanley J. Dudrick. ©2003 Landes Bioscience.

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Table 9.1.

Medications physically incompatible with enteral formulas8

Brompheniramine/phenylephrine elixir (Dimetane) Brompheniramine/phenylpropanolamine elixir (Dimetapp) Calcium glubionate syrup (Neo-Calglucon) Chlorpromazine concentrate (Thorazine) Ferrous sulfate elixir (Feosol) Guaifenesin elixir (Robitussin) Lithium citrate syrup (Cibalith-S) Medium chain triglyceride oil (MCT Oil) Methenamine suspension (Mandelamine Forte) Potassium chloride liquid 10% and 20% Potassium chloride syrup (Klorvess) Pseudoephedrine syrup (Sudafed) Sodium bisphophate (Fleets Phospho-soda) Thioridazine oral solution (Mellarill)

9

and were not prevented by diluting the syrup with water or enteral formula. The use of alternative dosage forms (i.e., tablets) is suggested in order to avoid problem syrups. To avoid physical incompatibilities, mixing of any medications with enteral formulas is discouraged. The investigators of one study evaluated the physical effects of a fiber-containing formula (Enrich), a nutrient-dense formula (TwoCal HN), and an free amino acid formula (Vivonex T.E.N.) when mixed with 39 common pharmaceutical preparations.9 Physical incompatibility was observed with 24 mixtures. All of the incompatibilities, except for one, resulted in clogged feeding tubes. Whole protein formulas were incompatible with any preparation which contained iron, calcium, zinc or phosphorus. Also, medications which lowered the pH of the enteral formula resulted in protein precipitation, resulting in demulsification of the formula. Flushing the tube with water before and after medication administration can be used to prevent masses from forming in the tube.

High Viscosity Formulations High viscosity formulations can cause tube occlusion if not properly diluted. Medications reported to repeatedly clog tubes due to their high viscosity formulations include psyllium, cholestyramine, co-trimoxazole suspension and clarithromycin suspension.10 Proper dilution and flushing allow for the administration of viscous drugs via large bore feeding tubes, such as nasogastric or gastrostomy tubes. Avoid administering these medications into small bore feeding tubes if other routes of administration are available.

Enteral Formulas Drugs are not always responsible for tube occlusions. One study determined the in vitro clotting characteristics of frequently used enteral formulas.11 Clotting was primarily observed with intact protein formulas, resulting in tube occlusion within 36 hours. The investigators suggest that gastric acid-induced precipitation of proteins in the enteral formulas may be an important factor in clotting. Intact protein formulas are more likely to clot when acidified to a pH below 5; therefore, reflux of gastric acid into the tube may cause formula precipitation. Flushing the feeding tube before and after feeds will minimize the possibility of the enteral formula

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occluding the tube. If the feeding tube frequently occludes and the patient is receiving an intact protein formula, consider moving the distal end of the feeding tube into the small intestine.11,12 Acid suppression therapy may be initiated to increase the pH of the stomach and decrease the likelihood of further precipitation.

Non-Compatible Drug Formulations Clogged feeding tubes are a major complication of physical incompatibilities. It is common practice to crush tablets into fine particles and dissolve them with water to ease administration through feeding tubes to avoid occlusion. Several solid dosage forms should never be crushed and administered via feeding tubes, these include sublingual tablets, buccal preparations, encapsulated beads, extended-release and controlled-release tablets, and wax matrix dosage forms. Physical alteration of any medication before administration via a nasogastric tube will alter the drug’s dissolution properties, ultimately affecting the bioavailability of the drug. Crushing extended-release or controlled-release tablets for administration into an enteral tube destroys the specialized matrix or enteric coating which convey the controlled-release properties to the tablet or capsule. These medications are typically very difficult to crush and result in rough, heterogeneous particles which may clog the feeding tube. Another potential complication of administering extended-release or controlled-release medications through a feeding tube is the possibility of toxic peak concentrations and subtherapeutic trough concentrations later in the dosing interval. Substitution of immediate-release products for controlled-release products will prevent erratic serum concentrations and decrease the possibility of tube obstruction. Medications which should not be crushed are included in Table 9.2. A comprehensive list is published periodically in Hospital Pharmacy.13

Methods of Restoring Tube Patency Administration of an enzymatic solution into a clogged tube is an effective method to restore tube patency. In one study, a pancreatic enzyme solution was successful in restoring tube patency in 96% of cases where the formula was believed to be the cause of the occlusion.14 The authors first injected 5 ml of warm water into the feeding tube and capped it for 5 minutes. If the tube remained occluded, one tablet of pancrelipase (Viokase) and one tablet of sodium bicarbonate (324 mg) were crushed and mixed in 5 ml of warm water. This enzyme solution was injected into the tube and capped for 5 minutes. The enzymatic solution was gently flushed with warm water using a 50 ml syringe. Administration of the enzyme solution at the site of the occlusion may be necessary. Enzymatic disintegration appears to be most effective when attempted within the first 24 hours of occlusion.15 Other strategies that have been effective in unclogging enteral feeding tubes include administration of carbonated beverages, cranberry juice, or distilled water into the clogged tube. A small amount of meat tenderizer diluted in water and instilled into the nasogastric tube has also been used. None of these therapies appear to be any more beneficial than administration of an enzymatic solution.15

Recommendations to Avoid Occlusion from Physical Incompatibilities For medication administration through feeding tubes, it is important to dissolve solid dosage forms and dilute the medication in approximately 30 ml of water, or 60-90 ml for viscous formulations. Flush the feeding tube with at least 15-30 ml of

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Table 9.2

9

Medications which should not be crushed or administered via feeding tubes13

Non-Crushable Medications (formulation) Aspirin (EC) Bisacodyl (EC) Chlorpromazine (Spansule) Diltiazem (CD, SR*) Divalproex Sodium (Cap, EC) Erythromycin (EC) Felodipine (SR) Glipizide (XL) Guaifenesin (LA*) Indomethacin (SR*) Isosorbide Dinitrate (SR) Lansoprazole*† (EC granules) Lithium (CR, SR) Methylphenidate (SR) Metoprolol (XL) Morphine (SR) Nifedipine (XL) Nitroglycerin (SL) Omeprazole*†(EC granules) Pancrelipase (EC) Pentoxifylline (CR) Potassium Chloride (XL) Procainamide (SR) Propranolol (LA) Quinidine (Extentabs) Theophylline (ER) Verapamil (SR)

EC = enteric coated SR = sustained-release XL = extended-release LA = long-acting CR = controlled-release SL = sublingual * Capsules may be opened and the contents may be administered via a nasogastric tube without crushing † Special formulation for NG or J-tube administration

warm tap water before and after medication administration. This procedure flushes drug particles from the tube into the stomach or small intestine and minimizes the number of drug particles exposed to the tubing. Water has been shown to be more effective than cranberry juice as an irrigant to prevent clogged tubes and just as effective as carbonated beverages.15 When feasible, syrups, solutions, and elixirs should replace solid tablets to decrease risk of tube occlusion.

Pharmacokinetic Interactions A pharmacokinetic interaction occurs when enteral feeding alters the bioavailability of medications. Decreased bioavailability may result in subtherapeutic serum concentrations with inadequate clinical response. Medications with potentially significant clinical interactions are phenytoin, carbamazepine and ciprofloxacin.

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Phenytoin Phenytoin is used in the critical care setting for seizure prophylaxis and treatment. Oral dosage forms are preferred over intravenous dosage forms for maintenance therapy because they are less likely to cause hypotension and thrombophlebitis. There is a lack of data on the use of phenytoin capsules administered via enteral feeding tubes. Phenytoin capsules are not recommended for tube administration, as crushing the extended-release granules negates its sustained-release formulation and increases the risk of tube occlusion due to poor dissolution of the medication. There is evidence that continuous enteral feeding affects the phenytoin serum concentration when using the suspension formulation. In one study, patients receiving simultaneous enteral feedings and phenytoin suspension displayed subtherapeutic phenytoin concentrations.16 Discontinuation of enteral feedings resulted in therapeutic phenytoin concentrations. In order to achieve higher phenytoin concentrations without sacrificing the nutritional needs of the patients, the investigators held enteral feeds 2 hours before and after phenytoin administration. This dosing technique improved phenytoin concentrations; however, higher doses were also required. It has been suggested that phenytoin binds to sodium caseinates, calcium caseinates and calcium chloride found in enteral formulas.17-19 Some researches have suggested that the majority of phenytoin remains in its nonionized form under acidic conditions in the stomach, allowing it to irreversibly bind to the nasogastric tubing.20 Others support the phenytoin suspension-enteral formula interaction, but the exact mechanism is still unknown. 21,22 Immediate-release phenytoin suspension should be used for enteral feeding tube administration. One study evaluated the administration of phenytoin suspension through a nasogastric tube using 10 different methods to simulate various patient scenarios.23 The suspension was administered undiluted and diluted with a variety of irrigants, and phenytoin concentrations were subsequently measured. Lower serum phenytoin concentrations were associated with the dosing methods that involved no dilution or irrigation. The type of irrigation fluid did not appear to have any influence on serum concentrations. In order to optimize phenytoin and enteral nutrition administration, it is recommended to administer the diluted suspension twice a day, holding enteral feeds for one hour before and after each dose. The chapter authors assume that the bioavailability of phenytoin suspension is 50-70% when administered via a feeding tube and adjust doses accordingly. The rate of the enteral nutrition should be adjusted to ensure the patient is receiving adequate nutrition based on a 20 hour versus 24 hour period. This method is successful at maintaining therapeutic phenytoin levels in critically ill patients. Phenytoin levels should be monitored closely when a patient is receiving concomitant enteral feeds and phenytoin suspension, especially when changes are made in phenytoin dose or enteral formula administration schedule.

Carbamazepine Carbamazepine is an anticonvulsant used as a first-line agent for treating several types of seizures. It is also used in pain syndromes, neurologic disorders, trigeminal neuralgia, diabetes insipidus, bipolar disorder and schizophrenia. Carbamazepine has a narrow therapeutic window, and requires serum level monitoring to guide therapy. Controlled studies have shown that the bioavailability of carbamazepine is compromised when administered through polyvinyl chloride (PVC) feeding tubes.24,25 One study found a significant loss of carbamazepine during an in vitro study when

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undiluted carbamazepine suspension was administered through PVC nasogastric tubes.25 No significant drug loss was reported with administration of diluted carbamazepine suspension through the nasogastric tubes. The study investigators postulate that carbamazepine binds to the PVC feeding tube and recommended that carbamazepine suspension be mixed with an equal volume of diluent before nasogastric tube administration.

Ciprofloxacin

9

Ciprofloxacin, a fluoroquinolone antimicrobial, is effective in the treatment of a variety of gram-positive and gram-negative bacterial infections. It is available in intravenous and oral dosage forms; however, oral ciprofloxacin has its drawbacks. These formulations chelate a variety of multivalent cations, such as iron, magnesium, calcium, aluminum and zinc; markedly decreasing ciprofloxacin absorption.26 One study showed a reduction in the bioavailability of ciprofloxacin from 67% to 27% in patients given enteral feedings orally, via gastrostomy and via jejunostomy tubes.27 Maximum serum ciprofloxacin concentrations were measured and corresponding values for area under the concentration-time curve were calculated for each of the treatment groups. The authors of this study suggest that the decreased absorption caused by enteral feedings may be clinically important, especially when enteral feedings and ciprofloxacin are co-administered by the oral or jejunostomy routes. Another investigator examined the oral bioavailabilities of ciprofloxacin and ofloxacin when they were co-administered with water or Ensure formula.28 Area under the concentration-time curves, maximum serum concentrations and absorption were significantly reduced by Ensure when compared to water. The Ensure formula reduced the absorption of ciprofloxacin significantly more than the ofloxacin. Subsequent studies evaluating the ciprofloxacin-enteral formula interaction have not confirmed these findings. A study evaluated the bioavailability of ciprofloxacin administered three ways: orally, through a nasogastric tube without enteral feeds, and through a nasogastric tube while receiving enteral feeds.29 No statistically significant difference between treatment groups were found in terms of area under the curve, maximum concentration in the serum, and time to peak concentration. Another study evaluated several pharmacokinetic properties in critically ill patients receiving 750 mg of ciprofloxacin every 12 hours via nasogastric tube with enteral feedings.30 Although the absorption of ciprofloxacin was decreased, the serum concentrations of ciprofloxacin were well above the minimum inhibitory concentrations for many pathogenic organisms. Published studies suggest that the bioavailability of ciprofloxacin is variable in patients receiving enteral nutrition. It is recommended to give ciprofloxacin 1 hour before and 2 hours after bolus nasogastric feeds and separate the dose from any cation administration. If a patient is on continuous feedings and not responding to ciprofloxacin therapy, especially when treating a ciprofloxacin sensitive organism, it may be reasonable to hold tube feeds for 1 hour before and after ciprofloxacin administration or switch to an intravenous formulation. The enteral tube feeding rate should be adjusted to meet the patients nutritional goals if tube feeds are held for medication administration.

Pharmacodynamic Interactions A pharmacodynamic interaction is one in which the effects of a drug are altered, in this scenario because of enteral nutrition. There are many case reports of warfarin

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resistance in patients who receive concomitant warfarin and enteral feedings.31-34 Researchers have shown that patients receiving enteral feedings require higher doses of warfarin to achieve therapeutic effects and a reduction in dose is necessary when feeds are discontinued.32 Investigators originally postulated that warfarin resistance was due to inhibition of warfarin by excessive amounts of vitamin K in enteral formulas. Manufacturers have reformulated most enteral formulas to contain only small amounts of vitamin K; however, warfarin resistance remains a problem. Newer evidence now suggests that warfarin is bound to several components of enteral formulas, such as soy protein or proteinaceous caseinate salts.35 Warfarin malabsorption has also been proposed as a possible mechanism of warfarin resistance.36 When approaching this problem, clinicians should first consider the quantity of vitamin K present in the enteral formula being administered. The vitamin K content/1000 ml of selected commercially available enteral formulas and are listed in Table 9.3. Vitamin K can antagonize the pharmacologic effect of warfarin in doses as low as 140 micrograms/day.31,34 Therefore, vitamin K intake < 140 micrograms/ day will optimize effect in a warfarin resistant patient. Minimizing protein in the enteral formula may also be prudent as warfarin is highly protein bound. Monitoring INR is essential when titrating warfarin or changing the enteral feeding formulation or regimen.

Influence of Tube Placement on Drug Efficacy A small number of medications require a specific pH to be absorbed and an understanding of these drug characteristics is crucial to prevent drug therapy failure. Ketoconazole (Nizoral), an imidazole antifungal agent, requires an acidic pH to be absorbed. Administration into the small intestine or into a buffered gastric environment will render this drug ineffective. Ketoconazole should be administered on an empty stomach to ensure an acidic environment for adequate absorption. For jejunostomy tube administration, an acidic fluid may be mixed with Ketoconazole for administration into the tube. Hydrochloric acid and acidic beverages, such as Coca-Cola, are suitable aqueous fluids and have been used successfully to improve Ketoconazole absorption.37,38 The absorption of itraconazole, a triazole antifungal, is dependent upon the dosage form being used. Itraconazole capsule absorption requires an acidic pH. The capsules should be opened and dissolved and given into the stomach with enteral feedings to improve solubility and absorption. Clinically significant differences in bioavailability occur if not given with food.39,40 Itraconazole oral solution absorption is not pH dependent, can be given via nasogastric or jejunostomy tube and should be separated from enteral feedings. Fasting conditions are not required, but such conditions will increase bioavailability.40 Sucralfate is an oral anti-ulcer agent commonly used to prevent upper gastrointestinal bleeding in ventilated patients in the ICU setting. It works by binding to proteins in the stomach, forming a protective barrier over ulcers. Sucralfate can bind to the protein components of enteral formulas and form insoluble complexes. It has been implicated in causing bezoar formation in patients receiving enteral feeds (Isocal).41,42 Not all patients receiving sucralfate appear to be at risk.42,43 Sucralfate should be administered directly into the stomach via a nasogastric tube or gastrostomy tube at least one hour before an enteral feeding, to facilitate drug binding to the stomach. Sucralfate should not be administered into the small intestine as it will fail to provide any clinical benefit.

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Table 9.3.

Vitamin K content of selected commercially available enteral formulas

Formula Kindercal Vivonex TEN Vivonex Plus Nutren 1.0 Replete Glytrol Respalor Glucerna Jevity Boost Plus Ultracal Nutren 1.5 Nutrivent Probalance Subdue Ensure

9

Vitamin K Content (µg/1000 ml) 32 40 44 50 50 50 56 57 61 68 68 75 75 80 83 83

Formula

Vitamin K Content (µg/1000 ml) Ensure Plus 83 Pulmocare 85 Nepro 85 Boost with Fiber 97 Nutren 2.0 100 Isocal HN 106 Magnacal Renal 118 Protain XL 12 Boost 125 TraumaCal 127 Criticare HN 131 Isocal 132 Comply 144 Promote 180 Deliver 250

Lansoprazole and omeprazole are proton pump inhibitors used for gastrointestinal bleeding in ventilated patients and have special administration issues in patients with feeding tubes. These drugs are available as capsules which contain acid labile enteric-coated granules designed to dissolve in the alkaline environment of the small intestine. When the enteric-coated granules are placed in water, the granules become soft, sticky, and clump together; greatly increasing the possibility of tube obstruction. To avoid tube obstruction with lansoprazole, mix the uncrushed enteric-coated granules with 40 ml of apple juice and administer into the nasogastric tube.44 Flush the tube with an additional 40 ml of apple juice to make sure the granules enter the stomach. The apple juice is acidic and will not affect the enteric coated granules; therefore, drug bioavailability is not compromised. Omeprazole pellets have been successfully administered through a jejunostomy tube after the omeprazole pellets were crushed and dissolved in a sodium bicarbonate solution (8 mmol/50 ml).45 Another study evaluated nasogastric administration of omeprazole.46 In this study, omeprazole pellets were dissolved in a syringe with 20 ml of 8.4% sodium bicarbonate injection. The nasogastric tube was flushed with 20 ml of water, the dose was administered, and the nasogastric tube was clamped for an hour. Data demonstrate that both omeprazole and lansoprazole formulations can be administered via the nasogastric and jejunostomy routes.

Optimizing Tolerance to Enteral Nutrition and Drug Therapy Gastric Residuals Increased gastric residuals are a possible manifestation of formula intolerance. Under these circumstances, prokinetic agents, such as metoclopramide (Reglan) and erythromycin (E-mycin) are used to increase gastric emptying. Although disease conditions, trauma, or surgical interventions may be the cause of decreased gastric emptying, drug causes must also be ruled out. There are many drugs which

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may decrease the rate of gastric smooth muscle contraction, including antihistamines, scopolamine, atropine, phenothiazines, propantheline, tricyclic antidepressants, narcotic analgesics, alcohol, aluminum hydroxide, amino acids, glucagon, and acidic solutions (i.e. fruit juices). There are also drugs which promote smooth muscle relaxation and decrease gastrointestinal contractions, these include antihypertensive agents (i.e. calcium channel blockers), antacids, hypnotics, anesthetic agents, and antiparkinsonian drugs. Drug causes of decreased gastric motility should always be considered or the nutritional needs of the patient may be unnecessarily compromised.

Gastrointestinal Adverse Effects Although enteral feeding is beneficial, gastrointestinal adverse effects sometimes present due to formula intolerance and include cramping, distension, vomiting and diarrhea. Researchers report the incidence of diarrhea in critically ill tube fed patients as high as 68%.47 However, there are many reasons a patient may develop diarrhea other than feeding intolerance, these include increased gastric emptying rate, clostridium difficile GI infections, low fiber or high osmolality formulas, and drugs. It is important to look for each of these causes as enteral formulas may be erroneously blamed for diarrhea and wrongfully stopped. Diarrhea is a side of effect of many medications, such as magnesium containing salts and antacids, electrolyte solutions (potassium chloride, sodium phosphate, potassium phosphate), laxatives, colchicine, quinidine, cholinergic agents, and others. However, the most common cause of diarrhea in the hospital setting may be sorbitol containing medications. Sorbitol is commonly used in the pharmaceutical industry as a sweetening agent with its primary drawback being an osmotic diarrhea. Sorbitol may cause gastrointestinal distress in the form of cramping and diarrhea in amounts of 10 to 20 g.48 In one study, intake of sorbitol was attributed to at least 48% of the causes of diarrhea in patients receiving tube feeding.49 Diarrhea resolved in every case when the sorbitol medications were discontinued. The sorbitol content may be highly variable depending on the manufacturer. Sorbitol is considered an inactive ingredient so the amounts of sorbitol in various products are not always readily available. Commonly used drugs with high concentrations of sorbitol include acetaminophen elixir, Mylanta® suspension, codeine phosphate solution, theophylline elixir, cimetidine solution, diazepam solution, digoxin elixir, lithium syrup, metoclopramide syrup, sodium polystyrene sulfonate, carbamazepine, guaifenesin, and aminophylline solution.50 Administration of high osmolality medications into a feeding tube without adequate dilution is another cause of diarrhea and cramping. Osmolality is the measure of the number and size of particles per kilogram of solution.51 The osmolality of a normal gastrointestinal tract ranges from 127-357 mOsm/kg and administration of liquid medications with higher osmolalities through a feeding tube will typically result in an osmotic diarrhea.51,52 Hypertonic medications should be diluted with 60-90 ml of water before administration into the feeding tube to avoid this complication. Commonly used hypertonic medications are presented in Table 9.4.

Summary Many potential interactions may occur between medications and enteral nutrition making it difficult to optimize the management of the critically ill patient. Physical incompatibilities, pharmacokinetic and pharmacodynamic interactions, tube placement and tolerance issues need to be considered. The efficacy of the medications

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Table 9.4.

Osmolalities of selected commercially available drugs53

Product

9

Acetaminophen elixir Acetaminophen with codeine Amoxicillin suspension Ampicillin suspension Cascara aromatic extract Cephalexin Cimetidine solution Co-trimoxazole suspension Dexamethasone solution Dextromethorphan syrup Digoxin elixir Diphenhydramine HCl elixir Diphenoxylate/atropine susp. Docusate sodium syrup Erythromycin E.S. susp. Ferrous sulfate liquid Furosemide solution Haloperidol concentrate Hydroxyzine syrup Kaolin-pectin suspension Lactulose syrup Lithium citrate syrup Magnesium citrate solution Metoclopramide HCl syrup Milk of magnesia suspension Multivitamin liquid Nystatin suspension Paregoric tincture Phenytoin sodium suspension Potassium chloride liquid Potassium iodide sat sol (SSKI) Prochlorperazine syrup Promethazine HCl syrup Sodium phosphate liquid Theophylline solution Thioridazine suspension

Average Osmolality (mOsm/kg) 5400 4700 2250 2250 1000 1950 5500 2200 3100 5950 1350 850 8800 3900 1750 4700 2050 500 4450 900 3600 6850 1000 8350 1250 5700 3300 1350 1500 3550 10950 3250 3500 7250 800 2050

administered, as well as the nutritional goals of the patient, may be compromised if undetected. A basic understanding of potential interactions, proper administration techniques and a multidisciplinary approach may improve drug and nutrition delivery. Critical care practitioners need to be aware of these drug-nutrient interactions and take the necessary steps for prevention.

Summary Guidelines for Medication Administration via Feeding Tubes: 1. Tube feeds should be stopped prior to administration of medications. The tube should be flushed with 30 ml of tap water BEFORE and AFTER each medication is administered.

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2. Medications should be crushed, dissolved, and DILUTED with 30-60 ml tap water (with the exception of proton pump inhibitors which have specific administration guidelines) 3. Liquid medications should be DILUTED with 30-60 ml of tap water prior to administration. Hypertonic medications should be administered with 60-90 ml of tap water. 4. Medications should be administered SEPARATELY. If multiple medications must be administered, the tube should be flushed with at least 15 ml of tap water between medications. 5. Medications should NOT be mixed with enteral feeds, especially syrups. 6. Specific drug considerations: a. Hold tube feeding 1 hour before and after phenytoin dose and adjust phenytoin for decreased bioavailability when given via feeding tube (assume 50-70% bioavailability) b. Never crush sustained or extended-release preparations c. Sucralfate, omeprazole*, lansoprazole*, antacids, iron salts, Ketoconazole, and itraconazole capsules should only be administered into the gastric ports of feeding tubes (*special formulations for NG or J tube administration)

Selected References 1. 2. 3. 4. 5. 6. 7. 8. 9. 10. 11. 12. 13. 14. 15.

Chiarelli A, Enzi G, Casadei A et al. Very early nutritional supplementation in burned patients. Am J Clin Nutr 1990; 51:1035-39. Gianotti L, Alexander JW, Nelson JL et al. Role of early enteral feeding and acute starvation on postburn bacterial translocation and host defense. Prospective randomized trials. Crit Care Med 1994; 22:265-272 Kudsk KA, Croce MA, Fabian TC et al. Enteral versus parenteral feeding. Ann Surg 1992; 215: 503-513. Moore EE, Jones TH. Benefits of immediate jejunostomy feeding after major abdominal trauma—a prospective, randomized study. J Trauma 1986; 26:874-881. Lin MT, Saito H, Fukushima R et al. Route of nutritional supply influences local systemic, and remote organ responses to intraperitoneal bacterial challenge. Ann Surg 1996; 223(1):84-93. Moore FA, Feliciano DV, Andrassy RJ et al. Early enteral feeding, compared with parenteral, reduces postoperative septic complications: the results of a meta-analysis. Ann Surg 1992; 216(2):172-183. Hasse JM, Blue LS, Liepa GU et al. Early enteral nutrition support in patients undergoing liver transplant. JPEN 1995; 19:437-443. Cutie AJ, Altman E, Lenkel L. Compatibility of enteral products with commonly employed drug additives. JPEN 1983; 7(2):186-191. Burns PE, McCall L, Wirshing R. Physical compatibility of enteral formulas with various common medications. J Am Diet Assoc 1988; 88:1094-1096. Guenter P, Jones S, Ericson M. Enteral nutrition therapy. Nurs Clin North Amer 1997; 32(4):651-668. Marcuard SP, Perkins AM. Clogging of feeding tubes. JPEN 1988; 12(4):403-405. Miyagawa C. Drug-nutrient interactions in critically ill patients. Crit Care Nurse 1993; Oct;13(5):69-90. Mitchell JF. Oral solid dosage forms that should not be crushed: 1996 revision. Hospital Pharmacy. 1996; 31:27-37. Marcuard SP, Stegall KS. Unclogging feeding tubes with pancreatic enzyme. JPEN 1990; 14:198-200. Nicolau DP, Davis SK. Carbonated beverages as irrigants for feeding tubes (letter). DICP 1990; 14:840.

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The Biology and Practice of Current Nutritional Support 16. 17. 18. 19. 20. 21. 22. 23. 24. 25. 26. 27.

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28. 29. 30. 31. 32. 33. 34. 35. 36. 37. 38. 39. 40.

Bauer LA. Interference of oral phenytoin absorption by continuous nasogastric feedings. Neurology 1982; 32:570-572. Smith OB, Longe RL, Altman RE et al. Recovery of phenytoin from solutions of caseinate salts and calcium chloride. Am J Hosp Pharm 1988; 45:365-368. Miller SW, Strom JG. Stability of phenytoin in three enteral nutrition formulas. Am J Hosp Pharm 1988; 45:2529-2533. Hooks MA, Longe RL, Taylor AT et al. Recovery of phenytoin from an enteral nutrient formula. Am J Hosp Pharm 1986; 43:685-688. Fleischer D, Sheth N, Kou JH. Phenytoin interaction with enteral feedings administered through nasogastric tubes. JPEN 1990; 14:513-516. Maynard GA, Jones KM, Guidry JR. Phenytoin absorption from tube feedings. Arch Intern Med 1987; 147:1821. Sakland JJ, Graves RH, Sharp WP. Interaction of oral phenytoin with enteral feedings. JPEN 1986; 10:322-323. Cacek AT, DeVito JM, Koonce JR. In vitro evaluation of nasogastric administration methods for phenytoin. Am J Hosp Pharm 1986; 43:689-92. Bass J, Miles MV, Tennison MB et al. Effects of enteral tube feeding on the absorption and pharmacokinetic profile of carbamazepine suspension. Epilepsia 1989; 30:364-369. Clark-Schmidt AL, Garnett WR, Lowe DR et al. Loss of carbamazepine suspension through nasogastric feeding tubes. Am J Hosp Pharm 1990; 47:2034-2037. Polk RE. Drug-drug interactions with ciprofloxacin and other fluoroquinolones. Am J Med 1989; 87(Suppl 5A):76S-81S. Healy DP, Brodbeck MC, Clendening CE. Ciprofloxacin absoprtion is impaired in patients given enteral feeding orally and via gastrostomy and jejunostomy tubes. Antimicrob Agents Chemother 1996; 40(1):6-10. Mueller BA, Brierton DG, Abel SR et al. Effect of enteral feeding with ensure on oral bioavailabilities of ofloxacin and ciprofloxacin. Antimicrob Agents Chemother 1994; 38(9):2101-2105. Yuk JH, Nightingale CH, Sweeney KR et al. Relative bioavailability in healthy vounteers of ciprofloxacin administered through a nasogastric tube with and without enteral feeding. Antimicrob Agents Chemother 1989; 33(7):1118-20. Cohn SM, Sawyer MD, Burns GA et al. Enteric absorption of ciprofloxacin during tube feeding in the critically ill. J Antimicrob Chemother 1996; 38(5):871-6. Lader E, Yang L, Clarke A et al. Warfarin dosage and vitamin K in Osmolite. Ann Intern Med 1980; 93:373-374. Howard PA, Hannaman KN. Warfarin resistance linked to enteral nutrition products. J Am Diet Assoc 1985; 85:713-715. Watson AJM, Pegg M, Green JRB. Enteral feeds may antagonize warfarin. BMJ 1984; 288:557. Parr MD, Record KE, Griffith GL et al. Effect of enteral nutrition on warfarin therapy (letter). Clin Pharm 1982; 1:274-276. Kuhn TA, Garnett WR, Wells BK et al. Recovery of warfarin from an enteral nutrient formula. Am J Hosp Pharm 1989; 46:1395-1399. Martin JE, Lutomski DM. Warfarin resistance and enteral feedings. JPEN 1989; 13:206-208. Chin TW et al. Effects of an acidic beverage (Coca Cola) on absorption of Ketoconazole. Antimicrob Agents Chemother 1995; 39(8):1671-5. Miyagawa CI. Hydrochloric acid given with Ketoconazole through a jejunostomy tube. Clin Pharm 1984; 3(2):205-207. Van Peer A, Woestenborghs R, Heykants J et al. The effects of food and soe on the oral systemic availability of itraconazole in healthy subjects. Eur J Clin Pharmacol 1989; 36:423-426. Product Information. Sporanox, itraconazole. Titusville: Janssen Pharmaceutica Inc., 1997.

Optimizing Drug Therapy and Enteral Nutrition 41. 42. 43. 44. 45. 46. 47. 48. 49. 50. 51. 52. 53.

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Algozzine GJ, Hill G, Scoggins WG et al. Sucralfate bezoar. N Engl J Med 1983; 309:1387. Quigley MA, Flicker M, Caldwell EG. Sucralfate bezoar-theory or fact? (letter). Am J Gastroenterol 1986; 81:724. Reddy AN. Reply to Quigley et al (letter). Am J Gastroenterol 1986; 81:725. Chun AHC, Shi HH, Achari R et al. Lansoprazole: Administration of the contents of a capsule dosage formulation through a nasogastric tube. Clin Therapeutics 1996; 18(5):833-842. Woods DJ, McClintock AD. Omeprazole administration (letter). Ann Pharmacother 1993; 27:651. Phillips JO, Metzler MH, Palmieri TL et al. A prospective study of simplified omeprazole suspension for the prophylaxis of stress-related mucosal damage. Crit Care Med 1996; 24(11):1793-1799. Kelly TWJ, Patrick MR, Hillman KM. Study of diarrhea in critically ill patients. Crit Care Med 1983; 11:7. Hyams JS. Sorbitol intolerance: an unappreciated cause of functional gastrointestinal complaints. Gastroenterology 1983; 84:30-33. Edes TE, Walk BE, Austin JL. Diarrhea in tube-fed pateints: feeding formula not necessarily the cause. Am J Med 1990; 88:91-93. Lutmoski DM, Gore ML, Wright SM et al. Sorbitol content of selected oral liquids. Ann Pharmacother 1993; 27:269-274. Estoup M. Approaches and limitations of medication delivery in patients with enteral feeding tubes. Crit Care Nurse 1994; 14:68-81. Niemiec P, Vanderveen TW, Morrison JI et al. Gastrointestinal disorders caused by medication and electrolyte solution osmolality during enteral nutrition. JPEN 1983; 7:387-389. Dickerson RN, Melnick G. Osmolaltiy of oral drug solutions and suspension. Am J Hosp Pharm 1988; 45:832-834.

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CHAPTER 10

Techniques and Monitoring of Total Parenteral Nutrition Renee Piazza-Barnett, Laura E. Matarese, Douglas L. Seidner and Ezra Steiger

Introduction This chapter discusses the techniques of Total parenteral nutrition (TPN), which include the provision of macro- and micro-nutrients and the various routes of access used for TPN delivery. Also reviewed are the appropriate monitoring parameters for minimizing TPN-associated complications. Finally, the short- and long-term complications of TPN are discussed and how these complications may be prevented and managed.

Macronutrients TPN formulas are composed of amino acids, carbohydrate, and fat in ratios tailored to meet the needs of the individual patient.1 The patient’s clinical status and institutional factors determine the type of delivery system used. A two-in-one system is a dextrose-amino acid combination with lipids infused separately. A three-in-one or a total nutrient admixture (TNA) combines dextrose, amino acids, and lipids in a single container. Lipid-based solutions are indicated in situations where restricting the carbohydrate load is desirable, such as in patients with persistent hyperglycemia or hypercapnia. Lipids are more expensive than dextrose and admixing fat creates concerns regarding the stability of the emulsion and compatibility with other additives.2 The TPN prescription begins with calculation of protein, energy, and fluid requirements.

Amino Acids The primary function of protein in parenteral nutrition is to achieve nitrogen equilibrium, thus preventing skeletal muscle from being degraded for gluconeogenesis.1 Crystalline amino acids provide a balanced mixture of essential and nonessential amino acids. They are available in concentrations ranging from 3.5% to 15%, with the dilute solutions most often used for peripheral administration and the more concentrated solutions used for central administration. Modified amino acid products have been developed for renal failure, hepatic failure, and metabolic stress.

Carbohydrate Parenteral carbohydrates are provided as anhydrous dextrose monohydrate in sterile water and are usually the primary calorie source in parenteral nutrition. The The Biology and Practice of Current Nutritional Support, 2nd Edition, edited by Rifat Latifi and Stanley J. Dudrick. ©2003 Landes Bioscience.

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concentration of parenteral dextrose solutions ranges from 5% to 70% and contain 3.4 calories per gram of dextrose. The minimum amount of carbohydrate that has been found to be necessary to suppress gluconeogenesis, and therefore protein catabolism, has been found to be 100 grams per day. The maximum oxidative rate for glucose is 5 mg/kg /minute3 or approximately 500 gm/day for a 70 kg patient. For critically ill patients it is suggested that carbohydrate intake be reduced to a maximum 4 mg/kg/ minute4 or approximately 400 gm/day for a 70 kg patient.

Lipid Intravenous lipid emulsions are composed principally of long-chain triglycerides. They contain soybean or safflower oil as a source of polyunsaturated fatty acids, egg phospholipid as an emulsifier, and water. Glycerol is added to make the emulsion isotonic. A 10% lipid emulsion provides 1.1 kcal/mL, a 20% lipid emulsion provides 2.0 kcal/mL, and a 30% lipid emulsion provides 3.0 kcal/mL. Parenteral lipids provide a source of essential fatty acids and calories. They can be substituted for dextrose calories for patients with glucose intolerance or used as a concentrated calorie source for patients requiring volume restriction.1 Intravenous lipid emulsion is used as the primary source of calories in a parenteral nutrition formula delivered by a peripheral vein (see Section on “Peripheral Access”).

Fluid When patients are started on nutrition support and are converted to an anabolic state, endogenous water production is decreased and daily requirements for exogenous fluids are increased.5 The following factors need to be considered when determining a patient’s fluid requirements: provision of maintenance requirements, correction of imbalances, replacement of ongoing losses, and extra fluid for anabolism. See Table 10.1 for calculation of fluid requirements.

Micronutrients/Additives Electrolytes Electrolyte requirements will vary among individuals and will depend on the patient’s current metabolic status as well as their underlying disease process.2 See Table 10.2 for daily electrolyte requirements for patients with adequate renal function receiving TPN. Appropriate electrolyte modifications will be discussed under Micronutrient-Related Complications.

Vitamins Adequate quantities of vitamins are required daily for the effective utilization of nutrients (see Table 10.3). Patients receiving nutrition support may have increased vitamin requirements because they are often highly stressed, catabolic, and are receiving high caloric and protein loads.2

Trace Elements Parenteral trace element injections are commercially available to provide multiple trace elements or individual nutrients. See Table 10.4 for trace element requirements in adults receiving TPN.

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Table 10.1. Calculation of fluid requirements Method 1 Fluid (mL/kg) Young, vigorous healthy adults 40 Other adults (18-55 years old) 35 Elderly adults 30 Method 2 For the first 10 kg of body weight, provide 100 mL/kg/d. For the second 10 kg of body weight, add 50 mL/kg/d. For weight above 20 kg of body weight, add 20 mL/kg/d if patient is 50 years of age or less, or add 15 mL/kg/d if patient is more than 50 years. Example: Maintenance needs for 55 year old man, weighing 70 kg 1,000 mL (1st 10 kg) + 500 mL (2nd 10 kg) + 750 mL (15mL x 50 kg) 2,250 mL

Reprinted with permission from: Estimating macronutrient requirements. In; Matarese LE, ed. Nutrition Support Handbook. Cleveland, OH: The Cleveland Clinic Foundationn; 1997:33.

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Table 10.2. Daily electrolyte requirements in patients with adequate renal function receiving TPN Electrolyte Sodium Potassium Chloride Calcium Magnesium Phosphorous

Usual Adult Daily IV Dose 100-150 mEq 60-120 mEq 100-150 mEq 9-22 mEq 8-24 mEq 15-30 mMol

RDA Adult (oral) 22 mEq* 40-50 mEq* 22 mEq* 20-30 mEq 11.5-14.4 mEq 26-39 mEq

*Minimum requirements of healthy persons Reprinted with permission from: Parenteral nutrition. In: Matarese LE, ed. Nutrition Support Handbook. Cleveland, OH: The Cleveland Clinic Foundation; 1997:52.

Zinc Zinc is essential for more than 90 enzyme reactions involving energy, carbohydrate metabolism, protein synthesis and degradation, nucleic acid synthesis, heme biosynthesis and carbon dioxide transport. The amount of parenteral zinc recommended for a stable adult patient is 2.5 to 4.0 mg per day.6 Patients with intestinal losses will need 12 mg zinc/L of output from the small bowel and 17 mg zinc/L for stool or ileostomy output.7

Copper Copper is associated with both intra and extracellular oxidation and plays an essential role in the proper formation of red blood cells, and in connective tissue

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Table 10.3. Parenteral vitamin supplementation Vitamin

RDA Adult Range

A, international units D, international units E, international units Ascorbic acid, mg Folic acid, mcg Niacin, mg Riboflavin, mg Thiamin, mg B6, mg B12, mcg Pantothenic acid, mg Biotin, mcg

2,667-3,333 200 11-14 60 180-200 13-20 1.2-1.8 1.0-1.5 1.6-2.0 2.0 4-7 30-100

Intravenous Multivitamin Formulation 3300 200 10 100 400 40 3.6 3.0 4.0 5.0 15 60

*RDA not established, estimated safe and adequate daily dietary intake Reprinted with permission from: Parenteral nutrition. In: Matarese LE, ed. Nutrition Support Handbook. Cleveland, OH: The Cleveland Clinic Foundation; 1997:55.

Table 10.4. Trace element requirements Element

Stable Adult

Chromium Copper Manganese Selenium Zinc

10-15 mcg 0.5-1.5 mg 150-800 mcg 50-120 mcg 2.5-4.0 mg +2 mg if catabolic

Adult with Intestinal Losses 20 mcg --------up to 200 mcg 12 mg/ml small bowel fluid lost; 17 ml/kg of stool or ileostomy output

1 mL of Multiple Trace Element 10 mcg 1mg 500 mcg ----5mg

Reprinted with permission from: Parenteral nutrition. In: Matarese LE, ed. Nutrition Support Handbook, Cleveland, OH: The Cleveland Clinic Foundation; 1997:57.

integrity.2 Intravenous requirements of copper for a stable adult are estimated to be between 0.5 to 1.5 mg/day.8

Manganese Manganese is a cofactor in a large number of enzyme systems and may have a potential role in glucose utilization. Intravenous manganese administration of 0.15 to 0.8 mg/day is recommended for a stable adult.9

Chromium Chromium is essential in the prevention of glucose intolerance. Ten to 15 mcg chromium/day appears to be adequate for a stable adult; 20 mcg chromium/day for the adult with intestinal losses.9

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Selenium Selenium is a component of glutathione peroxidase, an enzyme which protects cell membranes from lipid peroxides and free radicals.2 The usual intravenous dose of selenium is between 50 and 120 mcg per day.6

Iron Iron is primarily involved in the production of hemoglobin and myoglobin. Iron supplementation is generally not required during short-term TPN unless the patient is anemic. However, it is necessary to prevent anemia during long-term administration and in home TPN. Oral iron administration as either ferrous sulfate, ferrous gluconate, or polysaccharide iron complex is the preferred route of administration.2 If oral administration is not feasible, intravenous iron can be given as iron dextran. However, iron dextran should not be added to lipid-based TPN solutions because trivalent minerals could disrupt the lipid emulsion. Parenteral supplementation of the remaining trace elements (cobalt, cadmium, fluorine, iodine, nickel, silicon, molybdenum, and tin) is not currently recommended since deficiency states while on TPN in humans have yet to be described.2

Medications Although TPN is primarily designed to deliver nutrients and fluid, there are certain medications that can be added to the solution if consistent with institutional policy. Heparin and, when necessary, insulin can be added to improve both efficacy and safety of the TPN. Other medication, such as histamine H2 receptor antagonists, octreotide, and corticosteroids can be added to the solution to optimize the management of the patient’s underlying disease.

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Access/Delivery Central or peripheral veins can be used to provide parenteral nutrition. The type of access is selected according to how long it is expected to be needed, the limitations presented by the patient’s condition, and the availability of equipment and facilities.1

Central Central TPN is usually indicated in patients requiring long-term parenteral support who have increased nutritional requirements and/or a restriction on fluid intake.2 Veins that can be used for gaining central access include the subclavian, internal jugular, and femoral veins. Depending on institutional policy and overall patient status, central TPN can be provided as a mixture of dextrose and amino acids with fat emulsion given separately, or as a TNA with dextrose, amino acids, and fat emulsion combined into the same container.

Short-Term Short-term access is provided via a central catheter inserted percutaneously at the bedside under local anesthesia or under general anesthesia as part of a surgical procedure. These are changed via a guidewire if infection is suspected or by changing sites if infection is proven.

Long-Term Long-term venous access devices are usually required in patients leaving the hospital on home TPN. These include tunneled catheters, implanted ports, and

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peripherally inserted central catheters (PICCs). Tunneled catheters and implanted ports are available in single- or multiple-lumens and are placed by surgeons or radiologists trained in this procedure. Peripherally inserted central catheters are either placed in the operating room or at the bedside by specially trained nurses. These catheters may be used for the delivery of central TPN as long as the tip of the catheter is positioned in the superior vena cava or right atrium.

Peripheral Peripheral parenteral nutrition (PPN) is usually reserved for patients requiring short term parenteral nutrition who are not markedly hypermetabolic or fluid restricted and have good peripheral access.2 Peripheral veins in the hands are much smaller than centrally located veins and are subject to phlebitis and thrombosis when hyperosmolar products are infused.10 Since the amount of dextrose and protein in the PPN solution must be limited because they contribute to its osmolarity, PPN solutions are lipid-based and may be unable to provide adequate calories and protein for hypermetabolic patients.

Monitoring Parameters In order to maximize the efficacy of TPN and minimize its complications, it is essential that nutritional, metabolic, and infectious protocols be established and followed. General recommendations for TPN monitoring are summarized in Table 10.5.

Nutritional The amount of TPN infused is not always consistent with the amount prescribed. Daily documentation of the actual TPN infused is the most desirable method to assess the adequacy of the TPN delivered and minimize the risk of dehydration or fluid overload.11 For this reason, strict intake and output records, as well as weights, must be recorded daily. The daily physical exam should include listening to the lungs, and observing for tissue edema and other signs of excessive fluid retention.

Energy Patients receiving TPN require periodic reassessment of energy needs to avoid the complications of over- or under-feeding. Typically, the reassessment of energy needs should be done every 7 days to 10 days. Energy requirements are usually determined using formulas based on weight and height, such as the Harris-Benedict equation.12 Indirect calorimetry may be used in patients who are critically ill, severely overweight or underweight, or in cases where there is suspected overfeeding.

Protein The protein status of a patient receiving TPN may be followed by regular monitoring of visceral protein levels. Although serum albumin may be useful in a clinically stable patient, during acute illness serum values are largely affected by nonnutritional parameters such as altered vascular permeability, fluid imbalance, and hypermetabolic states.13 Other serum proteins with shorter half-lives that may be monitored to determine visceral protein response to nutrition support therapy include transferrin, prealbumin (transthyretin), and retinol-binding protein. Similar to albumin, these serum proteins are affected by non-nutritional factors that may invalidate its use as a tool for nutrition assessment, but are more valuable than serum albumin measurements in the acute care setting.

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Table 10.5. General recommendations for TPN monitoring Baseline Weight, height, body surface area Body composition (arm fat and muscle areas, bioelectrical impedance, subjective or functional measures) Serum electrolytes, glucose, creatinine, blood urea nitrogen Serum magnesium, calcium, phosphorus Serum triglyceride and cholesterol Liver function tests Serum albumin or prealbumin Complete blood count Energy (estimated or measured), protein, fluid, and micronutrient needs

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Routine Every 8 hours Vital signs Temperature Urine fractionals Daily Weight Fluid intake and output Serum electrolytes, glucose, creatinine, blood urea nitrogen until stable; then twice weekly Weekly Serum magnesium, calcium, phosphorus, albumin Liver function tests Complete blood count Review of actual oral, enteral, and TPN intake

As Clinically Indicated Fluid disorders Urine sodium or fractional sodium excretion Serum osmolality Urine specific gravity Protein status Nitrogen balance, serum prealbumin Lipid disorders Serum triglyceride or lipid clearance test Respiratory quotient Essential fatty acids (if fatfree TPN is necessary) Hepatic encaphalopathy Plasma amino acids Gastrointestinal losses Serum trace elements Stool electrolytes Respiratory compromise Paco2 Indirect calorimatry, respiratory quotient Acid-base disorders Blood pH Anion gap Long-term TPN Body composition measures Serum trace elements, vitamins

Reprinted with permission from: Management of Total parenteral nutrition. In: Skipper A, ed. Dietitian’s Handbook of Enteral and Parenteral nutrition. Gaithersburg, Maryland: Aspen Publishers, Inc; 1998:495.

Metabolic Serum electrolytes are monitored daily upon initiation of TPN until the levels stabilize within normal ranges. Monitoring electrolytes every 2 to 3 days thereafter in the hospital setting is usually sufficient. Serum phosphorous, magnesium, and potassium levels may need to be assessed more frequently, especially when there is a concern for the refeeding syndrome in a severely malnourished patient (See Table 10.6). Upon initiation of TPN, blood sugars should be checked every six hours during the initial two days to three days until the blood sugars remain at a consistent and acceptable level. Baseline serum triglyceride levels should be checked if there is a concern for preexisting hypertriglyceridemia in a patient receiving a lipid-based TPN solution.

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Table 10.6. Dosing and bolusing of minerals in TPN for adults Mineral

Calcium Phosphorous Magnesium

RDA Oral Minimum 800-1200 mg (20-30 mEq) 800-1200 mg (26-39 mM) 280-350 mg (11.5-14.4 mEq)

Usual Adult IV Dose TPN Range 9-22 mEq 15-30* mM 8-24 mEq

Techniques of Bolus Replacement 7-14 mEq not to exceed 0.7-1.8 mEq / minute 0.08-0.2 mM / kg IV over 6 hours ++ 24 mEq IV over 4-6 hours

*22-44 mEq of potassium phosphate or 20-40 mEq of sodium phosphate; ++1 mEq of potassium phosphate = 0.68 mM phosphorous; 1 mEq of sodium phosphate = 0.75 mM phosphorous Reprinted with permission from: Recognition and management of complications. In: Matarese LE, ed. Nutrition Support Handbook. Cleveland, OH: The Cleveland Clinic Foundation; 1997:77.

Serum trace elements are usually not routinely assessed upon initiation of TPN in the adult patient. Exceptions would be a severely malnourished patient, a patient manifesting signs and symptoms of trace element deficiency, or a patient anticipated to be on long-term TPN.14

Infectious Daily monitoring of body temperature and of the vascular device site are important due to the risk of catheter sepsis in patients receiving TPN. Catheter-related complications will be discussed in the following section.

Complications of Parenteral Nutrition Therapy Catheter-Related Complications Placement Central venous catheter complications occur in of 1-10% of patients.15 Complications of subclavian vein catheterization include pneumothorax, subclavian artery injury, air embolism, catheter embolization and catheter tip misplacement. Pneumothorax Pneumothorax is the most commonly reported complication of subclavian vein access reported at 4 %.16 It occurs when the needle tip penetrates or lacerates the pleura near the apex of the lung. It is most likely to occur in thin, malnourished patients due to the close proximity of the vein to the cupola of the lung with little intervening fat. Entry of the needle into the lung is recognized by aspiration of air instead of blood. If air is drawn into the syringe, or if a patient complains of pleuritic chest pain, the needle should be withdrawn immediately to prevent laceration of the lung. Other signs and symptoms may include tachycardia, dyspnea, persistent cough, or diaphoresis. If the patient has no respiratory distress, the landmarks should be reassessed and another attempt at cannulation made. If respiratory distress or chest pain occurs, the cannulation should be aborted and a chest x-ray obtained

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immediately. A small pneumothorax may resolve untreated. In some instances however, it may be necessary to place a chest tube. Occasionally a pneumothorax is not seen on the initial post-insertion chest x-ray film but is seen in a subsequent x-ray film, sometimes several days later.17 The incidence of pneumothorax can be reduced if the catheters are placed by or supervised by experienced personnel.18 Subclavian Artery Injury Subclavian artery injury can occur when the patient is dehydrated and the external jugular veins cannot be distended by Trendelenburg position or Valsalva maneuver. Penetration of the subclavian artery is recognized by the return of pulsatile bright red blood into the syringe. The needle should be withdrawn immediately and local pressure applied above and below the clavicle. Venous Air Embolism Venous air embolism occurs when the intrathoracic pressure becomes negative compared with the atmospheric pressure at the open needle during subclavian catheter insertion, while changing the intravenous tubing or accidental separation of the tubing.19 Patients who aspirate a small amount of air usually are asymptomatic. If massive, however, the patient will become severely hypotensive and have a cardiac murmur on auscultation. Cardiac arrest may result from blockage of blood flow through the heart by the air embolus. The patient should be placed in Trendelenburg position and rolled into a left lateral decubitus position in order to keep the air in the apex of the right ventricle until it is reabsorbed.20 The air may also be aspirated through a central catheter that is inserted into the right atrium.21

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Catheter Embolization With the use of the Seldinger technique for catheter insertion, intravascular catheter embolization is no longer a problem during placement since the catheter is not withdrawn through the insertion needle. However, it can occur if a portion of the catheter inside the vein is inadvertently sheared off during dressing changes or there is a breakage at a weakened or damaged area. The catheter tip can lodge any place from the subclavian vein to the pulmonary arterial system. Catheter embolization may cause cardiac arrhythmias. The embolized portion may be removed by transfemoral intravenous snaring of the fragment under fluoroscopy.22 When the fragment is lodged in the distal pulmonary arterioles, a thoracotomy may be necessary. Catheter Tip Dislocation The tip of the catheter should be in the mid or distal portion of the superior vena cava. However, the tip may enter the internal jugular vein, the opposite subclavian vein, axillary vein, internal thoracic vein, azygos vein, hemizygous vein, or pericardiophrenic vein.23-25 Improper tip location can be a result of venous vascular anomalies or improper placement by inexperienced personnel. Signs and symptoms of improper tip location include phlebitis, cardiopulmonary distress and possible thrombosis. The catheter should be removed over a guidewire and repositioned under fluoroscopy. Venous Thrombosis Subclavian vein thrombosis has been observed in up to 50% of patients with prolonged subclavian catheterization.26,27 Catheter induced thrombosis occurs as a result of irritation of the blood vessel wall. The thrombus is usually composed of

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fibrin. Precipitation of medication within the catheter does occur, but less frequently. Subclavian vein thrombosis should be suspected when collateral veins over the chest and shoulder begin to appear. The patient may also demonstrate swelling of the involved arm, neck and face. In some patients thrombosis is completely asymptomatic or symptoms are transient and are not noticed. The thrombosis may be identified when attempts at cannulating a vein is unsuccessful. Thrombosis is also a concern from a septic standpoint. Sepsis from an unknown source may be due to bacterial or fungal colonization of an unsuspected thrombus. Thrombosis can be confirmed with a venogram or duplex ultrasound. Heparin and low dose Warfarin have been used to help prevent subclavian vein thrombosis and to decrease thrombus formation at the catheter tip.28-29 Catheter Occlusion A catheter becomes occluded either by thrombus, drug precipitate, or lipid emulsion. If a fibrin thrombus has formed, a thrombolytic agent may be used to dissolve the thrombus.30,31 A precipitate from a medication may be treated with instillation of hydrochloric acid if the drug has an alkaline base.32 An occlusion caused by lipids may be lysed with 70% ethyl alcohol.33 Phlebitis Peripheral administration of hypertonic solution may result in phlebitis exhibited by redness, swelling, and pain at the peripheral site. The peripheral line site should be changed. The incidence of phlebitis may be minimized by keeping the osmolarity of the solution less than 900 mOsm/kg and by the addition of heparin to the parenteral nutrition solution.34 Catheter Sepsis Central venous catheter infections are the most serious potential complications of parenteral nutrition. These infections include catheter related sepsis, as well as tunnel infections and exit site infections in long-term tunneled catheters. They can be from poor technique during catheter insertion, contamination of the catheter hub or infection of the skin due to inadequate catheter care, hematogenous seeding from a distant source, and contamination of the nutrient solution. Diagnosing catheter infections can be difficult. When there is a change in the patient’s usual temperature or elevation in white blood cell count, a standard fever work-up including a history, physical exam, chest x-ray, urinalysis, and blood cultures through a peripheral and central line should be done to rapidly determine the probable source of the fever. The catheter should be changed over a guidewire and the tip cultured to help determine if catheter sepsis is present.35 If there is obvious pus coming out of the catheter exit site, the exit site should be cultured, the catheter removed and a new one placed at a different location. If the catheter tip replaced by guidewire is positive for infection, the new catheter should be removed and another catheter should be inserted in a new location. For suspected Hickman, Broviac or port infections, guidewire changes are not possible because of tissue growth into the dacron cuff in the tunnel and quantitative blood cultures should be obtained through the vascular access device along with peripheral venous blood cultures.36 The permanent vascular access device should not be used for TPN solutions until culture results are known. Quantitative blood cultures showing greater growth in the catheter as opposed to a peripheral blood sample is diagnostic of a vascular access device infection. If positive, the vascular access device should be treated with long-term

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antibiotics. If blood stream sepsis is still not controlled, the device should be removed. Intravenous VancomycinR is the usual drug of choice for empiric treatment since most of these infections are due to Staphylococcus aureus or coagulase-negative staphylococci (Staphylococcus epidermidis) bacteria, and should be started immediately once the preliminary cultures have been obtained.37,38 If the blood cultures are positive for fungus, the catheter should be removed.39 The best treatment for catheter-related sepsis is prevention and adherence to strict protocols.

Hepatic The cause of hepatic dysfunction in patients receiving TPN is usually multifactorial. Elevations of liver enzymes within the first three weeks of TPN infusion are associated with hepatic steatosis.40-43 The sequential laboratory abnormalities most likely to be found in hepatic steatosis are elevations in serum aminotransferase values, alkaline phosphatase, and bilirubin.42,44 The incidence of hepatic steatosis has decreased with more moderate provision of calories and the substitution of some of the dextrose calories with lipid. Long-term TPN has been associated with cholelithiasis,45 steatohepatitis, and cholestasis.46 The use of cyclic TPN, restriction of daily carbohydrate load to <5.0 mg/kg/min or <500 gm/day for a 70 kg patient, avoidance of overfeeding, and early enteral stimulation may minimize the risk of cholestasis.

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Lack of luminal nutrients during TPN is associated with villous hypoplasia of the small bowel, colonic mucosal atrophy, decreased gastric function, impaired gastrointestinal immunity, and gut bacterial translocation in experimental models.47,48 It is important to initiate enteral feedings as soon as possible. If full nutritional requirements are unable to be met by the enteral route, then small amounts of enteral nutrition may be delivered to the gastrointestinal tract while meeting the patient’s full nutritional requirements by TPN. Histamine H2 receptor antagonists are used to decrease gastric acid output, particularly in patients with massive small bowel resection, or to prevent stress ulcers.49 These medications can be added directly to the TPN solution so that they are titrated in over a 24-hour period.50 The dose of H2 receptor antagonists should be decreased in patients with decreased renal clearance.51

Macronutrient-Related Complications Calories Overfeeding calories, especially in the form of dextrose, above requirements can result in hyperglycemia, hepatic dysfunction from fatty infiltration, potential respiratory acidosis from increased CO2 production, and difficulty in weaning from ventilators.52-54 Underfeeding may result in depressed ventilatory drive, decreased respiratory muscle function, impaired immune function, and increased infection.55-57 Measurement of energy expenditure through indirect calorimetry may be desirable in some patients, especially those with high fever, acute pancreatitis, malignancy, critical illness, severe malnutrition, or obesity. Hyperglycemia Hyperglycemia is the most common complication associated with the administration of TPN. It occurs secondary to diabetes mellitus, insulin resistance due to

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ongoing stress, and infection. Depending on institutional policy, insulin may be added to the TPN solution or provided subcutaneously. Severe hyperglycemia (serum glucose >400) may necessitate an IV insulin infusion or discontinuation of the TPN. Hypoglycemia Hypoglycemia can result from excess insulin administration. Treatment may include initiation of a 10% dextrose infusion with concurrent decrease of the insulin-containing TPN solution, or administration of an ampule of 50% dextrose. Serum glucose levels should be monitored closely until they rise to acceptable levels. When TPN solutions are stopped abruptly for fluid and electrolyte management when glycemic control is good, a rebound hypoglycemia may occur. If a TPN solution cannot be weaned of gradually, 10% dextrose should be infused for one hour to two hours to avoid rebound hypoglycemia. Refeeding Syndrome The refeeding syndrome refers to the metabolic and physiologic shifts of electrolytes and mineral (e.g., potassium, phosphorous, and magnesium) which occur as a result of aggressive nutrition. The delivery of calories, especially in the form of carbohydrate, may induce the refeeding syndrome in a patient who is severly malnourished. For patients who are at risk for refeeding, calories should be initiated at 20 kcal/kg/day and advanced slowly over a period of three days to four days, while monitoring potassium, magnesium, and phosphorous levels on a daily basis.

Protein Protein provided in the form of crystalline amino acids in TPN solutions are well tolerated by patients with adequate renal and hepatic function. Prerenal azotemia may result from dehydration, excess protein, and/or inadequate non-protein calories. If the cause is thought to be excessive protein, these patients may benefit from a reduction in the amount of amino acids. Imbalances in plasma amino acids have been noted in a variety of clinical situations. Branched-chain enriched formulations that have reduced content of aromatic amino acids and methionine may help reverse hepatic encephalopathy, but should be reserved for patients who do not respond to conventional management.

Fat Hyperlipidemia is associated with an individual’s inability to clear lipid emulsions from the bloodstream. Critically ill patients with major organ dysfunction may exhibit less efficient clearance and thus require frequent monitoring for elevated blood lipids.58 Plasma triglycerides should be monitored routinely during TPN anytime hyperlipidemia is suspected. Acceptable serum triglyceride levels are less than 250 mg/dL four hours after lipid infusion for piggybacked lipids and less than 400 mg/dL for continuous lipid infusion.59 Reducing the dose for continuous infusion or lengthening the delivery time for piggybacked lipids usually lowers serum triglyceride levels. Stressed patients receiving fat-free TPN demonstrate biochemical evidence of essential fatty acid deficiency within a matter of weeks.60 Clinical manifestations occur as early as 6 weeks after the initiation of fat-free TPN.61 Essential fatty acid deficiency is prevented by providing 2-4% of total calories from linoleic acid. This translates into approximately 500 mL of 10% lipid emulsion or 250 mL of 20%

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lipid emulsion administered over 8 to 10 hours three times a week; or 500 mL of a 20% lipid emulsion once a week. There is a concern regarding the detrimental effect of parenteral long-chain triglycerides (LCTs) on immune function. To minimize the adverse effect of intravenous lipid delivery, fat intake should be restricted to less than 30% of total calories or 1g/kg/day for adults and provided slowly over 8 to 10 hours if administered as an IV supplement.

Micronutrient-Related Complications Once tolerance to the macronutrients has been established, the day-to-day management of TPN centers around fluid and electrolytes. Fluid and electrolyte shifts between the intracellular and extracellular space or changes in total body water or electrolyte content may require changes in the TPN composition and volume. When evaluating the fluid and electrolyte status of a patient receiving TPN it is important to evaluate the other intravenous fluids and medications that the patient is receiving. Although some institutions use the TPN prescription as a vehicle for fluid and electrolyte management, if a patient has excessive losses it may be necessary to replace these fluids and electrolytes with separate intravenous fluids (IVFs) outside of the TPN.

Fluid

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Fluid deficits may be due to extravascular, intravascular, interstitial, or total body water losses. Extracellular fluid deficits may result from abnormal losses from the gastrointestinal tract, kidneys, skin, hemorrhage, and fever. Appropriate intervention would be fluid replacement with fluid of similar composition to that lost (see Table 10.7). Intravascular to interstitial shifting of fluids is known as “third spacing.” Treatment involves maintaining intravascular volume while minimizing the fluid and sodium content of the TPN. Colloid therapy may be indicated in some instances. Total body water deficits can occur from losses associated with fever, gastrointestinal losses, diabetes insipidus, prolonged artificial ventilation, and inadequate water intake. Treatment consists of free water replacement. The calculated water deficit is computed as: water deficit (L) = 0.6 (wt. in kg) x [Na/140 - 1] (see refs. 62,63) Half of the deficit should be replaced over the first 24 hours and the remainder over the next one to two days.64 Extracellular fluid overload may result from renal dysfunction, nephrotoxic drugs, decreased renal blood flow, congestive heart failure, and liver disease. Treatment includes the administration of diuretics, sodium and fluid restriction, and the use of concentrated TPN solutions. Total body water overload occurs as a result of excessive free water intake or syndrome of inappropriate antidiuretic hormone (SIADH). Intervention involves decreasing the volume of the TPN solution and other IVFs.

Sodium Sodium is the most prevalent of the extracellular electrolytes and has a primary role in controlling the distribution of water throughout the body. The usual dose of sodium in TPN is 100-150 mEq/day (see Table 10.2).

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Table 10.7. Approximate electrolyte composition of various body fluids Electrolytes (mEq/L) Source Volume (mL/d) Gastric 2000-2500 pH<4 pH>4 Pancreatic 1000 Bile 1500 Small Bowel 3500 Diarrhea 1000-4000 Urine 1500 Sweat

Na 60 100 140 140 100 60 40 50

K 10 10 5 5 15 30 0 5

HCO3 ----90 35 25 45 -----

CL 90 100 75 100 100 45 20 55

Reprinted with permission from: Grant JP. Handbook of Total parenteral nutrition. 2nd ed. Philadelphia: W.B. Saunders Co; 1992:174.

Hyponatremia (see Table 10.8) Hyponatremia (sodium <130 mEq/L) represents a relative loss of sodium in proportion to water or a gain of water in proportion to sodium. Hyponatremia in a hypovolemic patient with a low serum osmolality should be treated with the administration of isotonic or hypertonic saline and by increasing the sodium in the TPN. The sodium deficit may be calculated as: Na deficit (mEq) =0.6 (Wt in kg) x (140 - Na) + (140) x (Volume Deficit in L) One half of the deficit should be replaced over the first 24 hours, then the remainder over the next one or two days. Hypertonic hyponatremia may be due to hyperproteinemia or hyperlipidemia since the volume of the aqueous component in which the sodium is dissolved is very high.64 Hyponatremia may also be seen with hyperglycemia. Each 100 mg/dL elevation of glucose above normal will decrease sodium by 1.6-2.0 mEq per liter. In each of these cases, the sodium will return to normal once the underlying problem is corrected. Dilutional hyponatremia results from excess free water and not by sodium deficit. When hyponatremia is associated with a low serum osmolality, and the patient is euvolemic or hypervolemic, water should be restricted and the TPN solution concentrated. Hypernatremia Hypernatremia (sodium >150 mEq/L) can result from dehydration, osmotic diuresis, hypoglycemia, hypocalcemia, antidiuretic hormone deficiency, head trauma, and pituitary tumors. Treatment includes fluid replacement if the patient is dehydrated (see section on Fluid) and/or decrease of the sodium in the TPN.

Potassium Potassium is the most prevalent intracellular cation and functions primarily in maintaining cell volume, hydrogen ion concentration (pH), enzyme function, protein synthesis, and cell growth. Therefore, potassium should be monitored frequently when starting TPN. The normal dose of potassium in TPN is 60-120 mEq/day (see Table 10.2)

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Table 10.8. Evaluation and treatment of hyponatremia in TPN patients Level High Normal Low

Osmolality (>285 mOsm) (280-285 mOsm) (<280 mOsm) Euvolemic or Hypervolemic Hypovolemic

Etiology Hyperproteinemia Hyperlipidemia Hyperglycemia H2O intoxication SIADH Renal failure Cardiac failure, Cirrhosis GI losses Renal losses Third-space losses

Treatment Underlying condition Restrict H2O

Isotonic saline

Reprinted with permission from: Recognition and management of complication. In: Matarese LE, ed. Nutrition Support Handbook. Cleveland, OH: The Cleveland Clinic Foundation; 1997:77.

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Hypokalemia Hypokalemia (K+ <3.5 mEq/L) results from a decrease in body potassium (more often due to increased losses than to insufficient intake) or a shift of potassium from the extracellular fluid (ECF) to the intracellular fluid (ICF).64 Shifts of potassium from the ECF to the ICF occur as a result of anabolism (e.g., part of the refeeding syndrome), metabolic alkalosis, and increased levels of insulin. Hypokalemia should be corrected prior to starting TPN since the resultant anabolism will worsen the hypokalemia. Total body potassium deficit may be calculated (see Table 10.9) or an estimate can be made based on serum values. In general, for serum potassium levels of 3.0-3.5 mEq/L, the estimated deficit is 100-200 mEq; for levels of 2.5-3.0 mEq/ L, the estimated deficit is 150-250 mEq; and for levels of 2.0-2.5 mEq/L, the estimated deficit is 200-300 mEq.63 In addition to providing potassium in the TPN, intravenous replacements of potassium should be given to patients for serum values less than 3.5 mEq/L who have urine output of at least 30 mL per hour. Replace half of the deficit over the first 12 to 24 hours. Typically, a dose of 20 mEq of potassium in 100 mL of saline over one hour can be expected to increase the serum potassium by 0.2 mEq/L. A repeat serum potassium measurement should be done at least one hour after the IV replacement to assure potassium has been adequately repleted. Hyperkalemia Hyperkalemia (K+ >5.5 mEq/L) can result from an increase in exogenous or endogenous potassium load, an extracellular potassium shift, or inadequate potassium excretion. When a TPN patient develops hyperkalemia it may be necessary to discontinue the TPN and infuse standard non-potassium-containing IVFs temporarily until the next TPN solution is hung.

Chloride Chloride is an extracellular anion that is found primarily in the interstitial and lymph fluid compartments. Sodium and chloride are usually added in a 1:1 ratio in TPN to prevent metabolic alkalosis and hyperchloremic acidosis. Generally chloride losses and gains follow those of sodium. The usual dose of chloride in TPN is 100-150 mEq/day (see Table 10.2)

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Table 10.9. Dosing and intravenous replacement of electrolytes in TPN Electrolyte RDA* Oral Sodium 500 mg (Na) (21.7 mEq) Potassium 2,000 (K) mg (51 mEq)

Usual Adult IV Dose 100-150 mEq

Chloride (Cl)

100-150 mEq

750 mg (21 mEq)

60-120 mEq

Calculation of Deficit Na deficit(mEq)= 0.6 wt(kg)x(140-Na)+ (140)x(Vol. def. in L) K deficit (mEq)= 100-200 mEq if serum K 3.0-3.5

Cl deficit (mEq)= 0.5 x wt (kg) x (103 measured Cl)

Technique of Intravenous Replacement Replace 1/2 deficit over 24 hours and repeat serum Na Replace 1/2 deficit in 12-24 hours with boluses of 20 mEq KCL in 100 mL D5W over 1-2 hours. Recheck K level 1 hour after bolus. If K < 3.5, repeat IV replacement. If K > 3.5, add additional K to next TPN bag. Replace 1/2 deficit over 24 hours.

*Minimum requirement for health persons. Reprinted with permission from: Recognition and management of complications. In: Matarese LE, ed. Nutrition Support Handbook. Cleveland, OH: The Cleveland Clinic Foundation; 1997:79.

Hypochloremia Hypochloremia usually occurs in conjunction with metabolic alkalosis. Hypovolemia due to overdiuresis or unreplaced nasogastric suctioning can also lead to contraction alkalosis. Treatment of hypochloremia due to metabolic alkalosis will be discussed in the section on acid-base disorders. Hyperchloremia Hyperchloremic metabolic acidosis is usually a result of excessive saline administration. Appropriate treatment includes reducing the chloride content of the TPN solution or changing to an IVF with a lower chloride concentration. Treatment of hyperchloremia due to metabolic acidosis will be discussed in section on acid-base disorders.

Calcium Calcium is an extracellular cation that regulates many neuromuscular functions and enzymatic processes. The usual dose of calcium in TPN is 9-22 mEq/day (See Table10.2). Sixty percent of serum calcium is bound to protein, primarily albumin. Therefore, patients with low albumin levels will have low serum calcium concentrations. An ionized calcium level should be measured when calcium balance is a concern. In states of hypoalbuminemia when only the total serum calcium is available, there is a 0.8 mg/dL decline in total serum calcium for each 1.0 mg/dL decrease in albumin concentration below 4.0 g/dL.11 Serum calcium concentration may be corrected for hypoalbuminemia as follows: corrected serum calcium = [(4.0 gm/dL-measured serum albumin) x 0.8] + measured serum calcium

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Hypocalcemia Hypocalcemia (total Ca++ corrected <8.0 mg/dL; ionized Ca++ <4.5 mg/dL) can result from many disorders that decrease calcium absorption, increase its loss, or alter its regulation. As long as the calcium-to phosphorous ratio is still acceptable, calcium may be increased in the TPN solution to treat hypocalcemia. The combination of calcium and phosphorous in TPN formulas has the potential to form a precipitate. If calcium in the TPN cannot be increased, or for acute, symptomatic hypocalcemia, intravenous calcium is indicated (see Table 10.6). Calcium gluconate can be administered, either as 10 to 20 mL of 10 percent calcium gluconate or as a continuous drip of 100 mL 10 percent calcium gluconate in 1000 mL of 5 percent dextrose in water, infused over at least four hours.65 Hypercalcemia Hypercalcemia (total Ca++corrected >11.0 mg/dL, ionized Ca++ >5.5 mg/dL) can occur with either a rise in total serum calcium level or an increase in the fraction of ionized calcium. The reduction or deletion of calcium from the TPN solution is the usual treatment of asymptomatic hypercalcemia. Symptomatic hypercalcemia is typically treated by the expansion of the ECF to increase urine output and administration of loop diuretics to increase calcium excretion.66

Phosphorus Phosphorus is the major intracellular anion and plays an important role in ATP synthesis, cell membrane integrity, energy metabolism, acid-base balance, and oxygen delivery to tissues. The usual dose of phosphorous in TPN is 15-30 millimoles (mmol) per day.11

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Hypophosphatemia Hypophosphatemia can be divided into two categories: moderate (1.0-2.5 mg/ dL) and severe (<1.0 mg/dL). The number reflects a reduction in serum phosphorus concentration rather than a decrease in cellular phosphate content.67 Gradual depletion of body phosphate stores occurs as a result of inadequate dietary phosphate intake or impaired absorption. Hypophosphatemia that develops suddenly is more common and can result from intracellular shifts, increased urine losses, or a sudden increase in phosphorus utilization (e.g., refeeding syndrome, anabolism).64,68,69 Moderate hypophosphatemia can be treated with oral sodium or potassium phosphate supplements if the patient has a functioning gastrointestinal (GI) tract. Intravenous phosphate replacement as sodium phosphate or potassium phosphate is indicated for severe hypophosphatemia or when the GI tract is nonfunctional. The recommended dose is 0.24 mmol/kg for severe symptomatic hypophosphatemia and 0.16 mmol/kg for severe asymptomatic hypophosphatemia.66 Intravenous phosphorus replacement should be done over a period of six hours to keep the serum calcium level from falling concomitantly. If the patient is receiving TPN, the amount of phosphorus in the solution should also be increased, providing that the calcium to phosphorus ratio remains within acceptable ranges. Continue to monitor serum levels until the phosphorus levels normalize and then periodically thereafter for further decreases as the phosphorus moves into the intracellular compartment. Hyperphosphatemia Hyperphosphatemia (PO4 >than 5.0 mg/dL) is usually asymptomatic, but it may induce hypocalcemia. If the calcium-phosphorus product in the blood exceeds

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70 mg/dL, calcification of soft tissue may occur.65 Phosphorus is reduced or eliminated from the TPN solution in cases of hyperphosphatemia. Also, the use of 20 percent rather than 10 percent lipid emulsion is recommended because the phosphorus content per calorie delivered is less.70

Magnesium Magnesium is an important coenzyme in the metabolism of both carbohydrate and protein. It is also involved in neuromuscular activity. The usual dose of magnesium in TPN is 8-24 mEq/day (see Table10.2). Hypomagnesemia Hypomagnesemia (Mg <1.5 mEq/L) can occur in patients with excessive GI losses , during anabolism, or with renal losses. Magnesium may appear low in patients with hypoalbuminemia. A corrected magnesium level may be calculated as: Corrected Mg++ = Mg++ + 0.005(40 - serum albumin) Patients with normal renal function can receive a replacement of 8-24 mEq IV over four to six hours (see Table10.6). The magnesium content of the TPN solution should also be increased. Serum magnesium levels should be monitored until the patient is repleted and periodically thereafter to minimize the risk of hypermagnesemia. Hypermagnesemia Hypermagnesemia (Mg++ >2.5 mEq/L) occurs infrequently and is most often seen with acute or chronic renal failure. Treatment of hypermagnesemia involves eliminating any exogenous sources of magnesium (e.g., reduction or elimination from the TPN solution) and correcting any volume deficits or acidosis.

Acid-Base Disorders Acid-base disorders include metabolic acidosis and alkalosis and respiratory acidosis and alkalosis. Acidosis or alkalosis may result from a variety of causes in the TPN patient. Metabolic Acidosis Metabolic acidosis is characterized by an arterial pH <7.35 and serum bicarbonate (HCO3-) <25 mEq/L. Chloride concentrations are normal or increased, sodium concentrations are normal, and potassium concentrations are increased. The increase in serum potassium occurs as the potassium moves from the ICF to the ECF. As the metabolic acidosis is corrected, the serum potassium level should return to normal. The causes of metabolic acidosis include increased generation/addition of acids (e.g., diabetic ketoacidosis, lactic acidosis, rhabdomyolysis), retention of acids (e.g., renal insufficiency), or loss of base bicarbonate (severe diarrhea, small bowel fistulas, pancreatic drainage, renal tubular acidosis). Treatment of metabolic acidosis is directed at treating the underlying disorder. Serum bicarbonate is not stable in TPN solutions because of the formation of insoluble calcium or magnesium carbonate. Therefore, acetate, its precursor, is added for regulation of acid-base balance. Acetate is rapidly metabolized to bicarbonate in the liver. Serum CO2 levels are used as a guide for administration of acetate additives. When the CO2 level is low, sodium or potassium should be added in the form of an acetate salt. When metabolic acidosis is caused by excessive saline administration,

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the chloride content of the TPN solution can be reduced by replacing some of the salts with acetate. Metabolic Alkalosis Metabolic alkalosis is characterized by a rise in arterial pH >7.45 and HCO3 >25 mEq/L and a decline in the H+ in the serum. Volume contraction is often present. Potassium concentrations are usually decreased in metabolic alkalosis secondary to an intracellular shift. Metabolic alkalosis occurs via the addition of HCO3 or its precursors (e.g., administration of excessive amounts of NaHCO3 or acetate), massive blood transfusions (citrate added as a buffer), loss of acid (e.g., via nasogastric suctioning, vomiting, excessive use of antacids), or loss of fluid containing more chloride than HCO3 (e.g., thiazide diuretics, chronic diarrhea, hyperadrenocorticism). Treatment of metabolic alkalosis is directed at correcting the underlying disorder. Normal volume needs to be restored in a hypovolemic patient and potassium needs to be replaced in cases of hypokalemia. Chloride replacement is indicated in cases where alkalosis is the result of diuretics or nasogastric losses. The chloride deficit can be calculated as follows: Cl- deficit (mEq) = 0.5 x wt (kg) x (103 - measured Cl-) (see ref. 62). Chloride may be increased in the TPN solution or provided as a separate infusion of potassium or sodium chloride.

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Respiratory Acidosis Respiratory acidosis is characterized by hypercapnia (pCO2 >40 mm Hg) and a pH <7.35. Hypercapnia can result from impaired alveolar ventilation or from excessive CO2 production, which can be caused by overfeeding, especially carbohydrate.2 This is primarily seen in patients with compromised respiratory function. Acute respiratory acidosis can result from sleep apnea, adult respiratory distress syndrome (ARDS), aspiration of a foreign body, asthma, pneumothorax, or hemothorax. Chronic respiratory acidosis can be secondary to chronic obstructive pulmonary disease (COPD), morbid obesity, neuromuscular diseases, hypothyroidism, and starvation cachexia. Treatment of respiratory acidosis is directed at treating the underlying cause. If there is increased CO2 production as a result of high dextrose concentrations, some of the dextrose calories should be replaced with fat. It is important to avoid overfeeding with any substrate. Respiratory Alkalosis Respiratory alkalosis is characterized by hypocapnia (PCO2 <40 mm Hg) and a pH >7.45. Primary respiratory alkalosis has not been reported to be a complication of TPN therapy. It can occur with central stimulation (e.g., anxiety, pain, head injury, cerebrovascular accident, tumors, salicylate overdose, and early gram negative sepsis) or peripheral stimulation (e.g., pulmonary embolism, congestive heart failure, pneumonia, interstitial lung disease, and high altitudes). As with all acid-base disorders, treatment should be directed at correcting the underlying disease.

Long-Term Complications Metabolic bone disease is reported as a complication of long-term TPN infusion.71-73 The etiology is thought to be multi-factorial. Increased urinary losses of calcium, phosphorous, and magnesium have been associated with cycled long-term TPN. Continuous TPN appears to promote mineral homeostasis better than cycled

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TPN.59 Hypercalcuria in home TPN patients can be minimized by providing adequate levels of vitamin D, calcium, and phosphorous; and avoidance of metabolic acidosis and high protein loads.

Cycling Total Parenteral Nutrition When a decision is made to send a patient home on TPN, cycling of the daily infusion in a stepwise fashion should begin. Infusion of TPN for only part of the day provides both metabolic and psychological benefits. Depending upon tolerance of fluid volume and glucose load, the desired infusion time may range from 8 -16 hours.

Conclusion Total parenteral nutrition enables feeding of patients who formerly would have succumbed to starvation. Adherence to technique and monitoring standards help to ensure the safety and efficacy of TPN. Periodic assessment of energy and protein needs assure that patients are receiving the appropriate amount of substrates. Strict catheter care and monitoring techniques help to minimize complications, while treating them as they occur. Finally, providing fluid and electrolyte requirements for maintenance, as well as extra renal or GI losses, is important to minimize the risk of metabolic complications

Selected References 1. 2. 3. 4. 5. 6. 7. 8. 9. 10. 11. 12.

Skipper A. Principles of parenteral nutrition. In: Matarese LE, Gottschlich MM, eds. Contemporary Nutrition Support Practice. Philadelphia: WB Saunders Co., 1998:227-242. Steiger E, Seidner D, McAdams MP et al. Parenteral nutrition. In: Matarese LE, ed. Nutrition Support Handbook. Cleveland: The Cleveland Clinic Foundation, 1997:45-62. Wolfe RR, O’Donnell TF, Stone MD et al. Investigation of factors determining the optimal glucose infusion rate in total parenteral nutrition. Metabolism 1980; 29:892-900. A.S.P.E.N. Board of Directors. Guidelines for the use of parenteral and enteral nutrition in adult and pediatric patients. JPEN 1993; 17:1SA-52SA. Steiger E, Seidner D, McAdams MP et al. Estimating macronutrient requirements. In: Matarese LE, ed. Nutrition Support Handbook. Cleveland: The Cleveland Clinic Foundation, 1997:27-34. Nutrition Advisory Group, AMA Department of Foods and Nutrition: Guidelines for essential trace element preparations for parenteral use. JAMA 1979; 241:2051-2054. Wolman SL, Anderson GH, Marliss EB et al. Zinc in total parenteral nutrition: Requirements and metabolic effects. Gastroenterology 1979; 79:458-467. Grant JP. Trace element requirements and deficiency syndromes. In: Handbook of Total parenteral nutrition. Philadelphia: WB Saunders Co., 1992:275-290. AMA Department of Foods and Nutrition. Guidelines for essential trace element preparations for parenteral use: A statement by an expert panel. JAMA 1979; 241:2052-2054. Weinstein S. Anatomy and physiology applied to inravascular therapy. In: Plumen’s Principles and Practice of Intravenous Therapy. 6th edition. Philadelphia: Lippincott, 1997:49-57. Lenssen, P. Management of total parenteral nutrition. In: Skipper A, ed. Dietitian’s Handbook of Enteral and Parenteral nutrition. 2nd edition. Gaitherburg: Aspen Publishers, 1998:481-525. Harris JA, Benedict FG. A biometric study of basal metabolism in man. Washington, DC: Carnegie Institute, 1919:publication no. 179.

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26. 27. 28. 29. 30. 31. 32. 33. 34. 35. 36.

Fleck A, Raines G, Hawker F, et al. Increased vascular permeability: A major cause of hypoalbuminemia in disease and injury. Lancet 1985; 1:781-784. Leung FY. Trace elements in parenteral micronutrition. Clin Biochem 1995; 28:561-566. Herbst CA. Indication, management and complications of percutaneous, subclavian catheters: An audit. Surg 1978; 113:1421-1425. Stizman JV, Townsend TR, Siler MC et al. Septic and technical complications of central venous catheterization. Ann Surg 1985; 202:766-770. Slezak FA, Williams GB. Delayed pneumothorax: A complication of subclavian vein catheterization. JPEN 1984; 8:571-574. Wendt JR. Avoiding serious complications with central venous access. Surg Rounds 1992; 7:637-642. Green HL, Nemir P Jr. Air embolism as a complication during parenteral alimentation. Am J Surg 1971; 121:614-616. Oppenheimer MJ, Durant TM, Lymes P. Body position in relation to venous air embolism and the associated cardiovascular respiratory changes. Am J Med Sci 1953; 225:362-373. Shires T, O’Banion J. Successful treatment of massive air embolism producing cardiac arrest. JAMA 1958; 167:1483-1484. Block PC. Transvenous retrieval of foreign bodies in the cardiac circulation. JAMA 1973; 224:241-242. O’Reilly RJ. Aberrant venous catheter position within the left chest. Contemp Surg 1978; 12:29-34. Dubar RD, Mitchell R, Lavine M. Aberrant locations of central venous catheters. Lancet 1981; 1:711-715. Brandi LS, Oleggini M, Frediani M et al. Inadvertent catheterization of the internal thoracic vein mimicking pulmonary embolism: A case report. JPEN 1988; 12:221-222. Sitzman JV, Townsend TR, Siler MC et al. Septic and technical complications of central venous catheterization. Ann Surg 1985; 202:766-770. Fabri PJ, Mirtallo JM, Ruber RL et al. Incidence and prevention of thrombosis of the subclavian vein during total parenteral nutrition. Surg Gynecol Obstet 1982; 115:238-240. Brismar B, Hardstedt C, Jacoson S et al. Reduction of catheter-associated thrombosis in parenteral nutrition by intravenous heparin therapy. Arch Surg 1982; 1196-1199. Bern MM, Bothe A Jr, Bistrian B, et al: Prophylaxis against central vein thrombosis with low-dose warfarin. Surgery 1986; 99:216-220. Holcombe B, Forloines-Lynn S, Garmhausen L. Restoring patency of long-term central venous access devices. J Intravenous Nurs 1992; 15(1):36-41. Haire WD, Lieberman RP. Thrombosed central venous catheters: restoring function with 6-hour urokinase infusion after failure of bolus urokinase. JPEN 1992; 16:129-132. Werlin SL, Lausten T, Jessen S et al. Treatment of central venous catheter occlusions with ethanol and hydrochloric acid. JPEN 1995; 19:416-418. Pennington CR, Pithie AD. Ethanol lock in the management of catheter occlusion. JPEN 1987; 11:507-508. Fuhrman MP. Management of Complications of Parenteral nutrition. In: Matarese LE, Gottschlich MM, eds. Contemporary Nutrition Support Practice. Philadelphia: WB Saunders Co., 1998:244. Bozzetti F, Terno G, Bonfanti G et al. Prevention and treatment of central venous catheter sepsis by exchange via a guidewire. Ann Surg 1983; 198:48-52. Mosca R, Curtas, Forbes B et al. The benefits of isolator cultures in the management of suspected catheter sepsis. Surgery 1987; 102(4):718-723.

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Williams WW. Infection control during total parenteral nutrition therapy. JPEN 1985; 9:735-746. O’Keefe SJ, Burnes JU, Thompson RL. Recurrent sepsis in home parenteral nutrition patients: an analysis of risk factors. JPEN 1994; 18:256-263. Buchman AL, Morkarzel A, Goodson B et al. Catheter-related infection associated with home parenteral nutrition and predictive factors for the need for catheter removal in their treatment. JPEN 1994; 18:297-302. Quigley EMM, Marsh MN, Shaffer JL et al. Hepatobiliary complications of total parenteral nutrition. Gastroenterology 1994; 104:286-301. Clarke PJ, Ball MJ, Kettlewell MGW. Liver function tests in patients receiving parenteral nutrition. JPEN 1991; 15:54-59. Meguid MM, Okakoshi MP, Jeffers S et al. Amelioration of metabolic complications of conventional total parenteral nutrition. Arch Surg 1984; 119:1294-1298. Tayek JA, Bistrin B, Sheard NF et al.: Abnormal liver function in malnourished patients receiving total parenteral nutrition: Aprospective randomized study. J Am Coll Nutr 1990; 9(1):76-83. Pitt HA, King W, Mann LL et al. Increased risk of cholelithiasis with prolonged total parenteral nutrition. Am J Surg 1983; 145:106-111. Bowyer BA, Fleming CR, Ludwig J et al. Does long-term home parenteral nutrition in adult patients cause chronic liver disease? JPEN 1985; 9:11-17. Dudrick PS, Souba WW. Special fuels in parenteral nutrition. In: Rombeau JL, Caldwell MD, eds. Clinical Nutrition: Parenteral nutrition. 2nd edition. Philadelphia: WB Saunders Co., 1993:209-222. Spitz J, Gandhi S, Hecht G et al. The effects of total parenteral nutrition on gastrointestinal tract function. Clin Nutr 1993; 12(suppl 1):S33-S37. Murphy JP, King DR, Dubois A. Treatment of gastric hypersecretion with cimetidine in the short-bowel syndrome. N Eng J Med 1979; 300:80-81. Baptista RJ. Role of histamine (H2)-receptor antagonists in total parenteral nutriiton patients. Am J Med, 1987; 83(6A):53-57. Fuhrman, MP. Management of complications of parenteral nutrition. In: Matarese LE, Gottschlich MM, eds. Cont Nutr Sup Pract Philadelphia: WB Saunders Co., 1998:243-263. Talpers SS, Romberger DJ, Bunce SB et al. Nutritionally associated increased carbon dioxide production. Chest 1992; 102:551. Dark SA, Pingleton SK, Kerby GR. Hypercapnia during weaning. Chest 1985; 88:141-143. Starker PM, LaSala PA, Forse A et al. Response to total parenteral nutrition in the extremely malnourished patient. JPEN 1985; 9:300-302. Murciano D, Rigaud D, Pingleton S et al. Diaphragmatic function in severely malnourished patients with anorexia nervosa. Effects of renutrition. Am J Respir Crit Care Med 1994; 150:1569-1574. Benotti PN, Bristrian B. Metabolic and nutritional aspects of weaning from mechanical ventilation. Crit Care Med 1989; 17(2):181-185. Chandra RK. Protein-energy malnutrition and immunological responses. J Nutr 1992; 122:596-600. Druml W. Nutritional support in acute renal failure. Clin Nutr 1993; 12:196-207. ASPEN Board of Directors: Guidelines for the use of parenteral and enteral nutrition in adult and pediatric patients. JPEN 1993 (4 Supple):1SA-52SA. Miller DG, Williams SK, Palombo JD et al. Cutaneous application of safflower oil in preventing essential fatty acid deficiency in patients on home parenteral nutrition. Am J Clin Nutr 1975; 2:258-263. Rudman D, Williams PJ. Nutrient deficiencies during total parenteral nutrition. In: Narins RG, Maxwell MH, Kleeman CR, eds. Clinical Disorders of Fluid and Electrolyte Metabolism. New York: McGraw-Hill, 1987:1437-1462.

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Inadomi DW, Kopple JD. Fluid and electrolyte disorders in total parenteral nutrition. In: Narins RG, Maxwell MH, Kleeman CR, eds. Clinical Disorders of Fluid and Electrolyte Metabolism. New York: McGraw-Hill, 1987:1437-1462. Steiger E, Seidner D, McAdams MP et al. Recognition and management of complications. In: Matarese LE, ed. Nutrition Support Handbook. Cleveland: The Cleveland Clinic Foundation, 1997:73-80. Whitmire SJ. Fluids and electrolytes. In: Matarese LE, Gottschlich MM, eds. Cont Nutr Sup Pract. Philadelphia: WB Saunders Co., 1998:127-144. Horne MM, Swearingen PL. Pocket Guide to Fluids, Electrolytes, and Acid-Base Balance. 2nd edition. St. Louis: Mosby-Year Book, 1993. Van Zee KJ, Barie PS, Lowry SF. Electrolyte disorders. In: Cameron JL, ed. Current Surgical Therapy. Fourth edition. St. Louis: Mosby-Year Book, 1992:1005-1029. Dwyer D, Barone JE, Rogers JF. Severe hypophosphatemia in postoperative patients. Nutr Clin Pract. 1992; 7(6):279-283. Solomon SM, Kirby DF. The refeeding syndrome: a review. JPEN 1990; 14:90-97. Marik PE, Bedigian MK. Refeeding hypophosphatemia in critically ill patients in an intensive care unit. Arch Surg 1996; 131:1043-107. Giner M, Curtas S. Adverse metabolix consequences of nutritional support: Macronutrients. Surg Clin North Am 1986; 66:1025-1047. Shike M, Shils ME, Heller A et al. Bone disease in prolonged parenteral nutrition: Osteopenia without mineralization defect. Am J Clin Nutr 1986; 44:89-98. Vargas JH, Klein GL, Ament ME et al. Metabolic bone disease of total parenteral nutrition: Course after changing from casein to amino acids in parenteral solutions with reduced aluminum content. Am J Clin Nutr 1988; 48:1070-1078. Korton MA, Rettner R, Lipkin EW et al. D-lactate and metabolic bone disease in patients receiving long-term parenteral nutrition. JPEN 1989; 13:132-135. Koo WWK. Parenteral nutrition-related bone disease. JPEN 1992; 16:386-394.

CHAPTER 1 CHAPTER 11

Radiologic Assessment of Nutritional and Metabolic Status Diane R. Horowitz, Rifat Latifi

Introduction Accurate metabolic measurements are essential for evaluating the nutri-tional status of patients requiring nutritional support. Many of the currently used biochemical and anthropometric methods for assessment of nutritional status, as discussed in the previous chapter, have inherent limitations which may result in inaccurate estimations of total body fat and protein status. These limitations have led to the search for new methods to assess metabolic status using body composition measurements. Typically, methods of determining body composition are based on the model which divides the body into two chemically distinct compartments: fat and fat free. The fat free compartment is further divided into three chemical groups: water, protein, and bone minerals. Additional methods for assessing body composition include: a) assessment of total body water using isotopes of hydrogen, deuterium and tritium, b) estimation of lean body mass from total body potassium or urinary creatinine excretion, and c) assessment of human body composition by densitometry and anthropometry. More recent methods, however, include measuring the multielemental composition of the human body via neutron activation analysis; determining total body skeletal muscle mass with total plasma creatinine and endogenous urinary 3-methylhistidine excretion; and determining fat free mass by electrical conductance techniques. Although, more specific, some of these methods require complex laboratory equipment and do not provide accurate estimates of body fat in an individual.1 Various radiologic examinations are now used to assess body composition, in the attempt to objectively determine the metabolic and nutritional status in patients requiring nutritional support. These methods of estimating body composition will be the focus of this chapter.

Ultrasound Use in Assessing Body Composition Ultrasound is used as a method for predicting body fat by measuring subcutaneous fat thickness.2 Ultrasound overcomes the limitations of the caliper method of measuring subcutaneous fat thickness such as variation in skinfold compressibility and difficulty in obtaining interpretable measurements especially on obese subjects.3 In addition to fat measurements, ultrasound is also useful for direct assessment of muscle tissue, which is helpful since loss of body protein usually is of greater concern than loss of body fat.4 Ultrasound uses an instrument in which electrical energy is converted within a probe to high frequency ultrasonic energy, which is then transmitted into the body The Biology and Practice of Current Nutritional Support, 2nd Edition, edited by Rifat Latifi and Stanley J. Dudrick. ©2003 Landes Bioscience.

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in short pulses. When the sound waves impinge perpendicularly upon interfaces of tissues with different acoustical properties, part of the ultrasonic energy is reflected back to the probe which contains a receiver. This is converted back to electrical energy and is displayed on a screen. High frequency transducers are best suited for characterizing the subcutaneous tissues. The ultrasound transducer is coupled to the skin with transmission gel to avoid compressing the underlying tissues. Skin is relatively echogenic and the subcutaneous fat is virtually anechoic.3,4 Ultrasound is used to estimate body density in a fashion similar to calipers. Subcutaneous fat thickness is measured at several sites using the electronic calipers directly on the screen. Regression equations are then used to predict body density and body fat. Measurements taken at the triceps, waist and thigh are found to correlate best with body density. While there is no correlation between triceps skinfold measurement obtained with calipers and measurement of fat thickness by ultrasound, there is a statistically significant correlation between the ultrasound measurements of midarm fat area (MAFA) and the triceps skinfold measurement.3 Sonographic measurements of subcutaneous fat at the waist and thigh sites are the best predictors of body density.3 When ultrasound is used to measure mean arm muscle mass (MAMA), it correlates with lean muscle mass which subsequently correlates with body protein stores.3 Ultrasound has the advantage over anthropometry of being able to calculate bone area and, hence, exclude it from measurements. Anthropometric MAMA does not accurately reflect actual muscle composition because no correction is made for the bone area. The ultrasound method begins with a two dimensional image of the arm taken at a point marked for anthropometric measurements. The subcutaneous fat thickness and muscle thickness of the posterior upper arm are measured on this image. The mid-arm muscle area and mid-arm fat area can be calculated using the ultrasound measurements and the mid-arm circumference. The formulas used assume that the cross section of the arm is circular and the components are made up of concentric rings.4 (Fig. 11.1) Although both anthropometry and ultrasound overestimate MAMA (22.8+/17% and 10+/-12% respectively, mean +/- SD) ultrasound measurements exclude bone area and are, therefore, more accurate than those obtained by anthropometry. In patients with advanced liver disease, measurement of MAFA by ultrasound, using triceps skinfold as the standard, was found to be an accurate index of fat stores.4 Further, when MAMA was measured by ultrasound, it correlated well with lean muscle mass, as estimated by using creatinine height index as the standard.4 Since ultrasonography accurately measures MAFA and MAMA and assesses fat and protein stores, it appears to provide more accurate measurements than anthropometric methods in nutritional and metabolic assessment. In addition, ultrasonography is a reproducible, noninvasive method that has been shown to be especially useful in quantitation of muscle and fat in malnourished children,5 where CT was used as a reference standard.

Computerized Tomography Computerized tomography (CT) can be used to analyze body fat, muscle, and bone composition because it generates high contrast between adipose tissue, muscle and bone tissue. CT scan may have several applications in assessment of nutritional status because it can be performed quickly, the radiation dose is minimal (<1 Rad) and it can be performed in healthy as well as ill patients.6

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11 Fig. 11.1. Transverse ultrasound image of the arm taken at the point marked for triceps skinfold thickness. The muscle thickness has been measured directly (26.3mm). The subcutaneous fat thickness is the total soft tissue thickness minus the muscle thickness (40.3-26.3=14.0 mm). Note that bone is excluded from measurement.

CT can be a useful tool for investigating whether abnormal body fat distribution is associated with the pathogenesis of abnormal glucose tolerance.7 When CT scanning of the thigh was compared with anthropometric and urinary creatinine determinations to assess nutrition in children with inflammatory bowel disease receiving TPN, it was found that there is a correlation between the thigh muscle area, as measured by CT scan, and muscle area calculated from urinary creatinine excretion rate.8 By CT studies it was found that total muscle thigh area is a better predictor of muscle mass as compared to the mid-arm muscle area. CT may be used to evaluate changes within the liver parenchyma following total parenteral nutrition (TPN). Because of the inability of the liver to metabolize the acute increase in protein load associated with TPN, protein accumulates in the liver and may cause hepatomegaly. Protein accumulation and hepatomegaly are more pronounced with severe malnutrition, however, the liver returns to normal size and density on CT studies within approximately three to four days as nutritional status and liver metabolism improves. 9

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Another application of CT is the measurement of intrabdominal fat. Because of its cross-sectional imaging capabilities and its high contrast resolution, CT is able to quantify subcutaneous fat, total body fat, and internal fat, and it does not rely on abdominal subcutaneous fat thickness to estimate total body fat as do ultrasound and anthropometry.7 (Figs. 11.2.A-F). The CT method begins with a cross sectional image of the body part of interest. The parameters of the structure of interest (i.e., total cross section of the image, subcutaneous fat, muscle plus bone, intraperitoneal and visceral fat) can be outlined using a cursor on the viewing console, and the cross-sectional areas can be determined for each image using a computerized planimetric method. Since the scan thickness is known, volume occupied by that tissue can be calculated.1 Subcutaneous fat may be calculated separately by first drawing lines around the area of interest.8 As the volume of each pixel is known, the volume of individual tissues can be determined by adding the number of pixels within a specific Hounsfield unit (HU) range for each slice and then adding the information from each slice.2 In order to evaluate fat and lean body composition, forearm or limb or trunk measurements are used. Techniques using a single CT slice and those using multiple CT slices have been described. Shuman et al describe using three scans, one in the thorax at the nipple level, one in the abdomen at the umbilicus and one in the thigh midway between greater trochanter and patella.7 Tokanuga et al.1 used five levels of measurements: 1. forearm at midpoint of elbow and wrist, 2. chest at fourth intercostal space; 3. abdomen at umbilical level; 4. thighs midway between crotch and popliteal fossa; and 5. calves at midpoint between popliteal and lateral malleolus. Computerized tomography has several advantages over both anthropometric and sonographic methods of estimating mid-arm adipose tissue. First, CT does not rely on the assumption that the arm and its compartments are concentric circles. Fat and muscle are distributed asymmetrically around the arm, and because CT provides a cross-sectional view of the arm with precise delineation of fat, bone and muscle, more accurate measurements of these individual compartments can be made.10 Second, since the CT scan does not include bone area in its assessment of mean arm muscle area as does anthropometry, it offers a more accurate measurement of muscle and muscle wasting in malnutrition. Third, as CT scan does not depend on the differences in compressibility between firm and flabby fat, it is not affected by fat which remains adherent to muscle when the triceps skinfold is gathered for measurement. CT is also more helpful in measuring mid-arm adipose tissue in obese people.9 CT of the lower extremity has been studied and compared with anthropometric measurements. As in the upper extremity, the formula used to assess muscle mass and fat by anthropometry in the lower extremity assume that the cross-sectional area of the various compartments is circular and concentric and may lead to an overestimation of total area, total volume, muscle plus bone area, and muscle plus bone volume and an underestimation of fat content.11 CT scan is not subject to these errors. CT scan evaluation of tissue compartments in the trunk has been performed using single scan and multiple scan techniques. Single scan techniques used to evaluate fat content generally involve obtaining a single axial scan at the umbilical level. The

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Fig. 11.2A. A small area of known fat density has been placed within a region of interest on a cross sectional CT image of the abdomen.

Fig. 11.2B. Graph of the region of interest in Figure 11.2A shows the range of Hounsfield units that will correspond to fat density.

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Fig. 11.2C. Cross sectional CT image of the abdomen where the area which will contain the subcutaneous fat has been placed within the region of interest using a cursor on the computer console.

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The Biology and Practice of Current Nutritional Support Fig. 11.2D. Using the range of Hounsfield units obtained from the graph in Figure 11.2B, a second graph has been formed plotting these pixel values by frequency. Subcutaneous fat area and volume are easily calculated using this graph.

Fig. 11.2E. Cross sectional CT image of the abdomen with the entire abdomen now included in the region of interest.

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Fig. 11.2F. Graph depicting the region of interest outlined in Figure 11.2E. Using this graph, total fat area and volume may be calculated. Visceral fat area and volume are then obtained by subtracting subcutaneous fat area (volume) from total fat area (volume).

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umbilicus is used because it is an easy landmark to identify, and the maximum ratio of fat to total tissue area is present at this level.12 As is the case with any other technique for nutritional assessment and estimation of body composition, the CT scan has its limitations. The primary limitation of estimating fat content from a single scan results secondary to regional variations in fat distribution which are not apparent when a single scan is used. Also, partial volume averaging effects cause inaccurate identification of pixels with attenuation values of fat. In addition, single scan analysis may not be accurate because of fat distribution differences between men and women.11 The ratio of body fat distribution at each level for a given sex is relatively constant regardless of whether the patient is obese or lean. However, the distribution of body fat between males and females changes at different levels and is most pronounced at the L1 level.6 Although total body fat does not differ between males and females, males store more fat within the abdominal cavity and women store more fat in the subcutaneous tissues. Therefore, abdominal CT scan may be more accurate in males.13 In summary, although CT scan as a method of assessing nutritional status and body composition has its limitations, (expensive, availability), it is of great value in energy-balance experiments in which high reproducibility is required,14 and it is the most appropriate technique in studies of adipose tissue distribution.

Magnetic Resonance Imaging (MRI) The possibility of utilizing MRI to evaluate changes in body fat, fatty involvement of the liver and fatty bone marrow changes has been recently studied. The most obvious advantage of utilizing MRI over CT scan is that MRI provides good tissue contrast without exposing the patient to ionizing radiation and contrast. MRI is based on the fact that atomic nuclei, made up principally of neutrons and protons, can behave like magnets. Furthermore, MRI depends on the density of hydrogen nuclei and the physical state of the tissue as reflected in the magnetic relaxation times. Tissue contrast between fat and muscle is high and can be enhanced by changing the magnetic relaxation time variable of the magnetic resonance instrument. 2 Hydrogen protons in fat are primarily held in aliphatic chain hydrocarbons and have nuclear magnetic properties distinct from protons in water or protein chains.15 Adipose tissue has a short longitudinal relaxation time (T1) compared with other tissues. Multiple scan techniques have been described which maximize the contrast between fat and muscle. In standard MR imaging, signal from protons of water and fat cannot be differentiated. Therefore, pixel intensity is the summed contribution from water and fat. A modified spin-echo technique exploits the differences between protons in water molecules and protons in fatty acid molecules. This proton spectroscopic imaging technique increases contrast between fat-containing tissues and other tissues and may help to detect smaller masses of fat containing tissue.13 This method also helps to identify tissue based on measured parameters rather than by image appearance, thereby allowing the individual contributions of fat and water to total signal intensity to be assessed. Whichever method is chosen, quantitation of fat volume in one image or in multiple images is accomplished by morphometric computer analysis similar to those methods described in the computerized tomography section (Figs 11.3.A-E). Subcutaneous fat area is measured by outlining the body surface in a slice and outlining the inner contour of the subcutaneous fat. The difference between these

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The Biology and Practice of Current Nutritional Support Fig. 11.3A. As with CT images, an area of known fat signal is measured to determine the range of values for fat containing tissues.

Fig. 11.3B. T1 weighted MR image where the subcutaneous fat area has been outlined using a computer console cursor.

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Fig. 11.3C. Graph depicting the region of interest in Figure 11.3B. Pixels having values chosen to represent fat are plotted by frequency. Subcutaneous fat area and volume are easily calculated from this graph.

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Fig. 11.3D. T1 weighted MR image with the entire abdomen included in the area of interest. Using the graph in Figure 11.3E, visceral fat area and volume may be tabulated by subtracting subcutaneous fat area (volume) from total fat area (volume).

Fig. 11.3E. Graph of the region of interest in Figure 11.3D. The range of fat “values” has been calculated previously (Fig. 11.3A). Total fat containing tissue area is calculated from this graph.

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two area measurements is the subcutaneous fat area.15 Measurement of visceral fat is accomplished in a manner similar to that described in the CT section. However, MRI does not use Hounsfield units or attenuation values. Instead, signal intensity of pixels is scaled in arbitrary units with zero as no signal (black) and +4095 as maximal signal (white).16 Tissue volume is calculated by multiplication of the area and the effective slice thickness (actual slice thickness + interslice gap thickness).17,18 Several problems inherent to MRI affect fat measurements obtained with this method. First, MRI is sensitive to respiratory motion and bowel peristalsis. These movements cause changes in relative area of fat in a slice. Using multiple slices with averaging of signals or using rapid scanning techniques decreases the effects of motion. Secondly, inhomogeneities in the magnetic field lead to slight intensity variations across an image plane. This can be minimized by proper gradient and RF tuning. Finally, bowel contents may have the same signal intensity as visceral fat. This problem can be minimized by emptying the bowel prior to imaging.15-19

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Although MRI can reliably measure fat areas with no radiation risk to the patient, it is not a very accurate method for determining the absolute amounts of visceral adipose tissue.16 Furthermore, this method is still very expensive and takes longer than ultrasound or CT scan to be performed. In the future, quantitative MRI may be able to predict trabecular bone density in the spine because trabecular bone varies inversely with fat deposition in the bone marrow. As hematopoietic marrow is replaced by fatty marrow, T1 and T2 relaxation times for lumbar vertebrae progressively decrease. The inverse relationship of hematopoietic to fatty bone marrow and the T1 and T2 relaxation times may be used to indirectly measure bone density.

Conclusion Accurate assessment of nutritional status and body composition is of great importance in patients requiring nutritional support. In addition to careful patient history, physical examination, and anthropometric and biochemical measurements, radiographic methods may prove to be helpful in assessing body composition of these patients. Current experience with radiographic methods used in assessing nutritional status, however, does not allow for the use of these methods as the only means of determining the level of malnutrition and the therapeutic interventions for correction of nutritional status.

Selected References 1. 2. 3.

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4. 5. 6. 7. 8. 9.

10. 11. 12. 13.

Tokunaga K, Matsuzawa Y, Ishikawa K et al. A novel technique for the determination of body fat by computed tomography. Internat J OB 1993; 7:437-445. Lukaski HC. Methods for the assessment of human body composition: traditional and new. Am J Clin Nutr 1987; 46:537-556. Fanelli MT, Kuxzmarski RH. Ultrasound as an approach to assessing body composition. Am J Clin Nut 1984; 39:703-709. Cuba T, Lat DA, Bowen A et al. Ultrasonography as a method of nutritional assessment. JPEN 1989; 13:529-534. Koskelo EK, Kivisaari LM, Saarinen UM et al. Quantitation of muscles and fat by ultrasonography: a useful method in the assessment of malnutrition in children. Acta Pediatr Scand 1991; 80:682-687. Grauer WO, Moss AA, Can CE et al. Quantification of body fat distribution in the abdomen using computed tomography. Am J Clin Nutr 1984; 39:631-637. Shuman WP, Morris LLN, Leonetti DL et al. Abdominal fat distribution detected by computed tomography in diabetic men. Invest Radiol 1986; 21:483-487. Lerner A, Feld LG, Riddlesberger MM et al. Computed axial tomographic scanning of the thigh: an alternative method of nutritional assessment in pediatrics. Pediatrics 1986; 77(5):732-737. Riddleberger MM Jr. Radiographic observations in patients receiving total parenteral nutrition. In: Lebenthal E, ed. Total parenteral nutrition: Indications, utilization, complications, and pathophysiological considerations. New York: Raven Press, 1986:207-218. Heymsfield SB, Olafson RP, Kutner MH et al. A radiographic method of quantifying protein- calorie undernutrition. Am J Clin Nutr 1979; 32:693-702. Mayo-Smith W, Hayes CW, Biller BMK et al. Body distribution measured with CT: correlation in healthy subjects, patients with anorexia nervosa, and patients with Cushing Syndrome. Radiology 1989; 170:515-518. Borkan GA, Gerzof SG, Robbins AH et al. Assessment of abdominal fat content by computerized tomography. Am J Clin Nutr 1982; 36:172-177. Dixon AK. Abdominal fat assessed by computed tomography: sex differences in distribution. Clin Rad 1983; 34:189-191.

Radiological Assessment of Nutritional and Metabolic Status 14. 15. 16. 17. 18. 19.

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Kvist H, Sjörström L, Tylen U. Adipose tissue volume determinations in women by computed tomography: technical considerations. Inter J Ob 1986; 10:53-67. Staten MA, Totty WG, Kohrt WM. Measurement of fat distribution by magnetic resonance imaging. Invest Radiol 1989; 24:345-349. Seidell JC, Bakker CJG, van der Kooy K. Imaging techniques for measuring adiposetissue distribution - a comparison between computed tomography and 1.5-T magnetic resonance. Am J Clin Nutr 1990; 51:953-957. Gerald EL, Ferry JA, Amrein PC et al. Compositional changes in vertebral bone marrow treatment for acute leukemia: assessment with quantitative chemical shift imaging. Radiology 1992; 183:39-46. Lancaster JL, Ghiatas AA, Alyassin A et al. Measurement of abdominal fat with T1- weighted MR images. JMRI 1991; 1:363-369. Gerard EL, Snow RC, Kennedy DN et al. Overall body fat and regional fat distribution in young women: quantification with MR imaging. AJR 1991; 157:99-104.

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CHAPTER 12

Enteral Nutrition: Indications, Monitoring and Complications Gayle Minard

Introduction The use of supplemental enteral nutrition in surgical patients has increased as more evidence of its benefit compared with parenteral nutrition (PN) has been demonstrated. Enteral feeding has been shown to decrease significant infections and length of hospital stay following trauma, speed the recovery of head-injured patients, and decrease complications in patients with pancreatitis although these benefits cannot necessarily be applied to all surgical patients. Enteral nutrition has also been shown to be less expensive than PN in all patient groups studied. Many clinicians also consider enteral supplementation easier than PN because formulas are prepackaged and manipulation of ingredients is generally unnecessary. However, neither enteral nor parenteral feeding can be safely administered without concomitant monitoring which is best done by a nutrition support team; however, if a team is not available, the surgeon must closely follow the patients for tolerance and complications. Despite this drawback, it is extremely worthwhile from a cost and patient care perspective to use enteral rather than parenteral feeding whenever possible.

Indications In many cases, the decision about whether or not to enterally supplement a patient is straightforward. For instance, awake, alert patients with no impediments to eating (i.e., a healthy young person who has just had an elective inguinal hernia repair) should be allowed to take an oral diet as soon as his or her anesthesia wears off. Conversely, no clinician would start enteral nutrition immediately after admission on a patient with a small bowel obstruction. The decisions become more complicated when the situations are between the above scenarios. Should a severely malnourished patient admitted for an elective procedure receive preoperative nutritional support? How long is it safe to withhold nutrition from a well-nourished patient following trauma or surgery? Is this time frame the same for all patients regardless of diagnosis? What other factors affect timing and route of feeding? There are three general categories of surgical patients who need enteral nutritional supplementation: 1. Patients who are malnourished 2. Those who are at high risk for becoming malnourished, and 3. Those in whom early enteral nutrition has been shown to provide benefits other than just prevention of malnutrition.

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Malnourished Patients Assessment of patients’ nutritional status can be done a number of ways. Certainly, patients who have a recent weight loss greater than 10% of their usual body weight are considered malnourished. Patients with cancer, active AIDS, and those with an acute exacerbation of inflammatory bowel disease may also fit into these categories. Overweight patients can be malnourished as can patients following unusual diets despite lack of weight loss. Each patient needs an individual assessment which can be as simple as performing a global assessment, or as complex as using a DXA scan to measure lean body mass.

High-Risk Patients Well-nourished patients entering the hospital for trauma, burns, or surgical procedures can quickly become malnourished during their hospitalization. In an unstressed state, healthy individuals can survive 4-6 weeks without eating before irreversible muscle depletion occurs. Major surgery and trauma add a large physiologic stress increasing catabolism, shortening this time period tremendously. Following major surgical procedures, well-nourished patients will need to be nutritionally supplemented if they are not able to take adequate oral nutrition within 5-7 days. In addition, nutrition support should be initiated in well-nourished surgical patients if they have an abnormal level of consciousness or other physical limitations such that oral feedings are precluded. Examples of this are patients with moderate head injuries, those undergoing major oropharyngeal resections for cancer, or those who will require prolonged ventilator support for poor pulmonary function. Since these patients will require nutrition support during their hospitalization, there is no reason to delay feeding if their gastrointestinal tract is functional. Many clinicians will place a feeding tube while performing a laparotomy for a major abdominal procedure (pancreatic resection, transplant) in order to start early postoperative nutrition support although there is not yet data to prove its benefit. When in doubt, it is better to initiate feedings than wait for malnutrition to develop.

Patient Populations with Improved Outcome from Enteral Nutrition Several patient populations have been shown to benefit from early enteral nutrition as compared with parenteral or delayed enteral nutrition. Severely injured trauma patients (i.e., those with an Abdominal Trauma Index ≥25 and/or an Injury Severity Score ≥20) have been shown to have a decreased incidence of infectious complications when compared with those fed parenterally. Although the data is conflicting, early enteral feeding has been associated with faster recovery and decreased infections in head-injured patients. Burn patients also benefit from early enteral nutrition; most burn specialists begin nutrition within hours of admission. Patients with pancreatitis have also been shown to have fewer infections from jejunal feeding compared with PN. Several studies have also shown decreased complications in patients with inflammatory bowel disease in whom early enteral nutrition was provided. In general, the more physiologically stressed the patient, the earlier they should be started on nutrition, and the adage “When the gut works, use it” should be followed. Any patient with a fully functional GI tract should be fed enterally; there is no place for PN in these patients.

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Contraindications Certain conditions preclude enteral feedings; however, common sense should easily identify most of them. Patients who are hemodynamically unstable or not fully volume resuscitated can have very serious complications if fed enterally. These patients shunt blood from their GI tracts so that feeding them, especially via the small bowel, can have disastrous consequences. Lack of enteral access also precludes feeding; however, this situation should be rare with modern endoscopic, surgical, and radiologic techniques. Enteral feeding should not be delivered proximal to a bowel obstruction or a high output fistula, and peritonitis should be resolved prior to feeding. However, a bowel anastamosis is not a contraindication to small bowel feeding nor is a low output distal fistula. Patients with mesh closure of their abdomens can also be fed, and patients with pancreatitis can be fed cautiously as long as jejunal access is obtained. Obviously, these types of patients need to be monitored closely.

Monitoring Monitoring patients receiving enteral feeding is a multidisciplinary task. For example, the nursing staff checks the gastric residuals periodically during enteral feeding and records events such as vomiting and diarrhea. The dietitian tracks the patient’s caloric intake and adjusts the nutrition prescription accordingly. The physician should question the patient about bowel habits and abdominal pain as well as assess the patient for abnormal physical signs such as abdominal distention and tenderness. The specifics of monitoring depend to some extent on the location of the access tube; however, some issues are common to all patients.

Tube Specific Monitoring Gastric Tubes

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Any patient with a gastric tube (whether it is a nasogastric tube or a gastrostomy) should have gastric residuals checked prior to each bolus feeding or every 4-6 hours if feeds are continuous. The cutoff for a “high” residual is controversial and probably depends on the rate of feeding but is generally accepted to be 100-200 cc’s in adults. If the gastric residual exceeds this amount, feeds are held for 4 hours or until the next bolus feeding. This is done to prevent gastric distention, vomiting, and aspiration. The measurement of gastric residuals is not always accurate; aspirating from a gastrostomy tube will only reveal fluid that is adjacent to the anterior gastric wall, and small bore nasogastric tubes frequently collapse when trying to aspirate residuals through them. Therefore, a high residual should be taken seriously, but a low residual does not eliminate the risk of aspiration. Aspirating for gastric contents also helps confirm correct placement of the tube.

Nasal Tubes Patients with nasal tubes, whether nasogastric or nasoenteric, are at higher risk for sinusitis than patients without them. Excessive or purulent nasal drainage should be investigated by obtaining sinus radiographs (usually CT). The diagnosis of sinusitis should be entertained in patients who have a fever of unknown origin and a nasal feeding tube. Nasal tubes can be easily displaced so the amount of tube exiting the nose should be noted, and the location of the tip of the tube should be sought on any radiograph that is taken. Some institutions recommend daily radiographs to

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monitor tube location; however, this is prohibitively expensive. At the very least, confirmation of tube placement should be done by insufflating with air while auscultating the abdomen.

Jejunal Tubes Because the jejunum is a narrow, relatively high flow area, checking residuals while feeding is not helpful. Patients with these tubes must be watched very closely for abdominal pain and distention because the small bowel can become ischemic if tube feeds are continued in the face of intolerance.

General Monitoring All patients receiving enteral nutrition should be monitored for certain complications, regardless of access site. The chart should be reviewed, and the patient should be questioned about nausea, vomiting, abdominal pain, and bloating. Patients should also be asked about diarrhea; adjustment of medications or the feeding formula or even stopping the feeding may be required if it is severe and recalcitrant to other maneuvers. The abdomen should be inspected for distention, auscultated for bowel sounds, and palpated for tenderness. Percussion to differentiate ascites from intraluminal air may be helpful. The tube insertion site should be inspected for necrosis, infection, and excessive bleeding. The patient’s airway should be observed, and any report of tube feedings in the airway should be quickly evaluated. Some institutions put blue food coloring in the tube feedings to help detect aspiration. Aspiration is frequently subclinical, so it should be suspected if the patient has a history of recurrent pneumonia or episodes of choking, wheezing, or tachypnea associated with feeds.

Metabolic Monitoring Patients receiving enteral feedings should be assessed for adequacy of caloric, protein, and micronutrient intake along with metabolic complications. Two common methods of monitoring adequacy of intake are the use of metabolic carts and measuring nitrogen balance. Volume status should also be estimated by following inputs and outputs, weights, skin turgor, or more sophisticated methods if available (i.e., pulmonary artery catheters). Feeding malnourished patients may initiate the “refeeding syndrome.” Therefore, potassium, magnesium and phosphate levels should be watched, along with standard electrolytes and liver functions tests. In addition, many stressed patients become hyperglycemic, so serum glucose levels should be followed closely until the patient is stable on feedings.

Complications Although the use of enteral nutrition is very safe, feeding via the enteral route is not without complications. Fortunately, many of these problems can be minimized or avoided with proper techniques and monitoring. Complications can be categorized into tube related, formula related, or metabolic complications.

Tube Related Complications Many complications of feeding tubes can be avoided with proper insertion and maintenance techniques. Complications that are common to all tubes include displacement, occlusion and rupture; however, some are related to the particular type of tube.

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Nasoenteric Tubes Like other tubes that traverse the nasal cavity, nasoenteric tubes can be associated with sinusitis, crico-pharyngeal ulceration, and nasal necrosis. The smallest bore tube available that can accommodate the patient and the formula should be used to help minimize these complications, and the insertion site should be watched for pressure sores. Nasoenteric tubes cross the gastroesophageal junction which many believe predisposes patients to esophageal reflux and aspiration. Again, a smaller tube will help minimize this. Keeping the head of the bed elevated at least 30˚ may also decrease the risk of aspiration.

Gastrostomy Tubes Insertion of a gastrostomy tube, whether done surgically, endoscopically, or radiologically, carries a risk of infection, bleeding, and bowel obstruction. Placing a gastrostomy surgically also carries the risk of anesthesia and dehiscence of the surgical wound. Perforation of other organs, such as the colon or liver, has been reported when inserting gastrostomy tubes non-surgically. In addition, their internal bolsters can erode through the stomach and migrate into the abdominal wall. Gastrostomy tubes should not be put on tension, and the external bolster can be loosened once a well-defined tract is formed.

Jejunostomy Tubes Similar to gastrostomy tubes, insertion of jejunostomy tubes can lead to infection, bleeding, and bowel obstruction. Instilling feeding into the small bowel when it is stressed (for example, when the patient is under-resuscitated) can lead to bowel ischemia, pneumatosis intestinalis, and ultimately bowel infarction. The clinician must be very diligent when monitoring patients receiving small bowel feedings and be acutely aware of new abdominal pain, acute distention, or any signs of sepsis.

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Instillation of tube feeding into the gut can lead to a number of complications, most of them minor and easily treatable.

Abdominal Distention Many patients develop mild abdominal distention while receiving tube feedings. In studies comparing patients receiving enteral feedings with those receiving parenteral feedings, an equivalent number of patients fed intravenously have this problem. Patients with distention should be closely monitored, however, and consideration should be given to slowing or holding feedings, particularly if the patient complains of bloating or pain.

Diarrhea Diarrhea is a common symptom in patients receiving enteral feeding. Although many clinicians will be quick to blame the tube feedings, frequently other factors are at fault. Many medications are associated with diarrhea including liquid formulations made with sorbitol, motility agents such as metoclopramide, H2 blockers, antibiotics, antacids and guafenison. Patients with impactions or pelvic abscesses can present with diarrhea, so these should be investigated. Patients receiving antibiotics may develop overgrowth of resistant bacteria such as Clostridium difficile. Loss of normal flora may be associated with diarrhea so the addition of Lactobacillus

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granules may be of benefit. In endemic areas, the stool should be tested for parasites such as Giardia. In the past, hyperosmolar feedings were a frequent cause of diarrhea; however, the osmolarity of modern formulas is much lower which has reduced this problem. Sometimes adding or even removing fiber from the formula may alleviate tube feeding related diarrhea. When all else fails, the formula can be diluted or slowed. Some patients, particularly those with gut atrophy, may benefit from changing to a low residue or elemental formula. Antimotility agents, such as loperamide, can be used but only after infectious causes have been rules out.

Aspiration Patients receiving tube feedings are at risk for aspiration, particularly if their mental status is poor. Although it is intuitive that patients who are at risk for aspiration would benefit from jejunal rather than gastric feedings, studies comparing this have been mixed. It seems that some patients will aspirate regardless of the site where nutrition is delivered. Checking gastric residuals and holding feeds if they are high may help decrease the incidence of aspiration. A higher caloric formula will allow a slower infusion rate and less volume to be delivered which may help gastric emptying. Keeping the head of the bed at least 30 degrees during gastric feeding may also help reduce the risk of aspiration. Obviously, the use of motility agents may decrease formula transit time in the stomach, reducing the risk of aspiration.

Metabolic Complications Metabolic complications related to feeding occur whether it is delivered enterally or parenterally. This is one area in which a nutritional support team can be invaluable in preventing and treating these problems.

Hyperglycemia Patients who are stressed secrete excess amounts of cortisol, glucagon, ACTH, catecholamines, and growth hormone that stimulate glycogen breakdown and glucose release, and they also have a relative insulin resistance all of which leads to hyperglycemia. In addition, many of these patients are infected which only worsens the situation. Provision of nutrition, particularly as carbohydrates, may exacerbate hyperglycemia; changing to a higher fat and lower carbohydrate formula may be helpful. Hyperglycemia can also be minimized by advancing feedings slowly and monitoring high-risk patients closely. Some patients will require sliding scale insulin or an insulin drip to control their sugars despite these maneuvers.

Refeeding Syndrome Patients who are malnourished (i.e., alcoholics) will quickly utilize nutrients, such as potassium, phosphorous and magnesium, leading to relative deficiencies. Therefore, these electrolytes should be followed closely in patients at risk. They may require substantial supplementation during the early phases of feeding.

Mineral Deficiencies Most enteral formulas are nutritionally complete; however, some of the specialty formulas are missing certain nutrients. For example, renal formulas may lack iodine, and some hepatic formulas lack vitamins. A dietitian can be very helpful in trying to keep track of these issues. As soon as patients’ metabolic problems are stable, they should be switched to a more complete formula.

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Elevated Liver Function Tests Some patients may develop elevated liver function tests during nutrition support. This is thought to be due to overfeeding and deposition of fat in the liver. This can be alleviated by reducing patients’ caloric intake. Obviously, other causes should be sought such as hepatitis, acalculous cholecystitis, and drug toxicity among others.

Conclusion Although somewhat labor intensive, the use of enteral nutrition is associated with decreased length of stay and infectious complications in many surgical patient populations. If the GI tract is intact, it is preferred over parenteral nutrition if for no other reason than it costs less. Although patients must be monitored, administering enteral nutrition rather than parenteral is the preferred nutritional support method in most patients.

Selected References 1. 2. 3. 4. 5. 6.

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7. 8. 9. 10. 11. 12. 13. 14. 15. 16.

Grahm TW, Zadrozny DB, Harrington T. The benefits of early jejunal hyperalimentation in the head-injured patient. Neurosurgery 1989; 25:729-735. Greenberg GR, Fleming CR, Jeejeebhoy KN et al. Controlled trial of bowel rest and nutritional support in the management of Crohn’s disease. Gut 1988; 29:1309-1315. Ibáñez J, Peñafiel A, Raurich JM et al. Gastroesophageal reflux in intubated patients receiving enteral nutrition: Effect of supine and semirecumbent positions. JPEN 1992; 16(5):419-422. Kalfarentzos F, Kehagias J, Mead N et al. Enteral nutrition is superior to parenteral nutrition in severe acute pancreatitis: Results of a randomized prospective trial. Br J Surg 1997; 84:1665-1669. Kudsk KA, Croce MA, Fabian TC et al. Enteral versus parenteral feeding. 1992; 215:503-513. Lazarus BA, Murphy JB, Culpepper L. Aspiration associated with long-term gastric versus jejunal feeding: A critical analysis of the literature. Arch Phys Med Rehabil 1990; 71:46-53. McClave SA, Greene LM, Snider HL et al. Comparison of the safety of early enteral vs parenteral nutrition in mild acute pancreatitis. JPEN 1997; 21:14-20. Metheny N. Minimizing respiratory complications of nasoenteric tube feedings: State of the science. Heart Lung 1993; 22:213-223. Minard G, Kudsk KA. Is early feeding beneficial? How early is early? New Horizons 1994; 2(2):156-163. Moore FA, Feliciano DV, Andrassy RJ et al. Early enteral feeding, compared with parenteral, reduces postoperative septic complications—the results of a meta analysis. Ann Surg 1992; 216:172-183. Moore FA, Moore EE, Jones TN et al. TEN versus TPN following major abdominal trauma—reduced septic morbidity. J Trauma 1989; 29:916-923. Rai J, Flint LM, Ferrara JJ. Small bowel necrosis in association with jejunostomy tube feedings. Am Surg 1996; 62:1050-1054. Rapp RP, Young B, Twyman D et al. The favorable effect of early parenteral feeding on survival in head-injured patients. J Neurosurg 1983; 58:906-911. The A.S.P.E.N. Nutrition Support Practice Manual. American Society for Parenteral and enteral nutrition. Silver Spring: 1998. Wood RH, Caldwell FT, Bowser-Wallace BH. The effect of early feeding on postburn hypermetabolism. J Trauma 1988; 28(2):177-183 Young B, Ott L, Twyman D et al. The effect of nutritional support on outcome from severe head injury. J Neurosurg 1987; 67:668-676.

CHAPTER 1 CHAPTER 13

Enteral Access: Open, Endoscopic & Laparoscopic Techniques Keith Zuccala, John M. Porter When the decision to provide long-term nutritional support to the patient has finally been made the surgeon has several options regarding specific technique. The debate of enteral vs. parenteral has been discussed elsewhere. Now that the decision has been made to provide enteral feedings, the choice of what type of enteral access comes to the forefront. Essentially two sites exist for enteral access; the stomach and the small bowel, more specifically the jejunum. Gastric devices are generally preferred because they offer the most flexibility in feeding schedules. Patients may be fed using either a continuous drip or with bolus feedings, which allow a more regular lifestyle. However, gastric feeding is only appropriate in those patients who have intact gag and cough reflexes, and adequate gastric emptying. The combination of poor gastric emptying, reflux with possible aspiration, and the inability to protect the airway can be deadly! Small bowel devices are indicated for those patients who may be at risk for aspiration due to any compromise in glottic closure, cough reflex, or gastric emptying. The choice of location of enteral feeding sites will also be affected by the type of surgery and/or pathology that the patient has. For instance, s/ p esophageal resection for adenocarcinoma, the patient would probably be better served by a jejunostomy than a gastrostomy access procedure. Once the decision has been made regarding where to place the enteral access, gastric vs. jejunal), the next decision is how to access the GI tract. In these next few sections we will assess the different surgical access procedures. (Fluoroscopically placed devices and procedures will not be discussed here.)

Gastrostomy Gastrostomies may be placed using essentially three main techniques that are within the scope of the general surgeon; 1. Open technique, 2. Endoscopic technique, and 3. Laparoscopic technique. Each has its own inherent advantages and disadvantages. The traditional approach, before the advent of laparoscopy and endoscopy involved surgical or “open” placement of the enteral access device. Although the first planned surgical gastrostomy is credited to Sedillot in 1846, Stamm was responsible at the turn of the century for the refinements involved in the procedure used today.1 Since that time the technique has been refined slightly but essentially remains the same. Although this procedure was the “gold standard” for close to 100 years, it has now been almost

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completely replaced by percutaneous endoscopic gastrostomy (PEG), except in the case where the surgeon is in the abdomen for other reasons and when PEG placement is contra-indicated or has already been attempted without success. Though the open technique has withstood the test of time, it still has its fair share of complications, some of which are common to almost all enteral access devices and some of which are related to gastric tube placement alone. Table 13.1 lists those complications generic to all enteral access. Those complications specific to enteral access in the stomach include esophageal reflux, gastric outlet obstruction from the catheter, and gastric ulceration. The most feared complication of enteral feeding is aspiration. This was reviewed by Minard2 and again by Lazarus et al3 who reviewed the literature for comparison of aspiration rates between patients receiving gastric versus jejunal feedings. The literature showed aspiration rates ranging from 0-40 percent in patients receiving gastric feedings and from 0-13 percent in those receiving jejunal feeding. Interestingly, more studies showed an aspiration of zero in gastric feeding than jejunal feeding. Thus the aspiration rate with jejunal feeding is not zero, as is commonly thought. Specifically, no aspiration with gastric feeding in 18 studies compared to no aspiration with jejunal feeding in only four studies. Most of the articles reviewed had one or more methodological problems and therefore, there is no conclusive evidence that aspiration is decreased with jejunal feedings compared to gastric feedings. The current standard of care is that patients who appear to be at high risk for reflux/ aspiration should be treated with a jejunostomy but this has not been conclusively proven in the medical literature.

Techniques Open All of the open techniques can be performed through either a left upper quadrant or upper midline incision. Although not proven, these patients should probably receive perioperative prophylactic antibiotics. Ancef is a reasonable choice.

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Stamm This is the classic temporary gastrostomy, although it can be used long-term. Once the feeding tube is removed; the site will close spontaneously over a relatively short period. The feeding tube is placed through the anterior abdominal wall via a separate stab incision. The feeding tube has an internal bolster or balloon, which once placed within the stomach holds the device in place after the two purse-string sutures are tied down. Tacking sutures are then used to attach the stomach to the anterior abdominal wall. These tubes can become displaced frequently and will close in a rapid fashion if the tract’s patency is not maintained by timely replacement. Dislodgment within the first two weeks post-operatively or any difficult reinsertion should have placement confirmed by a gastrograffin study. This can be accomplished at the bedside by placing 100 cc of gastrograffin into the tube and taking a plain film of the abdomen. Equivocal studies can be confirmed by a formal fluoroscopic study. Even tubes that have been in place for long periods can have their tracks close rather rapidly. Every effort should be made to reinsert a feeding tube or maintain tract patency with a Foley catheter within the first 4-6 hours after dislodgment.

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Table 13.1. Complications of enteral access • • • • • • • • • •

Abdominal wound infection, including necrotizing fasciitis Post-operative bleeding Dislodgment of the access device post-op Tube/device obstruction Intra-abdominal leakage at the enteral access site, +/- peritonitis “Intraoperative” iatrogenic injury to intraabdominal structures, including insertion into the “wrong” hollow viscus Tube site infection Persistent sinus/site leak Aspiration Failure to tolerate feedings (discussed elsewhere)

Dragstedt The same technique as the Stamm is used with the addition of an omental wrap around the tube, between the stomach and the anterior abdominal wall. This extra step is added to help reinforce the junction. This is to prevent any intraperitoneal leak, although there is no definite evidence of a lower leak rate. Janeway This technique involves the actual construction of a gastric ostomy. This is a permanent opening used for long term feeding. Using a stapling device, a tube of stomach is fashioned and brought out as the stoma. The tube must be long enough, usually 8-10cm, to prevent continual reflux of gastric contents onto the anterior abdominal wall. Its base should be large enough, usually 5-6cm, to prevent possible stricture or torsion. Again, this is a permanent stoma located in the left upper quadrant. Since this stoma is permanent, feeding tubes/devices can be inserted and removed as needed to conform to the patients feeding schedule. The patient is not encumbered by a tube permanently exiting from their anterior abdominal wall and all the attendant hazards and complications that go with an externalized feeding device.

Witzel The Witzel technique entails tunneling of the feeding catheter through the stomach wall before exiting to pass out through the anterior abdominal wall. This technique is also used to form a jejunostomy and is more fully explained under that section of the chapter. The purpose is to decrease the intraperitoneal leak rate.

Endoscopic Percutaneous Endoscopic Gastrostomy (PEG) This has now become the “gold standard” for obtaining either permanent or temporary gastric access. It is contraindicated in patients with esophageal tumors or strictures, altered anatomy (e.g., prior gastric surgery) that might interfere with the endoscopic portion of the technique, ascites, morbid obesity and esophageal/gastric varices.4 Previous upper abdominal incision is only a relative contraindication. This technique was initially described by Gauderer et al in 1980.5 There have been several modifications but overall the technique used by most endoscopists is similar. First, a standard esophagogastroduodenoscopy (EGD) is performed to exclude any pathology that may interfere with gastric feeding, such as gastric outlet obstruction,

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tumor or ulcer. The right upper quadrant of the abdomen is prepped and draped aseptically and the brightest transillumination point is palpated. If the light cannot be visualized the PEG should not be performed. This point cannot be overemphasized. Local anesthetic is used as needed and an incision is made in the skin approximately 1-1/2 times the diameter of the feeding tube to be used. A large bore needle and sheath are placed through the incision into the stomach and grasped by a snare passed through the endoscope. The needle is removed and a guide-wire is inserted through the sheath. The snare secures the guidewire and the endoscope, guidewire and snare are all removed out through the patient’s mouth. At this point there are now two different techniques that may be used to insert the feeding tube. The first is the pull method. In the pull method the feeding tube is attached to the guidewire and pulled back through the mouth, esophagus, stomach and out the anterior abdominal wall. Of note, once the feeding tube starts to emerge from the abdominal wall, the endoscope should be reinserted to directly visualize placement. This avoids over-exuberant pulling which may dislodge the tube from the stomach, as well as avoiding excessive tension of the internal bolster against the stomach wall. Excessive tension can lead to pressure necrosis and perforation of the stomach with subsequent leakage and peritonitis. Bleeding is also assessed at this time. It is of vital importance to visualize the stomach and the PEG after insertion. This needs to be documented in the chart. The second technique is the push method whereby the feeding tube is pushed over the guidewire, much like a central venous catheter is inserted using a Seldinger technique. Again, the endoscope should be reinserted to visualize the stomach and the PEG.

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Many standard operative techniques have been modified and incorporated into the armamentarium of the minimally invasive surgeon. One of the major advantages of using laparoscopy is that the peritoneal cavity can be examined for pathology grossly and iatrogenic injury to adjacent organs can be avoided, though this is somewhat counterbalanced by the risk of initial trocar insertion. Several different techniques have been described. Haggie6 described a technique which was in effect a laparoscopic Janeway gastrostomy, using a stapler to fashion the stomach tube and creating a stoma in the left upper quadrant. Edelman et al7 employed a technique that involved bringing the stomach up to the anterior abdominal wall with a grasper and then placing several Cope anchor sutures to fix the stomach to the anterior abdominal wall. These Cope sutures have an appearance similar to plastic price tag holders used in the clothing industry. Next, a large bore needle is passed percutaneously into the stomach at the site transfixed by the Cope sutures. A guidewire is then passed through the needle, the needle is removed and progressively largT) dilators are passed over the guidewire. The gastrostomy site is dilated up until a 17 French peel-away sheath can be inserted. A gastrostomy tube with balloon is then inserted through the sheath and the balloon is inflated. Once the balloon is inflated, the peel-away sheath is removed and the G-tube is pulled up against the anterior abdominal wall. Edelman et al report on twenty patients one of whom died secondary to complications from the surgery, specifically gastric necrosis. Although the laparoscopic techniques have advantages over the traditional open techniques, PEG still remains the gold standard.

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Devices There are different types of devices that may be used as gastrostomy tubes. There are several different products on the market from varying manufacturers but they share similar characteristics. Almost all are made of polyurethane today. Hunter first reported the delivery of feedings directly into the stomach in 1793 by way of a leather tube.8 Recently the use of “buttons” has become popular. These devices are low contour and avoid dangling tubes which may become entangled and lead to damage or injury to the feeding device. Buttons are primarily advocated for use in children and cognitively impaired adults. They require slightly more dexterity to access and may be difficult to engage for patients who have poor eyesight or who are obese. Also there are a variety of tubes that can be placed through the gastricostomy and fed through the pylorus into the duodenum or jejunum.

Jejunostomy Jejunostomies may be placed using three main techniques that are within the scope of the general surgeon: open, laparoscopic and endoscopic techniques. Each has its own inherent advantages and disadvantages. Bush performed the first open jejunostomy for nutritional purposes9 in 1858 in a patient with non-operable gastric cancer. In 1891, Witzel described his classic technique, which has undergone many modifications but is still utilized today. In 1973, Delany et al10 described the needle catheter technique. As previously mentioned Gauderer et al described the PEG in 1980, and it was not long after that, people were modifying this approach into a combined PEG/PEJ procedure. In the 1990s as minimally invasive surgery has become more widespread, laparoscopically placed jejunostomies have been performed. Table 13.2 lists the indications for placing a jejunostomy. They can be summarized as whenever enteral nutrition is desired and cannot be accomplished via the oral or gastric route. The main advantage of jejunostomies is the decreased risk of aspiration. However, as stated earlier, this rate is not zero, nor has it been conclusively shown to be less than that with gastrostomies. The contraindications for jejunostomy placement are listed in Table 13.3. As early post traumatic enteral feeding has become more popular, feeding “too early” when the small bowel is still relatively ischemic can lead to frank small bowel ischemia and necrosis. Table 13.1 listed the complications that are generic to both gastrostomy and jejunostomy. Complications specific to jejunostomies include small bowel obstruction from either the tube itself or volvulus and pneumotosis intestinale.

Technique Open This can be performed in conjunction with other procedures or as the primary procedure. Access to the abdomen is usually via midline incision, although other incisions, such as the left subcostal or paramedian can be used. Common to all techniques is the selection of the appropriate location for the jejunostomy. Specifically, it must be distal enough from the ligament of Treitz so to decrease the risk of aspiration. However, if it is too distal, there will not be enough absorptive surface for the enteral feedings to be effective. Also the loop of jejunum must be of sufficient length to reach up to the anterior abdominal wall without tension. The proper distance is 20-25 centimeters from the ligament of Treitz. Selection of the proper location cannot be overemphasized.

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Table 13.2. Indications for jejunostomy 1. 2. 3. 4.

enteral nutrition favored. Oral route inaccessible or inadequate Length of feeding > 6 weeks GI surgery with postoperative complications of; a. anastomotic dysfunction b. postop pancreatitis c. residual sepsis d. enterocutaneous fistula e. hypercatabolic patients (e.g. malignant neoplasia) f. moderate to severe malnourishment g. intraabdominal organ transplant recipients h. immunocompromised pts. i. prolonged fast j. gastric atony 5. Polytrauma

Witzel This is the classical technique for an open jejunostomy. The appropriate site of proximal jejunum is selected. Usually a red rubber catheter, 12-16 french, is used. It is passed through the anterior abdominal wall in an open fashion. A pursestring is placed in the small bowel and the jejunum is opened. The catheter is fed 10-15 centimeters distally and palpated to insure that it is not kinked. The pursestring is tied. From the pursestring site to 5-10 centimeters proximally, a serosal tunnel is created to “bury” the catheter. At the proximal end of this tunnel, the jejunum is secured to the anterior abdominal wall. The tunnel is created to decrease the incidence of leakage from the catheter. Tubes originally designed for other purposes have been adapted and used for feeding jejunostomies.11 The classic tube, as mentioned, is a red rubber catheter which is usually used in combination with a Witzel tunnel. Catheters with polyester-fiber cuffs such as the Hickman or the Tenchkhoff have also been used with some success.

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Needle Catheter Jejunostomy First described by Delany,12 the needle-catheter jejunostomy is another open technique. The site on the anterior abdominal wall is selected, as previously described. A 5-7 french catheter is inserted through the abdominal wall either via large bore needleor in an open fashion. A 7 french tube is required for feeding of casein-based protein supplements in order to prevent clogging. Administration of non-liquid medications through these tubes is not recommended. A purse string suture is placed on the anterior aspect of the jejunum and a large bore needle is passed into the bowel lumen through the purse-string suture. A subserosal tunnel prior to insertion into the lumen makes for a better seal and a less likely chance of leak when the tube is finally removed. The 5-7 french catheter is inserted through the needle, the needle is removed, and then the purse-string suture is tied around the catheter. A Witzel tunnel is an option. If desired, it is fashioned as described above. If not, then the jejunum is tacked up to the anterior abdominal wall at the site of the pursestring.

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Table 13.3. Contraindications for jejunostomy 1. Intestinal obstruction 2. Predisposing factors for enterocutaneous formation a. intestinal wall edema b. postradiation enteritis c. IBD affecting small intestine 3. Coagulopathies 4. Ascites 5. Serious immunodeficiency problems (increased risk of intraabdominal Infection or necrotizing fasciitis) 6. Ischemic bowel

Permanent The aforementioned techniques and catheters are for the most part pertinent to jejunostomies that are not meant to be permanent. For a more permanent jejunostomy, Maydl developed a technique in which a Roux-en-Y limb is brought out as a stoma. This is tunneled subcutaneously for several centimeters to prevent leakage of sucus onto the abdominal skin. The stoma is cannulated with a balloon-tipped catheter at each time of access. DeCou et al11 described a modification whereby a mushroom-tipped catheter is sewn into the end of the Roux-en-Y limb and brought out through a separate incision. The catheter is sewn in using two purse string sutures. This method seems to have the advantage of a lower leak rate compared with Maydl’s technique. Other The jejunal tube can also be placed via an open gastrostomy incision with an apparatus placed that serves a dual purpose of not only allowing gastric suction and decompression but also simultaneous feeding via a jejunostomy tube which passes trans-pyloric. “Theoretically, the risk of obstruction and volvulus should be lower than with other open jejunostomies because the stomach, not the intestine, is fixed to the abdominal wall.”12

Laparoscopic Several different techniques may be used to access the jejunum laparoscopically. One of the earliest successful techniques was described by Morris et al13 and involved bringing a piece of jejunum, as with open techniques 20-25 centimeters from the ligament of Treitz, out through the 10 mm, supraumbilical port. 3-0 silk seromuscular sutures are then used to secure the jejunum to the fascia. A red rubber catheter feeding tube is held in the jejunum by two concentrically placed purse-string sutures. The fascia is closed around the red rubber catheter, which is then tunneled for several centimeters subcutaneously before being brought out through a lateral trocar site. In fact, a purist might argue that this is a laparoscopically guided technique as a portion of the procedure is done “open” however, it started a wave of more completely laparoscopic techniques. Several different surgeons reported purely laparoscopic techniques that varied only slightly in how the jejunum is secured to the anterior abdominal wall. Duh and Way14 used T-fasteners to secure the small bowel; Sangster & Swanstrom describe a similar procedure using 3-0 silk on a Keith needle. Both similarly describe the

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obtainment of enteral access using a venous access kit with peel-away sheaths and dilators to create an opening large enough to insert the feeding tube, after the stay sutures/fasteners were in place. In circumstances where stay sutures are used they can be either tied over a fascial bridge or over a bolster externally16 or sutured entirely within the abdominal cavity. Rosser et al17 described a “simplified technique” which actually uses a similar technique as previously described but includes the use of advanced technology with special instruments specifically designed for laparoscopic jejunostomies, Endoclose and Endostitch [United States Surgical Corporation, Norwalk, Conn.] and the FLEXIFLO “LAP J” laparoscopic jejunostomy kit [Ross Laboratories, Columbus, Ohio].

Endoscopic Percutaneous endoscopic jejunostomy (PEJ) is a term applied to several different techniques whose only similarity is that the feeding tube ideally delivers nutrients into the second portion of the small bowel. As Clevenger and Rodriguez18 point out currently three jejunal tube placement techniques have been given the name ‘PEJ’.s The first and most common is simply placement of a jejunal feeding tube through a traditional PEG tube. The jejunal portion is passed trans-pyloric and down the jejunum either directly by via the endoscope or over a guidewire, which is placed initially by the endoscope. Sometimes a dual lumen tube is used with the shorter end opening into the stomach and used for gastric decompression, and the longer end being passed into the jejunum for feeding purposes. The second technique, which carries the label PEJ, involves endoscopic assistance in an open technique of jejunostomy tube placement.19 The purported advantage being that by using the endoscope to identify and deliver the jejunum that a smaller incision can be made. The third technique is a true PEJ. As described by Shike et al20 a 160-cm endoscope is required to place the tube directly into the jejunum. There have been no prospective studies to demonstrate one method’s clear-cut advantage over another.

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The benefits of providing nutrition in ill patients are myriad and well known. Once the decision has been made to provide this nutrition enterally, the surgeon is still faced with several options concerning the appropriate access. Both gastric and jejunal access have their complications and advantages. Each patient must be individually scrutinized and the specific circumstances examined. If long-term access is deemed appropriate then either gastrostomy or jejunostomy are appropriate. Certain patients are amenable to gastrostomy placement while others have certain relative contraindications—keeping in mind that it is truly by convention, and not necessarily documentation in the medical literature, that jejunostomy is considered less likely to put the patient at risk of aspiration. Next, the astute surgeon must decide which particular procedure is most appropriate for their patient—open, laparoscopic or endoscopic. Finally, once the particular technique is decided upon, the specific variant must be selected. Enteral access may seem a rather cut-and-dry topic surgically, but the multiple decisions involved, requiring thoughtful insight and astute clinical judgement, make this facet of surgery as much an art as it is a science.

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Selected References 1. 2. 3. 4. 5. 6. 7. 8. 9. 10. 11. 12. 13. 14. 15. 16. 17. 18. 19. 20.

Clevenger FW, Rodriguez RD. Decision-making for enteral feeding administration: The way behind where we are now. Nutr Clin Prac 1995; 10:104-113. Minard G. Enteral access. Nutr Clin Prac 1994; 9:172-182. Lazarus BA et al. Aspiration associated with long-term gastric versus jejunal feeding: A critical analysis of the literature. Arch Phys Med Rehab 1990; 70:46-53. Meguid MM et al. The delivery of nutritional support—a potpourri of new devices and methods. Cancer 1985; 55(suppl):279-289. Gauderer MWL et al. Gastrostomy without laparotomy: A percutaneous endoscopic technique. J Ped Surg 1980; 15:872-875. Haggie JA. Laparoscopic tube gastrostomy. Ann Rev Coll Surg Engl 1992; 74:258-259. Edelman DS et al. Laparoscopic gastrostomy or percutaneous endoscopic gastrostomy. Contemp Surg 1994; 44:269-272. Hunter J. A case of paralysis of the muscles of deglutition cured by an artificial mode of conveying food and medicines into the stomach. Trans Soc Improve Med Chir Know 1973; 1:182-188. Tapia J et al. Jejunostomy: Techniques, indications and complications. W J Surg 1999; 23:596-602. Delaney HM et al. Jejunostomy by needle catheter technique. Surgery 1973; 73:786. DeCou JM et al. Feeding Roux-en-Y jejunostomy in the management of severely neurologically impaired children. J Ped Surg 1993; 28:1276-1280. Minard G. Enteral access. Nutr Clin Prac 1004; 9:172-182. Morris JB et al. Laparoscopic-guided jejunostomy. Surgery 1992; 112:96-99. Duh QY, Way LW. Laparoscopic jejunostomy using T-fastener as retractors and anchors. Arch Surg 1993; 128:105-108. Sangster W, Swanstrom L. Laparoscopic-guided feeding jejunostomy. Surg Endosc 1993; 7:308-310. Shatz DV et al. Laparoscopic suturing technique for enteral access procedures. Surg Endosc 1994; 8:717-718. Rosser JC et al. A simplified technique for laparoscopic jejunostomy and gastrostomy tube placement. Am J Surg 1999; 177:61-65. Clevenger FW, Rodriguez RD. Decision-making for enteral feeding administration: The why behind where and how. Nutr Clin Prac 1995; 10:104-113. Adams DB. Feeding jejunostomy with endoscopic guidance. Surg Gyn Obstet 1991; 10:104-113. Shike M et al. Direct percutaneous endoscopic jejunostomies. Gastrointest Endosc 1991; 37:62-65.

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CHAPTER 14

Total Parenteral Nutrition: Current Concepts and Indications Rifat Latifi, Stanley J. Dudrick “ The decision to initiate and to maintain adequate nutrition via TPN should be based upon the achievement of a specific, definable, and realistic goal for each patient and each condition. It should always be borne in mind that the ultimate aim of the technique is to prolong meaningful life and not merely to prolong an active process of inevitable death.” Stanley J. Dudrick, M.D.

Introduction The majority of hospitalized patients with a normally functioning gastrointestinal tract usually do not require special nutritional support. However, significant malnutrition, as defined by anthropometric, biochemical measurements and weight loss, may be documented in up to 50% of surgical patients.1 This percentage may be even higher among indigents and patients in intensive care units. Although most patients are malnourished at the time of admission or diagnosis as a consequence of disease-induced poor food intake, a significant number of other patients become malnourished iatrogenically during hospitalization.2 Many factors are responsible for the development of malnutrition in the hospitalized patient, among which are the hypercatabolic states associated with trauma, sepsis, cancer, surgical interventions and many other interacting biologic and social factors. For patients who manifest signs and symptoms, of malnutrition including, 1) a history of unintentional or unexplained weight loss of 10 pounds or 10% of body weight during the previous two months; 2) a serum albumin concentration of less than 3.4g/dL; 3) impaired immunocompetence as determined by a standard battery of skin tests; and 4) a total lymphocyte count of less than 1200/mm3, prior to hospitalization, or who are likely to develop them during hospitalization as a result of stressful periods of diagnostic and therapeutic interventions, efforts should be directed toward maintenance or restitution of nutritional status. If a patient’s gastrointestinal (GI) tract cannot, or should not be used for oral or direct enteral feeding, or if a patient is unable to receive adequate amounts of nutrition via the oral or enteral route, then total parenteral nutrition (TPN) should be considered as the primary technique of providing all nutrient substrates and caloric needs until the GI tract can be used safely and effectively.

The Biology and Practice of Current Nutritional Support, 2nd Edition, edited by Rifat Latifi and Stanley J. Dudrick. ©2003 Landes Bioscience.

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Because it is not possible for a single parenteral nutritional formulation to be standardized for optimal use in all patients with a wide variety of disorders, nor for all age groups, nor for the same patient during all aspects of a specific pathologic process, specific parenteral nutrient regimens should be individually designed and tailored for each patient. As a result, a wide variety of maintenance and therapeutic parenteral nutritional formulas for pediatric and adult patients has evolved throughout the years, and many commercial products are now available for clinical use. Efforts are under way in many centers to understand and define the individually specific nutrient requirements for patients sustaining major trauma, single or multiple organ system failure syndromes, extensive full-thickness burns, sepsis, cancer, immunologically related diseases, primary gastrointestinal disorders and severe atherosclerotic cardiovascular disease. Current special substrate mixtures represent significant progress in clinical nutrition and are the seminal precursors of the anticipated specifically formulated and highly sophisticated parenteral nutrition regimens of the future. Total parenteral nutrition has not simply enabled us to establish an alternate feeding route for our patients, but has had a profound effect on the multimodal management of patients with inflammatory disease and has created an innovative tool that has allowed the rapid progression of a complex and diverse aspect of nutritional support.3-4 Current indications for use of TPN demand clear demonstration of therapeutic effects. In many conditions the use of TPN has been shown to be beneficial, and at times it is the only acceptable mode of providing all nutrients. In many others, the efficacy, cost effectiveness and outcome data have not clearly supported the hypothesis that TPN should be initiated in all malnourished or undernourished patients who cannot use their GI tracts optimally or at all during relatively short periods (5-7 days) of starvation induced by their pathophysiologic processes and therapies. However, most experienced clinicians agree that, ideally, patients should be fed optimally at all times, and that no pathological process can be treated better when the patient is starved than when the patient is well nourished. This chapter will briefly review some of the general principles of TPN therapy and the current indications for use of this modality which has provided a great stimulus for development of surgical nutrition and metabolic practice.

General Indications for Use of TPN The original goals of nutritional support3 were to provide adequate nutrients to meet the normal or increased metabolic requirements for: 1. growth and development, 2. restoration of body weight, 3. restoration of optimal bodily function, 4. achievement of homeostasis, 5. improvement of nitrogen balance, 6. improvement of protein status, 7. improvement of response to therapy, 8. restoration of immunocompetence, and 9. reduction of morbidity and mortality.5 The general indications for the use of TPN are: 1. provision of adequate nutrition for as long as necessary intravenously when use of the gastrointestinal tract is impractical, inadequate, ill-advised, or impossible; 2. reduction of mechanical and secretory activity of the alimentary tract to basal levels in order to achieve a state of “bowel rest”;

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3. provision of specially tailored formulas to improve nutritional status in patients with kidney or liver failure; and 4. reduction of the urgency for surgical intervention in patients who might eventually require operation, but in whom prolonged, progressive malnutrition will greatly increase the risk of operation and postoperative complications.3

Specific Indications for Total Parenteral Nutrition TPN efficacy has been demonstrated clearly in many pathophysiologic conditions including short-gut syndrome, fistulas, severe burns, renal failure, hepatic failure, inflammatory bowel disease, acute pancreatitis, chemotherapy and radiation induced enteritis, transplant patients and severely malnourished cancer patients in their perioperative management, when provision of nutrition enterally is not possible. Other conditions in which TPN is indicated but in which its efficacy has not been clearly demonstrated in the literature include acute exacerbations of chronic pancreatitis, anorexia nervosa, cardiac cachexia, hyperemesis gravidarum, prolonged respiratory support, chronic protein losses and cancer patients with mild malnutrition. In general, when GI tract cannot be used for more than five days in patients in a catabolic state with or without evidence of malnutrition, or when patients cannot be fed for 3 days after major surgery, parenteral nutrition should be started. Areas of intense clinical investigation in which TPN may eventually be shown to be of great value are cancer patients in general, sepsis and trauma, and general perioperative support to prevent or correct malnutrition.

Short Bowel Syndrome

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Short bowel syndrome is a complex entity characterized clinically by intractable diarrhea, steatorrhea, weight loss, dehydration, maldigestion and malabsorption, and eventually malnutrition. The intestinal adaptation and regeneration, together with the nutritional and pharmacologic aspects of management of short bowel syndrome, discussed comprehensively in Chapters 15, 16, and 18. The predominant manifestations of short-bowel syndrome depend on several factors, among which are: the extent and site of resection, associated diseases, age of onset of short bowel syndrome, the length and location of the intestinal tract, the residual function of the remaining GI tract (stomach, pancreas, biliary system and colon), the adaptive capacity of remaining intestinal segment, and finally the nature of the primary disease and the residual activity of the disease. Metabolically, this syndrome is manifested by anemia, bile salt depletion, cholelithiasis, lactic acidosis, hypokalemia, hypocalcemia, osteoporosis, renal stones, liver dysfunction, trace element and vitamin deficiency, and essential fatty acid deficiency (EFAD). Development of safe and efficacious TPN has revolutionized the treatment of patients with short-bowel syndrome by allowing maintenance of adequate nutrition until the remaining intestine can adapt optimally to oral feeding. TPN should be started on the second post-operative day and continued for as long as needed, through the immediate post-operative period, the bowel adaptation period, and the longterm management period. The patient with short bowel syndrome represents one of the greatest challenges to clinicians, and maintaining optimal nutritional and metabolic support until bowel adaptation can occur is the top priority in the management of these patients.

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Enterocutaneous Fistula The most frequent causes of enterocutaneous fistula are direct operative injury to the small bowel, disruption of an anastomosis, or a perianastomotic leak and abscess. Other causes include sharp or blunt trauma that results in fistula formation by direct penetration, compression, ischemia, or necrosis of the bowel; benign and malignant neoplasms of the bowel; inflammatory bowel diseases (Crohn’s disease); the presence of a foreign body, radiation injury, or open abdomen with exposure of bowel to mesh or dressings.7 Malnutrition is very common in patients with enterocutaneous fistulas and is often associated with electrolyte imbalance and sepsis. High-output fistulas that originate in the upper small bowel initially may drain as much as 3,000 ml or more of fluid daily. The difficulties presented by such massive losses of water, electrolytes, and nutrients are formidable. A significant but lesser degree of malnutrition is associated with moderate-output fistulas, which drain between 200 and 500 ml per day. Low-output fistulas with fluid losses of less than 200 ml daily have a much lower incidence of associated malnutrition. They usually take origin from the lower small bowel or colon. A major objective in nonoperative fistula management is to minimize its output. Absolutely nothing should be allowed by mouth, not even ice chips, if this goal is to be achieved. Gastric acid secretion and intestinal and pancreatic secretions are initially inhibited maximally by intravenous H2 receptor blockers, and parenteral somatostatin. TPN is initiated when fistula is recognized. This should be done after stabilizing the patients with an enterocutaneous fistula and correcting the blood volume and electrolyte and clotting deficits. Infusion of the nutrient solution is begun at levels to provide water (35 to 45 ml per kilogram body weight per day) and protein (1.5 to 2.0 g per kilogram body weight per day) requirements. Although the final caloric intake is calculated at 25-30 kcal per kilogram body weight per day, usually only one-third to one-half of the caloric ration is given as dextrose on the first day. After tolerance and utilization of the dextrose are established, the concentration and dosage are gradually increased over the next few days to meet full caloric requirements. Fat emulsion of 20 percent concentrations may be infused in 250 ml doses two to three times a week primarily to prevent essential fatty acid deficiency, although this is still a controversial issue. In patients with diabetes mellitus, congestive heart failure, or severe obstructive pulmonary disease, it is sometimes infused daily in 500 ml doses to provide high-density fat calories, thus reducing the dextrose and water in the ration and reducing the carbon dioxide produced subsequently by oxidation of the dextrose. Serum electrolyte, glucase, urea nitrogen, creatinine, calcium, phosphorus, and magnesium levels are determined daily during the first 5 to 7 days to facilitate prompt repletion of deficits and metabolic stabilization. Thereafter, serum electrolyte, glucase, urea nitrogen, and creatinine concentrations are determined two or three times a week, and calcium, phosphorus, magnesium, zinc, copper, and albumin levels, liver function tests, prothrombin time, activated partial thromboplastin time, complete blood count, differential count, and platelets are determined weekly. Adjustments in the formulation and volume of the infusate are made as indicated. Although it is often difficult or impossible to provide adequate enteral nutrition in the presence of an enterocutaneous fistula because of sepsis, ileus, and/or inadequate absorptive capacity, spontaneous fistula closure during enteral nutrition can be accomplished in a reasonable number of selected patients. If at least 4 feet of

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functioning small bowel exist between the ligament of Treitz and the fistula, oral feeding nasogastric or nasoduodenal tube feedings of highly absorbable, low-residue nutrients can be administered with reasonable results. Sometimes a small, soft tube can be passed into the bowel below a high fistula for continuous feeding by pump. The volume and concentration of tube feedings initially must be low, and subsequently increased incrementally to full volume and strength or to tolerance. This process ordinarily takes 3-5 days for achievement of caloric and nitrogen balance, during which time the patient should be supplemented with TPN. A combination of both of these techniques may be necessary to provide optimal nutrition in some patients. The use of TPN in managing enterocutaneous fistulas is usually associated with a prompt decrease in the ongoing protein losses from fistulas, and even when TPN does not induce definitive closure of the fistula, patients having received a course of TPN will be prepared better for operative interventions designed to close the fistulas.

Inflammatory Bowel Disease The etiology and specific treatment of Crohn’s disease and ulcerative colitis are not fully understood. Consequently, the treatment strategy for these patients is essentially symptomatic and supportive. Malnutrition that frequently accompanies inflammatory bowel disease (IBD) should be corrected with TPN, elemental enteral diets or both. TPN should be used in conjunction with multimodal medical management or as an adjunct to an operative procedure. Evidence exists that TPN is of value in IBD, and judicious nutritional therapy remains a cornerstone in the overall adjunctive management of these patients.8 For more details of nutrition support in patients with IBD (see Chapter 19).

Liver Failure

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Although nutritional support in chronic liver failure will be discussed in Chapter 22, we will briefly present some aspects of metabolic changes, and nutritional and metabolic support, of patients with liver failure. The complex metabolic derangements which accompany liver failure reflect the magnitude of the problems associated with insufficiency or decompensation of the liver as a “master” metabolic organ.9,10 Correction of these alterations, by manipulating nutrients and other biochemical substrates, forms the basis for maintaining adequate nutritional status, and represents one of the most important therapeutic strategies in the management of patients with severe liver disease.11 The primary abnormality of carbohydrate metabolism in chronic liver failure (CLF) is glucase intolerance. Decreased insulin activity, on the other hand, may be a consequence of a depletion of insulin receptors on target cells.12 As a result of decreased insulin activity, increased amounts of free fatty acids (FFA) are released into the circulation. Impaired degradation, portal systemic shunting, and increased plasma concentrations of ammonia and aromatic amino acids (AAA) are all responsible in part for elevated plasma levels of glucagon. The insulin:glucagon effective ratio and lipoprotein lipase activity are also decreased in chronic liver failure. The clearance capacity of exogenous triglycerides is reduced, and the patient may be intolerant of large amounts of fat. Impaired glucase and fat utilization are responsible for the increased catabolism of protein and are the limiting factors in providing the caloric needs of patients with advanced liver disease. One of the most important metabolic changes in CLF, however, is alteration of plasma amino acid patterns. Insufficiency of liver function and accentuated muscle

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breakdown induce an elevation in AAA and a reduction in branched chain amino acid (BCAA) levels. This rather consistent presentation of plasma amino acid profile in patients with CLF strongly suggests a role in the pathogenesis of hepatic encephalopathy and serves as an explanation for the attendant protein intolerance. Decreased clearance of AAA by the liver is a major cause of increased plasma and brain AAA concentrations. Decreased plasma BCAA concentrations contribute to the accumulation of AAA in the brain as well. The AAA together with methionine, glutamine, asparagine, and histidine undergo 80-100% first pass clearance by the liver. Spontaneous portal systemic shunting with significant partial bypass of the liver mainly affects the metabolism of these amino acids. The characteristic profile of amino acid disturbances observed in liver failure formed the basis for the initial formulation of an intravenous solution enriched in BCAA as a potentially effective nutritional modality for the treatment of CLF and hepatic encephalopathy. Experience since then has shown BCAA to ameliorate hepatic encephalopathy temporarily, but not to affect the ultimate outcomes of patients with CLF, either with or without accompanying encephalopathy. More work in this vital area is obviously urgently indicated. Protein malnutrition is a well known feature of advanced liver disease, and is characterized by decreased creatinine-height index, low plasma albumin and transferrin levels, reduced triceps skinfold thickness and total lymphocyte count. The most important nutritional indicator, however, is hypoalbuminemia, which is a consequence of decreased albumin synthesis, increased albumin degradation, malnutrition secondary to malabsorption and poor oral intake, and third space losses of albumin in ascitic fluid and in the extravascular compartment. Decreased plasma albumin concentration is one of the prominent biochemical indices in Child’s classification of cirrhotic patients and is a good indicator of hepatic functional reserve. Hypoalbuminemia causes decreased capillary colloid oncotic pressure which is a major contributing factor in the accumulation of ascites and edema, which in turn are persistent characteristics of patients with decompensated liver function. Daily nutritional monitoring of these patients is recommended, together with complete biochemical and metabolic studies. Plasma levels of vitamins, trace elements, and apolipoprotein A-IV have been reported to reflect intestinal absorption of nutrients,13 and may be useful in a comprehensive nutritional assessment. Measurement of other plasma proteins produced by the liver, such as fibrinogen, transferrin and prealbumin with their shorter half-lives, can be used to monitor acute changes in hepatic protein synthetic function. The hepatic mitochondrial redox potential represents the ratio of acetoacetate to B-hydroxybutyrate and can be expressed as the arterial blood ketone body ratio (A KBR).14 This reflects metabolic derangements of the whole body, characterized by hepatic mitochondrial accumulation of NADH, which consequently inhibits proton transport through the respiratory transport chain, and markedly depresses TCA cycle enzymes and other metabolic pathways. The arterial blood ketone body ratio is not a specific measurement of liver insufficiency, but it allows grading of the severity of liver damage. Different biological phenomena are associated with a decrease in the AKBR, most prominent being enhanced catabolism, impaired oxygen utilization, and deterioration of the immune response. Cirrhotic patients eventually manifest protein malnutrition with consequent functional alterations and histologic liver abnormalities. Protein deprivation profoundly depletes liver protein stores and adversely affects the breakdown and conversion of polysomes to free ribosomes.15 On the other hand, in chronic liver

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disease, alterations in visceral protein synthesis, cellular immunity and total lymphocyte count may be present independently of protein malnutrition.16 Plasma protein levels in general correlate inversely with the degree of liver damage. Other markers of lean body mass and fat stores are not true indicators of structural liver damage. Measurement of nitrogen balance in liver disease also has its limitations,17 because the hypercatabolic state makes it difficult to differentiate impaired hepatic protein synthesis from accelerated circulating protein breakdown. The main objective of nutritional support in liver failure is to provide adequate calories and protein needs without inducing or aggravating hepatic encephalopathy,18 thereby ensuring the availability of critical energy substrates for optimal function of the hepatic mitochondria. Nutritional support, even though controversial, should be initiated and actively maintained during the phase in which the AKBR is decreased.14 Adequate measures should be taken to increase the AKBR or at least to prevent a further decline, because AKBR ratios under 0.4 have ultimately been associated with markedly increased mortality. For patients unable to tolerate oral or enteral feeding, total parenteral nutrition is the only feasible means of providing nutrition support. Significant hypoalbuminemia and hypoproteinemia are almost always present in liver failure, and since dietary protein intolerance is the rule rather than the exception in liver insufficiency, serious consideration must be given to restoring plasma albumin and total protein levels to normal by infusing salt-poor human albumin intravenously. Adequate calories should be given in order to provide calculated requirements while maintaining blood glucase levels below 200 mg/dL. Fat emulsions can be given cautiously19 in dosages sufficient to prevent EFAD requirements (usually 250 ml 20% emulsion every other day). Vitamin K and folic acid may require supplementation above usual TPN dosages in patients with liver failure. In formulating the nutrient solution, the amino acid composition is of primary concern. Since it is apparent that plasma amino acid concentrations are frequently abnormal in hepatic failure, it seems logical that manipulation of the levels of the plasma amino acids, as well as brain amino acids, with correction of the observed abnormalities, should be an important task of physicians involved in the care of these complex patients. To date, however, the results of specialized nutritional support of liver failure have rather consistently shown that although parenteral and/or enteral BCAA enriched nutrient regimens may relieve the symptoms of hepatic encephalopathy and may improve the protein nutritional status of the patient with liver failure, the beneficial effects in both situations are usually transitory, and outcome remains the same—dismal.

Acute Pancreatitis Most episodes of acute pancreatitis are short-lived and self-limited, and extraordinary nutritional support in these patients is rarely indicated (20, 21). However, in those patients with severe pancreatitis who manifest any three of the adverse prognostic factors22 at admission or develop them subsequently within the first 48 hours of hospitalization, nutritional support with TPN should be undertaken as soon as possible. Aggressive nutritional support is essential to insure optimal provision of nutrient substrates, while maintaining the gastrointestinal tract and the pancreas “at rest.” Several reports have confirmed that administration of all nutrients parenterally has reduced morbidity and mortality substantially.21,23 Recently, use of TPN was

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evaluated in 29 patients with moderate to severe pancreatitis.24 Patients receiving TPN had a mortality rate of 7% compared with 45% in patients receiving conventional intensive therapy without TPN. TPN in pancreatitis should be administered continuously over 24 hours, with appropriate adjustments to infusion rate and to nutrient concentration and composition as indicated.20 Conscientious and meticulous biochemical and hematologic monitoring of these patients is necessary to identify and promptly treat any renal failure, hepatic decompensation, or fluid and electrolyte imbalances which might accompany unrelenting or capricious disease. Plasma total protein and albumin concentrations should be maintained at about 6.5 g/dL and 3.5g/dL, respectively, in order to minimize edema, ileus and plasma colloid osmotic pressure derangements. Positive nitrogen balance has been shown to have a striking beneficial influence on survival of the patient with severe pancreatitis, while failure to achieve positive nitrogen balance has been associated with an increase in the mortality rate. Patients with severe necrotizing or hemorrhagic pancreatitis may require rather large amounts of insulin to maintain normal blood glucase levels, especially in the presence of uncontrolled infection, occult abscesses or frank sepsis, and/or diabetic ketoacidosis. In addition, these patients have a high incidence of malnutrition and require aggressive nutritional support. Local and systemic complications, abdominal sepsis and repeated surgical interventions further complicate the course of the disease. The indications for the use of TPN in patients with severe acute pancreatitis are multiple. Not only may the nutritional status of these patients deteriorate very rapidly, but prolonged ileus, respiratory and renal failure, severe metabolic aberrations, and multiple major surgical interventions may interfere with provision of adequate oral or enteral feeding, further complicating or aggravating existing malnutrition. In other clinical conditions that may result from complications of pancreatitis, such as pancreatic fistulas, pseudocyst, and ascites, nutritional support with TPN has been shown to be a more effective therapy than enteral feeding. TPN bypasses cephalic, gastric and intestinal phases or pancreatic secretion; reduces the pancreatic acinar nuclear volume, cell volume, and synthetic activity; and significantly reduces the basal pancreatic proteolytic and bicarbonate secretions. Nonetheless, TPN is not indicated routinely in all forms of acute pancreatitis, but is recommended in patients with APACHE II scores >9 and in those having more than two of Ranson’s criteria.

Cancer and TPN: To Feed or Not to Feed? One of the areas of major debate over the past decade has been the adjunctive use of TPN in the treatment of patients with cancer. Thus far, a vast amount of data and experience has been acquired in understanding the interactions of neoplastic disease and nutrient regimens while treating and studying cancer patients. Because of the debilitating nature of most oncologic processes on the body cell mass, the proportion of patients with malignant disease experiencing a significant degree of malnutrition is larger than the number of hospitalized patients without malignant diseases.25 Cancer related malnutrition has a very poor prognosis, but may be treated or prevented to some extent with TPN or enteral nutrition. For this reason, it is especially important that the treatment of cancer patients be accompanied by adjunctive nutritional support in order to achieve the best possible therapeutic results with the lowest morbidity and mortality and, to prevent death from starvation rather than from the neoplastic process itself.

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Some cancer patients, especially those with a malignancy of the oral cavity, pharynx or cervical esophagus, may present with painful deglutition and progressive difficulty with ingesting and swallowing solid food. Moreover, patients with cancer of the head and neck often have a history of heavy smoking, excessive alcohol intake, and/or dietary indiscretions which render them protein-calorie malnourished prior to developing malignancies. Since most oncologic therapy impairs optimal oral nutritional repletion to some degree for a considerable period of time, such patients may enter a vicious cycle of compounded malnutrition. Surgical treatment of a patient with head and neck cancer also often results in diminished oral intake. Preoperative, postoperative, or primary radiation therapy induces severe stomatitis, mucositis and diminished salivary secretions. These adverse symptoms further aggravate the already decreased oral intake and accelerated weight loss of such patients. Patients with malignancies present the quintessential challenge to restoration or improvement of nutritional status while receiving primary oncologic therapy. Determining the best method for nourishing the cancer patient depends on three major factors: 1. the patient’s nutritional status; 2. the level and degree of residual gastrointestinal function; and 3. the type and magnitude of antineoplastic therapy. Ideally, adequate voluntary ingestion of food orally is the ultimate goal for all patients. However, most antineoplastic treatment modalities diminish optimal oral intake. If a patient is unable to obtain daily nutritional requirements voluntarily by oral ingestion of ordinary normal nutrients, oral supplementation together with aggressive dietary counseling should be initiated and maintained. Patients should also be encouraged and allowed to make dietary selections of their food preferences whenever feasible. Alert, well-motivated patients can often be urged to increase their daily calorie and protein intake through the ingestion of hospital-prepared or commercially formulated supplements. If, on the other hand, patients are unable to be fed by mouth, but have an intact and functioning alimentary tract, then tube feedings should be introduced. Although a functioning alimentary tract provides the best means of assuring normal digestion, absorption, and assimilation of foodstuffs, use of the enteral route is contraindicated in the presence of severe gastrointestinal dysfunction, such as intestinal obstruction, prolonged ileus, upper gastrointestinal bleeding, and/or intractable vomiting or diarrhea. If the alimentary tract is not available for use, or if rapid nutritional repletion is deemed essential, parenteral nutrition should be instituted. TPN should be used in cachectic cancer patients as a means of nutritional rehabilitation. Currently, studies suggest that TPN is of benefit in only malnourished cancer patients in whom treatment toxicity will preclude oral or enteral intake for longer than one week.26 Regardless of postulated or demonstrated tumor-induced abnormalities in the intermediary metabolism of the host, the predominant factor in the development of cancer cachexia is an imbalance between nutrient intake and host nutrient requirements, which can be treated beneficially in severely malnourished patients by enteral or parenteral nutrition, or both. Optimal results from surgical procedures, pharmacologic therapy, chemotherapy, radiotherapy, immunotherapy, respiratory therapy, physical therapy and other forms of care can only be obtained when the patient is maintained in optimal nutritional condition. Yet, a fear of potential stimulation of tumor growth with nutritional support (enteral or parenteral) has stimulated much controversy regarding nutritional

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support in cancer patients. Animal studies have clearly demonstrated that spontaneous tumor development and growth of established tumor can be stimulated or reduced by manipulating exogenous nutrient substrates.27 No data have been reported unequivocally documenting accelerated tumor growth in cancer patients receiving TPN. Increased caloric and fat intake has been associated with increased incidence of spontaneous tumorigenesis in animal models. Increased fat and caloric intake is also associated with breast carcinoma, ovarian carcinoma and colorectal cancer in humans. Acceleration of tumor growth in animal models has been demonstrated by increasing tumor volume, tumor mitotic activity, H3-thymidine labeling, tumor protein synthesis, increased S-phase and aneuploid tumor cells. Furthermore, cell-cycle kinetics are also altered during exogenous nutrient administration. Such induced tumorigenesis in animal models has not yet been demonstrated clinically in human studies, although few studies have attempted to address this important problem. Although, potentially the tumor mass growth may be accelerated, the metastatic effect of tumor can be enhanced, and the tumor cell cycle kinetics can be altered by vigorously feeding cancer patients, further clinical studies are needed to clarify all of these hypotheses. Until then, the ultimate goal in the nutritional management of patients with cancer is the same as with all other patients: provision of optimal nutrition to all patients under all conditions at all times, as long as there is a reasonable chance for curing or improving the quality of life of that patient. On the other hand, TPN should not be used in cancer patients who are completely unresponsive to therapy and in whom extraordinary measures to provide nutrients can serve only to prolong unrelieved suffering and inevitable death.

Selected References 1. 2. 3. 4. 5. 6. 7. 8. 9. 10. 11. 12.

Bistrian BR, Blackburn GL, Vitale J et al. Prevalence of malnutriton in general medical patients. J Am Med Assoc 1976; 235:1576-1570. Butterworth CE Jr. The skeleton in the hospital closet. Nutrition Today 4:1974. Dudrick SJ. Parenteral nutrition. In: Dudrick SJ, Baue AE, Eiseman B et al, eds. Manual of Preoperative and Postoperative Care. Philadelphia: WB Saunders Co, 1983:86-105. Dudrick SJ, Latifi R. Total parenteral nutrition: current status. Contemp Surg 1992; 41:41-48. Dudrick SJ, Wilmore DW, Vars HM et al. Long-term total parenteral nutrition with growth, development and positive nitrogen balance. Surgery 1968; 64:134-142. Dudrick SJ, Latifi R, Fosnocht D. Management of short bowel syndrome. Surg Clin North Am 1992; 71:625-643. Dudrick SJ, Mock TC. Enterocutaneous fistula. In: Cameron J, ed. Current Surgical Therapy, 3rd ed. Philadelphia: BC Decker, Inc., 1988:35-61. Dudrick SJ, Latifi R, Schrager R. Nutritional management of inflammatory bowel disease. Surg Clin North Am 1991; 71:609-623. Latifi R, Killam R, Dudrick SJ. Nutritional support in liver failure. Surg Clin North Am 1991; 3:567-578. Latifi R, Dudrick SJ. Hepatic encephalopathy: metabolic and nutritional implications of amino acids. In: Latifi R. Amino Acids in Criticial Care and Cancer. Austin: R.G. Landes, 1994:125-136. Hiyama DT, Fischer JE. Nutritional support in hepatic failure. Nutr Clin Prac 1988; 3:96-105. Rossi-Fanelli F. Nturitional support in liver failure. In: Tanaka T and Okada A, eds. Nutritional Support in Organ Failure. Amsterdam: Elsevier Science Publishers, 1990:261-265.

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15. 16. 17. 18.

19. 20. 21. 22. 23. 24. 25. 26. 27.

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Muto Y, Yoshida T, Yamatoh M. Nutritional treatment of liver cirrhosis with branched chain amino acids (BCAA). In: Tanaka T, Okada A, eds. Nutritional Support In Organ Failure. Amsterdam: Elsevier Science Publishers, 1990:267-276. Shimahara Y, Kiuchi T, Yamamoto Y et al. Hepatic mitochondrial redox potential and nutritional support in liver insufficiency. In: Tanaka T, Okada A, eds. Nutritional Support in Organ Failure. Amsterdam: Elsevier Science Publishers, 1990:295-308. Sidransky H. Regulatory effect of amino acids on polyribosomes and protein synthesis of liver. In: Popper H, Schaffner F, eds. Progress in liver disease, Vol. IV. New York: Grune and Stratton, 1972:31-43. Schenkin A. Assessment of nutritional status: The biochemical approach and its problems in liver disease. J Hum Nutr 1972; 33:341-349. McCullough AJ, Mullen KD, Smanik EJ et al. Nutritional therapy and liver disease. Gastroenterol Clin of North Am 1989; 18:619-643. Fischer JE. Hepatic Failure. In: Wilmore DW, Brennan MF, Harken AH et al, eds. Care of the Surgical Patient. A publication of The American College of Surgeons Committee on Pre and Postoperative Care. Scientific American Medicine. 1990:1-13. Nagayama M, Takai T, Okuno M et al. Fat emulsion in surgical patients with liver disorders. J Surg Res 1989; 47:59-64. Latifi R, McIntosh JK, Dudrick, SJ. Nutritional management of acute and chronic pancratitis. Surg Clin North Am 1991; 73:579-578. Pisters PWT, Ranson JHC. Nutritional support for acute pancratitis. Surg Gynecol Obstet 1992; 175:275-284. Ranson JHC. Etiological and prognostic factors in human acute pancreatitis: A review. Am J Gastroenterol 1983; 77:663-668. Blackburn GL, Williams LF, Bistrian B et al. New approaches to the management of severe acute pancreatitis. Am J Surg 1976; 131:114-124. Robin AP, Campbell R, Palani CK et al. Total parenteral nutrition during acute pancreatitis: Clinical experience with 156 patients. World J Surg 1990; 14:572-579. Copeland EM, Dudrick SJ. Nutritional aspects of cancer. Curr Probl Cancer 1976; 1:3-51. Pillar B, Perry S. Symposium proceedings—Part III. Evaluating total parenteral nutrition. Core statements of the technology assessment and practice guidelines forum. Nutrition 1990; 6:474-489. Torosian MH. Stimulation of tumor growth by nutrition support. JPEN 1992; 16(S):72-75.

CHAPTER 1 CHAPTER 15

Intestinal Adaptation: New Insights Jon S. Thompson

Introduction Normal intestinal structure and function is maintained by a complex interaction between luminal, humoral, local and neural factors. The intestine will adapt to changes in these regulatory mechanisms and in response to other stimuli, such as partial resection and injury. Alterations of intestinal structure and function may result in the intestine failing to meet one or more of its important roles. While malabsorption is perhaps the most common and easily recognized manifestation of intestinal failure, disordered motility, impaired barrier function, and immune dysfunction can also occur. Patients undergoing extensive resection of the small intestine clearly are at risk for intestinal failure. Although intestinal adaptation following intestinal resection is a widely recognized and well studied phenomenon, this process is still incompletely understood. The adaptive potential of the small intestine following resection was first noted more than 100 years ago.1 A historical perspective of the evolution of current concepts of intestinal adaptation has been published previously.2 However, during the past few years, there have been many advances in our understanding of the adaptive response of the intestine and its regulation. Apoptosis, or programmed cell death, has emerged as an important regulatory factor in mucosal adaptation. The functional changes, which occur in enterocytes, have been more clearly defined. While intestinal muscle adaptation had been recognized for some time, its role in functional adaptation has only recently been appreciated. The understanding of the motor changes, which occur, has also expanded. The role of specific nutrients continues to be investigated. The number of involved regulatory humoral factors has increased markedly. The relationship between the colon and the intestinal remnant has also recently attracted attention. Our concepts of the basic mechanisms of intestinal adaptation have evolved because of a better understanding of the molecular mechanisms involved. The intent of this chapter is to review the current understanding of intestinal adaptation and present new insights into this process.

Structural Changes Compensatory structural changes occur in all layers of the intestinal wall after resection. However, changes in the mucosa are predominant and have gained most attention. Adaptive structural changes are greater after proximal resection compared to distal resection and are also related to the extent of resection.3-10 Adaptation begins almost immediately following resection and continues for weeks to months. While adaptive structural changes have been clearly demonstrated in a variety of animal species, there has been some debate as to whether they occur as consistently in man.3-14 The Biology and Practice of Current Nutritional Support, 2nd Edition, edited by Rifat Latifi and Stanley J. Dudrick. ©2003 Landes Bioscience.

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Measurements of DNA, RNA and protein in intestinal mucosa increase within 24 to 48 hours after resection.4-9 These changes are associated with an increase of crypt cell production rate.15,16 Both the total number of cells and proportion of proliferating cells are increased in the crypt. Kinetic studies have indicated a shortening of the cell cycle.15 Cells migrate at a faster rate along the villus. A more recent observation is that rates of apoptosis increase during intestinal adaptation.17-20 This may represent a counter regulatory process in response to increased crypt production of cells. This increase in programmed cell death occurs in both crypt and villus cells. Similar to crypt cell production, apoptosis is rapidly induced but then diminishes as a new set point in enterocyte balance is reached. Endonuclease activity, which produces DNA cleavage in this process, and levels of pro-apoptotic gene products, e.g., Bax, increase transiently after resection and pro-survival products, e.g., Bcl, diminish.19,20 The increased number of cells results in an increase in villus height and crypt depth.3-11,14-16 Correspondingly mucosal weight increases. Villus lengthening occurs by cellular hyperplasia as indicated by an unchanged number of cells per unit length of villus, the overall increased number of cells, and an unaltered RNA/DNA ratio.21 While there do not appear to be consistent ultrastructural changes in the enterocytes, microvilli have recently been shown to lengthen.22,23 Ileal villi change their shape to that of the jejunum as they elongate.4 There is disagreement as to whether the number of villi increases in relation to crypts.4,24 However, crypt fission, or bifurcation, occurs at a greater rate resulting in an increased number of crypts.25 The thickness and length of the muscle layers also increase after resection and results primarily from hyperplasia rather than hypertrophy of the muscle cell.4,5,26,27 These changes are most marked in the longitudinal layer. Muscular hypertrophy occurs transiently proximal to the anastomosis.6 Muscle adaptation occurs at the later time and only after more extensive resection than does mucosal adaptation,4,5,26,27 These changes in the components of the intestinal wall result in marked thickening of the intestinal wall, up to 150% of normal thickness. The intestinal circumference and length also increase to 130% of initial values.11,14 These increases probably reflect primarily changes in circular and longitudinal muscle length. Thus, there is an overall increase in mucosal surface area due to both villus hypertrophy and the increases in length and circumference of the remnant.14

Functional Adaptation Intestinal Absorption

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In vivo studies confirm increased intestinal uptake of fluid, electrolytes and nutrients after resection.14,27-31 This improved function occurs primarily due to increased mucosal surface area.19,28 While formerly individual cells were not thought to increase their function, more recent in vitro studies have demonstrated both increased nutrient transport and enzyme activity.9,14,32-37 Increased nutrient absorption clearly occurs. The enterocyte response to intestinal resection involves a transcriptional increase of Na+/glucose transporter within hours of resection.33,34 This adaptive response is quite specific. For example, glucose dependent electrogenic Na+ absorption is increased but electroneutral NaC1 absorption is unchanged.35 Increased expression of the cotransporter gene correlates with increased glucose transport across the bowel wall.38 Increased transport of glutamine, alanine, and leucine has been demonstrated in a site specific fashion after

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enterectomy.37 Acid-base transporters may be down regulated after resection.40 Major changes in carrier mediated nutrient absorption are most likely to be achieved, from a kinetic perspective, by alterations in the Vmax.39 This appears to occur by both modulating the number of transporting vs. nontransporting enterocytes populating the villus, as well as increased transport capability of individual cells. Increased activity of digestive enzymes by the enterocyte also occurs after resection.41 As with transport properties, this is a specific response e.g., α-glucosidase but not neutral aminopeptidase increases. However, there is still no evidence to suggest that enterocytes can adopt specialized transport function not characteristic of that site.42

Intestinal Motility While less attention has been given to motor adaptation, it has an important role in improved nutrient absorption.28,43-49 Studies of gastric emptying and intestinal transit in the rat following various types of resection have demonstrated an adaptive response with slowed intestinal transit and delayed gastric emptying primarily following proximal resection.43,50 There is prolongation of the migrating motor complex (MMC), a reduction in MMC Phase I duration, an increase in MMC Phase II duration and a prolonged post-prandial inhibition of the MMC in the intestinal remnant.44-45 Thus, the remaining jejunum and proximal ileum developed motor characteristics typical of the intact distal ileum. Distal resection resulted in little change in motor parameters in the remnant. These findings are consistent with the presence in the terminal ileum of a mechanism which can sense unabsorbed fat within the ileal lumen and lead to delayed gastric emptying and slowed small intestinal transit-the so called “ileal brake”.46 Loss of even small segments of distal ileum could thereby influence transit along the entire gut. The response of the canine small intestine to varying degrees of resection has also been described.47 Fifty percent and 75% distal resections were associated with the development of clinical features of the short bowel syndrome, and though there was some improvement in this malabsorption during the 3-month study period, the 75% group, in particular, continued to demonstrate marked steatorrhea. In terms of motility changes, a biphasic motor response was identified. Initially, in the distal segment of the intestinal remnant in each of the resection groups and in the entire remaining small intestine in the 75% group, motility recordings were dominated by recurring bursts of clustered contractions. In the 75% group, these clusters were often prolonged and associated with a baseline tonic change. In this group, also, the incidence of jejunal MMCs was markedly reduced, and Phase II duration was significantly prolonged. Later, in the 25% and 50% groups, evidence of motor adaptation was noted with the development of a progressive slowing of intestinal transit and a return of MMC cycling. Furthermore, the propagation velocity of Phase III of the MMC progressively slowed to a rate seen in the ileum of intact control animals. Such adaptation did not, however, occur in the 75% group; prominent cluster activity continuing to be the dominant motor pattern. Long-term studies in humans demonstrate that the intestinal remnant develops a shorter duration of the MMC-cycle and fed pattern.48,50 These changes only occur after extensive resection (jejunal remnant 60-100 cm). Evidence of a biphasic response to resection such as that observed in canines comes from case reports.50,51 Small intestinal motility was studied 2 to 12 months after resection in an infant. Cluster activity dominated the early study while clusters diminished and the MMC period shortened in the later study. In an adult patient, Phase III of the MMC was

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absent during the first month after resection but returned thereafter.51 Thus, a consistent pattern of motor adaptation in the intestinal remnant has been identified. In vitro studies demonstrate a reduction in contractibility of intestinal muscle after resection.52 This may be due to muscarinic receptor activation. This response is specific to the intestinal remnant location and muscle type.53 Overall, however, these appear to be transient, modest effects.26

Intestinal Barrier and Immune Function There is little information about changes in barrier or immune function after intestinal resection. The number of horizontally oriented strands, which is a strong morphologic predictor of transepithelial permeability, is unchanged after resection.35 However, tight junction depth is slightly increased. In the suckling rat, there are decreases in the T and B-lymphocyte populations in gut-associated lymphoid tissue after massive bowel resection.54 There is also reduction in certain intraepithelial lymphocyte subpopulations after resection.55 Such changes might be associated with a risk of infectious complication in infants with the short bowel syndrome.

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Although a number of factors have been identified which influence intestinal adaptation (Table 15.1), this complex process is still not completely understood. From the mechanistic perspective, there are a number of aspects which need to be explained. These include the greater adaptive response after proximal resection and after more extensive resection, the rapid onset and prolonged duration of adaptation, and the termination of this response with maintenance of a new steady state for gut proliferation and function. Different components of the intestinal wall e.g., mucosa and muscle appear to have different mechanisms of adaptation. There is also apparent disassociation between the morphological and functional changes seen following resection. Loss of intestinal mass is obviously the important inciting event for postresection adaptation. In fact, synchronous autotransplantation of resected ileum will blunt the adaptive response.56 Adaptive changes which occur within a few hours imply that there are alterations in enterocytes already upon the villus. Modifications occurring within several days suggest that the mechanism for these changes relates to altered crypt cell production rate or cell turnover. Moreover, adaptive responses which persist for many weeks after removal of the inciting stimulus, suggest that permanent changes are occurring in the crypt cells. Functional adaptation is probably influenced by the same signals that control structural adaptation, i.e. systemic peptides, the ingestion of food, and neural influences. Food intake is most likely to have the greatest effect on nutrient transport. The role of dietary lipid has some interest since this might influence the physicochemical properties of cell membranes. However, it is apparent that luminal contents and regulatory peptides influence all aspects of adaptation. Each of the potential factors influencing adaptation will be considered.

Luminal Contents Luminal Nutrients An important role for luminal nutrition in postresectional adaptation has been recognized for some time. This is particularly true following proximal resection,

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Table 15.1. Factors promoting intestinal adaptation Luminal Contents Luminal Nutrients Luminal Secretions Gastrointestinal Regulatory Peptides Systemic Factors Growth Factors Hormones Cytokines Neural Influences Changes in Blood Flow Mesenchymal Factors

since the ileum is usually not exposed to high luminal concentrations of nutrients. This concept has been supported by the observations that transposition of the ileum and jejunum results in ileal hyperplasia and intestinal bypass results in atrophy.57-59 Luminal nutrients have both direct and indirect effects on the intestinal mucosa by virtue of local nutrition, gastrointestinal secretion and peptide release, stimulated motility and blood flow, and other effects. The adaptive response is blunted if nutrition is maintained intravenously rather than orally after resection.60,61 Bulk and other non-nutrition intake does not stimulate adaptation.62,63 The effect of fasting on adaptation is reversible with refeeding, however, suggesting that luminal nutrients are a permissive factor.64 Malnutrition due to inadequate enteral nutrition will also impair the adaptive response.65 The role of nutrient type, e.g., fat, protein or carbohydrate, and form e.g. amino acids versus peptides is less clear. Glucose stimulates proximal mucosa whereas fat stimulates the mid intestine.66 Disaccharides appear to stimulate mucosal adaptation to a greater extent than monosaccharides.67 Furthermore, carbohydrates stimulate intestinal growth via a variety of mechanisms suggesting that direct mucosal contact, absorption, osmolality and humoral factors may be involved.68 Casein and casein hydrolysates have similar effects on postresection mucosal adaptation.69 Lipids also influence the adaptive response.70 Long chain triglycerides stimulate intestinal adaptation to a greater extent than medium chain triglycerides.71 Whereas long chain triglycerides have their greatest effect on the mid-small intestine, medium chain triglycerides have a greater effect proximally.72 Polyunsaturated fatty acids are more effective at inducing adaptation in a dose dependent manner.70,73 Dietary pectin supplementation improved adaptation.74 Pectin also enhances while cellulose impairs fat absorption after resection.75 The importance of specific nutrients has been appreciated more recently. Glutamine, in particular, has an important role in adaptation which is related to its role as a major enterocyte fuel as well as stimulating release of various gut trophic factors.76,77 High glutamine diets may impair adaptation, however.76 Even provision of the enterocyte fuels glutamine and short chain fatty acids parenterally will stimulate intestinal adaptation.78-80 While arginine becomes an essential amino acid after massive resection, arginine supplementation does not enhance adaptation.81,82 Deficiency of nutrients can also influence adaptation. Zinc deficiency and essential fatty acid deficiency impair mucosal hyperplasia.83-85 Vitamin A deficiency impairs adaptation and provision of retinoic acid enhances adaptation.86,87

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Luminal Secretions A variety of experimental models have supported an important role for upper gastrointestinal and pancreaticobiliary secretions in the adaptive response.88-90 Transplanting the ampulla distally to the proximal ileum results in ileal hyperplasia.88-90 Both biliary and pancreatic secretions appear to be important.91 However, pancreaticobiliary secretions are not essential for adaptation in animals fed enterally.90 Furthermore, pancreaticobiliary secretions are not as strong a stimulus to mucosal growth as resection itself.7 Which components of the luminal secretions are the important growth promoters remains unclear. EGF from saliva and the duodenal Brunner’s glands may have a significant role.92 Increased salivary secretion promotes mucosal hyperplasia, while excision of submandibular glands abolishes this response.92 EGF recirculates in the bile and, thus, may play a role in the stimulatory effects of bile. There may be other growth promoting factors in the upper gastrointestinal secretions, as well.89

Gastrointestinal Peptides An important role for regulatory peptides in the adaptive response of the intestine to resection has long been appreciated and are related in large part to ingestion of nutrients.93,94 While initial studies focused on gastrointestinal hormones, more recently other regulatory peptides have been considered candidates for mediators of intestinal adaptation.95 It appears that intestinal adaptation is a complex process which involves multiple regulatory mediators functioning both locally and systemically. Furthermore, different mechanisms may be important depending on the extent and site of resection and interval since resection. As seen in Table 15.2, a regulatory peptide may influence one or more aspects of adaptation. Peptides currently under investigation for a potential role in intestinal adaptation are described below (Table 15.3).

Calcitonin Gene-Related Peptide

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The neuropeptide calcitonin gene-related polypeptide (CGRP) is found in the peripheral end of sensory neurons in the stomach and small intestine.96,97 It is released in response to various noxious stimuli. CGRP has several effects, including inhibition of gastric acid and pancreatic exocrine secretion, inhibition of gastrointestinal motility, stimulation of mesenteric blood flow, and release of somatostatin. Its precise role in the regulation of digestive function remains unclear. The intestinal effects suggest a possible role of CGRP in intestinal adaptation. CGRP content is increased two fold in jejunal and ileal mucosa after resection and seven fold in the muscle layers.98 While it may play a role in preventing gastric ulceration, it is not clearly trophic or cytoprotective for the small intestine.99 Since it may play a role on the intestinointestinal inhibitory reflex, CGRP might influence the motor response to intestinal resection.97

Cholecystokinin Cholecystokinin (CCK) is found both in the brain and the intestine, where it is localized to the mucosa of the duodenum and proximal jejunum. CCK is released by luminal digestion products of fat and protein appears to play a major role in the gastrointestinal response to feeding, including satiety. CCK has both direct and neurally mediated indirect effects on the small intestine.100 It also influences the release of other hormones.101 CCK might influence intestinal absorption both directly

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Table 15.2. Regulatory peptides and their potential role in adaptation Peptide CGRP CCK Enteroglucagon GLP-2 GIP Gastrin Motilin neuropeptide Y Neurotensin PP PYY Somatostatin VIP

Trophic Effect ? + ? + 0 ? 0 0 + ? ? – ?

Absorption – + 0 + – + – + 0 ? + – –

Motility – + 0 ? – ? + – + + + + –

Barrier/Immune Function ? + ? + ? ? ? ? + ? ? – ?

+ = increased or stimulated 0 = no change – = decreased or inhibited ? = response unclear

and via its effect on gastrointestinal secretion.102 CCK stimulates contractile activity. The fat induced enterogastric reflex, inhibiting gastric acid secretion, may be mediated in part by CCK.103 Basal and postprandial levels of CCK increase transiently after 75% distal intestinal resection in dogs, returning to normal within 3 months.104 Meal stimulated but not basal plasma CCK activity is diminished in adapted short bowel syndrome patients.105 Tissue CCK mRNA levels also increase.106 CCK administration increases DNA synthesis and intestinal weight.107 This trophic effect occurred in incontinuity but not bypassed intestinal segments, so this is probably an indirect effect mediated via stimulation of pancreaticobiliary secretion. CCK administration increases post resection mucosal adaptation in animals maintained on TPN but does not stimulate adaptation to the same extent as oral feeding.108 CCK might also influence motor and absorptive adaptation based on the effects observed in intact intestine. CCK mRNA and peptic levels are markedly increased during recovery from cytotoxic intestinal injury, suggesting that CCK may play a role in maintaining barrier function.109

Proglucagon-Derived Peptides The proglucagon gene is expressed in pancreatic A cells and the L cells of the distal intestine. Posttranslational processing gives rise to a variety of different peptides.110 Glucagon is the primary pancreatic peptide whereas the L cells produce several structurally related peptides, including glucagon-like peptide-1 (GLP-1), glucagon like peptide-2 (GLP-2), glicentin and oxyntomodulin. The two latter peptides contain glucagon in their sequence. Little is known about the biologic activities of glicentin and oxyntomodulin. GLP-1 regulates gastric emptying, stimulation of glucose-dependent insulin secretion and inhibition of glucagon secretion, appetite and food intake. Glucagon-like activity is stimulated by luminal nutrients, especially fat, 46 and inhibits intestinal motility and secretion. The physiologic

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Table 15.3. Changes in regulatory peptides during adaptation Peptide CGRP CCK Enteroglucagon GLP-2 GIP Gastrin Motilin neuropeptide Y Neurotensin PP PYY Somatostatin VIP

Serum Level Content 0 + + + + + + ? 0 + + 0 0

Tissue mRNA + + 0 – + 0 0 0 ? – + –

Receptors ? + + ? ? ? ? ? + ? + ? ?

? ? ? ? ? ? ? ? ? ? ? – ?

+ = increased or stimulated 0 = no change – = decreased or inhibited ? = response unclear

15

actions of these multiple peptides has formerly been attributed to the hormone enteroglucagon. Enteroglucagon was given early consideration as a humoral agent involved in intestinal adaptation due to a report of an enteroglucagon producing renal tumor in a patient who also demonstrated intestinal hypertrophy.111 Subsequently, it was demonstrated that serum enteroglucagon levels were elevated during the early adaptive phase after intestinal resection.104,112-116 These elevated levels appeared to correlate both temporally and quantitatively with increased mucosal proliferative activity.112,113,116 Enteroglucagon mRNA is elevated significantly in both jejunum and ileum after resection116 and this is related, in part, to increased cellular content.117,118 Tissue content of enteroglucagon decreases with time after resection.117 Despite all of these suggestive findings, the role of enteroglucagon in the postresection adaptive response remains unclear. Although enteroglucagon appeared to be mitogenic in vitro, administration of enteroglucagon in vivo failed to increase crypt cell production rate or stimulate mucosal growth.108,119,120 Gregor et al121 found that infusion of a monoclonal antibody against enteroglucagon did not alter the postresection adaptive response. Thus, there is no direct evidence that elevated enteroglucagon levels are responsible for intestinal adaptation after resection. Elevated enteroglucagon levels do not correlate with changes in small bowel transit time.114 Whether or not enteroglucagon enhances absorptive function also remains unclear.122 Glucagon-like peptide-2 has emerged as an important regulator of the adaptive response.123-129 GLP-2 administration rapidly induces intestinal mucosal growth in a dose dependent manner via a variety of routes.123 This augmented growth subsides when GLP-2 is withdrawn. GLP-2 stimulates crypt cell proliferation and inhibits apoptosis. Administration of GLP-2 augments the adaptive response to massive intestinal resection.124 GLP-2 also enhances nutrient digestion and absorption.125

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Plasma, but not tissue, GLP-2 levels increase after resection.126 Meal stimulated GLP-2 release is impaired in patients with the short bowel syndrome.127 GLP-2 administration in short bowel patients improves intestinal absorption.128 GLP-2 also enhances intestinal barrier function.129 GLP-2 is metabolized by dipeptidyl peptidase IV and mRNA levels of this enzyme diminish during intestinal adaptation which may enhance GLP-2 activity.130

Gastric Inhibitory Polypeptide Gastric inhibitory polypeptide (GIP) is a potent hormone localized to K cells in the upper small intestine and released in response to ingested nutrients.131 GIP inhibits gastric secretion and motility and stimulates insulin secretion. It inhibits fluid and electrolyte absorption in the small intestine. GIP also increase mesenteric blood flow. 132 Basal and postprandial levels of GIP are elevated after distal intestinal resection and remain so for several months.104 However, these elevations were not found long term after ileal resection in humans.114 Basal GIP levels are not influenced by proximal resection but meal stimulated levels are reduced for as long as 6 months.131 GIP levels correlate with length of resection and diminished GIP activity is seen in humans where less than 150 cm jejunum remains.133 However, GIP activity and glucose metabolism begin to correct at 6 weeks. Since the response of the pancreas to GIP does not appear to be altered, these changes in GIP after resection appear to be due to the initial loss and then adaptation of GIP containing cells.134 Postresective increases in GIP levels may play a role in motor adaptation. These elevations might be related to change in gastric secretion and gastrin levels, as well.

Gastrin Gastrin, found primarily in antral G cells, is released by peptides, amino acids, and calcium in the gastric lumen, by neural reflexes and by circulating factors. Its release is inhibited by low luminal pH, prostaglandins, and several peptides, including somatostatin. While its major effects are stimulation of gastric secretion, motility and mucosal growth, it does influence the lower intestinal tract as well. Gastrin was one of the initial hormones considered for an important role in the regulation of intestinal adaptation. Gastric hypersecretion and hypergastrinemia have been demonstrated to occur, at least transiently, in man and various animal species after resection.135-138 Both increased fasting and postprandial serum gastrin levels are affected and these changes occur within the first few days after resection. However, while gastrin is generally agreed to have a trophic effect on the stomach and large intestine, its effect on the small intestine is less clear.139-142 Results have been conflicting and supraphysiologic doses may be required. performing antrectomy to abolish gastrin secretion after resection did not prevent postresection hyperplasia.140,143 In a long-term canine study, we found that serum gastrin levels did not correlate with changes in parameters of intestinal adaptation.144 Neither mean gastrin levels or duration of hypergastrinemia correlated with remnant length or villus hypertrophy. Evidence does exist to suggest that gastrin influences intestinal absorption. Luminal perfusion but not subcutaneous administration of gastrin increases carbohydrate and protein absorption in the rat.145,146 Thus, gastrin may play a role in altered intestinal absorption postresection. However, the associated gastric hypersecretion may actually impair absorption.145 Gastrin does not appear to have a significant effect on intestinal motor activity.147

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Motilin Motilin, found in highest concentration in the mucosa of the proximal small intestine, appears to be the physiologic mediator of interdigestive motility.148 It is released during fasting but also by vagal stimulation and duodenal nutrients. Motilin’s primary biologic effect is contraction of gastrointestinal smooth muscle. Motilin is thought to influence jejunal motor activity via indirect rather than direct means.149 Depending on the composition of luminal contents, motilin either decreases absorption or enhances secretion of electrolytes.150 Whereas serum motilin levels were not increased up to 6 months after resection in dogs, humans with ileal resection had a four fold increase in both basal and postprandial levels.104-114 This discrepancy might be explained by the heterogenous resections performed in humans and their underlying disease. While it has not been clearly demonstrated, motilin may have a role in postresective motor adaptation. Neuropeptide Y neuropeptide Y (NPY) is found in peripheral sympathetic nerves and enteric nerves of the gut and neuroendocrine cells of the mucosa.151 NPY is released postprandially. It appears to have primarily an inhibitory effect on motility.152 This effect occurs by interrupting excitatory pathways rather than affecting muscle directly. NPY has a proabsorptive effect on the intestine which is mediated by the á2-adrenergic receptor system.152 NPY may counteract the stimulatory effects of VIP on gut secretion.153 Tissue NPY levels are preserved after intestinal resection.98 It remains unclear whether or not NPY plays a role in adaptation of motor and absorptive function after resection.

Neurotensin

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Neurotensin, which is found primarily in N cells of the ileum, has several effects on the gut, including mesenteric vasodilation, stimulation of pancreaticobiliary secretions, inhibition of gastric secretion and inhibition of intestinal motility.155-157 Neurotensin changes intestinal motility from a fasting to fed pattern and prolongs intestinal transit time.156,157 Neurotensin is released from the ileum in response to fat in the proximal gut and this response is abolished after ileal resection.158 Neurotensin has trophic effects on the rat small intestine.159 The effect is most pronounced on the jejunum while the effect on the ileum was transient. Disaccharidase activity is also increased.160 Serum neurotensin levels are normal after distal intestinal resection.104,114,115 Neurotensin mRNA levels increase within hours.161 Presumably a posttranslational mechanism is involved.162 Neurotensin exerts a systemic effect independent of luminal factors on the proliferation of proximal gut mucosa in addition to an indirect effect produced by stimulation of endogenous luminal secretions.163 An indirect mechanism appears to predominant in its effect in distal gut mucosa.164 However, given its effect on motility, one could speculate that following distal resection, a diminished effect of neurotensin leads to increased acid secretion and disruption of the normal fed motor response.

Pancreatic Polypeptide Pancreatic polypeptide (PP) is secreted from the pancreas and, to a lesser extent, the distal small intestine in response to a meal, mediated via vagal cholinergic stimulation and hormones, especially CCK, bombesin and neurotensin.165,166 PP inhibits

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pancreatic secretion. Plasma PP levels correlate with changes in migratory motor complexes, similar to motilin, suggesting a causal relationship.167 It may increase gastric and intestinal transit. PP does not appear to affect intestinal absorption and secretion. PP may also reduce food intake. Fasting PP levels are increased after resection.104,114 Any trophic effect of PP might be related to stimulated pancreaticobiliary secretion. Whether it has a primary motility effect after resection remains unclear.

Peptide YY PYY is produced by L cells of the ileum and colon and has several physiological effects in the gastrointestinal tract, including inhibited pancreatic exocrine secretion, reduced gastric acid secretion, delayed gastric emptying, and increased small intestinal transit.168,169 PYY also appears to have proabsorptive effects on the small intestine and may regulate postprandial absorption.170 PYY is released by stimulatory signals arising from the proximal jejunum and bile acids and fatty acids in the colon and thus, may contribute to the “ileal brake”.171 Peptide YY levels, both basal and postprandial, increase after intestinal resection.104,172,173 These changes occur within hours after experimental studies and are associated with increased PYY mRNA levels.173 Tissue content falls.173 These elevated serum levels may be transient in dogs but long lasting in humans.104,172 Unlike enteroglucagon, fasting and postprandial PYY levels were not increased after limited (250 cm) resection of normal ileum in humans, suggesting that levels change only with extensive resection and intestinal disease.174 In fact, despite colocalization of PYY and enteroglucagon to the same cell type, there appears to be a gene specific response to resection.175 While PYY may be responsible for the changes in absorption and motility seen after intestinal resection, it remains unclear whether or not it has trophic effects. Immunoneutralization of PYY failed to prevent intestinal adaptation after resection in rats.176 Interestingly, central PYY administration causes hyperphagia which may play a role in intestinal adaptation.177

Somatostatin Somatostatin is found in the nervous system, pancreas and gastrointestinal mucosa. It is primarily released in response to meals. Somatostatin has many biological effects, which are produced by paracrine, endocrine and neurocrine mechanisms. It inhibits the release of growth hormone, thyroxine, insulin, glucagon, gastrin, secretin, VIP, motilin and other polypeptides.178 Somatostatin also has direct effects on the intestinal tract, inhibiting secretion, decreasing absorption and altering motility.179 There is evidence that somatostatin inhibits proliferative activity of intestinal cells in vitro and intact intestine in vivo.180-183 Somatostatin suppresses the release of EGF from the salivary glands and Brunner’s glands.181,184 Somatostatin has been shown to inhibit the growth promoting effects of both exogenous and endogenous gastrin.181 Sucrase and maltase activity were diminished in jejunal cells by somatostatin.181 Somatostatin inhibits intestinal adaptation after intestinal resection.185,186 Presumably the effect is mediated in part by inhibiting epithelial cell migration and proliferation and via indirect effects on other hormones. The somatostatin analogue octreotide also predisposes enterocytes to apoptosis.187 Plasma somatostatin levels are not increased after resection.104 Tissue somatostatin concentration is increased and binding sites decreased in the intestine several weeks after intestinal resection

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when resection stimulated proliferation begins to subside.188-189 However, levels are normal later.98,189 This further suggests that somatostatin might have a regulatory role in the adaptive response to intestinal resection. The binding capacity for somatostatin is greater in the jejunum than the ileum which might explain the greater adaptive potential of the ileum.190

Vasoactive Intestinal Polypeptide Vasoactive intestinal polypeptide (VIP) is thought to be the major inhibitory transmitter of the gut and is distributed throughout the submucous and mesenteric plexuses of the intestinal wal.191,192 Its release is stimulated by a variety of neural, hormonal and mechanical stimuli, including bile.192,193 VIP stimulates intestinal and pancreatic secretion. It relaxes intestinal smooth muscle. Circulating VIP levels have been reported to be unchanged or increased after intestinal resection, but since circulatory VIP arises primarily from outside the gut, this is not unexpected.115,194 We found that tissue content of VIP decreases markedly after 75% resection in dogs.98 With its major effects on blood flow and secretion, VIP might alter intestinal adaptation. One can speculate about a possible trophic effect for VIP since VIP stimulates secretion of EGF from Brunner’s glands.183 Given its major motor effects, VIP may have a role in adaptive changes in motility after resection.

Summary At the present time, GLP-2 and neurotensin are the most likely trophic hormones during intestinal adaptation. In fact, neurotensin augments the enterotropic effects of GLP-2.195 While PYY stimulates absorption it does not clearly have a trophic effect. CCK, gastrin, and neuropeptide Y also have proabsorptive effects and questionable trophic effects during adaptation. Several hormones have important motility effects and thus might participate in motor adaptation(Table 15.2). PYY, neurotensin and enteroglucagon are potential mediators of the “ileal brake” reflex which may influence motor adaptation after proximal resection. Given the small amount of data available, the importance of hormones in barrier and immune function is only speculative.

Systemic Factors

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Systemic factors may also play a role in intestinal adaptation, including growth factors, systemic hormones, and other intermediary agents e.g. cytokines (Table 15.4). Their effects may be primary or they may function as mediators of the effects of other regulatory factors. These factors appear to have their greatest effect on the trophic changes in the adaptive intestine.

Local Growth Factors Epidermal Growth Factor Epidermal growth factor (EGF) is secreted by the salivary glands and Brunner’s glands in the duodenum and plays an important role in maintenance of normal intestine and structure.196 EGF receptors are present throughout the gastrointestinal tract. EGF has trophic and proabsorptive effects on the intestine.197,198 EGF stimulates both epithelial cell proliferation and migration in a dose dependent fashion whether given systemically or luminally.199 Gastrointestinal hormones influence EGF secretion, including VIP and somatostatin.184

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Table 15.4. Systemic factors and adaptation Growth Factors EGF IGF-1 System Factors Growth hormone Insulin Prostaglandins Thyroxine Cytokines TNF IL-1 IL-11

Trophic Effect + +

Absorption + +

Motility 0 0

Barrier/Immune Function + +

+ + + +

? + 0 0

0 0 + 0

? ? + 0

– ? +

– ? ?

? – ?

– ? ?

+ = increased or stimulated 0 = no change – = decreased or inhibited ? = response unclear

The role of EGF in intestinal adaptation has recently been reviewed.200 Endogenous EGF is increased in saliva and diminished in urine after intestinal resection. This suggests increased tissue utilization of endogenous EGF during adaptation.201 Intestinal EGF receptor activity is increased after resection.202 Intestinal adaptation is impaired in animals with defective EGF receptors.203 Thus, EGF receptor activity is important during adaptation. The results of experimental studies suggest that EGF administered at the time of resection enhances intestinal adaptive function.200 Both structural and functional adaptation are augmented. The route, dose and timing of EGF administrations are important factors.201 EGF has additive effects with glutamine and growth hormone.205,206 Current information suggests that to stimulate adaptations EGF should be given early after resection. Even transient administration, whether enteral or parenteral, is effective. Luminal nutrients are not essential to an EGF mediated effect.

Insulin Like Growth Factor Insulin like growth factors I (IGF-I), and II (IGF-II), structurally similar to insulin, are synthesized and secreted in the liver via a growth hormone-dependent process. IGF-I has major endocrine, autocrine and paracrine effects.207-209 IGF-I is a potent mitogen which stimulates glucose and amino acid transport.208 Its effects are modulated by membrane receptors and soluble binding proteins. IGF-I receptors are present in intestinal epithelium, with the highest concentration in crypt cells.209 They are even more abundant in the muscularis. The highest density occurs in the ileum. IGF-II receptors have a higher density in the mucosa whereas IGF-I is more predominant in the lamina propria. IGF influences paracellular permeability.207 Intestinal resection is associated with increased IGF-I mRNA.210 The number of cells expressing IGF-I receptors increases transiently several fold within the first 2 days. This occurs even with IGF administration.211 IGF-II receptor binding is increased in the intestine within the first 2 days and prior to increased cell mass.212 IGF-I administration enhances mucosal adaptation after jejunoileal resection.210-21

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IGF has a greater trophic effect on the ileum.210 This effect is modulated, in part, by altered IGF binding protein levels. IGFBP-4 mRNA increases but IGFBP-3 mRNA decreases in ileum after resection.210 IGF binding protein levels diminish within hours which may permit IGF to regulate adaptation.215,216 Glutamine and IGF-I have additive trophic effects.217 Thus, there is convincing evidence that IGF I plays a role in intestinal adaptation.

Systemic Hormones Growth Hormone Growth hormone (GH) is a pituitary peptide that binds to a specific cell receptor but also binds to GH-binding protein. GH receptors are distributed throughout the gastrointestinal tract with highest activity in distinct epithelial cell populations.218 GH stimulates IGF production locally and in the liver.218 Chronic growth hormone excess results in growth of intestinal mucosa.219 This may be secondary to an effect on cell life span rather than increased proliferation. GH excess increases IGF-I mRNA in the gut. Growth hormone releasing and inhibitory factors may also regulate this response. 220 Growth hormone appears to have an important role in intestinal adaptation. Hypophysectomy impairs the normal adaptive response and this effect is not due entirely to hypophagia.221 Growth hormone increases amino acid uptake by the intestine.222 Exogenous GH administration stimulates mucosal but not muscle hyperplasia after intestinal resection.222-225 This effect may be region specific since a GH-analog augmented the adaptive response in the proximal but not distal intestinal remnant.225 Growth hormone does enhance amino acid absorption after resection.226 This occurred despite normal IGF-1 levels suggesting that GH probably works via direct and indirect mechanisms. Disaccharidase activity was not increased. Thus, GH may be an important mediator of the trophic response after resection.

Insulin

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The pancreatic hormone insulin appears to have several effects in the small intestine. These include regulation of brush border enzymes, absorption of nutrients, and cell proliferation and differentiation.227,228 Specific receptors for insulin in the gastrointestinal tract have been identified which are distinct from other growth factors.229 Plasma insulin levels are not altered by small bowel resection.227 Affinity but not binding capacity of intestinal insulin receptors decreases after resection.227 This loss of binding correlates with accelerated proliferation. Interestingly, the enteroinsular axis is disrupted by intestinal resection.230 Oral glucose administration results in lower insulin levels which might influence overall metabolism. Thus, insulin may have a variety of effects during intestinal adaptation.

Prostaglandins The eicosanoids, particularly, prostaglandins of the E series, appear to play an important role in the gastrointestinal tract. They participate in motility, secretion, blood flow, pancreatic biliary secretion and maintenance of barrier function.231-235 Both endogenous and exogenous eicosanoids have a cytoprotective function which is related to effects on the mucosal microcirculation, motor activity, glycoprotein production, bicarbonate secretion, mucus production, tight junctions, lysosomal membrane stabilization, hydrophobility, and epithelial restitution.231 PGE analogues restore MMC’s after feeding.234 Given these diverse actions, particularly the mitogenic

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and motility effects, prostaglandins may play a role in intestinal adaptation. An increased trophic response after resection has been demonstrated with prostaglandins E2.236 The effects of the prostaglandins do not appear to be mediated via other peptides.233,237 It is more likely that prostaglandins are mediators of the response of hormones. Cytokines also increase prostaglandin production.238

Thyroxine Thyroxine is a known mitogen of intestinal crypt cells and hypothyroidism is associated with mucosal hypoplasia.239 Mucosal hyperplasia follows the induction of hyperthyroidism experimentally.240 Changes in food intake may be an important factor. The growth promoting properties of thyroxine may also be mediated in part via local changes in EGF activity.241 Structural changes are more prominent than functional ones. Thus, the extent of the role of thyroid hormone in adaptation is poorly defined.

Cytokines Cytokines have been demonstrated to have a number of potential effects on the small intestine. Intestinal epithelial cell populations have been found to express and/ or respond to several cytokines, including IL-1, IL-2, IL-6, TNF and interferon-α.242 Tumor necrosis factor (TNF) reduces intestinal blood flow and limits fuel glutamine availability to the intestine.242 It reduces mucosal cellularity and may impair barrier function. TNF down regulates collagen synthesis during wound healing and thus, may influence intestinal adaptation at the subepithelial level.244 Interleukin-1 (IL-1) inhibits gastric acid secretion and suppresses postprandial motility in the duodenum and jejunum. 245 These effects appear to be mediated both via corticotropin-releasing factor and prostaglandins. Interleukin 11 promotes cell proliferation and differentiation and enhances postresection adaptation.246 It has an additive effect with EGF. The marked interactions between cytokines and both local growth factors and gastrointestinal peptides suggests that there may be an important integration between the epithelium and the mucosal immune system which can influence the adaptive response.247,248

Neural Influences Intestinal structure and function are under the influence of both the intrinsic and extrinsic enteric nervous systems.249-250 Interruption of innervation at various levels results in marked changes in cell proliferation, intestinal motor responses, and enteric peptide release.251-254 Following intestinal transplantation the capacity for adaptation remains, suggesting that neurohormonal regulation is re-established.255 Thus, neural influences are important in the regulation of the intestinal adaptive response.

Changes in Blood Flow Mucosal blood flow increases transiently after intestinal resection.256 These changes are most marked distal to the resection. While it has been speculated that this increased blood flow might contribute to trophic changes, there is not a correlation between blood flow and hyperplasia.257 The transient nature of blood flow changes also argues against a significant role. These findings suggest that hormonal rather than metabolic factors are responsible for the mucosal hyperemia that occurs. Vasodilators such as glucagon, gastrin and cholecystokinin may be responsible for increased splanchnic blood flow.258 It is not clear that ischemia diminishes the adaptive response.

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Mesenchymal Factors Intestinal structure and function may be profoundly influenced by tissues adjacent to the epithelium, including the basement membrane and other subepithelial constituents and lymphoid tissue. Basement membrane components influence epithelial cell migration, proliferation and differentiation.259,260 While there are interactions between matrix proteins and growth factors, they appear to have independent effects on epithelial cell proliferation and migration,261-263 There is evidence that the composition of such components, e.g., laminin, may be altered after resection.264 There are numerous lymphoepithelial interactions.265 Lymphoid tissues are an important source of cytokines and growth factors.266 Both epithelium and lymphoid tissue are influenced by gastrointestinal hormones.267,268 Given the importance of neuroimmune regulation of intestinal transport of water and electrolytes, one might speculate about a role for the immune system in functional adaptation.269

Cellular Mechanisms

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It is now recognized that intestinal resection results in changes in molecular events in the intestinal epithelial cells within hours.270,271 There is immediate increase in genes which encode transcription factors. These include not only genes influencing cell proliferation, but also those augmenting nutrient trafficking and heat shock genes which maintain normal cellular function.272 Many of these are novel genes, not normally present in intestinal epithelium.272,273 These responses are spatially and temporally regulated.273 Regulation of enzyme synthesis can be either pre- or posttranslational.271 The specific triggers for these events are not clear and there are obviously many candidates. It is also likely that this molecular response will be altered by nutrients and other factors.275 Further evidence for the importance of specific regulatory gene products in the adaptive response comes from studies in knockout mice. P21 is a nuclear protein whose production is influenced by P53. In P21 null mice apoptosis but not proliferation increases after intestinal resection. 276 Bax is a pro-apoptotic gene. Bax-null mice have the normal proliferative response but do not increase apoptosis after resection.277 Intracellular polyamine content appears to have an important role in cell proliferation. The polyamines bind nucleic acids, influence RNA polymerase activity and may be the final signal for initiation of protein synthesis and cell division.278-280 Their effect occurs by virtue of their ability to regulate proto-oncogene expression.281 The enzymes responsible for synthesizing (ornithine decarboxylase) and degrading (diamine oxidase) polyamines change rapidly during the intestinal adaptive response.278-284 Inhibition of ornithine decarboxylase and diamine oxidase activity by specific inhibitors reduces and increases intestinal adaptation, respectively.285,286 Polyamine synthesis is a common mediator of the trophic effect of many of the important stimuli during intestinal adaptation.287-292. There are multiple regulatory pathways and epithelial cells can also alter their ability to take up polyamines.291,292 The ubiquitous nature of the polyamine synthetic pathway and its tight regulatory mechanism suggest that it has an important role in the initiation of cell proliferation and perhaps its termination during intestinal adaptation. The molecular mechanisms of hormone production are receiving increasing attention. Levels of mRNA for CCK, enteroglucagon, neurotensin and PYY increase within hours after resection. This provides evidence that these peptides play an important role in the early phases of intestinal adaptation.

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The importance of membrane glycoproteins in the regulation of cell proliferation and function has recently been appreciated.293,294 Tyrosine kinase receptors play a prominent role.295 As has been reported earlier, receptor activity for various peptides is modulated after intestinal resection. These alterations may be more important than changes in circulating concentrations of these regulatory peptides in determining their effect on adaptation. This may provide a mechanism for terminating the response to various regulatory factors.293

Role of the Colon Evidence is increasing that the colon plays an important role in adaptation of the small intestine. Bypass or resection of the colon depresses epithelial cell production in the small intestine.297-298 This effect may be mediated by short chain fatty acids (SCFA), which are products of bacterial fermentation of fiber in the colon.297 SCFA infused into the colon cause jejunal mucosal hyperplasia.299-300 Butyrate alone does not have a comparable effect.299 This enhanced proliferation is related to increased tissue content of gastrin but not increased plasma levels.300-301 Plasma enteroglucagon levels do correlate with crypt cell production rate during administration of fermentable fiber into the colon.301 Thus, the colon appears to have a role in intestinal adaptation if it is in continuity and processing nutrients.

Clinical Implications Understanding the mechanism of intestinal adaptation is important for planning strategies for clinical management. An obvious goal is to maximize the normal adaptive response. This might be achieved by providing the optimal dietary constituents, augmenting critical growth factors and regulators, and suppressing stimuli which inhibit this process (Table 15.5). The complexity of this response with its numerous interrelationships will make manipulating the regulatory factors difficult. Restoration of intestinal continuity, including to the colon remnant, may also increase the small intestinal adaptive response. Another important aspect of clinical management is to use our understanding of postresection gut structure and function to implement the diet most likely to be absorbed effectively.

Table 15.5. Strategies for maximizing intestinal adaptation Provide optimal dietary constituents Type of nutrients Form of nutrients Specific nutrients Glutamine Augment growth factors and regulatory peptides EGF IGF-1 GLP-2 Growth hormone Suppress inhibitory factors Restore intestinal continuity Small intestine Large intestine

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Fargeas MJ, Fioramonti J, Bueno L. Central Action of interleukin-1α on intestinal motility in rats: Mediation by two mechanisms. Gastroent 1993; 104:377-383. Fiore NF, Ledmczky G, Lin CL et al. Comparison on interleukin-11 and EGF in residual small intestine after massive small bowel resection. J Ped Surg 1998; 33:24-29. Steinfos HH, Hunt TK, Scheueustuhl H et al. Selective effect of tumor necrosis factor-alpha on wound healing in rats. Surgery 1989; 106:171-176. Hurst SM, Stanisz AM, Sharkey KA et al. Interleukin 1α-induced increase in substance P in rat myenteric plexus. Gastroent 1993; 105:1754-1760. Cooke HJ. Neurobiology of the intestinal mucosa. Gastroent 1986; 90:1057-81. Tutton PJM. Neural and endocrine control systems acting on the population kinetics of the intestinal epithelium. Med Biol 1977; 55:201-208. Galligan JJ, Furness JB, Costa M. Migration of the myoelectric complex after interruption of the myenteric plexus: Intestinal transection and regeneration of enteric nerves in the guinea pig. Gastroent 1989; 97:1135-1146. Nelson DK, Sarr MB, Go VLW. In vivo neural isolation of the canine jejunoileum: temporal adaptation of enteric neuropeptides. Gut 1991; 32:1336-1341. Deitz E, Gebhardt JH, Preissner C et al. Distribution of gastrointestinal hormones in the adaptive response after small bowel transplantation. Gut 1987; 28:217-220. Tutton TJM, Helme RD. The influence of adrenoreceptor activity on crypt cell production in the rat jejunum. Cell Tiss Kinet 1974; 7:125-136. Kirsch AJ, Kirsch SS, Kimura K et al. The adaptive ability of transplanted rat small intestine. Surgery 1991; 109:779-787. Touloukian RJ, Spencer RP. Ileal blood flow preceding compensatory intestinal hypertrophy. Ann Surg 1972; 175:320-325. Urich-Baker MG, Hollwarth ME, Kvietys PR et al. Blood flow responses to small bowel resection. Am J Physiol 1986; 251:G815-G822. Premen AJ, Kvietys PR, Granger DN. Postprandial regulation of intestinal blood flow: Role of gastrointestinal hormones. Am J Physiol 1985; 249:G250-G255. Hahn V, Stallmach A, Hahn EG et al. Basement membrane components are potent promoters of rat intestinal epithelial cell differentiation in vitro. Gastroent 1990; 98:322-335. Thompson JS. Basement membrane components stimulate epithelialization of intestinal defects in vivo. Cell Tissue Kinetics. 1990; 23:443-451. Basson MD, Modlin IM, Flynn SD et al. Independent modulation of enterocyte migration and proliferation by growth factors, matrix proteins and pharmacologic agents in an in vitro model of mucosal healing. Surgery 1992; 112:299-308. Benya RV, Duncan MD, Mishra L et al. Extracellular matrix composition influences insulin like growth factor I receptor expression in rat IEC-18 cells. Gastroent 1993; 104:1705-1711. Schuppan D, Riecken EO. Molecules of the extracellular matrix: potential role of collagens and glycoproteins in intestinal adaptation. Digestion 1990; 46:2-11. Beaulieu JF, Vachon PH. Reciprocal expression of laminin A chain isoforms along the crypt-villus axis in the human small intestine. Gastroent 1994; 106:829-839. Brandtzaeg P, Sollid LM, Thrane PS et al. Lymphoepithelial interactions in the mucosal immune system. Gut 1988; 29:1116-1130. Higashiyama S, Abraham JA, Miller J et al. A heparin-binding growth factor secreted by macrophage-like cells that is related to EGF. Science 1991; 251:936-939. Freier S, Evan M, Faber J. Effect of cholecystokinin and its antagonist, of atropine, and of food on the release of IgA and IgG specific antibodies in the rat small intestine. Gastroent 1987; 93:1242-1246. Boirivant M, Fais S, Aumbale B et al. VIP modulates the in vitro immunoglobulin A production by intestinal lamina propria lymphocytes. Gastroent 1994; 106:576-582.

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Gelbmann CM, Barrett KE. Neuroimmune regulation of human intestinal transport. Gastroent 1993; 105:934-936. Sacks AI, Warwick G, Barnard JA. Early proliferative events following proximal intestinal resection in the rat. Gastroent 1993; 102:A240. Ehrenfied JA, Townsend CM, Thompson JC et al. Increase in nup 475 and cjun are early molecular events that precede the adaptive hyperplastic response after small bowel resection. Ann Surg 1995; 222:51-56. Dodson BD, Wang JL, Swietlicki E et al. Analysis of cloned CDNA’s differentially expressed in the adapting remnant small intestine after partial resection. Am J Physiol 1996; 271:G347-G356. Rubin DC, Swietlicki E, Wang JL et al. Enterocyte gene expression in intestinal adaptation: evidence for a specific cellular response. Am J Physiol 1996; 270:G143-G152. Yeh M, Shiau YF, Yeh KY. Expression of alkaline phosphatase, lactase, and sucrase in hyperplastic ileum after small bowel resection is differentially regulated. Gastroent 1994; 106:A641. Tappenden KA, McBurney MI. Systemic short chain fatty acids rapidly alter gastrointestinal structure, function and expression of early response genes. Dig Dis Sci 1998; 43:1526-1536. Stern LE, Falcone RA, Kemp CJ et al. P21 is required for the mitogenic response to intestinal resection. J Surg Res 2000; 90:45-50. Stern LE, Huang F, Kemp CJ et al. Bax is required for increased enterocyte apoptosis after massive small bowel resection. Surgery 2000; 128:165-170. Pegg AE, McCann PP. Polyamine metabolism and function. Am J Physiol 1982; 243:C212-C221. Luk GB, Baylin SB. Polyamines and intestinal growth: increased polyamine synthesis after jejunectomy. Am J Physiol 1983; 245:G656-G660. Hosomi M, Lirussi F, Stace NH et al. Mucosal polyamine profile in normal and adapting (hypo and hyperplastic) intestine: Effects of DFMO treatment. Gut 1987; 28:103-107. Wang JY, McCormack SA, Viar MJ et al. Polyamines modulate small intestinal crypt cell growth through a mechanism involving protooncogenes. Gastroent 1992; 102:A584. Luk GD, Yang P. Distribution of polyamines and their biosynthetic enzymes in intestinal adaptation. Am J Physiol 1988; 254:G194-200. Mennigen R, Kusche J, Erpenbach K. Adaptive response of the rat small bowel to 70% resection: Is the intestinal diamine oxidase involved in mucosal growth regulation. Biogenic Amines 1988; 5:55-68. Buts JP, Theys S, Keyser ND et al. Changes in serum and intestinal diamine oxidase activity after proximal enterectomy in rats. Dig Dis Sci 1989; 34:1393-1398. Kingsnorth AN, Abukhalaf M, LaMuraglia GM et al. Inhibition of ileal and colonic ornithine decarboxylase activity by alpha-difluoromethylinthine in rats: Transient atrophic changes and loss of postresectional adaptive growth. Surgery 1986; 99:721-727. Erdman SH, Park JHY, Thompson JS et al. Suppression of diamine oxidase activity enhances postresection ileal proliferation in the rat. Gastroenterol 1989; 96:1533-1538. Chung DH, Evers M, Townsend CM et al. Cytokine regulation of gut ornithine decarboxylase gene expression and enzyme activity. Surgery 1992; 112:364-369. Rountree DB, Ulshen MH, Selub S et al. Nutrient-independent increases in proglucagon and ornithine decarboxylase messenger RNAs after jejunoileal resection. Gastroent 1992; 103:462-468. Kuwayama H, Naito T. Effects of prostaglandins on ornithine decarboxylase activity in rat small intestine. Dig Dis Sci 1993; 38:1087-1090.

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Buts JP, Keyser ND, Romain N et al. Response of rat immature enterocytes to insulin: Regulation by receptor binding and endoluminal polyamine uptake. Gastroent 1994; 106:49-59. Ginty DD, Marlowe M, Pekala PH et al. Multiple pathways for the regulation of ornithine decarboxylase in intestinal epithelial cells. Am J Physiol 1990; 258:G454-G460. Bardocz S, Grant G, Brown DS et al. Effect of fasting and refeeding on basolateral polyamine uptake and metabolism by the rat small bowel. Digestion 1991; 50:28-35. Tauber R, Reutter W, Gerok W. Role of membrane glycoproteins in mediating trophic responses. Gut 1987; 28:S1:71-77. Gorelick FS. Second messenger systems and adaptation. Gut 1987; 28:S1:79-84. Ullrich A, Schlessinger J. Signal transduction by receptors with tyrosine kinase activity. Cell 1990; 61:203-212. Thompson JS, Saxena SK, Sharp JG. Effect of the duration of infusion of urogastrone on intestinal regeneration. Cell Tissue Kinetics 1989; 22:303-309. Sakata T. Depression of intestinal epithelial cell production rate by midgut bypass in rats. Scand J Gastroent 1988; 23:1200-1202. Buchholtz TW, Malamud D, Ross JS et al. Onset of cell proliferation in the shortened gut: Growth after subtotal colectomy. Surgery 1976; 80:601-607. Kripke SA, Fox AD, Berman JM et al. Stimulation of intestinal mucosal growth with intracolonic infusion of short-chain fatty acids. JPEN 1989; 13:109-116. Reilly KJ, Frankel WL, Klurfeld DM et al. Gastrin mediates trophic effects of colonic short chain fatty acids on rat jejunum. Gastroent 1994; 106:A629. Goodlad RA, Lenton W, Ghatei MA et al. Effects of an elemental diet, inert bulk and different types of dietary fibers on the response of the intestinal epithelium to refeeding in the rat and relationship to plasma gastrin, enteroglucagon and PYY concentrations. Gut 1987; 28:171-180.

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CHAPTER 16

Intestinal Regeneration and Nutrition Jon S. Thompson, Shailendra K. Saxena and John G. Sharp

Introduction The response of the intestine to a variety of insults or injury depends on the depth of injury to the intestinal wall. Intestinal restitution is the repair of damaged epithelium above the lamina propria due to a process primarily involving epithelial cell migration or spreading along the surviving intact layer. Injury to the lamina propria and into the deeper areas will cause a more generalized response with the regenerating cells being derived from all the surviving components of the intestine. This intestinal regenerative process is more complicated. It involves not only epithelial cell migration, but epithelial cell proliferation, alterations in cell function and adaptation of the subepithelial tissues. Furthermore, contraction of an injured area will occur if the defect is a deep partial thickness or full thickness wound. Thus, the regenerative response is associated with adaptive changes in the adjacent intestine. Regulation of these processes involves communications and interactions of multiple cell types by mechanisms that are still incompletely understood. The intestinal regenerative response has important clinical implications. Both local ulcerative lesions and more diffuse intestinal injuries that occur in response to ischemia, irradiation and other inflammatory insults, heal by variants of this regenerative process. Furthermore, nutrients appear to be important regulatory factors of regeneration, acting both directly and indirectly e.g., via stimulation of gastrointestinal peptide secretion. Thus, nutrients have a potential therapeutic role in the treatment of various intestinal injuries.

Mechanism A detailed description of regeneration for discrete, full thickness intestinal defects has been published, and only an updated summary will be presented.1 One of the earliest events is migration of epithelial cells onto the defect surface. Epithelial cell migration involves a change in epithelial cell shape (columnar to squamous), movement of cells onto the injured defect and provision of migratory cells from the surrounding mucosa. This phenomena is enhanced in vivo by luminal contents and a variety of systemic and local factors, including associated intestinal resection, location within the intestinal tract, basement membrane components, and immune cells.212 Clearly endogenous peptides, chemotaxis, stimulated proliferation and cell adhesive factors are important in this migratory response. Recent in vitro studies of cell migration in restitution suggest that migration is regulated by both epidermal growth factor receptor (EGFR) ligands (EGF and TGFα) and EGFR independent factors (bFGF, IGF-1, IL-IB, and trefoil peptides.13 A number of inhibitory factors have The Biology and Practice of Current Nutritional Support, 2nd Edition, edited by Rifat Latifi and Stanley J. Dudrick. ©2003 Landes Bioscience.

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also been identified in vivo, including the inhibitory polypeptide somatostatin, corticosteroids, and thiphenamil.10,11,14,15 The response to these factors may be pharmacologic or a toxic effect, rather than physiologic. Another important component of the intestinal regeneration response is stimulated epithelial cell proliferation, as this will supply the cells for migration and promote crypt and villus development in the regenerating mucosa. Proliferation is transiently increased in the crypts adjacent to the injured area with elongation and bifurcation of the crypts (crypt fission). Thus, proliferation is increased both by increasing the rate of cell production per crypt and increasing the number of crypts. The adjacent villi become reduced in height, suggesting that proliferating cells are directed to repair the injury. This priority is maintained until cell density is increased and cell to cell contact re-established. Stimulated proliferation continues until normal villus architecture is achieved. In the regenerating mucosa, crypts form by invagination of the intestinal cells into the underlying connective tissue and cell proliferation is stimulated for a longer period of time until normal structure is reestablished. Eventually there is nearly complete restitution of crypts and villi. These processes are stimulated by growth factors, luminal contents, and associated intestinal resection and are also influenced by the crypt density around the injured area.2-11 EGF, in particular is an important mitogenic factor. Intracellular processes, such as polyamine metabolism, are also important stimuli for this process. A decrease in polyamine levels by inhibition of ODC activity will transiently decrease mucosal proliferative activity and reduce crypt fission.10,16,17 Increasing polyamine levels by stimulating ODC activity or by decreasing polyamine degradation via diamine oxidase activity increases the intestinal regenerative response.2,9,18 Recently, many other potential regulatory factors have been identified.19 Mucosal development, i.e., mucosal structure and function, is enhanced by the same factors that promote increased proliferation, indicating the predominant influence of proliferation on mucosal development. The mucosal response to injury involves a specific alteration in enterocyte phenotype and the response of enterocytes to regulatory factors. 20,21 Differentiation is initially delayed to permit migration and proliferation. Recent evidence suggests that regulation of apoptosis may also play an important role in the regenerative response.22-26 Apoptosis of epithelial cells in the intestine adjacent to the full thickness defect is reduced during the proliferative response.23,24 Apoptosis is reduced in the presence of mitogenic agents such as EGF and GLP-2.24,25 Counter-regulatory factors, such as somatostatin and TGFβ, induce apoptosis.23,26 Extracellular matrix components enhance regeneration, in part, by reducing the apoptosis induced by disruption of cellular connections to the extracellular matrix.27 Interestingly, the short chain fatty acid butyrate induces apoptosis.20 Regeneration of subepithelial tissue also occurs, but more slowly.28 Presumably basement membrane components are produced by the advancing epithelium and mesenchymal elements. The inflammatory response and angiogenesis stimulate connective tissue development which becomes important in villus and crypt development. Muscle regeneration occurs later. Muscularis mucosa repairs only after epithelialization is nearly complete. It is not clear if muscularis propria regenerates of if scarring persists in this layer.8 Contraction of deep partial thickness and full thickness intestinal defects is another important aspect of regeneration and appears to be independent of epithelialization.28,29

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This reduces the effective size of the injured area. This is initially related to smooth muscle-like contractibility which begins within hours.14,29 However, contraction is related temporally to increased collagen content within a few days. Contraction is regulated by both local and systemic factors. This process is influenced by the tissue in the depth of the wound, and can be prevented mechanically by splinting the injured defect. Corticosteroids and smooth muscle antagonists, e.g., thiphenamil, inhibit contraction.14,15 However, the transient effects of smooth muscle antagonists suggest that the contractile properties of the subepithelial tissues do not heavily influence this response. Increased collagen content may be important. Furthermore, epidermal growth factor at high doses inhibits contraction by an as yet unknown effect on subepithelial tissues.10 Regenerating intestine re-establishes normal functional activity. Nutrient uptake, mucosal enzyme activity and protein content progressively return to normal levels.5,28 Specific transport capabilities of the adjacent mucosa are maintained in regenerative mucosa.5 Whether or not regenerating intestine is able to participate in integrated gut function, e.g., motility and immune function remains unclear. Intestinal regeneration has high biologic priority and will occur eventually despite inhibition of the various steps involved. Inhibition of increased proliferation will delay but not prevent epithelialization and mucosal development.10,16 If contraction is inhibited, epithelialization will occur over the larger injured defect.12 The initial signal for initiation of regeneration is unclear. The inciting factor may be tissue injury, loss of integrity of the intestinal wall, intraluminal exposure of the deeper tissue layers or other undefined determinants. Different factors may be important during different phases of the regenerative response. For example, loss of cell to cell contact or a denuded basement membrane may be important early regulators. There has been recent progress in identifying possible molecular mechanisms, but these remained largely undefined.19 Furthermore, it remains unclear if the mechanisms important in maintaining normal intestinal structure and function are the same as those involved in the regenerative response. Regeneration of more diffuse intestinal injury has several distinct differences from that occurring in discrete, full thickness injury. Inflammation and ischemia are perhaps more significant in this setting. The injury is more heterogeneous, with more superficial injury, leaving various tissue layers intact. These lesions are potentially more extensive with resultant changes in the intraluminal environment such as altered absorption and secretion and dysmotility. Thus, the mechanism and regulation of a more diffuse regenerative response may not be the same as for discrete lesions. We are just beginning to understand the importance of nutrients in this regenerative process (Table 16.1). Nutrients are important in gene expression, including transcriptional responses, translation, and post translational modification.30 Nutrients also affect the production, release, and activity of a variety of peptides which may play a role in regeneration. Both nutrient composition, e.g. fat, protein or glucose, and specific nutrients, e.g. glutamine and arginine may influence regeneration.31,32 The response to nutrients may be region specific. For example, in the distal intestinal tract short chain fatty acids may similarly be important.20 Most research in the area of intestinal injury has focused on prevention of the injury rather than the regenerative response. However, a better understanding of this response may provide new therapeutic strategies for the management of inflammatory conditions of the small intestine (Table 16.2).

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Table 16.1. Potential mechanisms of nutrient effects on intestinal regeneration • Nutrient stimulation of production and release of gastrointestinal peptides and other potentially beneficial molecules • Nutrient enhanced peptide function via improved absorption or inhibited inactivation • Nutrient modulation of transcription/translation in target cells • Nutrient specific effects on enterocyte structure and function • Nutrient modulation of local immune responses

Clinical Implications Repair of Intestinal Injury Intestinal Ulceration Whereas gastroduodenal ulceration is a common, well studied phenomena, local ulcerative lesions in the small intestine are more unusual. Small intestinal ulceration in the clinical setting is commonly related to steroid and other immunosuppressant therapy, inflammatory bowel disease, radiation therapy and intestinal ischemia.33,34 Often the etiology is not clear and the ulcers are termed nonspecific. Recently, nonsteroidal anti-inflammatory drugs in particular have been implicated in this condition.34,35 The gastrointestinal lesions caused by these anti-inflammatory agents are due to reduction of mucosal prostaglandin levels, reduction of mucosal blood flow, stimulation of neutrophil activation and increased apoptosis.36 These agents have also been shown to inhibit the normal increase in cell proliferation observed in the adjacent mucosa during the regenerative response to duodenal ulcer.37 Thus, inflammation caused by nonsteroidal inflammatory agents may results in abnormal healing with stricture formation.35 Many discrete, nonspecific ulcers will heal spontaneously. while others may require operation for complications. General medical therapy for this problem has included nonspecific anti-inflammatory treatments such as corticosteroids and sulfasalazine for ulcerations in Crohn’s disease. The prostaglandin E analog, Misoprostol, has been shown to be efficacious in the management of anti-inflammatory drug induced gastroduodenal ulceration.38 Misoprostol inhibits injury by increasing mucosal blood flow. It also enhances intestinal regeneration by protecting proliferative cells from injury, preventing the drug induced reduction in epithelial cell proliferation and stimulating cell proliferation. However, misoprostol is less effective at reducing small intestinal injury compared to gastric injury.39 Little is known about the effects of either systemic or luminal nutrients on healing of discrete ulcers. Nutrients may enhance intestinal regeneration by stimulating the release and/or activity of gastrointestinal peptides. Several peptide growth factors appear to have a role in healing of gastrointestinal ulcers. EGF, which has significant effects on epithelial migration and proliferation, not only stimulates intestinal regeneration, but has cytoprotective properties, which are mediated in part by prostaglandins.40 EGF and its receptor are overexpressed in the mucosa at the ulcer margin.41 In fact, ulceration may induce a novel EGF-secreting cell lineage in the surrounding tissue.42 Exogenous EGF has a beneficial effect on gastric ulcer healing.43 Another EGF receptor ligand, TFGα, is increased in injured gastric mucosa, and thus may also play an important role in repair.44 Platelet derived growth factor

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Table 16.2. Interactions of tissue injury and nutrition Type of Tissue Injury Localized epithelial damage

Effect on Nutrition Minimal

Role of Nutrition Potential Solutions “Luminal” nutrition, Peptide stimulation of polyamines restitution

Diffuse intestinal damage (radiation, chemotherapy, inflammation)

Significant, debilitating

Short chain fatty acids elemental diets, glutamine

Dietary protection, growth factors, e.g. KGF

Full thickness loss (necrosis, resection)

Significant, loss of mucosal absorption

Enhanced absorption in surviving bowel

Reduction of contracture stimulation of regeneration, cell transplantation and tissue engineering

(PDGF) significantly accelerates the healing of cysteamine induced duodenal ulcers and indomethacin induced gastric ulcers.45,46 Fibroblast growth factor (FGF) accelerates the healing of acetic acid induced gastric ulcers and alcohol and aspirin induced gastric mucosal lesions.47 Thus, a variety of local growth factors that may be effective in the presence of or which interact with nutrients may be involved in regeneration of discrete ulcers. The role of specific nutrients in treating discrete ulcers has been studied to a limited extent in experimental models. Polyamines, for which arginine is a precursor, are important in the regulation of intestinal regeneration. Polyamine levels are increased during healing of mucosal injury and inhibition of polyamine synthesis inhibits mucosal repair.48,49 Luminal polyamines can substitute for endogenous polyamines in the regenerative response to stress ulcers in the duodenum and increase the normal healing rate by stimulating proliferation.50 Inhibiting diamine oxidase activity, the primary degradative enzyme of the polyamines, with aminoguanidine also increases the healing of stress induced gastric lesions in rats.51 Clearly more investigation is necessary in this area.

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More diffuse inflammation and injury in the small intestine occurs in response to ischemia, stress, radiation, and various toxins such as alcohol.52-54 Depending on the chronicity and extent of injury a variety of chronic intestinal lesions develop. A common injury is acute mucosal necrosis which results from a variety of stressful stimuli.52 These injuries may or may not be associated with a significant inflammatory response. Intestinal ischemia, when reversible, results in intestinal lesions secondary to both ischemia and reperfusion. Radiation induces both an acute mucosal injury and a chronic ischemic condition secondary to vasculitis.53 Alcohol causes an acute mucosal injury which is usually superficial and heals by restitution alone.54 While there has been considerable research into protecting the gut mucosa from the damaging effects of radiation and other insults, less investigation has occurred into enhancing the regenerative response. Elemental diets may be beneficial during both acute and chronic radiation enteritis.55 Acutely elemental diets may protect the

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mucosa by inhibiting release of pancreatico biliary secretions and generation of free radicals. Elemental diets may be absorbed more effectively from intestine with chronic radiation injury. Nutrient enhanced peptides have been studied in diffuse injury. In contrast to many discrete full thickness ulcers, diffuse injuries such as radiation often leave progenitor cells at the base of the crypts.56 One therapeutic possibility would be stimulation of gastrointestinal progenitor cells using cell growth regulators, an approach which has proven beneficial in stimulating recovery in the stem cell compartment of bone marrow of irradiated patients.57 FGF expression is induced after radiation injury and enhances intestinal stem cell survival.58 Keratinocyte growth factor (KGF) also has significant gastrointestinal radioprotective effects. There are other potential benefits of growth factors on the healing of diffuse intestinal injury. TGFα not only accelerates healing of radiation induced injury, but partially reverses steroid impairment of intestinal wound strength which may be related to fibroplasia and increased collagen content of the intestine.59,60 Recombinant growth hormone also improved anastomotic healing in irradiated bowel in one study.61 Nutrient enhanced peptides have been evaluated in a variety of inflammatory conditions as well. EGF improved healing of intestinal lesions caused by lipids and methotrexate.62 EGF has been used clinically to treat necrotizing enterocolitis in one infant.63 Specific nutrients have also been evaluated in intestinal repair of diffuse injury. Dietary arginine accelerates mucosal regeneration following radiation enteritis in rats.64 Glutamine has been studied in both animals and humans. Oral, but not intravenous glutamine accelerates the healing of intestinal injury in rats caused by whole abdominal irradiation.30,65 Glutamine enriched feedings also promote healing of the intestinal injury caused by fluorouracil.66 While glutamine has been demonstrated to maintain gut integrity during TPN in humans, studies in repair of intestinal injury are less common.67 Both glutamine and butyrate suppositories have had benefit in the resolution of pouchitis following restorative proctocolectomy.68 The beneficial effects of short chain fatty acids are related both to their role as enterocyte fuel as well as influencing the molecular response to injury.69 Other nutrients, such as trace elements e.g., zinc, and vitamins e.g., vitamins A deserve clinical evaluation based on their effects on intestinal adaptation.70,71

Intestinal Regeneration for Increasing Absorption There has been interest in using the regenerative powers of the intestine to expand the intestinal surface area as a therapeutic modality in patients with the short bowel syndrome. Several strategies have been employed to achieve this.72 Full thickness intestinal defects can be created and patched with a variety of different surfaces, including serosal surfaces and various prosthetic materials.73-77 Lateral ingrowth of the intestinal layers from the surrounding mucosa results in regenerated intestine, which is functionally similar to the normal adjacent intestinal mucosa. It remains unclear, however, whether sufficient intestinal surface area can be produced by intestinal patching to significantly increase intestinal absorption.74,76,77 While several studies suggested that this, in fact, might occur, our own experience was less favorable.78 Serosal patching after extensive intestinal resection in dogs, in fact had a deleterious effect on intestinal absorption and nutritional status compared to resection alone. Malnutrition and malabsorption occurred despite prolongation of intestinal transit time by intestinal patching. Furthermore, marked contraction of the

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patched defects limited the increase in surface area which could be achieved. The deleterious effect of serosal patching on intestinal function may be related to several factors, including impairing the normal postresection adaptive response, amplifying the gastric hypersecretion which occurs after intestinal resection, and altering intestinal motility.78-80 Thus, while this approach may prove useful in the clinical setting to preserve intestinal length by treating stricture and perforation, it does not appear to be efficacious for expanding intestinal surface area. Other surgical approaches to expanding the surface area via regeneration have been investigated. There have been attempts to grow new intestine into tubular structures rather than via the lateral enterotomies.81,82 Replacement of colon mucosa with small intestinal mucosa has also been evaluated.83,84 More recently, efforts have been directed at tissue engineering.85 Intestinal epithelial organoid units transplanted on porous biodegradable polymer tubes can successfully vascularize, survive and regenerate into complex tissue resembling small intestine. This tissue engineered intestine has been successfully anastomosed to native small intestine.86 Intestinal stem cell transplantation and other innovative techniques such as transfection to transfer genetic information are also being studied.87 Obviously, the ideal solution might be to advance our understanding of the mechanisms of the intestinal regenerative response such that the normal intestine could be induced to undergo supranormal growth to increase surface area.

Selected References 1. 2. 3. 4. 5. 6. 7. 8. 9. 10.

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Saxena SK, Thompson JS, Sharp JG. Intestinal Regeneration. Austin: RG Landes Co 1993. Thompson JS, Bragg LE, Saxena SK. The effect of intestinal resection and urogastrone on intestinal regeneration. Arch Surg 1990; 125:1617-1621. Thompson JS. Basement membrane components stimulate epithelialization of intestinal defects in vivo. Cell Tissue Kinetics 1990; 23:443-451. Thompson JS, Tempero MA, Haun JL et al. The importance of luminal factors in neomucosal growth. J Surg Res 1986; 40:126-132. Thompson JS, Vanderhoof JA, Davis SJ et al. Effect of intestinal location on growth and function of neomucosa. J Surg Res 1985; 39:68-75. Bragg LE, Thompson JA. The influence of serosal patch size on the growth of small intestinal neomucosa. J Surg Res 1986; 40:426-431. Bragg LE, Thompson JS. The influence of intestinal resection on the growth of intestinal neomucosa. J Surg Res 1989; 46:306-310. Thompson JS. Growth of neomucosa after intestinal resection. Arch Surg 1987; 122:316-319. Thompson JS, Sharp JG, Saxena SK et al. Stimulation of neomucosal growth by systemic urogastrone. J Surg Res 1987; 42:402-410. Thompson JS, Saxena SK, Sharp JG. Effect of eflornithine on intestinal regeneration. Arch Surg 1989; 124:454-457. Thompson JS, Nguyen BT, Harty RF. Somatostatin analog inhibits intestinal regeneration. Arch Surgery 1993; 128:385-389. Saxena SK, Thompson JS, Sharp JG. Role of organized intestinal lymphoid aggregates in intestinal regeneration. J Invest Surg 1997; 10:97-103. Kato K, Chen MC, Nguyen M et al. Effects of growth factors and trefoil peptides on migration and replication in primary oxyntic cultures. Am J Physiol 1999; 276:1105-1116. Thompson JS, Hollingsed TC, Saxena SK. Prevention of contraction of patched intestinal defects. Arch Surg 1988; 123:428-430.

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Thompson JS. Effect of a smooth muscle antagonist on contraction of patched intestinal defects. J Surg Res 1992; 53:257-262. Thompson JS, Saxena SK, Sharp JG. Difluromethylornithine inhibits urogastrone stimulation of neomucosal growth. J Surg Res 1988; 44:589-595. Thompson JS, Saxena SK, Sharp JG. Difluromethylornithine inhibits crypt fission. J Gastroentest Surg 1999; 3:662-667. Erdman SH, Park JHY, Thompson JS et al. Suppression of diamine oxidase activity enhances postresection ileal proliferation in the rat. Gastroenterol 1989; 96:1533-1538. Thompson JS, Saxena SK, Sharp JG. Regulation of intestinal regeneration: New insights. Microscopy Research and Techniques 2000; 51:129-137. Basson M.D., Turowski G, Modlin IM et al. Butyrate induced enterocyte differentiation and mucosal wound healing. Gastroent 1993; 104:A235. Liu Yiw, Sanders MA, Basson MD. Loss of matrix-dependent cytoskeletal tyrosine kinase signals may regulate intestinal epithelial differentiation during mucosal healing. J Gastrointest Surg 1999; 3:82-94. Kucharzik T, Lugering A, Lugering N et al. Apoptosis of M cells during chronic intestinal ileitis in rats. Gastroent 1999; 116:A755. Thompson JS. Somatostatin analogue predisposes enterocytes to apoptosis. J Gastrointest Surg 1998; 2:167-173. Thompson JS. EGF inhibits somatostatin induced apoptosis. J Surg Res 1999; 81:95-100. Tsai CH, Hill M, Asa SL et al. Intestinal growth-promoting properties of glucagon-like peptide 2 in mice. Am J Physiol 1998; 273:E77-E84. Jones BA, Gores GJ. Physiology and pathophysiology of apoptosis in epithelial cells of the liver, pancreas and intestine. Am J Physiol 1997; 273:G1174-G1188. Thomas FT, Contreras JL, Bilbao G et al. Anoikis, extracellular matrix, and apoptosis factors in isolated cell transplantation. Surgery 1999; 126:299-304. Thompson JS, Vanderhoof JA, Antonson DL et al. Comparison of techniques of growing small bowel neomucosa. J Surgery Res 1984; 36:401-406. Bragg LE, Thompson JS, Hollingsed TC et al. Contraction of serosa-patched intestinal defects. Curr Surg 1987; 44:388-390. Berdanier CD. Nutrient-gene interactions. Nutr Today 2000, 35:8-17. Klimberg VS, Salloum RM, Kasper M et al. Oral glutamine accelerates healing of the small intestine and improves outcome after whole abdominal radiation. Arch Surg 1990; 125:1040-1045. Kubes P, Tepperman BA, Sutherland RL et al. L-Arginine protects the small intestine against reperfusion injury. Gastroent 1993; 104:A258. Thomas WEG, Williamson RCN. Enteric ulceration and its complications. World J Surg 1985; 9:876-886. Allison MC, Howatson AG, Torrance CJ et al. Gastrointestinal damage associated with the use of nonsteroidal anti-inflammatory drugs. NEJM 1992; 327:749-754. Bjarnason I, Price AB, Zanell G et al. Clinicopathological features of nonsteroidal anti-inflammatory drug-induced small intestinal strictures. Gastroent 1988; 94:1070-1074. Levin S, Shaw-Smith C. Nonsteroidal antiinflammatory drugs: how do they damage the gut? Br J Rheumatol 1994; 33:605-612. Levin S, Goodlad RA, Lee GY et al. Non-steroidal antiinflammatory drugs inhibit the process of mucosal cell proliferation associated with duodenal ulcer healing. Digestion 1992; 53:129-133. Walt RP. Misoprostol for the treatment of peptic ulcer and anti-inflammatory, drug-induced gastroduodenal ulceration. NEJM 1992; 327:1575-1580. Playford RJ, Floyd DN, Macdonald CE et al. Bovine colostrum is a health food supplement which presents NSAID induced gut damage. Gut 1999; 44:653-658.

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Itoh M, Joh T, Imai et al. Experimental and clinical studies in epidermal growth factor for gastric mucosal protection and healing of gastric ulcers. J Clin Gastroent 1988; 10:S7-S12. Tarnawski A, Santos AM, Stachura J et al. Sucralfate increases expression of EGF and its receptor in the margins of experimental gastric ulcer: A key to improved quality of ulcer healing. Gastroent 1994; 106:A194. Wright NA, Pike C, Elia C. Induction of a novel epidermal-growth factor-secreting cell lineage by mucosal ulceration in human gastrointestinal stem cells. Nature 1990; 343:32-85. Konturek SJ, Dembinski A, Warzecha Z et al. Role of epidermal growth factor in healing of chronic gastroduodenal ulcers in rats. Gastroent 1988; 94:1300-1307. Polk WH, Dempsey PJ, Russell WE et al. Increased production of transforming growth factor á following acute gastric injury. Gastroent 1992; 102:1467-1474. Vattay P, Gyomber E, Morales RE et al. Effect of orally administered plateletderived growth factor (PDGF) on healing of chronic duodenal ulcers and gastric secretion in rats. Gastroent 1991; 100:A180. Gughetta A, Nardi RV. PDGF-BB accelerates healing of indomethacin-induced gastric lesions in rats. Gastroent 1992; 102:A77. Fitzpatrick LA, Jakubowska A, Martin GE et al. Acidic fibroblast growth factor accelerates the healing of acetic acid induced gastric ulcers in rats. Digestion 1992; 53:17-27. Wang JY, Johnson LR. Polyamines and ornithine decarboxylase during repair of duodenal mucosa after stress in rats. Gastroent 1991; 100:333-343. Chung DH, Evers BM, Townsend CM. Burn induced transcriptional regulation of small intestinal ornithine decarboxylase. Am J Surg 1992; 163:157-164. Wang JY, Johnson LR. Luminal polyamines substitute for tissue polyamines in duodenal mucosal repair after stress in rats. Gastroent 1992; 102:1109-1117. Brzozowski T, Konturek SJ, Majka J et al. Epidermal growth factor, polyamines, and prostaglandins in healing of stress induced gastric lesions in rats. Dig Dis Sci 1993; 38:276-283. Bounous G. Acute necrosis of the intestinal mucosa. Gastroent 1982; 82:1457-1467. Churnratanakul S, Wirzba B, Lam T et al. Radiation and the small intestine. Dig Dis 1990; 8:45-60. Beck IT, Dinda PK. Acute exposure of small intestine to ethanol: effects on morphology and function. Dig Dis Sci 1981; 26:817-838. McCardle AH. Elemental Diets in Treatment of Gastrointestinal Injury. Adv Bio Sci 1996; 94:201-206. Potten CS. A comprehensive study of the radiobiological response of the murine small intestine. Int J Radiat Biol 1990; 58:925-973. Sharp JG. The Potential Use of Cytokines to Ameliorate the Effects of Gastrointestinal Radiation Injury. Adv Bio Sci 1976; 94:217-31. Houchen CW, George RJ, Sturmoski MA et al. FGF-2 enhances intestinal stem cell survival and its expression is induced after radiation injury. Am J Physiol 1999; 6:249-G258. Cromack DT, Povras-Reyes B, Purdy JA et al. Acceleration of tissue repair by transforming growth factor b: Identification of in vivo mechanism of action with radiotherapy-induced specific healing defects. Surgery 1993; 113:36-42. Slavin J, Nash JR, Kingsnorth AN. Effect of transforming growth factor b and basic fibroblast growth factor on steroid impaired healing intestinal wounds. Br J Surg 1992; 79:69-72. Silver DF, Simon A, Dubin NH et al. Recombinant growth hormones effects on the strength and thickness of radiation injured ileal anastomoses: A rat model. J Surg Res 1999; 85:66-70.

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Ootani A, Itoh M, Joh T et al. EGF enhances repair of intestinal mucosa damage by oral administration of methotrexate in rats. Gastroent 1994; 106:A1044. Sullivan PB, Bructon MJ, Tabaza ZB et al. Epidermal growth factor in necrotizing enteritis. Lancet 1991; 338:53-54. Gurbuz AT, Kunzelman J, Ratzer EE. Supplemental dietary arginine accelerates intestinal mucosal regeneration and enhances bacterial clearance. J Surg Res 1998; 74:149-154. Scott TE, Moellman JR. Intravenous glutamine fails to improve gut morphology after radiation injury. JPEN 1992; 16:440-444. Jacobs DO, Evans A, O’Dwyer ST et al. Disparate effects of 5-fluorouraal on the ileum and colon of enterally fed rats with protection by dietary glutamine. Surg Forum 1987; 38:45-49. VanderHulst RR, VanKreel BK, Von Meyerfeldt MF et al. Glutamine and preservation of gut integrity. Lancet 1993; 341:1363-1365. Sandborn WJ, McLeod R, Jewell DP. Medical therapy for induction and maintenance of remission in pouchitis; a systematic review. Inflamm Bowel Dis 1999; 5:33-39. Tappenden KA, McBurney MZ. Systemic short chain fatty acids rapidly alter gastrointestinal structure, function, and expression of early response genes. Dia Dis Sci 1998; 43:1526-1536. Tamada H, Nezu R, Matseo Y et al. Zinc-deficient diet impairs adaptive changes in the remaining intestine after massive small bowel resection in the rat. Br J Surg 1992; 79:959-963. Swartz-Basile DA, Rubin DC, Levin MS. Vitamin A modulates intestinal adaptation after partial small bowel resection. J Parenter Ent Nutr 2000; 24: 81-84. Thompson JS. Surgical considerations in the short bowel syndrome. Surg Gynecol Obstet 1993; 176:89-101. Thompson JS, Kampfe PW, Newland JR et al. Growth of intestinal neomucosa on prosthetic materials. J Surg Res 1986; 41:484-492. Binnington HB, Tumbleson ME, Ternberg JL. Use of jejunal neomucosa in the treatment of short gut syndrome in pigs. J Ped Surg 1975; 10:617-621. Lillemoe KD, Berry WR, Harmon JW et al. Use of vascularized abdominal wall pedicle flaps to grow small bowel neomucosa. Surgery 1982; 92:293-300. Gaton E, Czernobilsky B, Kraus L et al. The neomucosa and its surroundings after jejunoserosal patching in dogs. J Surg Res 1980; 29:451-465. Watson LL, Friedman HI, Griffin DG et al. Small bowel neomucosa. J Surg Res 1980; 28:280-291. Thompson JS, Harty RJ, Saigh JA et al. Morphologic and nutritional responses to intestinal patching following intestinal resection. Surgery 1988; 103:79-86. Bragg LE, Thompson JS. Serosal patching impairs intestinal adaptation following enterectomy. J Surg Res 1992; 52:118-122. Thompson JS, Quigley EMM. Motor and absorptive function of the canine intestine following serosal patching. J Invest Surg 1991; 4:203-215. Nothiger F, Oesch I, Zimmerman A. Entwicklung von Duundarim Neomucosa. Schweiz Med Wschr 1982; 112:530-531. Thompson JS. Neomucosal growth in serosa lined intestinal tunnels. J Surg Res 1990; 49:1-7. Williams NS, King RFG, Smith AH et al. Replacement of colonic mucosa by free and pedicled grafts of ileal mucosa in the dog. J Surg Res 1983; 35:391-401. Banerjee AK, Chadwick SJD, Peters TJ. Adaptation of jejunal to colonic mucosal autografts in experimentally induced short bowel syndrome. Dig Dis Sci 1990; 35:340-348.

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Kim SS, Kaihara S, Benvenuto MS et al. Regenerative signals for intestinal epithelial organoid units transplanted on biodegradable polymer scaffolds for tissue engineering of small intestine. Transplantation 1999; 67:227-233. Kaihara S, Kim SS, Benvenuto M et al. Successful anastomoses between tissueengineered intestine and native small bowel. Transplantation 1999; 67:241-245. Khan FH, Nass PH, Matin SC et al. Transfection of murine gastrointestinal tissue in vivo using a reporter gene: a work in progress. Gastroenterology 2000; 118:A520.

CHAPTER 1 CHAPTER 17

Nutritional and Metabolic Management of Short Bowel Syndrome Stanley J. Dudrick, Frizan Abdullah and Rifat Latifi

Introduction The short bowel syndrome is a clinical entity characterized primarily by intractable diarrhea, steatorrhea, dehydration, malnutrition, weight loss, and malabsorption of fats, vitamins and other nutrients, and not defined anatomically by a specific length of remaining functioning small intestine. Subsequent adverse consequences of short bowel syndrome include hypovolemia, hypoalbuminemia, hypokalemia, hypocalcemia, hypomagnesemia, hypozincemia, hypocupticemia, fatty acid and vitamin deficiencies, anemias, hyperoxaluria and metabolic acidosis. The actual clinical presentation of the patient with short bowel syndrome depends on several factors, including: 1. the extent of the bowel resection; 2. the site(s) of the resection; 3. the presence or absence of the ileocecal valve; 4. the residual function of the remaining small bowel, stomach, pancreas, biliary tree and colon; 5. the adaptation capacity or the intestinal remnant; 6. the primary disease of disorder that precipitated the loss of the small bowel; 7. the amount and activity of the residual disease in the intestinal remnant; 8. the general condition of the organ systems of the patient.1-5 The minimum length of small bowel sufficient for adequate absorption is controversial. Standardization of the adaptive potential is difficult because of the variable residual absorptive capacity of the remaining remnant, the wide variation in the length of the normal small intestine, and the difficulty in obtaining reproducible measurements of the length of the remaining bowel following massive resection. Depending upon the state of contraction or relaxation of the intestinal musculature, intraoperative estimates of the length of the normal intact small intestine in the adult vary from 260 to 800 cm (approximately 8-26 feet). On the other hand, the mean length of normal small intestine measured during life is 350 cm (11-12 feet) and post-mortem is 600 cm (20 feet). Because of this large variability, it is virtually impossible to determine the exact length of the remaining small bowel, and it is very difficult to estimate the percentage of the total length of small bowel represented by the segment remaining following massive intestinal resection. Moreover, many surgeons not only measure the length of the resected small bowel, rather than measuring the length of the remaining intestinal segment, but then fail to describe accurately

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the nature, condition and extent of the remaining small bowel in the patient’s medical record for future reference. Furthermore, since inflamed intestine generally shortens after operation, the absorptive functions following massive small bowel resection often do not correlate well with the intraoperative estimated length of the remaining intestine.6 Because of the rather ample functional reserve capacity of the small bowel, segmental resections of the small intestine usually do not result in significant problems with digestion and absorption.7-8 Indeed, resection of as much as 40% of the small intestine is usually well tolerated, provided that the duodenum, the distal half of the ileum, and the ileocecal valve are spared.9 On the other hand, resection of 50% or more of the small intestine usually results in significant malabsorption initially, but can be tolerated eventually without extraordinary parenteral or enteral nutritional support. However, resection of 75% or more of the small intestine usually leaves the patient with 70 to 100 cm (2-3 feet) of remaining intestine, resulting in a short bowel syndrome which can significantly impair the ability of the patient to maintain normal nutrition and metabolism. Such patients will likely require special nutritional care on a long-term or permanent basis, especially with the loss of the terminal ileum and the ileocecal valve, if normal body cell mass and function are to be preserved. The severity of symptoms following massive small bowel resection is related both to the extent of the resection and the specific anatomic site(s) of the resected small bowel.10 However, the minimal residual small intestinal absorptive surface required to sustain life without permanent parenteral nutritional support appears to vary somewhat with each patient.11,12 Development of effective total parenteral nutrition has revolutionized the treatment of the short bowel syndrome by allowing maintenance of adequate nutrition indefinitely or until the remaining bowel can adapt maximally to oral feeding, thus reducing the morbidity and mortality significantly.1318 Prolonged survival has now been achieved in a number of patients having only an intact duodenum and 15 cm (6 inches) of residual jejunum, with or without the colon.2,8,19 If approximately 60 cm (2 feet) of jejunum or ileum remain functional, in addition to the entire duodenum, survival has been the rule rather than the exception. Preservation of the ileocecal valve is of paramount importance during massive small bowel resection, and by significantly increasing the intestinal transit time, allows a longer exposure time of the intestinal chyme to the residual absorptive mucosa. Salvage of the ileocecal valve, whenever possible, has the clearly beneficial effect of increasing the absorptive capacity of the remaining small bowel to approximately twice that anticipated for the same length of small bowel without an intact ileocecal valve. Primarily as a result of mucosal hyperplasia and villous hypertrophy, absorption by the residual intestinal segments of patients with short bowel syndrome can increase as much as four-fold. Therefore, in a patient with an intact ileocecal valve, the total absorptive capability of the remaining bowel potentially can be increased maximally about eight-fold. The most common clinical conditions which precipitate massive small bowel resections are those which compromise the vascular supply of the small intestine.2022 These include venous thrombosis and arterial occlusion as a consequence of primary vascular disease, heart failure with attendant mesenteric low flow state, various coagulopathies, volvulus, malrotation of the gut, and internal or external herniation of the bowel with strangulation. Short bowel syndrome can also occur as a result of necrotizing enterocolitis or massive atresia of the small intestine in newborn infants.

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Inflammatory bowel disease involving large segments of the small bowel, or recurrent exacerbations of inflammatory bowel disease over a prolonged period of time, can eventually result in the short bowel syndrome secondary to massive or multiple intestinal resections. Excision of retroperitoneal malignancies which involve the superior mesenteric vessels can mandate secondary resection of most or all of the small bowel in order to accomplish palliation or cure. Major abdominal blunt or sharp trauma involving transection, disruption or avulsion of the mesenteric vasculature can result in ischemic necrosis of large segments of the small bowel, resulting in short bowel syndrome. Post-irradiation or postoperative complications such as extensive severe radiation enteritis, multiple small bowel fistulas, and intestinal gangrene can also result in irreversible short bowel syndrome.

Pathophysiology The intestinal absorption of water, electrolytes and other specific nutrients is dependent upon the extent and site of the small bowel resection. The intestinal phase of digestion occurs initially in the duodenum, where pancreatic enzymes and bile acids promote digestion of all nutrients and enhance fat absorption. It is uncommon for the duodenum to be resected together with extensive segments of the small bowel, primarily because of the differences in blood supply, however, total duodenectomy leads to malabsorption of calcium, folic acid and iron.1 Proteins, carbohydrates, and fats are absorbed virtually completely in the first 150 cm of the jejunum, therefore, only small quantities of these nutrients ordinarily reach the ileum.23 The small intestine acquires and handles about 8 liters of fluid daily, including dietary ingestion and endogenous secretions. Normally, approximately 80% of the water transported is absorbed in the small bowel, leaving approximately 1.5 liters of fluid to traverse the colon. The colon usually absorbs about one to two liters of fluid with maximal absorptive capacity of approximately six liters of fluid per day.24 Because the ileum and colon have a large capacity for absorbing excess fluid and electrolytes, proximal small bowel (jejunal) resections only rarely result in diarrhea. On the other hand, extensive or total resection of the ileum results in a much greater potential for malabsorption and diarrhea. Not only will such resections increase the volume of fluid reaching the colon, but depending upon the length of ileum resected, bile salt diarrhea (cholerrhea) or steatorrhea may ensue with subsequent loss of essential fatty acids and fat soluble vitamins. If the ileocecal valve has been resected, transit time is likely to decrease, and bacterial colonization of the small bowel will eventually occur, further aggravating cholerrhea and steatorrhea. As the length of ileal or colonic resections increases, essential absorptive surface area is lost, resulting in proportionally increased dehydration, hypovolemia, and electrolyte derangements. If the colon remains in continuity with the remaining small bowel following massive intestinal resection, malabsorbed bile salts can be deconjugated by colonic bacteria, stimulating increased colonic fluid secretion and further compounding existing diarrhea. Following extensive ileal resection, the enterohepatic circulation is interrupted and irreversible loss of bile salts results, with or without the colon in continuity. Although the excess fecal losses stimulate hepatic synthesis of bile salts, a higher incidence of cholelithiasis occurs in these patients. Because the transit time in the ileum is usually slower than in the jejunum, residual intestinal transit is slowed, and fecal output is diminished as the length of remaining ileum increases.

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Following extensive small bowel resections, intestinal lactase activity may be decreased, resulting in lactose intolerance.25 The presence of unhydrolyzed lactose causes increased hyperosmolality in the intestinal lumen. Moreover, fermentation of lactose by colonic bacteria produces a large amount of lactic acid that can further aggravate osmotic diarrhea.1 The water soluble vitamins (vitamin B-complex and C) and minerals (Ca2+, Fc3+, Cu2+) are absorbed in the proximal small intestine, whereas magnesium diffuses passively throughout the entire small bowel.1 The ileum is the only absorption site for vitamin B12 and bile salts. Resection of the jejunum with preservation of the ileum produces no permanent impairments of protein, carbohydrate, and electrolyte absorption.26 The ileum can compensate for most absorptive functions, but not for the secretion of jejunal enterohormones. Following jejunal resections, diminished secretions of cholecystokinin and secretin decrease gallbladder contraction and emptying and decrease pancreatic secretion. Additionally, after jejunal resection, gastric hypersecretion is greater than after ileal resection. This results from the loss of inhibitory hormones such as gastric inhibitory polypeptide (GIP) and vasoactive intestinal polypeptide (VIP), which are secreted in the jejunum, thus causing gastrin levels to rise, stimulating gastric hypersecretion.27 Significant gastric hypersecretion can be documented within 24 hours postoperatively, and the gastric and small bowel mucosa can be injured by the high gastric acid output causing gastritis, ulceration and bleeding. Subsequently, the high salt and acid load secreted by the stomach, together with the inactivation of digestive enzymes by the inordinately low intraluminal intestinal pH, serves to compound the other causes of diarrhea associated with short bowel syndrome. Ordinarily, the colon is a major site of water and electrolyte absorption, and as the ileal effluent increases, the colon may increase its absorptive capacity to three to five times normal.28 Moreover, the colon has a moderate capacity to absorb other nutrients, and concomitant colon resections can adversely affect the symptomatic and nutritional courses of patients with massive small bowel resections. Malabsorbed carbohydrates which reach the colon are fermented there by indigenous bacteria to yield short chain fatty acids, principally acetate, butyrate and propionate.29,30 The short chain fatty acids can be absorbed by the colon in quantities representing up to 500 calories per day and enter the portal circulation to serve as a fuel source.31,32 Although retention of the colon is highly desirable during massive bowel resections, its presence can be associated with potential complications. In addition to cholerrheic diarrhea, a patient with a massive small bowel resection and an intact colon often develops hyperoxaluria and a tendency to form calcium oxalate renal stones. These result from the increased absorption of dietary oxalate, which is normally rendered insoluble by binding with calcium in the intestinal lumen and, therefore, ordinarily unabsorbable. However, in patients with short bowel syndrome and steatorrhea, intestinal calcium ion is bound preferentially to the increased quantities of unabsorbed fatty acids, leading to decreased binding and increased coloic absorption of the oxalate.10 Finally, preservation of the ileocecal valve is important in preventing abnormal metabolic sequelae because the ileocecal valve not only slows intestinal transit and passage of chyme into the colon, but prevents bacterial reflux from the colon into the small bowel. Nutrients which reach the colonic lumen, especially vitamin B12, become substrates for bacterial metabolism rather than being absorbed by the mucosa.1 Furthermore, bacterial overgrowth in the small bowel in patients with short bowel syndrome appears to increase the incidence of liver dysfunction.33

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Nutritional and Metabolic Management In the metabolic and nutritional management of patients with the short bowel syndrome, three different but overlapping therapeutic periods having rather distinctive characteristics can be designated arbitrarily (Table 1).34 During the first two months (immediate postoperative period), the clinical picture and course are dominated by problems related to fluid and electrolyte balance, adjustment of organ blood flow patterns, especially the portal venous flow, and other effects of the major operative insult and its accompanying specific and general complications. During the second period, from about two months up to two years postoperatively (bowel adaptation period), efforts are directed toward defining maximum oral feeding tolerances for various nutrient substrates, encouraging and maximizing intestinal and bowel adaptation, and determining and formulating the most effective patient-specific feeding regimens. Usually within two years, 90-95% of the bowel adaptation potential has been accomplished, and only 5-10% further improvement in absorption and bowel adaptation can be anticipated. The third period (long-term management period) constitutes the period after two years, by which time nutritional and metabolic stability have ordinarily occurred. By this time, the patient has either adapted maximally so the nutritional and metabolic homeostasis can be achieved entirely with oral feeding, or the patient is committed to receiving specialized supplemental or complete nutritional support for the remaining life-span, either by ambulatory home TPN and/or specially prepared enteral or oral feedings.

Immediate Postoperative Period During the immediate postoperative period, for up to two months, virtually all nutrients, including water, electrolytes, fats, proteins, carbohydrates, and all vitamins and trace elements are absorbed from the gastrointestinal (GI) tract poorly, or not at all.34 Fluid losses via the GI tract are greatest during the first few days following massive small intestinal resection, and anal or ostomy effluent frequently reaches volumes in excess of five liters per 24 hours. In order to minimize life-threatening dehydration, hypovolemia, hypotension and electrolyte imbalances, vigorous fluid and electrolyte replacement therapy must be instituted promptly and judiciously. Frequent vital signs, fluid intake and output, and central venous pressure measurements together with regular hematologic and biochemical indices are mandatory in monitoring the patient during this period of rapid metabolic change and instability. All patients with short bowel syndrome exhibit some abnormalities in their liver profiles, and the vast majority of them experience at least transient hyperbilirubinemia.34 This has been advocated by some to be secondary to the translocation of microorganisms and/or their toxins through the ischemic or gangrenous intestinal mucosa into the portal vein and thence to the liver.35,36 Others attribute the hyperbilirubinemia to impaired blood flow to the liver through the portal vein by as much as 50% as a result of greatly diminished mesenteric venous return secondary to the massive small bowel resection.37 Still others attribute this phenomenon to a combination of both factors and/or other etiologies.38 Broad spectrum anaerobic and aerobic antibiotic therapy should be instituted and maintained for several days to one week following massive intestinal resection. Typical patient management efforts during this period are directed toward achievement of four primary goals: fluid and electrolyte replacement, antisecretory/ antimotility therapy, antacid therapy, and total parenteral nutrition. During the first 24-48 hours, replacement therapy usually consists of 5% dextrose in lactated Ringer’s

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Table 1. Synopsis of short bowel syndrome management Immediate Postoperative Period (First Two Months) Fluid and Electrolyte Replacement Lactated Ringer’s solution Dextrose 5% in water Human serum albumin (low salt) K+, Ca++, Mg++ supplementation Strict intake and output Daily body weight Graduated metabolic monitoring

Antacid Therapy Mylanta liquid Camalox suspension Amphogel suspension Gelusil liquid (30-60 ml via N-G tube q 2 hr clamp N-G tube 20 min) Antiulcer Therapy Sucralfate liquid 1 gm po q 6 hr (Clamp N-G tube 20 min) Antisecretory/Antimotility Therapy Cimetidine 300 mg IV q 6 hr Ranitidine 150 mg IV q 12 hr Famotidine 20 mg IV q 12 hr Pantoprazole 40 mg IV daily Codeine 60 mg IM q 4 hr Loperamide 4-16 mg po daily Lomotil 20mg po q 6 hr Hyoscyamine sulfate 0.125 mg sc q 4 hr Cholestyramine 4 gm po q 8 hr Total Parenteral Nutrition 1 liter on second postop day Gradually increase dosage as tolerated Supplement fluids, electrolytes and colloids as needed

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Bowel Adaptation Period (First Two Years) Progression of Oral Diet Water, tea, broth Simple salt solutions Simple sugar solutions Complex salt/sugar solutions Dilute chemically defined diets High carbohydrate, high protein Modified fiber, low fat diet Near-normal, normal diet

Bowel Adaptation Period (First Two Years) (Cont’d) Enteral Supplementation Coconut oil 30 ml po tid Safflower oil 30 ml po tid Multiple vitamins 1 ml bid Ferrous sulfate 1 ml tid Ca gluconate 6-8 gm/day Na bicarbonate 8-12 gm/day

Parenteral Supplementation Electrolytes, Trace elements Divalent cations (Mg, Zn) Vit B12, Vit K, Folic acid Albumin, Packed red cells Fat emulsion Antisecretory/Antimotility Famotidine 20 mg po q 12 hr ProBanthine 15 mg po q 4-6 hr Dicyclomine 20 mg po q 6 hr Omeprazole 20 mg po q day Deodorized tincture of opium 10-30 gtts q 4 hr Codeine 30-60 mg po q 4 hr Paregoric 5-10 ml po q 4 hr [Refer to column one for additional agents] Growth Hormone/Glutamine50,51 Long-Term Management (After Two Years) Apply Previous Principles As indicated individually

Ambulatory Home TPN Supplemental or Total Continuous, Cyclic or Intermittent Surgical Management Treat operative Complications Drain abscesses Resect fistulas Lyse adhesions Reduce obstructions Restore bowel continuity Probable cholecystectomy Intestinal Lengthening Intestinal Transplantation34

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solution administered intravenously concomitantly with appropriate amounts of potassium chloride and/or acetate, calcium chloride or gluconate, magnesium sulfate, and fat- and water-soluble vitamins. Low salt human albumin (12.5-25 g) usually is added exogenously to the intravenous regimen every eight hours for the first 24-48 hours postoperatively in order to maintain normal plasma albumin concentrations and normal plasma colloid oncotic pressure. In patients with severe diarrhea, zinc losses can increase to as much as 15 mg/day and require appropriate aggressive parenteral replacement.39 Anti-acid therapy can reduce the increased tendency for peptic ulceration, which commonly occurs following massive small bowel resection. Antacids are given through a nasogastric tube every two hours in doses of 30-60 ml, and the tube is clamped for 20 minutes before reapplying suction. Alternatively, or concomitantly, liquid sucralfate can be given by mouth or via the nasogastric tube in a dose of one gram every six hours, clamping the tube for 20 minutes after each dose. To counteract the hypergastrinemia and associated gastric hypersecretion which follows massive small bowel resection in the majority of patients, and H2 receptor blocker is infused.40 The intravenous administration of 300-600 mg of cimetidine every six hours can have a profound effect in reducing gastric acid and intestinal fluid production. Alternatively, ranitidine 150 mg can be given IV every 12 hours, or preferably, famotidine 20 mg can be given IV every 12 hours or an intravenous form of a proton pump inhibitor, pantoprazole, can be given daily in 40 mg doses. In selected short bowel patients, somatostatin analog (octreotide) has reduced fecal losses when administered in a dosage of 50-150 mcg IV or subcutaneously every six hours.41,42 If diarrhea persists despite these measures, an opiate can be prescribed. Preferably, codeine is given intramuscularly in doses of 60 mg every four hours. Improvement in fluid and electrolyte management can also be achieved in selected patients with stomal access to a distal defunctionalized bowel loop by reinfusing the chyme from the proximal ostomy into the distal bowel segment.43 Later in the course of the postoperative period, when the patient is tolerating liquids by mouth, antimotility therapy can be achieved by giving loperamide 4-16 mg orally in divided doses daily, cholestyramine 4 gm every four to eight hours and/or diphenoxlylate 20 mg every six hours. Codeine 30-60 mg, paregoric 5-10 ml, or deodorized tincture of opium (DTO) 10-30 drops every four hours orally can be used to impede bowel motility. The major advantages of giving DTO are that it is readily absorbed by the upper alimentary tract and that the patient’s bowel hypermotility and diarrhea can be titrated to tolerable levels by adjusting the dosage up or down a few drops at a time to optimize dose effectiveness and to minimize undesirable side effects. By the second or third postoperative day, the patient’s cardiovascular and pulmonary status have usually stabilized sufficiently to allow TPN to be initiated. The average adult patient can usually tolerate two liters of TPN solution daily administered by central vein. By titrating levels of plasma glucose and glycosuria, the daily nutrient intake can be increased gradually to desired levels or to patient tolerance. In a patient with diabetes mellitus, or in one who is glucose intolerant, crystalline regular human insulin is added to the TPN solution in doses up to 60 units per 1000 calories. Following an operation of the magnitude of massive small bowel resection, most patients require at least 3000 ml of TPN solution (about 3000 calories) per day to maintain nutritional and metabolic homeostasis. Supplemental fluid and electrolyte infusions may be necessary for several days or weeks to replace excessive losses as diarrhea. The patient is offered a clear liquid diet as soon as the postoperative

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condition is stabilized, and fecal output is controlled with antidiarrheal medications. It may take several days to several weeks before the patient is able to discontinue TPN support in favor of oral or enteral feedings. It is essential to provide adequate nutritional supplementation with TPN for as long as the patient requires such support to maintain optimal nutritional status. The TPN ration is reduced gradually in an equivalent manner as oral intake and intestinal absorption of required nutrients are increased. The patient’s diet is advanced slowly and gradually to a low lactose, low fat, high protein, high carbohydrate composition according to individual tolerances to the nutrient substrates and to the water volume and osmolality of the dietary regimen.44

Bowel Adaptation Period

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During the period of bowel adaptation from two months to two years postoperatively, the patient is allowed to consume increasing amounts of water, simple salt solutions and simple carbohydrates. Various fruit and other flavorings can be added to 5% dextrose in lactated Ringer’s solution as a relatively inexpensive and practical oral nutrient solution. Gradually, dilute solutions of chemically defined diets containing simple amino acids and short chain peptides are given as tolerated in increasing volumes and concentrations as bowel adaptation progresses toward a normal or near normal diet consisting of high carbohydrate, high protein, and low fat and comprised of foods most preferred by the patient as the next stage of nutritional rehabilitation. Alternatively, the major nutrients can be provided as required in commercially prepared modular feedings tailored to the needs of individual patients until ordinary food is well tolerated. All essential vitamins, trace elements, essential fatty acids and minerals are initially supplied in the patient’s balanced intravenous nutrient ration. Subsequently the oral diet may be supplemented most economically by short- and medium-chain triglycerides in the form of coconut oil, 30 ml two or three times daily; essential fatty acids as safflower oil, 30 ml two or three times daily; multiple fat and water soluble vitamins in pediatric liquid form, 1 ml twice daily; vitamin B12, 1 mg intramuscularly every four weeks; folic acid, 15 mg intramuscularly weekly; and vitamin K, 10 mg intramuscularly weekly. Some patients may require supplemental iron, which can be administered initially by deep intramuscular injection as iron-dextran according to the recommended patient-specific dosage schedule, or as an IV infusion after testing the patient for sensitivity. Alternatively, an oral liquid iron preparation can be given one to three times daily. A strong tendency for patients with short bowel syndrome to develop metabolic acidosis usually requires the use of sodium bicarbonate tablets, powder, wafers or liquid in doses of 8-12 g/day for as long as 18-24 months, but usually not for fewer than six months. It is often helpful to alternate the form of sodium bicarbonate prescribed in order to encourage maximal patient compliance. Because of the difficulty in absorbing adequate dietary calcium, supplemental calcium gluconate should also be prescribed as tablets, wafers, powder or liquid in doses of 6-8 g/day. As bowel adaptation progresses, the doses of sodium bicarbonate and calcium gluconate can be decreased concomitantly or discontinued. However such oral supplements may be necessary for as long as two years or more in some patients in order to maintain homeostasis. Occasionally, on the other hand, a patient may become severely acidotic (pH 7.0-7.2) as a result of obviously copious diarrhea, but sometimes more subtly, and may require urgent or emergency intravenous infusion of sodium

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bicarbonate. Usually the patient responds promptly to the therapy within a few hours and without untoward sequelae. Rarely, calcium gluconate must be given intravenously as a supplement to correct recalcitrant hypocalcemia (<8.0 mg/dL). Dietary advancement and nutrient supplementation must obviously be individualized for each patient. When solid foods are given, they should be dry and followed 1 hour later with isotonic fluids to minimize diarrhea and to improve nutrient absorption. Lactose intolerance should be anticipated and treated as required with a low lactose diet and/or lactase, 125-250 mg by mouth. Clearly, milk products should be avoided as much as possible if intolerance persists. As progress occurs during the bowel adaptation period of management of the short bowel syndrome, fat can be increased in the diet as tolerated, and supplementation with short- and medium-chain triglycerides and essential fatty acids may no longer be necessary. Serum-free fatty acid levels and triene:tetraene ratios are monitored periodically to determine the efficacy of treatment and need for supplementation. Contrary to early reports, high fat diet apparently are comparable to high carbohydrate diets when evaluated in reference to calories absorbed, blood chemistries, stool or ostomy output, urine output and electrolyte excretions.43 However it has been suggested that enteral intake of fat should approach 50-100% greater than expected goals to compensate for malabsorbed nutrients.39 Patients who cannot tolerate or utilize a normal oral diet should be given a trial of continuous infusion of enteral formula. Low residue, polymeric chemically defined or elemental diets offer the putative advantage of high absorbability in the short bowel patient. However, some investigators have recently shown no differences in caloric absorption, stomal output of electrolyte loss among elemental, polymeric and normal diets in patients with short bowel syndrome.43,46,47 Depending upon the results of periodic hematologic and biochemical studies, adjustments are made in the patient’s intake of sodium, potassium, chloride and calcium.48 Additionally, intermittent supplemental infusions of solutions containing magnesium, zinc, and copper may be required. As malabsorption and diarrhea become less troublesome, the vitamin and trace element requirements may be satisfied by multivitamin capsules, tablets or chewable tablets containing therapeutic doses of vitamins or minerals, one dose twice daily. Relatively large amounts of magnesium, zinc, vitamin C and B-complex can be administered in the form of several commercially available therapeutic vitamin and mineral preparations.34 In some patients, it may be necessary periodically to correct individual nutrient substrate deficiencies intramuscularly or intravenously for prolonged periods of time. Intermittent infusions of human serum albumin and packed erythrocytes may be required to treat recalcitrant hypoalbuminemia and anemia and to restore the plasma albumin level and the hematocrit to normal. Cholestryramine can be administered to counteract bile salt diarrhea if indicated, but intraluminal cholestyramine itself can cause or aggravate diarrhea. Fatty acid, electrolyte, trace element, vitamin and acid-base imbalances must be promptly corrected enterally or parenterally as required when manifested clinically or by laboratory assessment. Serum vitamin B12 levels must be monitored and its deficiency corrected immediately. Hyperoxaluria should be assessed regularly, and if documented, foods containing high levels of oxalate such as chocolate, spinach, celery, carrots, tea and colas should be restricted. In patients with severe forms of short bowel syndrome in which little or no small intestine is present distal to the duodenum, or in which the remaining small intestine has residual disease, hypermotility and recalcitrant or intractable diarrhea may

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require continuous long-term antimotility/antisecretory treatment with oral and/or parenteral forms and dosages of the previously described pharmaceutical agents. Additional oral medications which have been helpful in selected patients include omeprazole, 20 mg daily; propantheline bromide, 15 mg every 4-6 h; dicyclomine hydrochloride, 20-40 mg every 6 h; hyoscyamine sulfate, 0.125-0.250 mg every 4-6 h as needed.

Long-Term Management Period Long-term management of the short bowel syndrome can be accomplished successfully in most patients by conscientious attention to the principles and practices outlined above. However, in a few patients who have undergone massive small bowel resection, total or supplemental parenteral nutrition must be provided in a continuous or cyclic manner for extended periods of time, and sometimes for life. The metabolic management and nutritional therapy of patients with the short bowel syndrome must be tailored specifically to each patient, and the clinical responses following massive intestinal resection depend upon many and varied factors. Patients with the short bowel syndrome pass through several stages of nutritional and metabolic support during their recovery, convalescence and rehabilitation. Most of them can ultimately be maintained on a normal or near normal diet. However, depending upon the adaptability of their remaining bowel, they may have to settle for receiving parenteral nutritional requirements via a modified oral diet, an enteral total or supplemental diet supplemented with intravenous fluid and/or electrolyte replacement, a parenteral nutrition regimen supplemented with a variable oral or enteral diet, or reliance entirely upon total parenteral nutrition. Almost all patients with the short bowel syndrome eventually develop gallstones, most usually requiring cholecystectomy within two years following massive intestinal resection if their gallbladder had not been previously removed. Indeed, the high propensity of patients who have undergone massive intestinal resection to develop stones in their gallbladders, has stimulated some physicians to advocate cholecystectomy prophylactically at the time of bowel resection.49 However, gallstone formation in the common bile duct and elsewhere in the biliary tree is also increased in these patients even after cholecytectomy. Therefore surveillance with periodic abdominal ultrasonography may be useful in identifying and monitoring echogenic changes in the gallbladder and biliary tree. Finally, some otherwise stable patients occasionally develop recalcitrant diarrhea secondary to colonization or bacterial overgrowth of the residual small bowel segment, requiring stool culture and bacterial antigen studies followed by parenteral treatment with appropriate antibiotics.

Growth Hormone, Glutamine, and Hormone Modified Diet

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A rather extensive study has been completed to determine if growth hormone or nutrients, given alone or together, could enhance absorption from the small bowel after massive intestinal resection, especially in patients who continued to experience malabsorption and require long-term parenteral nutrition.50 The effects of high carbohydrate, low-fat diet, the amino acid glutamine, and growth hormone, administered alone or in combination, were studied in 47 adult patients with short bowel syndrome who were dependent on TPN to some extent for an average of 6 years. The average age of the patients was 46 years, and the average residual small bowel length was 50 cm in those with all or a portion of colon remaining, and 102 cm in

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those with no colon remaining. During the 28 days of therapy, recombinant growth hormone was given by subcutaneous injection at a dose ranging from 0.03 to 0.14 mg/kg/day (average dose 0.11 mg/kg/day). Supplemental glutamine was provided by both the parenteral and enteral routes. The parenteral glutamine dosage averaged 0.6 g/kg/day whereas a standard daily dose of 30 gm glutamine was administered orally in six equal portions of 5 gm mixed with a hypotonic cold beverage. In addition to the growth hormone and glutamine, all patients underwent extensive diet modification and nutritional education, the details of which have been reported extensively elsewhere.31 On completion of the four week protocol, growth hormone was discontinued, and the patients were discharged home on oral glutamine, 30 gm/day, and the modified oral diet. The initial balance studies indicated improvement in absorption of protein by 39% accompanied by a 33% decrease in stool output with the regimen. In evaluation of the long-term results, averaging one year and extending as long as five years, 40% of the study remain off TPN, and an additional 40% have reduced their TPN requirements, with no change in TPN requirements in the remaining 20%. These changes had occurred in a subset of patients that had previously failed to adapt to the provision of enteral nutrients, and this therapy may offer an alternative to long-term dependence on TPN for some patients with severe short bowel syndrome. Subsesquently, a more comprehensive clinical study of greater than 300 patients has been reported by the same group of investigators.52,53

Surgical Considerations Total parenteral nutrition is the mainstay of early, and sometimes late management of the short bowel syndrome.52 Prior to the widespread use of TPN, patients often survived the initial surgical insult of massive small bowel resection and its early complications only to die ultimately of fluid, electrolyte and nutritional imbalances. Today, however, patients can usually be managed successfully and often rehabilitated with the judicious use of TPN. In this regard the surgeon is required to insert, maintain and supervise a temporary and permanent indwelling central venous catheter or catheter port for administration of TPN solutions. As stated previously, massive small bowel resection is associated with a prompt and inordinate increase in the secretion of gastrin and gastric acid. The resulting hypersecretion can readily cause or aggravate existing gastritis, ulceration, bleeding, diarrhea, and fluid and electrolyte depletion. Because the hypersecretion is thought to be hormonally mediated, truncal vagotomy and pyloroplasty have been performed in humans with good results.1 Now that effective H2 receptor blockers have been developed for clinical use, the surgical treatment of hypersecretion is seldom indicated or required. Currently, vagotomy or other acid-reducing operations should be reserved for those short bowel syndrome patients who develop complicated peptic ulceration problems resistant to conservative medical therapy. In patients with the short bowel syndrome, parenteral nutrition should be given for at least 6-12 months to assure that optimal bowel adaptation has occurred before contemplating the use of any surgical procedures to increase absorption of nutrients.35 In most short bowel syndrome patients, sufficient bowel adaptation occurs during the first year following massive intestinal resection that parenteral nutrition can be discontinued and the contemplated surgical intervention can be avoided. Attempts to ameliorate the untoward effects of the short bowel syndrome surgically by interposing isoperistaltic or antiperistaltic bowel segments, intestinal valves

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or recirculating loops; pacing the intestinal electrically; growing new intestinal mucosa; and transplanting small intestine have been of limited additional value to date.57 Therefore, no operative procedure for adjunctive management of the short bowel syndrome currently is sufficiently safe and effective to recommend its routine use.19 Long-term parenteral nutrition remains the cornerstone of successful management of short bowel syndrome, and its judicious use is recommended in appropriate amounts and formulations for as long as needed not only to insure maximal gastrointestinal adaptation and nutritional rehabilitation of the patient, but to support the optimal size and function of the body cell mass.

Selected References 1. 2. 3. 4. 5. 6. 7. 8. 9. 10. 11. 12. 13. 14. 15. 16.

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Allard J, Jeejeebhoy K. Nutritional support and therapy in the short bowel syndrome. Gastroenterol Clin N Am 1989; 18:589-601. Detiel M, Wong KH. Short bowel syndrome. In: Deitel M, ed. Nutrition in Clinical Surgery. 2nd ed. Baltimore: Williams & Wilkins, 1985:255-275. Dudrick SJ, Jackson D. The short bowel syndrome and total parenteral nutrition. Heart Lung 1983; 12:195-201. Goutrebel M, Saint-Aubert B, Astre C et al. Total parenteral nutrition needs in different types of short bowel syndrome. Dig Dis Sci 1986; 31:713-723. Weser B. Nutritional aspects of malabsorption. Short gut adaptation. Clin Gastroenterol 1983; 12:443-461. Tilsom MD. Pathophysiology and treatment of short bowel syndrome. Surg Clin N Am 1980; 60:1273-1284. Dudrick SJ, Englert DM. Management of the short bowel syndrome. In: Miller TA, Dudrick SJ, eds. The Management of Difficult Surgical Problems. Austin: The University of Texas Press, 1981:225-235. Dudrick SJ, O’Donnell JJ, Englert DM. Ambulatory home parenteral nutrition for short bowel syndrome and other diseases. In: Deitel M, ed. Nutrition in Clinical Surgery. 2nd ed. Baltimore: Williams & Wilkins, 1985:276-287. Trier JS, Lipsky M. The short bowel syndrome. In: Sleidenger MH, Fordtran JS, eds. Gastrointestinal Disease: Pathophysiology, Diagnosis, Management, 4th ed. Philadelphia: WB Saunders, 1989:1106-1112. Weser B, Fletcher JT, Urban E. Short bowel syndrome. Gastroenterology 1979; 77:572-579. Wilmore DW, Dudrick SJ. Effects of nutrition on intestinal adaptation following massive small bowel resection. Surg Forum 1969; 20:398-400. Wilmore DW, Holtzapple PG, Dudrick SJ et al. Transport studies, morphological and histological findings in intestinal epithelial cells following massive bowel resection. Surg Forum 1971; 22:361-363. Conn HJ, Chavez CM, Fain WR. The short bowel syndrome. Ann Surg 1972; 175:803-814. Dudrick SJ. A clinical review of nutritional support of the patients. Am J Clin Nutr 1981; 34:1191-1198. Sheldon DF. Role of parenteral nutrition in patients with short-bowel syndrome. Med J Aust 1979; 67:1021-1029. Stewart GR. Home parenteral nutrition for short-bowel syndrome. Med J Aust 1989; 2:317-319. Wilmore DW, Johnson DJ. Metabolic effects of small bowel reversal in treatment of short bowel syndrome. Arch Surg 1968; 97:784-791. Wilmore DW, Dudrick SJ, Daly JM et al. The role of nutrition in the adaptation of small intestine after massive resection. Surg Gynecol Obstet 1971; 132:673-680. Dudrick SJ, Latifi R, Fosnocht D. Management of the short bowel syndrome. Surg Clin N Am 1991: 71:625-643.

Nutritional and Metabolic Management of Short Bowel Syndrome 20. 21. 22. 23. 24. 25. 26. 27. 28. 29. 30. 31. 32. 33. 34. 35. 36. 37. 38. 39. 40. 41. 42.

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Garcia VF, Templeton JM, Eichelberger MR et al. Colon interposition for the short bowel syndrome. J Pediatr Surg 1981; 16:994-995. Levine GM. Short gut syndrome and intestinal adaptation. In: Kurtz RD, ed. Nutrition in Gastrointestinal Disease. New York: Churchill Livingstone, 1981:101-111. Thompson JS, Rikkers LF. Surgical alternatives for the short bowel syndrome. Am J Gastroenterol 1987; 22:97-105. Borgstrom B, Dahlquist A, Lundh G et al. Studies of intestinal digestion and absorption in the human. J Clin Invest 1957; 36:1521-1536. Debongnie J, Philips S. Capacity of the human colon to absorb fluid. Gastroenterology 1978; 74:698-703. Ricotta J, Zuidema FD, Gadacz RT et al. Construction of an ileocecal valve and its role in massive resection of the small intestine. Surg Gynecol Obstet 1981; 152:310-314. Wright HK, Tilson MD. Short gut syndrome: pathophysiology and treatment. Curr Probl Surg 1971; 8:1-51. Strause E, Gerson E, Yalow RS. Hypersecretion of gastrin associated with the short bowel syndrome. Gastroenterology 1974; 66:175-180. Philips SF, Giller J. The contribution of the colon to electrolyte and water conservation in man. J Lab Clin Med 1973; 81:733-746. Bond JH, Currier BE, Buchwald H et al. Colonic conservation of malabsorbed carbohydrates. Gastroenterology 1980; 78:444-447. Bond JH, Levitt MD. Fate of soluble carbohydrate in the colon of rats and humans. J Clin Invest 1976; 57:1158-1164. Haverstad T. Studies of short-chain fatty acid absorption in man. Scand J Gastroenterol 1980; 21:257-260. Pomare EW, Branch WJ, Cummings JH. Carbohydrate fermentation in the human colon and its relation to blood acetate concentration in venous blood. J Clin Invest 1985; 75:1148-1154. Capton JP, Gineston JL, Herve MA et al. Metronidazole in prevention of cholestasis associated with total parenteral nutrition. Lancet 1983; 1:446-447. Dudrick SJ, Latifi R. Management of patients with short-bowel syndrome. In: Kirby DF, Dudrick SJ, eds. Practical Handbook of Nutrition in Clinical Practice. Boca Raton: CRC Press, 1994:215-225. Barnett WO, Oliver RI, Elliot RL. Elimination of the lethal properties of gangrenous bowel segments. Ann Surg 1968; 167:912-919. Bounous G, McArdle AH. Release of intestinal enzymes in acute mesenteric ischemia. J Surg Res 1968; 9:33-348. Ratych RE, Smith GW. Anatomy and physiology of the liver. In: Zuidema GD, ed. Shackleford’s Surgery of the Alimentary Tract, 3rd ed. Philadelphia: WB Saunders, 1991:273-286. Sarr WG, Tito WA. Intestinal obstruction. In: Zuidema GD, ed. Shackleford’s Surgery of the Alimentary Tract, 3rd ed. Philadelphia: WB Saunders, 1991; 372-413. Woolf GM, Miller C, Kurian R et al. Nutritional absorption in short bowel syndrome: Evaluation of fluid, calorie and divalent cation requirements. Dig Dis Sci 1987; 32:8-15. Cortot A, Fleming CR, Malagelada JR. Improved nutrient absorption after cimetidine in short bowel syndrome with gastric hypersecretion. N Eng J Med 1979; 300:79-80. Ladefoged K, Christiansen K, Hegnhoj J et al. Effect of long-acting somatostatin analog SMS 201-995 on jejunostomy effluents in patients with severe short bowel syndrome. Gut 1989; 30:943-949. Nightingale J, Walker E, Burnham W et al. Short bowel syndrome. Digestion 1990; (suppl 1):77-83.

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The Biology and Practice of Current Nutritional Support 43. 44. 45. 46. 47. 48. 49. 50. 51. 52. 53. 54. 55. 56. 57.

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Levy E, Frileux P, Sandrucci S et al. Continuous enteral nutrition during the early adaptive stage of the short bowel syndrome. Br J Surg 1988; 75:549-553. Ovesen L, Chu R, Howard L. The influence of dietary fat on jejunostomy output in patients with severe short bowel syndrome. Am J Clin Nutr 1983; 38:270-277. Woolf GM, Miller C, Kurian R et al. Diet for patients with short bowel: High fat or high carbohydrate? Gastroenterology 1983; 84:823-828. McIntyre P. The short bowel. Br J Surg 1985; 72:893-899. McIntyre P, Fitchew M, Lennard-Jones J. Patients with a high jejunostomy do not need a special diet. Gastroenterology 1986; 91:25-33. Ladefoged K. Intestinal and renal loss of infused minerals in patients with severe short bowel syndrome. Am J Clin Nutr 1982; 36:59-67. Thompson JS. Surgical considerations in the short bowel syndrome. Surg Gynecol Obstet 1993; 36:59-67. Byrne TA, Persinger RL, Young LS et al. A new treatment for patients with short-bowel syndrome. Ann Surg 1995; 222:243-255. Byrne TA, Morrissey TB, Nattakorn TV et al. Growth hormone, glutamine and a modified diet enhance nutrient absorption in patients with severe short bowel syndrome. J Parent Ent Nutr 1995; 19:296-02. Wilmore DW, Byrne TA, Persinger RL. Short bowel syndrome: new therapeutic approaches. Curr Prob Surg 1997; 34:389-444. Wilmore DW. Growth factors and nutrients in the short bowel syndrome. JPEN 1999; 23:S117-120. Devine RM, Kelly KA. Surgical therapy of short bowel syndrome. Gastroenterol Clin N Am 1989; 18:603-617. Gibson LE, Carter R, Hinshaw DB. Segmental reversal of small intestine after massive bowel resection: successful case with follow-up exam. JAMA 1962; 182:952-956. Abu-Elmagd K, Todo S, Tzakis A et al. Three years clinical experience with intestinal transplantation. J Am Coll Surg 1994; 179:385-400. Thompson JS, Langnas AN, Pinch LW et al. Surgical approach to short-bowel syndrome. Experience with 160 patients. Ann Surg 1995; 222:600-605.

CHAPTER 1 CHAPTER 18

Pharmacologic Aspects of Short Bowel Syndrome Patricia Pecora Fulco, Donald F. Kirby Short bowel syndrome (SBS) results when surgical removal or physiologic dysfunction alters the ability of the gastrointestinal tract to perform its usual functions of digestion and absorption. The sequellae of this dysfunction can cause maldigestion and malabsorption that lead to dehydration and potentially lethal metabolic derangements often culminating in malnutrition and possibly death. There is a wide spectrum of this syndrome that depends on the location and length of either resected or dysfunctional intestine.1 Acute and chronic phases of this syndrome exist and depend upon the length of time from the inciting insult and the amount of adaptation that evolves. The latter is dependent upon the health and integrity of the remaining intestine. The availability of total parenteral nutrition (TPN) has improved survival during the acute phases and may be necessary during the adaptation phase or even required life long. As seen in Table 18.1, SBS can result from surgical bypass, intrinsic disease, and/ or extensive surgical resection. It is usually defined as having less than 150 cm of small intestine with estimates of the actual length of the small intestine varying from 365-600 cm (12-20 feet) due to the variations in musculature and method of measurement.2,3 Thus, severe SBS not only affects how fluids, electrolytes and nutrients are ultimately absorbed, but also the ability to absorb and metabolize medications. Many of the severely affected SBS patients are dependent on central venous access catheters to receive fluids, electrolytes and nutrition. These patients pose a unique challenge to the clinician who must also administer medications for acute or chronic needs.4 This chapter will briefly review the pathophysiology of SBS and long term adaptation, issues regarding intravenous access, patient variation, pharmacologic routes of administration and special pharmacologic considerations in the TPN dependent population.

Physiologic Considerations The normal GI tract has an amazing absorptive capacity where 7-9 liters of fluid from oral intake and intrinsic production are reduced to an average of 100-200 cc of formed stool that is excreted daily. The small intestinal mucosa has coiled folds which have small projections (villi) into the lumen and each villus has multiple cells (microvilli) lining it providing a multiplication effect of the small bowel surface area. In man, the surface area of the small intestine has been estimated to be equivalent to the area of a doubles tennis court.5 During the transit from mouth to anus nutrients are digested into sizes that can be accepted by the mucosal enterocyte for

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Table 18.1. Short bowel syndrome etiologies Crohn’s disease with or without surgery Radiation therapy injury with or without surgery Surgery related Bypass Carcinomas Congenital anomalies Error Obesity procedures Strangulated hernias Trauma Vascular infarctions Embolism or thrombosis Volvulus

either immediate absorption or further digestion by brush border enzymes followed by absorption. The eventual severity of SBS depends on a number of factors: 1. Extent and location of resection (>80% less favorable); 2. absorptive capacity of the remaining small intestine; 3. presence or absence of the ileocecal valve; 4. function capacity of colon, if present; and, 5. time from onset of the syndrome.6 Adaptation can take as long as 1-2 years to reach its maximal potential.

Site Specific Contributions

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It is beyond the scope of this chapter to detail all the intricacies of intestinal absorption, but it is important to understand some of the specialized functions of the different regions of the GI tract. Figure 18.1 illustrates the areas of the GI tract with some of their regular and specialized functions. The bowel not only absorbs fluid and nutrients, but also secretes and excretes certain substances. The colon is particularly efficient in absorbing sodium chloride and water while exchanging these for potassium and bicarbonate to be excreted. The stomach is not necessary for life except for its function in producing intrinsic factor. Without intrinsic factor vitamin B12 should be provided parenterally, especially if ileal absorption sites are diseased or have been resected. The stomach also functions in the slow release of food stuffs, which helps to maximize their mixing with bile and pancreatic juice as digestion progresses. A substantial amount of digestion occurs in the duodenum due to the high concentration gradient of enzymes and bile present so that absorption ensues in the distal duodenum, jejunum, and ileum. The duodenum is also highly efficient in absorbing iron and some of the divalent cations such as calcium, magnesium and zinc. The ability to absorb these cations does not appear to be dangerously reduced in severe SBS, but zinc may be the most difficult to maintain at normal levels.7,8 Isolated resection of the jejunum is well tolerated when the remainder of the bowel is healthy. All absorptive functions can be performed by the ileum.9 Since the

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Fig. 18.1. Specialized functions of the GI tract.

intrinsic motility is faster in the ileum, adaptation to jejunal resection includes further slowing of ileal transit. The ileum has specialized functions of absorbing vitamin B12 and bile acids. Diarrhea and/or steatorrhea can occur if there is not at least 100 cm of ileum, which appears crucial for complete absorption of bile salts.10 Altered fat absorption can also negatively affect the absorption of fat soluble vitamins, as well as any medications that depend on lipid transport systems. The ileocecal valve provides a pressure gradient from the terminal ileum to the large intestine. It is a specialized muscle that is responsive to α-adrenergic agonists and according to many sources its absence increases the severity of SBS.11,12 The valve is believed to be important in increasing transit time and in preventing bacterial reflux, which can lead to bacterial overgrowth and reduced intestinal absorption.11,13 The colon can have special importance in the overall fluid and electrolyte management of patients with SBS. It is highly efficient in absorbing water and sodium

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and excreting potassium and bicarbonate.14 The colon can also absorb oxalate, which can be important in the genesis of kidney stones.6 In patients with extreme short bowel, the presence of an ostomy may increase patient comfort and allow better quantification of effluent losses.

Adaptation The body’s adaptation to the insult of short bowel syndrome is quite crucial in the patient’s eventual quality of life, but can take as long as two years to reach its maximum potential. In the initial phase of SBS, survival is dependent on maintaining fluid and electrolyte balance. This is immediately followed by providing nutrition, usually parenterally, but also enterally, as soon as feasible. If there is residual intestinal disease from the underlying etiology of the SBS, then this may hinder the adaptation process. In this process there is dilatation and lengthening of the remaining small bowel.15 Adaptation is further characterized by hormonal changes, cellular hyperplasia, villous hypertrophy, altered motility and intestinal lengthening, all of which result in improved lumenal absorptive capacity.16 It is important to provide lumenal nutrients as soon as possible since villous atrophy can occur with TPN alone, but in humans this is reversed by oral feeding.17 All of the above adaptation responses can have ramifications with regard to medication absorption, and absorption of some oral medications may improve with time. Based on recent work by Gruy-Kapral and colleagues, it is now common to give SBS patients conjugated bile acids to help improve fat absorption.18 Calcium absorption was also increased without a significant increase in stool output. The effects of glutamine and growth hormone are awaiting further trials. However, their use does seem to result in some modest improvements in electrolyte absorption, but no change in small bowel morphology, macronutrient absorption or stool losses.19

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While this chapter is not exclusively written for the SBS patient who is dependent upon intravenous nutrition support, the principles will better apply to this population since less severely affected SBS patients may absorb oral medications better if they can maintain themselves without TPN. For the patient who is dependent upon TPN for sufficient fluid, electrolytes and nutrients for survival, the central venous catheter is a lifeline. Many variations are now available for use in the hospitalized or home patient. A major decision will be whether the patient requires a single lumen or multilumen catheter. For short-term use in the hospitalized patient, multilumen catheters may be vital when multiple medications are required. However, these catheters are often subject to higher catheter-related sepsis rates.20-22 Part of the reason for this is that these catheters are entered many times for various medications and perhaps under less than sterile technique, but it has recently been shown that bacterial translocation can be important in the genesis of catheter-related sepsis in the SBS population.23 It is best to use as few lumens as possible and to adhere to strict technique when using these catheters. In home TPN patients it has been demonstrated that implantable devices are not safer than standard tunneled catheters.24 Tunneled catheters such as Hickman® and Groshong® catheters (Bard Access Systems, Inc., Salt Lake City, Utah) are the most common in home patients, but a percutaneously placed subclavian catheter (Hohn® catheter, Bard Access Systems, Inc., Salt Lake City, Utah) has been found useful for short term patients requiring less than six weeks of parenteral therapy.

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The use of heparin placed in the TPN solution or oral administration of low dose warfarin can help decrease the incidence of venous thrombosis.25-27 This becomes increasingly important as thrombosis usually means that the site will not be usable again for intravenous access, and there are a limited number of large vessels that can be used for this type of hyperosmolar infusion.21

Patient Variation Drug Absorption The oral absorption of medications is affected by several factors, including whether or not the gastrointestinal (GI) tract is intact or has been resected. The extent of drug absorption is determined by the physiological capabilities of the remaining GI tract, formulation, physicochemical properties, pharmacodynamics and pharmacokinetics of the drug. Changes in any of these parameters will markedly determine the amount of drug available to produce its pharmacodynamic effect. The overall impact of changes in absorption will be the extent to which therapeutic efficacy is achieved. An increase in the variability of absorption is observed when a portion or all of the GI tract is removed. A decrease in intestinal length will result in a decrease in absorptive surface area. If all other factors affecting drug absorption were to remain constant, the extent of absorption would be limited to the length of residual bowel. However, not all factors affecting drug absorption remain constant when intestinal resection occurs. Physiological changes in the mucosal integrity and intestinal motility occur, resulting in an increase or decrease in absorption, depending on how the GI tract adapts to this anatomical change. Thus, GI physiology is directly affected by GI anatomy, but the effects on drug absorption may not be the same. The extent of a drug’s absorption as determined by its formulation, physicochemical properties and pharmacokinetics, is evaluated with the assumption that GI anatomy and physiology are normal. Resection of the GI tract will alter any or all of these parameters, resulting in a single or multifactorial effect on absorption. Drugs are formulated in a variety of ways to be released in various areas of the GI tract to take advantage of the physicochemical requirements to enhance absorption. Such modes of release include tablets, capsules, suspensions, elixirs, enteric coated tablets, film coated tablets and sustained release tablets and capsules. However, a sustainedrelease capsule that is designed to release medication throughout the entire small intestine may not be therapeutically useful if there is not enough small bowel surface area for absorption to effectively take place. The physicochemical requirements that enhance a drug’s absorption may include, but are not limited to, 1. solubility; 2. an acidic or alkaline environment; 3. the presence of bile acids; 4. the presence of an ileum; or, 5. the presence of site-specific receptors. Removal of the section of bowel responsible for meeting these requirements could result in minimal drug absorption. Physicochemical properties that enhance the absorption of certain drugs are listed in Table 18.2. Pharmacokinetic parameters that influence drug absorption include the site, extent, and rate of absorption. At the site of absorption, drugs bind to or localize in the

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Table 18.2. Select drugs and the physicochemical properties that enhance their absorption Physicochemical Property Acidic environment Alkaline environment Bile acids Drug-drug interactions Food-drug interactions Ileal absorption Receptor site dynamics

18

Select Drugs Ketoconazole penicillin nitrofurantoin procainamide cyclosporine ergocalciferol ferrous sulfate levofloxacin penicillin sucralfate cyanocobalamin diazepam propranolol

tissues. Depending on the physicochemical requirements of the drug, biotransformation may take place to allow for absorption. The molecule may become ionized or an enzymatic process may take place to affect absorption. Circulation to the absorption site will determine the extent and rate of absorption into the bloodstream. Once absorbed, the drug will distribute to various body compartments. It may or may not be metabolized before being eliminated. Administration of some drugs via a jejunal tube, for example, markedly affects their absorption, distribution, metabolism and elimination. Normally a drug dissolves in the stomach and is absorbed in the duodenum. Intrajejunal administration of propranolol oral solution, for example, results in significantly higher serum concentrations of the drug.28 The absorption of propranolol occurs in the duodenum and then passes directly through the blood stream to the liver. A significant first-pass metabolism occurs and markedly reduces the serum concentrations. With intrajejunal administration the portal system (and first-pass metabolism) is bypassed, the drug is absorbed, and higher serum concentrations result. This example demonstrates the importance of the site, extent and rate of absorption on the pharmacokinetics of propranolol. Two other clinically significant factors that influence drug absorption are food and other drugs.29 The presence of food in the GI tract may increase or decrease the extent and/or rate of absorption. A dose of theophylline oral syrup, for example, may be completely absorbed, but the rate of absorption is slower, resulting in decreased peak serum concentrations. A dose of levofloxacin, administered with a dose of a calcium-containing antacid, will be poorly absorbed (i.e., decreased extent of absorption) because of calcium chelation with the drug.30 A second type of drug-drug interaction that affects the relative absorption of drugs involves the effects one drug may have on metabolism or elimination of another. Once the drug is absorbed, metabolism may be increased or decreased resulting in serum concentrations that are lower or higher, respectively, than expected. Phenobarbital, for example, may induce the metabolism of phenytoin, decreasing serum concentrations of the latter. Cimetidine, for example, may inhibit the metabolism of theophylline, thereby increasing the theophylline’s serum concentration.

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When the small bowel is resected, the most significant impact on absorption occurs because of the reduction or removal of the site of absorption. Consequently the extent of absorption will change; the rate of absorption may be affected if the necessary enzymatic transformation does not occur. The extent of this effect will be directly proportional to the amount of bowel removed. Unfortunately, for the patient with SBS, drug absorption is almost always reduced, requiring the use of alternate therapy or higher oral doses. Furthermore, the food-drug and drug-drug interactions described above must be accounted for when administering medications to SBS patients via the oral route. Alternative routes may have to be considered. Limited research has been conducted to quantify the pharmacokinetic effects of bowel resection on drug absorption. The administration of oral doses of nortriptyline, amitriptyline, procainamide, warfarin, digoxin, cyclosporine and tacrolimus to patients with SBS has been reported.31-43 In these case reports, various lengths and segments of bowel had been resected. Serum concentrations were obtained to modify dosing necessary to achieve a therapeutic concentration, as in the case of digoxin, or desired therapeutic effect, as in the case of warfarin. The process of using serum concentration determinations to manage therapy is the most useful information presented. The information in these case reports is not generalizable due to their limited utility. Broyles et al discussed oral administration of nortriptyline to one SBS patient with 5-6 feet of small intestine and 40-50 cm of colon remaining.31 Normal serum concentrations (50-140 ng/ml) were achieved with a nortriptyline dose of 25 mg every morning and 50 mg every night. Approximately two months after initiating therapy, the serum concentration was 90 ng/ml. Robbins and Reiss administered amitriptyline buccally to a SBS patient with approximately 18 inches of small bowel remaining.32 Dosage titration to 75 mg of amitriptyline lead to a therapeutic combined amitriptyline and nortriptyline concentration (100-250 ng/ml) for 12 consecutive months. Subjective improvement in the patient’s depressive symptoms were also noted. In these two reports, following serum nortriptyline or combined amitriptyline/nortriptyline concentrations was an effective way to determine the extent of drug absorption and subsequent clinical response. Felser and Hui evaluated oral administration of procainamide to one SBS patient with 6 cm of jejunum and 20 cm of terminal ileum remaining.33 Serum trough concentrations greater than 4 µg/ml were achieved after 24 hours with a dose of 500 mg every four hours (therapeutic range of 4-12 µg/ml) and suppression of the patient’s ventricular arrhythmia was observed when in this range. Careful monitoring of serum procainamide concentrations was instrumental in determining the extent of absorption in this patient. Four separate case reports describe experience with oral warfarin administration to patients with SBS.34,35,37,39 Mitchell et al describe the oral administration of warfarin to one SBS patient with 100 cm of small bowel remaining.39 The normal length of the small intestine was approximated at 350-600 cm. Warfarin therapy was initiated at 10 mg per day and adjusted to maintain therapeutic prothrombin time (PT) values. Serum warfarin concentrations were not obtained. Absorption was assumed based on the PT values observed, but was not quantified. Lehman et al described oral administration of warfarin to one SBS patient with 12-15 cm of jejunum remaining.34 After administering a loading dose of 20 mg, the warfarin dose was titrated downward to maintain a PT between 1.5-2.0 times control.

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By day 59 of therapy, a PT of 1.6 times control was maintained using a dose of 2.5 mg per day. Jejunostomy drainage collections were made after a 10 mg and 2.5 mg dosage, at different times during therapy, to determine the amount of warfarin absorbed. The estimated percent of absorption was 92.8 and 96.1, respectively. This compares to values obtained in healthy volunteers, having percentage absorption greater than 90%. This is to be expected, since warfarin is nonpolar at pH 5.1 or less and would be expected to be almost completely absorbed in the duodenum. In this case, warfarin concentrations in the jejunostomy drainage, instead of serum concentrations, were used to determine absorption. Kearns and O’Reilly described oral administration of warfarin to a SBS patient with 30 cm of jejunum remaining.37 After five weeks of therapy, a daily dose of 5 mg was necessary to maintain a desired PT between 16-20 seconds. Serum and fecal concentrations were obtained during the fasting and fed states to determine the extent of absorption. The serum values observed were comparable or better than those observed in normal patients. Neither warfarin nor its metabolites were retrieved from the stool samples. Hence, serum concentrations proved useful in quantifying drug absorption. Brophy et al described a warfarin-resistant SBS patient who needed anticoagulation for recurring deep venous thrombosis.35 The patient had a total duodenectomy, gastrojejunostomy (unknown length of jejunem) with a completely retained ileum. Anticoagulation was initiated with warfarin 5 mg daily and titrated to a dosage of 20 mg daily over a period of 14 days. No change in the International Normalized Ratio was demonstrated with a peak value of 1.2. Warfarin serum concentrations were not evaluated. This report emphasizes the pharmacokinetic properties of warfarin. Warfarin is absorbed primarily within the proximal small bowel, specifically the duodenum. All of the previous cases included patients with intact duodenum with ultimately successful anticoagulation. These reports demonstrate that SBS patients may be successfully anticoagulated if the proximal small bowel, including the duodenum, is retained. Oral administration of digoxin has been reported in three separate patients with SBS.36,38,40 Beerman et al described a patient from which the distal jejunum and ileum, approximately 4 meters, and ascending colon had been removed.40 Radiolabeled digoxin, 0.25 mg, was administered, followed by GI aspiration after three hours. Aspirates were assayed to determine the absorption of radioactivity. Seventytwo percent of the drug was retrieved from the duodenum, suggesting only 28% absorption. Since only a single dose of digoxin was administered, the results of this report are of limited clinical utility. Krausz et al described a patient with the duodenum and only 15 cm of jejunum remaining.38 After a two day digitalization period, 0.25 mg daily was administered as indicated. Serum digoxin concentrations were maintained within the therapeutic range of 0.8-2.2 ng/ml. Renal clearance of the drug was normal. Therapeutic efficacy, as evidenced by a decrease in heart rate, was achieved with no reported side effects. Therapeutic serum concentrations suggest that the extent of absorption was adequate. Vetticaden et al described a patient with the duodenum and 12-15 cm of jejunum remaining.36 Digoxin elixir, 0.5 mg, was administered for nine days, after steady-state was achieved using 0.25 mg of digoxin intravenously. Serum and jejunostomy drainage concentrations were assayed. The trough serum concentration was 0.77 ng/ml and the cumulative amount of digoxin in the drainage, after 24 hours,

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was 0.302 mg. This suggests that approximately 60% of the 0.5 mg dose was absorbed. Since the trough serum concentration was less than the therapeutic concentration of 0.8 ng/ml, a higher dose of digoxin may be necessary to achieve a therapeutic serum concentration. The oral administration of cyclosporine and tacrolimus in SBS patients has been reported.41-43 Roberts et al described two patients in whom therapeutic serum concentrations of cyclosporine could not be achieved when administered orally.41 However, desired concentrations were achieved with intravenous therapy. Whittington et al found a relationship between the length of the small intestine and the oral dose of cyclosporine necessary to achieve therapeutic serum concentrations in children after liver transplant.42 Patients received both intravenous and oral cyclosporine to maintain a therapeutic serum concentration. As the intravenous dose was decreased, the oral dose was increased. Large doses of oral cyclosporine were required to achieve therapeutic concentrations; these doses were inversely proportional to the length of the small bowel. That is, the shorter the small bowel, the larger the dose required to achieve serum concentrations in the therapeutic range. Thielke et al described the pharmacokinetic evaluation of cyclosporine, microemulsion cyclosporine and tacrolimus in a SBS patient with approximately two feet of small intestine.43 Single doses of 250 mg cyclosporine, 250 mg microemulsion cyclosporine and 5 mg tacrolimus were administered on separate occasions. The results demonstrated undectable blood concentrations with conventional cyclosporine. Both microemulsion cyclosporine and tacrolimus pharmacokinetic parameters were slightly reduced compared to normal reference values. The results suggested that increased doses of the microemulsion cyclosporine formulation or tacrolimus may be successfully orally administered with blood concentration evaluation. Quantifying Drug Absorption The cases described above substantiate the usefulness of determining drug concentrations, in serum and other body fluids, to evaluate the extent of absorption in the SBS patient. For many medications, a therapeutic range for serum concentrations has been established; however, the efficacy of other medications may be independent of the serum concentration. Regardless of the establishment of a therapeutic range, the ability to quantitatively and qualitatively measure drug concentrations in various body fluids may be of tremendous help to the clinicians managing the SBS patient. Quantitative measurements reflect the approximate amount of drug in the sample. Qualitative measurements reflect the presence of a drug only in the sample. Most hospital toxicology laboratories are capable of determining concentrations of aspirin, acetaminophen, tricyclic antidepressants, anticonvulsants, cyclosporine, tacrolimus, digoxin, warfarin, barbiturates, methylxanthines, benzodiazepines, opiate agonists, and class 1a antiarrhythmics (e.g., procainamide, quinidine). Body fluid concentrations of other drugs may be measured, both qualitatively and quantitatively, at other laboratories. Table 18.3 offers a representative, but not exhaustive, list of drugs other than the common ones listed above, that may be measured.

Routes of Administration Medications may be administered by several routes and categorized as either enteral, parenteral or topical, as shown in Table 18.4. Enteral drug delivery includes oral, buccal, sublingual, gastric tube, jejunal tube and rectal routes of administration.

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Table 18.3. Qualitative and quantitative assessment of drug absorption

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Drug acyclovir allopurinol atenolol bethanechol brompheniramine captopril carbidopa chlorthiazide chlorpheniramine cimetidine clonidine colchicine dapsone diclofenac diflunisal diltiazem dipyridamole enalapril ergotamine famotidine fenoprofen fluphenazine glipizide glyburide haloperidol hydralazine hydrochlorothiazide hydroxychloroquine ibuprofen indomethacin ketoprofen labetalol levadopa lisinopril lithium loperamide meclizine meclofenamic acid mercaptopurine methocarbamol methyldopa metoclopramide metolazone metoprolol metronidazole naltrexone naproxen nifedipine oxybutynin pentazocine

Qualitative

X

X X

X

X

X

X

X X

Quantitative X X X X X X X X X X X X X X X X X X X X X X X X X X X X X X X X X X X X X X X X X X X X X X X X X X

continued on next page

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Table 18.3. Qualitative and quantitative assessment of drug absorption (continued) Drug pentoxyfylline perphenazine phenylbutazone phenylpropanolamine piroxicam probenecid propoxyphene propranolol propylthiouracil pseudoephedrine ranitidine rifampin sulfamethoxazole terbutaline terfenadine thioridazine thiothixene tolbutamide tolmetin trifluoperazine trihexyphenidyl trimethoprim triprolidine verapamil

Qualitative X X

X X

X X X X

Quantitative X X X X X X X X X X X X X X X X X X X X X

X X

X X

The above list was compiled from the following sources: 1) 1991 Professional Service Manual. American Medical Laboratories, Inc., Fairfax, Virginia; 2) January 1990 Professional Manual. National Medical Services, Willow Grove, Pennsylvania.

In the SBS patient, buccal, sublingual, and rectal administration may be suitable routes since the small intestine has been resected. Enteral drug delivery is the least expensive, and should be utilized whenever possible, even if higher doses of medication need to be administered to obtain the desired effect. However, many oral dosage forms have neither been formulated nor administered sublingually, buccally, or rectally. Consequently, other methods of drug delivery must be utilized. Parenteral drug delivery includes subcutaneous, intra-arterial, intramuscular, intrathecal, intraperitoneal, intravenous, and intraventricular routes of administration. Of the parenteral routes, subcutaneous (SC), intramuscular (IM), and intravenous (IV) administration of medications to SBS patients are the most common. Prolonged release of drug from the administration site e.g., depot formulations may decrease the frequency of dosing a drug when it is administered IM or SC. In fact, some medications may be given IM as infrequently as every 28 days. IV delivery of medications may either be continuous or intermittent. Continuous infusions are usually used for medications requiring a constant serum concentration and having a very short half-life. Intermittent infusions are usually used for medications requiring peak and trough serum concentrations, such as antibiotics.

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Table 18.4. Common methods of drug delivery Enteral Oral Buccal Sublingual Rectal Parenteral Subcutaneous Intra-arterial Intramuscular Intrathecal Intraperitoneal Intravenous Intermittent vs. continuous Intraventricular Pulmonary Aerosol Dry-powder Topical Eye Implantable Mucous membrane Skin Ointment Transdermal Cream

Reprinted with permission from McFadden MA, DeLegge MH, Kirby DF. JPEN 1993; 17:180-186.

Topical drug delivery includes respiratory, nasal, ophthalmic, otic, implantable, mucous membrane and skin routes of administration. Drugs administered to the mucous membranes that do not include the buccal, sublingual and rectal routes may be in the form of vaginal suppositories, creams, ointments and aerosols. Drugs administered to the skin may be in the form of ointments, creams, gels, pastes, powders, or transdermal patches. In many cases, topical drug delivery is intended for its topical effect; however, systemic absorption of medications via the topical route is necessary in some cases.

Buccal and Sublingual Administration

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Buccal administration of a medication refers to placement of a solid oral dosage form (e.g., tablet) into the cheek, where it dissolves and is absorbed. Sublingual administration refers to placement under the tongue. Absorption from the buccal and sublingual sites is enhanced when the mucosal pH and lipid solubility increase until the pH is 2 units above the pKa of the drug, then absorption tapers off.44 The advantages of these sites of administration for SBS patients include the following: 1. high systemic and lymphatic vascularity allows for rapid absorption and onset of effect; 2. therapy may be interrupted abruptly if necessary;

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3. direct delivery to the systemic circulation occurs, bypassing first-pass hepatic and intestinal metabolism; 4. the tablet may be retained for an extended period of time to provide a sustained effect; and, 5. intestinal absorption is not necessary to achieve the desired therapeutic effect.44 Buccal and sublingual administration may be limited when 1. the tablet is accidentally chewed or swallowed; 2. the dosage form dissolves too quickly; and, 3. the taste of the tablet is not pleasing to the patient. Medications that may be administered by the buccal and sublingual routes are listed in Table 18.5.44-82

Rectal Administration Rectal administration refers to the placement of a dosage form, whether liquid or solid, into the rectum. Rectal suppositories and enemas have been specifically formulated for such administration. Some of these formulations are commercially available; others have to be compounded extemporaneously. When a suppository cannot be prepared, some liquids which have been formulated for oral and intravenous use may be given rectally. Drug absorption from the rectum is determined by the drug form administered, the surface area of the rectum, the pH of the rectum, the pKa of the drug, and the extent of first-pass metabolism that may occur. It may be enhanced when the drug is in solution and is highly lipophilic. The advantages of rectal administration are recognized when a patient is acutely ill and neither oral nor intravenous administration is desirable. In the chronically ill patient, such as the SBS patient, rectal administration may preclude the less desirable intramuscular or intravenous route. Rectal administration may also lead to enhanced bioavailability as a result of decreased first pass metabolism.46,83 For example, metoprolol, an agent with extensive first pass metabolism, has demonstrated increased serum concentrations when administered rectally as compared to oral administration.83 The disadvantages of the rectal route include the following: 1. an unpredictable extent of absorption; 2. an unpredictable onset of action; 3. difficulty in achieving therapeutic serum concentrations; and, 4. difficulty maintaining the medication in the rectal cavity until it is absorbed. Medications that have been administered rectally include antiemetics, antidepressants, anticonvulsants, antihypertensives, antipyretics, anti-inflammatories, sedative/hypnotics and laxatives. Table 18.6 lists specific medications; some are not commercially available, but may be compounded by a pharmacist.45,83-129

Subcutaneous Administration Subcutaneous (SC) administration is the direct parenteral injection of a medication into the top half-inch of skin. The extent and rate of drug absorption will be determined by the site of injection and the extent of vascular circulation to the area. In most cases, the medication will be absorbed more slowly than in intravenous (IV) administration, but not as slowly as the intramuscular (IM) route. The advantages of SC administration are recognized when the oral or IV routes are neither available nor desirable and when a prolonged duration of effect may be desired. The

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Table 18.5. Drugs that can be used by buccal and sublingual routes* Buccal amitriptyline amphetamine fentanyl methylamphetamine methyltestosterone midazolam morphine nicotine nitroglycerin pemoline prochlorperazine testosterone

Sublingual alprazolam methyltestosterone buprenorphine midazolam captopril morphine desmopressin nifedipine ergoloid mesylates nitroglycerin ergotamine mesylate prazepam fentanyl propranolol hyoscyamine sulfate sotalol isosorbide dinitrate triazolam lorazepam

*References 44-82

disadvantages of SC administration include pain on injection, unpredictable peak serum concentrations and tissue hypertrophy that may occur after multiple injections. Table 18.7 lists medications that may be administered using the SC route.130-133

Intramuscular Administration Several medications prepared for IV use may be given by the IM route; however, some may be administered as depot injections. Depot injections are administered deep into a muscle, primarily the deltoid, gluteals or the thigh. These drugs are formulated to allow a dose of medication to be released slowly over an extended period of time—as long as a month in some cases. Absorption, therefore, is slow and continuous giving a steady concentration of drug in the serum. The advantages of such administration include decreased frequency of injections, fewer dermal complications, an alternate route when the oral and intravenous routes are not desirable and a prolonged duration of effect. The disadvantages of IM depot injection include pain on injection and difficulty reversing the drug’s therapeutic or adverse effects once administered. Table 18.8 lists medications that may be administered by IM depot injection.134-135

Continuous Infusion

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Intravenous, or direct, administration of medications into the systemic circulation allows for complete drug absorption. When no other alternatives are available, some medications may have to be administered by continuous infusion to the SBS patient. When a continuous effect is desired and a medication has a short elimination half-life, a constant IV infusion may be required. The advantages of continuous infusion include continuous effect and use when the oral route is not desirable. The disadvantages of continuous infusions include the requirement for continuous intravenous access, interrupted therapeutic effect when the infusion is disrupted, an increased risk for thrombophlebitis and extravasation at the site of infusion and higher costs. The medications most commonly infused include opiate analgesics, heparin, immunosuppressants, insulin and H2-antagonists. Table 18.9 lists medications administered by continuous infusion.136 Some of these medications may be admixed with TPN and administered simultaneously.

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Table 18.6. Drugs that can be used by rectal administration* acetaminophen allopurinol aminophylline amitriptyline aspirin atropine bisacodyl bumetanide carbamazepine chloral hydrate chlorpromazine cimetidine clonazepam clonidine codeine dextroamphetamine diazepam diclofenac digoxin dimenhydrinate docusate doxepin ergotamine fluoxetine glycerin hydrocortisone ibuprofen indomethacin insulin isoproterenol ketoprofen lactulose levodopa/carbidopa

methadone methohexital metoclopramide metoprolol metronidazole midazolam mineral oil morphine N-acetylcysteine nalbuphine naproxen nifedipine omeprazole ondansetron oxybutynin paraldehyde pentobarbital phenobarbital piroxicam prochlorperazine progesterone promethazine propranolol propylthiouracil sodium phosphate sodium polystyrene sorbitol sulfasalazine sumatriptan temazepam thiopental trimethobenzamide valproic acid

*References 45,83-129

Oral and Nasal Inhalation Medications may be inhaled by either the oral or nasal route and be administered by using a nebulizer or inhaler. The process of nebulization involves the dispersion of liquid medication via oxygen or compressed air into a mask from which the patient breathes orally and/or nasally. Inhalers are provided for either nasal or oral use. The nasal, and some oral, inhalers deliver medication that is dispersed via a propellant. Other oral inhalers involve the use of dispersing powdered drug from a capsule that is placed inside an activating device or dry powder that is released from a breath-actuated inhaler. In every case, the topical effect of the medication brings about a therapeutic systemic effect. In some cases, the amount of drug absorbed systemically is significant enough to cause side effects, but they are not nearly as significant as those resulting from oral or systemic administration. The advantages of administering medications by inhalation include minimal systemic effect and they do not require a functioning GI tract. The disadvantages

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Table 18.7. Drugs that can be used by subcutaneous injection* bethanecol buprenorphine corticotropin dalteparin danaparoid deferoxamine desmopressin dihydroergotamine enoxaparin ephedrine epinephrine erythropoietin ethacrynic acid G-CSF GM-CSF glucagon vitamin K

heparin insulin insulin aspart insulin glargine insulin lispro interferon isoproterenol morphine naloxone prochlorperazine pyridostigmine somatostatin terbutaline thyrotropin tinzaparin triamcinolone

*References 130-133

Table 18.8. Drugs that can be used by intramuscular depot injection* aurothioglucose benzathine penicillin bromocriptine estradiol estradiol + testosterone fluphenazine decanoate haloperidol decanoate methylprednisolone medroxyprogesterone octreotide testosterone

*References 134-135

are usually limited to the patient’s ability to properly administer the doses and the irritation to the throat/nares that may occur with the oral/nasal inhalers. Table 18.10 lists medications that may be administered by nasal and/or oral inhalation.137-156

Topical Administration

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Topical routes include ointments, transdermal systems, implantable devices, and creams that can be used on the skin and some are used vaginally. Table 18.11 summarizes the topical medications available.157-181 Transdermal drug administration refers to the delivery of medication from a drug reservoir through the skin and into the systemic circulation. The degree of

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Table 18.9. Drugs that can be used by continuous intravenous infusions cimetidine famotidine* fentanyl heparin hydromorphone insulin meperidine morphine octreotide ranitidine tacrolimus

*In vitro compatibility data only.136

Table 18.10. Drugs that can be used by nasal and oral inhalation* albuterol amikacin amphotericin liposomal atropine azelastine beclomethasone budesonide butorphanol colistin cromolyn sodium deferoxamine desmopressin acetate dexamethasone ephedrine epinephrine ergotamine fentanyl flunisolide fluticasone gentamicin glycopyrrolate ipratropium isoetharine isoproterenol levalbuterol

lidocaine metaproterenol methylprednisolone midazolam mometasone naphazoline nedocromil nicotine nitroglycerin oxymetazoline oxytocin pentamidine propylhexedrine phenylephrine propranolol salmeterol sufentanil sumatriptan terbutaline tetrahydrozoline tobramycin triamcinolone vasopressin zanamivir

*References 137-156. Adapted and updated with permission from McFadden MA, DeLegge MH, Kirby DF. JPEN 1993; 17:180-186.

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Table 18.11. Drugs that can be used by topical route I.

Ointment nitroglycerin II. Transdermal patches* clonidine nicotine scopolamine III. Implantable devices levonorgestrel IV. Cream betamethasone conjugated estrogen miconazole terconazole

estradiol nitroglycerin testosterone

fentanyl salicylic acid

capsaicin fluocinonide nystatin

clotrimazole hydrocortisone triamcinolone

*References 157-181. Reprinted with permission from McFadden MA, DeLegge MH, Kirby DF. JPEN 1993; 17:180-186.

drug absorption is comparable to that of a continuous infusion without the use of an IV catheter. The advantages of transdermal drug delivery include the following: 1. provides a steady serum concentration of drug; 2. does not require GI tract for absorption; 3. it has less variability in absorption when compared to GI absorption; 4. therapy may be discontinued abruptly if necessary; 5. dosing may be as infrequent as once weekly; and, 6. patient adherence may be better.181 The disadvantages of these systems are primarily related to the limited number of medications which may be administered transdermally.

Special Considerations Home Antibiotics

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Patients with SBS may require central venous access to provide adequate nutrition and to administer intravenous medications. In-dwelling catheters pose a significant risk of infection. This, coupled with the potential for other infections, may necessitate the use of intravenous antimicrobials. In an effort to minimize cost, patients may be managed at home with IV antimicrobial therapy. Common catheterrelated infections result from Staphylococcus aureus (S. aureus ) and Candida species (C. species) including C. albicans and Torulopsis glabrata (T. glabrata). Other infections caused by Gram-negative organisms may need to be managed as well. In many cases, S. aureus is resistant to methicillin, requiring the use of vancomycin. Oxacillin or nafcillin may be used if the organism is sensitive. Amphotericin B is the drug of choice for sepsis caused by C. species. Fluconazole is an acceptable alternative in the case of a C. albicans line infection. C. krusei and T. glabrata are primarily fluconazoleresistant species and necessitate the use of amphotericin.182 The aminoglycosides and third generation cephalosporins are commonly utilized to manage infections caused by Gram-negative organisms. Table 18.12 lists some useful antimicrobials for outpatient therapy home use based on their dosing regimens, solution stability and the bacterial/fungal coverage.30,182-197

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Table 18.12. Useful antibiotics for home therapy Antibiotic Name Amikacin Amphotericin

Cefazolin Ceftazidime

Ceftriaxone

Cefoxitin Ciprofloxacin Clindamycin

Gatifloxacin

Gentamicin Levofloxacin

Nafcillin Oxacillin

TicarcillinClavulanate

Tobramycin Vancomycin

Half-Life* 2-3 hours

Dosing Interval Every 8-24 hours

Special Information Monitor serum concentrations and renal function up to 15 days Every 24 hours Monitor renal function and potassium, phosporus and magnesium 1-2 hours Every 8 hours Gram + coverage including methicillin sensitive S. aureus 1.5-2 hours Every 8 hours Good coverage Pseudomonas aeruginosa and acinetobacter 5-11 hours Every 12-24 hours Good gram + coverage, but not enterococci, listeria or methicillin resistant S. aureus, many pseudomonas resistant < 1 hour Every 6 hours Gram – coverage including anaerobic bacteria 3-4 hours Every 12 hours Gram – coverage including Pseudomonas aeruginosa 2-3 hours Every 8 hours Gram + aerobic and anaerobic coverage; diarrhea with Clostridium difficile 7-14 hours Every 24 hours Gram + and gram- coverage including Streptococcus pneumoniae 2-3 hours Every 8-24 hours Monitor serum concentrations and renal function 6-7 hours Every 24 hours Gram + and gram- coverage including Streptococcus pneumoniae < 1 hour Every 4-6 hours Gram + coverage including methicillin sensitive S. aureus < 1 hour Every 4-6 hours Gram + coverage including methicillin sensitive S. aureus; strong association with phlebitis 1 hour Every 4-6 hours Gram + coverage including methicillin sensitive S. aureus; Gram - and anaerobic coverage including Bacteroides fragilis 2-3 hours Every 8-24 hours Monitor serum concentrations and renal function 4-6 hours Every 12-24 hours Monitor renal function and serum concentrations when appropriate

*References 30,182-197. Reprinted with permission from McFadden MA, DeLegge MH, Kirby DF. JPEN 1993; 17:180-186

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Culture and sensitivity data are always important in the final decision of antimicrobials to assure that the patient is being effectively managed. The dosage regimen, solution stability, and toxicity must also be considered to provide optimal care.183-185 Minimizing the number of doses that need to be administered will decrease cost and increase patient compliance.194 The implementation of portable multiple-dose electronic infusion pumps have allowed easier antimicrobial administration.183 These infusion pumps deliver medication via drug reservoirs for either intermittent or continuous infusions. These pumps negate the need for IV administration sets for each dose. The cost of these systems are increased but a wider variety of antimicrobials may be utilized in the outpatient setting.183 Monitoring serum concentrations and renal function is encouraged with the use of the aminoglycosides. Assessment of renal function is also necessary with vancomycin. Vancomycin trough concentrations should only be measured if renal function deteriorates or a poor clinical response is demonstrated.198 Amphotericin B may have significant effects on renal function and electrolyte homeostasis; routine monitoring is suggested. Some TPN vendors who supply TPN for the home patient use two-in-one infusions while other companies use three-in-one infusions. Table 10.13 shows compatibility data of whether the antimicrobial may be co-infused or put into the TPN directly. 195

Cyclic Infusion Techniques The infusion of total parenteral nutrition (TPN) over a 24-hour period is commonly practiced when a patient is in the hospital. This practice may not be optimal for the outpatient, particularly when a relatively active lifestyle may be maintained. If the SBS patient has central venous access, the duration of TPN infusion may be decreased from the usual 24 hour period to a 10-12 hour period. Several approaches may be taken to achieve this goal. One method may involve maintaining the same volume and dextrose concentration while decreasing the infusion time a couple hours each day until the patient tolerates a 10-12 hour infusion. The rates of infusion may be increased or decreased when initiating and discontinuing the TPN infusion, respectively. However, Krzywda et al suggest that patients may tolerate abrupt initiation and discontinuation of 3-in-1 TPN without significant hyper- or hypoglycemia.196

Home Infusion Devices

18

The infusion of IV fluids, medications and TPN at home may be accomplished by the use of several devices. Standard infusion pumps may be utilized to administer large volumes of fluid, particularly TPN and fat emulsion. H2-antagonists that have been admixed with the TPN would consequently be delivered by the same method. Antibiotics, provided in piggyback form or in concentrated drug reservoirs, could be co-infused with an IV fluid or TPN using the same device. However, when antibiotics are provided in predrawn syringes, the use of a syringe pump may be more practical, especially when the extra fluid from the IV infusion and piggyback may compromise patient care. Narcotic analgesics, including fentanyl, hydromorphone, meperidine and morphine, may be infused for management of chronic pain. This may be accomplished using microinfusion devices that allow fairly concentrated solutions to be administered continuously. Still other infusion devices are designed to allow for continuous, subcutaneous administration. The medication most commonly infused by this

295

Pharmacologic Aspects of Short Bowel Syndrome

Table 18.13. Medication administration with TPN† Medication Acyclovir Amikacin Aminophylline Amiodarone Amphotericin Amphoterin cholesterol sulfate complex Ampicillin Azithromycin Aztreonam Cefazolin Cefepime Cefotaxime Cefoxitin Ceftazidime Ceftriaxone Cefuroxime Cidofovir Cimetidine Ciprofloxacin Clindamycin Cyclosporine Digoxin Doxycycline Erythromycin Famotidine Fentanyl Fluconazole Foscarnet Furosemide Ganciclovir Gatifloxacin Gentamicin Heparin Hydromorphone Imipenem-Cilastin Insulin Iron Dextran Levofloxacin Linezolid Meperidine Meropenem Methicillin Metoclopramide Metronidazole Morphine Nafcillin Ofloxacin

2 in 1 Co-Infusion In Solution No ND* Yes ND Equivocal Yes ND ND No ND

3 in 1 Co-Infusion In Solution ND ND No ND ND Yes ND ND ND ND

ND Equivocal ND Yes Equivocal ND Yes Yes Yes Yes Yes ND Yes No Yes Equivocal Yes Yes Yes Yes Yes Yes Yes Equivocal Equivocal ND Equivocal Yes Yes Yes Yes Equivocal ND ND Yes ND Yes No Yes Yes Yes Yes

ND Yes ND ND Yes ND ND Yes ND ND ND ND ND ND Yes ND Yes ND Yes ND ND ND ND Yes ND ND Yes ND ND ND ND ND ND ND ND ND ND ND ND ND ND ND

ND Equivocal ND ND Yes ND Yes Yes Yes Yes Yes ND Yes ND Yes ND ND ND ND Yes ND ND ND ND No ND Yes Yes ND No Yes Yes ND ND Yes ND Yes Yes ND Yes Yes ND

ND ND ND ND ND ND ND ND ND ND ND ND Yes ND ND ND ND ND ND Yes ND ND ND ND ND ND ND ND ND ND ND Equivocal ND ND ND ND ND ND ND ND ND ND

continued on next page

18

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The Biology and Practice of Current Nutritional Support

Table 18.13. Medication administration with TPN† (continued) Medication Oxacillin Penicillin G K+ Penicillin G Na+ Piperacillin Piperacillin/tazobactam Quinupristin/dalfopristin Ranitidine Tacrolimus Ticarcillin Ticarcillin/clavulanate Tobramycin Trimethoprim-Sulfa Vancomycin

2 in 1 Co-Infusion In Solution Yes ND Yes Yes Yes Yes Yes No Yes ND ND ND Yes Yes Yes Yes Yes Equivocal Yes ND Yes ND Yes ND Yes Yes

3 in 1 Co-Infusion In Solution Yes ND Yes ND ND ND ND ND ND ND ND ND ND Yes ND ND Yes ND ND ND Yes ND ND ND ND ND

* ND - No Data; †Reference 195. Adapted and updated with permission from McFadden MA, DeLegge MH, Kirby DF. JPEN 1993;17:180-186.

method is insulin. In the case of chronic iron toxicity, deferoxamine may also be infused by this method.

Conclusion The chronic care of the SBS patient can be extremely rewarding, yet challenging. It may often tax the ingenuity of the most resourceful clinician. The availability of newer drugs and delivery systems has made it easier, but it is clear that more work is needed in the pharmacologic approach to patients with limited GI absorption. The new millenium holds the promise of even greater advancements and improvements in the quality of life for these patients.

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Golden S, Teets SJ, Lehman EB et al. Effect of topical nasal azelastine on the symptoms of rhinitis, sleep, and daytime somnolence in perennial allergic rhinitis. Ann Allergy Asthma Immunol 2000; 85:53-57. Onrust SV, Lamb HM. Mometasone furoate: a review of its intranasal use in allergic rhinitis. Drugs 1998; 56:725-745. Ryan R, Elkind A, Baker CC et al. Sumatriptan nasal spray for the acute treatment of migraine: results of two clinical studies. Neurology 1997; 49:1225-1230. Purcell IF, Corris PA. Use of nebulised liposomal amphotericin B in the treatment of Aspergillus fumigatus empyema. Thorax 1995; 50:1321-1323. Chapple KJ, Hendrick AE, McCarthy MW. Zanamivir in the treatment and prevention of influenza. Ann Pharmacother 2000; 34:798-801. Coveny Davis K, Small RE. Budesonide inhalation powder: a review of its pharmacologic properties and role in the treatment of asthma. Pharmacotherapy 1998; 18:720-728. Asmus MJ, Hendeles L. Levalbuterol nebulizer solution: is it worth five times the cost of albuterol. Pharmacotherapy 2000; 20:123-129. Meyer JM, Wenzel CL, Kradjan WA. Salmeterol: a novel, long-acting beta2-agonist. Ann Pharmacother 1993; 27:1478-1487. Okuyemi KS, Ahluwalia JS, Harris KJ. Pharmacotherapy of smoking cessation. Arch Fam Med 2000; 9:270-281. Brogden RN, Sorkin EM. Nedocromil sodium: an updated review of its pharmacological properties and therapeutic efficacy in asthma. Drugs 1993; 45:693-715. Jarvis B, Faulds D. Inhaled fluticasone propionate: a review of its therapeutic efficacy at dosages [500 µg/day in adults and adolescents with mild to moderate asthma. Drugs 1999; 57:769-803. Pakes GE, Brodgen RN, Heel RC et al. Ipratropium bromide: A review of its pharmacologic properties and therapeutic efficacy in asthma and chronic bronchitis. Drugs 1980; 20:237-266. Hill AB, Bowley CJ, Nahrwold ML et al. Intranasal administration of nitroglycerine. Anesthesiology 1981; 54:346-348. Grover VK, Sharma S, Mahajan RP et al. Intranasal nitroglycerine attenuates pressor response to tracheal intubation in beta-blocker treated hypertensive patients. Anaesthesia 1987; 42:884-887. Graham JJ, Wise PH, Harding PE. DDAVP (R) in the treatment of diabetes insipidus: A clinical study. Med J Aust 1977; 2:113. Hussain A, Foster T, Hirai S et al. Nasal absorption of propranolol in humans. J Pharm Sci 1980; 69:1240. Theroux MC, West DW, Corddry DH et al. Efficacy of intranasal midazolam in facilitating suturing of lacerations in preschool children in the emergency department. Pediatrics 1993; 91:624-627. Weber MA, Dreyer JIM. Clinical experience with rate-controlled delivery of antihypertensive therapy by a transdermal system. Am Heart J 1984; 108:231-236. McMahon FG, Jain AK, Vargas R et al. A double-blind comparison of transdermal clonidine and oral captopril in essential hypertension. Clin Ther 1990; 12:88-100. White WB, Gilbert JC. Transdermal clonidine in a patient with resistent hypertension and malabsorption (letter). N Engl J Med 1985; 313:1418. Josse S, Danays T, Lafferre M et al. Substitution of oral clonidine with transdermal clonidine in hypertensive patients. Curr Ther Res 1987; 42:579-585. Laufer LR, Defazio JL, Lu JKH et al. Estrogen replacement therapy by transdermal estradiol administration. Am J Obstet Gynecol 1983; 146:533-540. Padwick ML, Endcott J, Whitehead MI. Efficacy, acceptability and metabolic effects of transdermal estradiol in the management of postmenopausal women. Am J Obstet Gynecol 1985; 152:1085-1091.

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Bredfelt RC, Sutherland JE, Kruse JE. Efficacy of transdermal clonidine for headache prophylaxis and reduction of narcotic use in migraine patients : A randomized crossover trial. J Fam Pract 1989; 29:153-156. Place VA, Powers M, Darley PE et al. A double-blind comparative study of Estraderm (R) and Premarin (R) in the amelioration of postmenopausal symptoms. Am J Obstet Gynecol 1985; 152:1092-1099. Gourley GK, Kowalski SR, Plummer JL et al. The efficacy of transdermal fentanyl in the treatment of postoperative pain: A double-blind comparison of fentanyl and placebo systems. Pain 1990; 40:21-28. Caplan RA, Ready LB, Oden RV et al. Transdermal fetanyl for postoperative pain management. JAMA 1989; 261:1036-1039. Mulligan SC, Masterson JG, Devane JG et al. Clinical and pharmacokinetic properties of a transdermal nicotine patch. Clin Pharmacol Ther 1990; 47:331-337. Hurt RD, Lauger GG, Offord KP et al. Nicotine-replacement therapy with use of a transdermal nicotine patch: A randomized double-blind placebo-controlled trial. Mayo Clin Proc 1990; 65:1529-1537. Rajfer SI, Demma FJ, Goldberg LI. Sustained beneficial hemodynamic responses to large doses of transdermal nitroglycerine in congestive heart failure and comparison with intravenous nitroglycerine. Am J Cardiol 1984; 54:120-125. Rose JE, Levin ED, Behm FM et al. Transdermal nicotine facilitates smoking cessation. Clin Pharmacol Ther 1990; 47:323-330. Elkayam U, Roth A, Henriquez B et al. Hemodynamic and hormonal effects of high-dose transdermal nitroglycerine in patients with congestive heart failure. Am J Cardiol 1989; 56:555-559. Greco R, Schiattarella M, Wolff S et al. Long-term efficacy of nitroglycerine patch in stable angina pectoris. Am J Cardiol 1990; 65:9J-15J. Lin S, Flaherty JT. Crossover from intravenous to transdermal nitroglycerine therapy in unstable angina pectoris. Am J Cardiol 1985; 56:742-748. Attias J, Gordon C, Ribak J et al. Effects of transdermal scopolamine against seasickness: A 3-day study at sea. Aviat Space Environ Med 1987; 58:60-62. Jordan RA, Seth L, Henry A et al. Dose requirements and hemodynamic effects of transdermal nitroglycerine compared with placebo in patients with congestive heart failure. Circulation 1985; 71:980-986. Shupak A, Gordon CR, Spitzer O et al. Three-years experience of transdermal scopolamine: Long-term effectiveness and side-effects. Pharmatherapeutica 1989; 5:365-370. Dahl E, Offer-Ohlsen D, Lillevold PE et al. Transdermal scopolamine, oral meclizine and placebo in motion sickness. Clin Pharmacol Ther 1984; 36:116-120. Place VA, Nichols KC. Transdermal delivery of testosterone with Testoderm (R) to provide a normal circadian pattern of testosterone. Ann N Y Acad Sci 1991; 618:441-449. Cunningham GR, Cordero E, Thornby JI. Testosterone replacement with transdermal therapeutic systems: Physiological serum testosterone and elevated dihydrotestosterone levels. JAMA 1989; 261:2525-2530. Findlay JC, Place V, Snyder PJ. Treatment of primary hypogonadism in men by the transdermal administration of testosterone. J Clin Endocrinol Metab 1989; 68:369-373. Ridout G, Santus GC, Guy RH. Pharmacokinetic considerations in the use of newer transdermal formulations. Clin Pharmacokinet 1988; 15:114-131. Raad I. Intravascular-catheter-related infections. Lancet 1998; 351:893-898. Gilbert DN, Dworkin RJ, Raber SR et al. Outpatient parenteral antimicrobial– drug therapy. N Engl J Med 1997; 337:829-838. Leggett JE. Ambulatory use of parenteral antibacterials: contemporary perspectives. Drugs 2000; 59(Suppl 3):1-8.

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Strehl E, Kees F. Pharmacological properties of parenteral cephalosporins: Rationale for ambulatory use. Drugs 2000; 59(Suppl 3):9-18. Esposito S. Parenteral cephalosporin therapy in ambulatory care: advantages and disadvantages. Drugs 2000; 59(Suppl 3):19-28. Wright AJ. The penicillins. Mayo Clin Proc 1999; 74:290-307. Marshall WF, Blair JE. The cephalosporins. Mayo Clin Proc 1999; 74:187-195. Kasten MJ. Clindamycin, metronidazole, and chloramphenicol. Mayo Clin Proc 1999; 74:825-833. Kasmer RJ, Hoisington LM, Yukniewicz S. Home parenteral antibiotic therapy, Part I: An overview of program design. Home Health Nurse 1987; 5:12-18. Kasmer RJ, Hoisington LM, Yukniewicz S. Home parenteral antibiotic therapy, Part II: Drug preparation and administration considerations. Home Health Nurse 1987; 5:19-23. Harris LF, Buckle TF, Coffey FL. Intravenous antibiotics at home. South Med J 1986; 79:193-196, Bernstein LH. An update on home intravenous antibiotic therapy. Geriatrics 1991; 46:47-54. Gulledge AD, Gipson WT, Steiger E et al. Home parenteral nutrition for the short bowel syndrome. Psychological issues. Gen Hosp Psychiatry 1980; 2:271-281. Trissel LA. Handbook on Injectable Drugs, 10th ed. Bethesda: American Society of Hospital Pharmacists, 1998:1-1324. Krzywda EA, Andris DA, Whipple JK. Glucose response to abrupt initiation and discontinuation of total parenteral nutrition. JPEN 1993; 17:64-67. Hoellmann DB, Lin G, Jacobs MR et al. Anti-pneumococcal activity of gatifloxacin compared with other quinolone and non-quinolone agents. J Antibicrob Chemother 1999; 43:645-649. Leader WG, Chandler MHH, Castiglia M. Pharmacokinetic optimisation of vancomycin therapy. Clin Pharmacokinet 1995; 28:327-342.

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CHAPTER 19

Nutritional Support in Inflammatory Bowel Disease John H. Seashore, Melissa F. Perkal

Introduction Crohn’s disease and ulcerative colitis are chronic remitting diseases of unknown etiology characterized by abdominal pain, diarrhea and other gastrointestinal symptoms. Both diseases, but Crohn’s in particular, are associated with nutritional deficiencies for a variety of reasons including malabsorption, increased nutrient losses, increased energy requirements and inadequate nutrient intake. Acute malnutrition, evidenced by weight loss, anemia and hypoalbuminemia, is common during acute attacks of inflammatory bowel disease (IBD). A smaller number of patients have chronic malnutrition with cachexia and multiple nutrient deficiencies. Malnutrition may be responsible for considerable morbidity and even mortality in inflammatory bowel disease (IBD), although there is no evidence that it exacerbates either condition. The classic papers by Dudrick and Wilmore in 1968 describing the first successful method for total parenteral nutrition sparked a resurgence of interest in clinical nutrition and led to the development of new techniques and formulas for both parenteral and enteral nutrition.1,2 There has been intense interest in the role of nutritional therapy in IBD during the 25 years since. Much of the literature is based on anecdotal, retrospective or uncontrolled data, and spontaneous remissions and exacerbations are characteristic of IBD which makes it difficult to know whether a specific treatment is responsible for observed improvement. However, the large amount of information and the available prospective, randomized, controlled studies make it possible to draw some general conclusions.

Malnutrition in Inflammatory Bowel Disease Incidence Acute malnutrition, as evidenced by weight loss of more than 10% or serum albumin less than 3 g/dl, has been reported in 30-60% of patients during flare-ups of Crohn’s disease.3,4 Chronic malnutrition, or undernutrition is less common but probably occurs in about 10% of adult patients. Ulcerative colitis is characterized by long periods of well being and periodic severe flare-ups of disease. It is not surprising, then, that acute malnutrition occurs in 50-75% of patients, but chronic malnutrition is quite rare. Approximately 85% of children have weight loss during acute attacks of Crohn’s disease, and 65% suffer weight loss during flares of ulcerative colitis. 4 Chronic malnutrition is a particular problem in children because of their unique growth The Biology and Practice of Current Nutritional Support, 2nd Edition, edited by Rifat Latifi and Stanley J. Dudrick. ©2003 Landes Bioscience.

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requirements. About 20% of patients have onset of IBD in childhood, usually during adolescence, when children normally have a rapid increase in skeletal growth and muscle mass, and undergo sexual maturation.5 Growth failure occurs in 15-30% of children with Crohn’s disease and 10% of children with ulcerative colitis.5,6

Mechanisms of Malnutrition Table 19.1 lists a host of factors which may contribute to malnutrition in patients with IBD.

Malabsorption Malabsorption is most likely in the face of extensive mucosal disease, decreased transit time from active disease, multiple resections resulting in short bowel syndrome, or bacterial overgrowth which occurs in up to 30% of patients with Crohn’s disease.8 Carbohydrate absorption, measured by D-xylose studies, was reported to be abnormal in 16-40% of adults and children with Crohn’s disease.8,9 Lactose intolerance is the most common manifestation of malabsorption in IBD and has been assumed by many clinicians to be nearly universal. However, decreased lactase levels in jejunal biopsy specimens could be demonstrated in only 9-12% of patients.10 Transient lactose intolerance is probably somewhat more common during acute attacks of disease. The hydrogen breath test, a sensitive indicator of lactose malabsorption, was abnormal in 15% of children with ulcerative colitis and 34% of children with Crohn’s disease.11 Extensive ileal disease or resection may disrupt the enterohepatic circulation and lead to depletion of the bile salt pool resulting in fat and fat soluble vitamin malabsorption. Many patients with bile salt deficiency have difficulty maintaining a normal weight. Deficiency of vitamins A, D, E, and K have been reported, but the incidence is not known.9 Vitamin B12 is absorbed in the terminal ileum independent of bile salts and may also become depleted.9 Serum zinc levels are low in IBD patients as in other diarrheal diseases.12,13 Many of the common medications used to treat IBD may exacerbate malabsorption. Corticosteroids inhibit calcium absorption, sulfasalazine impairs folate absorption by competitive inhibition and cholestyramine binds bile acids and aggravates bile salt deficiency.

Increased Gastrointestinal Losses Acute or chronic GI bleeding from the inflamed mucosal surfaces is very common in IBD. The bleeding may be occult or gross, the latter more prominent in ulcerative colitis. Iron deficiency anemia is therefore common, but since other micronutrient deficiencies can cause anemia (folate, B12), further evaluation may be necessary. Mean corpuscular volume less than 80 and a serum ferritin less than 18 mg/ml are the best evidence of iron deficiency anemia.14 The inflamed mucosa characteristic of IBD may lead to an exudative enteropathy and loss of protein from the gut, above and beyond protein malabsorption. This excessive protein loss may exacerbate hypoalbuminaemia and other protein deficiency. Increased losses of protein from the gut have been demonstrated by abnormal fecal excretion of 51chromium labeled albumin or clearance of alpha-1-antitrypsin.15 The diarrhea seen during acute attacks of IBD is multifactorial in origin, but is in part a secretory diarrhea causing active loss of water and electrolytes through the diseased mucosa. Excessive losses of trace metals, including, zinc, copper and magnesium have also been reported.16,17

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Table 19.1.

Possible causes of malnutrition in inflammatory bowel disease

Inadequate intake Anorexia, altered taste, avoidance behavior Abdominal pain, diarrhea, nausea, vomiting Restrictive diets Malabsorption Diminished digestive function secondary to decreased bile salt concentration or bacterial overgrowth Decreased absorptive surface area secondary to extensive disease and/or previous bowel resections Drug-induced malabsorption(e.g., steroids/calcium; sulfasalazine/folate; cholestyramine/fat-soluble vitamins Increased gastrointestinal losses Protein-losing enteropathy Gastrointestinal bleeding Electrolyte and mineral loss Increased nutritional requirements Fever, fistula, infection ? corticosteroid therapy Need for repletion of body mass

Reproduced with permission of WB Saunders Co from Perkal, MF and Seashore, JH. Nutrition and inflammatory bowel disease. Gastroenterology Clin NA, 1989; 18(3):567-578.7

Increased Nutritional Requirements Fever associated with active disease, sepsis, peritonitis or abscess increases energy expenditure substantially and therefore increases caloric requirements.18 In the absence of fever, however, most of the evidence suggests that patients with IBD do not have an increased caloric requirement.19 Motil et al showed that Crohn’s disease patients have the same whole body nitrogen flux, rates of protein synthesis and breakdown and net protein retention as normal controls.20 Chan, et al found that the measured energy expenditure(by indirect calorimetry) in patients with Crohn’s disease was virtually identical to that predicted by the Harris-Benedict equation for normal adults.21

Inadequate Oral Intake This is the single most important reason for nutritional deficiency. Nausea, cramps and diarrhea tend to be worse after eating and may condition patients to food avoidance. The anorexia which accompanies many chronic illnesses may contribute. Specific complications including obstruction and fistula clearly impair eating. Self-selected or physician-recommended diets may restrict intake by eliminating desired foods and by interfering with palatability. The most compelling evidence that inadequate intake is responsible for malnutrition comes from studies showing that children with growth failure can achieve normal growth rates when their diet is supplemented with parenteral or enteral nutrition.

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Nutritional Support in Inflammatory Bowel Disease Patients with inflammatory bowel disease are at risk for developing nutritional deficiencies which may in turn increase morbidity and mortality. Maintenance of good nutrition is a desirable goal, but the best methods, timing and route of nutritional support are not always clear. The role of nutritional therapy in IBD can be considered in the following areas.

Nutritional Management of Acute Attacks and Induction of Remission Corticosteroids have long been the mainstay of medical treatment for IBD. In the National Cooperative Crohn’s disease Study, treatment of active Crohn’s disease with prednisone achieved a 47% rate of remission of symptoms compared with 26% in placebo treated patients.22 Truelove described treating severe attacks of IBD with a period of bowel rest and intravenous steroids with good results.23 This approach has become commonplace in the management of IBD. However, even healthy, well nourished adults may develop evidence of malnutrition after 10 days NPO. Patients who are already malnourished from IBD should not be allowed to starve for more than a few days. Finally, most patients who fail medical therapy require surgery which is better tolerated in the nutritionally repleted patient. For all these reasons, it is prudent to give parenteral nutrition to patients who are NPO during treatment with steroids and bowel rest. The concept of bowel rest in the treatment of gastrointestinal inflammatory processes is based on several theoretical considerations. Peristalsis is decreased in the absence of enteral feeding so there is less physical movement of the bowel which could function as a medical “splint” to aid in healing of the inflammatory process. Withholding oral feedings minimizes gastrointestinal secretions. In the absence of digestion and absorption, the metabolic work and oxygen consumption of the gut mucosa is minimal, which may also permit better healing. It has been suggested that the multiplicity of foreign antigens introduced into the gut with oral feeding may worsen the disease.24 There is no direct evidence to support these hypotheses, but bowel rest has been widely used in the treatment of gastrointestinal disease. The introduction of total parenteral nutrition (TPN) in 1968 made it possible to provide intravenous nutrition for more than a few days. There has been considerable interest over the years in using longer periods of bowel rest for treating IBD leading to the concept of TPN as primary therapy. Early experience was encouraging and led to widespread use of a 3-12 week period of bowel rest with in hospital and home TPN. Greenberg, et al reported a 77% remission rate in 43 patients, 79% of whom remained well for 2 years.25 A subsequent prospective but non-randomized study of 100 patients from the same institution again reported a 77% remission rate in hospital and 54% of patients still in remission at 1 year.26 Most of the patients continued to receive steroids during TPN. Other workers have not been able to duplicate these results, however. Reported remission rates have been from 30-70%.27-35 More important, remissions have not generally been sustained, relapses or surgical intervention occurring in 15-80% of patients within 1-2 years. Muller et al reported that 83% of patients had remission and avoided surgery acutely, but that the recurrence rate was 65% at 2 years and 85% at 4 years.36 This relapse rate was 4 times higher than that following surgical resection. One of the few prospective, randomized, controlled studies was reported by Dickinson, et al who found no difference in outcome between those patients

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treated with standard medical therapy alone and those treated with medical therapy plus TPN.37 While most of the studies in the literature are retrospective and uncontrolled and the definitions of disease severity, remission and relapse vary somewhat, certain conclusions seem appropriate. A prolonged period of bowel rest and TPN may be more effective in inducing remission than the standard 10 day course of treatment, but the cost and complications of TPN must be considered. Remission is not well sustained compared with long term steroid therapy or surgical resection. The role of TPN is adjunctive rather than primary. The concept of bowel rest has been challenged in recent years for several reasons.35,38,39 As noted above, there is no hard evidence that bowel rest works. Second, there is accumulating evidence that prolonged bowel rest is damaging to the gut. Small bowel mucosal atrophy as measured by villous height, DNA content and mucosal wet weight, occurs in patients who are NPO and receiving TPN.40,41 It is now recognized that mucosal atrophy may be associated with bacterial translocation from the bowel lumen to the portal circulation and may be a source of sepsis in TPN patients.42 Intraluminal nutrients, especially glutamine, appear to be critical to maintain the health of the small bowel mucosa.41,43 Third, recent studies suggest that bowel rest may not be necessary in the treatment of acute episodes of IBD. O’Morain, et al in 1980 reported substantial clinical improvement in 27 patients treated with an elemental diet with or without steroids for acute exacerbations of Crohn’s disease.44 Morin, et al induced remission in 10 newly diagnosed children with moderately severe Crohn’s disease using elemental diet without steroids.45 Since then, a number of prospective, randomized controlled studies have confirmed that elemental diets, with and without steroids, are effective in inducing remission during acute attacks of IBD.46-52 Remission rates in these studies range from 60-90%. Elemental diet was equal or superior to steroids,46-48,50 bowel rest, TPN and bowel rest49,52 or polymeric diet,51 in inducing remission in both children and adults. Results were generally maintained for up to 3 months, but most of these studies did not provide long-term follow-up. One retrospective study that did report long term follow up data showed a 22% relapse rate at 6 months, then an 8-10% annual relapse rate thereafter.53 A third study from the Toronto group, this one prospective and randomized, found no significant differences in outcome among groups treated with: 1. TPN, bowel rest and steroids, 2. elemental diet and steroids, and 3. regular diet plus steroids.54 In this study, remission was maintained in over 50% of patients for up to 2 years. Teahon, et al showed that the abnormal permeability of the bowel mucosa found in active Crohn’s disease was reversed during treatment with an elemental diet, suggesting improved integrity of the mucosal barrier.55 These studies clearly demonstrate that bowel rest is not essential in the management of acute attacks of IBD. Elemental diets are superior in most cases and obviate the need for TPN with its attendant cost and risks. However, there is still a place for a short course of TPN and bowel rest in patients who fail other therapy.

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Once remission has been achieved, the goal of treatment is to keep patients symptom free while they return to their usual activities and diet. Dietary management in this phase remains controversial. Restrictive diets often lead to inadequate

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nutrition because of exclusion of favorite foods or unpalatability and should be avoided unless there is good evidence of need and efficacy.24,39 A low residue or low fiber diet has traditionally been recommended in IBD, but there is no scientific evidence that it works. Levenstein et al randomized patients to either a regular or a low fiber diet and found no difference in symptoms or relapse.56 Heaton et al treated a group of patients with a diet low in refined carbohydrate and high in fiber content.57 They found a lower incidence of hospitalization and surgery in the diet treated patients compared with historical controls taking a regular diet. A subsequent larger, randomized study failed to confirm this observation.58 Many clinicians advise their patients to eat a regular diet, avoiding only those foods which bother them. AlunJones provides some evidence for this approach in a small randomized study59 and a larger non-randomized study49 in which one new food was introduced each day. Any food which caused symptoms was eliminated from the patient’s diet. The majority of the patients were sensitive to 1-4 foods, the most common being wheat, dairy products, corn, yeast, tomatoes, citrus and eggs. A prospective multicenter trial using a similar exclusion diet technique found a 2 year relapse rate of 62% compared with 79% in patients treated with steroids and regular diet.60

Growth Failure in Children About 20 % of patients with inflammatory bowel disease have onset of symptoms in childhood.5 Children suffer the same nutritional consequences of IBD as adults, namely acute weight loss, chronic undernutrition and micronutrient deficiencies. In addition, children normally are growing, especially during the pubertal growth spurt, and significant numbers of children with IBD have impaired linear growth and delayed sexual maturation. Growth failure occurs in 15-40% of children with Crohn’s disease and 10% of children with ulcerative colitis.4,61-63 Growth failure, as opposed to weight loss, is most commonly defined as a height for age less than the 5th percentile on standard growth curves. A single static measurement of growth, however, may represent constitutional short stature rather than the effect of disease. Estimating predicted adult height from mean parental height may be helpful. Even better is to obtain old height measurements and plot the child’s growth history over time on the standard growth charts. Adult height can be predicted fairly accurately if a child has been growing steadily along a particular percentile curve. If height begins to cross percentiles over a year or two, the child almost certainly has growth failure from disease. The most accurate method to assess growth failure is to plot linear growth (cm/year) on normal growth velocity curves64 A child whose linear growth is less than the 3rd percentile (2 SD below the mean) may be considered to have growth failure. Growth velocity measurements are particularly useful to assess the nutritional effects of treatment. The majority of studies in the literature, however, have used height for age percentile as the initial definition of growth failure and changes in height percentile as the outcome measurement. The etiology of growth failure in children is not entirely clear and may well be multifactorial. The nutritional consequences of IBD discussed earlier could certainly contribute to poor growth, but these are usually operative during acute attacks of the disease, whereas growth failure is a chronic problem. One of the striking observations about Crohn’s disease in children is that growth failure often predates gastrointestinal symptoms by a year or more.65 In one study, 46% of children with Crohn’s disease had a decrease in height velocity before the onset of symptoms,66 which suggests the presence of a systemic factor. It is not uncommon for children who

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eventually develop Crohn’s disease to be referred to an endocrinologist for evaluation of short stature. Endocrine evaluation is invariably normal. Several studies have shown normal pituitary and adrenal function, and normal secretion of thyroid hormone, growth hormone and somatomedin.6,67,68 Thus, there is no evidence of an endocrine basis for growth failure in Crohn’s disease. Corticosteroids are a mainstay of therapy for moderate to severe Crohn’s disease and have well known antianabolic properties. Long term treatment with high dose corticosteroids may contribute to growth failure,69 but patients who require high dose therapy are more likely to have severe disease and poor nutrition, and it is not clear that corticosteroid use is an independent variable. Most patients are treated with relatively low dose and/or alternate day steroids which are less likely to impair growth.70,71 Motil et al found no association between corticosteroid use and rates of protein synthesis or breakdown20 The most likely explanation for growth failure is inadequate nutrition. Several balance studies have shown that children with Crohn’s disease and growth failure spontaneously take in only 50-80% of their estimated caloric requirements.6,67,72 Some studies also suggest that energy expenditure may be higher than normal in these children which would further compound the effect of poor intake.73 It is particularly difficult for adolescents to eat enough to achieve normal pubertal growth rates. The most convincing evidence that inadequate intake is responsible for growth failure is the excellent response to caloric supplementation which has been documented in numerous studies. Layden et al first demonstrated enhanced growth in children with Crohn’s disease using bowel rest and total parenteral nutrition for 4-6 weeks.73 Kelts et al67 and Strobel et al74 also reported increased growth velocity during TPN. Some, but not all, of these children had continued improved growth for up to a year after TPN was stopped. Subsequent studies by Morin et al,75 Kirschner et al72 and Motil et al20 have shown that the same result can be achieved using enteral supplementation. Dietary counseling and the use of high calorie snacks and liquid oral supplements may be sufficient to achieve adequate nutrition in some children. If growth is still not adequate, administration of a defined formula diet at night through a nasogastric tube will usually work.76 Parenteral nutrition as primary treatment for growth failure should be reserved for children who have documented failure of enteral supplements. It is particularly important to attend to the nutritional needs of adolescents during the period of rapid growth and sexual maturation beginning at puberty. Permanent short stature may result if the epiphyses close before normal pubertal growth is complete. Small size and delayed appearance of secondary sex characteristics can be emotionally devastating to teenagers who are already struggling with the problems of chronic disease. Control of the disease by medical and/or surgical therapy and careful monitoring of caloric intake and growth rates are essential.

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Morbidity and mortality rates following major abdominal surgery are clearly higher in malnourished patients than in those who are nutritionally replete.77-79 Since many patients with inflammatory bowel disease have significant malnutrition, it is logical to assume that nutritional support in the perioperative period might decrease postoperative complications. Unfortunately, there are no prospective studies which examine the role of either preoperative or postoperative TPN in patients with IBD. Mullen, et al reported a retrospective series of general surgical patients with a variety

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of gastrointestinal conditions including some with IBD.80 Among patients who were malnourished preoperatively, the complication rate was significantly lower in those who had received at least 7 days of preoperative TPN.81 Other studies show no benefit from preoperative TPN.82,83 Most patients scheduled for elective surgery for IBD are only minimally malnourished, and there are no data to support preoperative TPN. Many patients come to surgery urgently after failure of medical therapy for acute exacerbation or complication of IBD and these patients often have a significant period of time with inadequate enteral intake of calories. TPN during this time may prevent or treat malnutrition and in turn reduce the morbidity of subsequent surgery.84 Whether surgery should be deferred to allow a period of preoperative TPN must be decided on an individual basis. Severely malnourished patients might benefit, but other patients may have worsening nutritional status from ongoing fever and loss of blood and protein from the gut.85 Routine postoperative TPN is not indicated, but it is appropriate to give TPN to patients who have moderate to severe malnutrition or whose postoperative course may be prolonged.86

Enterocutaneous Fistula Entero-enteral and entero-vesical fistulas are well known complications of Crohn’s disease as a result of chronic inflammation and transmural disease. Entero-cutaneous fistulas may occur spontaneously but are more common as a postoperative complication. Entero-cutaneous fistulas are much less common in ulcerative colitis and are almost always postoperative. Loss of fluid and electrolytes, rapid transit time, malabsorption and bypass of distal bowel all contribute to malnutrition in patients with fistulas, particularly fistulas from the proximal gastrointestinal tract. Wound healing is impaired in patients with moderate to severe malnutrition; the longer the fistula persists, the worse the malnutrition and the ever diminishing likelihood of spontaneous closure, in the absence of nutritional support. The devastating consequences of enterocutaneous fistulas were well described by Edmunds, et al, who reported a 63% rate of malnutrition and a 59% mortality rate in patients with enterocutaneous fistula from a variety of causes, including Crohn’s disease.87 Death is usually due to a combination of malnutrition and failed attempts at surgical closure of the fistula. Since the introduction of TPN, there has been considerable interest in the role of nutritional support in the management of patients with enterocutaneous fistulas, and early reports of spontaneous closure using TPN to restore and maintain normal nutritional status were encouraging.88-90 Various retrospective series of patients with fistulas from a spectrum of causes have shown spontaneous healing in 20-80% of patients treated with bowel rest and nutritional support, as reviewed by Meguid.91 The reported mortality in these series was 5-28%. However, there have been no prospective or randomized studies, so it is not known how much of the improvement compared with historical controls is a result of TPN and how much to other factors such as improved general care, ICU’s, newer antibiotics, etc. The results with enterocutaneous fistulas in inflammatory bowel disease have been less encouraging. The rate of spontaneous permanent closure of fistulas has ranged from 10-50%.26,29,32,80 This is perhaps not surprising since chronic inflammation and infection are well known impediments to healing. High dose intravenous steroids to treat active IBD may also interfere with healing. In the absence of prospective studies, it is not possible to draw firm conclusions about the treatment of enterocutaneous fistulas in IBD. Given the high incidence of

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malnutrition in these patients, it is imperative to provide some sort of nutritional support which can often be as an enteral elemental diet for distal small bowel or colonic fistulas, but usually should be as TPN and bowel rest for proximal fistulas. Whether nutritional support has a primary therapeutic benefit above and beyond its adjunctive role is uncertain. It seems reasonable to offer a short course(2-6 weeks) of nutritional support with or without bowel rest, combined with medical treatment of active disease and appropriate management of infection. If the fistula has not closed in that time, surgical treatment is usually indicated.

Short Bowel Syndrome and Home TPN A small but significant number of patients with Crohn’s disease(rarely ulcerative colitis) are nutritional cripples and become dependent on TPN. Some patients have intractable symptoms, non-closing fistulas, high output stomas or other complications of the disease, and are unable to eat because of symptoms or cannot maintain adequate nutrition with enteral feeding alone. Other patients have diffuse disease throughout the gastrointestinal tract and are poor candidates for operation. Still others have had multiple resections leaving them with short gut syndrome and chronic malnutrition. Prolonged TPN both in the hospital and at home may be life-saving for these unfortunate patients. In the large Home TPN Registry maintained by the Oley Foundation, Crohn’s disease is the second most common indication for home TPN, accounting for 17% of all patients through 1987.92 The reported experience with long-term TPN is similar to that already described for short to medium duration TPN, which is that the patients nutritional status improves, but the overall course of the disease is not changed. Fleming reported a small group of patients who had severe, intractable Crohn’s disease who were treated with home TPN for up to 17 months.93 Weight and albumin improved, but none of the patients achieved sustained remission. Strobel treated 17 adolescents with home TPN(2-12 months) for moderately severe Crohn’s disease and also found improved nutrition, including increased growth velocity and catch up growth in 10.74 One-third of the children had sustained remission of symptoms for a mean of 331 days, but the majority had persistence or relapse requiring ongoing medical or surgical treatment. More recently, the Cleveland Clinic group reported 41 patients with Crohn’s disease who were treated by bowel rest and home TPN for 1-8 years after failure of medical and surgical treatment.94 Nutritional status as measured by albumin and transferrin, improved in most patients as did quality of life scores. However, the frequency of operations did not change compared with the pre-TPN period, and the frequency of hospitalization actually increased, primarily due to complications related to the TPN. It is clear that TPN is effective in restoring and maintaining good nutrition but has little primary therapeutic benefit. Patients with severe IBD ultimately need definitive medical or surgical treatment of their disease, and a prolonged course of TPN hoping to avoid such treatment is probably fruitless. A modest course of treatment to replete a malnourished patient, to allow intra-abdominal inflammation to settle down, or to provide time to prepare the patient for operation may be useful but should not be prolonged unduly. Long-term home TPN is reserved for those few patients who have failed all conventional treatment or who are not candidates for surgery.

19

Summary Nutrition and inflammatory bowel disease are inextricably related. The nutritional requirements of these patients need constant attention. Micronutrient

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deficiencies are relatively common and require dietary supplementation. Macronutrient deficiency may lead to acute or chronic protein-calorie malnutrition, and increased morbidity and mortality. Growth failure is a particular problem in adolescent children. Nutritional support, either enteral or parenteral, is effective in treating or preventing malnutrition and is an essential part of management. Enteral nutrition is at least as effective as TPN to induce remission, maintain remission and to treat growth failure; it is also safer and less expensive, and protects the integrity of the intestinal mucosal barrier. There is no clear evidence for a primary therapeutic role for TPN in these patients; prolonged courses of bowel rest and TPN do not alter the ultimate course of the disease. Definitive medical or surgical treatment should be provided once the patient is nutritionally repleted and stable. Nutritional support is an important adjunct perioperatively and in the management of complications including enterocutaneous fistula and short bowel syndrome. Prolonged, potentially lifelong, TPN at home is lifesaving and provides a reasonable quality of life for patients with short bowel syndrome or whose disease is refractory to medical and surgical therapy.

Selected References 1. 2. 3. 4. 5. 6. 7. 8. 9. 10. 11. 12. 13. 14. 15. 16.

Dudrick SJ, Wilmore DW, Vars HM et al. Long-term total parenteral nutrition with growth, development, and positive nitrogen balance. Surgery 1968; 64(1):134-142. Wilmore DW, Dudrick SJ. Growth and development of an infant receiving all nutrients exclusively by vein. JAMA 1968; 203(10): 860-864. Driscoll Jr RH, Rosenberg IH. Total parenteral nutrition in inflammatory bowel disease. Med Clin North Am 1978; 62(1):185-201. Seidman E, LeLeiko N, Ament M et al. Nutritional issues in pediatric inflammatory bowel disease. J Pediatr Gastroenterol Nutr 1991; 12(4):424-438. Michener WM, Wyllie R. Management of children and adolescents with inflammatory bowel disease. Med Clin North Am 1990; 74(1): 103-117. Kirschner BS, Voinchet O, Rosenberg IH. Growth retardation in inflammatory bowel disease. Gastroenterology 1978; 75(3):504-511. Perkal MF, Seashore JH. Nutrition and inflammatory bowel disease. Gastroenterol Clin North Am 1989; 18(3):567-578. Beeken WL, Kanich RE. Microbial flora of the upper small bowel in Crohn’s disease. Gastroenterology 1973; 65(3):390-397. Gerson CD, Cohen N, Janowitz HD. Small intestinal absorptive function in regional enteritis. Gastroenterology 1973; 64(5):907- 912. Pena AS, Truelove SC. Hypolactasia and ulcerative colitis. Gastroenterology 1973; 64(3):400-404. Kirschner BS, DeFavaro MV, Jensen W. Lactose malabsorption in children and adolescents with inflammatory bowel disease. Gastroenterology 1981; 81(5):829-832. Fernandez-Banares F, Mingorance MD, Esteve M et al. Serum zinc, copper, and selenium levels in inflammatory bowel disease: effect of total enteral nutrition on trace element status. Am J Gastroenterol 1990; 85(12):1584-1589. Takagi Y, Okada A, Itakura T et al. Clinical studies on zinc metabolism during total parenteral nutrition as related to zinc deficiency. JPEN 1986; 10(2):195-202. Thomson ABR, Brust R, Ali MAM et al. Iron deficiency in inflammatory bowel disease-diagnostic efficacy of serum ferritin. Dig Dis 1978; 23(8):705-709. Florent C, L’hirondel C, Desmazures C et al. Intestinal clearance of a1-antitrypsin. Gastroenterology 1981; 81:777-780. McClain C, Soutor C, Zieve L. Zinc deficiency: a complication of Crohn’s disease. Gastroenterology 1980; 78(2):272-279.

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The Biology and Practice of Current Nutritional Support 17. 18. 19. 20. 21. 22. 23. 24. 25. 26. 27. 28. 29. 30. 31. 32. 33. 34. 35. 36. 37. 38. 39.

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Main ANH, Morgan RJ, Russell RI et al. Mg deficiency in chronic inflammatory bowel disease and requirements during intravenous nutrition. JPEN 1981; 5(1):15-1915. Beisel W. Effect of infection on human protein metabolism. Fed Proc 1966; 25:1682-1687. Barot LR, Rombeau JL, Steinberg JJ et al. Energy expenditure in patients with inflammatory bowel disease. Arch Surg 1981; 116:460-462. Motil KJ, Grand RJ, Maletskos CJ et al. The effect of disease, drug, and diet on whole body protein metabolism in adolescents with Crohn disease and growth failure. J Pediatr 1982A; 101(3):345-351. Chan AT, Fleming CR, O’Fallon WM et al. Estimated versus measured basal energy requirements in patients with Crohn’s disease. Gastroenterology 1986; 91(1):75-78. Summers RW, Switz DM, Sessions Jr JT et al. National cooperative Crohn’s disease study: results of drug treatment. Gastroenterology 1979; 77(4):847-869. Truelove SC, Jewell DP. Intensive intravenous regimen for severe attacks of ulcerative colitis. Lancet 1974:1067-1070. Rhodes J, Rose J. Does food affect acute inflammatory bowel disease? The role of parenteral nutrition, elemental and exclusion diets. Gut 1986; 27:471-474. Greenberg G, Haber G, Jeejeebhoy K. Total parenteral nutrition(TPN) and bowel rest in the management of Crohn’s disease. Gut 1976; 117:828. Ostro MJ, Greenberg GR, Jeejeebhoy KN. Total parenteral nutrition and complete bowel rest in the management of Crohn’s disease. JPEN 1985; 9(3):280-287. Fischer JE, Foster GS, Abel RM et al. Hyperalimentation as primary therapy for inflammatory bowel disease. Am J Surg 1973; 125:165-175. Anderson DL, Boyce Jr HW. Use of parenteral nutrition in treatment of advanced regional enteritis. Am J Dig Dis 1973; 18(8):633-640. Vogel CM, Corwin TR, Baue AE et al. Intravenous hyperalimentation. Arch Surg 1974; 108:460-467. Reilly J, Ryan JA, Strole W et al. Hyperalimentation in inflammatory bowel disease. Am J Surg 1976; 131:192-200. Harford Jr FJ, Fazio VW. Total parenteral nutrition as primary therapy for inflammatory disease of the bowel. Dis Colon Rectum 1978; 21(8):555-557. Elson CO, Layden TJ, Nemchausky BA et al. An evaluation of total parenteral nutrition in the management of inflammatory bowel disease. Dig Dis Sci 1980; 25(1):42-48. Seashore JH, Hillemeier AC, Gryboski JD. Total parenteral nutrition in the management of inflammatory bowel disease in children: a limited role. Am J Surg 1982; 143:504-507. Shiloni E, Coronado E, Freund HR. Role of total parenteral nutrition in the treatment of Crohn’s disease. Am J Surg 1989; 157:180-184. Whittaker JS. Nutritional therapy of hospitalized patients with inflammatory bowel disease. Dig Dis Sci 1987; 32(12):89S-94S. Muller JM, Keller HW, Erasmi H et al. Total parenteral nutrition as the sole therapy in Crohn’s disease—a prospective study. Br J Surg 1983; 70:40-43. Dickinson RJ, Ashton MG, Axon ATR et al. Controlled trial of intravenous hyperalimentation and total bowel rest as an adjunct to the routine therapy of acute colitis. Gastroenterology 1980; 79(6):1199-1204. Payne-James JJ, Silk DBA. Total parenteral nutrition as primary treatment in Crohn’s disease - RIP? Gut 1988; 29:1304-1308. Culpepper-Morgan JA, Floch MH. Bowel rest or bowel starvation: defining the role of nutritional support in the treatment of inflammatory bowel disease. Am J Gastroenterol 1991; 86(3):269-271.

Nutrition Support in Inflammatory Bowel Disease 40. 41. 42. 43. 44. 45. 46. 47. 48. 49. 50. 51. 52. 53. 54. 55. 56. 57. 58. 59. 60. 61.

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Johnson, LR, Copeland, EM, Dudrick, SJ et al. Structural and hormonal alterations in the gastrointestinal tract of parenterally fed rats. Gastroenetrology 1975; 68(5):1177-1183. O’Dwyer, ST, Smith, RJ, Hwang, TL and Wilmore, DW. Maintenance of small bowel mucosa with glutamine-enriched parenteral nutrition. J Parenteral Enteral Nutr; 13(6):579-585. Wilmore DW, Smith RJ, O’Dwyer ST et al. The gut: a central organ after surgical stress. Surgery 1988; 104(5):917-923. Burke, DJ, Alverdy, JC and Moss, GS. Glutamine-supplemented total parenteral nutrition improves gut immune function. Arch Surg; 124(12):1396-1399. O’Morain C, Segal AW, Levi AJ. Elemental diets in treatment of acute Crohn’s disease. Brit Med J 1980; 281:1-7. Morin CL, Roulet M, Roy CC et al. Continuous elemental enteral alimentation in the treatment of children and adolescents with Crohn’s disease. JPEN 1982; 6(3):194-199. O’Morain C, Segal AW, Levi AJ. Elemental diet as primary treatment of acute Crohn’s disease: a controlled trial. Br Med J 1984; 288:1859-1862. Saverymuttu S, Hodgson HJF, Chadwick VS. Controlled trial comparing prednisolone with an elemental diet plus non-absorbable antibiotics in active Crohn’s disease. Gut 1985; 26:994-998. Sanderson IR, Udeen S, Davies PSW et al. Remission induced by an elemental diet in small bowel Crohn’s disease. Arch Dis Child 1987; 61:123-127. Jones VA. Comparison of total parenteral nutrition and elemental diet in induction of remission of Crohn’s disease: Long-term maintenance of remission by personalized food exclusion diets. Dig Dis Sci 1987; 32(12):100S-107S. O’Keefe SJD, Ogden J, Rund J et al. Steroids and bowel rest versus elemental diet in the treatment of patients with Crohn’s disease: the effects on protein metabolism and immune function. JPEN 1989; 13(5):455-460. Giaffer MH, North G, Holdworth CD. Controlled trial of polymeric versus elemental diet in treatment of active Crohn’s disease. Lancet 1990; 335:816-819. Cravo M, Camilo ME, Correia JP. Nutritional support in Crohn’s disease: which route? Am J Gastroenterol 1991; 86(3):317- 321. Teahon K, Bjarnason I, Pearson M, Levi A. Ten years experience with an elemental diet in the management of Crohn’s disease. Gut 1990; 31:1133-1137. Greenberg GR, Fleming CR, Jeejeebhoy KN et al. Controlled trial of bowel rest and nutritional support in the management of Crohn’s disease. Gut 1988; 29:1309-1315. Teahon K, Smethurst P, Pearson M et al. The effect of elemental diet on intestinal permeability and inflammation in Crohn’s disease. Gastroenterology 1991(101):84-89. Levenstein S, Prantera C, Luzi C et al. Low residue or normal diet in Crohn’s disease: a prospective controlled study in Italian patients. Gut 1985; 26:989-993. Heaton KW, Thornton JR, Emmett PM. Treatment of Crohn’s disease with an unrefined-carbohydrate, fibre-rich diet. Br Med J 1979; 2:764-766. Ritchie JK, Wadsworth J, Lennard-Jones JE et al. Controlled multicentre therapeutic trial of an unrefined carbohydrate, fibre rich diet in Crohn’s disease. Br Med J 1987; 295:517-520. Jones VA, Workman E, Freeman AH et al. Crohn’s disease: maintenance of remission by diet. Lancet 1985:177-180. Riordan A, Hunter J, Crampton J et al. Treatment of active Crohn’s disease by exclusion diet: East Anglian multicentre controlled trial. Lancet 1993; 342:1131-1134. Gryboski JD, Sprio HM. Prognosis in children with Crohn’s disease. Gastroenterology 1978; 74(5):807-8917.

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The Biology and Practice of Current Nutritional Support 62. 63. 64. 65. 66. 67. 68. 69. 70. 71. 72. 73. 74. 75. 76. 77. 78. 79. 80. 81. 82.

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Berger M, Gribetz D, Korelitz BI. Growth retardation in children with ulcerative colitis: the effect of medical and surgical therapy. Pediatrics 1975; 55(4):459-467. Markowitz J, Grancher K, Rosa J et al. Growth failure in pediatric inflammatory bowel disease . J Pediatr Gastroenterol Nutr 1993; 16(4):373-380. Falkner F, Tanner J. Human Growth. New York: Plenum PRESS; 1978; V.2,p 144. McCaffery TD, Nasr K, Lawrence AM et al. Severe growth retardation in children with inflammatory bowel disease. Pediatrics 1970; 45(3):386-393. Kanof ME, Lake AM, Bayless TM. Decreased height velocity in children and adolescents before the diagnosis of Crohn’s disease. Gastroenterology 1988; 95(6):1523-1527. Kelts DG, Grand RJ, Shen G et al. Nutritional basis of growth failure in children and adolescents with Crohn’s disease. Gastroenterology 1979; 76(4):720-727. Braegger CP, Torresani T, Murch SH et al. Urinary growth hormone in growthimpaired children with chronic inflammatory bowel disease. J Pediatr Gastroenterol Nutr 1993; 16(1):49-52. Blodgett FM, Burgin L, Iezzoni D et al. Effects of prolonged cortisone therapy on the statural growth , skeletal maturation and metabolic status of children. N Engl J Med 1956; 254(14):636- 641. Sadeghi-Nejad A, Senior B. The treatment of ulcerative colitis in children with alternate-day corticosteroids. Pediatrics 1969; 43(5):840845. Whittington PF, Barnes V, Bayless TM. Medical management of Crohn’s disease in adolescence. Gastroenterology 1977; 72(6):1338-1344. Kirschner BS, DeFavaro MV, Jensen W. Lactose malabsorption in children and adolescents with inflammatory bowel disease. Gastroenterology 1981; 81(5):829-832. Layden T, Rosenberg J, Nemchausky et al. Reversal of growth arrest in adolescents with Crohn’s disease after parenteral alimentation. Gastroenterology 1976; 70(6):1017-1021. Strobel CT, Byrne WJ, Ament ME. Home parenteral nutrition in children with Crohn’s disease: an effective management alternative. Gastroenterology 1979; 77(2):272-279. Morin CL, Roulet M, Roy CC et al. Continuous elemental enteral alimentation in children with Crohn’s disease and growth failure. Gastroenterology 1980; 79(6):1205-1210. Belli DC, Seidman E, Bouthillier L et al. Chronic intermittent elemental diet improves growth failure in children with Crohn’s disease. Gastroenterology 1988; 94(3):603-610. Studley HO. Percentage of weight loss - a basic indicator of surgical risk in patients with chronic peptic ulcer. Nutr Int 1936; 106:458-460. Thomas L, Robert D. Nutritional status and body composition in critically ill patients. Correlation between results and mortality. Am J Clin Nutr 1979; 32:510-511. Seltzer M, Slocum B, Cataldi-Betcher E et al. Instant Nutritional Assessment: Absolute Weight Loss and Surgical Mortality. J Parenteral Enteral Nutr 1982; 6(3):218-221. Mullen JL, Hargrove WC, Dudrick SJ et al. Ten years experience with intravenous hyperalimentation and inflammatory bowel disease. Ann Surg 1979; 187(5):523-529. Mullen JL, Buzby GP, Matthews DC et al. Reduction of operative morbidity and mortality by combined preoperative and postoperative nutritional support. Ann Surg 1978; 192(5):604-613. Higgens CS, Keighley MRB, Allan RN. Impact of preoperative weight loss and body composition changes on postoperative outcome in surgery for inflammatory bowel disease. Gut 1984; 25:732-736.

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Lashner BA, Evans AA, Hanauer SB. Preoperative total parenteral nutrition for bowel resection in Crohn’s disease. Dig Dis Sci 1989; 34(5):741-746. Dempsey DT, Mullen JL, Buzby GP. The link between nutritional status and clinical outcome: can nutritional intervention modify it? Am J Clin Nutr 1988; 47352-356. Werlin SL, Grand RJ. Severe colitis in children and adolescents: diagnosis, course, and treatment. Gastroenterology 1977; 73(4):828-832. Rombeau JL, Barot LR, Williamson CE et al. Preoperative total parenteral nutrition and surgical outcome in patients with inflammatory bowel disease. Am J Surg 1982; 143:139- 143. Edmunds Jr LH, Williams GM, Welch CE. External fistulas arising from the gastrointestinal tract. Ann Surg 1960; 152(3): 445-466. Chapman R, Foran R, Dunphy JE. Management of intestinal fistulas . Am J Surg 1964; 108:157-164. MacFayden BV, Dudrick SJ, Ruberg RL. Management of gastrointestinal fistulas with parenteral hyperalimentation. Surgery 1973; 74(7):100-105. Eisenberg HW, Turnbull Jr RB, Weakley FL et al. Hyperalimentation as preparation for surgery in transmural colitis (Crohn’s disease). Dis Colon Rectum 1974; 17(4):469-475. Meguid MM, Campos AC, Hammond WG. Nutritional support in surgical practice: part II. Am J Surg 1990; 159:427-443. Howard L, Heaphey L, Fleming CR et al. Four years of North American Registry home parenteral nutrition outcome data and their implications for patient management. JPEN 1991; 15(4):384-393. Fleming CR, McGill DB, Berkner S. Home parenteral nutrition as primary therapy in patients with extensive Crohn’s disease of the small bowel and malnutrition. Gastroenterology 1977; 73(5): 1077-1081. Galandiuk S, O’Neill M, McDonald P et al. A century of home parenteral nutrition for Crohn’s disease. Am J Surg 1990; 159:540-545.

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CHAPTER 20

Nutrition Support of Acute Pancreatitis Rifat Latifi, Stanley J. Dudrick

Introduction Acute pancreatitis ranges in severity from a minimal edematous in-flammation, which usually resolves spontaneously and completely, to a fulminant process that can progress to an often fatal, necrotizing hemorrhagic pancreatitis. Mild forms of pancreatitis are manifested by abdominal pain, nausea, vomiting, and anorexia and may be confused with many other gastrointestinal disorders. About l0-20% patients with acute pancreatitis develop severe necrotizing pancreatitis, which is characterized by profound hemodynamic, cardiovascular, pulmonary, renal, hematologic, and metabolic aberrations and is associated with high mortality.1,2 Total parenteral nutrition (TPN) and metabolic support are essential in patients with severe acute pancreatitis and should be started as soon as possible when the patient has developed more than two of Ranson’s prognostic criteria. When prescribing nutrient substrates in acute pancreatitis, consideration must be given to their specific effects on pancreatic enzyme secretion, as well as their general effects on nutritional and metabolic homeostasis. This chapter deals with the pathophysiology of acute pancreatitis including the effects of alcohol, biliary disease, oxygen-derived free radicals, and the role of pancreatic ischemia in inducing acute pancreatitis. Furthermore, associated metabolic changes, nutritional support with TPN as an essential component of the care of these patients, and rationales for the use of TPN, as well as the effects of the nutrient substrates in this disorder are elaborated.

Pathophysiology of Acute Pancreatitis A variety of factors can predispose a patient to acute pancreatitis. Depending on the population studied, a history of alcohol abuse and biliary tract disease is found in 80-90% of patients with acute pancreatitis. In addition to these primary causes of acute pancreatitis, other operative, traumatic, metabolic, infectious, and pharmacologic factors have been implicated in the pathogenesis of this disease (Table 20.1). The mechanism by which these multiple factors initiate and sustain pancreatic inflammation have not been established. It is apparent, however, that pancreatic enzymes are activated from within the pancreas and are released into the interstitium of the pancreas, leading to the subsequent autodigestion of the gland, which may have devastating effects on its function. The activated pancreatic enzymes subsequently enter the bloodstream and leak into the peripancreatic tissue producing characteristic fat necrosis and exudation. Activation and release of proteolytic enzymes (trypsinogen, chymotrypsinogen, proelastase, and phospholipase A) are stimulated by a variety of factors, such as endotoxins, exotoxins, ischemia, anoxia, trauma, The Biology and Practice of Current Nutritional Support, 2nd Edition, edited by Rifat Latifi and Stanley J. Dudrick. ©2003 Landes Bioscience.

Causes of acute pancreatitis

Nutritional and Metabolic

Operative, Traumatic, Obstructive

Infectious

Drugs

Others

Alcohol ingestion Biliary tract disease Hypertriglyceridemia Tropical pancreatitis Hypercalcemia Hyperparathyroidism Renal failure Fatty liver of pregnancy Biliary sludge

Intra-abdominal operations ERCP Biopsy of pancreas Kidney transplant Abdominal trauma (open or blunt) CABG Translumbar aortography Neoplastic obstruction of ampulla of Vater Crohn’s disease Duodenal diverticulum Penetrating peptic ulcer Pancreatic divisum Gastrostomy tube Foreign body in the duodenum

Mumps Viral hepatitis Coxsackie Virus Echovirus Ascariasis Mucoplasma Rotavirus

Steroids Azathioprine Thiazides Estrogens Tetracycline Valproic acid Chlorthalidone Ethacrynic acid Procainamide L-asparaginase Sulfamethoxaz ole-Trimethoprin Oleic acid

Idiopathic Systemic lupus erythematosus Necrotizing angiitis Thrombocytopenic purpura Vascular disease (mesenteric thrombosis) Hereditary Food allergy

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Table 20.1.

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viral infections, lysomal hydrolases, etc. Trypsin activates all of the pancreatic zymogens that participate in autodigestion, which starts with erosion of the cellular membranes and may end with extensive destruction of pancreatic tissue. It appears, at least in experimental pancreatitis, that the secretion of zymogen granules is blocked in individual acinar cells.3 In turn, this blockade results in the fusion of zymogen granules with intracellular lysosomes. Consequently, lysosomal enzymes activate the zymogen proenzyme trypsinogen, yielding active intracellular trypsin which is capable of cellular autodigestion.4 The findings of acinar cell zymogen granule enlargement and the formation of large auto-phagosomes during acute pancreatitis were confirmed by pathologic examination of human tissue by electron microscopy.3 The constellation of morphologic changes in acute pancreatitis may include interstitial edema, proteolysis, vascular damage with pancreatic hemorrhage, fat necrosis, and parenchymal necrosis. The ultimate consequences may be abscess formation, infection, sepsis, and pancreatic failure, which can progress to multiple organ systems failure and death.

Alcohol and Biliary Disease Many theories have been proposed to explain the cause and progression of acute pancreatitis. Alcohol, the major cause of acute pancreatitis, is thought to induce pancreatic enzyme secretion by way of chlorhydric-acid-induced secretin release and increased ampullary sphincter tone. Alcohol is thought to cause pancreatitis by: a. pancreatic enzyme extravasation, which is facilitated by an increase in pancreatic ductal permeability during exocrine hypersecretion and partial ampullary obstruction; b. protein plugging of a pancreatic duct, which may initiate extravasation and injury; and c. transient hypertriglyceridemia. Toxic levels of free fatty acids released from the lipolysis of triglycerides may damage acinar cells or induce endothelial injury. The mechanism by which biliary tract disease causes pancreatitis is not clear. Recent experiments in animals suggest that pancreatic duct obstruction is the critical event that triggers acute pancreatitis in the opossum, however, bile duct obstruction alone or the reflux of bile into the pancreatic duct are important determining factors in the development of acute pancreatitis.5 Furthermore, bile reflux into the pancreatic duct, via a common biliopancreatic channel, is not necessary for the development of pancreatitis and does not worsen the severity of pancreatitis associated with pancreatic duct obstruction.5

Oxygen-Derived Free Radicals The cellular and molecular mechanisms involved in the actual pancreatic injury and extrapancreatic organ involvement are unknown. Regardless of experimental models of acute pancreatitis (gallstones, ischemia, or alcohol), endothelial injury and increased capillary permeability have been documented. Alterations in the pancreatic microvasculature have been attributed to increased activity of oxygen-derived free radical activity. These unstable but highly reactive toxic metabolites of molecular oxygen have wide-ranging effects on cells and tissues, including peroxidizing lipids, denaturing enzymes and proteins, and accelerating tryptic activity. The effects of oxygen-free-radical activity, and inhibition with superoxide dismutase, were examined recently in experimental pancreatitis.6 In this study, chemiluminescence (a phenomenon based on emission of light during chemical reactions that

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depends on oxygen-free-radical activity) was used as an index of oxygen-free-radical activity. Rats treated with superoxide dismutase, the activity of which depends on scavenging free radicals, after induction of severe hemorrhagic pancreatitis with sodium taurocholate, had significantly reduced chemiluminescence and hyperamylasemia. Increased oxygen-free radical activity paralleled evolving pancreatitis, and superoxide dismutase was thought to have a therapeutic role in pancreatitis. Whether superoxide dismutase will induce the same effects if administered systemically remains to be seen. However, when experimental pancreatitis was induced in dogs by the intraductal infusion of activated trypsin and taurocholate, pretreatment with catalase and superoxide dismutase prevented the rise in mean blood pressure, moderated the rise in pulmonary vascular resistance, and decreased the rate and extent of the fall in cardiac index.7 Furthermore, with an ex vivo blood-perfused canine lung lobe, the lung injury induced by α-chymotrypsin was significantly attenuated by pretreatment with a combination of the reactive oxygen scavengers, superoxide dismutase and catalase.8 However, pretreatment of the lobe with superoxide dismutase alone did not protect the lobe from α-chymotrypsin-induced injury in this study.8 The data suggest that reactive oxygen metabolites may play some role in extra-abdominal organ manifestations, such as early cardiopulmonary changes of acute pancreatitis, in addition to local effects.

Pancreatic Ischemia in Experimental Acute Pancreatitis Necrosis of pancreatic and peripancreatic tissue is a key factor in the evolution of pancreatitis from mild to severe. The question as to whether necrotizing injury is caused by enzymes or ischemia is receiving more and more attention.9 That ischemia is the initiating or aggravating factor in acute pancreatitis is well documented. Hemorrhagic-necrotizing pancreatitis has been produced with intra-arterial injection of 8 µm to 20 µm microspheres that irreversibly obstruct terminal arterioles. On the other hand, obstruction of larger, more proximal vessels results only in pancreatic edema.10 Furthermore, ischemia superimposed on pancreatic edema leads to necrotizing pancreatitis. The relationship between splanchnic hypoperfusion and acute pancreatitis has been identified,11 and changes in pancreatic microcirculation during acute pancreatitis are well documented.9 These specific disturbances of pancreatic microcirculation are characterized by heterogeneous and low capillary blood flow and increased blood viscosity. Possible contributory mechanisms for these changes include chemical-induced vasoconstriction, injury to a vessel wall, intravascular coagulation, and increased endothelial permeability resulting in pancreatic edema, hemoconcentration, and impaired venous drainage. Protecting the pancreas from secondary injury caused by the early ischemic phase of acute pancreatitis, or correcting existing changes in microcirculation by restoring volume with a dextran preparation and increasing pancreatic perfusion, may prove to be the indicated treatment at the early stages of this potentially fatal disease.9

Metabolic Changes and Other Complications in Acute Pancreatitis Regardless of the cause and mechanism of acute pancreatitis, a broad spectrum of systemic disturbances can ensue secondary to circulating hydrolytic enzymes and toxins, compounding the severity of local or regional disturbances (Table 20.2). Local activation of inflammatory cells may result in the systemic release of inflammatory mediators that not only relate to the severity of the pancreatitis, but that can

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Table 20.2.

Potential complications of acute pancreatitis Systemic METABOLIC Hypoproteinemia Hypoalbuminemia Hyperglycemia Hypertriglyceridemia Hypocalcemia Hypomagnesemia Hyperamylasemia Hyperlipasemia Hyperbilirubinemia Abnormal liver function Pancreatic encephalopathy Fat necrosis Decreased BCAA/AAA ratio CARDIOVASCULAR Hypotension Hypovolemia Sudden death Nonspecific ST-T changes in electrocardiogram simulating myocardial infarction Pericardial effusion

PULMONARY Pleural effusion Atelectasis Pneumonitis Mediastinal abscess Adult respiratory distress syndrome RENAL Oliguria Azotemia Renal artery and/or renal vein thrombosis HEMATOLOGIC Anemia Thrombocytopenia Disseminated intravascular coagulopathy CNS Psychosis Fat emboli

The Biology and Practice of Current Nutritional Support

Local and Regional Pancreatic phlegmon Pancreatic abscess Pancreatic pseudocyst Pain Rupture Hemorrhage Obstruction of GI tract (stomach, duodenum, colon) Paralytic ileus Pancreatic ascites Disruption of main pancreatic duct Leaking pseudocyst Involvement of contiguous organs by necrotizing pancreatitis Massive intraperitoneal hemorrhage Thrombosis of blood vessels Bowel infarction Common bile duct obstruction

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subsequently influence gut permeability. Among the inflammatory products identified in early pancreatitis, granulocyte elastase and interleukin 6 (IL-6) correlate best with severity of pancreatitis and mortality of the disease.12 These products and other mediators, such as interleukin-1, tumor necrosis factor (TNF), or histamine, may directly or indirectly alter gut permeability by damaging intestinal mucosa. Increased gut macromolecular permeability in early acute pancreatitis has recently been documented and also correlates with the extent of injury in patients with burns.13,14 Furthermore, a direct relationship between gut permeability and the severity of pancreatitis has also been shown, although the clinical implications of enhanced gut permeability in this disease is still ill-defined. The gut permeability that was seen only in the presence of pancreatitis was thought to be a response to changes in homeostasis or to the acute inflammatory reaction initiated by the pancreas. Although acute pancreatitis originates locally, extensive tissue destruction may generate profound systemic metabolic derangements, adversely affecting multiple organ systems accompanied by hemodynamic and cardiovascular changes. Acute pancreatitis induces hypermetabolism with increased protein hypercatabolism. Often, this disease occurs in patients with severe nutritional depletion secondary to extensive alcohol intake, chronic liver or biliary tract disease, and protein malnutrition. The increased metabolic rate further accelerates depletion of endogenous protein and fat stores. The severity of the metabolic disorders or nutritionally related complications correlates well clinically with the severity and duration of acute pancreatitis. Resting energy expenditure (as a percent of predicted energy expenditure) was significantly (p<.02) greater in patients with pancreatitis complicated by sepsis (120% ± 11%) than in patients with non-septic chronic pancreatitis (105% ± 14%).15 Patients with severe acute pancreatitis (more than three prognostic signs) had a mean energy expenditure of 126% to 149% of predicted energy compared with those having two or less prognostic signs (111% ± 15%) (p<.03).15 Patients with severe acute pancreatitis, defined by poor general physical condition, multiple organ systems failure, positive peritoneal signs, ascites, pancreatic enlargement with exudate confirmed by non-invasive imaging techniques (ultrasound, CAT scan or magnetic resonance imaging), and at least two abnormal clinical chemistries, usually present with significant metabolic alterations.16,17

Biochemical Abnormalities Patients with severe acute pancreatitis present with metabolic, cardiovascular, and hemodynamic features similar to those observed in sepsis. In addition to glucose intolerance, ureagenesis is increased, net protein catabolism is accentuated by 70%-80%, and in some patients with acute pancreatitis, net nitrogen losses increase to as much as 20 g to 40 g/day.18,19 Decreased levels of total plasma proteins and rapid turnover proteins, together with a marked decrease of the branched-chain amino acid/aromatic amino acid (BCAA/AAA) ratio, further illustrate a hypercatabolic state with significant protein breakdown. Significant decreases in plasma essential amino acids, with marked reductions of almost all amino acids in the liver and increased uptake of endogenous amino acids by the skeletal muscle mass, have been reported clinically and experimentally.17 Other biochemical abnormalities are also present and are considered to be useful indicators of the severity of acute pancreatitis. Gross elevations in plasma concentrations of the pancreatic enzymes usually accompany severe forms of the disease. However, although widely used in the clinical setting, the degree of elevation of plasma

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amylase does not correlate well with the degree of severity of acute pancreatitis.20 However, the ratio of the amylase clearance to the creatinine clearance has not been found to be reliable in diagnosing acute pancreatitis. Other enzymes that may be elevated in severe acute pancreatitis include plasma lipase, phospholipase A, elastase, trypsin, chymotrypsin, and acid catalase. Plasma levels of glucose, bilirubin, alkaline phosphatase, lactic dehydrogenase, and triglycerides become moderately to highly elevated as the severity of the disease increases. Increased plasma concentration of pancreas-specific protein (PASP) has been found in acute pancreatitis and offers some promise as a novel assay for pancreatic cellular damage.21 Recently, an acute-phase protein, the pancreatitis-associated protein (PAP), has been found to be increased at least l00-fold in pancreatic tissue during the acute phase in experimentally induced pancreatitis in rats.22 This new protein was first observed 6 hours after induction of experimental pancreatitis with taurocholate or cerulein, reached maximal levels at 48 hours, and disappeared during recovery (day 5). This molecule is synthesized on the rough endoplasmic reticulum and stored in zymogen granules before being secreted as are other pancreatic secretory proteins. Other substances produced by the pancreas are reported to be increased during acute pancreatitis. Among them, serum pancreatic phospholipase A2(PLA2), which is secreted by pancreatic acinar cells as an enzymatically inactive proenzyme (pro PLA2) but that is activated by trypsin, is significantly increased in patients with acute pancreatitis and in the active phase of chronic pancreatitis. This enzyme is also increased in patients in the early stage of pancreatic cancer; however in the terminal state of pancreatic cancer, the serum PLA2 level is low. An important biochemical abnormality resulting from acute pancreatitis is the depletion of intravascular albumin. Consequently, circulating protein-bound calcium decreases, precipitating hypocalcemia, which may be accompanied by increased plasma levels of parathormone and calcitonin.23 In addition, plasma magnesium levels decrease in patients with the more severe forms of acute pancreatitis. Other trace elements are depleted24 as a result of long standing secondary malnutrition and not primarily because of the pancreatitis itself.

Lung Injury Acute respiratory distress syndrome is a well recognized complication of acute pancreatitis. Although the mechanism of action is unknown, the effects of pancreatic elastase in pulmonary vascular injury has been suggested.25 Recent studies have found that circulatory pancreatic proteases (alpha-chymotrypsin) can cause acute lung injury that is mediated, at least in part, by toxic oxygen metabolites that are not of neutrophil origin.8 Elevated levels of free fatty acids or phospholipase associated with pulmonary surfactant destruction, which consequently leads to the development of atelectasis and fluid exudation, have been proposed as possible mechanisms of injury.26 Chymotrypsin may trigger proteolytic conversion of xanthine dehydrogenase into the oxygen radical-producing xanthine oxidase in pulmonary artery endothelial cells. Furthermore, alpha-chymotrypsin may stimulate radical oxygen metabolite production in pulmonary endothelial cells.8

Nutritional Management in Acute Pancreatitis The severity of acute pancreatitis depends on the action of elevated pancreatic enzymes associated with an inflammatory response of variable intensity that is

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mediated by the activation of proteolytic systems and inflammatory cells. The prevalence of specific nutritional deficiencies in patients with acute pancreatitis depends also on a number of other factors. Among them, the cause of the pancreatitis and the severity of the disease, combined with premorbid nutritional status are the most important. Because almost 80-90% of episodes of acute pancreatitis are short and self-limited, exceptional nutritional measures in these patients are rarely indicated. However, in those patients with severe pancreatitis who manifest more than two adverse prognostic factors27-30 (Table 20.3) at admission or who experience them subsequently during the first 48 hours of hospitalization, individualized nutritional support should be started as soon as possible. The current general therapeutic principles in the nutritional management of acute pancreatitis involve: aggressive nutritional support, essential to insure optimal provision of nutrient substrates, and reducing pancreatic exocrine secretion and maintaining the gastrointestinal tract and the pancreas “at rest.” Several reports have confirmed that total parenteral nutrition (TPN) has substantially reduced morbidity and mortality in this disease.31-35 In one series, TPN reduced mortality from 26.1% to 14%.33 In another study of 29 patients with moderate to severe pancreatitis, those receiving TPN had a mortality rate of 7% whereas those receiving only conventional intensive therapy but without TPN had a mortality rate of 45%.17 Yet others found no distinct advantage to the use of early TPN in acute pancreatitis as measured by the number of days before oral feeding was started, length of hospital stay, and number of complications.36 This failure to show an advantage of TPN early in the course of acute pancreatitis may be secondary to the study population and design, and perhaps the composition of TPN formula. Most of the patients had mild pancreatitis, which would resolve anyway, and in patients with fulminant pancreatitis and in those with multiple organ systems failure, nutritional support was not carefully and individually tailored. The high rate of catheter-related infections in this study was not explained. Recently, TPN was found to be beneficial in patients with complex metabolic alterations resulting from severe acute pancreatitis and in patients with underlying malnutrition, before or after surgical intervention.37 Thus, early aggressive nutritional support is strongly recommended in these subgroups of patients. This recommendation is based primarily on the potential benefits of TPN in acute pancreatitis, which include, among others, the preservation or restoration of nutritional status in patients who have not been fed for long periods, yet who are in a hypercatabolic state with increased caloric and nitrogen demands, and on the beneficial impact of TPN on the disease process by suppressing pancreatic secretion.

The Effects Of Nutrient Substrates The effects of specific nutrient substrates on the exocrine pancreas and the best route of their administration have been debated. Ingested nutrients stimulate exocrine pancreatic secretion by activating enterohepatic reflexes and enteral hormones and by directly affecting the pancreas. Total parenteral nutrition not only provides all the nutrients but bypasses the effects of enterohepatic reflexes and enteral hormones. Intravenous infusion of 20% dextrose or 30% dextrose and 12% amino acid solution significantly inhibited the secretion of secretin-pancreozymin stimulated pancreatic juice and amylase in dogs with chronic fistulas.38 Intravenous administration of some amino acids, individually or in combination, also depressed pancreatic exocrine secretions.38,39 Moreover, it is well known that free amino acids infused into the duodenum also decrease pancreatic secretion.

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Table 20.3.

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Factors adversely influencing survival in acute pancreatitis

I. At admission to hospital Age >55 years Hypotension Abnormal pulmonary findings Abdominal mass Hemorrhagic or discolored peritoneal fluid Increased serum LDH levels (> 350 IU/dL) SGOT >259 U/dL Leukocytosis (> l6,000/mm3) Hyperglycemia (>200 mg/dL, no diabetic history) Neurologic deficit (confusion localizing signs) II. During initial 48 h of hospitalization Fall in hematocrit > 10% with hydration and/or hematocrit <30% Necessity for massive fluid and colloid replacement Hypocalcemia (< 8 mg/dL) Arterial PO2 < 60 mm Hg with or without adult respiratory distress syndrome Hypoalbuminemia (< 3.2 g/dL) Base deficit > 4 mEq/L Azotemia

Inhibition of Pancreatic Secretion Somatostatin is considered to be the best inhibitor of pancreatic secretion, and its use in the treatment of acute pancreatitis, to directly inhibit pancreatic secretion, is becoming standard clinical practice. In a large multicenter study, somatostatin, when used with TPN, yielded the best results in a group of patients with necrotizing-hemorrhagic pancreatitis.40 In humans, somatostatin inhibits HCL-induced and alcohol-induced secretin secretion; inhibits cholecystokinin release; markedly inhibits pancreatic enzyme secretion; may reduce duodenal output of trypsin, chymotrypsin, and amylase by 65% to 90%; affects gut motility; slows gallbladder and gastric emptying rates; and reduces the sphincter of Oddi basal pressure.41 To suppress or neutralize pancreatic enzymes, the synthetic anti-proteases (gabexate mesilate and nafamostat mesilate) have also been used to treat acute pancreatitis. In a recent study, these two agents were useful in the treatment of experimental acute pancreatitis.42 The strongest depressant of pancreatic exocrine secretion, other than somatostatin and glucagon, is the infusion of hypertonic salts and dextrose into the jejunum. On the other hand, hydrochloric acid, meat extracts, antral distention, fat, protein, calcium, and magnesium all increase pancreatic exocrine secretion. In acute experimental pancreatitis, pancreatic exocrine secretion has been found to be suppressed.43 The secretory blockade was found in different models of acute pancreatitis and reflected the severity of the disease. Cholecystokinin-stimulated secretion was almost abolished in vivo and in vitro at the time of maximal histological damage.43 Clinical studies indirectly evaluating pancreatic secretory function indicated that pancreatic secretion is reduced in most patients between 3 and l0 days after the onset of pancreatitis,44 but secretions gradually improve in most patients after a few months, although, in patients with severe necrotizing pancreatitis, complete functional recovery may take more than one year.45 Because pancreatic secretion, especially pancreatic secretory response to cholecystokinin, is reduced during

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acute pancreatitis, experimentally and possibly clinically, this secretory blockade might, at least in part, explain why acute pancreatitis is not treated effectively by inhibiting secretion with atropine, cimetidine, glucagon, calcitonin, and somatostatin.41

Rationale for TPN in Acute Pancreatitis The indications for the use of TPN in severe acute pancreatitis are multiple and usually urgent.28,32,46,47 Not only may the nutritional status of these patients deteriorate rapidly, but prolonged ileus, respiratory and renal failure, severe metabolic aberrations, and multiple major surgical interventions will interfere with adequate oral or enteral feeding, further complicating existing malnutrition. Indeed, providing complete nutrient substrates via TPN while allowing pancreatic rest has been an effective modality of nutritional support and has reduced morbidity and mortality in these patients.48-50 Other investigators17,34 have concluded that the use of TPN in the treatment of acute severe pancreatitis has decreased complications, has effectively suppressed exocrine secretion, and has been an essential adjunct to conventional intensive care. Adequate nutrition provided parenterally not only promotes restoration of damaged pancreatic tissue, but enhances spontaneous closure of pancreatic fistulas,48,51 and stimulates and maintains immunocompetence, thus potentially improving the patient’s general condition before and after surgery. This will allow surgical treatment of late-stage complications, such as pseudocyst, pancreatic abscesses or fistulas.52 Additionally TPN bypasses the cephalic, gastric, and intestinal phases of pancreatic secretion, reducing by up to 50% the pancreatic acinar nuclear volume, cell volume, and synthetic activity and substantially reducing the basal pancreatic and proteolytic and bicarbonate secretions.28,53,54 If, on the other hand, the patient undergoes pancreatic debridement, surgeon should obtain long term gut access by placing a surgical jejunostomy or at least a naso-jejunal feeding tube, and start enteral feedings as soon as possible.

Dextrose and Amino Acids Intravenous nutritional formulations should be selected on the basis of the effects that the individual nutrient substrates have on pancreatic secretions. Each nutrient has a different specific effect and a different potency for stimulating the release of each peptide hormone. Intravenous hypertonic dextrose suppresses both the fluid volume and the proteolytic enzyme concentration of pancreatic secretion, an action attributed in part to increased serum osmolality. The effect of amino acids in suppressing pancreatic exocrine secretion is also well known. Even though patients with severe acute pancreatitis are metabolically similar to septic patients with significantly depressed uptake of the exogenous carbohydrate load, dextrose remains the nutrient of choice as the main energy source in acute pancreatitis. Patients with hemorrhagic necrotizing pancreatitis show persistent nitrogen loss with low intracellular glutamine concentrations in skeletal muscle,17 in addition to a marked decrease in the BCAA/AAA ratio that correlates inversely with the progression of the disease.38 Therefore, administering highly concentrated amino acid solutions, augmented with extra valine, isoleucine, alanine, and arginine, which are significantly decreased in plasma and tissue, has been recommended in the nutritional support of patients with severe acute pancreatitis.38 Nitrogen balance and amino acid profiles have also improved when metabolically stressed patients were given BCAA enriched solutions.55

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Lipids

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The use of intravenous lipids as an energy source during acute pancreatitis has been controversial.56 Although infused intravenous lipid emulsions may appear to be a safe and effective calorie source and may be helpful in acute pancreatitis compounded by severe lung failure and by an elevated pCO2, each patient must be closely monitored because fat infusion may aggravate pancreatitis in a significant number of patients.57 Intravenous fat administration has actually been identified as the cause of pancreatitis in a patient with Crohn’s disease being treated with lipidbased TPN, and patients receiving lipid-based TPN formulations have been known to have significantly elevated serum AST.56 A reduction in survival rate occurred in patients receiving lipid emulsion combined with dextrose compared with patients who received dextrose as their only energy source in the parenteral nutrition regimen.17 Lipid emulsions should be avoided in patients with acute pancreatitis and abnormal triglyceride metabolism . In laboratory animals with acute severe pancreatitis, studies with infused radioactive lipid emulsions have indicated that uptake of the emulsion with production of CO2 was slightly to moderately depressed, depending on the structure of the fatty acids.38 Others50 have suggested that excess free fatty acids damage capillary membranes and cause the consequent release of pancreatic enzymes, implying that elevated fatty acid levels may promote pancreatic exocrine secretion. Increased plasma triglyceride levels also cause acute pancreatitis. Another clear contraindication to the use of intravenous lipid emulsions as the major energy source in patients with acute pancreatitis is a lipid disorder (type I, IV and V hyperlipoproteinemia). Because intravenous lipids also significantly increase pancreatic output in the form of bicarbonate and protein concentrations,58 it appears that the best dietary formulation for patients with severe pancreatitis is a fat-free intravenous solution of crystalline amino acids and hypertonic dextrose to which appropriate daily requirements of electrolytes, vitamins, minerals and trace elements have been added.

Administration and Monitoring of TPN Total parenteral nutrition is administered continuously over 24 hours, with appropriate adjustments to infusion rate and nutrient concentration and composition.46 Conscientious and meticulous biochemical and hematologic monitoring of these patients is necessary to identify and promptly prevent and treat any renal failure, hepatic decomposition, or fluid, electrolyte and trace element imbalances that might accompany unrelenting disease. Restoring nitrogen balance has a striking beneficial influence on survival of the patient with severe pancreatitis, whereas failure to achieve nitrogen balance has been associated with a ten-fold increase in mortality (2.5% vs. 2l.4%, p<.0l).56 H2 receptor blockers should be added to the infusion in standard intravenous doses to thwart gastric secretion, and human insulin should be added as needed to control hyperglycemia. Both are compatible with TPN formulations. Patients with severe necrotizing hemorrhagic pancreatitis may require rather large amounts of insulin to maintain normal blood glucose levels, especially in the presence of uncontrolled infection, occult abscesses or frank sepsis, and diabetic ketoacidosis, alone or in combination. The preferred route of nutritional support depends on the acuity and severity of the disease, as well as an understanding of the physiology of pancreatic stimulation. While parenteral nutrition has become a standard component of therapy in the treatment of severe acute pancreatitis, enteral feedings, preferably immune-enhancing

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diets, should be used whenever possible. Enteral feeding may supply nutrients if the major responses to cephalic, gastric, and intestinal phases of pancreatic stimulation are bypassed by infusion distal to the duodenum. Significant increases in pancreatic secretions and protein output mediated by CCK-PZ stimulation are induced with intraduodenal infusion of elemental diets in dogs;59 therefore, intrajejunal feeding is the method of choice. However, small bowel obstruction, enteritis, entero-enteric and entero-cutaneous fistulas, or severe paralytic ileus often preclude enteral feeding in patients with severe pancreatitis. Maintenance of intestinal mucosal integrity and the gut mucosal barrier has been suggested as a potential benefit of enteral feeding.60 However, the most practical feeding method in patients with severe pancreatic inflammation, abscesses, and fistulas is TPN. Failure to reduce pancreatic stimulation and to reverse malnutrition as a major complication of severe acute pancreatitis may profoundly affect survival of these patients.56 Total parenteral nutrition should be continued until the symptoms abate, pancreatic encephalopathy and ileus resolve, and all serious metabolic derangements disappear. Only when enteral intake can maintain optimal nutrition without exacerbating the symptoms of pancreatitis should TPN be discontinued.

Selected References 1. 2. 3. 4. 5. 6. 7. 8. 9. 10. 11. 12. 13. 14.

Renner IG, Savage WT III, Pantoja JL et al. Death due to acute pancreatitis: a retrospective analysis of 405 autopsy cases. Dig Dis Sci 1985; 30:1005. Wilson C, Imrie CW, Carter DC. Fatal acute pancreatitis, Gut 1988; 29:782. Kloppel G, Dreyer T, Willemer S et al. Human acute pancreatitis: its pathogenesis in the light of immunocytochemical and ultrasound findings in acinar cells. Virch Arch (Pathol Anat) 1986; 409:791. Steer ML, Meldolesi. The cell biology of experimental pancreatitis. NEJM 1987; 316:144. Lerch MM, Salnja A, Kunzi M et al. Pancreatic duct obstruction triggers acute necrotizing pancreatitis in the opossum. Gastroent 1993; 104:853-861. Gough DB, Boyle B, Joyce W et al. Free radical inhibition and serial chemiluminescence in evolving experimental pancreatitis. Br J Surg 1990; 77:1256-1259. Chardavoyne R, Asher A, Bank S et al. Role of reactive oxygen metabolites in early cardiopulmonary changes of acute hemorrhagic pancreatitis. Dig Dis Scien 1989; 34:1581-1584. Toung JKT, Senda KJ, Rosenfeld BA et al. Lung injury produced by pancreatic proteases in dogs. Surgery 1992; 112:68-75. Klar E, Messmer K, Warshaw AL et al. Pancreatic ischaemia in experimental pancreatitis: mechanism, significance and therapy. Brit J Sur 1990; 77:1205-1210. Pfeffer RB, Lazzarini-Robertson A Jr, Safadi D et al. Gradation of pancreatitis, edematous through hemorrhagic, experimentally produced by controlled injection of microspheres into blood vessels in dogs. Surgery 1962; 51:764-769. Warshaw AL, O’Hara PJ. Susceptibility of the pancreas to ischemic injury in shock. Ann Surg 1984; 188:197-201. Leser HG, Gross V, Scheibenboger C et al. Elevation of serum interleukin-6 concentration precedes acute-phase response and reflects severity in acute pancreatitis, Gastroenterol 1991; 101:782-785. Ryan CM, Yarmush ML, Burkee JF et al. Increased gut permeability early after burns correlates with extent of injury. Crit Care Med 1992; 20:1508-1512. Ryan MC, Schmidt J, Lewandrowski K et al. Gut macromolecular permeability in pancreatitis correlates with severity of disease in rats. Gastroenterol 1993; 10:890-895.

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16. 17.

18. 19. 20. 21. 22. 23. 24. 25. 26. 27. 28. 29. 30. 31. 32. 33. 34. 35. 36. 37.

Dickerson RN, Wehe KL, Mullen JL et al. Resting energy expenditure in patients with pancreatitis. Crit Care Med 1991; 19:484-490. Di Carlo V, Nespoli A, Chiesa R et al. Hemodynamic and metabolic impairment in acute pancreatitis. World J Surg 1981; 5:329. Fujita H, Tanaka SH, Nakagawara G et al. Clinical and experimental evaluation of total parenteral nutrition in the treatment of acute pancreatitis. In: Tanaka T, Okada A, eds. Nutritional Support in Organ Failure. Amsterdam: Elsevier Science Publishers, 1990. Bouffard YH, Delafosse BX, Annat GJ et al. Energy expenditure during severe acute pancreatitis. JPEN 1989; 13:26. Shaw JHF, Wolf RR. Glucose, fatty acid, and urea kinetics in patients with severe pancreatitis. Ann Surg 1986; 406:665. Imrie CW, Wilson C. Systemic manifestations and the hematological and biochemical consequences of acute pancreatitis. In: Glager G and Ransom JHC, eds. Acute pancreatitis. Bailliere Tindall, 1988. Fernstad R, Pousette A, Carlstrom K et al. A novel assay for pancreatic cellular damage: Serum concentrations of pancreas-specific protein (PASP) in acute pancreatitis and other abdominal diseases. Pancreas 1990; 5:1:42-49. Klein V, Iovanna JL, Rohr G et al. Characterization of a rat pancreatic secretory protein associated with pancreatitis. Gastroenterol 1991; 100:775-782. Imrie CW, Allam BF, Ferguson JC. Hypocalcemia of acute pancreatitis: the effect of hypoalbuminemia. Current Medical Research and Opinion 1976; 4:101-116. William RB, Russel RM, Dutta SK. Alcoholic pancreatitis - patients at high risk of acute zinc deficiency. Am J Med 1979; 66:889-893. Lungarella G, Gardi C, De Santi MM et al. Pulmonary vascular injury in pancreatitis: evidence for a major role played by pancreatic elastase. Exp Mol Path 1985; 43:44-49. Guice KS, Oldham KT, Wolfe RR et al. Lung injury in acute pancreatitis: primary inhibition of pulmonary phospholipid synthesis. Am J Surg 1987; 153:54-61. Grant JP, James S, Grabowski V et al. Total parenteral nutrition in pancreatic disease. Ann Surg 1984; 200:627-631. Pitchumoni CS, Scheele GA. Interdependence of nutrition and exocrine pancreatic function. In: Go VLW, Dimagno EP, Gardner JD et al, eds. The pancreas: biology, pathobiology and disease, 2nd ed. New York: Raven Press 1993:449-473. Ranson JHC. Etiological and prognostic factors in human pancreatitis: a review, Am J Gastroenterol 1983; 77:663-668. Ranson JHC. Prognostication in acute pancreatitis. In: Glazer G, Ranson JHC, eds. Acute pancreatitis, Bailliere Tindal, 1988. Blackburn GL, Williams LF, Bistrian B et al. New approaches to the management of severe acute pancreatitis. Am J Surg 1976; 131:114-124. Copeland EM, Dudrick SJ. Intravenous hyperalimentation in inflammatory bowel disease, pancreatitis and cancer. Surg Ann 1980; 12:83-101. Feller JH, Brown RA, Toussaint GPM et al. Changing methods in the treatment of severe pancreatitis. Am J Surg 1974; 127:196-201. Funakoshi A, Yamada Y, Migita Y et al. Simultaneous determination of pancreatic phospholipase A2 and prophospholipase A2 in various pancreatic diseases. Dig Dis Scien 1993; 38;3: 502-506. Goodgame JT, Fischer JE. Parenteral nutrition in the treatment of acute pancreatitis: effect on complications and mortality. Ann Surg 1977; 186:651-658. Sax HC, Warner BW, Talanimi MA et al. Early total parenteral nutrition during acute pancreatitis: lack of beneficial effects. Am J Surg 1987; 153:117-124. Robin AP, Campbell R, Palani CK et al. Total parenteral nutrition during acute pancreatitis: clinical experience with l56 patients. World J Surg 1990; 14:572-579.

Nutrition Support of Acute Pancreatitis 38. 39. 40. 41. 42. 43. 44. 45. 46. 47. 48. 49. 50. 51. 52. 53. 54. 55. 56. 57. 58. 59. 60.

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Ohyanagi H, Usami M, Nishimatsu SH et al. Metabolic changes and their management in acute pancreatitis. In Tanaka T, Okada A, eds.. Nutritional support in organ failure. Amsterdam: Elsevier Science Publishers, 1990:351-363. Saitoh Y, Honda T, Matsuno S et al. Effect of eight amino acids on the exocrine and endocrine function. Tohoku J Exp Med 1979; 129:257-272. Ladas SD, Raptis SA. Conservative treatment of acute pancreatitis: the use somatostatin. Hepato-Gastroenterol 1992; 39:466-469. D’Amico D, Favia G, Biasiato R et al. The use of somatostatin in acute pancreatitis: results of a multicenter trial. Hepato-Gastroenterol 1990; 37:92-98. Dobosz M, Sledzinski Z, Babicki A et al. Synthetic antiproteases in acute pancreatitis. Mount Sinai J Med 1992; 59:43-46. Niederau C, Niederau M, Lüthen R et al. Pancreatic exocrine secretion in acute experimental pancreatitis. Gastroenterol 1990; 99:1120-1129. Mitchell CJ, Playforth MJ, Kelleher J et al. Functional recovery of exocrine pancreas after acute pancreatitis. Scand J Gastroenterol 1983; 18:5-8. Angelini G, Pederzoli P, Caliary et al. Long-term outcome of acute necrohemorrhagic pancreatitis. Digestion 1984; 30:131-137. Latifi R, McIntosh JK, Dudrick SJ. Nutritional management of acute and chronic pancreatitis. Surg Clin North Am 1991; 73:579-595. Mooton G, Pistorelli C, Fracastoro G et al. Role of complete parenteral treatment nutrition in acute pancreatitis. In: Hollender LF, ed. Controversies in Acute pancreatitis. Berlin: Springer-Verlag, 1982:293-296. Dudrick SJ, Wilmore DW, Steiger E et al. Spontaneous closure of traumatic pancreatoduodenal fistulas with total intravenous nutrition. J Trauma 1970; 10:542-553. Variam FP. Central vein hyperalimentation in pancreatic ascites. Am J Gastroenterol 1983; 78:178-181. White TT, Heinbach DM. Sequestrectomy and hyperalimentation in the treatment of hemorrhagic pancreatitis. Am J Surg 1976; 132:270-275. Rowlands BJ, Dudrick SJ. Nutritional support of the infected patient. In: Powanda MC, Canonica PG, ds. Infection: The Physiologic and Metabolic Responses of the Host. Amsterdam: Elsevier Science Publishers, 1981:359-397. MacFadyen BV, Dudrick SJ, Ruberg RL. Management of gastrointestinal fistulas with parenteral hyperalimentation. Surgery 1973; 74:100-105. Johnson LR, Schanbacher LM, Dudrick SJ et al. Effect of long-term parenteral feeding on pancreatic secretion and serum secretin. Am J Physiol 1977; 233:E524-E529. Paviat WA, Rodgers W, Cameron JL. Morphologic analysis of pancreatic acinar cells from orally fed and intravenously fed rats. J Surg Res 1975; 19:267-276. Havalo T, Shrouts E, Cerra F. Nutritional support in acute pancreatitis. Gastroenterol Clinic North Am 1989; 18:528-541. Sitzman FJ, Steinborn PA, Zinner MJ et al. Total parenteral nutrition and alternate energy substrates in treatment of severe acute pancreatitis. Surg Gyn Obstet 1989; 168:311-317. Leibowitz AB, O’Sullivan P, Iberti TJ. Intravenous fat emulsions and the pancreas: a review. Mount Sin J Med 1990; 59:38-42. Konturek SJ, Tasler J, Cieszkowski M et al. Intravenous amino acids and fat stimulation of pancreatic secretion. Am J Physiol 1979; 233:E 678-684. Wolfe BM, Keltner FM, Zkraminski DL. The effect of an intraduodenal elemental diet on pancreatic secretion. Surg Gyn Obstet 1975; 140:241-245. Deitch EA, Bridges RM. Effect of stress and trauma on bacterial translocation from gut. J Surg Res 1987; 42:536-.

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CHAPTER 21

Nutritional Management of Chronic Pancreatitis: Current Concepts Rifat Latifi, Paul G. Perch and Stanley J. Dudrick

Introduction Chronic pancreatitis is characterized histologically by progressive, destructive, irregular, and irreversible fibrosis of the pancreas. Ultimately, it is manifested by intermittent or persistent abdominal pain and signs and symptoms related to the loss of pancreatic exocrine and endocrine functions, including maldigestion and malabsorption, diarrhea, steatorrhea, and azotorrhea with subsequent muscle wasting, weight loss, and pancreatic diabetes. The recurrent inflammatory process results in constrictive fibrosis and destruction of pancreatic tissue, leading to a significant reduction of pancreatic cell mass. An anatomical and functional deterioration of the pancreas progresses with each recurrence of inflammation. The most prominent complaints are persistent dull epigastric pain radiating to the back particularly in the region of the upper lumbar vertebrae, accompanied by anorexia, nausea, vomiting and diarrhea that are intensified by eating. These unpleasant, uncomfortable and often recalcitrant signs and symptoms regularly result in the systemic complications of malabsorption and malnutrition, multiple operations, narcotic dependency, and associated debilitating psychological and social problems. In addition, chronic pancreatitis may be manifested by a number of well-recognized secondary complications such as common bile ductobstruction, gastric outlet or duodenal obstruction, pancreatic ductstones, strictures or obstruction, pancreatic pseudocysts, pancreatic fistulas, (pancreatico-pleural, pancreatico-enteric, pancreatico-cutaneous), portal vein thrombosis and splenic vein thrombosis.12 These serious conditions often indicate the need for complex surgical interventions, which further aggravate overall poor nutritional and metabolic status of these patients. Other less common complications associated with chronic pancreatitis include gastrointestinal bleeding, ascites, pleural effusion, development of carcinoma, retinal changes, metastatic fat necrosis, intermedullary calcification and parotid hypertrophy. Physiologic changes in gallbladder motility and CCK secretion are also associated with pancreatic insufficiency due to chronic pancreatitis.53 It has also been demonstrated that the chronic inflammatory process in chronic pancreatitis alters the distribution and function of immunocompetent peripheral blood lymphocytes.49 The pancreas has multiple important functions, treating a patient who has lost pancreatic function and has persistent and intractable abdominal pain represents a very difficult challenge for all involved. Correcting nutritional deficiencies and maintaining optimal nutritional and metabolic status for these patients is of utmost

The Biology and Practice of Current Nutritional Support, 2nd Edition, edited by Rifat Latifi and Stanley J. Dudrick. ©2003 Landes Bioscience.

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importance in achieving a favorable outcome. This chapter reviews current concepts in nutritional and metabolic support of patients with chronic pancreatitis, with special attention to the role of exogenous pancreatic enzyme administration for the optimal enhancement of digestion and absorption.

Etiologic and Risk Factors of Chronic Pancreatitis The most common cause of chronic pancreatitis is excessive and prolonged alcohol consumption (about 75% of all cases). The remaining 25% of patients with chronic pancreatitis have idiopathic, nutritional, hereditary, post-traumatic, congenital or metabolic etiologies.3 Among the metabolic initiating factors, hyperparathyroidism, hyperlipidemia, diabetes mellitus, and renal failure are the most common. Other less common conditions or etiologies which are known to induce chronic pancreatitis include pancreas divisum, cystic fibrosis, Ehlers-Danlos syndrome, vascular insufficiency, Crohn’s disease, and tuberculosis. The precise role of gallstones or dysfunction of the sphincter of Oddi in the etiology of chronic pancreatitis remain controversial but it appears at the least to be a significant collateral factor. Although many alcoholic patients also smoke, an independent and separate causal relationship between smoking and chronic pancreatitis may exist, especially in men. Other factors placing the patient at increased risk for chronic pancreatitis include protein deprivation, cyanogenetic glycosides in cassava and chronic cyanide toxicity (from smoking or cassava).1 Deficiencies of trace elements such as zinc, selenium, or copper may also play a role in the development of chronic pancreatitis. Regardless of the original cause of chronic pancreatitis, recurrent inflammation can lead to an obstructive process in the minor ducts. The morphologic changes observed at the microscopic level include acinar cell apoptosis, ductular proliferation and fibrosis. In addition the pancreatic ducts exhibit tortuosity and periductal fibrosis. These alterations are the suspected result of a defensive assault against elevated pancreatic duct pressures.58 Eventually, ductal obstruction leads to a generalized deleterious effect throughout the entire organ with atrophy of both the acinar and islet cells. The tissue remodeling that occurs appears to be correlated with the up regulation of the lectins, galectin-1 and galectin-3.59 However, these morphologic changes will only result in the clinical manifestation of pancreatic exocrine insufficiency if more than 90% of the gland has been destroyed and pancreatic lipase and trypsin output has decreased to less than 10% of normal.

Nutritional Deficiencies in Chronic Pancreatitis In pancreatic failure caused by chronic pancreatitis, incomplete digestion of nutrients secondary to deficiencies of proteolytic, lipolytic, and amylolytic enzymes occurs gradually but progressively. As dietary fat, protein, and vitamins are lost in the stool, full-blown malabsorption eventually occurs with diarrhea, steatorrhea, and azotorrhea. In normal individuals, fecal fat content does not change appreciably after the ingestion of a high-fat diet. In contrast, the patient with chronic pancreatitis may have normal fecal fat levels while consuming a normal-fat diet, but will have a high fecal fat level after ingesting a high-fat meal. Incomplete triglyceride digestion is generally believed to be the primary cause of steatorrhea and eventual weight loss. The patient with chronic pancreatitis may also reach a stage in which not only fat is lost in the stool, but also incompletely hydrolyzed proteins resulting in impaired visceral and skeletal protein synthesis and muscle wasting. Deficiencies of the fat soluble vitamins, A, D, E and K, are occasionally manifested as syndromes that

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include night blindness, osteomalacia, neuropathy and coagulopathy, respectively. Vitamin B12 malabsorption and its secondary hematologic and neurologic effects can occur secondary to deficiency of pancreatic protease, which is necessary to degrade the proteins bound to vitamin B12 R-binding protein. Deficiencies of other nutrients and essential minerals such as iron, magnesium, zinc, copper, and selenium also occur.4

Pancreatic Diabetes Although islet cells account for only1-2% of the total pancreatic cellular mass, this is ordinarily sufficient to maintain glucose homeostasis in the body. In chronic pancreatitis patients, qualitative changes occur with fibrotic infiltration into the islets of Langerhans, often splitting the islets into separate lobules.5-7 Fasting serum insulin levels in patients with chronic pancreatitis are normal to mildly elevated, whereas insulin release is reduced after glucose stimulation, indicating a depletion of insulin reserve. These effects on serum insulin levels have been hypothesized to be secondary not only to a decrease in islet cell mass, but also to fibrosis that adversely affects islet integrity by impairing local circulation and glucose diffusion. Beta cells exhibit more susceptibility to sclerotic changes than α cells.6 Studies to date have not demonstrated abnormalities in the function or number of δ cells in chronic pancreatitis. Abnormalities in glucose metabolism in chronic pancreatitis occur as a result of a combination of diminished production of endogenous insulin together with insulin resistance.8 Furthermore, new evidence also suggests that the insulin mediated reduction of the facilitative glucose transport protein GLUT2 is impaired in chronic pancreatitis and may also contribute to impaired glucose tolerance.48 The overall incidence of impaired glucose tolerance in chronic pancreatitis varies between 40-90%, yet overt diabetes develops in only 20-30% of these patients.9 The usual onset of apparent diabetes in patients with chronic pancreatitis occurs between 7 and 15 years after the initial diagnosis of pancreatitis. Pancreatic diabetes may not differ clinically from other forms of diabetes, but nonetheless has unique characteristics. Unlike other diabetics, chronic pancreatitis patients generally have low plasma cholesterol and lipid levels, especially if steatorrhea is pronounced. Furthermore, although regarded as insulin dependent, pancreatic diabetes has a number of metabolic characteristics that distinguish it from Type I diabetes. For example, long-term complications such as retinopathy and nephropathy are less frequent.10 Vasculitis also an infrequent finding in pancreatic diabetes. Keto-acidosis and diabetic coma occur only rarely, and when it occurs, the coma is usually hyperosmolar and nonketotic.

Diagnosis of Malabsorption in Chronic Pancreatitis A reduction in exocrine pancreatic cell mass results from the irreversible pancreatic fibrosis which occurs inevitably with chronic pancreatitis. Under normal conditions, the acinar cells synthesize pro-teolytic, lipolytic, and amylolytic enzymes that are secreted ultimately into the pancreatic ducts. However, small amounts of these pancreatic enzymes are secreted into the bloodstream when their intraductal passage has been partially or completely obstructed. As fibrosis progresses, the integrity of the pancreatic tissue is disrupted, and large amounts of these enzymes diffuse into the blood stream causing plasma amylase, lipase, and trypsin levels invariably to become elevated. However, in chronic pancreatitis the plasma pancreatic enzyme levels vary with the course and severity of the disease. The progressive destructive

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fibrosis of the gland eventually causes plasma enzyme levels to decrease as the number of remaining functioning acinar cells capable of secreting digestive enzymes is significantly reduced. During a relapse of chronic pancreatitis, the plasma enzyme levels often rise transiently, but rarely to the levels seen in acute pancreatitis. On the other hand, patients with chronic pancreatitis who have pseudocysts frequently present with elevated plasma enzyme levels. The two principal biochemical techniques for investigating exocrine pancreatic function in patients with pancreatic inflammation involve direct and indirect methods. Direct function tests measure the composition of pancreatic secretions (bicarbonate and enzymes) obtained by intubation of the duodenum either in the normal state or following a 90-minute intravenous infusion of secretin and cerulein.11 Demonstration of subnormal pancreatic enzymes or bicarbonate secretion is diagnostic of chronic pancreatitis, however, pancreatic cancer must be excluded. Indirect testing estimates the diminished digestive capability in pancreatic insufficiency by measuring plasma chymotrypsin and trypsin.12 These tests are able to demonstrate only severely decreased exocrine function, which is characteristic of late stages of chronic pancreatitis, but not early stages of the disease. Other measurements of intraluminal digestion such as stool examination for undigested meat fibers, or determining enzyme effectiveness by fecal fat quantitation or plasma amino acid levels following hormonal stimulation may also be useful in assessing pancreatic insufficiency.13 In general, if pancreatic function tests are carried out appropriately, they are reliable in documenting the severe exocrine insufficiency of chronic pancreatitis. For example, direct intubation of the duodenum has a sensitivity of 97% and a specificity of 98%.11 The 14C-triolein breath test has been shown to be sensitive and sufficiently specific to screen for fat malabsorption. More recently the cholesterol 13C-octanoate breath test has been introduced and offers unique possibilities. Unlike direct duodenal intubation, this new technique measures the overall functional level of lipase activity in the intestinal lumen.14 However, the relevance of these tests is greater in the management of mild or moderate cases of chronic pancreatitis, in which they can not only predict the necessity for supplemental enzyme therapy, but also stage the severity of the disease.12 Although the previously outlined studies are reliable in diagnosing chronic pancreatitis, none the less these procedures can be cumbersome, time consuming, unpleasant for patients and potentially dangerous.

Principles of Clinical Management of Chronic Pancreatitis Regardless of whether an episode of pancreatitis is an initial presentation of acute pancreatitis or an acute exacerbation of chronic pancreatitis, the preeminent symptom is usually a rather constant, severe, and unrelenting pain in the epigastrium and mid-abdomen that penetrates directly posterior to the vertebral column and is aggravated by oral ingestion. Postprandial abdominal pain is very common in chronic pancreatitis, and fear of pain may further contribute to reduction of food intake. Persistent anorexia, nausea, and vomiting will eventually lead to weight loss, as discussed earlier. The nutritional management of chronic pancreatitis depends on the stage of the disease. For critically ill patients in the acute phase, absolute restriction of all food intake is required in order to minimize and to prevent exacerbations of the disease by preventing stimulation of the gland. Nutrients should be supplied by total parenteral nutrition (TPN) to ensure maximal rest of the pancreas and to maintain

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an optimal nutritional and metabolic status. For less severely ill patients who are able to maintain nourishment by mouth, the main goals of judicious dietary intervention are: to correct existing nutrient deficiencies, to compensate for exocrine pancreatic deficiency, and to attempt to relieve or obviate pain. The initial approaches to treatment of such patients is dependent to some extent upon the nature and severity of the pancreatitis, on the training and experience of the responsible physicians, and on the resources and technology available.15-17 The most mild forms of pancreatitis can usually be managed conservatively by admitting the patient to the hospital and instituting a regimen of adequate analgesia, H2 receptor blockers, and a low-fat diet. Should severe pain and vomiting persist or should the patient’s general condition deteriorate, more aggressive management may be required which may include prohibition of oral intake, nasogastric suction, and various invasive diagnostic and drainage procedures. Excessive alcohol intake and/or dietary indiscretions are the most frequent precipitating factors of acute exacerbations of chronic pancreatitis. Thus, it is essential to insist upon absolute abstinence from alcoholic beverages in all patients with chronic pancreatitis not only for the purposes of prophylaxis and treatment of the primary disorder, but to maintain long-term optimal nutrition status. Dietary carbohydrates should be limited in patients manifesting glucose intolerance. On the other hand, protein is usually well tolerated in patients with chronic pancreatitis. A high protein, high carbohydrate diet is the primary nutritional goal, supplemented with medium-chain triglycerides as tolerated. TPN should be instituted when these measures fail to meet nutritional requirements. In addition to providing adequate energy and protein intake, other important components of comprehensive oral therapy include multiple vitamins, minerals, trace elements and pancreatic enzymes.

Enteral Feeding Hypercatabolism associated with chronic pancreatitis can lead to prolonged negative nitrogen balance, making nutritional support vital to these patients. A trial of pancreatic rest is considered beneficial because it results in reduction of pancreatic secretions and minimizes exposure of damaged tissues to endogenous proteolytic enzymes. The fundamental goal of therapy in chronic pancreatitis, therefore, is to provide optimal nutritional support with minimal stimulation of pancreatic exocrine secretory function while allowing the inflammatory process to resolve. Whereas oral feeding of regular food obviously stimulates pancreatic exocrine secretion, oral elemental diets produce much less pancreatic volume and enzyme secretion.18,19 If elemental diets are infused by tube into the duodenum rather than into the stomach, the volume of pancreatic secretions is reduced further, but without a concomitant decrease in enzyme secretion, in a manner similar to the response produced by intravenous CCK infusion.20,21 The effects of jejunal infusion of elemental diets have been variable and controversial.22,23 It appears, however, that pancreatic rest with enteral feeding can be best achieved if elemental diets are in fused intrajejunally or nasojejunally rather than intragastrically or intraduodenally. Obviously, the decisions regarding the route and type of feeding must be individualized. Although patients with mild forms of chronic pancreatitis can often be managed with intrajejunal feeding of an elemental formula, satisfying the requirements for calories and protein may be difficult to achieve enterally, primarily because enteral feeding must be introduced at low volumes and concentrations and increased gradually and slowly, and intestinal intolerance of the feedings may require that the infusion be

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reduced to a less than optimal rate and volume. Moreover, enteral feeding is often precluded by ileus or some other gastrointestinal malfunction, often related to a complication of the primary disease. Should a patient require operative intervention for any reason, a feeding jejunostomy should be inserted for postoperative nutrient infusion controlled by a continuous pump equipped with safety monitors and alarms.

Total Parenteral Nutrition TPN has become an important adjunct to conventional medical and surgical therapy, particularly in a patient having an acute exacerbation of chronic pancreatitis. TPN can replenish previously acquired nutritional deficiencies and restore immune function to normal, thus reducing morbidity and increasing survival.24 During anacute exacerbation of chronic pancreatitis, time honored supportive management requires the cessation of all oral intake. Nasogastric tube aspiration may further reduce the stimulatory effect of intraluminal contents on pancreatic secretions. These measures obviously compound existing nutritional depletion, which may be reduced or obviated by early initiation of TPN. An additional beneficial effect of TPN is that the nutrient infusion greatly reduces both the volume and enzyme content of pancreatic exocrine secretion to basal levels. In general, TPN is usually indicated early in the course of severe disease and early post operatively, wit h gradual conversion to enteral feeding as the patient ’s condition improves.

Nutrient Substrates in Chronic Pancreatitis Amino Acids TPN regimens should consist initially of only dextrose and amino acids together with essential vitamins, minerals and trace elements until levels of serum triglycerides and lipids have been determined. Although daily energy requirements can be estimated by various techniques with appropriate activity factors and stress factors added, the total nonprotein calorie ration required is usually less than 2500 kcal/ day. Since the calorie:nitrogen ratio should be approxi-mately 100:1, the total protein provided should be approximately 2-2.5 g/kg/day. In patients with severe pancreatitis, the changes in skeletal muscle protein metabolism and amino acid concentrations are similar to those observed in patients following major operations or major trauma, during sepsis, or with multiple systems organ failure.24 The total free amino acid pool decreases to about 40% of normal, and intracellular skeletal muscle glutamine declines to levels as low as 15% of normal. These changes in specific amino acid concentrations indicate that parenteral infusion of replacement nutrient solutions richin branched chain amino acids and/or in glutamine may support the underlying metabolic derangement and may be beneficial clinically to patients with severeforms of pancreatitis. No clinical studies to date, however, have demonstrated that the administration of branched chain amino acid preparations, nor of glutamine, have a beneficial effect on the ultimate outcome of severe chronic pancreatitis.

Dextrose In seriously ill patients with pancreatitis, glucose clearance and utilization may be significantly impaired and below maximal capacity. Accordingly, intravenous dextrose substrates should never be administered in excess of the maximal capacity to metabolize glucose (4-5 mg/kg/min). Moreover, if dextrose is infused in an amount exceeding the glucose utilization rate, hepatic steatosis will inevitablydevelop.25

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Therefore, dextrose should provide no more than 60% of a patient’s total caloric needs and should not be infused at a rate greater than 3.0 mg/kg/min.8 Insulin can be added to the nutrient mixture or, if preferred, in a separate infusion as required to achieve this goal without exceeding it. Serum glucose levels should be closely monitored, and insulin should be added either as a separate peripheral infusion ordirectly to the TPN solution in order to maintain the serum glucose level below 200 mg/dL.

Lipids The use of lipid emulsions in the nutritional management of patients with chronic pancreatitis continues to be controversial primarily because of the etiologic association of hyperlipidemia with pancreatitis.26-30 Because some patients may have a previously unrecognized lipid disorder or impaired ability to metabolize lipids, the administration of lipid emulsions to patients with pancreatitis requires careful consideration and observation. Patients who have had previous episodes of pancreatitis may have an impaired ability to clear circulating lipid and may, therefore, be susceptible to the development of hyperlipidemia while receiving an infusion containing fat emulsion. Thus, it is imperative to determine serum lipid levels both before infusion in patients with pancreatitis and after infusion to demonstrate adequate clearance of the lipid from the plasma. Numerous clinical trials have reported the relative safety of administration of intravenous fat emulsions in patients who have pancreatitis and in whom hypertriglyceridemia was not an etiologic factor for their disease. If it is determined that the serum triglyceride level is normal and intravenous lipids are desirable to meet caloric needs, the TPN regimen should supply no more than 1.5 g fat/kg/day, and the fat should not provide more than 30% of total nonprotein calories.

Enzyme Treatment of Exocrine Pancreatic Insufficiency Pancreatic exocrine insufficiency, endocrine insufficiency and pain are leading manifestations of chronic pancreatitis.2 Because of the large functional reserve of the gland, steatorrhea secondary to incomplete digestion of ingested fats does not occur in exocrine pancreatic insuf ficiency until approximately 90% of pancreatic secretory function is lost, at which point exogenous pancreatic enzyme administration becomes necessary for maintaining adequate digestion and absorption. A variety of commercially available pancreatic enzyme preparations allow successful supplemental or replacement therapy in exocrine pancreatic insufficiency or failure. Pancreatin, which is derived from porcine or bovine pancreas, by alcohol extraction, is a major source of these enzymes. Lipase-augmented pancreatin, known generically as pancrelipase, may reduce steatorrhea more effectively than pancreatin on an equal-weight basis.31 In addition, a vegetable-derived form of pancreatin is available for patients with sensitivities to porcine or bovine protein. Based on normal pancreatic secretion after maximal stimulation with cerulein and secretin, a secretory capacity of 10% corresponds approximately to 100,000 units of lipase activity.46 Accordingly, effective control of steatorrhea will ordinarily require the administration of at least 100,000 units of lipase per day. Therapeutic success has been documented by a 50% reduction in stool fat with this dosage, and a 70% reduction with a dosage of 200,000 units of lipase per day. Only rarely is complete restoration of lipid hydrolysis possible, and as much as 100,000 units of lipase are required per meal. Most pancreatic preparations containonly 3,500 to 10,000 units of lipase per dose,32 requiring patients to take a large number of tablets

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daily. However, a high potency enzyme tablet is now available that contains 22,500 units of lipase and 180,000 units each of protease and amylase, respectively. Degradation in an acid environment is the major problem with these enzyme preparations, especially lipase which is irreversibly denatured at a pH <4.33. Improved digestive efficiency has been achieved by the simultaneous administration of antacids or H2 receptor blocking agents, thereby substantiating the clinical relevance of acid degradation. Patients with refractory steatorrhea may benefit by the addition of H2 antagonists and proton pump inhibitors to their pancreatic enzyme replacement therapy.52 Enteric coated preparations that release the hydrolytic enzymes at a pH above 5.5 have been developed and are currently available. The current recommendations for using the ph-sensitive pancreatin microspheres are at a dose of 25,000 to 40,000 units per meal.47 Nonetheless, these preparations still lose much of their activity along the gastrointestinal tract because only approximately 22% of trypsin activity and 8% of lipase activity delivered by pancreatin have been found postprandially past the ligament of Treitz.34 In addition, because fiber has been shown to inhibit pancreatic enzymes in vitro and in vivo, a fiber enriched diet should not be given together with pancreatic enzymes.12 Side effects of pancreatic enzymes may occur, but only rarely are of clinical significance. Allergies to porcine preparations are possible and should be considered following any immediate hypersensitivity reaction to powdered pancreatic extracts.35 Oral pancreatic extracts can form insoluble complexes with folic acid and, by impairing folate absorption36 can affect iron absorption, especially in patients with cystic fibrosis.37 Hyperuricemia and hyperuricosuria can also occur in patients using these preparations. Most patients respond well to pancreatic enzymes. With failure of the patient to respond to exogenous pancreatic enzymes, one must consider the patient’s noncompliance, incorrect diagnosis (or overlooking other diseases or conditions ), incorrect prescription of medication, or incorrect choice of pancreatic enzyme preparation.38 Total elimination of steatorrhea may be prevented by the concomitant existence of other factors and diseases that cause steatorrhea, such as celiac sprue, giardiasis, and bacterial overgrowth; incomplete gastric emptying of the pancreatic enzyme preparation and food; low micellar concentrati on of bile salts; and susceptibility of lipase to gastric acidity and chymotrypsin hydrolysis.38

The Role of Exogenous Pancreatic Enzymes in Pain Management It has been hypothesized that enzyme preparations relieve pain accompanying chronic pancreatitis.39-41 The cause of this pain is poorly understood but is thought to be secondary to multiple factors including ductal hypertension and obstruction, recurrent auto-digestion, and increased nerve infiltration. 40 Alterations in intaduodenal bile acids and plasma CCK concentrations may also be implicated in the pathogenesis of pain.54 In addition increased proliferation of peripheral mononuclear cells and their demonstrated increase release of in vitro tumor necrosis factor-alpha and interleukin-10 have been hypothesized to contribute to pain development. 55 In several controlled studies, most patients experienced a reduction in pain with administration of pancreatic enzyme supplements that increased the levels of intraluminal proteases.40-42 More profound effects of pain relief were noted with moderate pancreatic insufficiency than with severe pancreatic insufficiency.42 Greater

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relief of pain was achieved in patients who ingested the enzymes adlibitum in response to the pain in addition to ingesting thei rprescribed standard doses of digestive enzyme tablets.41 The effect of acid-protected porcine pancreatic extracts on pain was studied in a prospective placebo-controlled, double-blinded, multicenter study.43 In 43 patients with chronic pancreatitis, pain improved in most patients irrespective of study group, thus the two treatment arms did not significantly differ. Nonetheless, most authorities recommend that enzyme preparations, taken as required to relieve pain in patients with chronic pancreatitis, should be given at least a two-month trial. If the pain does not decrease within that time, treatment should be discontinued if analgesia rather than digestive enzyme replacement has been the only reason for prescribing the medication. The choice of enzyme replacement therapy depends on the dominant symptoms present. If used for relief of pain only, enzymes high in protease are more desirable; however, if used for amelioration of malabsorption, enzymes high in lipase and low in protease should be used. In patients having both pain and malabsorption, preparations with high lipase and trypsin but without chymotrypsin should be used.38 Antioxidant therapy with a complex of L-methionine, beta-carotene, vitamin C, vitamin E, and organic selenium may also have a positive effect in patients who suffer from pancreatic inflammatory pain.50 Efforts to limit the stimulation of the exocrine pancreas by decreasing CCK release through dietary modulation may be beneficial in relieving postparandial pain.51

The Effect of Exogenous Enzymes in Gastrointestinal Hormones The effect of exogenous pancreatic enzymes on the enteropancreatic axis is complete.44 The “feedback” control of pancreatic secretion clearly depends on the dose and the site of the administration of exogenous enzymes. Intraluminal duodenal perfusion of pancreatic enzymes inhibits protease activity in patients with chronic pancreatitis. This protease-mediated negative feed back of pancreatic secretion appears to be controlled largely by a duodenal mechanism. When infused into the duodenum, exogenous pancreatic enzymes have no effect on gastrin release. On the other hand, they do affect gastric inhibitory polypeptide (GIP) and following exogenous exocrine enzyme replacement in patients with chronic pancreatitis, increased levels of GIP have been measured.45-47

Conclusion Chronic pancreatitis is a complex disorder induced by different causes, but manifested by exocrine and endocrine insufficiency. Multiple nutritional and metabolic derangements result from maldigestion and malabsorption, resulting in malnutrition with severe weight loss. Persistent abdominal pain and potentially multiple various complications requiring surgical intervention further diminish the patient’s already compromised quality of life. Caring for this group of patients demands conscientious teamwork, persistence and dedication. Although very important, nutritional support is only one aspect of comprehensive care. Nutritional management ranges from simple dietary manipulation, with or without administration of digestive enzymes, to enteral supplementation with modular or chemically defined diets to total parenteral nutrition, depending on the stage, severity, manifestations and complications of the disease.

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Thus, close follow-up of patients with chronic pancreatitis is necessary and should include:25 1. individually tailored dietary counseling; 2. conscientious monitoring of glucose metabolism; 3. judicious administration of pancreatic enzyme supplements which must be tailored to meet the need for adequate disease and possibly pain control; 4. control of gastric hyperacidity; 5. reduction of intestinal hypermotility; 6. definitive surgical management of biliary lithiasis; and 7. absolute abstinence from alcohol. Even with all these measures, chronic pancreatitis can be a disabling disease. As the pathophysiology of this complex process becomes better defined and understood, new avenues for treatment likely to be developed. At the frontier, pancreatic regeneration and autoislet transplantation are in their infancy but may prove promising for managing these chronically ill patients.56,57

Selected References 1. 2. 3. 4. 5. 6. 7. 8. 9. 10. 11. 12. 13. 14. 15.

Lillimore KD, Cameron DL. Complications of chronic pancreatitis. In: Zuidema GD, ed. Shackelford’s Surgery of the Alimentary Tract, Vol III, 3rd ed. Philadelphia: WB Saunders Company, 1991:46-58. Mulholland MU. Chronic pancreatitis. In: Greenfield LJ, Mulholland MW, Oldham et al, eds. Surgery. Scientific Principles and Practice. Philadelphia: Lippincott Company, 1993:805-816. Holt S. Chronic pancreatitis. South Med Jour 1993; 86:201-206. Twersky Y, Banks S. Nutritional deficienciesin chronic pancreatitis. Gastroenterol Clin North Am 1989; 18:543-565. Boumer G, Heitz PU, Kloppel G. Immuno-histological and ultrastrukturelle Untersuchungen des endokrinen Pankreas beichronischer Pankreatitis. Verh Dtsch GesPathol 1976; 60:485. Kloppel G, Bonner G, Commandeur G et al. The endocrine pancreas in chronic pancreatitis: Immunocytochemical and ultrastructural studies, Virchows Arch 1978; 377:157-174. Sarner M, Cotton PB. Classification of pancreatitis. GUT 1984; 25:756-759. Cavalini G, Vaona B, Bovo P et al. Diabetes in chronic alcoholic pancreatitis: Role of residual β cell function and insulin resistance. Dig Dis Sci 1993; 38:497-501. Bank S Chronic pancreatitis. Clinical features and medical managment. Am J Gastroenterol 1986; 81:153-166. Simon M. Le diabete de la pancreatite chronique calcificante. Acta Gastro-Enterol Belg 1986; 49:197-204. Gullo L. Direct pancreatic function test (duodenal intubation) in the diagnosis of chronic pancreatitis. Gastroenterology 1986; 90:799-800. Lankisch PG. Value of indirect pancreatic function tests. In: Berger HG, Bucjer M, Ditschuneit H et al. eds. Chronic pancreatitis. Berlin: Springer-Verlag, 1990:291-301. Hosoda S. Evaluation of digestion-absorption test for measuring exocrine pancreatic function: Present and perspective. J Jpn Pancreas Soc 1988; 3:145-152. Romano TJ, Dobbins JW. Evaluation of the patient with suspected malabsorption. Gastroenterol Clin N Am 1989; 18:467-483. Helton WS. Intravenous nutrition in patients with acute pancreatitis. In: Rombeau JL, Caldwell MD, eds. Clinical Nutritional. Parenteral nutrition. 2nd ed. Philadelphia: W.B. Saunders, Co., 1993:442-461.

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Howard L, Michalek AV, Alger SA. Enteral nutrition and gastrointestinal, pancreatic, and liver disease. In: Rombeau JL, Caldwell MD, eds. Clinical Nutrition. Enteral and Tube Feeding. 2nd ed. Philadelphia: WB Saunders, Co., 1990:416-449. Rowlands BJ, Brown MG. The role of parenteral nutrition in the management of pancreatitis. In: Tanaka T, Okada A, eds. Nutritional Support in Organ Failure. Amsterdam: Elsevier Science Publishers BV, 1990:321-331. McArdle AH, Echave W, Brown RA et al. Effect of elemental diet on pancreatic secretion. Am J Surg 1974; 128:690-692. Neviackas JA, Kerstein MD. Pancreatic enzyme response with an elemental diet. Surg Gynecol Obstet 1976; 142:71-74. Kelly GA, Nahrold DL. Pancreatic secretion in response to an elemental diet and intravenous hyperalimenation. Surg Gynecol Obstet 1976; 143:7-91. Wolfe BM, Keltner RM. The effect of an intraduodenal elemental diet on pancreatic secretion. Surg Gynecol Obst et 1975; 140:241-245. Cassim MM, Allardyce DB. Pancreatic secretion in response to jejunal feeding of elemental diet. Ann Surg 1973; 180:228-231. Ertan A, Borrks F, Ostrow J D et al. Effect of jejunal amino acid perfusion and exogenous cholecystokinin on the exocrine pancreatic and biliary secretions in man. Gastroenterology 1971; 61:686-692. Rowlands BJ, Dudrick SJ. Nutritional support of the infected patient. In: Powanda MC, Canonica PG, eds. Infection: The Physiologic and Metabolic Responses of the Host. Amsterdam: Elsevier, 1981:359-397. Latifi R, McIntosh JK, Dudrick SJ. Nutritional management of acute and chronicpancreatitis. Surg Clin North Am 1991; 71:579-595. Cerra FB. Hypermetabolism, organ failureand metabolic support. Surgery 1987; 101:1-14. Cameron JL, Capuzzi DM, Zuidema GD et al. Acute pancreatitis with hyperlipemia: Evidence for a persistent defect in lipid metabolism. Am J Med 1974; 56:4382-487. Gossum AV, Memoyne M, Greig OD et al. Lipid-associated to total parenteral nutrition in patients with severe acute pancreatitis. J Parenter Enteral Nutr 1988; 12:250-255. Davidoff F, Tishler S, Rosoff C. Marked hyperlipidemia and pancreatitis associated with oral contraceptive therapy. N Engl J Med 1973; 289:552-553. Guzman S, Nervi F, Llanos O et al. Impaired lipid clearance in patients with previous acute pancreatitis. Gut 1985; 26:888-891. Noseworthy J, Colodny AH, Erakalis AJ. Pancreatitis and intravenous fat: An association in patients with inflammatory bowel disease. J Pediatr Surg 1983; 18:269-272. Howard J M. Treatment of pancreatic malabsorption syndrome. In: Howard JM, Jordan GL Jr, Reber HA, eds. Surgical Diseases of the Pancreas. Philadelphia: Leaand Febiger, 1987:522-527. Otte M, Ridder P, Pageforde J. In vitro Intersuchungen zur Pankreas-Enzym-substitution. Dtsch Med Wochenschr 1987; 112:1498-1502. Heizer WD, Cleveland CR, Iber FL. Gastric inactivation of pancreatic enzyme supplements. Bull Johns Hopkins Hosp 1965; 116:261-270. DiMagno EP, Malagelada JR, Go VLW et al. Fate of orally ingested enzymes in pancreatic insufficiency. Comparison of two dosage schedules. New Engl J Med 1977; 296:1318-1322. Otte M, Riddler P, Gutowski HD. Substitutions Behandlung der Pankreas Inaffinuffzienz mit Pankreatin-Fertigarz Neien. Inter Prax 1989; 29:185-189. Dutta SK, Russell RM, Iber FL. Impaired acid neutralization in the duodenum in pancreatic insufficiency. Dig Dis Sci 1979; 24:775-780.

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Zempsky WT, Rosenstein BJ, Carrol JA et al. Effect of pancreatic enzyme supplements on iron absorption. Am J Dis Child 1989; 143:969-972. Lankisch PG. Enzyme treatment of exocrine pancreatic insufficiency in chronic pancreatitis. Digestion 1993; 54(Suppl 2):21-29. Ihse I, Andersson R, Axelson J. Pancreatic pain: Is there a medical alternative to surgery? Digestion 1993; 54(Suppl 2):30-34. Ihse I, Permeth S. Enzyme supplementation for pain in chronic pancreatitis. In: Berger HG, Buchler M, Ditschuneit H et al, eds. Chronic pancreatitis. Berlin: Springer-Verlag, 1990:354-357. Isaksson G, Ihse I. Pain reduction by an oral pancreatic enzyme preparation in chronic pancreatitis. Dig Dis Sci 1983; 28:97-102. Ramo OJ, Puolakkaimen PA, Seppalok et al. Self-administration of enzyme substitution in the treatment of exocrine pancreatic insufficiency. Scand J Gastroenterol 1989; 24:688-692. Mossner J. Is there a place for pancreatic enzymes in the treatment of pain in chronic pancreatitis? Digestion 1993; 54(Suppl2):35-39. Malfertheimer P, Dominguez-Munoz JE. Effect of exogenous pancreatic enzymes on gastrointestinal motility. Digestion 1993; 54(Suppl 2): 15-20. Trifan A, Balan G, Stanciu C. Pancreatic enzymes replacement therapy in chronic pancreatitis: an update. Rev Med Chir Soc Med Nat Iasi 2001; 105(4):646-650. Layer P, Keller J, Lankisch AP. Pancreatic enzyme replacement therapy. Curr Gastroenterology Rep 2001; 3(2):01-8. Nathan JD, Zdankiewicz PD, Wang J et al. Impaired hapatocyte glucose transport protein (GLU2) internalization in chronic pancreatits. Pancreas 2001 Mar; 22(2):172-8. Gansauge F, Gansauge S, Eh M et al. Distributional and functional alterations of immunocompetent peripheral blood lymphocytes in patients with chronic pancreatitis. Ann Surg 2001 Mar; 233(3):365-70. De las Heras Castano G, Garcia de la Paz A, Fernandez MD et al. Use of antioxidants to treat pain in chronic pancreatitis. Rev Esp Enferm Dig 2000 Jun; 92(6):375-85. Shea JC, Hopper IK, Blanco PG et al. Advances in nutritional management of chronic pancreatitis. Curr Gastroenterol Rep 2000 Aug; 2(4):323-6. Scolapio JS, Malhi-Chowla N, Ukleja A. Nutrition supplementation in patients with acute and chronic pancreatitis. Gastroenterol Clin North Am 1999 Sep; 28(3):695-707. Gielkens HA, Eddes EH, Vecht J et al. Gallbladder motility and cholecystokinin secretion in chronic pancreatitis: relationship with exocrine pancreatic function. J Hepatol 1997 Aug; 27(2):306-12. Garces MC, Gomez-Cerezo J, Alba D et al. Relationship of basal and postrandial intraduodenal bile acid concentrations and plasma cholecystokin levels with abdominal pain in patients with chronic pancreatitis. Pancreas 1998 Nov; 17(4):397-401. Ockenga J, Jacobs R, Kemper A et al. Lymphocyte subsets and cellular immunity in patients with chronic pancreatitis. Digestion 2000; 62(1):14-21. Sumi S, Tamura K. Frontiers of pancreas regeneration. J Hepatobiliary Pancreat Surg 2000; 7(3):286-94. Robertson RP, Lanz KJ, Sutherland DE et al. Prevention of diabetes for up to 13 years by autoislet transplantation after pancreatectomy for chronic pancreatitis. Diabetes 2001 Jan; 50(1):47-50. Ashizawa N, Niigaki M, Hamamoto N et al. The morphological changes of the exocrine pancreas in chronic pancreatitis. Histol Histopathol 1999 Apr; 14(2):539-52. Wang L, Friess H, Zhu Z et al. Galectin-1 and galectin-3 in chronic pancreatitis. Lab Invest 2000 Aug; 80(8):1233-41.

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CHAPTER 22

Nutritional Support in Liver Failure and Liver Transplantation Rifat Latifi

Introduction Liver transplantation (LT) has evolved into the most successful form of treatment for end-stage liver disease (ESLD), with operative survival exceeding 90% for the firstgraft, retransplant free survival greater than 85% at one year,1,2 and predicted actuarial survival over 75%.3 Although the indications for LT have become more standardized (in adults as well as in children), 89% of adult patients undergoing LT have advanced cirrhosis (secondary to primary cholestatic liver disease, alcoholism, hepatitic C/non-A-non-B, autoimmune hepatitis, 0 or hepatitis B), followed by fulminant hepatic failure (5.5% -7.0%), metabolic disease (4%), malignant and benign neoplasms (3%-6% and 0.5% respectively), biliary atresia (0.5%), and other miscellaneous indications (1.8%-2%).3 On the other hand, the most common indications for LT in children are extrahepatic atresia (>50%) and alpha-1-antitrypsin deficiency (9%-14%), followed by metabolic diseases (12%-13%), cirrhosis (7%) and other indications.4 Patients who have undergone LT, or are awaiting LT, represent the most complex medical challenges. These patients are often plagued with multiple comorbid diseases and require meticulous, well-planned and executed, highly individualized medical care. Since the liver plays a major function in metabolic homeostasis, nutritional and metabolic support becomes one of the most important therapeutic interventions. Malnutrition and its associated sequella are common features in patients with chronic liver disease in general, and most patients awaiting LT are no exception. Malnutrition in this group of patients is a consequence of increased nutrient requirements in the presence of hypermetabolism, anorexia and inadequate oral intake, associated with concomitant impaired digestion, absorption, and assimilation of nutrients. Maintaining adequate nutrition represents a significant therapeutic challenge, considering the profound metabolic alterations that impair the incorporation of nutrient substrate into tissue. A vicious cycle then occurs, in which the patient is profoundly hypoproteinemic, reflecting the depleted stores and synthetic activity of the liver, and hypercatabolic, while at the same time provision of protein may result in hyperammonemia and aggravation of existing encephalopathy. Although poor nutritional status increases morbidity and mortality perioperatively, it is difficult to correctly identify and quantify the impact of individual nutrient therapy on patients with ESLD requiring LT.

The Biology and Practice of Current Nutritional Support, 2nd Edition, edited by Rifat Latifi and Stanley J. Dudrick. ©2003 Landes Bioscience.

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Malnutrition in Patients with Chronic Liver Disease The complex metabolic derangements that accompany liver failure reflect the magnitude of the problems associated with liver failure (Table 22.1).5 The frequency and the degree of malnutrition varies among patients studied.6 In one study, malnutrition was present in all 74 patients undergoing LT.7 Patients with primary biliary cirrhosis retained their hepatic synthetic function better than others despite extreme wasting of muscle and fat.8 Others9 found malnutrition present less frequently (79%) and no differences in nutritional status with regard to the etiology of chronic liver disease. The etiologic factors of malnutrition in chronic liver disease are multiple and synergistic in nature.10 Among these factors, anorexia, nausea, vomiting, poor dietary habits, malabsorption, frequent large volumes therapeutic paracenteses, and inadequate protein and caloric intake are the most common. The mechanisms of malnutrition varies and may include catabolism and altered hepatic metabolism of key nutrients: carbohydrates, fat and protein.10-12 The hepatocellular dysfunction that causes unique changes of protein, carbohydrate and fat metabolism becomes more prominent during the fasting state,10,11 when a starvation type metabolism develops. Hepatic glycogen depletion occurs rapidly (10-12 h instead of 36-48 h) resulting in accelerated and premature protein catabolism. Hepatic glucose production and peripheral glucose oxidation are significantly decreased. This prevents fasting hypoglycemia. Serum free fatty acids are increased secondary to increased peripheral lipolysis, which in turn stimulates ketogenesis.12 Ketogenesis, however, ultimately fails with worsening of liver failure. In addition to protein, fat, and carbohydrate metabolic abnormalities, impaired hepatic function results in vitamin and mineral deficiencies. When patient condition deteriorates and nutrient metabolism becomes insufficient to maintain body homeostasis, as in the late stages of cirrhosis, or infulminant hepatic failure, liver transplantation becomes the only current, long-term live saving intervention.

Hepatic Encephalopathy When the liver fails or blood is shunted past the liver, hyperammonemia results and brain function deteriorates. This frequent complex syndrome in patients with ESLD, known as hepatic encephalopathy, is manifested by varies signs and symptoms that range from rapidly developing delirium, convulsions and coma in acute failure to more gradually impairment of intellect that eventually leads to stupor and coma in chronic liver failure13 (Table 22.2). Progression and severity depend on whether the disease is in an acute or chronic stage and on the magnitude of the insult to the liver. Although, the exact biochemical mechanisms and neurochemical pathways of this complex condition are not known, one or more of several mechanisms may adversely affect the brain function of patients with liver failure14 (Table 22.3). The blood-brain barrier (BBB) consists of tight junctions of endothelial cells in the cerebral capillary bed. If substances are to affect the brain and tissues, they must penetrate this barrier. Transport of substrates through the BBB is strictly regulated and depends on their lipid solubility and on specific transport systems. For example, amino acids and glucose have their own unique and distinct carrier systems for transportation into the brain. The effectiveness of this physiologic barrier protects the organisms from the potentially adverse effects of serious metabolic changes. In HE, however, the BBB commonly breaks down, as demonstrated by the uptake of substances that otherwise are not taken up by the brain. 15 In addition, hepatic

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Table 22.1. Metabolic alterations in chronic liver disease*

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Alteration

Mechanism

Increased plasma glucagon

Portosystemic shunting Impaired hepatic degradation Hyperammonemia Hyperinsulinemia Increased peripheral insulin resistance Decreased effective insulin to glucagon ratio Impaired hepatic function Impaired hepatic function

Increased plasma aromatic amino acids

Increased plasma epinephrine and cortisol Decreased liver and muscle carbohydrate Accelarated gluconeogenesis Hyperglycemia

Hyperammonemia Increased plasma aromatic amino acids

Increased plasma methionine, glutamine, asparagine, histidine Decreased plasma branched-chain amino acids

Accelarated glycogenolysis Impaired glycogenesis Hyperglucagonemia Portosystemic shunting Increased glucose production Decreased insulin-dependent glucose uptake Decreased insulin-dependent hepatic glycolysis Deamination and accelerated bacterial degradation of protein in the colon Decreased hepatic clearance Increased release into circulation Hypoalbuminemia, hyperbilirubinemia Decreased incorporation of aromatic amino acids into proteins Decreased hepatic clearance Hyperinsulinemia Excessive uptake Increased use of BCAA as energy source

*Adapted from Latifi R, Killam J, Dudrick SJ: Nutritional support in liver failure. Surg Cli North Am 1991; 71:567-578.

encephalopathy significantly alters the BBB which affects specific transport systems of neutral amino acids, glucose, ketone bodies, and basic amino acids. Transport of neutral amino acids into the brain significantly increases, whereas the transport of glucose, ketone bodies, and basic amino acids decreases.16,17 On the other hand, BBB alteration may be consequence of a generally nonspecific increased permeability, which can expose the brain to a variety of neurotoxic substances circulating in the blood and possibly cause cerebral edema. Portal-systemic shunting of blood is associated with hyperammonemia, increased glutamine concentration in the brain, an altered plasma neutral amino acid pattern, and high levels of several large neutral amino acids in the brain. An altered amino acid pattern is caused by liver disease as much as by portal-systemic shunting. The amino acids of great importance in hepatic encephalopathy are tyrosine, phenylalanine, and tryptophan because they are involved in the synthesis of the catecholamines dopamine, noradrenaline, and serotonin and are potential precursors of “false” neurotransmitters, such as octopamine or tryptamine.18 These amino acids together

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Table 22.2. Clinical grading of hepatic encephalopathy Grade

Mental Status and Tremors

EEG Findings

I. Prodome

Euphoria, occasional depression; fluctuant, mild confusion; slowness of mentation and affect; slurred speech; disordered sleep rhythm; tremor slight

Usually no EEG changes

II. Impending coma

Accentuation of state I: drowsiness; inappropriate behavior; inability to maintain sphincter control; tremor present (easily elicited)

Generalized slowing pattern, abnormal

III. Stupor

Asleep most of the time but can be roused; incoherent speech; marked confusion; tremor usually present (patient may not be able to cooperate)

Abnormal

IV. Deep cerebral coma

May or may not respond to painful stimuli, and tremor usually absent

Abnormal

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with leucine, isoleucine, valine, methionine, threonine, and histidine compromise the group of large neutral amino acids that have a common blood-brain transport system. Other amino acids, such as glutamate, aspartate, taurine, and glycine, can also act as neurotransmitters. Because some of these amino acids are precursors for neurotransmitters and other potentially neuroactive substances, high central nervous sytem levels of these amino acids may contribute to the development of encephalopathy. Changes in the blood-to-brain transport of neutral and basic amino acids, in part, may be caused by an increase in the V-max of the respective carrier system, which is possible a consequence of hyperammonemia.19

Amino Acids in Hepatic Encephalopathy Hepatic encephalopathy is associated with increased plasma and brain concentrations of the aromatic amino acids (AAA): phenylalanine, tyrosine and tryptophan (free form) and decreased concentrations of the branched-chain amino acids (BCAA): valine, leucine and isoleucine.18-23 Because large neutral amino acids share a common transport carrier in crossing the BBB, decreased BCAA concentrations in the blood may in fact facilitate increased transport AAA into the brain.23 High concentrations of the aromatic amino acids and methionine could limit the cerebral uptake of BCAA because the higher AAA concentrations result in greater competition at the BBB for the carrier-mediated transport system used by BCAA. When brains of normal dogs were perfused with AAA a hepatic-like coma and an abnormal neurotransmitter pattern were induced. These findings are, in part, responsible for the “false” neurotransmitter-amino acid hypothesis of hepatic encephalopathy.18 The hepatic-like coma induced by AAA may be prevented when AAA and BCAA were infused simultaneously.24 During liver failure or diversion of the blood around the liver, amines and their amino acid precursors accumulate in the circulation and enter the brain and the peripheral autonomic nervous sytem, replacing the true neurotransmitter

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Table 22.3.

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Mechanisms that may affect brain function in hepatic encephalopathy

Mechanisms

Consequences

Disruption of integrity of the brain-blood barrier Alterations of specific transport systems

Exposure of the brain to undesireable neuroactive compounds Increased transport of neutral amino acids Decreased transport of glucose, ketone bodies, and basic amino acids Functional alterations of the brain

Accumulation of neurotoxic substance in the blood Changes in the substrate supply Lack of nutrients, e.g., glucose

Alterations and catabolism of normal neurotransmitters in the brain Impairment of brain energy metabolism

norepinephrine with weak or “false neurotransmitters”, such as octopamine, tyrosine, phenylethylamine, of phenylethanolamine. On the other hand, patients with liver failure have increased levels of norepinephrine and the other catecholamines.25 Nonetheless, it is thought that this imbalance of neurotransmitters has serious consequences which may be manifested as brain dysfuction and high cardiac output, low peripheral vascular resistance states, as well as hepatorenal syndrome. Whether amino acid imbalance precipitates encephalopathy, possibly, by promoting the synthesis of toxic aromatic amines, is not clear, but attempts to correct this imbalance have been the rationale for metabolic and nutritional therapy of patients with liver failure in which the protein ration is enriched with BCAA and low in AAA is administered (Tables 22.4,5). The administration of BCAA to rats with portocaval shunts reduces the concentration of tryptophan, serotonin, and 5-HIAA in brain indoles.20 Formation of “false” or “weak” adrenergic neurotransmitters may contribute to hepatic coma, possibly by displacing norepinephrine and dopamine from their storage granules at nerve terminals.

Nutritional Assessment Accurate assessment of nutrition status of patients with chronic liver disease is very important, albeit characterized by many encumbrances to performing and interpreting clinical and biochemical studies. Identifying and differentiating the impact of malnutrition from the effects of liver disease and the therapy represent the main predicament. Common methods of determining the nutritional status of these patients have obvious practical limitations. Total body weight and measurements of tricepts skinfold thickness and mid-arm circumference are influenced by ascites and edema. Hypoalbuminemia is an important indicator of nutritional status and a good index of hepatic functional reserve. The absolute rate of albumin synthesis is significantly lower in patients with cirrhosis and correlates well with the Child-Turcotte score and with its Pugh modification. However, when analyzed separately the rate of albumin synthesis does not correlate with serum albumin concentration, intravascular albumin mass, or with other clinical indexes of liver function or integrity. Hypoalbuminemia decreases the colloid oncotic pressure, which contributes to the

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Table 22.4.

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Use of branched-chain amino acids in hepatic encephalopathy

When gluconeogenesis and ketogenesis are depressed, BCAAs* may furnish as much as 30% of energy requirements for skeletal muscle, heart and brain. The BCAAs may regulate the movement of other amino acids across the myocyte membrane. The BCAAs increase hepatic protein synthesis when given with glucose and decrease aromatic amino acid concentrations. Theoretically, BCAAs may improve peripheral catecholamine synthesis. The BCAAs complete with aromatic amino acids for transport across the blood-brain barrier. *BCAA=Branched-chain amino acids

accumulation of ascites and edema, a persistent characteristic of decompensated liver function. Close metabolic monitoring of these patients is of utmost importance. In addition to routine biochemical indices which include transferring, prealbumin and retinol-binding protein, plasma levels of vitamins, trace elements and apolipoprotein A-IV may be useful in a comprehensive nutritional assessment. The new metabolic tool that is coming in the clinical practice is the measurements of the hepatic mitochondrial redox potential,26 but its role in CLD has not been studied to date. The hepatic mitochondrial redox potential represents the ratio of acetoacetate to β-hydroxybutyrate and can be expressed and measured as the arterial blood ketone body ratio (AKBR). The AKBR is not a specific measurement of liver insufficiency, but does allow the severity of liver damage to be graded and reflect the state of perfusion of splanchnic bed. Different clinical and biologic phenomena are associated with a decrease in the AKBR, of which most prominent are enhanced catabolism, impaired oxygen utilization, hypoperfusion and deterioration of the immune response. Protein malnutrition is a characteristic feature of patient with cirrhosis. Moreover, functional alterations and histologic abnormalities of the liver are known consequences of malnutrition. Protein deprivation profoundly depletes liver protein stores and adversely affects the breakdown and conversion of polysomes to free ribosomes. On the other hand, in chronic liver disease, alterations in visceral protein synthesis, cellular immunity, and total lymphocyte count may be present independently of protein malnutrition. Plasma protein levels correlate inversely with the degree of liver damage and are its best indicators. Serum concentrations of AAA can indicate the severity of chronic and acute liver disease as well. Furthermore, because patients with hepatic encephalopathy have the lowest BCAA:AAA ratio, this determination may serve as an index of liver function impairment. Other markers such as lean body mass and fat stores are not reliable indicators of structural liver damage. Measurement of nitrogen balance has its limitation, because it is difficult to differentiate impaired hepatic protein synthesis from accelerated breakdown of endogenous protein. Standard tests of hepatic metabolic capacity and blood flow (aminopyxine breath test, galactose elimination capacity and clearance of idiocyanine green) are less sensitive indicators of prognosis than the Child-Pugh classification of liver disease.7 The recognized, but less applied clinically prognostic nutritional index, which relies mostly on plasma protein lacks the predictive value in patients with ESLD.8

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Table 22.5.

General treatment of hepatic encephalopathy

Identify and treat other medical problems Balance protein intake Avoid antidepressants and hypnotics unless severe mania is present

22

Avoid extensive paracentesis or abrupt removal of fluids by dialysis Avoid vigorous diuresis Avoid use of acetazolamide Slowly correct hyponatremia Do not overhydrate Monitor hemodynamic status and blood gases closely Monitor arterial blood ketone body ratio Avoid lumbar puncture if possible Supplement vitamins Avoid use of strong cathartics

Peritransplant Nutrition: Support In a retrospective study of 160 adults with liver transplant, malnutrition score was one of the six variables that highly correlated with patient survival. High malnutrition score was associated with increased postoperative morbidity and mortality.27 The degree of postoperative malnutrition has been shown to predict the postoperative morbidity and mortality in liver transplant patients.9 This study demonstrated a relationship between moderate to severe malnutrition and increased morbidity (increased requirements for ventilatory support, and ICU and hospital stay) and mortality.9 Identifying the correct caloric and protein requirements in patients before and after undergoing LT is not an easy task. In a prospective study of 16 adults patients scheduled to undergo LT, nitrogen balance, 24-hour urinary cratinine, 3-methyl histidine and resting energy expenditure (REE) were determined before transplantation and on days 1,2,5,14 and 28 posttransplant.28 Only 15% of patients in this study achieved a positive balance, although parental nutrition (containing 1.29 gm/ protein/kg, 30% and 70% of calories were given as fat and dextrose respectively) was started within 24 hours. Calculation of malnutritional needs on this study was based on the Harris-Benedict equation, and parenteral feeds were continued until solid oral intake reached 1200 calories in 24 hours in females and 1500 in males. These investigators have suggested to use the Harris-Benedict formula for calculation of nutritional requirements and to add 20% more calories in order to provide nutritional support in LT patients. In another, most recent study,29 150 patients with ESLD undergoing LT prospectively were assessed and followed for an average of 46 months after LT. Body composition analysis (24 hour urinary creatinine excretion, anthropometric measurements and bioelectrical impedance analysis), changes of REE and other variables were analyzed. Patients with severe hypermetabolism (changes in REE >20%) and reduced body cell mass (<35% of body weight) had reduced survival after LT. Based on the degree of hypermetabolism and malnutrition a prognostic risk profile

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predicted the survival. Patients with high risk profile had a 5-year survival of 88% (P<.01). Others, have also found that nutritional status indices predict survival after LT in children.30 Although nutritional assessment in adult patients with ESLD is difficult and complex, and the current indices cannot be applied optimally to all patients, it is clear that hypermetabolism and malnutrition are present in a significant number of patients undergoing LT and that perioperative nutritional and metabolic status of these patients has great prognostic value.

Metabolic Changes Hypermetabolism as a systemic manifestation of cirrhosis is closely related to splanchnic hemodynamics and malnutrition.31 Following LT patients are in a hypercatabolic state, however their postoperative metabolic state (as measured by REE) is a reflection of their preoperative state.32,33 The degree of hemodynamic abnormality, when studied intraoperatively, correlates with the stage of the disease.34 LT does not reverse the existing splanchnic and systemic hemodynamic abnormalities of ESLD completely.31 The splanchnic hyperemia persists for at least two weeks, and the closure of porto-collateral circulation occurs at a much slower rate, even though the portal pressure returns to normal.35 Total liver blood flow markedly increases after LT, although the effects of persistent high liver blood flow on metabolism are not known.31 Immediately following LT (in the first 6 hours ) glucose utilization by the graft is impaired until mitochondrial redox potential improves.36 During this period, the liver preferentially uses fatty acid oxidation for ATP generation. After 6 hours, if transplanted liver have normal function, substrate utilization shifts from fat to glucose. On the other hand, failing grafts will continue to utilize fat. These significant metabolic changes may be followed by the serial measurements of arterial ketone body ratio (acetoacetate/3-beta-hydroxybuturate) or AKBR. The AKBR reflects the hepatic mitochondrial redox potential (oxidized nicotinamide adenine dinucleotide (NAD)/reduced nicotinamide adenine dinucleotide (NADH). The ketone body ratio reflects one of the most fundamental regulatory factors of energy production in the liver. The AKBR changes may be used to predict the function of transplanted liver. Low values of AKBR associated with low levels of ketone bodies should be regarded as a strong indicator of graft failure.37,38 Furthermore, fatty acid oxidation and ketogenic pathways are accelerated to compensate for energy deficits immediately after LT. Administration of small quantities of glucose in post operative period has been suggested.38 Glucose infusion may be increased as mitochondrial redox potential recovers (AKBR >0.07). Low AKBR values (<0.07) have been associated with increased mortality and morbidity.39 Following LT low levels of some amino acids such as glutamine, asparagine, citrulline and taurine have been reported.40,41 All of the existing studies have involved patients undergoing standard cadaveric donor LT. The use of partial liver grafts is becoming increasingly common, however. These grafts are typically less than 50% of normal adult liver mass. The ability of these organs to utilize nutrient substrates in the early postoperative period has not been systematically studied and the optimal nutritional support for these patients in unknown.

Nutrition Status of Donors The nutritional status of donors has not received adequate attention, although it has been suggested that the nutritional state of the donor may affect the outcome of

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LT.42 Often times organ donors receive little, if any, nutritional support during their hospitalization, and are subjected to acute starvation that may last for days in an ICU. This period could substantially deplete the liver energy stores. The role of acute nutritional repletion on the outcome of LT was examined experimentally.42 Donor pigs were divided into three groups and pretreated for seven days before harvesting their livers. Group I was given intravenous saline; Group II was fed orally regular animal diet; and Group III was fasted, but given 20% glucose intravenously. Harvested livers were stored for four hours in cold Euro-Collins solution before transplantation. The glycogen content of the liver at harvesting was consumed completely in Group I, but was well preserved in Groups II and III. The ATP content of the liver in all three groups were similar at harvesting and were markedly reduced four hours after cold preservation. The amount of ATP recovered one hour after reperfusion was 26% of that before preservation for Group I, and 48% and 73% for Goups II and III, respectively. The mean survival for Group III was 37.2 days vs 5.8 ± 0.7 days and 9.8 ± 2.0 days in Group I and II (P<0.01). Other investigators,43,44 have also shown that livers from nutritionally repleted animals have improved function when compared with livers from fasted animals after cold preservation. It has been demonstrated that glycogen stores could be rapidly repleted in pigs by intraportal infusion of glucose over 3 hours.45 Studies in humans using this technique46 have shown that glycogen stores in human allograft are good and glycogen is needed

throughout the transplantation procedure. Futhermore, newly synthesized glycogen is superior to preformed glycogen and glycogen repletion improves outcome of liver transplantation in humans. It appears that glucose infusions lower peak transaminase levels, and protects against the effects of prolonged warm ischemia.46 Rapid hepatic glycogenation was shown to be beneficial in maintaining adenine nucleotide levels in a large animal model.47 Moreover, livers harvested from hyperglycemic donors receiving insulin infusion during the procurement operation have significantly lower reperfusion hepatocellular injury.48 On the other hand, others have reported that livers from fasted rats were more tolerant to long-term hypothermia than livers from fed donors.49,50 More contrasting data were reported recently, were both extensive donor fasting and glucose feeding enhanced outcome in LT.51 Nonetheless, prevention of the nutritional status of the donor liver prior to harvesting may be a method to improve function of the livers for transplantation, as the evidence suggests that nutritional status of organ donors matters. Furthermore, nutritional modulation of hepatic reperfusion may have greater influence on liver preservation of LT, and nutritional supplementation may precondition the liver.52 Until a large human randomized clinical trial answers this question definitively, organ doors should be treated principally the same as other critically ill patients: once fully resuscitated, start the nutritional support, and when possible use the gastrointestinal tract to deliver nutrition. Based on animal studies, during prolonged pretransplant period, a higher percentage of glucose infusion may have theoritical advantage.

How to Feed Liver Transplant Patients Attempts to reverse malnutrition in patients with advanced cirrhosis are very complex and often are compounded by nutrient substrate intolerance and encephalopathy requiring some protein restriction. The principle question to be answered is not do these patients need to be fed, but rather how to do it and when to start? Until recently TPN was the preferred form of postoperative nutritional support in LT as it

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provides all the nutrients even in a face of significant gut dysfunction. In a randomized prospective, partially blinded, study, 28 patients were studied for seven days following liver transplant.53 Patients were randomized into three groups: Group I (N=10) was given isotonic intravenous fluids with glucose; Group II (N=8) was given standard TPN providing 1.5 g/protein/kg/day; and Group III (N=10) isocaloric isonitrogenous TPN fortified with 3.5% branched-chain amino acids. All patients were similar with regard to their disease stage, muscle wasting, albumin levels and jaundice. Nitrogen balance was significantly improved in both TPN groups (Group I vs Group II, P<0.0001; Group I vs Group III, P<0.0011). Furthermore, both TPN groups were extubated earlier than the control and had a shorter ICU stay (an average 2.4 days), although these differences did not achieve statistical significance. This study53 demonstrates that patients post LT can tolerate aggressive nutritional support and protein load of 1.5 gm/kg/d without evidence of precipitating encephalopathy. Urea nitrogen and creatinine were also not effected by protein intake. Achievement of nitrogen balance in patients with liver transplant has been reported previously.54,55 Since TPN has its inherent potential problems (metabolic, infectious, mechanical) the provision of nutrients enterally when possible is an attractive concept. The efficacy and the tolerance of early enteral feeding via a double-lumen nasojejunal tube, placed at the time of transplant, was studied in 14 LT patients.56 These patients were compared with 10 patients who received TPN as a main of provision of nutritional support. Tube feeding was started within 18 hours after transplantation, while TPN within 24 hours for most patients. These investigators concluded that with early tube feeding after LT, the nutritional status can be maintained as efficiently as with TPN, although nitrogen balance studies were not performed. All patients in this study underwent studies of intestinal absorptive capacity and intestinal permeability before and after transplant. These studies showed no significant differences in intestinal permeability between the enterally and parenterally fed patients within the first seven days of provision of nutritional support.56 This technique of provision of early enteral feeding may be difficult to achieve in cases when choledocho-enteric biliary drainage is performed. In another study,57 early enteral feeding immediately after LT was shown to be safe but early postoperative feeding did not effect the ICU or hospital stay, or ventilatory dependence. Thirty one (out of 51) patients completed the study. Tube feeding was tolerated well by 14 patients— and these patients had a better nitrogen balance on post transplant day 4 than control (P<.03) and greater cumulative 12-day nutrient intake (P<0.002) and lower viral infection rate (P<.05). The major deficiency of this study is that the control group received no nutritional support until they were able to eat. The means and technique of delivering enteral feedings has been a matter of debate.58 Because of associated discomfort of the nasojejunal tubes to the patient and other technical difficulties, routine placement of feeding jejunostomies at the same time of transplant has been recommended.59 Many surgeons avoid this procedure due to the high incidence of complications and infrequent need for prolonged tube feeding. Although 15% of the patients had some type of complication related to placement of J-tubes, placement of these tubes at the time of operation can be done safely, with very low risk of serious complications and without adding significant operative time. J-tubes may, however, be best reserved for those patients who are at risk for prolonged postoperative malnutrition (i.e., prolonged ventilation).

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Naoenteric tubes are generally well tolerated in the short term and do not carry potential the risk of J-tubes. Based on these and other studies, enteral nutrition should be the primary mode of nutrition support whenever possible. When to start the feeding is another question. In general if the patients is fully resuscitated as documented by normal lactic acid, base excess and gastric pHi (when measured) enteral nutrition support may be started and advanced as tolerated. On the other hand, TPN should be reserved for patients that cannot be fed enterally or their resuscitation is prolonged and/or complicated by multiple returns to the operating room, for those with prolonged ileus, abdominal distention, abdominal sepsis, or chylous ascites.60

Conclusion Malnutrition is very common in patients undergoing liver transplantation and poor nutritional status is associated with increased morbidity and mortality. Correction and prevention of malnutrition and metabolic support of these patients in their perioperative period is of utmost importance. Enteral feeding should be initiated as soon as possible after LT. Enteral feeding should be used, even when all nutritional needs cannot be met with this technique, and requires supplementation with TPN. Use of specialized nutritional formulas need to be evaluated further, while individualized dietary consult with the patient and the family is of great importance and should be part of the therapeutic interventions.61 The use of type and the amount of lipids in nutrition support of patients with liver failure and transplant have not been studied. It is clear, however that too much lipids, or when most of lipids are given in a form of omega-6-fatty acids have deleterious effects on the immune status of the critically ill patients. The nutritional therapeutic interventions should be oriented toward reducing patient's protein catabolism and to provide sufficient nutrient substrates in a form of amino acids and dextrose to improve nitrogen balance without aggravating the hepatic encephalopathy.7

Selected References 1. 2. 3. 4. 5. 6. 7. 8. 9.

Lake JR, ed. Advances in liver transplantation. Gastroenterolo Clin North Am 1993; 22:2. Health Resources and Services Administration, bureau of health resources report of center-specific graft and patient survival rates. Rockville: US Dept of Health and Human Services, 1992:8-10. Clavien PA, Krk AD. Liver transplantation. In: Sabiston DA Jr, ed. Textbook of Surgery, 15th ed. W.B. Saunders, 1997:461-473. Belle SH, Beringer KC, Detre KM. Trends in liver transplantation in the United States. In: Tersaki PI, Cecka JM, eds. Clinical Transplants. Los Angeles, UCLA Tissue Typing Laboratory, 1993. Latifi R, Dudrick SJ. Hepatic encephalopathy: Metabolic and nutritional implications. In: Latifi R, ed. Amino Acids in Critical Care and Cancer. Austin: R.G. Landes Company, 1994. Porayko MK, DiCecco SR, O’Keefe SJD. Impact of malnutrition and its therapy on liver transplantation. Seminars in Liver Disease 1991; 11:4:305-314. DiCecco SR, Wieners EJ, Wiesner RH et al. Assissment of nutritional status of patients with end-stage liver disease undergoing liver transplantation. Mayo Clin Proc 1989; 64:92-102. Pikul J, Sharpe MD, Lowndes R et al. Degree of preoperative malnutrition is predictive of post-operative morbidity and mortality in liver transplant recipients. Transplantation 1994; 57:469-472. Munoz SJ. Nutritional therapies in liver disease. Semin Liv Dis 1991; 11:278-290.

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Romign JA, Endert E, Sauerwein HP. Glucose and fat metabolism during shortterm starvation in cirrhosis. Gastroenterology 1981; 100:1017-1024. Petrides AS, DeFonzo RA. Glucose and insulin metabolism in cirrhosis. J Hepatol 1989; 8:107-114. Riggio O, Merli M, Cantafora A et al. Total and individual free fatty acids concentrations in liver cirrhosis. Metabolism 1984; 33:646-651. Latifi R, Killam RW, Dudrick SJ. Nutritional support in liver failure. Surg Clin North Am 1991; 71:567-578. Morgan MY. The treatment of chronic hepatic encephalopathy. Hepatogastroenterol 1991; 38:377-387. Horowitz ME, Schafer DF, Molnar P et al. Increased blood-brain transfer in a rabbit model of acute liver failure. Gastroenterology 1983; 84:1003-1011. Mans AM, Biebuyck JF, Shelly K et al. Regional blood-brain barrier permeability to amino acids after portocaval anastomosis. J Neurochem 1982; 38:705-717. James JH, Escourrou J, Fischer JE. Blood-brain neutral amino acids transport activity is increased after portocaval anastomosis. Science 1978; 200:1395-1397. Fischer JE, Baldessarini R. False neurotransmitters and hepatic failure. Lancet 1971; 2:75-80. Cardelli-Cangiano P, Cangiano C, James JH et al. Uptake of amino acids by brain micro vessels isolated from rats after portocaval anastomosis. J Neurochem 1981; 36;627-632. Soeters P, Wilson JHP, Meijer AF et al. Advances in ammonia metabolism and hepatic encephalopathy. Amsterdam: Elsvier, 1988. Howkins RA, Jessy J, Mans AM et al. Effect of reducing brain glutamine synthesis on matabolic symptoms of hepatic encephalopathy. J Neurochem 1993; 60:1000-1006. Munro HN. Interaction of liver and muscle in the regulation of metabolism in response to nutritional and other factors. In: Arias I et al, eds. The liver: biology and pathobiology. New York: Raven Press, 1982. Bergeron M, Layrargues Pomier G, Butterworth RF. Aromatic and branched-chain amino acids in autopsied brain tissue from cirrhotic patients with hepatic encephalopathy. Met Brain Dis 1989; 4:169-176. Rossi-Fanelli F, Freud H, Krause R et al. Induction of coma in normal dogs and its prevention by the additional of branched-chain amino acids. Gastroenterology 1982; 83:664-670. Mizock BA, Sabelli HC, Dubin A et al. Septic encephalopathy. Evidence for altered phenylalanine metabolism and comparison with hepatic encephalopathy. Arch Inter Med 1990; 150:443-499. Yamamoto Y, Ozawa K, Okamoto R et al. Prognostic implications of postoperative suppression of arterial ketone body ratio. Time factor involved in the suppression of hepatic mitochondrial redox potential. Surgery 1990; 107:289-294. Shaw BW Jr, Wood RP, Stratta RJ et al. Stratifying the causes of death in liver transplant recipients. Arch Surg 1989; 124:895-900. Plevak DJ, DiCecco SR, Wiesner RH et al. Nutritional support for liver transplantation: Identifying caloric and protein requirements. Mayo Clin Proc 1994; 69:225-230. Seleberg O, Bottcher J, Tusch G et al. Identification of low-risk patietns before liver transplantation: A prospective cohort study of nutritional and metabolic parameters in 150 patients. Hepatology 1997; 25:652-657. Redox B, Multer M, Kardorff R et al. Liver transplantation in children with chronic end-stage liver disease. Transplantation 1996; 62:1071-1076. Henderson JM. Abnormal splanchnic and systemic hemodynamics of end-stage liver disease: What happens after liver transplantation? Editorial. Hepatology 1993; 17:514-516.

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The Biology and Practice of Current Nutritional Support 32. 33. 34.

22

35. 36. 37.

38. 39.

40. 41. 42. 43. 44. 45. 46. 47. 48. 49. 50. 51. 52. 53.

Shanbhogue RLK, Bistrain BR, Jenkins RL et al. Increased protein catabolism without heper metabolism after human orthotoic liver transplantation. Surgery 1987; 101:146-149. Muller MJ, Loyal M, Schwarce M et al. Resting energy expenditure and nutritional state in patients with liver cirrhosis before and after liver transplantation. Clin Nutr 1994; 13:145-152. Paulsen AW, Lintmalm GBG. Direct measurement of hepatic blood flow in native and transplanted organs, with accompanying systemic hemodyanamics. Hepatology 1992; 16:100-111. Navasa M, Feu F, Garcia-Pagan JC et al. Hemodynamic and Humoral changes after liver transplantation in patients with cirrhosis. Hepatology 1993; 17:355-360. Ozaki N, Ringe B, Bunzendahl N et al. Ketone body ratio as an indicator of early graft survival in clinical liver transplantation. Clin Transplant 1991; 5:48-54. Takada Y, Ozawa K, Yamaoka Y et al. Arterial ketone body ratio and glucose administration as an energy substrate in relation to changes in ketone body concentration after liver related liver transplantation in children. Transplantation 1993; 55: 1314-1319. Ozaki N, Ringe B, Gubernatis G et al. Changes in energy substrates in relation to arterial ketone body ratio after liver transplantation. Surgery 1993; 113:403-409. Shimahara Y, Yamamoto N, Kobayashi N et al. Hepatic mitochondrial redox potential and its application in metabolic care and nutrition support in liver failure. In: Latifi R, Dudrick SJ, eds. Surgical Nutrition: Strategies in critically ill patietns. New York/Austin: Springer-Verlag/R.G. Landes, 1995:171-194. Iapichino G, Rodrizzani D, Bonetti G et al. Early metabolic treatment after liver transplant: Amino acid tolerance. Inten Care Med 1995; 21:802-807. Iapichino G, Ronzoni G, Bonetti G et al. Determination of the best amino acid input after orthotopic liver transplantation. Minerva Anestiol 1992; 9:593-508. Sadamori H, Tanaka N, Yagi T et al. The effects of nutritional repletion on donor for liver transplantation in pigs. Transplantation 1995; 60:317-321. Morgan GR, Sanabria JR, Clavien PA et al. Correlation of donor nutritional status with sinusoidal lining cell viability and liver function in the rat. Transplantation 1991; 51:1176-1183. Boudjema K, Lindell SL, Belzer FO et al. Effects of methods of preservation of livers from fed and fasted rabbits. Cryobiology 1990; 28:227-236. Cywes R, Clavien PA, Sanabria JR et al. Glycogen repletion and metabolism during the porcine hepatic allograft retrival and preservation (abstract). Hepatology 1991; 14:574. Cywes R, Greig PD, Sanabria JR et al. Effects of intraportal glucose infusion on hepatic glycogen content and degradation, and outcome of liver transplantation. Ann Surg 1992; 216:235-247. Cywes R, Greig PD, Morgan G et al. Rapid donor nutritional enhancement in a large animal model. Hepatology 1992; 16:1271-1279. Shulman G, Rossetti. Influence of the route of glucose administration on hepatic glycogen repletion. Am J Physiolo 1989; 257:E681-685. Sumimoto R, Southard JH, Belzer Fo et al. Livers from fasted rats acquire resistance to warm and cold ischemia. Transplantation 1993; 55:728. Sankary H, Foster P, Brown E et al. Relevance of the nutritional status of donors in viability of transplanted hepatic allograft. Transplantation 1992; 54:170. Lindell SL. Hansen T, Rankion M et al. Donor nutritional status—a determinant of live preservation injury. Transplantation 1996; 61:239-247. Helton WS. Nutritional issues in hepatobiliary surgery. Sem Liv Dis 1994; 14:140-157. Reilly J, Mehta R, Teperman L et al. Nutritional support after liver transplantation: Prospective study. JPEN 1990; 14:386-391.

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O’Keefe S, Williams R, Calne R. Catabolic loss of body protein after human liver transplantation. BMJ 1980; 280:1107-1108. Johnson P, O’Grady J, Calvey H et al. Nutrition in liver transplantation. In: Calne R, ed: Liver transplantation. New York: Gune and Straton, 1987:113-117. Wicks S, Somasundaram S, Bjarnason I et al. Comparison of enteral feeding and total parenteral nutrition after liver transplantation. Lance 1994; 344:837-840. Hasse JM, Blue LS. Liepa GU et al. Early enteral nutrition support in patients undergoing liver transplantation. JPEN 1995; 19:437-443. Lowel JA. Liver transplant recipient and enteral feeding. (Letter). Surgery 1995; 119:357-358. Pescovitz MD, Mehta PL, Leapman SB et al. Tube jejunostomy in liver transplant recipients. Surgery 1995; 117:642-647. Shapiro JAM, Bain GV, Sigalet D et al. Rapid resolution of chylous ascites after liver transplantation using somatostating analog and total parenteral nutrition. Transplantation 1996; 61:140-1411. Brougham TA, Murray NG. Nutrition in chronic liver disease and liver transplant. In: Latifi R, Dudrick SJ eds. Surgical Nutrition: Strategies in critically ill patients. Austin/Heidelberg: RG Landes/Springer-Verlag, 1995:155-170.

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CHAPTER 23

Nutritional Support in Renal Transplantation Susan T. Crowley, Richard Formica and Antonio Cayco

Introduction Because of the high prevalence and adverse impact of malnutrition in the pretransplant end stage renal disease (ESRD) population, the effects of renal transplantation on the nutritional state of the recipient is of interest. This Chapter reviews the available published literature on selected aspects of nutrition in the kidney transplant recipient (KTR). Because of their correlation with increased risk of morbidity and mortality and their high prevalence among KTRs, the treatments of protein malnutrition and dyslipidemia are examined. The impact of vitamin supplementation on modification of another potential cardiovascular risk factor in the KTR, hyperhomocysteinemia is also considered. Finally, because serious morbidity secondary to osteoporosis in the KTR has been recognized, bone metabolism in the KTR is discussed.

Protein Malnutrition and Nitrogen Balance The attributable impact of the restoration of renal function on nitrogen balance in the KTR has been confounded by the requisite use of immunosuppressive therapy. The latter has been well known to independently influence protein turnover. In particular, glucocorticoids have been repeatedly shown to increase protein catabolic rate (PCR) and result in negative nitrogen balance. Over a decade ago, multiple investigators demonstrated that PCR doubled within 6-11 days post-renal transplantation, independent of protein intake and in parallel with changes in steroid dose. Studies reported that despite restoration of renal function and intake of at least 1.2 gm protein/kg IBW/day, glucocorticoid therapy had a major impact on PCR and was associated with dramatic nitrogen wasting. Fortunately, it has been demonstrated that protein wasting is a not an invariable consequence of glucocorticoid therapy. In nondiabetic renal transplant patients, increased dietary protein intake (1.5 gm/kg/day) in the immediate postoperative period diet accompanied by 30-35 kcal/kg/day of caloric intake is able to effect neutral nitrogen balance, whereas more protein restricted patients develop negative nitrogen balance. Thus, dietary manipulation is effective in maintaining nitrogen balance, even in the immediate post-transplant period when high dose steroid therapy is typically utilized. More aggressive dietary protein supplementation has been shown to be a means of further reducing negative nitrogen balance associated with high-dose steroids in the early post-transplant period. In one study, isocaloric diets of approximately 30 kcal/kg/day, adjusted for the differences in the protein content of the diets, were The Biology and Practice of Current Nutritional Support, 2nd Edition, edited by Rifat Latifi and Stanley J. Dudrick. ©2003 Landes Bioscience.

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consumed by 12 nondiabetics, randomized to either the control (1 gm/kg/day) or experimental (3 gm/kg/day) diet. Over the study period of four weeks, both groups lost a mean of 3 kg, yet a net increase of 4.5 kg of lean body mass was noted in the experimental group. For both groups, nitrogen balance was directly proportional to the nitrogen intake. Regression analysis of daily protein intake and nitrogen balance suggested that neutral nitrogen balance was achieved at an intake of 1.3 gm protein/ kg/day. Thus, in the setting of adequate caloric intake, it is possible to improve nitrogen balance by protein supplementation without suffering undue side effects such as clinically significant hyperkalemia or azotemia. Dietary protein intake recommendations in the long term KTR requires a balance between the potentially beneficial and the potentially detrimental effects of a high protein diet. Diminished muscle mass, as evidenced by reduced forearm muscle circumference, has been demonstrated in a significant proportion (38%) of diabetic and nondiabetic patients even two years after successful renal transplantation, when consuming 1 gm/kg/day protein and 25-35 kcal/kg/day. This occurs despite improvement in other nutritional parameters (weight, serum albumin) and minimal steroid use. It has also been shown, by computerized tomographic assessment of mid-thigh muscle area, that marked muscle atrophy occurs in the otherwise stable kidney transplant patient. Given the apparent extent of muscle wasting and protein malnutrition in the stable KTR, dietary protein restriction for any reason would appear questionable. Some investigators however, have postulated that chronic rejection is a forme-fruste of hyperfiltration induced vascular damage. Over the long term, therefore, a normal or high protein diet might potentially be detrimental to renal graft survival by exacerbating hyperfiltration. A short-term study examining the effect of a low protein (0.55 gm/kg/day) diet on a small cohort of KTRs revealed that urinary protein excretion significantly diminished during low protein dietary intake, and neutral nitrogen balance was achieved. However, significant declines in serum total protein, albumin, as well as transferrin occurred which would suggest that this was too restrictive a diet to maintain overall protein balance. Whether dietary protein restriction in the long term renal transplant recipient is adequate to maintain nitrogen balance has been investigated by others as well. Among a small cohort of long term nondiabetic KTRs with moderate renal insufficiency consuming a diet containing 0.6 gm protein/kg/day with a caloric intake of 30 kcal/ kg/day, no significant changes in inulin-measured glomerular filtration rate or serologic nutritional parameters were noted over a four week follow-up period. While nitrogen balance did not significantly change ( baseline = -0.88 ± 1.14 gm/day; at three weeks = -1.59 ± 0.5 gm/day) nitrogen balance did correlate with protein intake (r=0.42, p< 0.05). Furthermore, caloric intake was positively correlated with nitrogen balance, with near-neutral nitrogen balance being achieved in subjects consuming greater than 25 kcal/kg/day, regardless of protein intake. Thus, there appears to be a threshold for caloric intake (28 kcal/kg/day) which must be met to maintain weight and neutral nitrogen balance. Because it appears difficult to achieve a protein-restricted diet without compromising essential caloric intake, protein restriction should probably be avoided in the renal transplant recipient. A diet containing at least 1 gm/kg/day of protein and 25-35 kcal/kg/day appears to be the best compromise in the stable, long term renal allograft recipient (Table 23.1).

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Table 13.1.

Suggested dietary protein intake in the KTR Time Period Postoperative

23

Long-Term

Protein

1.5 gm/kg/d

1 gm/kg/d

Calories

30-35 kcal/kg/d

25-35 kcal/kg/d

Dyslipidemia Cardiovascular disease remains a leading cause of death in renal transplant recipients. In Europe, among long term KTRs, coronary artery disease is responsible for 32% of deaths, approximately equivalent to the number of deaths caused by infection. In the United States, 18% of all long-term KTRs die of coronary artery disease. Despite these findings, there are few studies elucidating the risk factors for cardiovascular disease in the kidney transplant patient. A recent retrospective review of 54 long term KTRs demonstrated significantly greater LDL and TC levels in KTRs vs. normal controls. Furthermore, blood lipid levels in KTRs with coronary artery disease were significantly greater than in KTRs without coronary disease suggesting an association between blood lipids and atherogenesis in the transplant population, analogous to their relationship in the general population. In another study, a Cox proportional hazard analysis of vascular disease risk factors for a large cohort of both cyclosporine and non-cyclosporine treated KTRs, determined that low serum high density lipoprotein (HDL) level was an independent relative risk factor for ischemic heart disease. Thus, in addition to other traditional risk factors for coronary artery disease, such as diabetes mellitus and hypertension that KTRs may have, it seems reasonable to conclude that elevated serum lipids place these patients at increased risk of cardiovascular disease and that lipid lowering strategies may be beneficial (Table 23.2). The incidence of hyperlipidemia post transplantation is high; approximating 40% in one large study of over 500 subjects. The cause of hyerlipidemia in the KTR has multiple factors (Table 23.3). Diabetes mellitus, insulin resistance and weight gain all play a role. Additionally, immunosuppressive medications have a role. Prednisone has been shown to increase serum lipids in patients with systemic lupus erythematosis in a dose-related fashion. For each 10 mg increase in dose, prednisone increased TC by 7.5 mg/dl. In KTRs, prednisone has also been shown to increase LDL and TC while reducing HDL. Blood lipids are also affected by cyclosporine. In a trial evaluating the effectiveness of cyclosporine in treating psoriasis, TC and triglycerides were significantly increased during cyclosporine treatment and diminished after discontinuation of cyclosporine. Studies in KTRs have shown cyclosporine treatment to be associated with a significant increase in serum lipids. However, because of concomitant use of prednisone, the attributable effect of cyclosporine on blood lipids in these studies could not be independently assessed. With regard to treatment of dyslipidemias, it has been well established that reduction of TC and LDL in hypercholesterolemic patients in the general population significantly reduces the number of coronary events and coronary deaths. This has been

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Table 13.2.

363

Cardiovascular risk factors in the KTR

Hypertension Dyslipidemia—low HDL Diabetes Mellitus Hyperhomocysteinemia?

Table 13.3.

Causes of hyperlipidemia in the KTR

Medications: Prednisone, Cyclosporine Diabetes Mellitus Insulin Resistance Obesity

shown in both primary and secondary prevention trials. It has also been established that reduction of TC and LDL in patients in the general population who have coronary artery disease but, whose cholesterol is in the normal range by western standards, also reduces coronary artery disease endpoints. In all of these trials success was achieved through the combined use of dietary modification and HMG CoA reductase inhibitors. The use of the HMG CoA reductase inhibitors, lovastatin and fluvastatin, has been shown to be safe and effective in reducing TC and LDL, and in raising HDL in KTRs receiving azathioprine and/or cyclosporine and prednisone. Of note, in patients being treated with cyclosporine, HMG CoA reductase inhibitors did not change cyclosporine blood levels. Side effects such as muscle aches, frank myositis or laboratory abnormalities in creatinine phosphokinase, AST or ALT were minimized by reducing the maximum dose of the statin in KTRs to 20 mg per day. It should be pointed out that although these medications have been shown to be safe and effective in lowering TC and LDL as well as in raising HDL in KTRs, long-term efficacy and a survival benefit have not yet been demonstrated in this population. It is still a reasonable assumption however, that serum lipid lowering therapy in the hyperlipidemic KTR is beneficial because there is no evidence to suggest that elevated serum lipids in the KTR behave differently than in the general population. There is limited published research concerning the use of alternative lipid lowering agents in the renal transplant population (Table 23.4). A second line agent that has been shown to be very effective at reducing TC, LDL, and triglycerides, and can raise HDL in cyclosporine and noncyclosporine treated KTRs is nicotinic acid. While most patients in one study tolerated the dose of 1 gm twice a day without undue side effects, conclusions about safety must be limited due to the small number of subjects. Similarly, experience with the use of the bile acid sequestrant cholestyramine, is limited. Bile acid sequestrants significantly reduce TC and LDL in hypercholesterolemic patients but, there has been concern about impairment of cyclosporine absorption by the sequestrants. In one small study in KTRs, cholestyramine taken as a single 4 gm dose at least 4 hours after the last dose of cyclosporine did not affect the absorption of cyclosporine from the gastrointestinal tract. However, no information

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Table 13.4.

Treatment of hyperlipidemia*

Agent

23

Note

HMG Co-A r.i.s (ex. lovastatin, fluvastatin)

Preferred agent Reduces TC, LDL No change in CYA level Myositis Max dose of statin 20 mg qd

Nicotinic Acid

Reduces TC, LDL, TG Increases HDL Safety?

Cholestyramine

Reduces TC, LDL Impaired CYA absorption? Compliance?

Fish oil

Reduces TG Decreases platelet adhesion Fishy eruction

* in addition to dietary fat reduction

on efficacy of lipid lowering was provided. The strict compliance required to properly use cholestyramine, the large amount needed, the somewhat unpleasant taste, and the constipation associated with its use diminish enthusiasm to evaluate this agent further. Based on epidemiological evidence from the Greenland Eskimo population, who have a very low rate of CAD and a fish-rich diet, fish oil tablets have also been used in an effort to reduce blood lipids. In one study conducted in KTRs however, the administration of fish oil tablets had no effect on TC, LDL, or HDL. Fish oil did significantly reduce serum triglycerides and decrease platelet adhesion in response to ADP which may be beneficial in reducing atheromatous plaque thrombus formation. The only significant side effect from fish oil consumption was fishy eruction, which, overtime, the participants in the study reportedly grew accustomed to.

Vitamin Supplementation In addition to lipid lowering agents, vitamin supplementation has been proposed as an intervention to lower the risk of coronary artery disease in patients at risk. Folic acid supplementation, in particular, has been the subject of considerable investigation. Folic acid is a requisite factor in one of the metabolic pathways of the sulfur-containing amino acid, homocysteine (HCY), which was first linked with accelerated atherosclerosis nearly three decades ago. In vitro evidence suggests that HCY can both directly and indirectly, via enhancement of lipid peroxidation, produce endothelial injury. Epidemiological investigations have demonstrated a strong correlation between elevated plasma HCY levels (hyperhomocysteinemia) and the frequency of vascular disease. In fact, hyperhomocysteinemia has been shown to be an independent risk factor for primary as well as secondary cardiovascular disease in the general population. Increased levels of plasma HCY have been demonstrated in a variety of acquired disease states including folate deficiency and renal insufficiency. Present in 75% of

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ESRD patients in one study, hyperhomocysteinemia was 33 times more common in ESRD patients than in controls, and was far more common (2- to 15-fold) than traditional risk factors for cardiovascular disease. Longitudinal follow up to determine if HCY levels correlate with incident cardiovascular disease rates in ESRD is ongoing. The effect of restoration of renal function through transplantation and of the administration of folic acid supplements on homocysteine metabolism in the KTR has been recently examined. In 27 long-term, non-cyclosporine treated KTRs with creatinines ranging from normal to 0.5 mmol/l, plasma HCY level in the KTR was inversely proportional to renal clearance. In addition, it was possible to reduce HCY levels via folate supplementation (1-5 mg/day) as similarly demonstrated in normal patients, dialysis patients, and in patients with renal insufficiency. Immunosuppressive therapy may have an independent effect on HCY metabolism. Specifically, cyclosporine therapy can raise plasma HCY independently of renal function and may abrogate the HCY lowering effect of folic acid via interference with the folate dependent metabolism of homocysteine. Despite the aforementioned studies, the clinical relevance of hyperhomocysteinemia to cardiovascular disease in the KTR population is unclear. In a previous multivariate analysis of cardiovascular risk factors in stable long-term renal transplant patients, HCY levels were not considered. Past cross-sectional comparison of HCY levels in KTRs with and without cardiovascular disease demonstrated significantly greater HCY levels in transplant patients with cardiovascular disease compared to patients without it. Since comparisons were uncontrolled for differences in time at which sampling of plasma HCY and the cardiovascular event occurred, and lacked matching for other cardiovascular risk factors, conclusions about causality could not be firmly drawn. Hence, the contributory role of hyperhomocysteinemia in the development of cardiovascular disease in the KTR requires further investigation. Vitamin supplementation with alpha tocopherol, vitamin E, as a means of reducing cardiovascular disease risk has also been a subject of considerable investigation in the general population. In vitro, vitamin E supplementation increases the resistance of LDL to oxidation which may result in improved endothelial cell vasodilator function, decreased foam cell formation, and decreased chemotactic signals for monocytes—all proposed mechanisms which contribute to the atherogenic process. In addition, growing epidemiological evidence suggests that vitamin E supplementation reduces the risk of myocardial events and possibly reduces the risk of death from myocardial infarction in the general population. However, no data currently exists to support the efficacy or safety of supplemental vitamin E in the kidney transplant population.

Bone Metabolism Kidney transplantation is the second most frequently used modality of renal replacement therapy in the United States, serving the needs of 27.1% of the end-stage renal disease population. As KTRs live longer, long term complications, such as post transplantation bone disease start to impact on patient morbidity. Osteoporosis is a condition wherein bone density is reduced such that fracture risk is dramatically increased. Significant declines in vertebral bone mineral density (BMD) have been observed not only during the first years after kidney transplantation, but continuously for rates up to -1.7% per year for several years post transplantation.

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In a recently conducted cross-sectional study among long-term KTRs, the prevalence of osteoporosis at the hip or spine was 42%. Osteoporosis has been reported not only in KTRs but in heart and liver transplant recipients as well. These findings suggest that the loss of bone is quite prevalent and may be attributed not entirely to previous renal osteodystrophy but to transplantation itself. Various mechanisms have been proposed to explain the pathogenesis of bone loss in KTRs (Table 23.5). Bone mass is governed by the two dynamic and opposing forces of bone resorption and bone formation. Previously, bone loss during the first year post transplantation, was attributed to a decrease in bone formation rate, or a low bone turnover state, as a result of corticosteroid therapy. Recently however, long-term KTRs more than a year after transplantation were found to have a high bone resorption and turnover state. Furthermore, their high bone resorption rate was correlated with reduced BMDs. The etiology of this accelerated resorption of bone tissue remains unknown. Despite the restoration of normal renal function and calcium homeostasis by a functioning allograft, a hyperplastic parathyroid gland could occasionally fail to involute and lead to persistent hyperparathyroidism. This residual hyperparathyroidism could cause the high bone resorption and turnover which would eventually lead to bone loss. The immunosuppressive drugs, cyclosporine and FK506, have also been shown to cause a high turnover bone loss. Vitamin D deficiency does not appear to be a major cause of reduced bone mass in KTRs with decent allograft function. Several studies have consistently shown adequate stores of 25(OH)-Vitamin D and 1,25 (OH)2-Vitamin D in KTRs even in those with reduced BMD. Several treatment regimens have been evaluated to reduce the high turnover bone loss associated with transplantation. The agents, calcitonin (40 IU IM daily) or disodium etidronate (400 mg/day p.o. for 15 days every three months), increased vertebral BMD in liver transplant patients compared to the untreated historical control group. In a randomized study, a regimen consisting of 40 µg of 25(OH) -Vitamin D3 and 3 grams of calcium taken daily significantly minimized the reduction in the lumbar, femoral and total body BMD in KTRs. However, these studies are limited by their relatively short duration of follow up. Further studies are needed to evaluate and compare the long-term efficacy and safety of these different regimens in the prevention and treatment of post transplant bone disease.

Summary Malnutrition is highly prevalent in the pretransplant ESRD population and is associated with increased morbidity and mortality. Hence, attention to nutritional prescription in the perioperative period is particularly important to avoid compounding an already compromised nutritional state. The well known protein catabolic effect of glucocorticoid therapy can be abrogated by ensuring adequate caloric and dietary protein intake. Optimally, the protein and caloric intake in the perioperative period should be at least 1.5 gm protein/kg/day and 30-35 kcal/kg/day. The optimal long-term dietary prescription of the KTR is controversial. Maintenance of nitrogen balance needs to be balanced by the theoretical risk of hyperfiltration induced by dietary protein loading. In summary, because it appears difficult to achieve a protein restricted diet without compromising essential caloric intake, protein restriction should probably be avoided in the long term renal transplant recipient. A diet containing 1 gm/kg/day and 25-35 kcal/day appears to be the best compromise in the stable renal allograft recipient.

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Table 13.5.

367

Causes of bone loss in the KTR

Residual Hyperparathyroidism Medications— Corticosteroids Cyclosporine FK506

A major cause of mortality in the KTR remains cardiovascular disease which has been linked to markers of malnutrition in other populations, specifically to alterations in lipid metabolism. In conjunction with a low fat diet, careful pharmacological therapy with HMG CoA reductase inhibitors appears to be safe and effective in the short-term treatment of dyslipidemias in the transplant patient. Since there is currently no evidence to suggest that lipids in the KTR behave differently than in the general population, it is reasonable to assume that KTRs will benefit from serum lipid reduction until a treatment outcomes study suggests otherwise. An alternate nutritional parameter that may be associated with enhanced cardiovascular disease risk in the KTR, hyperhomocysteinemia, should also be considered. In non-cyclosporine treated KTRs, hyperhomocysteinemia can be modified by nutritional supplementation with folic acid. Since folate supplementation is relatively innocuous, modest repletion (5 mg/day) should be considered in this group. The utility of folate supplementation in the vitamin-replete cyclosporine treated KTR is less clear. Bone disease remains a significant cause of morbidity in the long-term renal allograft recipient. Further studies are needed to evaluate and compare the long-term efficacy and safety of different regimens in the prevention and treatment of post transplant bone disease. Several therapeutic interventions hold promise for attenuating the debilitating bone-associated side effects of immunosuppressive medications. Because of limited original research concerning nutrition in the KTR, the true impact of altered nutrition in the KTR is poorly understood. Additional investigations correlating measures of nutrition to specific renal transplant patient and allograft outcomes are needed.

Selected References 1. 2.

3. 4. 5. 6.

Ikizler TA, Hakim RM. Nutrition in end-stage renal disease. Kidney Intl 1996; 50:343-357. Cogan MA, Sargent JA, Yarbrough SG et al. Prevention of prednisone-induced negative nitrogen balance:effect of dietary modification on urea generation rate in patients on hemodialysis receiving high-dose glucocorticoids. Ann Int Med 1981; 95:158-161. Whittier FC, Evans DH, Dutton S et al. Nutrition in renal transplantation. Am J of Kidney Dis 1985; 6(6):405-411. Miller DG, Levine SE, D’Elia JA et al. Nutritional status of diabetic and nondiabetic patients after renal transplantation. Am J Clin Nutr 1986; 44:66-69. Horber FF, Zurcher RM, Herren H et al. Altered body fat distribution in patients with glucocorticoid treatment and in patients on long-term dialysis. Am J Clin Nutrition 1986; 43:758-769. Salahudeen AK, Hostetter TH, Raatz SK et al. Effects of dietary protein in patients with chronic renal transplant rejection. Kidney Intl 1992; 41;183-190.

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11. 12. 13. 14. 15. 16. 17. 18. 19. 20.

Windus DW, Lacson S, Delmez JA. The short-term effects of a low-protein diet in stable renal transplant recipients. Am J Kidney Dis 1991; 17(6): 693-699. Kasiske BL, Guijarro C, Massy ZA et al. Cardiovascular disease after renal transplantation. J Am Soc Nephrol 1996; 7:158-165. Hilbrands LB, Demacker PNM, Hoitsma AJ et al. The effects of cyclosporine and prednisone on serum lipid and (apo)lipoprotein levels in renal transplant recipients. J Am Soc Nephrol 1995; 5:2073-2081. Goldberg R, Roth D. Evaluation of fluvastatin in the treatmentof hypercholesterolemia in renal transplant recipients taking cyclosporine. Transplantation 1996; 62:1559-1564. Lal SM, Hewett JE, Petroski GF et al. Effects of nicotinic acid and lovastatin in renal transplant patients: A prospective, randomized, open-labeled crossover trial. Am J Kidney Dis 1995; 25:616-622. Jensen RA, Lal SM, Diaz-Arias A et al. Does cholestyramine interfere with cyclosporine absorption? A prospective study in renal transplant patients. ASAIO J 1995; 41:M704-706. Urakaze M, Hamazaki T, Yano S et al. Effect of fish oil concentrate on risk factors of cardiovascular complications in renal transplantation. Trans Proc 1989; 21:2134-2136. Nygard O, Nordrehaug JE, Refsum H et al. Plasma homocysteine levels and mortality in patients with coronary artery disease. New Engl J Med 1997; 337:230-236. Arnadottir M, Hultberg B, Vladov V et al. Hyperhomocysteinemia in cyclosporinetreated renal transplant recipients. Transplantation 1996; 61(3):509-512. Kirkman RL, Strom TB, Weir MR et al. Late mortality and morbidity in recipients of long-term renal allografts. Transplantation 1982; 34:347-351. Pichette V, Bonnardeaux A, Prudhomme L et al. Long-term bone loss in kidney transplant recipients: A cross-sectional and longitudinal study. Am J Kidney Dis 1996; 28:105-114. Cayco AV, Wysolmerski J, Simpson C et al. Posttransplant bone disease: Evidence for a high bone resorption state. J Am Soc Nephrol 1997; 8:549A. Valero MA, Lonaz C, Larrodera L et al. Calcium and biphosphonates in bone loss after liver transplantation. Calcif Tissue Int 1995; 57:15-19. Talalaj M, Gradowska L, Marcinowska-Suchowierska E et al. Efficiency of preventive treatment of glucocorticoid-induced osteoporosis with 25-hydroxyvitamin D3 and calcium in kidney transplant recipients. Transplant Proc 1996; 28:3485-3487.

CHAPTER 1 CHAPTER 24

Biology of Nutrition Support in the Critically Ill Patient Rifat Latifi, Selman Uranües

Introduction The vocabulary and the practice of nutrition support of critically ill patients have changed significantly in recent years, and new era of nutri-pharmaceutics has become integral part of patients’ care. The question to be answered is not any longer should critically ill patients be fed or not, but rather when to feed and what to feed them. The benefit of early institution of enteral or parenteral nutrition in the overall management of critically ill patients has been well established. Following injury, energy requirements are greatly increased to sustain the increased metabolism and wound repair. Similarly protein requirements are also greatly increased to provide substrate for protein synthesis. In this situation, provision of calories and nitrogen in a ratio of 150:1 has been shown to be most efficacious in achieving a positive balance. However it is not yet completely understood whether improved nitrogen balance in patients receiving TPN is achieved by an increase in protein synthesis or a decrease in protein (muscle) catabolism. Irrespective of these results, it is well established that TPN is associated with improved nitrogen balance in critically ill patients. In general, the optimal route of providing nutrition in critically ill patients has been established: use the gastrointestinal tract whenever possible. If, on the other hand, a patient will not receive all needed nutrient substrates and calories enterally, then nutrition should be provided parenterally. Because of recent advances, in identifying and recognizing fundamental metabolic changes of key nutrient substrates in critically ill patients, nutritional formulas are being designed to overcome these changes and support the organism during critical illness, infection, trauma or severe sepsis. Example of such approach to nutritional support of critically ill patients is the provision of immune-enhancing formulas (IEF) that have been shown to improve immune response in laboratory animals and in critically ill patients. These enteral formulas contain increased amounts of peptides, arginine, glutamine, vitamins E, A, and C, nucleotides and nucleosides, branched- chain amino acids and omega 3-fatty acids. It is suggested that these key nutrients can modulate and affect a variety of inflammatory, metabolic, and immune processes if given in doses higher than those recommended. Based on current evidence derived from randomized prospective controlled trials, early provision of nutrition in critically ill patients is a Level I recommendation,1 however the controversy exists on what type of nutrition formula should be used.

The Biology and Practice of Current Nutritional Support, 2nd Edition, edited by Rifat Latifi and Stanley J. Dudrick. ©2003 Landes Bioscience.

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Protein and Nitrogen Metabolism in Critically Ill Patients

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Severely injured and critically ill patients characteristically demonstrate significant muscle losses and consequently are in negative nitrogen balance. During critical illness, dietary amino acid requirements are increased two to three times as a result of hypercatabolism and inefficient reutilization of endogenous nitrogen. Furthermore, amino acids are redistributed from peripheral tissues to splanchnic organs to maintain protein synthesis in the gut mucosa and immune system. Although different tissues have varies rates of protein synthesis and, respond differently to stress and trauma, both muscle protein and albumin synthesis rate correlate with the metabolic status and severity of the disease. A brief period of accentuated proteolysis, ureagenesis and negative nitrogen balance is tolerated by the stressed, but well-nourished patient. If the patient is malnourished prior to injury or surgery, or develops a complication that precludes adequate oral intake or if a patient sustain a prolonged catabolic phase, then special nutritional support is indicated. Metabolic response to injury is the striking increase in protein catabolism along with a marked increase in urinary losses of nitrogen, phosphorus, sulfur, potassium, magnesium, and creatinine. Skeletal muscle and nitrogen losses following injury may occur secondary to actual destruction of tissue by injury, blood loss, and exudates from wounds, and muscle wasting secondary to atrophy. The process of increased nitrogen losses is complex and correlates with increased metabolic rate, which peaks several days after injury and gradually returns towards normal over several weeks.1-5 This phenomenon occurs consistently following major fractures or major blunt injury, burns, sepsis and various other injuries.6-10 The mechanism for net protein increase is not entirely clear, although hormonal effect of insulin resistance, cortisol effects, and proinflammatory cytokines activity have synergistic effects. Diminished activity of antioxidants such as gluthatione may effect protein stability within the cell it self. Metabolic response to severe surgical illness is associated with mobilization and utilization of nutrient substrates such as fatty acids, amino acids and glucose. Although, there is a well orchestrated redistribution of body protein from carcass to visceral organs, the rates of tissue protein synthesis varies with different trauma, but correlates with clinical status and overall metabolic indices and is clearly exacerbated during criticall illness and directly is influenced by the illness it self, the PO2, pH, and hemoglobin.11 An increased muscle protein catabolism following injury has been demonstrated by measuring the excretion of 3-methyhistidine, which serves as an index of muscle protein catabolism.9 As protein is broken down, 3-methylhistidine is released and excreted unchanged by the kidneys especially following critical injury, burns, post- operative trauma, infections and other critical illness.10 The primary origin of the 3-methylhistidine is skeletal muscle, but some of it is derived from the smooth muscle of the gastrointestinal tract. During periods of starvation and bowel rest, the intestine may become the source for large portion muscle losses and increased amount of excreted 3-methylhistidine.

Amino Acid Metabolism Although plasma amino acid levels have been measured in critically ill and injured patients in an effort to identify specific changes related to the catabolic response, the results have been inconsistent.12 The mobilization of amino acids from muscle protein leads to an irretrievable loss of nitrogen from the body in the form of urea, ammonia, uric acid, creatinine and other excreted compounds. If left uncorrected, the adverse consequences for the critically ill patient are a rapid loss of muscle

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mass and subsequent marked debility. All amino acids are required for optimal protein synthesis; however, alanine and glutamine are the major carriers of nitrogen from muscle, constituting as much as 70% of the amino acids released from skeletal muscle following injury.13 Alanine is a major substrate for production of glucose by the liver, and during that conversion, the nitrogen released is incorporated into urea. This represents the final breakdown step of the protein and results in an irreversible loss of nitrogen from the body’s metabolic pool. Glutamine, a nonessential amino acid, serves as an important respiratory substrate for the enterocytes and other rapidly dividing cells, including the bone marrow, endothelial cells, and proliferating cells in wounds and areas of inflammation.14,15 Following surgical interventions, glutamine consumption by the gastrointestinal tract is greatly increased.16,17 Glutamine has been identified as primary fuel for enterocytes, and for other rapidly dividing masses of cells where it is converted to alanine The utilization of glutamine by the intestine as an oxidative fuel has a sparing effect on glucose. During the sepsis, glutamine depletion is even more severe and lasts longer than that associated with the hypercatabolism following injury. In sepsis, the lung and the kidney, in addition to the skeletal muscle, becomes an organ of net glutamine release.18,19 Furthermore, during the sepsis the liver has increased glutamine uptake, and becomes the primary organ for glutamine utilization.19 In the presence of endotoxemia, glutamine may be used in the liver for gluconeogenesis, ureagenesis and synthesis of proteins, nucleotides, and glutathione.20,21 Following surgery, severe injury or sepsis, the rapid fall in the concentration of glutamine in the plasma and in the intracellular pool is greater than that of any other amino acid and is inversely correlated with the severity of the underlying insult. It is reversed only late in the course of recovery.21 This marked decline in glutamine concentrations in blood and tissues during critical illness indicates that glutamine is being consumed at a greater rate than endogenous synthesis. Thus, it has been hypothesized that glutamine is a conditionally essential nutrient, especially following injury. Glutamine supplementation has been shown to exert trophic effects on intestinal mucosa. TPN solutions enriched with glutamine22 increase jejunal mucosal weight, nitrogen and DNA content, and significantly decrease atrophy of the villi. Furthermore, glutamine prevents deterioration of gut permeability,23 and has been proven beneficial for patients with intestinal mucosal injury secondary to chemotherapy and radiation.24,25 Reduction of hepatic steatosis,26 pancreatic atrophy27 and in bacterial translocation from the gut,28 associated with standard TPN solutions have been reported with the use of glutamine supplemented TPN solutions. Glutamine also improves the nitrogen balance and reduces the skeletal muscle glutamine loss in patients following elective cholecystectomy29 and other major surgeries. Administration of glutamine in TPN as glutamine-containing dipeptides has decreased the incidence of infections in bone marrow transplant patient.31 Arginine is considered a nonessential amino acid in the diet of healthy adults because the endogenous synthetic pathways provide adequate amounts of this amino acid. Arginine stimulates release of growth hormone and prolactin, and also induces a marked release of insulin.32 Supplementing the diet with arginine has been shown to improve weight gain, increase nitrogen retention, and accelerate wound healing in animals and in human beings.33 The trophic effects of arginine on the immune system in human beings have also been demonstrated.34 In both animals and human beings, plasma arginine levels decreases significantly following a burn injury.35 Experimentally, arginine and glutamine as well as dehydroepiandrosterone reversed

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the susceptibility to infections caused by prednisone and may be useful agents for preventing infections in patients treated with steroids.36

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Following injury and sepsis, an energy deficit that may develop in skeletal muscle is met by an oxidation of the BCAA. BCAA oxidation is increased after trauma and sepsis, and evidence indicates that skeletal muscle is the major site of BCAA degradation.37-41 Most recent study has demonstrated that when critically ill patients, unable to be fed enterally, were given total parenteral nutrition fortified with BCAA of 23% and 45% respectively, as compared with standard TPN which provided 1.5 g/kg/day of protein, they had significantly lower morbidity and mortality (42). The decrease in mortality correlated with higher doses of BCAA to or > 0.5 g/kg/day). Furthermore, BCAA rich parenteral nutrition formulas have been shown to correct the plasma amino acids imbalance that consistently exist in critically ill patients, and improves plasma concentrations of pre-albumin and retinol binding protein in septic patients. In a series of trauma patients, nitrogen retention, transferrin level and lymphocyte counts were all improved with BCAA supplementation. Since the concentration of BCAA is low in septic patients, probably as a result of over utilization, supplementation of feeding regimen with BCAA may be beneficial.

Nucleotides and Nucleic Acids in Nutritional Support Nucleotides, as building blocks of DNA and RNA, are essential to genetic mechanism, protein synthesis, regulation and structure. These low molecular weight, highly biological compounds, are involved in virtually all biochemical processes.43-61 They consist of a nitrogenous base, a 5-carbon sugar, and at least one phosphate group. RNA and DNA are high-molecular-weight compounds that are made up of long chains of nucleotides. They form the genetic code and are essential for protein synthesis. They function as an energy source in cellular metabolism and as intermediates in biosynthetic and oxidative pathways. The synthesis of nucleotides is a major activity of the cell. Next to protein synthesis, nucleotide synthesis consumes more amino acids than any other biologic activity. Nucleotides contain either purine or pyrimidine bases. Adenine, inosine, and guanine, are purine bases, while thymidine, cytosine and uracil are pyramidine bases. Purine nucleotides are synthesized de novo from glutamine, glycine, aspar tate, CO2, and phosophoribosylpyrophosphate (PRPP), while pyrimidines are synthesized from aspartate or glutamine, NH3, and CO2. Purine nucleotides, with their high-energy phosphate side chains are fundamental to cellular energy metabolism and are intermediaries in biosynthetic and oxidative pathways. Purine nucleotide biosynthesis produces inosine monophosphate (IMP). IMP is synthesized by the de novo pathway of purine biosynthesis from glycine and is then converted to AMP and GMP. The three main sources of nucleotides are: dietary nucleotides, salvage of nucleotides released by intracellular metabolism, de novo synthesis from amino acids and sugars. The addition of a pentose sugar to a nitrogen base produces a nucleoside. Depending on which sugar is added to the nitrogen base, a nucleoside can be ribonucleoside or a deoxyribonucleoside. Nucleosides are produced by intracellular metabolism and are used for purine biosynthesis via the salvage pathway. The most common pathway is the resynthesis of IMP from inosine, which is a product of adenosine nucleotide metabolism.

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The adenosine monophosphate (AMP), adenosine diphosphate (ADP) and adenosine triphosphate (ATP), are energy sources and participants in carbohydrate, protein, and lipid synthesis. Nucleotides are required in all cells undergoing proliferation, but they are especially important in tissues with rapid cell proliferation such as intestine, liver, and lymphoid tissue. T lymphocytes require nucleotides to maintain a normal cellular immune response. Various tissues in the body, such as liver, are capable of synthesizing nucleotides de novo. When tissues are unable to synthesize purine nucleotides, purines are transported from another tissue. For example, adenosine is released from the liver and taken up by the lung in large amounts. The small intestinal mucosa requires a constant supply of nucleotides to produce DNA and RNA. In these rapidly proliferating cells, the content of DNA and RNA must double for cell division to occur. However, in these cells, the enterocyte has a limited capacity for de novo biosynthesis. The small intestine must rely on the salvage pathway to synthesize nucleotides from nucleosides. The nucleosides—inosine, adenosine, and so on, come either from the blood, or from luminal nucleosides. The latter may come from the diet, and the sloughing of enterocytes, or from bacterial breakdown. In addition, nucleotides themselves can be absorbed from the intestinal lumen. It is clear that the small intestinal mucosa relies partially on intestinal nucleotides and nucleosides to meet synthetic demands. There are at least two significant implications. The first is that diets that contain no nucleotides or nucleosides may not offer sufficient support to the intestinal diets that contain no nucleotides or nucleosides may not offer sufficient support to the intestinal mucosa in some circumstances. This includes many enteral diets, especially elemental diets, and includes all varieties of total parenteral nutrition (TPN). The second implication is that nucleotide or nucleoside supplementation could be beneficial to critically ill patients. This type of supplementation has been implemented clinically in certain enteral products. Nucleotides exert multiple protective actions on the intestinal mucosa and facilitate repair of injured mucosa. Experimental rats receiving TPN supplemented with nucleotides showed higher protein and DNA content in intestinal mucosa, increased maltase activity, higher villous height, and more proliferative activity in crypt cells compared with rats receiving nucleotide-free TPN. In mice, intraperitoneal and oral administration of a mixture of nucleotides and nucleosides reduced bacterial translocation and improved repair of mucosal injuries. Clinically, the frequency of diarrhea in children was reduced from 68% to 52% when milk formulas were supplemented with nucleotides. While the basis for this protective action is unclear, although it is known that dietary nucleotides enhance intestinal epithelial proliferation and differentiation. The metabolic fate of any exogenously administered nucleotide depends on its entry position in the overall pathway of purine metabolism. Nucleic acids undergo partial hydrolysis in the stomach, after which they are subjected to pancreatic nuclease to yield nucleotides. Phosphodiesterases and alkaline phosphatases cleave phosphate groups to form nucleosides. The presence of charged phosphates in nucleotides impedes their transport across cell membranes. Phosphates remove the charged phosphates and together with nucleotidase facilitate transport across the cell membrane. Dietary nucleotides converge in the cell cytoplasm in the form of nucleosides, which are then used in the salvage pathway to reform nucleotides. Nucleotides may be supplied either enterally or parenterally. Parenterally administered purine and pyrimidine derivatives are effectively used throughout the salvage pathway. TPN

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formulas supplemented with a mixture of nucleotides and nucleosides can promote ulcer healing in rats by restoring villous architecture and accelerating cell proliferation. TPN supplemented with a mixture of nucleotides and nucleosides in animals undergoing massive intestinal resection resulted in significantly higher residual jejunal total mucosa weight, protein, DNA, RNA, and the ratio of proliferating cells per crypt a compared with a standard TPN formula. The clinical use of nucleotides in liver disease has been suggested in order to improve healing of the liver. Experimental studies have suggested beneficial effects. A mixture of nucleotides and nucleosides given subcutaneously prevented ethionine-induced liver injury by suppressing the accumulation of triglycerides in the liver, reducing the increase of liver enzymes, and preventing the decrease of hepatic ATP concentration. In rats undergoing a 70% hepatectomy, supplementation of TPN regimens with nucleotides and nucleosides improved both nitrogen balance and whole body protein turnover. Nucleotide supplementation was beneficial in galactosamine induced liver injury by reducing the extent of injury histologically and by improving clinical biochemical liver indices. Currently, nucleotides are not included in standard TPN solutions, however there are now enteral formulas fortified with nucleotide (in addition to arginine, omega-3 fatty acids, and glutamine) that are intended to enhance the immune system in patients receiving them. The immunologic role of nucleotides has been studied mainly in experiments with nucleotide-free diets. In the early 1980’s it was observed that renal transplant patients receiving standard nucleotide-free TPN had better graft function with few rejection episodes and required lower doses of immunosuppressants. Once on a regular diet, these patients required increased doses of immunosuppressants to maintain graft function and prevent rejection. Clearly, the patients were immunosuppressed on TPN. It was postulated that lack of preformed nucleotides in TPN was a cause of this immunosuppression. Animal studies have demonstrated the effects of nucleotide-free diets. Such diets diminish T cell mediated immune responses such a delayed-type cutaneous hypersensitivity to various antigens, decreased mitogenic response, and reduced interleukin-2 production. There is also evidence of decreased survival from systemic infections caused by Staphylococcus aureus and Candida albicans in animal fed a nucleotide-free diet. The increased susceptibility to systemic infections has been shown to reverse with RNA supplementation. Furthermore, nucleotide deficiency reduces splenic stem cell proliferation. This can be reversed with RNA supplementation. Dietary nucleotides modulate T helper cell –mediated antibody production and have a preferential effect on antigen-driven T helper cell-mediated immune response. Nucleotides and nucleosides are major and essential components of all cells. The metabolic rate of nucleotides is accelerated in hypermetabolic conditions such as sepsis, trauma, or surgical stress. Substantial evidence suggests that these nutrients are conditionally essential for normal stress responses. The conditions that increase nucleotide requirements are rapid cellular proliferation and include hepatic injury or resection, intestinal development and adaptation following massive intestinal resection, and other nonspecific challenges to the host immune system. Nucleotides are a component of several “immune-enhancing” formulas that also contain glutamine, arginine, and omega 3-fatty acids. These formulas have been shown to be beneficial in multiple clinical trials. Glutamine, arginine, nucleic acid, and omega 3-fatty acid supplemental enteral feeding in severe trauma patients

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reduced major infection rate, decreased the use of antibiotics, and shortened hospital stays, In a prospective, randomized, placebo-controlled, double-blinded, multicenter trial of patients in the surgical intensive care unit, early enteral feeding supplemented with arginine, nucleotides, and omega 3-fatty acids was shown to reduce postoperative and wound complications. Septic patients fed early enterally with the same supplemented diet (in another double blinded multi-center study) had a substantial reduction in the hospital stay. No clinical study has examined the beneficial effect of isolated nucleotide supplementation in enteral feeding formulas critically ill or trauma patients. However, as a component of an immune-enhancing formula, nucleotides have a role in nutritional support of the critically ill. Nucleotides should not be administered as a calorie source, only as a promoter of protein synthesis and cellular immunity. It seems likely that nucleotides will become an essential component of nutri-pharmacologic intervention in critically ill and trauma patients. Published studies have used different terms to describe various nucleotide supplementation regimens including nucleotides, polynucleotides, nucleotide-nucleoside mixtures, RNA, and purines and pyrimidines Purine nucleotides with their high-energy phosphate chains are fundamental to cellular energy metabolism and are intermediaries in biosynthetic and oxidative pathway. Nucleotides exert multiple protective actions on intestinal mucosa and facilitate repair of injured mucosa. They prevent ethionine-induced liver injury by suppressing accumulation of triglycerides in the liver, reducing the increase of liver enzymes, and preventing the decrease of hepatic ATP concentration. In rats undergoing a 70% hepatectomy, supplementation of TPN with nucleotides and nucleosides improved both nitrogen balance and whole body protein turnover. Furthermore, nucleotide supplementation was beneficial in galactosamine-induced liver injury by reducing the extent of injury histologically and by improving clinical biochemical indices. The turnover rate of nucleotides is accelerated in hypermetabolic conditions such as sepsis, trauma or surgical stress. Substantial evidence suggests that these nutrients are conditionally essential for normal stress response.

Omega 3-Fatty Acids The ability of omega 3-fatty acids to incorporate into a cell membrane and their use during the inflammatory process, as well as their ability to modify the inflammatory response, is the rationale for their use in dietary formula in critically ill patients.62 Omega 3-fatty acids affect cytokine production, decrease both tumor necrosis factor (TNF α) and IL-1 synthesis and significantly modulate the inflammatory response in adult respiratory distress syndrome (ARDS).63

Growth Hormone Growth hormone has been shown to attenuate the protein catabolic response after major surgery, induce nitrogen retention in patients undergoing gastrointestinal surgery with epidural anesthesia and TPN, and attenuate forearm glutamine, alanine, 3-methylhistidine and total amino acid efflux. Moreover, growth hormone has been shown to preserve both muscle protein synthesis and the decrease in muscle-free glutamine, and improve the whole-body nitrogen economy after surgery.64 In addition, growth hormone has been shown to reduce skeletal muscle release of glutamine. Most recently growth hormone and insulin-like growth factor 1 was shown to promote intestinal uptake and hepatic release of glutamine in sepsis.65 Use of growth hormone in critically ill patients, however, has become controversial66-74

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While GH administration was shown to accelerate protein gain in stable adult patients receiving aggressive nutritional support, and attenuate the catabolic response to injury, surgery, and sepsis, more recently GH treatment in critically ill patients has been associated with increased mortality and morbidity. In a prospective, multi-center, double blind, randomized placebo-controlled trial, patients treated with high dose GH (0.1 mg/kg body weight) had higher mortality rate then patients who did not receive GH (p<0.001).66 Because of conflicting results of studies, administration of high dose GH is not recommended in critically ill patients.

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Enteral formulas fortified with immune-enhancing substrates are associated with significant reduction in the risk of infectious complications as well as reduction of overall hospital stay. Providing adequate standard enteral or parenteral nutrition support does not necessarily protect critically ill patients from developing nosocomial infections. Since most critically ill patients are immuno-commpromized modulating or enhancing their immune status with nutrient substrates has great potential.75-80 It has been demonstrated that certain nutrients can modulate inflammatory, metabolic and immune processes. Amino acids such as arginine and glutamine, improve body defenses, tumor cell metabolism, increase wound healing and reduce nitrogen losses. RNA and omega 3-fatty acids also modulate the immune function. To this end, supplementation of enteral diets in critically ill patients with specific immuno-nutrients such as arginine, glutamine, nucleotides, nucleosides, and omega 3-fatty acids in critically ill patients have been shown to be clinically beneficial. These immune-enhancing formulas improve immune response experimentally as well as clinically. Studies performed in burn, trauma, or surgical patients have shown outcome advantages with reduction in infections, total complications, or length of stay. The majority of the prospective, randomized, clinical trials published to date used formula fortified with arginine, RNA, omega-3 and omega-6 fatty acids. Although various formulas are used they all were associated with improved outcome. The mortality rate however, has not been reduced by the use of these immune-enhancing formulas. The effect of the first immune-enhancing formula on the length of hospital stay and complication rate of critically ill and septic patients was studied in a multi-center study of 296 traumas, post-surgery and septic patients.75 The patients in this study had entry requirements of an APACHE II score greater then 10 and therapeutic intervention score (TIS) greater than 20, and were stratified by age (less than 60 or greater than 60 years) and whether they had sepsis or systemic inflammatory response syndrome (SIRS), highlighted by fever and leukocytosis. One hundred sixty-eight patients were randomized to receive the fortified formula, while 158 were fed with isonitrogenous enteral diet. Both groups tolerated early feeding well, had a low tube-feeding related complication rate, and achieved similar nitrogen balance. Patients receiving diet supplemented with arginine, nucleotide and fish oil had higher levels of plasma arginine and ornithine concentration. Furthermore, their plasma fatty-acids profiles demonstrated higher concentration of linoleic acid in patients with common formula (control group) while patients receiving immune-enhancing formula had higher concentrations of eicosapentaenoic acid and docosahexaenoic acid. There were no differences in mortality between the groups, however both groups had overall lower than expected mortality. Moreover, patients who received at least

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821 mL/day of enteral diet had an average length of hospital stay reduced by 8.1 days. Most beneficial effects were demonstrated in severely and septic patients with reduction of length of hospital stay by 10 predicted days along with a major reduction in frequency of acquired infections (p< 0.01). In a subgroup of septic patients in whom early enteral feeding goals were achieved, the median length of stay was reduced by 11.5 days. In a group that was stratified as SIRS, there were no statistical differences in benefits between the groups. These investigators concluded that early enteral feeding in severely ill patients is safe and is associated with significant benefits, especially if patients were septic.75 Another immune-enhancing enteral diet containing glutamine reduced septic complications in patients with severe trauma.76 This study, unlike the previous study, had an isonitrogenous (INIC) control not receiving the immune enhancing diet (IEF). In a prospective, blinded study 35 severely injured patients with abdominal trauma supplemented with glutamine, arginine, nucleotides, and omega-3 fatty acids, or INIC diet (N=18). Nineteen other patients without enteral access served as a control. Significantly fewer major infections complications (6%) developed in patients that received IEF than in patients receiving INIC diet (41%, p = 0.02) or the control group (58%, p = 0.002). The hospital stay, antibiotic use, and the development of intra-abdominal infections were significantly lower in IEF group. Patients that were not fed had the highest rate of complications. In another prospective, randomized, placebo, double blind, multicenter study of surgical intensive care patents that underwent upper gastrointestinal surgery, clinical outcome and costs were compared.77 Early enteral feeding with arginine, dietary nucleotides, and omega-3 fatty acids was associated with significant reduction in the frequency rate of late post-operative infection and wound complications. Furthermore, the treatment cost was substantially reduced in the immune-nutrition group as compared with the control group. Immuno-nutrition (Impact, Novartis Nutrition, Minneapolis, MN) was given to 77 patients, while an isocaloric and isonitrogenous diet was given to 77 patients. Enteral feeding was initiated within 12-24 hours after surgery and advanced to a target volume of 80 mL/hr by post-operative day 5. There were no differences in early post-operative complications between the groups: however, there were significantly fewer late complications were significantly fewer in immune-nutrition group. Achieving nutritional goals early in critically ill patients with immune-enhancing enteral diet has been shown to greatly reduce morbidity and shorten time on mechanical ventilation.78 These investigators studies 390 critically ill surgical and medical patients. Of the 101 patients achieving early enteral nutrition (within 72 hours), 50 patients fed with Impact had a significant reduction in requirements for mechanical ventilation compared with controls. There was also an associated reduction in the length of hospital stay. The administration of immune-enhancing enteral nutrition had no clear benefits over standard high-protein enteral diets in burn patients, and was even found to increase the incidence of adult respiratory distress syndrome.41 Recent prospective double- blind, randomized trial of patients with major burns (>50% body surface) demonstrated that supplemental intravenous glutamine infused continuously over 24 hours was significantly better than just isonitrogenous amino acid solutions. In this study, 26 severely burned patients (20%-90% were randomized to either intravenous glutamine (0.57 g/kg/body weight) or isonitrogenous amino acid solutions (to give patients 0.57 g/kg/body weight, without glutamine) administered continuously in addition to enteral nutrition support,

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or enteral and parenteral nutrition, for those patients unable to achieve nutritional goals with enteral nutrition alone. The study group receiving glutamine had lower incidence of Gram-negative bacteremia (8% vs 43%; p=<0.04), and significant improvements in serum transferrin and prealbumin at 14 days after the injury (p<0.01 and 0.04, respectively). Furthermore, there was a trend toward lower mortality, decreased bacteremia incidence, and antibiotic usage in glutamine group.79 Other studies have shown similar results in multiple trauma patients, where use of glutamine was associated with significant reduction in the incidence of bacteremia, septic episodes, and pneumonia.80 Patients treated with glutamine, had no episodes of Gram- negative bacteremia, where as the 54% of all bacteremia and 63% of sepsis were caused by Gram-negative bacteria. Although the mechanism is not entirely clear, it appears from both these studies that glutamine protects from Gram- negative bacteria in these most critically ill patients. Meta-analysis of 11 randomized controlled clinical trials of enteral nutrition with immune-enhancing formula) that included 1009 patients,81 concluded that nutritional support supplemented with key nutrients (arginine, glutamine, branched-chain amino acids, nucleotides, and omega-3 fatty acids) results in a significant reduction in the risk of developing infectious complications and reduces the overall hospital stay in critically ill patients and in patients with gastrointestinal cancer. Although multiple studies have shown beneficial effect of IED, non- the less their use is not wide spread yet. A consensus panel from a recent conference on immune-enhancing enteral therapy,82 recommend the use of IED in the following patients: a) severely malnourished patients (albumin <3.5 g/dL) undergoing upper GI surgery, or patients with albumin <2.8 g/dL, undergoing lower GI surgery; b) patients with blunt or penetrating torso trauma with an ISS of >18/or or abdominal trauma index >20. Although there are insufficient data to recommend use of IED, non the less patients undergoing elective aortic surgery with preexisting chronic pulmonary disease, or those undergoing major head and neck surgery with preexisting malnutrition, severe head injury patients (GCS <8 with an abnormal CT scan), burns patients (>30%, third degree) and ventilatory dependent patients at risk of subsequent infections may benefit from early IED use.

Summary The biology of nutrition support has become much better understood, although we far from knowing all we need to know in this complex field. Amino acids are a key component of the nutritional and metabolic management of critically ill patients. As our current knowledge of the altered regulation of amino acid metabolism in critically ill patients increases, the formulation and administration of more effective parenteral and enteral therapeutic feeding regimens will inevitably evolve. The use of specific amino acids in pharmacological doses and in special combinations and ratios is likely to be beneficial to critically ill patients. A working knowledge of the multiple and complex functions of amino acids is essential to the competent and efficacious practice of medicine. Because derangements in amino acid metabolism are common in pathologic states and are detrimental to optimal metabolic function, reversal of these path physiologic alterations by optimal nutritional support will be obligatory if the outcome of critically ill patients is to be significantly improved. Metabolic changes of amino acid pool and milieu simply cannot be ignored any more, and will need to be taken in account when creating new formulation of nutrient formulas, enteral as well as parenteral. Standardization of methodology of

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studying end points of nutrition support, clinical criteria for specialized nutrient substrate such as those fortified with BCAA, patients selection and other variables will resolve the contradictory findings of future clinical studies. The main difficulty in obtaining evidence-based data in surgical nutrition support, when different nutrient substrates are used, lie the patients selection criteria and study end point, as well as multiple other variables. The use of specific immune-enhancing formulas with amino acids in higher pharmacological doses and in special combinations and ratios is beneficial to critically ill patients. One should compare nutrition support and advances that need to be made with other fields such as management of anemia in critically ill patients. Today one can manage anemia virtually without transfusing blood using genetically created recombinant erythropoietin (Procrit®- Ortho Biotech).83 So, just as we can support anemic patient with substrates that will stimulate bone marrow to produce blood and blood products, without transfusing blood, we should strive to use in the future genetically altered nutrient substrates that will mimic, or better off, substitute the perfect nutrient substrates for most critically ill patients and correct exactly the cellular imbalances caused by the injury, severe sepsis or other disorders. Derangement in amino acid metabolism, nucleotides, vitamins and trace elements are common in critically ill patients. Reversal of these pathophysiologic alterations by optimal nutritional support with immune-enhancing formulas is obligatory if the outcomes of critically ill patients are to be significantly improved. Ideally the formula used for nutrition and metabolic support in critically ill patients should contain high doses of arginine, glutamine, taurine, BCAA, nucleotide and nucleoside, omega 3-fatty acids, zinc, selenium, and vitamins A, E, C. It is also important for this formula to be inexpensive and should be available in the enteral as well parenteral form.

Selected References 1. 2. 3. 4. 5. 6. 7. 8. 9.

Latifi R, Caushaj PE. Nutrition support in critically ill patients: Current status and practice. Jour Clin Ligand Assay 1999; 22:279-284 Cuthbertson DP. Observations on disturbance of metabolism produced by injury to the limbs. Q J Med 1932; 25:233-246 Wilmore DW, Orcutt TW, Mason AD Jr et al. alterations in hypothalamic function following thermal injury. J Trauma 1975; 15:697-703. Birkhahn RH, Long CL, Fitkin D et al. Effects of major skeletal trauma on whole body protein turnover in man measured by L- [1, 14C]-leucine. Surgery 1980; 88:294-308. Kien CL, Young VR, Rohrbaugh DK et al. Increased rates of whole body protein synthesis and breakdown in children recovering from burns. Ann Surg 1978; 187:383-391. Levenson SM, Pulaski EJ, del Guercio LRM. Metabolic changes associated with injury. In: Zimmerman LM, Levine R, eds. Physiological Principles of Surgery, 2nd ed. Philadelphia: WB Saunders, 1964:5-7. Young VR, Munro HN. N-Methylhistidine (3-methylhistidine) and muscle protein turnover: An overview. Fed Proc 1978; 37:2291-2300. Bilmazes C, Kien CL, Rohrbaugh DK et al. Quantitative contributors by skeletal muscle to elevated rates of whole-body protein breakdown in burned children as measured by 3-methylhistidine output. Metabolism 1978; 27:671-676. Williamson DH, Farrell R, Kerr A et al. Muscle protein catabolism after injury in man as measured by urinary excretion of 3-methylhistidine. Clin Sci Mol Med 1977; 52:527-533.

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24 16. 17. 18. 19. 20. 21. 22. 23. 24. 25. 26. 27. 28. 29.

30. 31.

Long Cl, Schiller WR, Blakemore WS et al. Muscle protein catabolism in the septic patient as measured by 3-methylhistidine excretion. Am J Clin Nutr 1977; 30:1349-1352. Essen P, McNurlan MA, Gamrin L et al. Tissue protein synthesis rates in critically ill patients. Crit Care Med 1998; 26:92-100. Latifi R, Dudrick SJ, eds. Surgical Nutrition: Strategies in Critically Ill. Austin: Springer-Verlag/R.G.Landes, 1995. Garber AJ, Karl IE, Kipnis DM. Alanine and glutamine synthesis and release from skeletal muscle. I: Glycolysis and amino acid release. J Biol Chem 1976; 251:826-835. Souba WW, Wilmore DW. Postoperative alteration of arteriovenous exchange of amino acids across the gastrointestinal tract. Surgery 1983; 94:342-350. Souba WW, Klimberg VS, Plumley DA et al. The role of glutamine in maintaining a healthy gut and supporting the metabolic response to injury and infection. J Surg Res 1990; 48:383-391. Fox AD, Kripke SA, Berman JM et al. Dexamethasone administration induces increased glutaminase specific activity in the jejunum and colon. J Surg Res 1988; 44:391. Souba WW, Smith RJ, Wilmore DW. Effect of glucocorticoids on glutamine metabolism in visceral organs. Metabolism 1985; 34:450-456. Plumley DA, Souba WW, Hautamaki D et al. Accelerated lung amino acid release in hyperdynamic septic surgical patients. Arch Surg 1990; 125:57. Austgen TR, Chen MK, Flynn TC et al. The effects of endotoxin on the splanchnic metabolism of glutamine and related substrates. J Trauma 1991; 6:742-51. Austgen TR, Chen MK, Moore W et al. Endotoxin and renal glutamine metabolism. Arch Surg 1991; 126:23. Souba WW, Smith RJ, Wilmore DW. Glutamine metabolism by the intestinal tract. JPEN 1985; 9:608-617. Hwang TL, O’Dwyer ST, Smith RJ et al. Preservation of small bowel mucosa using glutamine-enriched parenteral nutrition. Surg Forum 1986; 38:56 Zapata-Sirvent RL, Hnasbrough JF, Ohara MM et al. Bacterial translocation of various diets including fiber-and glutamine enriched enteral formulas. Crit Care Med 1994; 22:690-696. Fox AD, Kripke SA, DePaula J et al. Effect of a glutamine-supplemented enteral diet on methotrexate-induced enterocolitis. JPEN 1988; 12:325-331. Klimberg VS, Souba WW, Dolson DJ et al. Prophylactic glutamine protects the intestinal mucosa from radiation injury. Cancer 1990; 66:62-68. Li S, Nussbaum MS, McFadden DW et al. Addition of L-glutamine to total parenteral nutrition and its effects on portal insulin and glucagon and the development of hepatic steatosis in rats. J Surg Res 1990; 48:421-426. Helton WS, Jacobs Do, Bonner-Weir S et al. Effects of glutamine-enriched parenteral nutrition on the exocrine pancreas. JPEN 1990; 14:344-352. Burke DJ, Alverdy JC, Aoys E et al. Glutamine-supplemented total parenteral nutrition improves gut immune function. Arch Surg 1989; 124:1396-139. Hammarqvist F, Wernerman J, Ali R et al. Addition of glutamine to total parenteral nutrition after elective abdominal surgery spares free glutamine in muscle, counteracts the fall in muscle protein synthesis, and improves nitrogen balance. Ann Surg 1989; 209:455-461. Stehle P, Zander J, Mertes N et al. Effect of parenteral glutamine peptide supplements on muscle glutamine loss and nitrogen balance after major surgery. Lancet 1989; 1:231-233. Stein TP, Yoshida S, Yamasaki K et al. Amino acid requirements of critically ill patients. In: Latifi R, ed. Amino Acids in Critical Care and Cancer. Austin: RG Landes Company, 1994:9-25.

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Barbul A. Arginine and immune function. Nutrition 1990; 6:59-62. Barbul A, Sisto DA, Wasserkrug HL et al. Arginine stimulates lymphocyte immune response in healthy humans. Surgery 1981; 90:244-251. Stinnett J, Alexander JW, Watanabe C et al. Plasma and skeletal muscle amino acids following severe burn injury in patients and experimental animals. Ann Surg 1982; 195:75-89. Xiao-jun C, Chih-chun Y, Wei-shia H et al. Changes of serum amino acids in severely burned patients. Burns 1983; 10:109-115. Gennari R, Alexander JW. Arginine, glutamine, and dehydroepiandrosterone reverse the immunosuppressive effect of prednisone during gut-derived sepsis. Crit crae Med 1997; 25:1207-1214. Blackburn GL, Moldawer LL, Usui SS et al. Branched-chain amino acid administration and metabolism during starvation, injury and infection. Surgery 1979; 86:307-314. Yoshida S, Lanza-Jacoby S, Stein TP. Leucine and glutamine metabolism in septic rats. Biochem J 1991; 276:405-409. Freund HR, James JH, Fischer JE. Nitrogen-sparing mechanisms of singly administered branched-chain amino acids in the injured rat. Surgery 1981; 90:237-243. Cerra FB, Upson D, Angelico R et al. Branched-chain amino acids support postoperative protein synthesis. Surgery 1982; 92:192-199. Mendez C, Jurkovich GJ, Wener MH et al. Effects of supplemental dietary arginine, canola oil, and trace elements on cellular immune function in critically injured patients. Shock 1996; 6:7-12. Garcia-de-Lorenzo A, Ortiz-Leyba C, Planas M et al. Parenteral administration of different amounts of branch-chain amino acids in septic patients: clinical and metabolic aspects. Randomized Controlled Trial. Crit Care Med 1997; 25(3):418-24, Grimble G. Why are dietary nucleotides essential nutrients? Br J Nutr 1996; 76:475. Ilijima S, Tsujinaka T, Kishibuchi M et al: Total parenteral nutrition solution supplemented with nucleoside and nucleotide mixture sustains intestinal integrity, but does not stimulate intestinal function after massive bowel resection in rats. Am J Nutr 1995; 126:589-595. Jyonouchi H, Sun S, Sato S. Nucleotide-free diet suppresses antigen-driven cytokine production by primed T cell: Effects of supplemental nucleotides and dietary fatty acids. Nutrition 1996; 12:608-615. Kishibuchi M, Tsujinaka T, Yano M et al. Effects of nucleosides and a nucleotide mixture of gut mucosal barrier function on parenteral nutrition in rats. J Parenteral Enteral Nutr 1997; 21:104-111. Kulkarni AD, Rudolph FB, Van Buren CT. The role of dietary sources of nucleotides in immune function: A review. Am J Nutr 1994; 124(8 Suppl):1442S-1446S. LeLeiko NS, Walsh MJ. The role of glutamine, short-chain fatty acids, and nucleotides in intestinal adaptation to gastrointestinal disease. Perdiatr Gastroenterol 1996; 43:451-469. LeLeiko NS, Walsh MJ, Abraham S. Gene expression in the intestine. The effect of dietary nucleotides. Adv Pediatr 1995; 42:145-166. Martinez-Augustin O, Boza JJ, Navarro J et al. Dietary nucleotides may influence the humoral immunity in immncompromised children. Nutrition 1997; 13:465-469. Matsumoto Y, Adjei AA, Yamauchi K et al. A mixture of nucleosides and nucleotides increase bone marrow cell and peripheral neutrophil number in mice infected with methicillin-resistant Staphylococcus aureus. Am J Nutr 1995; 125:817-822. Matsumoto Y, Adjei AA, Yamauchi K et al. Nucleoside-nucleotide mixture increases peripheral neutrophils in cyclophosphamide-induced neutropenic mine, Nutrition 1995; 11:296-299.

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The Biology and Practice of Current Nutritional Support 53. 54. 55. 56. 57. 58.

24 59. 60. 61. 62. 63. 64. 65. 66. 67. 68. 69. 70. 71. 72. 73. 74.

Sukumar P, Loo A, Magur E et al. Dietary supplementation of nucleotides and arginine promotes healing of small bowel ulcers in experimental ulcerative ileitis. Dig Dis Sci 1997; 42:1530-1536. Tsujinaka T, Ilijima S, Kido Y et al. Role of nucleosides and nucleotide mixture in intestinal mucosal growth under total parenteral nutrition. Nutrition 1994; 10:203-204. Uauy R. Quan R, Gil A. Role of nucleotides in intestinal development and repair: Implications for infant nutrition. Am Inst Nutr 1994; 1436S-1441S. Van Buren CT, Rudolph F. Dietary nucleotides: A conditional requirement. Nutrition 1997; 13:47-472. Walker WA. Exogenous nucleotides and gastrointestinal immunity. Transplant Proc 1996; 28:2438-2441. Yamamoto S, Wang MF, Adjei AA et al. Role of nucleosides and nucleotides in the immune system, gut reparation after injury and brain function. Nutrition 1997; 13:372-374. Ogoshi S, Iwasa M, Ynoezawa T et al. Effect of nucleotide and nucleoside mixture on rats given total parenteral nutrition after 70% hepatectomy. JPEN 1985; 9:339-404. Usami M, Furuchi K, Ogino M et al. The effect of nucleotide-nucleoside solution on hepatic regenration after partial hepatectomy in rats. Nutrition 1996; 12:797-803. Latifi R, Burns G. Nucleic acids and nucleotides in nutritional support. In: Van Way C, ed. Nutrition Secrets. Philadelphia: Hanley & Belfus, Inc., 1999:173-177. Alexander JW. Immunonutrition: The role of omega 3-fatty acids. Nutrition 1998; 14:627-633. Gadek JE, DeMichele SJ, Karlstad MD et al. Effect of enteral feeding with eicosapentaenoic acid, g-linolenic acid, and antioxidants in patients with acute respiratory distress syndrome. Crit Care Med 1999; 27:1409-1420. Desai SA, Jacobs DO. Role of growth hormone in the septic, trauma and surgical patient. In: Torosian MH, ed. Growth hormone in critical illness. Austin: R.G. Landes, 1996:119-40. Baue AE, Durham R, Faist E. Systemic inflammatory response syndrome (SIRS), multiple organ dysfunction syndrome (MODS), multiple organ failure (MOF): are we winning the battle? Shock 1998; 10:79-89 Takala J, Ruokonen E, Webster NR et al. Increased mortality associated with growth hormone treatment in critically ill adults. N Engl. J Med 1999; 341:785-92. Ziegler TR, Young LS, Ferrari-Baliviera E et al. Use of human growth hormone combined with nutritional support in a critical care unit. JPEN J 1990; 14:574-81. Knox J, Demling R, Wilmore D et al. Increased survival after major thermal injury: the effect of growth hormone therapy in adults. J Trauma 1995; 39:526-30. Herndon DN, Barrow RE, Kunkel KR et al. Effect of recombinant human growth hormone on donor-site healing in severely burned children. Ann Surg 1990; 212:424-429. Gore DC, Honeycutt D, Jahoor F et al. Effect of exogenous growth hormone on glucose utilization in burn patients. J Surg Res 1991; 51:518-23. Bone RC, Balk RA, Cerra FB et al. Definitions for sepsis and organ failure and guidelines for the use of innovative therapies in sepsis. Chest 1992; 101:1644-1655. Fleming RY, Rutan RL, Jahoor F et al. Effect of recombinant human growth hormone on catabolic hormones and free fatty acids following thermal injury. J Trauma 1992; 32:698-702. Kowal-Vern A, Sharp-Pucci MM, Walenga JM et al. Trauma and thermal injury: comparison of homeostatic and cytokines changes in the acute phase of injury. J Trauma 1998; 44:325-9. Ruokonen E, Takala J. dangers of growth hormone therapy in critically ill patients. Ann Med 2000; 32: 317-322.

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76. 77. 78. 79. 80. 81. 82. 83.

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Bower RH, Cerra FB, Bershadsky B et al. Early enteral administration of a formula (Impact) supplemented with arginine, nucleotides, and fish oil in intensive care unit patients: Result of multicenter, prospective, randomized, clinical trial. Crit Care Med 1995; 23: 436-449. Kudsk K, Minard G, Groce M et al. A randomized trial of isonitrogenous enteral diets after severe trauma. An immune-enhancing diet reduces septic complications. Ann Surg 1996; 224:531-543. Senkal M, Mumme A, Eickhoff U et al. Early postoperative enteral immunonutrition: Clinical outcome and cost-comparison analysis. Crit Care Med 1997; 25:1489-1496. Atkinson S, Sieffert E, Bihari D et al. A prospective, randomized, double blind, controlled clinical trial of enteral immunonutrition in the critically ill. Crit Care Med 1998; 26:1164-1172. Vischmeeyer PE, Lynch J, Liedel J et al. Glutamine administration reduces Gram – negative bacteremia in severely burned patients: A prospective, randomized, double blind trial versus isonitrogenous control. Crit care Med 2001; 29:2075-2080. Houdijk AP, Rijnsburger ER, Jansen J et al. Thijs LG. van Leeuwen PA. Randomized trial of glutamine-enriched enteral nutrition on infectious morbidity in patients with multiple trauma. Lancet 1998; 352(9130):772-6. Heys SD, Walker LG, Smith I et al. Enteral nutrition supplementation with key nutrients in patients with critical illness and cancer. Meta-analysis of randomized controlled clinical trials. Ann Surg 1999; 229:446-477.93. A consensus panel from a recent conference on immune-enhancing enteral therapy (95) (Proceedings from Summit on Immune-Enhancing Enteral Therapy. JPEN 2001; 25-S1-S63. Corucin HL, Gettinger A, Rodriguez RM et al. Efficacy of recombinant human erythropoietin in the critically ill patient: A randomized, double-blind, placebo-controlled trial. Crit Car Med 1999; 27:2346-2350.

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CHAPTER 25

Nutrition Support in Patients with Pulmonary Failure and ARDS Vanessa Fuchs, A.K. Malhotra and Rifat Latifi

Malnutrition and Lung Functions Malnutrition is a leading cause of impaired respiratory muscle strength, endurance and contractility, as well as lung function and their dynamics. In addition, malnutrition causes deleterious changes in the structure and function of the diaphragm muscle mass and thickness which are reduced in proportion to the reduction in body weight. While the diseases associated with somatic wasting cause atrophy of the respiratory muscles, respiratory muscle strength and endurance are reduced more dramatically than the weight loss. Patients suffering from chronic obstructive pulmonary disease (COPD) frequently exhibit profound malnutrition both as a consequence of and result of their disease. Patients with acute respiratory failure, secondary to sepsis, trauma, or intrinsic lung disease, may rapidly progress to a state of nutritional embarrassment due to multiple factors. Furthermore, patients with ARDS, or those sufferings from conditions rendering them susceptible to develop ARDS, similar to other critically ill patients, have increased caloric requirement, are hyperglycemic and have triglyceride intolerance, and overall net increase in protein catabolism. Subsequently most patients with pulmonary failure have an attendant compromise in nutrition status. Malnutrition may precede or follow respiratory failure and if nutritional status is not preserved or malnutrition reversed with aggressive nutritional support, the condition will progress into severe malnutrition with significant clinical deterioration.1 Malnutrition can adversely affect lung function and the adverse effects of such malnutrition include: decreased ventilatory drive, decreased respiratory muscle function, alterations of lung parenchyma and depressed lung defense mechanism. The incidence of post-operative pneumonia or atelectasis is higher in protein-depleted patients as compared with well-nourished patients.2,3

Anatomy of Respiratory Failure Three categories of pulmonary failure are of special clinical interest: acute respiratory failure (ARF) or acute respiratory distress syndrome (ARDS) and chronic obstructive pulmonary disease (COPD), and post operative

Acute Respiratory Failure Acute respiratory failure (ARF) occurs when the respiratory system is no longer capable of providing sufficient oxygenation or is unable to eliminate enough CO2. Several disorders including alveolar edema, fungal infections, lung cancer, tuberculosis

The Biology and Practice of Current Nutritional Support, 2nd Edition, edited by Rifat Latifi and Stanley J. Dudrick. ©2003 Landes Bioscience.

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and COPD may cause acute respiratory failure, which is classified in three types. Type I respiratory failure is hypoxemic, caused mostly by shunting, thus is unresponsive to supplemental oxygen therapy. Alveoli are basically flooded with purulent material such is in pneumonia, blood in lung contusion, or edema in ARDS caused by sepsis, aspiration, massive transfusion, shock, severe pancreatitis, fat emboli syndrome or amniotic fluid emboli. While many scoring systems have been used in an attempt to define the severity of ARF, the PaO2/FiO2 (P/F) ratio is most useful. When this ratio is between 300 and 200 there is acute lung injury, and when this ratio drops below 200, then this is considered ARDS. If, on the other hand, the P/F ratio is <100, this is considered to be a severe ARDS. Because Type I respiratory failure causes significant respiratory dysfunction with decreased lung compliance, and dramatic increase in work of breathing, the majority of patients with ARF require some form of mechanical ventilation. Chronic pulmonary failure is characterized by abnormal expiratory flow that does not change markedly over several months. Because expiration is obstructed, breathing requires more effort and more energy. Type II of respiratory failure is characterized by elevation of CO2 which is caused by hypoventilation as a result of loss of respiratory drive, impaired mechanics of breathing or simply excessive work load. Type III respiratory failure occurs mainly in the postoperative patients, and is typically associated with hypoxemia and hypoventilation. While this type of ARF is considered to be mainly from atelectasis and decreased movement of diaphragm, which could progress in to pneumonia, the weakness of diaphragmatic muscle secondary to perioperative malnutrition should be strongly considered.

Chronic Respiratory Failure Two major causes of COPD are chronic bronchitis and emphysema. Often this type of respiratory failure is termed acute on chronic respiratory failure, when a patient with relatively compensated respiratory failure experiences an insult such as trauma or infection and deteriorates in full respiratory failure requiring mechanical ventilatory support. This group of patients is at increased risk for significant malnutrition since increased metabolic demands and reduction of nutrient substrate intake result in a malnutrition state.1,4,5 Chronic obstructive pulmonary disease (COPD) is associated with a variety of nutritional and metabolic abnormalities. These abnormalities include protein and caloric malnutrition, associated muscular atrophy, alteration in carbohydrate metabolism, and altered respiratory drive. In addition, COPD is often associated with hypermetabolism that is caused by an increase in the work of breathing. During pulmonary failure, superimposed starvation may rapidly lead to worsening of respiratory muscle function and inability to wean mechanical ventilatory support. It has been demonstrated that during the period of acute illness and starvation, that muscle degradation occurs primarily as a result of decreased protein synthesis and increases muscle protein catabolism.6,7 It has been also shown that malnutrition and immunity may play a very important role in the pathogenesis of COPD. Furthermore, malnourished patients have lower cellular immune function, although their humoral immune function was similar to healthy subjects.8

Acute Respiratory Distress Syndrome (ARDS) ARDS is a common, devastating syndrome of lung injury affecting both surgical and medical patients. It is estimated that approximately 75 per 100,000 populations

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will suffer from ARDS. Although ARDS was described for the first time in 1967, it was not until 1994 that a new definitions was created by the American-European Consensus Conference Committee, that defined ARDS as a syndrome occurring particularly in subset of patients with severe of acute lung injury (ALI), characterized by a constellation of clinical, radiological, and physiologic abnormalities that cannot be explained by, but may coexist with left arterial or pulmonary capillary hypertension. In particular, this syndrome must have acute onset, bilateral infiltrates on chest radiography, pulmonary- artery wedge <18 mm Hg, and P/F ratio less than 200.9-11 There are numerous predisposing factors and clinical disorders associated with development of the ARDS, including direct acute lung injury (aspiration, pneumonia or inhalation injury), and indirect causes such as sepsis, severe multiple traumas, shock, massive blood transfusion, and pancreatitis. Other less common causes of ARDS are pulmonary contusion, fat emboli, near- drowning, and reperfusion pulmonary edema after lung transplantation or pulmonary embolectomy, cardiopulmonary bypass and drug overdose.11 Overall mortality from ARDS is typically reported to be greater than 50%, mainly because of underlying predisposing illness, sepsis, or multiple organ dysfunctions. The primary reason for high mortality is multiple organ system failure and sepsis, rather than primary respiratory causes, although death may be related to the lung injury with high tidal volumes therapy.12 The long-term consequences of ARDS are often very serious, although full return of pulmonary function in a patient who survives ARDS is seen, with pulmonary function returning to normal within 6-12 months. If on the other hand, patient had suffered long period of ventilatory support, sepsis, then the residual impairment of lung function is present although may be asymptomatic. Currently patients with ARDS are supported with mechanical ventilation and other supportive measures directed at reducing and reversing the lung injury, such as low tidal volumes, pressure control ventilation with or without inverse ratio ventilation and other techniques such as prone positioning of the patients and aggressive pulmonary toilet. Failure of standard advanced therapeutic measures to resolve ARDS have prompted the use of other techniques such as tracheal gas insufflations, inhaled nitric oxide, extra corporeal membrane oxygenation (ECMO) or partial liquid ventilation. Most impressive progress in ventilatory support of patients with ARDS was reported recently.12 In an randomized, multicenter trial patients with acute lung injury and ARDS, mechanical ventilation with lower tidal volume than traditionally used low tidal volumes decreased mortality rate and decreased ventilatory days. Patient with ALI and ARDS, were enrolled in a study that compared ventilatory support involving high tidal volume (12 ml per kg body weight) with low tidal volume (6 ml per kg). The primary outcomes were the death before discharge home and breathing without assistance. The trial of 861 patients was stopped because patients with lower tidal volumes had significantly lower mortality rate (31% vs 39.8%; p=0.007) as well as had fewer days in the ventilator (12+/-11 vs 10+/-11;P=0.007), than those with high tidal volume. Most of these techniques, however, do not address the main issue in ARDS: the molecular basis for the condition and, as such are supportive only. Until such treatment becomes available, we will continue to support these patients with multiple modalities, hoping to reduce effectively high morbidity and mortality of ARDS.

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Nutritional Assessment Respiratory Quotient In the process of converting the macronutrients such as protein, fat and carbohydrates to energy, oxygen is consumed and carbon dioxide is produced.13,14 Utilization of caloric sources is estimated from the respiratory quotient (RQ), which is the ratio of carbon dioxide produced to oxygen consumed. The RQs produced from carbohydrate, fat, and protein is 1.0, 0.7, and 0.8, respectively. For a given amount of oxygen consumed, more carbon dioxide is produced from metabolism of carbohydrates then from fat or protein. Metabolism of fat yields the lowest RQ (0.7). The RQ of a typical mixed diet is 0.85. Since patients with COPD and respiratory failure suffer from carbon dioxide retention and oxygen depletion in the blood, the goal of therapy is to decrease the blood level of carbon dioxide. Administration of a diet with and increased proportion of fat calories and decreased carbohydrate calories can reduce carbon dioxide production and RQ, thus diminishing ventilatory requirements. The end result is desirable both for the patient with COPD, for whom hypercapnia may lead to respiratory failure, and for patient with respiratory failure who must be weaned from mechanical ventilation. Although providing sufficient protein for anabolism is important, the overfeeding of protein should be avoided. Protein intake has little effect on carbon dioxide production but has been demonstrated to augment the ventilatory drive mechanism. High protein diets will stimulate ventilatory drive and minute ventilation in normal persons. An increase in respiratory drive can be beneficial for patients able to respond to stimulus. However, for patients unable to increase minute ventilation, the stimulus can increase the work of breathing and cause dyspnea.15,16 Excess nutrient administration in patients on mechanical ventilation could aggravate respiratory failure by augmenting CO2 production.17-19 Thus, provision of caloric intake that exceeds metabolic requirements can lead to net lipogenesis with associated RQ >1. At the same token, estimation of energy requirements of patients with respiratory disease can be difficult.20-23 In normal subjects only a small fraction of REE is devoted to supporting the metabolic activity of respiratory muscles. Both COPD patients and patient with respiratory failure of various causes have increased work of breathing. Therefore, commonly used prediction models for estimation of metabolic requirements, which typically use parameters attempting to estimate the lean tissue mass, may have limited accuracy in the patient with pulmonary disease. While indirect calorimetry can be used as an assessment of energy expenditure to predict metabolic needs more accurately, there is a specific equation to predict energy requirements for COPD patients. Men (11.5 x weight (kg) + 952 Women (14.1 x weight (kg) + 515 Energy requirement may be estimated based on indirect calorimetry. However, the most accurate method for determination of estimated caloric requirements is the indirect measurement of actual energy expenditure with a metabolic chart, although these devices are subject to significant error because of short sampling time, usually 10 to 15 minutes. The goals of nutritional support and nitrogen requirements of patients with pulmonary disease are not significantly different from other patients. The optimal support entail establishing neutral or positive nitrogen balance. This is usually

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accomplished by giving 0.16 to 0.24 g of nitrogen per kilogram per day for mild to moderate stress and 0.32 g/kg per day for marked stress. The composition of nutrient substrates however should be directed to the individual disease process, in order to address the basic molecular needs as well as derangement at the molecular level. The goal of nutritional assessment is to identify those patients at high risk for an adverse outcome. Once identified, the nutritional assessment parameters can be used to identify the response of selected patients to an intervention program. Effective screening tools must be safe, cost effective, wildly applicable, an accurate in predicting adverse sequale. Anthropometrical measurements are limited by the assumption of uniform distribution of total body fat. However, they remain useful in patients with end stage pulmonary disease (ESPD) because they identify an adverse nutritional effect that is not evident with the monitoring of body weight alone. Weight gain in patients with ESPD may be interpreted as favorable, but weight gain of primarily fat mass is unlikely to be beneficial. The use of anthropometrical assessment can provide valuable insight into the patient’s progress during a rehabilitation program if measured and interpreted correctly. Hepatic secretory proteins such as albumin, prealbumin, transferrin, and retinol-binding protein are often measured as part of a comprehensible nutritional assessment program as indicators of visceral protein stores. Malnourished ESPD patients generally do not present with decrements in these parameters, based on a number of clinical trials of nutritional support in COPD patients, and routine serum measurements are probably not indicated. An alternative approach to nutritional assessment involves a more functional assessment. Examples of these are adductor policis muscle for a functional nutritional assessment owing the ready accessibility of the ulnar nerve for neural stimulation. The respiratory muscles demonstrate similar neurophysiologic properties to peripheral muscles during electrical stimulation; a simpler, less precise alternative to neurophysiologic testing is the use of voluntary tests of maximal muscle strength, such as handgrip dynamometry or respiratory muscle pressure. Handgrip dynamometry provides an inexpensive and simple method of assessing muscle function and is easily obtained in the output setting; it can be incorporated into an initial assessment with little difficulty and used serially to confirm strength changes by nutrition and exercise. Muscle mass is a difficult parameter to assess in ESPD patients. A standard index is the 24-hour collection of urinary creatinine. This measurement requires a controlled diet and meticulous collection of the urine sample, making it impractical in the outpatient setting. When the more practical indices of muscle mass such as body weight or arm muscle circumference are compared with urinary index, the correlation is poor. Another functional assessment tool is a measurement of immune function. Undernourished COPD patients demonstrate abnormalities in these markers that appear to improve following the institution of nutritional support. Although useful, this test may be affected by multiple factors such as such as aging, corticosteroid use, chronic infection, and malnutrition, all of which are typically present in the patient with ESPD. This relationship limits the ability of these functional assessment tools to identify patients at nutritional risk, although the tools are still valuable for assessing the response to a nutritional intervention program. All physiological and historical findings are used to identify the specific nutritional problems of the individual patient and to develop a comprehensive care plan.13-20 Patients with obstructive disease

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(COPD) and those who suffer from adult respiratory distress syndrome (ARDS) are at high nutritional risk.16,21 Merely providing adequate calories to the severely ill ventilated patient is not sufficient. Specialized nutrition support regimens for patients with respiratory disease should include carbohydrate doses below the maximal oxidative rates for glucose and omega 3-fatty acid fat emulsions as a daily continuous infusion.21 Early enteral feeding is clearly most beneficial.

Molecular Basis Nutritional Management In order to help patients with ARDS as well as those with COPD, we must understand the pathophysiology of this complexes disease process, especially in patients with ARDS. The molecular basis of inflammatory process and lung injury has been advanced significantly in recent years.10,11 While the issue is far from being resolved, the evidence of neutrophil predominance in the pulmonary edema fluid and bronchoalveolar –lavage obtained from patients with ARDS and animal models has been accumulated, although ARDS may develop in neutropenic patients as well.10 At the same time, a complex cadre of prroinflammatory cytokines is activated locally or systemically and initiate or exacerbate the inflammatory response in ALI and ARDS. Most important though is the balance between the pro-inflammatory and anti-inflammatory cytokines. If this process can be reversed effectively or prevented than one will expect that ARDS will not progress into fibrosing alveolitis or fibrotic lung injury, as this finding clearly corresponds with increased mortality. Interleukin-1 (IL-1) is known to promote the development of fibrosing alveolitis, and procollagen III peptide, a precursor of collagen synthesis that is elevated very early in the course of disease process. The strategies to improve the resolution of ARDS should be closely related to arrest the inflammatory process of lung injury. Fluid and hemodynamic support of these patients, surfactant therapy, use of inhaled nitric oxide and other vasodilators and glucocorticoids as well as use of other anti-inflammatory agents are part of the current pharmacological armamentarium in the treatment of ARDS. However, the concept that we may feed patients with a specially formulated diet, that will maintain optimal nutritional status, prevent or reverse malnutrition, and at the same time reverse effectively or arrest the inflammatory process of sepsis or other causes induced acute lung injury is certainly very appealing. For practical purposes we will separate nutritional management of patients with COPD and those with ARDS. Although most patients with COPD, except those with acute on chronic respiratory failure do not require special dietary measurement. While nocturnal nasoenteric feeds are well tolerated by most patients and results in weight gain, the termogenic effect of a large meal may include significant metabolic demand and ventilatory workload due to excess CO2 production and could precipitate acute respiratory failure.22 In COPD patients with acute respiratory failure, a hyper caloric nutrition may induce complications that result mainly from an excessive CO2 production. The use of a specially formulated lipid enriched diet has been recently proposed in these patients to facilitate weaning from ventilatory support. Nutritional regimen providing optimal calorie and protein is associated with weight gain, nitrogen retention, and improvement in muscle. physiologic parameters. On the other hand, for the patient with severe pulmonary disease or requiring mechanical ventilation, the over-provision of carbohydrate may have serious theoretical sequale, although practically this is not very common. As part of the

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conversion of excess carbohydrate to fat, additional CO2 is produced. To maintain acid-base balance, the excess CO2 must be eliminated, thus increasing the amount of respiratory work. This process has been shown to increase VO2, VCO2, VE, REE, and ventilatory response to hypoxia, hypercapnea, and respiratory work.23 In order to avoid this, the optimal amount of carbohydrate utilization has been determined. It has been shown that patients do not oxidize more than 5 to 7 mg glucose/kg body weight/min given intravenously. Higher rates of administration can lead to fat storage. In septic patients, the maximal amount of glucose oxidized may even be lower. Initially, the excess glucose is used to replete glycogen stores in the liver. Because this is a finite pool of glucose, it is quickly replenished and the body converts all excess glucose into triglyceride. Therefore, in most circumstances, the rate of infusion should not exceed 4 to 5 mg/kg/min. In average size patient, daily provision should not be greater than 300 to 400 g/day.23 Another interesting point of nutritional therapy in pulmonary failure is the achievement of most accurate combination and proportion of nutrients.22 When nutrient substrates provision in both enteral and parenteral formulas is properly calculated and provided, caloric goals can be achieved with less potential for carbohydrate overfeeding. To avoid the provision of all non-protein calories as carbohydrate, approximately 30% of caloric requirements are usually supplied as lipids. The provision of lipids, traditionally as long chain triglycerides, has been associated with immunological abnormalities including reticuloendothelial system dysfunction, impaired phagocytosis, increased gram-positive bacterial survive and depression of cardiac function. While the lipids are useful to prevent essential fatty acids deficiency, the amount and the type of fatty acids provided is very important element of nutritional support of patient with respiratory failure. This may be true for other critically ill patient as well. A recent study compared hemodynamic and gas exchange alterations in septic patients with ARDS receiving long-chain triglycerides (LCT) versus medium chain triglycerides (MCT). The results showed that, in septic patients with respiratory failure, LCT administration was associated with more significant changes of Qva/ Qt, MPAP and P/F ratio compared to an infusion of an LCT/MCT 1:1 emulsion. Clinically, these transient alterations might cause serious problems in patients with marginal arterial oxygenation and cardio-respiratory impairment.14 High fat, low carbohydrate enteral feeds appeared to be beneficial in patients with acute respiratory failure requiring ventilatory support.24 Furthermore, there have been experimental studies in which it was demonstrated that supplementation of parenteral nutrition with γ-linolenic acid increased dihomo γ-linolenic acid, and prostaglandin E, increased the plasma arachidonic acid ratio, and favorably reduced the ratio of thromboxane B2 and 6-ketoprostaglandin F 1α in injured rats. These reflect the potential capacity of γ-linolenic acid enriched emulsions to increase dihomo γ-linolenic, fatty acid precursor of anti-inflammatory eicosanoids, prostaglandin E1; and to modulate arachidonic acid-deviated prostaglandin after injury.25 In another study, the researches demonstrated that dietary fish oil and borage oil suppressed intrapulmonary proinflamatory eicosanoid biosynthesis and attenuates pulmonary neutrophil accumulation in endotoxic rats. Fish oil and fish and borage oil when compared with corn oil may ameliorate endotoxin-induced acute lung injury by suppressing the levels of proinflammatory eicosanoids (but not TNFα or MIP-2) in broncho-alveolar lavage fluid and reducing pulmonary neutrophil accumulation.26 In addition dietary fish oil and borage oil significantly alter the fatty acid composition of lung phospholipids by decreasing

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arachidonic acid and increasing eicosapentanoic acid (EPA) with fish oil and increasing dihomo-gama-linolenic acid when fish oil and borage oil were used in combination.26 These changes are consistent with suppression of eicosanoids associated with SIRS. There is evidence that incorporation of EPA into phospholipids shifts eicosanoid metabolism to the less biologically actively 3-series prostaglandins and 5-series leukotrienes.27-29 Others have shown that following enteral feeds, as short as only three days; there is significant incorporation of EPA and GLA with displacement of arachidonic acid in lung alveolar macrophage phospholipids.30 Leukotrienes are considered to be the mediators in lung inflammation and have also been found to be in high concentrations in the bronchoalveolar lavage fluid of patients with ARDS. Inhibition of leukotriene B4 formation significantly reduces lung microvascular permeability and edema formation in experimental animals. Fish oil and borage oil diet was shown to reduce the synthesis of B4 leukotriene. Lower levels of leukotriene B4 reduces the effect of neutrophils and increased microvascular protein permeability in endotoxic rats. Most importantly animals fed with this diet, did not mount the expected response in eicosanoid production when challenged with endotoxins.26 Entirely specialized diets enriched in eicosapentanoic acid (EPA) and γ-linolenic acid, precursors of trienoic and monoenoic eicosanoids, respectively, have proven to attenuate cardiopulmonary dysfunction during acute injury in pigs. These diets improve gas exchange and O2 delivery, presumably in part through a modification of thromboxane B2 (TxB2) production with decrease in pulmonary vascular resistance and an increase in cardiac index, and acute lung injury (ALI).31 Using this background,24-32 a prospective, multicenter, double-blind, randomized controlled trial was reported recently.33 One hundred and forty-six patients with ARDS were randomized to receiving enteral tube feeds with either eicosapentaenoic acid (EPA) and gamma- linolenic acid (GLA) or isonitrogenous isocaloric standard diet for at least 4-7 days. Patients who were fed with EPA+GLA had significantly lower neutrophils in the bronchoalveolar lavage, significantly improved in the P/F oxygenation ratio, had lower ventilatory variables (Fio2, PEEP, minute ventilation) than controls. Furthermore, patients fed with EPA and GLA had fewer days in a ventilator support and a decreased stay in the ICU. In addition, only 8% of patients with ARDS fed EPA+GLA developed multiple organ system failure when compared to 28% of the controlled group. The beneficial effects of the EPA+GLA diet on neutrophil recruitment, gas exchange, requirement for mechanical ventilation, ICU stay and reduction in development of multiple organ system failure were clearly demonstrated. Specialized diet with EPA+GLA and antioxidants modulates neutrophil mediated lung injury, and it is thought the mechanism of action is anti-inflammatory and vasodilator properties of EPA and GLA.

Chronic Obstructive Pulmonary Disease (COPD) The occurrence of weight loss in obstructive lung disease has been described in 50% of COPD patients who require hospitalization. Positive energy balance in weight losing COPD patients is associated with nitrogen retention and weight gain. These finding distinguishes the patient with COPD from other diseases models associated with hypercatabolism, such as sepsis or trauma, in which positive balance does not produce nitrogen retention. Studies associated with positive energy and nitrogen balance have produced improvements in measured muscle strength parameters, as well as walking distance, dyspnea, and quality of life.21,23,34 COPD flares are often

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associated with increased respiratory muscle metabolism, inactivity, limited caloric intake, systemic inflammation, and frequent steroid use. When approaching the patient with ESPD and ongoing weight loss, the contribution of these individual factors must be addressed and appropriate solutions incorporated into the treatment plan. Nutrition counseling to address the planning, preparation and the use of nutritionally adequate meal plan, food supply at home, the use of nutritional supplements, and other details is essential to the success of any intervention program. The benefits of altering fat-to-carbohydrate ratios in the provision of non-protein calories in ambulatory COPD patients remain to be proven. However, there are studies that attempt to surpass daily caloric requirement with nutritional manipulation in favor of a low carbohydrate, high fat diet may be an important consideration for patients with COPD. When compared to standard liquid diets, a diet with a high percentage of fat results in decrease carbon dioxide production and retention. In another study in which it was study the effects of refeeding a high fat enteral diet versus a high carbohydrate one in patients with COPD, the authors showed that the high fat diet resulted in lower oxygen consumption and carbon dioxide production than the high-carbohydrate formula. They concluded that metabolic response to each regimen was primarily related to dietary content and composition. These functional changes were primarily related to feeding duration.24 Nutrition intervention for COPD patients should be viewed as complementary to the other components of a comprehensive rehabilitation program. There is strong evidence that the onset of weight loss is a poor prognostic indicator, and that modest weight gain facilitated improves in muscle function. Excessive weight gain, especially of body fat, would likely have deleterious effect in these patients and should be avoided. Investigations that address the mechanisms of weight loss in an effort to better understand the decline of patients with severe emphysema are indicated.

Summary General goals of nutritional therapy in the patient with respiratory failure include maintenance of lean body mass and positive nitrogen balance. Weight gain should be reserved for more protracted phase of respiration failure, such as malnourished patients requiring long-term ventilatory support. The key for the treatment of those patients is mainly not to overfeed them, especially with carbohydrates, and to reassess them as frequent as possible in order to adjust their diet according to their nutritional requirements depending on their disease and state. Nutrition therapy is an important part of the treatment of patients with pulmonary failure and should be taken into consideration since the onset of the disease, and should be monitored throw the evolution of these patients.

Selected References 1. 2. 3. 4. 5.

Pinard B, Geller E. Nutritional support during pulmonary failure. Crit Care Clin 1995; 11(3):705-15. Dureuil B, Matuszczak Y. Alteration in nutritional status and diaphragm muscle function. Reprod Nutr Dev 1998; 38(2):175-80. Ferrari-Baliviera E, Pierdominici S. Effects of nutritional status on respiratory system. Minerva Anestesiol 1989; 55(11):443-50. Grant J. Nutrition Care of patients with acute and chronic respiratory failure. NCP 1994; 9:11-17 Blair G, Sharpe L. Nutrition support in Respiratory Disorders. NCP 1989.4:173-175

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Ireton-Jones C, Borman K, Turner W. Nutrition considerations in management of ventilator-dependent patients. NCP 1993; 8:60-64 Branson R, Hurst J. Nutrition and respiratory function: Food for thought. Resp Care 1988; 33(2):89-92. Song Y, Kang XM, Xia XR. The nutritional status and immune function of patients with chronic obstructive pulmonary disease. Chung Hua Nei Ko Tsa Chih 1993; 32(1):33-6. Bernard GR, Artigas A, Brigham KL et al. The American-European consensus conference on ARDS: Definitions, mechanism, relevant outcomes and clinical trial coordination. Am J Respir Crit Care Med 1994; 149:818-24 Ware BL, Matthay M. The acute respiratory distress syndrome. NEJM 2000; 342:1334-1349. Tobin MJ. Culmination of an era in research on the acute respiratory distress syndrome. NEJM 2000; 342:1360-1361 The Acute Respiratory Distress Syndrome Network. Ventilation with lower tidal volumes as compared with traditional tidal volumes for acute lung injury and the acute respiratory distress syndrome. NEJM 2000; 342;1301-1308. Pingleton S, Harmon G. Nutritional management in acute respiratory failure. JAMA 1987; 257(22):3094-3099. Smirniotis V, Kostopanagiotou G, Vassiliou J et al. Long chain versus medium chain lipids in patients with ARDS: Effect on pulmonary homodynamic and gas exchange. Intensive Care Med 1998; 24(10):1029-33. Azkenazi J, Weissman C, Rosenbaum H et al. Nutrition and respiratory system. Crit. Care Med 1982; 10(3):163-72. Blair G, Sharpe L. Nutrition support in respiratory disorders. Nutr Clin Prac 1989; 4:173-175 Cerra FB, Hypermetabolism, organ failure and metabolic support- clinical review. Surgery 1987; 101:1-14 Clemmer TP, Orme JF. Nutritional support in the adult respiratory distress syndrome. Clin Chest Med 1982; 3:101-8. Spector N. Nutritional Support of the ventilator dependent-patient. Nurs Clin North Am. 1989; 24:2 Glodstien SA, Thomashow B, Azkenazi J. Functional changes during nutritional repletion in patients with lung disease. Clin Chest Med 1986; 7(1):141-151. Mowatt-Larssen CA, Brown RO. Specialized nutrition support in respiratory disease. Clin Pharm 1993; 12(4):276-92 Ryan CF, Road JD, Buckley PA et al. Energy balance in stable malnourished patients with chronic obstructive pulmonary disease. Chest 1993; 103(4):1038-44. Donahue M. Nutritional aspects of lung disease. Resp Care Clin North America. 1998; 4(1):85-111. Al-Saady NM, Blackmore CM, Bennet ED. High fat, low carbohydrate, enteral feeding lowers PaCO2 and reduces the period of ventilation in artificially ventilated patients. Int Care Med 1989; 15:290-295. Karlstad M, DeMichelle S. Effects of intravenous lipid emulsions enriched with α-linolenic acid on plasma n-6 fatty acids and prostaglandin biosynthesis after burn and endotoxin injury in rats. Crit Care Med 1993; 21(2):1740-49. Mancusco P, Whelan J. Dietary fish oil and fish and borage oil suppress intrapulmonary proinflammatory eicosanoid biosynthesis and attenuate pulmonary neutrophil accumulation in endotoxic rats. Crit Care Med 1997; 25:1198-1206. Lee TH, Mencia-Huerta J, Shih C, et al: Characterization and biologic properties of 5,12-dihydroxy derivatives of eicosapentaenoic acid including leukotriene B5 and double lipoxygenase product. J Biol Chem 1984; 259:2383-2389 Fischer S. Weber PC. Prostaglandin I3 is formed in vivo in man after dietary eicosapentaenoic acid. Nature 1984; 307:165-168

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Needleman P, Raz A, Minkes MS et al. Triene prostagladins: Prostacyclin and thromboxane biosynthesis and unique biological properties. Proc Natl Acad Sci USA 1979; 76:944-948 Palombo JD, DeMichele SJ, Lyndon E et al. Rapid modulation of lung and liver macrophage phospholipids fatty acids in endotoxemic rats by continuous enteral feeding with n-3 and gamma-linolenic acids. Am J Clin Nutr 1996; 63:208-219. Mancusco P, Whelan J, DeMichele SJ et al. Effects of eicosapentaenoic acid and gamma-linolenic acid on lung permeability and alveolar macrophage eicosanoid synthesis in endotoxic rats. Crit Care Me