Vascular Surgery Principles and Practice Third Edition, Revised and Expanded
Robert W Hobson I& M B . UMDNJ-New Jersey Medical School Newark, New Jersey, U.S.A.
Samuel E. Wilson, M B . University of California Irvine Orange, California, U.S.A.
Frank$ Veith, M B . Montefiore Medical Center-Albert Einstein College of Medicine New York, New York, U.S.A.
m MARCEL
DEKKER
MARCEL DEKKER, INC.
NEWYORK BASEL
The previous edition was published as Vascular Surgery: Principles and Practice, Second Edition, q 1994, McGraw-Hill, Inc. Although great care has been taken to provide accurate and current information, neither the author(s) nor the publisher, nor anyone else associated with this publication, shall be liable for any loss, damage, or liability directly or indirectly caused or alleged to be caused by this book. The material contained herein is not intended to provide specific advice or recommendations for any specific situation. Trademark notice: Product or corporate names may be trademarks or registered trademarks and are used only for identification and explanation without intent to infringe. Library of Congress Cataloging-in-Publication Data A catalog record for this book is available from the Library of Congress. ISBN: 0-8247-0819-9 This book is printed on acid-free paper. Headquarters Marcel Dekker, Inc. 270 Madison Avenue, New York, NY 10016, U.S.A. tel: 212-696-9000; fax: 212-685-4540 Distribution and Customer Service Marcel Dekker, Inc. Cimarron Road, Monticello, New York 12701, U.S.A. tel: 800-228-1160; fax: 845-796-1772 Eastern Hemisphere Distribution Marcel Dekker AG Hutgasse 4, Postfach 812, CH-4001 Basel, Switzerland tel: 41-61-260-6300; fax: 41-61-260-6333 World Wide Web http://www.dekker.com The publisher offers discounts on this book when ordered in bulk quantities. For more information, write to Special Sales/Professional Marketing at the headquarters address above. Copyright q 2004 by Marcel Dekker, Inc. All Rights Reserved. Neither this book nor any part may be reproduced or transmitted in any form or by any means, electronic or mechanical, including photocopying, microfilming, and recording, or by any information storage and retrieval system, without permission in writing from the publisher. Current printing (last digit): 10 9 8 7 6 5 4 3 2 1 PRINTED IN THE UNITED STATES OF AMERICA
Foreword
The third edition of Vascular Surgery is a thoroughly revised and expanded work. Ten chapters have been rewritten by new contributors and 15 chapters on current developments have been added. Much of the new material was written by the new generation of leaders in vascular surgery. As an appropriate reflection of the interests and expertise of the editors, the endovascular section is entirely new. The relevance of venous pathology in a vascular practice translates into six new chapters on this subject. This is not an encyclopedic treatise but rather a manageable textbook focused on the diagnosis and treatment of vascular disease. It is a handsome compilation of the vascular surgery field as it now stands. It is accessible, mercifully concise, and to the point. It provides an excellent tool to review the vascular field or to brush up on a specific subject for discussion or presentation. The editors and the contributors are to be congratulated for this accomplishment. Ramon Berguer, M.D., Ph.D. Professor and Chief of Vascular Surgery Wayne State University Detroit Medical Center Detroit, Michigan, U.S.A.
iii
Preface
Vascular surgery is a challenging and exciting discipline that has redefined itself during the last decade. Our interface with colleagues from vascular medicine, cardiology, and interventional radiology has resulted in new treatments and the performance of less invasive procedures for management of carotid occlusive disease, abdominal aortic aneurysm, and peripheral vascular insufficiency. Including coronary artery disease, observed in many of our patients, vascular disease is the major cause of morbidity and mortality in this country. In the third edition of Vascular Surgery: Principles and Practice, our approach has been to present a single comprehensive source of information on pathophysiology, diagnosis, and therapeutic options for surgeons and other specialists in our field. Chapters from the second edition have been extensively revised and new chapters have been added on the evolving practice in endovascular surgery. Insofar as possible, technical updates and descriptions have been added to each chapter detailing new techniques used in surgical and endovascular procedures. However, we have also retained the popular final chapter describing the classical operations for correction of vascular disorders. Contributions have been received from nearly 200 acknowledged authorities in vascular surgery and associated specialties. This effort has achieved a balance that we believe will be useful to the surgeon caring for patients with vascular disease. We have also added an introductory chapter outlining the specialty’s future and its aspirations for independence, as supported by a substantial majority of all recognized vascular societies in this country. Our specialty’s commitment to the noninvasive diagnosis of vascular disease is also emphasized in this textbook and should provide the reader with an authoritative review of current diagnostic modalities. This textbook could not have become a reality without supervision from our publisher, Marcel Dekker, Inc. We are indebted to its staff including Geoff Greenwood, Joseph Stubenrauch, and Kerry Doyle for their organizational talents and much appreciated recommendations. Furthermore, the editors are personally indebted to Estrellita Alejo-Broadie in Irvine, California, Katherine Turlington in Newark, New Jersey, and Jackie Simpson and Julie Harris in New York. Their countless hours of work and devotion to the completion of this textbook have been remarkable and most appreciated. Robert W. Hobson II, M.D. Samuel E. Wilson, M.D. Frank J. Veith, M.D.
v
Contents
Foreword Ramon Berguer Preface Contributors
I.
iii v xiii
Assessment of Vascular Disease
1.
The Evolution of Vascular Surgery James C. Stanley
1
2.
Pathophysiology of Atherosclerosis Russell Ross
15
3.
Pathophysiology of Human Atherosclerosis Christopher K. Zarins and Seymour Glagov
31
4.
Epidemiology of Atherosclerosis and Its Modification Allen W. Averbook and Samuel E. Wilson
55
5.
Hemodynamics of Abnormal Blood Flow David S. Sumner
81
6.
Clinical Examination of the Vascular System Joshua A. Beckman and Mark A. Creager
103
7.
Noninvasive Studies of Peripheral Vascular Disease James S. T. Yao
113
8.
Noninvasive Cerebrovascular Diagnostic Techniques Thomas G. Lynch and Robert W. Hobson II
123
9.
Noninvasive Diagnosis of Venous Disease J. Leonel Villavicencio, David L. Gillespie, and Sandra Eifert
153
10.
Angiography Timothy M. Koci, Frances Chiang, and C. Mark Mehringer
169
11.
Design of Clinical Trials for Evaluation of New Treatments and Methodology James M. Cook and Robert W. Barnes
211
vii
viii
Contents
12.
Outcomes Assessment for the Vascular Surgeon John V. White
221
13.
Computers and Vascular Surgery Richard F. Kempczinski
227
II.
Medical Treatment
14.
Medical Management of Atherosclerotic Vascular Disease Ralph G. DePalma and Donna L. Kowallek
235
15.
Regression and Stabilization of Atherosclerosis by Medical Treatment Howard N. Hodis, Wendy J. Mack, and Albert E. Yellin
249
16.
Hyperthrombotic States in Vascular Surgery Jonathan B. Towne
273
17.
Anticoagulants Timothy K. Liem and Donald Silver
285
18.
Thrombolytic Therapy Sunita Srivastava and Kenneth Ouriel
297
19.
Antiplatelet Agents Richard M. Green and James A. DeWeese
303
20.
Pentoxifylline, Vasodilators, and Metabolic Agents Samuel R. Money and W. Charles Sternbergh III
309
21.
Perioperative Evaluation and Management of Cardiac Risk in Vascular Surgery Piotr Sobieszczyk, Joshua A. Beckman, and Michael Belkin
315
22.
The Biology of Restenosis and Neointimal Hyperplasia Robert A. Larson and Michael A. Golden
325
III.
Endovascular Intervention
23.
Basic Nomenclature Edward B. Diethrich
341
24.
Peripheral Atherectomy Samuel S. Ahn and Kyung M. Ro
351
25.
Endovascular Grafts for Aneurysms, Occlusive Disease, and Vascular Injuries Takao Ohki, Evan C. Lipsitz, and Frank J. Veith
363
26.
Adjunctive Endovascular Procedures: Techniques to Facilitate Operative Vascular Surgery Reese A. Wain and Frank J. Veith
395
Contents
ix
IV.
Peripheral Occlusive Disease
27.
Acute Arterial Insufficiency F. William Blaisdell and James W. Holcroft
405
28.
Microcirculatory Dysfunction in the Pathophysiology of Skeletal Muscle Ischemia Walter N. Dura´n, Mauricio P. Boric´, Peter J. Pappas, and Robert W. Hobson II
413
29.
Arterioarterial Atherothrombotic Microemboli of the Lower Limb Dhiraj M. Shah, R. Clement Darling III, Benjamin B. Chang, Philip S. K. Paty, Paul B. Kreienberg, Sean P. Roddy, and Robert P. Leather
427
30.
Aortoiliofemoral Occlusive Disease K. Wayne Johnston and Peter G. Kalman
439
31.
Femoral-Popliteal-Tibial Occlusive Disease Frank J. Veith and Evan C. Lipsitz
455
32.
In Situ Saphenous Vein Arterial Bypass Robert P. Leather, Dhiraj M. Shah, R. Clement Darling III, Benjamin B. Chang, Philip S. K. Paty, and Paul B. Kreienberg
485
33.
Combined Aortoiliac and Femoropopliteal Occlusive Disease David C. Brewster and Frank J. Veith
495
34.
Adventitial Cystic Disease and Entrapment Syndromes Involving the Popliteal Artery Norman M. Rich, George J. Collins, Jr., Jerry R. Youkey, James M. Salander, Hugh J. Donohue, and Bruce M. Elliott
513
35.
Extraanatomic Bypasses Steven M. Hertz, Bruce J. Brener, Donald K. Brief, and Frank J. Veith
527
36.
Surgery of the Deep Femoral Artery: Profundaplasty Jonathan B. Towne
545
37.
Amputation in the Dysvascular Patient James M. Malone
555
38.
Rehabilitation of the Vascular Amputee Sudesh Sheela Jain and Joel A. DeLisa
575
39.
Lumbar Sympathectomy James S. T. Yao
595
40.
Diabetes and Peripheral Vascular Disease Cameron M. Akbari and Frank W. LoGerfo
601
41.
Biologic and Synthetic Prosthetic Materials for Vascular Conduits William M. Abbott and Thomas F. Rehring
611
42.
Prevention and Management of Prosthetic Graft Infection P. Allen Hartsell, Keith D. Calligaro, Matthew J. Dougherty, and Frank J. Veith
621
x
Contents
V.
Aneurysms
43.
Abdominal Aortic Aneurysms Peter G. Kalman and K. Wayne Johnston
631
44.
Thoracoabdominal Aortic Aneurysms Larry H. Hollier, Marcus D’ayala, and Alfio Carroccio
641
45.
Popliteal Artery Aneurysm Timothy P. Connall and Samuel E. Wilson
653
46.
Splanchnic Artery Aneurysms Russell A. Williams and Samuel E. Wilson
659
47.
Infected Aneurysms Bruce A. Perler and Calvin B. Ernst
669
VI.
Cerebrovascular Disease
48.
Symptomatic Extracranial Vascular Disease: Natural History and Medical Management William S. Fields and James C. Grotta
695
49.
Carotid Pathology Anthony M. Imparato
711
50.
Management of Ulcerative Lesions of the Carotid Artery: Symptomatic and Asymptomatic Hugh A. Gelabert and Wesley S. Moore
729
51.
Cerebral Protection During Carotid Artery Surgery Allan Callow
737
52.
Extracranial Carotid Artery Occlusive Disease Samuel E. Wilson and Robert W. Hobson II
745
53A. Occlusive Disease of the Branches of the Aortic Arch Ramon Berguer
765
53B. Vertebrobasilar Ischemia: Reconstruction of the Vertebral Artery and Proximal Portion of the Subclavian Artery Ramon Berguer
771
54.
Carotid Arterial Tortuosity, Kinks, and Spontaneous Dissection J. Timothy Fulenwider and Robert B. Smith III
783
55.
External Carotid Endarterectomy Karl A. Illig, Richard M. Green, and James A. DeWeese
795
56.
Extracranial Carotid Artery Aneurysms James A. Gillespie and Samuel E. Wilson
803
57.
Carotid Body Tumors Frank T. Padberg, Jr., and Alfred V. Persson
811
Contents
VII.
xi
Visceral Arterial Disease
58.
Renovascular Disease Richard H. Dean and Kimberley J. Hansen
823
59.
Acute Mesenteric Vascular Disease Ronald Nathaniel Kaleya and Scott J. Boley
839
60.
Chronic Visceral Ischemia: A Surgical Condition Darren B. Schneider, Louis M. Messina, and Ronald J. Stoney
861
61.
Sexual Function and Vascular Surgery Ralph G. DePalma
877
VIII.
Vascular Disorders of the Upper Extremity and Vasculitis
62.
Thoracic Outlet Disorders: Thoracic Outlet Compression Syndrome and Axillary Vein Thrombosis Herbert I. Machleder
889
63.
Raynaud’s Syndrome and Upper Extremity Small Artery Occlusive Disease James M. Edwards, Lloyd M. Taylor, Jr., and John M. Porter
903
64.
Vasculitis and Dysplastic Arterial Lesions Hisham S. Bassiouny and Bruce L. Gewertz
915
IX.
Venous and Lymphatic Disorders
65.
Natural History of Deep Venous Thrombosis and Its Implications for Sequelae in the Involved Limb Matthew Waltham, Alberto Smith, and Kevin G. Burnand
929
66.
Pathophysiology of Chronic Venous Insufficiency Peter J. Pappas, Walter N. Dura´n, and Robert W. Hobson II
937
67.
Etiology and Surgical Management of Varicose Veins John J. Bergan
949
68.
Deep Vein Thrombosis: Prevention and Management Lazar J. Greenfield and Mary C. Proctor
963
69.
Chronic Venous Insufficiency: Natural History and Classification Robert L. Kistner, Bo Eklof, and Elna M. Masuda
979
70.
Surgical Management of Lower Extremity Chronic Venous Insufficiency Jae-Sung Cho and Peter Gloviczki
991
71.
Lytic Therapy and Venous Stenting: Indications and Results Anthony J. Comerota
1003
72.
Management of Portal Hypertension Atef A. Salam and Tarek A. Salam
1015
xii
Contents
73.
The Lymphatic System Timothy A. Miller and Andrew E. Turk
X.
Vascular Trauma
74.
Thoracic and Abdominal Vascular Trauma David V. Feliciano and Kenneth L. Mattox
1049
75.
Vascular Injuries in the Neck and Thoracic Outlet Malcolm O. Perry
1071
76.
Vascular Injuries of the Extremities Robert W. Hobson II and Norman M. Rich
1081
77.
Iatrogenic Vascular Injuries Charles D. Franco, Jamie Goldsmith, Takao Ohki, and Frank J. Veith
1095
78.
Vascular Complications Related to Drug Abuse Richard A. Yeager, Robert W. Hobson II, and Creighton B. Wright
1107
79.
Complex Regional Pain Syndromes (Posttraumatic Pain Syndromes: Causalgia and Mimocausalgia) Ali F. AbuRahma
1123
XI.
Compartment Syndrome, Vascular Access, Malformations, and Transplantation
80.
Compartment Syndrome David A. Kulber, Geoffrey S. Tompkins, and Jonathan R. Hiatt
1133
81.
Principles of Vascular Access Surgery Robert S. Bennion and Samuel E. Wilson
1145
82.
Vascular Anomalies: Hemangiomas and Malformations Hugh H. Trout III and Sandra Eifert
1161
83.
Vascular Aspects of Organ Transplantation Jorge Ortiz, T. S. Dulkanchainun, and D. K. Imagawa
1173
XII. 84.
Index
1037
Surgical Techniques Vascular Surgical Techniques Frank J. Veith
1187
1261
Contributors
William M. Abbott, M.D. [41] Department of Surgery Harvard Medical School Chief of Vascular Surgery Division of Vascular Surgery Massachusetts General Hospital Boston, Massachusetts, U.S.A.
Hisham S. Bassiouny, M.D. [64] Department of Surgery The University of Chicago Chicago, Illinois, U.S.A. Joshua A. Beckman, M.D. [6, 21] Cardiovascular Division Department of Medicine Brigham and Women’s Hospital Boston, Massachusetts, U.S.A.
Ali F. AbuRahma, M.D. [79] Chief of Vascular Surgery Division of Vascular Surgery Department of Surgery Robert C. Byrd Health Sciences Center of West Virginia University Charleston, West Virginia, U.S.A.
Michael Belkin, M.D. [21] Chief of Vascular Surgery Department of Surgery Brigham and Women’s Hospital Boston, Massachusetts, U.S.A.
Samuel S. Ahn, M.D. [24] Director, Endovascular Surgery Division of Vascular Surgery UCLA School of Medicine Los Angeles, California, U.S.A.
Robert S. Bennion, M.D. [81] Department of Surgery UCLA School of Medicine Los Angeles, California, U.S.A. John J. Bergan, M.D. [67] Department of Surgery University of California, San Diego La Jolla, California, U.S.A.
Cameron M. Akbari, M.D. [40] Department of Surgery Washington Hospital Center Washington, D.C., U.S.A.
Ramon Berguer, M.D., Ph.D. [53A, 53B] Chief of Vascular Surgery Wayne State University Detroit Medical Center Detroit, Michigan, U.S.A.
Allen W. Averbook, M.D. [4] Pinehurst Surgical Clinic Pinehurst, North Carolina, U.S.A. Robert W. Barnes, M.D. [11] Professor and Chairman Department of Surgery University of Arkansas for Medical Sciences Little Rock, Arkansas, U.S.A.
F. William Blaisdell, M.D. [27] Department of Surgery University of California Davis School of Medicine Sacramento, California, U.S.A.
The numbers in brackets following the contributor name refer to chapter(s) authored or co-authored by the contributor.
xiii
xiv
Contributors
Scott J. Boley, M.D. [59] Montefiore Medical Center Bronx, New York, U.S.A. Mauricio P. Boric´, Ph.D. [28] Departamento de Ciencias Fisiolo´gicas Facultad de Ciencias Biolo´gicas P. Universidad Cato´lica de Chile Santiago, Chile Bruce J. Brener, M.D. [35] Director, Peripheral Vascular Surgery Department of Surgery Newark Beth Israel Medical Center Newark, New Jersey, U.S.A. David C. Brewster, M.D. [33] Department of Vascular Surgery Massachusetts General Hospital Boston, Massachusetts, U.S.A. Donald K. Brief, M.D. [35] Director of Surgery Department of Surgery Newark Beth Israel Medical Center Newark, New Jersey, U.S.A.
Benjamin B. Chang, M.D. [29, 32] Department of Vascular Surgery Albany Medical College Albany, New York, U.S.A. Frances Chiang, M.D. [10] Department of Radiology Harbor – UCLA Medical Center Torrance, California, U.S.A. Jae-Sung Cho, M.D. [70] Division of Vascular Surgery Department of Surgery University of Pittsburgh Pittsburgh, Pennsylvania, U.S.A. George J. Collins, Jr., M.D. [34] Department of Surgery Uniformed Services University of the Health Sciences Bethesda, Maryland, U.S.A. Anthony J. Comerota, M.D. [71] Director Jobst Vascular Center Toledo, Ohio Professor of Surgery University of Michigan Ann Arbor, Michigan, U.S.A.
Kevin G. Burnand, M.S., F.R.C.S. [65] Division of Vascular Surgery Department of Surgery St. Thomas’ Hospital London, England
Timothy P. Connall, M.D. [45] Chief, Division of Plastic Surgery Department of Surgery USAF Medical Center Wright-Patterson Air Force Base Dayton, Ohio, U.S.A.
Keith D. Calligaro, M.D. [42] Chief, Division of Vascular Surgery Department of Surgery Pennsylvania Hospital Philadelphia, Pennsylvania, U.S.A.
James M. Cook, M.D. [11] Division of Vascular Surgery Department of Surgery The Everett Clinic Everett, Washington, U.S.A.
Allan Callow, M.D. [51] Departments of Medicine and Surgery Boston University School of Medicine Boston, Massachusetts, U.S.A.
Mark A. Creager, M.D. [6] Cardiovascular Division Department of Medicine Brigham and Women’s Hospital Boston, Massachusetts, U.S.A.
Alfio Carroccio, M.D. [44] Department of Surgery Mount Sinai Medical Center New York, New York, U.S.A.
Marcus D’ayala, M.D. [44] Department of Surgery Mount Sinai Medical Center New York, New York, U.S.A.
Contributors
R. Clement Darling III, M.D. [29, 32] Department of Vascular Surgery Albany Medical College Albany, New York, U.S.A. Richard H. Dean, M.D. [58] President and CEO Wake Forest University Health Sciences Winston-Salem, North Carolina, U.S.A. Joel A. DeLisa, M.D., M.S. [38] Professor and Chairman Department of Physical Medicine and Rehabilitation UMDNJ—New Jersey Medical School Newark, New Jersey, U.S.A. Ralph G. DePalma, M.D., F.A.C.S. [14, 61] National Director of Surgery Department of Veterans Affairs Washington, D.C. Uniformed Services University of the Health Sciences Bethesda, Maryland, U.S.A. James A. DeWeese, M.D. [19, 55] Chair Emeritus, Cardiothoracic Surgery and Vascular Surgery University of Rochester Medical Center Rochester, New York, U.S.A. Edward B. Diethrich, M.D. [23] Medical Director Department of Cardiovascular Surgery Arizona Heart Institute and Foundation Phoenix, Arizona, U.S.A. Hugh J. Donohue, M.D. [34] Department of Surgery Medical College of Virginia Richmond, Virginia, U.S.A. Matthew J. Dougherty, M.D. [42] Division of Vascular Surgery Department of Surgery Pennsylvania Hospital Philadelphia, Pennsylvania, U.S.A. T. S. Dulkanchainun, M.D. [83] Division of Transplantation Department of Surgery University of California Irvine Orange, California, U.S.A.
Walter N. Dura´n, Ph.D. [28, 66] Professor Department of Pharmacology and Physiology Director, Program in Vascular Biology Division of Vascular Surgery UMDNJ—New Jersey Medical School Newark, New Jersey, U.S.A. James M. Edwards, M.D. [63] Division of Vascular Surgery Oregon Health and Science University Portland, Oregon, U.S.A. Sandra Eifert, M.D. [9, 82] Department of Surgery Uniformed Services University of the Health Sciences Bethesda, Maryland, U.S.A. Bo Eklof, M.D. [69] Department of Vascular Surgery Straub Clinic and Hospital University of Hawaii Honolulu, Hawaii, U.S.A. Bruce M. Elliott, M.D. [34] Head of Vascular Surgery Medical University of South Carolina Charleston, South Carolina, U.S.A. Calvin B. Ernst, M.D. [47] Wayne, Pennsylvania, U.S.A. David V. Feliciano, M.D. [74] Chief of Surgery Grady Memorial Hospital Department of Surgery Emory University School of Medicine Atlanta, Georgia, U.S.A. William S. Fields, M.D. [48] Department of Neurology University of Texas Health Science Center at Houston Houston, Texas, U.S.A. Charles D. Franco, M.D. [77] New Brunswick, New Jersey, U.S.A. J. Timothy Fulenwider, M.D. [54] Northwest Georgia Surgical Associates Gainesville, Georgia, U.S.A.
xv
xvi
Contributors
Hugh A. Gelabert, M.D. [50] Division of Vascular Surgery Department of Surgery UCLA Medical Center Los Angeles, California, U.S.A.
Lazar J. Greenfield, M.D. [68] Interim Vice President for Medical Affairs and Chief Executive Officer University of Michigan Ann Arbor, Michigan, U.S.A.
Bruce L. Gewertz, M.D. [64] The Dallas B. Phemister Professor and Chairman Division of Vascular Surgery Department of Surgery The University of Chicago Chicago, Illinois, U.S.A.
James C. Grotta, M.D. [48] Department of Neurology University of Texas Health Science Center at Houston Houston, Texas, U.S.A.
James A. Gillespie, M.D. [56] Department of Surgery St. George’s Hospital London, England David L. Gillespie, M.D. [9] Chief, Division of Vascular Surgery Department of Surgery Uniformed Services University of the Health Sciences Bethesda, Maryland, U.S.A. Seymour Glagov, M.D. [3] Department of Pathology University of Chicago Chicago, Illinois, U.S.A. Peter Gloviczki, M.D. [70] Vice-Chair, Division of Vascular Surgery Gonda Vascular Center Mayo Clinic Rochester, Minnesota, U.S.A. Michael A. Golden, M.D. [22] Division of Vascular Surgery Department of Surgery University of Pennsylvania Medical Center Philadelphia, Pennsylvania, U.S.A. Jamie Goldsmith, M.D. [77] Montefiore Medical Center—Albert Einstein College of Medicine New York, New York, U.S.A. Richard M. Green, M.D. [19, 55] Department of Surgery University of Rochester Medical Center Rochester, New York, U.S.A.
Kimberley J. Hansen, M.D. [58] Division of Surgical Services Wake Forest University Health Sciences Winston-Salem, North Carolina, U.S.A. P. Allen Hartsell, M.D. [42] Department of Surgery Texas A&M University Temple, Texas, U.S.A. Steven M. Hertz, M.D. [35] Division of Vascular Surgery Department of Surgery Newark Beth Israel Medical Center Newark, New Jersey, U.S.A. Jonathan R. Hiatt, M.D. [80] Department of Surgery Cedars-Sinai Medical Center Los Angeles, California, U.S.A. Robert W. Hobson II, M.D. [8, 28, 52, 66, 76, 78] Director, Division of Vascular Surgery UMDNJ—New Jersey Medical School Newark, New Jersey, U.S.A. Howard N. Hodis, M.D. [15] Departments of Medicine and Preventive Medicine Atherosclerosis Research Unit University of Southern California School of Medicine Los Angeles, California, U.S.A. James W. Holcroft, M.D. [27] Department of Surgery University of California Davis School of Medicine Sacramento, California, U.S.A.
Contributors
Larry H. Hollier, M.D. [44] Franz W. Sichel Professor and Chairman Division of Vascular Surgery Department of Surgery Mount Sinai Medical Center New York, New York, U.S.A. Karl A. Illig, M.D. [55] Department of Surgery University of Rochester Medical Center Rochester, New York, U.S.A. D. K. Imagawa, M.D. [83] Division of Transplantation Department of Surgery University of California Irvine Orange, California, U.S.A. Anthony M. Imparato, M.D. [49] Division of Vascular Surgery Department of Surgery New York University Medical Center New York, New York, U.S.A. Sudesh Sheela Jain, M.D. [38] Consultant Kessler Medical Rehabilitation Research and Education Corporation West Orange, New Jersey, U.S.A. K. Wayne Johnston, M.D. [30, 43] Department of Surgery Toronto General Hospital Toronto, Ontario, Canada Ronald Nathaniel Kaleya, M.D. [59] Department of Surgery Montefiore Medical Center Bronx, New York, U.S.A. Peter G. Kalman, M.D. [30, 43] Division of Vascular Surgery Department of Surgery Loyola University Medical Center Maywood, Illinois, U.S.A. Richard F. Kempczinski, M.D. [13] Professor Emeritus University of Cincinnati Medical Center Cincinnati, Ohio, U.S.A.
Robert L. Kistner, M.D. [69] Department of Vascular Surgery Straub Clinic and Hospital University of Hawaii Honolulu, Hawaii, U.S.A. Timothy M. Koci, M.D. [10] Department of Radiology Washoe Medical Center Reno, Nevada, U.S.A. Donna L. Kowallek, R.N., M.S.N., C.V.N.† [14] VA Sierra Nevada Health Care System Reno, Nevada, U.S.A. Paul B. Kreienberg, M.D. [29, 32] Department of Vascular Surgery Albany Medical College Albany, New York, U.S.A. David A. Kulber, M.D. [80] Division of Plastic Surgery Department of Surgery Cedars-Sinai Medical Center Los Angeles, California, U.S.A. Robert A. Larson, M.D. [22] Division of Vascular Surgery Department of Surgery University of Pennsylvania Medical Center Philadelphia, Pennsylvania, U.S.A. Robert P. Leather, M.D. [29, 32] Professor Emeritus Department of Vascular Surgery Albany Medical College Albany, New York, U.S.A. Timothy K. Liem, M.D. [17] Division of Vascular Surgery Department of Surgery University of Missouri –Columbia Columbia, Missouri, U.S.A. Evan C. Lipsitz, M.D. [25, 31] Department of Surgery Montefiore Medical Center Bronx, New York, U.S.A.
†
Deceased.
xvii
xviii
Contributors
Frank W. LoGerfo, M.D. [40] William V. McDermott Professor of Surgery Harvard Medical School Chief, Division of Vascular Surgery Department of Surgery Beth Israel Deaconess Medical Center Boston, Massachusetts, U.S.A. Thomas G. Lynch, M.D. [8] Chief, Section of Vascular Surgery Department of Surgery University of Nebraska Medical Center Omaha, Nebraska, U.S.A. Herbert I. Machleder, M.D. [62] Division of Vascular Surgery Department of Surgery UCLA Medical Center Los Angeles, California, U.S.A. Wendy J. Mack, M.D. [15] Department of Preventive Medicine Atherosclerosis Research Unit University of Southern California School of Medicine Los Angeles, California, U.S.A. James M. Malone, M.D. [37] Chairman, Department of Surgery Scottsdale Healthcare Shea Scottsdale, Arizona, U.S.A. Elna M. Masuda, M.D. [69] Department of Vascular Surgery Straub Clinic and Hospital University of Hawaii Honolulu, Hawaii, U.S.A. Kenneth L. Mattox, M.D. [74] Vice Chairman of Surgery Department of Surgery Baylor College of Medicine Houston, Texas, U.S.A. C. Mark Mehringer, M.D. [10] Department of Radiology Harbor – UCLA Medical Center Torrance, California, U.S.A.
Louis M. Messina, M.D. [60] Chief of Vascular Surgery University of California Medical Center San Francisco, California, U.S.A. Timothy A. Miller, M.D. [73] Chief, Division of Plastic and Reconstructive Surgery Department of Surgery UCLA Medical Center Los Angeles, California, U.S.A. Samuel R. Money, M.D. [20] Head, Section of Vascular Surgery Department of Surgery Ochsner Clinic Foundation New Orleans, Louisiana, U.S.A. Wesley S. Moore, M.D. [50] Division of Vascular Surgery Department of Surgery UCLA Medical Center Los Angeles, California, U.S.A. Takao Ohki, M.D. [25, 77] Chief, Vascular and Endovascular Surgery Department of Surgery Montefiore Medical Center—Albert Einstein College of Medicine Bronx, New York, U.S.A. Jorge Ortiz, M.D. [83] Division of Transplant Surgery Department of Surgery Albert Einstein Medical Center Philadelphia, Pennsylvania, U.S.A. Kenneth Ouriel, M.D. [18] Chairman, Department of Vascular Surgery The Cleveland Clinic Foundation Cleveland, Ohio, U.S.A. Frank T. Padberg, Jr., M.D. [57] Division of Vascular Surgery Department of Surgery UMDNJ—New Jersey Medical School Newark, New Jersey, U.S.A. Peter J. Pappas, M.D. [28, 66] Associate Professor of Surgery Department of Surgery Chief, Section of Vascular Surgery UMDNJ—University Hospital Newark, New Jersey, U.S.A.
Contributors
Philip S. K. Paty, M.D. [29, 32] Department of Vascular Surgery Albany Medical College Albany, New York, U.S.A.
Sean P. Roddy, M.D. [29] Department of Vascular Surgery Albany Medical College Albany, New York, U.S.A.
Bruce A. Perler, M.D. [47] Chief, Division of Vascular Surgery Department of Surgery The Johns Hopkins University School of Medicine Baltimore, Maryland, U.S.A.
Russell Ross, M.D.† [2] University of Washington School of Medicine Seattle, Washington, U.S.A.
Malcolm O. Perry, M.D. [75] Professor Emeritus Department of Surgery University of Texas Southwestern Medical Center Dallas, Texas, U.S.A. Alfred V. Persson, M.D. [57] Metrowest Medical Center Framingham, Massachusetts, U.S.A. John M. Porter, M.D.† [63] Division of Vascular Surgery Oregon Health and Science University Portland, Oregon, U.S.A. Mary C. Proctor, M.D. [68] Department of Surgery University of Michigan Ann Arbor, Michigan, U.S.A. Thomas F. Rehring, M.D. [41] Department of Vascular Surgery Massachusetts General Hospital Boston, Massachusetts, U.S.A. Norman M. Rich, M.D. [34, 76] Chairman, Department of Surgery Uniformed Services University of the Health Sciences Bethesda, Maryland, U.S.A. Kyung M. Ro, M.P.H., M.S. [24] Division of Vascular Surgery Department of Surgery UCLA School of Medicine Los Angeles, California, U.S.A. †
Deceased.
Atef A. Salam, M.D. [72] Department of Surgery Emory University School of Medicine Atlanta, Georgia, U.S.A. Tarek A. Salam, M.D. [72] Department of Surgery Ain-Shams University Cairo, Egypt James M. Salander, M.D. [34] Department of Surgery Uniformed Services University of the Health Sciences Bethesda, Maryland, U.S.A. Darren B. Schneider, M.D. [60] Divisions of Vascular Surgery and Interventional Radiology University of California Medical Center San Francisco, California, U.S.A. Dhiraj M. Shah, M.D. [29, 32] Director, Institute for Vascular Health and Disease Albany Medical College Albany, New York, U.S.A. Donald Silver, M.D. [17] Chairman, Department of Surgery University of Missouri –Columbia Columbia, Missouri, U.S.A. Alberto Smith, Ph.D. [65] Department of Surgery St. Thomas’ Hospital London, England Robert B. Smith III, M.D. [54] Associate Chairman of Surgery Department of Surgery Emory University School of Medicine Atlanta, Georgia, U.S.A. †
Deceased.
xix
xx
Contributors
Piotr Sobieszczyk, M.D. [21] Cardiovascular Division Department of Medicine Brigham and Women’s Hospital Boston, Massachusetts, U.S.A. Sunita Srivastava, M.D. [18] Department of Vascular Surgery The Cleveland Clinic Foundation Cleveland, Ohio, U.S.A. James C. Stanley, M.D. [1] Head, Section of Vascular Surgery Department of Surgery University of Michigan Ann Arbor, Michigan, U.S.A. W. Charles Sternbergh III, M.D. [20] Program Director Vascular and Endovascular Surgery Department of Surgery Ochsner Clinic Foundation New Orleans, Louisiana, U.S.A. Ronald J. Stoney, M.D. [60] Professor Emeritus Division of Vascular Surgery Department of Surgery University of California Medical Center San Francisco, California, U.S.A. David S. Sumner, M.D. [5] Chief, Division of Peripheral Vascular Surgery Department of Surgery Southern Illinois University School of Medicine Springfield, Illinois, U.S.A. Lloyd M. Taylor, Jr., M.D. [63] Division of Vascular Surgery Oregon Health and Science University Portland, Oregon, U.S.A. Geoffrey S. Tompkins, M.D. [80] Division of Orthopaedic Surgery Department of Surgery Santa Rosa Memorial Hospital Santa Rosa, California, U.S.A. Jonathan B. Towne, M.D. [16, 36] Chief, Vascular Surgery Medical College of Wisconsin Milwaukee, Wisconsin, U.S.A.
Hugh H. Trout III, M.D. [82] George Washington Medical Center Bethesda, Maryland, U.S.A. Andrew E. Turk, M.D. [73] Department of Plastic Surgery Cleveland Clinic, Naples Naples, Florida, U.S.A. Frank J. Veith, M.D. [25, 26, 31, 33, 35, 42, 77, 84] The William J. von Liebig Chair of Vascular Surgery Division of Vascular Surgery Department of Surgery Montefiore Medical Center—Albert Einstein College of Medicine New York, New York, U.S.A. J. Leonel Villavicencio, M.D. [9] Department of Surgery Uniformed Services University of the Health Sciences Bethesda, Maryland Director, Venous and Lymphatic Teaching Clinics Walter Reed Army and National Naval Centers Washington, D.C., U.S.A. Reese A. Wain, M.D. [26] Chief of Vascular Surgery Weiler Hospital of the Albert Einstein College of Medicine New York, New York, U.S.A. Matthew Waltham, M.A., F.R.C.S. [65] Department of Surgery St. Thomas’ Hospital London, England John V. White, M.D. [12] Clinical Professor of Surgery University of Illinois at Chicago Department of Surgery Advocate Lutheran General Hospital Park Ridge, Illinois, U.S.A. Russell A. Williams, M.D. [46] Department of Surgery University of California Irvine Orange, California, U.S.A.
Contributors
Samuel E. Wilson, M.D. [4, 45, 46, 52, 56, 81] Department of Surgery University of California Irvine Orange, California, U.S.A. Creighton B. Wright, M.D. [78] Cardiovascular & Thoracic Surgeons, Inc. Cincinnati, Ohio, U.S.A. James S. T. Yao, M.D., Ph.D. [7, 39] Magerstadt Professor of Surgery Division of Vascular Surgery Northwestern University The Feinberg School of Medicine Chicago, Illinois, U.S.A. Richard A. Yeager, M.D. [78] Surgical Service Portland VA Medical Center Portland, Oregon, U.S.A.
Albert E. Yellin, M.D. [15] Associate Chief of Staff Department of Surgery University of Southern California School of Medicine Los Angeles, California, U.S.A. Jerry R. Youkey, M.D. [34] Department of Surgery Uniformed Services University of the Health Sciences Bethesda, Maryland, U.S.A.
Christopher K. Zarins, M.D. [3] Chairman, Division of Vascular Surgery Department of Surgery Stanford University Medical Center Stanford, California, U.S.A.
xxi
CHAPTER 1
The Evolution of Vascular Surgery James C. Stanley from India, where Sushruta used hemp fibers for blood vessel ligations around 700 B.C.[5] Celsius made an important contribution in the 1st century, when he ligated vessels both above and below the site of injury, then transected the involved vessel so that it might retract from the wound, thus lessening the risk of hemorrhage which often accompanied wound infections. A century later Galen had ligated many vessels and Antyllus ligated both entering and exiting vessels of an aneurysm, but infection continued to compromise such efforts. Venous disease was also well recognized by the ancients, including Hippocrates, who recommended treating venous varicosities with compressive dressings and avoidance of standing.[3] Celsius used bandages and plasters to treat venous ulcerations in the 1st century and Galen suggested multiple ligations as a therapeutic intervention in the 2nd century. Little change occurred in the management of venous disease over the next 1500 years. The dark ages of European history witnessed few advances in vascular surgery. It wasn’t until the 16th century that Ambrose Pare´ successfully ligated vessels in the battlefields at Danvilliers and used stringent agents to lessen wound infections.[6] This was a major contribution in the treatment of controlling hemorrhage from arteries and veins. During the 18th century considerable efforts were extended to the treatment of aneurysms, led by John Hunter, who made many extraordinary contributions to the scientific classification and treatment of vascular diseases.[7 – 10] One of his more noteworthy accomplishments involved ligation of the femoral artery for the treatment of a popliteal artery aneurysm. This procedure provided the impetus for his interest in the relevance of the collateral circulation in the extremities. During the ensuing 19th century many other physicians described arterial ligature in the management of aneurysms. One of the most inventive of those practitioners was Ashley Cooper,[11,12] a student of Hunter, who ligated the carotid artery for an aneurysm in 1805.[13] The patient subsequently died, but he undertook a second successful ligation for the same disease 3 years later in 1808.[14] Cooper also ligated the aorta for an iliac artery aneurysm and treated a femoral artery aneurysm by ligation during this same era. Shortly thereafter
Contemporary vascular surgery has evolved slowly over many years with notable exceptions that catapulted new paradigms into clinical practice. Most landmark contributions occurred during the last half of the 20th century, resulting from a better understanding of the physiologic consequences of vascular disease, the availability of heparin anticoagulation, the introduction of synthetic grafts, development of noninvasive testing, improved anatomic imaging, and the maturation of technical skills from simple vascular ligations to complex open surgical and endovascular procedures. Although vascular surgery had its beginning in many other disciplines, it has evolved into an independent medical specialty with a defined body of knowledge and established standards of practice. The history of vascular surgery is best addressed by reviewing four specific time periods: antiquity to the end of the 19th century, the early 20th century, the last half of the 20th century, and the early 21st century. A select group of listings of landmark contributions have been created as a reference to the historical events affecting certain aspects of vascular surgery, including aortic occlusive disease (Table 1), nonanatomic revascularization of the lower extremities (Table 2), endovascular therapies for arterial disease (Table 3), femoral, popliteal, and tibial arterial occlusive disease (Table 4), aortic aneurysms (Table 5), femoral and popliteal artery aneurysms (Table 6), splanchnic and renal artery disease (Table 7), cerebrovascular disease recognition (Table 8), cerebrovascular disease-surgical treatment (Table 9), and venous disease (Table 10). Many contributors not included in the aforenoted listings because of this review’s brief nature have added both depth and breadth to our knowledge of vascular surgery. Four excellent works on the history of vascular surgery have been published that offer further insight into the evolution of this discipline.[1 – 4]
ANTIQUITY TO THE END OF THE 19TH CENTURY Arterial disruptions due to trauma and ruptured aneurysms were confronted by the ancients, whose earliest vascular surgical procedures related to controlling bleeding from these vessels.[3] Perhaps the first recorded reports on this topic were
Hobson/Wilson/Veith: Vascular Surgery: Principles and Practice, Third Edition, Revised and Expanded DOI: 10.1081/0819-9-120024969 Copyright q 2004 by Marcel Dekker, Inc.
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Part One. Assessment of Vascular Disease
in 1817 Valentine Mott ligated the innominate artery for a subclavian aneurysm.[15] Mott also ligated the common iliac artery for an external iliac artery aneurysm in 1820. His work, performed in New York City, was some of the earliest vascular surgery undertaken in the United States. Rudolph Matas was the most widely recognized contributor to vascular surgery towards the end of the 19th century.[16] In 1888 he successfully performed a brachial artery aneurysm endoaneurysmorrhaphy.[17] His technique of ligating the entering and exiting vessels from within the aneurysm proved essential in preserving collateral vessels and maintaining the viability of distal tissues. Matas applied this procedure to the treatment of aortic aneurysms in the next century. Chronic occlusive disease came to the forefront during the 19th century, when Barth described claudication for the first time in 1835, affecting a patient with an aortic thrombosis.[18] His report went unrecognized for many decades, but clearly established the concept that arterial obstructions could cause chronic symptoms amenable to later reconstructive procedures. In 1896 a critical contribution to the understanding of vascular diseases came about with Wilhelm Roentgen’s initial discovery of x-rays,[19] followed 3 months later by an actual arteriogram performed in an amputated upper extremity.[20] It would be decades before the usefulness of arteriography would become apparent in clinical practice. Jaboulay and Briau successfully performed an end-to-end reanastomosis of the carotid artery in 1896.[23] This was remarkable, given the previously held belief that sutures placed in a vessel would result in its early thrombosis. John Murphy, a year later in 1897, described a successful end-toend arterial anastomosis of a femoral artery that had been injured with a gunshot wound with development of a pseudoaneurysm.[22] His case followed considerable experimental work with vascular anastomoses in both canine and bovine subjects and set the stage for subsequent advances in the succeeding century.
EARLY 20TH CENTURY Alexis Carrel, a student of Jaboulay, had an early interest in vascular anastomoses.[23,24] Carrel came to the United States shortly after the turn of the century and joined Charles C. Guthrie in the Department of Physiology at the University of Chicago.[25,26] These two individuals took the concept of inserting a vein into the arterial circulation and demonstrated that such was feasible in animal experiments.[27 – 29] Together they coauthored 28 papers. This work was the basis of Carrel’s receiving the Nobel Prize in Medicine and Physiology in 1912. Given an awareness of the novelty of successful vascular anastomoses performed in the laboratory, Jose´ Goyanes resected a patient’s popliteal artery aneurysm and replaced it with a popliteal vein graft in 1906.[30] This was considered the first clinically successful arterial reconstruction using a vein graft. The treatment of aortic aneurysms at the beginning of the 20th century continued to involve nonreconstructive procedures. Instillation of large amounts of wire into an aneurysm as a means of inducing thrombosis and external
wrapping to limit aneurysmal expansion proved inadequate and were soon discarded as acceptable therapies. Rudolph Matas, who successfully ligated the infrarenal aorta for treatment of an aortic aneurysm in 1923,[31] reported his life’s experience in 1940 with 62 similar lesser operations for aneurysms with a commendable mortality of only 15%.[32] Although the natural history of untreated aortic and peripheral aneurysms became better defined during the early 20th century, adequate treatment would not become commonplace until the second half of the century. The management of lower extremity ischemia advanced quickly toward the end of the first half of the 20th century. In 1946 Joa˜o Cid dos Santos undertook a number of extensive endarterectomies for arteriosclerotic arterial occlusions.[33,34] He is often credited as the founder of arterial endarterectomy, although similar procedures had been performed earlier by Bazy and colleagues for aortic occlusive disease.[35] Endarterectomy was a landmark contribution to the evolution of vascular surgery. In 1948, Jean Kunlin performed a successful femoropopliteal bypass with reversed autogenous saphenous vein and established a therapeutic approach that continues to present times.[36] William Holden, 6 months following Kunlin’s achievement, was first in the United States to perform a lower extremity bypass with vein,[37] and his success was followed by that of many others. Although not directly related to treating lower extremity ischemia, the surgical therapy of thoracic isthmic coarctations during the early mid-20th century established the feasibility of clamping the aorta and undertaking its operative reconstruction. Clarence Crafoord in 1944 first resected the coarcted segment and reconstructed the aorta with an end-toend anastomosis.[38] Robert Gross did the same in 1945,[39] and in 1948 he replaced the coarctated aortic segment with a homograft.[40,41] These achievements allowed others to treat aortoiliac occlusive disease later with much greater confidence. Attention to diseases of the distal aorta followed Rene´ Leriche’s 1923 report on the clinical manifestations of thrombotic occlusion of the arteriosclerotic aortic bifurcation.[42] His experience with the treatment of this disease was later described in a widely heralded report of 1948.[43] The treatment of aortoiliac occlusive disease by operative means progressed rapidly thereafter in the early days of the last half of the century. Recognition of diseases affecting the renal artery during the first half of the 20th century would wait many years before they were successfully treated surgically. Harry Goldblatt in elegant studies performed in the 1920s and 1930s documented that renal artery constrictions in experimental animals caused hypertension.[44] In 1938 the clinical relevance of his observations became apparent when Leadbetter and Burkland removed a small ischemic kidney in a child with renal artery occlusive disease and cured his severe hypertension.[45] Unfortunately, the next few decades saw many kidneys removed without benefit, namely because the careful selection of patients having a renin-mediated form of hypertension was undeveloped and vascular procedures for reconstructing the renal arteries were nonexistent. The classic description of occlusive disease of the splanchnic arteries causing intestinal angina was proposed
Chapter 1.
in J. Englebert Dunphy’s classic paper of 1936.[46] He recognized the importance of postprandial abdominal pain as a manifestation of arteriosclerotic narrowings of the major arteries to the gut and noted its potential to eventuate in intestinal infarction. As was the case with renal artery disease, many years would pass before the successful vascular surgical treatment of intestinal angina occurred. During the first half of the 20th century the role of the extracranial internal carotid artery as a cause of stroke received little attention. There were a number of reasons for this. First, cerebral angiography, initially performed by Egas Moniz in 1927,[47] was not to be used as a diagnostic test for many decades to come. Second, neck vessels were rarely examined during routine autopsy studies, and the existence of extracranial carotid artery arteriosclerosis was usually overlooked. In fact, the most commonly perceived cause of a cerebrovascular accident during the midcentury was thrombosis of the middle cerebral artery, with no understanding that thromboembolism from the region of the carotid bulb may have played a role in the occlusive process. The treatment of venous diseases was one of the mainstays of practice among physicians caring for vascular diseases during the first half of the 20th century. Varicose veins were known to have plagued man since antiquity, and external compression continued to be the basis of most therapies at the close of the century. A noteworthy contribution was the plaster dressing introduced by Unna, which became the forerunner of the dressing carrying his name a century later.[48] In 1905 Keller undertook stripping of extremity veins,[4] and Babcock in that same year developed an intraluminal stripper for vein removal.[49] John Homans subsequently made many observations that advanced our understanding of venous disease. During the century’s second decade he emphasized the importance of saphenofemoral vein ligation in the prevention of varicosities.[50,51] A little more than 20 years later, in 1938, Robert Linton described the importance of incompetent communicating veins and subsequently developed a technique for subfascial ligation of these veins.[52] More direct surgical interventions on the veins themselves to prevent venous hypertension would await another 3 decades. The lethal nature of pulmonary emboli was well known in the early 20th century, and prevention of this complication of venous thrombosis became important. In 1934 Homans advocated femoral vein ligation to prevent pulmonary embolism.[53] By 1945 ligation of the inferior vena cava Table 1-1.
The Evolution of Vascular Surgery
was reported by Northway, Buxton, and O’Neill as a means of preventing fatal pulmonary embolism.[54,55] Ligation of the cava for prevention of septic emboli had been reported a few years earlier.[56] A major advance in the evolution of vascular surgery during the early 20th century was the introduction of translumbar aortography in 1929 by Raynaldo dos Santos.[57] Imaging of blood vessels was to prove essential to the continued advancement of vascular surgery. A second major advance was the use of heparin anticoagulation to prevent perioperative thromboses that affected the vast majority of vascular interventions during the very early 20th century. Although heparin had been discovered in 1918 by Jay McLean in W. H. Howell’s laboratory,[58] it was not purified and readily available for use until the 1930s and 1940s. It was only then that its value in treating arterial thromboses became widely recognized.[59,60] Thus, the first half of the 20th century witnessed the ability to approximate injured vessels, remove arteriosclerotic plaque by the technique of endarterectomy, and replace chronically diseased arteries with bypass grafts, all under the influence of anticoagulation. These achievements laid the foundation for the many advances of the last half of the 20th century in vascular surgery.
THE LAST 50 YEARS OF THE 20TH CENTURY The second half of the century witnessed profound changes in the practice of vascular surgery. These events are best discussed by addressing those contributions unique to specific disease entities.
AortoiliacArteriosclerotic OcclusiveDisease Treatment of arteriosclerotic aortic disease was first successfully undertaken by Jacques Oudot in 1950 with a homograft replacement of a thrombosed aortic bifurcation.[61,62] With the recognition of homograft degeneration and the initial use of synthetic grafts, this form of aortic reconstruction fell into disuse. Although the earliest aortoiliac endarterectomy may have been performed by Bazy and colleagues,[35] this technique was first undertaken in 1951 in the United States by Norman
Aortic Occlusive Disease
Raynaldo dos Santos Clarence Crafoord Rene´ Leriche
1929 1944 1948
Robert Gross Jacques Oudot
1949 1950
Norman Freeman
1951
3
Translumbar aortography Thoracic coarctation resection, aortic reanastomosis Treatment of thrombotic occlusion of atherosclerotic ortic bifurcation, first described in 1923 Homograft replacement of thoracic aortic coarctation Homograft replacement of thrombosed aortic bifurcation Aortoiliac endarterectomy; followed shortly thereafter in 1951 by Wylie, who popularized the open technique first described by Bazy and colleagues in 1949
4
Part One. Assessment of Vascular Disease Table 1-2. Nonanatomic Revascularization of the Lower Extremities Jacques Oudot Norman Freeman
1951 1952
J.J. McCaughan Jr., S.F. Kahn R. Mark Veto F. William Blaisdell, A.D. Hall Lester Savage P.M. Guida, S.W. Moore
1958 1960 1962 1966 1969
Freeman,[63] and shortly thereafter popularized by his former colleague in practice, Edwin Wylie.[64,65] The introduction of synthetic bypass grafts for the treatment of aortic diseases changed the treatment paradigm dramatically, and for the next 40 years these grafts, serving as aortofemoral bypasses, were the most common means of treating aortoiliac occlusive diseases.[66 – 73] Nonanatomic revascularization procedures also evolved during the 1950s and 1960s for the treatment of aortoiliac occlusive lesions in high risk situations. These unconventional interventions were used most often in reoperations for an infected or failed earlier bypass, avoidance of a hostile abdomen, or concerns about the operative hazards of a more extensive procedure. Many types of nonanatomic procedures evolved over a short period of time. The first of these nonanatomic reconstructions was by Jacques Oudot in 1951, who performed a cross-over ilioiliac arterial bypass.[74] Subsequently, Norman Freeman used an endarterectomized superficial femoral artery in 1952 to perform a femorofemoral arterial cross-over bypass.[75] An iliac artery to contralateral popliteal artery bypass was constructed by McCaughan and Kahn in 1958.[76] Little attention was paid to these operations by most practitioners in the earlier days of contemporary vascular surgery. It was only in the 1960s that nonanatomic procedures became popular, after reports by Veto of a femorofemoral arterial cross-over bypass in 1960,[77] as well as by Blaisdell and Hall of an axillofemoral bypass using a synthetic graft in 1962.[78] An important contribution to the latter procedure came from Lester Savage, who in 1966 introduced the addition of a cross-over femorofemoral arterial bypass to a unilateral axillofemoral bypass as a means of revascularizing
Table 1-3.
Ilioiliac bypass Femorofemoral bypass with endarterectomized superficial femoral artery Iliopopliteal bypass Femorofemoral bypass Axillofemoral bypass Axillobifemoral bypass Obturator bypass
both lower extremities.[79] Although unrelated to the primary treatment of aortoiliac occlusive disease, the performance of an obturator bypass, first reported by Guida and Moore in 1969,[80] allowed lower extremity revascularizations with avoidance of an otherwise hostile groin area. Endovascular balloon dilation provided a major advance in the treatment of aortoiliac occlusive disease during the past quarter century, becoming widely used in the 1990s. This technology evolved from the pioneering work of Charles Dotter using percutaneous coaxial dilation of peripheral arteries first reported in 1964,[81] and Andreas Gruntzig, who introduced percutaneous balloon angioplasty in 1974.[82] Treatment of iliac artery stenoses by less invasive percutaneous means markedly reduced the frequency with which open aortobifemoral bypass procedures were performed. The use of balloon-assisted intraluminal stents, developed by Palmaz in 1988,[83] lessened complications associated with balloon-related dissections. The rapid application of stent technology to angioplasty of many arterial stenoses, in addition to iliac artery lesions, followed during the next decade.
Infrainguinal Arteriosclerotic Occlusive Disease Jean Kunlin reported 17 patients who had undergone autogenous vein lower extremity revascularizations in 1951,[84] just 3 years after he performed the first such operation. This was followed by similar bypass procedures in the United States by many surgeons including Julian, Lord, Dale, DeWeese, Linton, Darling, and Szilagyi, that confirmed the utility of reversed saphenous vein femoropopliteal
Endovascular Therapies for Arterial Disease
Arteriosclerotic occlusive disease Charles Dotter Andreas Gruntzig Julio Palmaz Thromboembolism Thomas Fogarty Aneurysmal disease Juan Parodi Frank Veith, Michael Marin Frank Veith, Takao Ohki
1964 1974 1988
Percutaneous coaxial dilation Percutaneous transluminal balloon angioplasty Balloon-assisted stent placement
1963
Balloon catheter for embolectomy
1991 1994 1999
Aortic endograft Endograft exclusion of traumatic arterial disruptions and pseudoaneurysms Aortic endograft treatment of ruptured aneurysms
Chapter 1. Table 1-4.
The Evolution of Vascular Surgery
5
Femoral, Politeal, and Tibia1 Arterial Occlusive Disease
Joa˜o Cid dos Santos Jean Kunlin
1946 1948
Eduardo Palma Karl Hall Peter Martin Herbert Dardik
1956 1962 1971 1976
Robert Leather
1979
Frank Veith, John Bergan, Victor Bernhard
1982, 1985
reconstructions. Extension of vein graft procedures to the more distal infrageniculate arteries was first reported by Palma, who undertook a femorotibial bypass in 1956.[85] This too was followed with similar revascularizations by many others. The use of the saphenous vein in situ after rendering its valves incompetent was first reported by Karl Hall in 1962.[86] This technology saw limited use until 1979, when Robert Leather and his colleagues introduced a new valve cutter for in situ revascularizations.[87] Subsequently, the procedure became widely used during the next decade. Although some have questioned the advantage to these reconstructions, their use in many distal revascularization procedures appeared valid. An alternative biologic graft for use instead of autogenous vein was the tanned human umbilical vein, reported initially by Herbert Dardik in 1976.[88,89] Although utilization of Dacron grafts for lower extremity reconstructions waned with the success of vein revascularizations, the introduction of extruded polytetrafluroethylene (PTFE) grafts caused a resurgence in synthetic graft use for the treatment of lower extremity ischemia. In two hallmark papers, John Bergan, Frank Veith, Victor Bernhard and their colleagues demonstrated the utility of PTFE grafts for femoropopliteal reconstructions, with lesser benefits when used for distal infrageniculate procedures.[90,91] The importance of the profunda femoris artery was initially reported in 1971 by Peter Martin, who described an extended profundoplasty as a means of improving blood flow to the ischemic extremity.[92] Although unrelated to his report, the importance of the profunda femoris artery in completing the distal anastomosis of an aortofemoral bypass was well recognized during the same time period, and an extension of the graft limb onto this vessel became standard practice.
Embolic Arterial Occlusions of the Lower Extremity One of the major advances in vascular surgery was introduced in Thomas Fogarty’s 1963 report on balloon catheter
Femoral endarterectomy Reversed autogenous saphenous vein femoral popliteal bypass Femoral-tibial bypass with vein In situ saphenous vein bypass Extended profundoplasty Use of human umbilical vein grafts in lower extremity revascularizations In situ saphenous vein bypass popularized with introduction of new valve cutter Comparison of PTFE and saphenous vein grafts in lower extremity revascularizations
extractions of thromboembolic material from distant vessels.[95] Given the risks of open procedures for saddle aortic emboli that often followed a myocardial infarction and the difficulties in removing emboli originating from atrial fibrillation in the smaller arteries of the leg, the ability to remove occlusive material through a femoral artery under local anesthesia must be considered a sentinel contribution to the discipline of vascular surgery.
Aortic Aneurysms The lethal nature of aortic aneurysms led to many direct therapeutic advances, once clamping of the aorta proved tolerable and the postoperative management of these patients became better recognized. Charles Dubost was the first to successfully treat an abdominal aortic aneurysm in 1951.[94] He replaced the aneurysm with a thoracic aortic homograft in a relatively complex procedure. Shortly thereafter, in 1953, Michael DeBakey and Denton Cooley replaced a thoracic aortic aneurysm with a similar homograft.[95] These reconstructions occurred during a time of considerable interest in the use of homografts for a variety of vascular procedures. The inevitable degenerative changes affecting these conduits led to their later abandonment in the clinical practice of aortic surgery. Aortic aneurysm treatment changed dramatically shortly after Arthur Voorhees, Arthur Blakemore, and Alfred Jaretzki reported the successful implantation of Vinyon-N cloth grafts in animals in 1951.[72] Two years later, in 1953, they used this type of graft in a patient with a ruptured aortic aneurysm who subsequently died of a myocardial infarction. However, their case was made, and in 1954 they described the use of this type of synthetic graft in 17 patients.[96] Unfortunately, this nylon material proved too brittle. These grafts were replaced by conduits constructed of Teflon and Dacron, with the latter being popularized by DeBakey in the mid-1950s. Subsequent refinements involved lessening the risk of graft-enteric erosions by covering the implanted graft with the aneurysm shell, which in earlier times was usually excised en toto, and using synthetic sutures rather than silk, which with its deterioration led to late anastomotic separations of the graft
6
Part One. Assessment of Vascular Disease Table 1-5.
Aortic Aneurysms
Rudolph Matus
1923
Charles Dubost
1951
Arthur Voorhees, Arthur Blakemore, Alfred Jaretzki
1952
Michael DeBakey, Denton Cooley
1953
Michael DeBakey
1955
E. Stanley Crawford
1974
from the vessel and eventual development of pseudoaneurysms. A major innovation in the therapy of aortic aneurysmal disease was the 1974 reported success of E. Stanley Crawford in using intraluminal grafts to treat thoracoabdominal aneurysms that involved the renal and splanchnic arteries.[97] Although improvements in conventional open aortic aneurysm repair occurred during the succeeding years, the next major advance would not be until 1991 when Juan Parodi reported using an endograft to treat an abdominal aortic aneurysm.[98] This single contribution revolutionized the management of aortic aneurysms, and the subsequent decade witnessed many contributions to this new paradigm of vascular surgery. In the following years Veith and his colleagues extended the use of endografts to treatment of traumatic arterial disruptions,[99,100] and recently they reported the successful treatment of ruptured abdominal aortic aneurysms with endografts.[101,102] It would be an understatement to note that this technology has had a major impact on patient care and indeed the very definition of vascular surgery. The common association of femoral and popliteal artery aneurysms with aortic aneurysms, especially in male patients, was clearly established in the last half of the 20th century.[103 – 105] Few changes in the clinical management of these peripheral aneurysms occurred during recent decades, other than for lytic therapy for thrombosed popliteal artery aneurysms before their operative exclusion and bypass.
First successful ligation for treatment of abdominal aortic aneurysm; unsuccessful attempt by Ashley Cooper in 1817 Homograft replacement of abdominal aortic aneurysm Development of synthetic aortic graft (Vinyon-N) in experimental subjects. First clinical results with these grafts reported in 1953 Homograft replacement of thoracic aortic aneurysm Repair of abdominal aortic aneurysms with prosthetic grafts Intraluminal graft repair of thoracoabdominal aneurysms
performed by Marion S. DeWeese in 1958, was subsequently more widely used than endarterectomy.[108] Stoney and his colleagues favored using autologous iliac artery for reconstructing the renal arteries,[109] and DeCamp’s first successful nonanatomic renal revascularization by a splenorenal bypass in 1957 offered yet another alternative means of renal revascularization.[110] Despite these early contributions, the surgical treatment of renal artery occlusive disease was uncommon until after a series of publications from the Cooperative Study of Renovascular Hypertension in the mid-1970s. [111 – 115] Shortly thereafter large surgical series appeared from Vanderbilt University[116] and the University of Michigan[117] which firmly established the appropriateness of operation for renovascular hypertension. During the same time period a definitive classification of renal artery occlusive disease followed two publications, one from the Mayo Clinic in 1971[118] and the other from the University of Michigan in 1975.[119] Andreas Gruntzig and his colleagues reported the first successful percutaneous balloon dilation of an arteriosclerotic renal artery occlusive lesion in 1978.[120] This technology had revolutionized the treatment of renovascular hypertension by the close of the 20th century. Recent experiences suggest that percutaneous angioplasty is preferred for the treatment of most fibrodysplastic disease, and with the use of stents is efficacious in treating many arteriosclerotic ostial stenoses.
Renal Artery Occlusive Disease The first renal artery endarterectomy was performed by Norman Freeman in 1953,[106] a procedure popularized later by Edwin Wylie and his colleagues.[107] Nevertheless, aortorenal bypass using autogenous saphenous vein, first
Splanchnic Artery Occlusive Disease Acute intestinal ischemia, usually a consequence of embolism to the superior mesenteric artery, continued to be a lethal illness throughout latter half of the 20th century. Klass in
Table 1-6. Femoral and Popliteal Artery Aneurysms Ashley Cooper Jose´ Goyanes
1808 1906
Femoral aneurysm ligation (patient lived 18 years) Popliteal aneurysm excision, replaced with vein (first vein bypass graft used in clinical practice)
Chapter 1.
The Evolution of Vascular Surgery
7
Table 1-7. Splanchnic and Renal Artery Disease Renal artery disease Harry Goldblatt W.F. Leadbetter, G.E. Burkland Norman Freeman Marion DeWeese Andreas Gruntzig Splanchnic artery disease J. Englebert Dunphy J. Klass R.S. Shaw, E.P. Maynard W.P. Mikkelsen
1929 1938 1953 1958 1978
Established importance of renal artery occlusion and secondary hypertension Nephrectomy for renovascular hypertension (First treated case of renovascular hypertension) Renal artery endarterectomy Aortorenal bypass with autogenous vein Percutaneous renal artery balloon dilation
1936 1951 1958 1959
Description of chronic intestinal ischemia Superior mesenteric artery embolectomy Operative treatment of acute and chronic intestinal ischemia Operative treatment of chronic intestinal ischemia
1951 was the first to successfully treat acute intestinal ischemia by performance of a superior mesenteric artery embolectomy.[121] The operative treatment of both acute and chronic intestinal ischemia leading to today’s endarterectomy and bypass procedures was subsequently advanced by Shaw and Mikkelsen with their colleagues in the late 1950s.[122,123] Additional experience during the last few decades of the 20th century affirmed the generally accepted tenets that aortomesenteric bypasses with synthetic grafts were preferable to vein graft reconstructions, and that multiple vessel revascularizations were more likely to provide greater longterm benefits than single vessel reconstructions. However, no large clinical studies existed that properly compared the differing vascular options. Thus the surgical management of intestinal ischemia due to splanchnic arteriosclerosis must be considered somewhat anecdotal compared to treatment of other vascular diseases. The same conclusion applies to the therapy of many splanchnic artery aneurysms, with few definitive experiences reported since two widely quoted reviews were published in the 1970s.[124,125]
Cerebrovascular Disease Miller Fisher reported autopsy findings in 1951 that for the first time presented irrefutable evidence that extracranial
Table 1-8.
carotid artery bifurcation arteriosclerosis was likely to be a common cause of a stroke.[126] This led to a series of remarkable advances in the surgical treatment and prevention of stroke. The first reported operation for carotid artery stenotic disease was in 1951 by Raul Carrea, Mahelz Molins, and Guillermo Murphy, who resected the affected carotid artery and reanastomosed the internal carotid artery to the external carotid artery.[127] Three years later, in 1954, Felix Eascott, George Pickering, and Charles Rob reported a similar procedure with resection of the diseased carotid bifurcation and a reanastomosis of the internal carotid artery to the common carotid artery.[128] In 1953, the first conventional carotid endarterectomy was performed by Michael DeBakey.[129] One year later, in 1954, Davis, Grove, and Julian reported having performed the first innominate artery endarterectomy,[130] and in 1958 E. Stanley Crawford, Michael DeBakey, and William Fields reported endarterectomy as a means of treating vertebral artery occlusive disease.[131] The benefits of treating cerebral ischemic syndromes with a bypass was also first recognized during the mid-1950s. Lyons and Galbraith in 1956 performed a subclavian-tocarotid artery bypass,[132] and in 1958 Michael DeBakey and his associates reported an innominate artery-to-subclavian and carotid arterial bypass.[133] A vertebral artery bypass was also reported by Crawford, DeBakey, and Fields that same
Cerebrovascular Disease: Recognition
Egas Moniz Miller Fisher
1927 1951
Henry Barnett
1991, 1998
Robert Hobson
1993
James O’Toole
1995
Cerebral angiography Postmortem exam of 373 patients suggested arteriosclerosis of the extracranial carotid artery bifurcation might be a common cause of cerebrovascular accident North American Symptomatic Carotid Endarterectomy Trial (NASCET) documented benefit of surgical therapy for symptomatic stenotic lesions greater than 50% Surgical benefit documented for select treatment of asymptomatic carotid artery stenoses Asymptomatic Carotid Artery Study (ACAS) documented surgical benefit for asymptomatic lesions greater than 70%
8
Part One. Assessment of Vascular Disease
Table 1-9. Cerebrovascular Disease: Surgical Treatment Raul Carrea, Mahelz Molins, Guillermo Murphy Michael DeBakey H.H.G. (Felix) Eascott, George Pickering, Charles Rob C. Lyons and G. Galbraith J.B. Davis, W.J. Grove, O.C. Julian Michael DeBakey, George Morris, G.L. Jordan, Denton Cooley Stanley Crawford, Michael DeBakey, William Fields M. Gazi Yasargil, Hugh A. Krayenbuhl, Julius H. Jacobson II
1951
Resected arteriosclerotic carotid, with external to internal carotid reanastomosis (first operation for carotid stenotic disease) Carotid artery endarterectomy Resected carotid bifurcation, with common carotid to internal carotid reanastomosis Subclavian-carotid artery bypass Innominate artery endarterectomy Innominate-subclavian-carotid arterial bypass Vertebral artery endarterectomy and bypass Extracranial-intracranial arterial bypass
1953 1954 1956 1954 1957 1958 1970
year.[137] A more dramatic approach to these diseases was by an extracranial –intracranial arterial bypass, championed by Yasargil and his colleagues in the early 1970s.[134] This has been used infrequently following a still-controversial clinical study of the technique published by Henry Barnett and his colleagues in 1989.[135] One of the most important effects on the surgical treatment of carotid artery arteriosclerosis resulted from a series of welldesigned and -conducted prospective clinical studies initially published in the 1990s that better defined the indication for operative intervention. The first, the North American Symptomatic Carotid Endarterectomy Trial (NASCET), led by Henry Barnett, was published initially in 1991 and updated in 1998.[136,137] These studies documented the benefit of carotid endarterectomy in lessening the risk of subsequent stroke in patients with symptomatic stenotic lesions greater than 50%. Two other studies, one from Europe[138] and the other from Veterans Hospitals in the United States,[139] supported the NASCET conclusions. The beneficial effects of carotid endarterectomy in preventing stroke in patients with
Table 1-10.
asymptomatic carotid stenoses greater than 70% was subsequently reported by James O’Toole and Robert Hobson.[140,141] Although some may dispute the details of any of these studies, the benefits of a carefully performed carotid endarterectomy in a properly selected patient were definitively established. At the conclusion of the 20th century carotid endarterectomy was the most common vascular operation performed in the United States. At the close of the last century the introduction of percutaneous carotid artery dilation and stenting was touted as an appropriate alternative to carotid endarterectomy. However, its proper place in preventing stroke will only be established by yet-to-be-performed controlled clinical trials, not by individually reported series.
Venous Disease Prevention of embolization and venous hypertension arising from deep venous thromboses led to a number of
Venous Disease
Removal of varicose veins W.W. Babcock John Homans Correction of venous hypertension Robert Linton Jean Kunlin Eduardo Palma E.A. Husni Robert Kistner S.A. Taheri G. Hauer Prophylactic prevention of pulmonary embolism John Holmans O. Northway, Robert Buxton, E. O’Neill Marion S. DeWeese Kazi Mobin-Uddin Lazar J. Greenfield
1905 1916
Intraluminal stripper for vein removal Saphenofemoral vein ligation
1938 1952 1958 1970 1975 1982 1985
Subfascial division of incompetent perforating veins Saphenous vein bypass of obstructed external iliac vein Saphenofemoral vein crossover bypass Saphenopopliteal vein bypass Valvuloplasty Vein-valve transplant Endoscopic interruption of incompetent perforating veins
1934 1944 1958 1967 1974
Femoral vein ligation IVC ligation Suture plication of the IVC Transvenous IVC umbrella filter Percutaneous IVC conical-strut filter
Chapter 1.
important surgical interventions during the last half of the 20th century. Although ligation of the inferior vena cava had been performed earlier for prevention of pulmonary embolism, and often was used as the treatment of choice for septic emboli, the morbidity of this therapy was considerable. In 1958 Marion S. DeWeese was the first to partially interrupt the vena cava for the prevention of pulmonary emboli, using a suture plication technique.[142,143] In 1967 Kazi Mobin-Uddin introduced an umbrella device to trap emboli in transit.[144,145] This remarkable innovation was followed by Lazar Greenfield’s conical vena cava filter,[146] which was initially placed through the jugular vein with an open procedure, but was later inserted percutaneously through a femoral vein route. Subsequently, other caval devices have been developed to trap emboli from the lower body veins. The reduction in fatal pulmonary embolism using vena cava filters represents a major accomplishment of vascular surgeons. Treatment of venous hypertension in the last half of the 20th century focused on both direct venous reconstructive surgery and on less invasive procedures for interrupting incompetent perforating veins. In 1952 Jean Kunlin performed a saphenous vein bypass of an obstructed external iliac artery vein,[147] and 6 years later in 1958, Eduardo Palma performed a saphenofemoral vein crossover bypass.[148] A more distal decompressive procedure, a saphenopopliteal vein bypass, was accomplished by Husni in 1970.[148] More direct means of reducing elevated venous pressures in the lower extremity were introduced by Robert Kistner, who was the first to perform venous valvuloplasty procedures.[150,151] Taheri was the first to undertake transplantation of a vein valve to reduced venous hypertension.[152] Hauer in 1985 reported on the endoscopic interruption of incompetent perforating veins.[153] This less invasive means of interrupting perforating veins is undergoing current clinical study.[154] Durable treatment of venous diseases continued to challenge the surgical skills of vascular surgeons at the close of the 20th century.
THE EARLY 21ST CENTURY The diagnosis of vascular disease in the early years of the current millennium will evolve in two primary arenas. The first relates to genetic analysis technology that will identify patients at risk for various arteriosclerotic disorders, matrix problems leading to aneurysms, and other vascular diseases. This will revolutionize the selection of patients for early
The Evolution of Vascular Surgery
9
interventions, both medical and surgical, and will affect vascular surgery more than any other advance since the introduction of vascular grafts and heparin. The second relates to new modalities of imaging that will define both the anatomic presence or absence of disease, as well as the functional relevance of vascular lesions. These changes will occur within years. The therapy of vascular diseases will also change dramatically, with the most immediate change related to the endovascular treatment of many diseases heretofore amenable only to open surgical procedures. Two other events are on the horizon, but have not come to fruition. The first relates to the production of antithrombotic biologic vascular prostheses through the cloning of human tissues. Although the ethics of this may be questioned, the benefits are too important to patients who have no available conduits for treatment of their diseases to believe that the technology will not rapidly become available to practitioners. Lastly, gene therapy with the introduction of DNA responsible for specific proteins that will affect the status of a vascular disease or improve the outcome of an interventional procedure will likely become available within the first half of this century. Again, the ethical concerns regarding this are important, but are unlikely to slow the introduction of this therapy for somatic cell treatment of vascular diseases, The practice of vascular surgery, especially in industrial nations during the early decades of the 21st century, will be impacted by increasing costs of technology, a greater number of patients needing therapy as the population ages, and the involvement of third parties in controlling affordable medical practice. Given society’s greater medical literacy and availability of the internet there will also be an increasing patient demand for better care in relation to outcomes. Vascular surgery, because of its easily documented clinical endpoints, should be the beneficiary of evidence-based care. Lastly, there will be complementary and competing practices in the new millennium. This will likely result in the establishment of true multidisciplinary care and the elimination of those disciplines that are unable to adapt to new paradigms of practice. Vascular surgery can ill afford to not adapt to change. This relates to training and certification in a bureaucratic era, where benefits of treatment, and surgical intervention in particular, must outweigh the risk of alternative therapies. Durable benefits must be afforded patients. The evolution of vascular surgery during the last half of the 20th century was one of enormous success. The challenge now is to enhance the knowledge base and practice patterns enacted by our discipline’s forebears as we enter the 21st century.
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Part One. Assessment of Vascular Disease Palma, E.C. The Treatment of Arteritis of the Lower Limbs by Autogenous Vein Grafts. Minerva. Cardioangiol. Eur. 1960, 8, 36– 49. Hall, K.V. The Great Saphenous Vein Used In Situ as in Arterial Shunt After Extirpation of the Vein Valves. Surgery 1962, 51, 492– 495. Leather, R.P.; Powers, S.R., Jr.; Karmody, A.M. The Reappraisal of the In Situ Saphenous Vein Arterial Bypass: Its Use in Limb Salvage. Surgery 1979, 86, 453–461. Dardik, H.; lbrahim, I.M.; Sprayregan, Dardik, II. Clinical Experiences with Modified Human Umbilical Cord Vein for Arterial Bypass. Surgery 1976, 79, 618– 624. Dardik, H.; Miller, N.; Dardik, A.; Ibrahim, I.M.; Sussman, B.; Silvia, M.; Berry, M.; Wolodiger, F.; Kahn, M.; Dardik, I. A Decade of Experience with the Glutaraldehyde-Tanned Human Umbilical Cord Vein Graft for Revascularization of the Lower Limb. J. Vasc. Surg. 1988, 7, 336– 346. Bergan, J.J.; Veith, F.J.; Bernhard, V.M.; Yao, J.S.T.; Flinn, W.R.; Gupta, S.K.; Scher, L.A.; Samson, R.H.; Towne, J.B. Randomization of Autogenous Vein and Polytetrafluoroethylene Grafts in Femoral Distal Reconstruction. Surgery 1982, 92, 921– 930. Veith, F.J.; Gupta, S.K.; Ascer, E.; White-Flores, S.; Samson, R.H.; Scher, L.A.; Towne, J.B.; Bernhard, J.J. Six-Year Prospective Multicenter Randomized Comparison of Autologous Saphenous Vein and Expanded Polytetrafluoroethylene Grafts in Infrainguinal Arterial Reconstructions. 1985, 3, 104– 114. Martin, P.; Renwick, S.; Stephenson, C. On the Surgery of the Profunda Femoris Artery. Br. J. Surg. 1971, 55, 539–542. Fogarty, T.J.; Cranley, J.J.; Krause, R.J.; Strasser, E.S.; Hafner, C.D. A Method for Extraction of Arterial Emboli and Thrombi. Surg. Gynecol. Obstet. 1963, 116, 241– 244. Dubost, C.; Allary, M.; Oeconomos, N. Resection of an Aneurysm of the Abdominal Aorta: Reestablishment of the Continuity by a Preserved Human Arterial Graft, with Results After Five Months. Arch. Surg. 1952, 64, 405–408. DeBakey, M.E.; Cooley, D.A. Successful Resection of Aneurysm of Thoracic Aorta and Replacement by Graft. J. Am. Med. Assoc. 1953, 152, 673– 676. Blakemore, A.H.; Voorhees, A.B., Jr. The Use of Tubes Constructed from Vinyon “N” Cloth in Bridging Arterial Defects—Experimental and Clinical. Ann. Surg. 1954, 140, 324– 334. Crawford, E.S. Thoraco-Abdominal Aortic Aneurysms Involving Renal, Superior Mesenteric and Celiac Arteries. Ann. Surg. 1974, 179, 763– 772. Parodi, J.; Palmaz, J.C.; Barone, H.D. Transfemoral Intraluminal Graft Implantation for Abdominal Aortic Aneurysms. Ann. Vasc. Surg. 1991, 5, 491– 499. Marin, M.L.; Veith, F.J.; Cynamon, J.; Panetta, T.F.; Bakal, C.W.; Kerr, A.; Parodi, J.C. Transfemoral Endoluminal Repair of a Penetrating Vascular Injury. J. Vasc. Intervent. Radiol. 1994, 5, 592– 594. Marin, M.L.; Veith, F.J.; Panetta, T.F.; Cynamon, J.; Sancez, L.A.; Schwartz, M.L.; Lyon, R.T.; Bakal, C.W.;
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Suggs, W.D. Transluminally Placed Endovascular Stented Graft Repair for Arterial Trauma. J. Vasc. Surg. 1994, 20, 466– 472. Ohki, T.; Veith, F.J.; Sanchez, L.A.; Cynamon, J.; Lipsitz, E.C.; Wain, R.A.; Morgan, J.A.; Zhen, L.; Suggs, W.D.; Lyon, R.T. Endovascular Graft Repair of Ruptured Aortoiliac Aneurysms. Am. Coll. Surg. 1999, 189, 102– 112. Ohki, T.; Veith, F.J. Endovascular Grafts and Other Image-Guided Catheter-Based Adjuncts to Improve the Treatment of Ruptured Aortoiliac Aneurysms. Ann. Surg. 2000, 232, 466– 479. Diwan, A.; Sarkar, R.; Stanley, J.C.; Zelenock, G.B.; Wakefield, T.W. Incidence of Femoral and Popliteal Artery Aneurysms in Patients with Abdominal Aortic Aneurysms. J. Vasc. Surg. 2000, 31, 863– 869. Graham, L.M.; Zelenock, G.B.; Whitehouse, W.M., Jr.; Erlandson, E.E.; Dent, T.L.; Lindenauer, S.M.; Stanley, J.C. Clinical Significance of Arteriosclerotic Femoral Artery Aneurysms. Arch. Surg. 1980, 115, 502– 507. Whitehouse, W.M., Jr.; Wakefield, T.W.; Graham, L.M.; Kazmers, A.; Zelenock, G.B.; Cronenwett, J.L.; Dent, T.L.; Lindenauer, S.M.; Stanley, J.C. Limb Threatening Potential of Arteriosclerotic Popliteal Artery Aneurysms. Surgery 1983, 93, 694– 699. Freeman, N.E.; Leeds, F.H.; Elliott, W.G.; Roland, S.I. Thromboendarterectomy for Hypertension Due to Renal Artery Occlusion. J. Am. Med. Assoc. 1954, 156, 1077– 1079. Wylie, E.J.; Perloff, D.L.; Stoney, R.J. Autogenous Tissue Revascularization Techniques in Surgery for Renovascular Hypertension. Ann. Surg. 1969, 170, 416– 428. Stanley, J.C. Surgical Treatment of Renovascular Hypertension. Am. J. Surg. 1997, 174, 102– 110. Stoney, R.J.; DeLuccia, N.; Ehrenfeld, W.K.; Wylie, E.J. Aortorenal Arterial Autografts, Long-Term Assessment. Arch. Surg. 1981, 116, 416– 422. DeCamp, P.T.; Snyder, G.H.; Bost, R.B. Severe Hypertension due to Congenital Stenosis of Artery to Solitary Kidney: Correction by Splenorenal Arterial Anastomosis. Arch. Surg. 1957, 75, 1023– 1026. Bookstein, J.J.; Abrams, H.L.; Buenger, R.E.; Reiss, M.D.; Lecky, J.W.; Franklin, S.S.; Bleifer, K.H.; Varady, P.D.; Maxwell, M.H. Radiologic Aspects of Renovascular Hypertension: Part 2. The Role of Urography in Unilateral Renovascular Disease. J. Am. Med. Assoc. 1972, 220, 1225– 1230. Bookstein, J.J.; Abrams, H.L.; Buenger, R.E.; Reiss, M.D.; Lecky, J.W.; Franklin, S.S.; Bleifer, K.H.; Varady, P.D.; Maxwell, M.H. Radiologic Aspects of Renovascular Hypertension Part 3. Appraisal of Arteriography. J. Am. Med. Assoc. 1972, 221, 368– 374. Bookstein, J.J.; Maxwell, M.H.; Abrams, H.L.; Buenger, R.E.; Lecky, J.; Franklin, S.S. Cooperative Study of Radiologic Aspects of Renovascular Hypertension. Bilateral Renovascular Disease. J. Am. Med. Assoc. 1977, 237, 1706– 1709. Foster, J.H.; Maxwell, S.S.; Bleifer, K.H.; Trippel, O.H.; Julian, O.C.; DeCamp, P.T.; Varady, P.D. Renovascular Occlusive Disease: Results of Operative Treatment. J. Am. Med. Assoc. 1975, 231, 1043– 1048.
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Franklin, S.S.; Young, J.D.; Maxwell, M.H.; Foster, J.H.; Palmer, J.M.; Cerny, J.; Varady, P.D. Operative Morbidity and Mortality in Renovascular Disease. J. Am. Med. Assoc. 1975, 231, 1148– 1153. Foster, J.H.; Dean, R.H.; Pinkerton, J.A.; Rhamy, R.L. Ten Years Experience with Surgical Management of Renovascular Hypertension. Ann. Surg. 1973, 177, 755– 766. Ernst, C.B.; Stanley, J.C.; Marshall, F.F.; Fry, W.J. Autogenous Saphenous Vein Aortorenal Grafts. A TenYear Experience. Arch. Surg. 1972, 105, 855– 864. Harrison, E.G., Jr.; McCormack, L.J. Pathology Classification of Renal Arterial Disease in Renovascular Hypertension. Mayo. Clin. Proc. 1971, 46, 161–167. Stanley, J.C.; Gewertz, B.L.; Bove, E.L.; Sottiurai, V.; Fry, W.J. Arterial Fibrodysplasia. Histopathologic Character and Current Etiologic Concepts. Arch. Surg. 1975, 110, 551– 556. Gruntzig, A.; Kuhlmann, U.; Vetter, W.; Lutolf, U.; Meier, B.; Siegenthaler, W. Treatment of Renovascular Hypertension with Percutaneous Transluminal Dilatation of a Renal-Artery Stenosis. Lancet 1978, 1, 801– 802. Klass, J. Embolectomy in Acute Mesenteric Occlusion. Ann. Surg. 1951, 134, 913– 917. Shaw, R.S.; Maynard, E.P. Acute and Chronic Thrombosis of the Mesenteric Arteries Associated with Malabsorption. Report of Two Successful Cases Treated by Thromboendarterectomy. N. Engl. J. Med. 1958, 258, 874– 878. Mikkelsen, W.P.; Zaro, J.A. Intestinal Angina: Report of a Case with Preoperative Diagnosis and Surgical Relief. N. Engl. J. Med. 1959, 260, 912– 914. Deterling, R.A. Aneurysm of the Visceral Arteries. J. Cardiovasc. Surg. 1971, 12, 309– 322. Stanley, J.C.; Thompson, N.W.; Fry, W.J. Splanchnic Artery Aneurysms. Arch. Surg. 1970, 101, 689– 697. Fisher, M. Occlusion of the Internal Carotid Artery. Arch. Neurol. Psychiatry 1951, 65, 346– 377. Carrea, R.; Molins, M.; Murphy, G. Surgical Treatment of Spontaneous Thrombosis of the Internal Carotid Artery in the Neck. Carotid-Carotideal Anstomosis. Report of a Case. Acta Neurol. Latinoamer 1955, 1, 71– 78. Eastcott, H.H.G.; Pickering, G.W.; Rob, C.G. Reconstruction of Internal Carotid Artery in a Patient with Intermittent Attacks of Hemiplegia. Lancet 1954, 2, 994– 996. DeBakey, M.E. Successful Carotid Endarterectomy for Cerebrovascular Insufficiency: Nineteen Year Follow-Up. J. Am. Med. Assoc. 1975, 233, 1083– 1085. Davis, J.B.; Grove, W.J.; Julian, O.C. Thrombotic Occlusion of the Branches of the Aortic Arch; Martorll’s Syndrome: Report of a Case Treated Surgically. Ann. Surg. 1956, 144, 124– 126. Crawford, E.S.; DeBakey, M.E.; Fields, W.S. Roentgenographic Diagnosis and Surgical Treatment of Basilar Artery Insufficiency. J. Am. Med. Assoc. 1958, 168, 514. Lyons, C.; Galbraith, G. Surgical Treatment of Atherosclerotic Occlusion of the Internal Carotid Artery. Ann. Surg. 1957, 146, 487– 498. DeBakey, M.E.; Morris, G.C.; Jordan, G.L.; Cooley, D.A. Segmental Thrombo-Obliterative Disease on Branches
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of Aortic Arch. J. Am. Med. Assoc. 1958, 166, 998– 1003. Yasargil, M.C.; Krayenbuhl, H.A.; Jacobson, J.H., II. Microneurosurgical Arterial Reconstruction. Surgery 1970, 67, 221– 233. Extracranial/Intracranial Bypass Study Group; Failure of Extracranial—Intracranial Anterior Bypass to Reduce the Risk of Ischemic Stroke. N. Engl. J. Med. 1985, 313, 1191– 1200. North American Symptomatic Carotid Endarterectomy Trial Collaborators; Beneficial Effect of Carotid Endarterectomy in Symptomatic Patients with High-Grade Carotid Stenosis. N. Engl. J. Med. 1991, 325, 325– 453. Barnett, H.J.; Taylor, D.W.; Eliasziw, M.; Fox, A.J.; Ferguson, G.G.; Haynes, R.B.; Rankin, R.N.; Clagett, G.P.; Hacinski, V.C.; Sackett, D.L.; Thorpe, K.E.; Math, M.; Meldrum, H.E. Benefit of Carotid Endarterectomy in Patients with Symptomatic Moderate or Severe Stenosis. N. Engl. J. Med. 1998, 339, 1415– 1425. European Carotid Surgery Trialists’ Collaborative Group; MRC European Carotid Surgery Trial: Interim Results for Symptomatic Patients with Severe (70 – 99%) or with Mild (0 – 29%) Carotid Stenosis. Lancet 1991, 337, 1235 – 1243. for the Veterans Affairs Cooperative Studies Program 309 Trialist Group; Mayberg, M.R.; Wilson, S.F.; Yatsu, F.; Weiss, D.G.; Messina, L.; Hershey, L.A. Carotid Endarterectomy and Prevention of Cerebral Ischemia in Symptomatic Carotid Stenosis. J. Am. Med. Assoc. 1991, 266, 3259– 3295. Executive Committee for the Asymptomatic Carotid Atherosclerosis Study; Endarterectomy for Asymptomatic Carotid Artery Stenosis. J. Am. Med. Assoc. 1995, 273, 1421– 1428. The Veterans Affairs Cooperative Study Group; Hobson, R.W., II.; Weiss, D.G.; Fields, W.S.; Goldstone, J.; Moore, W.S.; Towne, J.B.; Wright, C.B. Efficacy of Carotid Endarteretomy for Asymptomatic Carotid Stenosis. N. Engl. J. Med. 1993, 328, 221–227. DeWeese, M.S.; Hunter, D.C., Jr. A Vena Cava Filter for the Prevention of Pulmonary Emboli. Bull. Soc. Int. Chir. 1958, 1, 1 – 19. DeWeese, M.S.; Kraft, R.O.; Nichols, K.W. Fifteen-Year Clinical Experience with Vena Cava Filter. Ann. Surg. 1973, 178, 247– 257. Mobin-Uddin, K.; Smith, P.E.; Martinez, L.D.; Lombardo, C.R.; Jude, J.R. A Vena Cava Filter for the Prevention of Pulmonary Embolus. Surg. Forum 1967, 18, 209– 211. Mobin-Uddin, K.; McLean, R.; Bolooki, H.; et al. Caval Interruption for Prevention of Pulmonary Embolism. Long-Term Results of a New Method. Arch. Surg. 1969, 99, 71l– 715. Greenfield, L.J.; Peyton, M.D.; Brown, P.P.; Elkins, R.C. Transvenous Management of Pulmonary Embolic Disease. Ann. Surg. 1974, 180, 461– 468. Kunlin, J. The Reestablishment of Venous Circulation with Grafts in Cases of Obliteration from Trauma or Thrombophlebitis. Mem. Acad. Clin. 1953, 79, 109. Palma, E.C.; Esperon, R. Vein Transplants and Grafts in the Surgical Treatment of the Post Phlebitic Syndrome. J. Cardiovasc. Surg. 1960, 1, 94– 107.
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Husni, E.A. In Situ Saphenopopliteal Bypass Graft for Incompetence of the Femoral and Popliteal Veins. Surg. Gynecol. Obstet. 1970, 2, 279– 284. 150. Kistner, R. Surgical Repair of a Venous Valve. Straub. Clin. Proc. 1968, 34, 41– 43. 151. Kistner, R. Surgical Repair of the Incompetent Femoral Vein Valve. Arch. Surg. 1975, 110, 1336– 1342. 152. Taheri, S.A.; Lazar, L.; Elias, S.; Marchand, P.; Heffner, R. Surgical Treatment of Posphlebitic Syndrome with Vein Valve Transplant. Am. J. Surg. 1982, 144, 221– 224.
153. Hauer, G. The Endoscopic Subfascial Division of the Perforating Veins—Preliminary Report. Vasa 1985, 14, 59– 61. 154. The North American Study Group; Gloviczki, P.; Bergan, J.J.; Rhodes, J.M.; Canton, L.G.; Harmsen, S.; Ilstrup, D.M. Mid-Term Results of Endoscopic Perforator Vein Interruption for Chronic Venous Insufficiency: Lessons Learned from the North American Subfascial Endoscopic Perforator Surgery Registry. J. Vasc. Surg. 1999, 29, 489– 502.
CHAPTER 2
Pathophysiology of Atherosclerosis Russell Ross†
number of T lymphocytes together with varying numbers of smooth-muscle cells. Both the macrophages and smooth muscle contain deposits of cholesterol and cholesterol oleate. Fatty streaks can be found in increasing numbers between the ages of 8 and 18 years. Fatty streaks appear in the coronary arteries at about the age of 15 years and continue to increase in amount in these vessels through the third decade of life.[4] The lesions are yellowish and sessile and cause little or no obstruction of the affected artery and no clinical sequelae. The fatty streak is ubiquitous in young people and even in those populations that do not appear to develop severe atherosclerosis. This observation suggests that lipid deposition does not inevitably lead to the advanced lesions of atherosclerosis but that a number of other factors are associated with the progression of the lesions and with the development of the more complex form of atherosclerosis, the fibrous plaque.
THE DISEASE PROCESS The lesions of atherosclerosis take different forms depending upon their anatomic site; the age, genetic, and physiological status of the affected individual; and the so-called risk factors to which each individual may have been exposed. The examination of atherosclerotic lesions with modern techniques of cell and molecular biology has revealed that each lesion contains significant elements of a specialized chronic inflammatory fibroproliferative response. These consist of accumulated monocyte/macrophages and T lymphocytes followed by smooth-muscle proliferation; the formation by the proliferated cells of large amounts of connective tissue matrix, including collagen, elastic fibers, and proteoglycans; and the accumulation of intracellular and extracellular lipid.[1,2] In each instance, the relative degree to which each of the cells responds to different atherogenic stimuli determines the unique combination of these three elements that defines the type and extent of the resulting lesion. The lesions of atherosclerosis occur principally within the innermost layer of the artery wall, the intima. They include the fatty streak, the fibrous plaque, and the so-called complicated lesions.[2,3] Secondary changes have been noted in the media of the artery underlying the lesion, principally in association with the more advanced lesions of atherosclerosis.
The Fibrous Plaque More advanced lesions begin to develop around the age of 25 in those populations in which there is a high incidence of atherosclerosis and its clinical sequelae. The fibrous plaque is grossly white; it becomes elevated and therefore may protrude into the lumen of the artery. If this lesion progresses sufficiently, it can occlude the lumen and compromise the vascular supply of the involved tissue. The principal change that occurs within the arterial intima during the development of the fibrous plaque consists of the proliferation of smoothmuscle cells. These cells usually form a fibrous cap due to the deposition by the cells of new connective tissue matrix and to the accumulation of intracellular and extracellular lipids. The fibrous cap covers a deeper deposit of varying amounts of extracellular lipid and cell debris.[5] It has been suggested that fibrous plaques are derived from fatty streaks that continue the process of cell proliferation, lipid accumulation, and connective tissue formation and that the deep core of lipid and cell debris results from inadequate blood supply and cell necrosis. Such a relationship has not been proved, since—although fatty streaks in young persons are often found at the same
The Lesions The Fatty Streak The process of atherosclerosis begins in childhood with the development of flat, lipid-rich lesions called fatty streaks. These lesions consist of lipid-laden macrophages and variable
Portions of this chapter are reprinted from Hurst JW (ed): The Heart, 7th ed., q 1990 by McGraw-Hill, Inc. Used with permission of J. Willis Hurst and McGraw-Hill, Inc. †
Deceased.
Hobson/Wilson/Veith: Vascular Surgery: Principles and Practice, Third Edition, Revised and Expanded DOI: 10.1081/0819-9-120024885 Copyright q 2004 by Marcel Dekker, Inc.
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anatomic location in the coronary and extracranial cerebral arteries as fibrous plaques in older persons—fatty streaks can also occur at anatomic sites that are different from those at which fibrous plaques appear. The reasons for these differences are not understood. It has been suggested that in those instances in which their location is different, the fatty streaks have simply regressed and disappeared, whereas in the instances in which the anatomic location is the same, lesion progression has occurred. This remains a matter of controversy.[6]
The Complicated Lesion The complicated lesions of atherosclerosis occur with increasing frequency with increasing age. The fibrous plaque can become vascularized from both the luminal and medial aspects. In the complicated lesion, the necrotic “lipid-rich core” increases in size and often becomes calcified. The lesions may become increasingly complex as a result of hemorrhage and calcification, and the intimal surface may disintegrate, fissure, or ulcerate and become involved with thrombotic episodes that may lead to occlusive disease. Such thrombi may then organize and further increase the thickness of the plaque while progressively reducing the size of the arterial lumen. Sometimes, as the intimal lesions progress, the number of smooth muscle cells in the underlying media decreases and the media atrophies; this can result in aneurysmal changes rather than thrombotic occlusion of the artery. There is quite a range in the degree of severity of the atherosclerotic lesions in different arteries. The recognition that smooth-muscle proliferation, connective tissue formation, and lipid accumulation represent the key elements of the developing lesions of atherosclerosis has led to the use of a number of models of experimentally induced atherosclerosis to study this process in different animal species.
Plaque Rupture Plaque rupture and the thrombosis that usually results from the rupture have been shown to be responsible for 50% or more of the cases of acute coronary syndromes, myocardial infarction, and sudden death.[7,8] Plaque erosion and rupture usually occur from irregular thinning of the fibrous cap that covers the necrotic core in most advanced lesions. Thinning often happens at the shoulder of the lesion where monocytederived macrophages accumulate and elaborate metalloproteases.[9] These proteins can degrade the matrix, lead to instability of the fibrous cap, and cause rupture at sites of high stress. Macrophages may be activated by numerous factors, including activated T cells. Macrophage activation is often accompanied by increased levels of tissue factor and other hemostatic factors, which help to increase the probability of blood coagulation and, ultimately, thrombosis. These dangerous plaques present a formidable problem because they may be no more than 40% occlusive and not necessarily picked up on angiographic examination.[7,10,11] Control of macrophage activation is an important part of dealing with
the chronic inflammatory response that represents every phase of the process of atherogenesis.[10]
Studies in Experimental Animals Five species have been widely used in studying atherogenesis: rabbits, chickens, swine, mice, and nonhuman primates. Most early work was performed in rabbits; however, swine and nonhuman primates are generally considered to develop lesions that correspond more closely with those that occur in human beings. Atherosclerosis has been induced in most of the animal models by a high-fat, high-cholesterol diet. A principal shortcoming of this approach, however, is that to produce more advanced lesions, it is necessary to maintain animals on such diets for years. Even though it is possible to induce the lesions in a relatively short period (1– 3 years in the monkey), it is not clear that the lesions produced in this manner actually simulate those that may require 20– 30 years to form in human beings. On the other hand, the rate at which the lesions form in humans is not entirely clear; some may progress more rapidly than had heretofore been considered to be possible.[12] Other approaches to studying the smooth-muscle proliferative changes associated with atherosclerosis have included endothelial injury resulting from mechanical trauma from various types of intraarterial catheters,[13,14] chemically induced injury from sources such as chronic hypercholesterolemia[15] or chronic homocystinemia,[16] immune-type injury from exposure to antigen-antibody complexes,[17] and, more recently, virally induced injury in diseases such as Marek’s disease.[18] In a recent study of diet-induced hypercholesterolemia in nonhuman primates, Faggiotto et al.[19,20] and Masuda and Ross[21,22] described the changes that lead to fatty streak development and the manner in which some fatty streaks progress to become more complicated fibrous plaques. Within 12 days after the induction of high levels of plasma cholesterol (. 700 mg/dL), numerous monocytes and T lymphocytes were observed attached to the surface of the endothelium throughout the arterial tree. These leukocytes probe between junctional complexes of the endothelium, migrate, and localize subendothelially, where they accumulate lipid and become foam cells that establish the initial fatty streak. These fatty streaks form at branches and bifurcations and accumulate increasing numbers of macrophages, T cells, and smooth-muscle cells and in the process create a markedly uneven surface contour and stretch the overlying endothelium exceedingly thin. After about 5 months, breaks occur between endothelial cells, exposing the lipid-filled macrophages, some of which appear to enter the circulation. Many of the exposed macrophages serve as sites where platelets adhere and form mural thrombi. These sites of platelet-macrophage interactions were first observed in the iliac arteries; after longer periods of hypercholesterolemia, similar changes occur at higher levels in the abdominal and then the thoracic aorta and finally in the coronary arteries. Interestingly, the sites that are first involved with platelet-macrophage interactions are the same sites that 1–2 months later contain the proliferative smooth-muscle lesions of atherosclerosis. These findings further support observations that endothelial injury and
Chapter 2.
platelet-macrophage interactions may be important in atherogenesis. Some of the most recent advance in the use of experimental animals has come with the development of genetically modified mice. With the development of the homozygous apolipoprotein E –deficient (ApoE -/-) and the homozygous low-density lipoprotein receptor – deficient (LDL-R -/-) mice, small murine models of atherogenesis have opened remarkable opportunities to study and understand the process of atherogenesis. The ApoE -/- mouse, in particular, has been of great benefit because it develops lesions of atherosclerosis at sites analogous to those in humans.[23,24] The cellular events at every stage of lesion formation and progression are identical to those in humans. Thus, upregulation of adhesion molecules in outflow tracks, branches, and bifurcations leads to lymphocyte and monocyte adhesion and entry. Fatty streaks form and then develop into intermediate lesions and, finally, advanced lesions.[24,25] It is possible to examine the impact of the addition or removal of specific factors in mice. For example, one can mate the ApoE -/- mouse with the M-CSF – deficient mouse[26] or with mice that lack vascular adhesion molecules. One can make mice chimerically deficient in a growth factor in subsets of their hematopoietic precursor cells or in sitespecific alterations to make a tissue or organ, such as the arterial system, devoid of given molecules. The development of such mice represents a powerful approach that may rapidly shed light on the process of atherogenesis, which can be confirmed in larger animals, such as nonhuman primates, and, ultimately, in humans.
HYPOTHESES OF ATHEROGENESIS Atherosclerosis has been recognized in humans for thousands of years. Lesions of atherosclerosis were identified in Egyptian mummies as early as the fifteenth century B.C. Long[27] discussed the development of clinical-pathological correlations during the era when autopsy permitted an understanding of the relationship between the degree of atherosclerosis and the incidence of myocardial infarction and stroke. In the mid-nineteenth century, Virchow[28] proposed that some form of injury to the artery wall associated with an inflammatory response results in what was then considered to be the degenerative lesion of atherosclerosis. This idea was subsequently modified by Anitschkow[29] and further included the role of platelets and thrombogenesis in atherosclerosis, as expounded by Duguid[30] in 1948. Many of the modern views of atherogenesis stem from the work of John French,[31] who suggested that the structural integrity of the endothelial lining of the artery represents a key element in the maintenance of normal arterial function and that alterations in endothelial integrity may precede a sequence of events that lead to the various lesions in atherosclerosis. Thus, over the years, a number of theories concerning the etiology and pathogenesis of atherosclerosis have been developed. At least one of these deserves elaboration and comment: the response-to-injury hypothesis.
Pathophysiology of Atherosclerosis
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The Response-to-Injury Hypothesis One basis for the response-to-injury hypothesis of atherosclerosis[2,15,32] lies in the marked similarity, observed by many investigators, between the ubiquitous fibromusculoclastic lesions noted at autopsy and a similar lesion that can be induced in a number of animal species—including nonhuman primates, rabbits, and swine—after experiencing different forms of arterial endothelial injury. This hypothesis states that some form of “injury” to the endothelium results in structural and/or functional alterations in the endothelial cells. Factors such as chronic hypercholesterolemia,[15] decreased shear stress from the flow of blood over the endothelial cells, as may occur at branch points or bifurcations in arteries in hypertension,[33] and dysfunction induced by toxins or other injurious agents may lead to changes in the nature of the permeability barrier established by the endothelial cells. In the normal artery, the endothelial cells form a continuous monolayer that regulates the passage of substances from the plasma to the underlying artery wall. Injury to the endothelial cells may alter their permeability characteristics and change endothelial cell-cell or endothelial cell –connective tissue relationships, permitting hemodynamic forces to induce focal endothelial cell dysfunction and thus permit interactions to occur between elements from the blood and the wall of the artery. Not only do the endothelial cells play an important role as a permeability barrier, but they also form a thromboresistant surface that promotes the continuous flow of blood throughout the vascular tree. The thromboresistant character of the endothelium appears to be due principally to three factors produced by the cells. These have been identified, but their physiological roles are relatively poorly understood. They are nitric oxide (NO), the glycoproteins and proteoglycans, which form the surface coat of the endothelial cells, and a prostaglandin derivative, prostacyclin (PGI2).[34] Nitric oxide and prostacyclin are two of the most potent vasodilatory agents thus far isolated, as well as being potent inhibitors of platelet aggregation. Both of these substances can be formed by endothelium and smooth muscle. Nitric oxide appears to be responsible for the normal vasodilatory tone maintained in arterial homeostasis.[35] This is discussed in greater detail below. Endothelial injury that results in alterations in permeability would permit plasma constituents such as lipoproteins to have more ready access to the artery wall. Endothelial dysfunction could also alter the thromboresistant character of the lumen of the artery so that leukocytes and platelets could interact directly at the sites of endothelial injury. If the injury were sufficiently severe, the endothelial cells might detach and be lost into the bloodstream, exposing the underlying connective tissue to platelets and to other elements in the circulation. The response-to-injury hypothesis suggests that the interaction between leukocytes and the endothelium and between platelets and the subendothelial connective tissue, principally collagen, can result in entry of monocytes into the intima and/or platelet adherence, platelet aggregation, and the release of contents normally stored within the granules of the platelets, in particular a mitogen, the platelet-derived growth factor (PDGF). At the sites of injury the exposure of the artery wall to factors derived from
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Part One. Assessment of Vascular Disease
the activated monocyte-derived macrophages and/or platelets, together with components from the plasma, such as lipoproteins and hormones, would then lead to the focal proliferation of arterial smooth-muscle cells. According to the hypothesis, this smooth-muscle proliferation would be derived from two sources: preexisting intimal smooth-muscle cells and medial smooth-muscle cells that are attracted to and
migrate and proliferate within the intima at the sites of injury. Such a local stimulus could also lead to the formation of new connective tissue matrix constituents by the proliferating smooth-muscle cells and to the deposition of lipids both within and around the proliferated cells (Fig. 2-1). According to this hypothesis, if the injury to the endothelium were a self-limited event and endothelial
Figure 2-1. The response-to-injury hypothesis. Advanced intimal proliferative lesions of atherosclerosis may occur by at least two pathways. The pathway demonstrated by the clockwise long arrows has been observed in experimentally induced hypercholesterolemia. Injury to the endothelium (A) may induce growth factor secretion (short arrow ). Monocytes attach to endothelium (B ), which may continue to secrete growth factors (short arrow ). Subendothelial migration of monocytes (C ) may lead to fatty-streak formation and release of growth factors such as platelet-derived growth factor (PDGF) (short arrow ). Fatty streaks may become directly converted to fibrous plaques (long arrow, C to F ) through release of growth factors from macrophages or endothelial cells or both. Macrophages may also stimulate or injure the overlying endothelium. In some cases, macrophages may lose their endothelial cover and platelet attachment may occur (D), providing three possible sources of growth factors—platelets, macrophages, and endothelium (short arrows ). Some of the smooth-muscle cells in the proliferative lesion itself (F ) may form and secrete growth factors such as PDGF (short arrows ). An alternative pathway for the development of advanced lesions of atherosclerosis is shown by the arrows from A to E to F. In this case, the endothelium may be injured but remain intact. Increased endothelial turnover may result in growth factor formation by endothelial cells (A ). This may stimulate migration of smooth-muscle cells from the media into the intima, accompanied by endogenous production of PDGF by smooth muscle as well as growth factor secretion from the “injured” endothelial cells (E ). These interactions could then lead to the formation of fibrous plaques and further progression of the lesion (F ). (Reproduced from Ross.[2])
Chapter 2.
functional integrity were restored, the proliferative lesions would be capable of regressing. If this were the case, the lesions would be reversible, and if they had not reached a critical size, they would be clinically silent. There is evidence both in experimental animals and in human beings that the lesions of atherosclerosis can, under certain conditions, regress.[36] On the other hand, if the injury at focal sites in the artery wall is either sufficiently long-standing or chronically repeated over periods of many years, the lesions could continue to progress, become increasingly complex in composition, and eventually lead to the principal clinical sequelae of atherosclerosis, myocardial infarction, and cerebral infarction. The capacity of the endothelium to regenerate and to restore functional integrity at sites of injury may be critical in determining whether the lesions of atherosclerosis enlarge, remain relatively constant in size, or regress. The superimposition of risk factors possibly affects this balance by providing a chronic source of injury or by somehow altering the normal balance so that lesions become slowly progressive. As an example, the increased levels of plasma low-density lipoproteins (LDL) associated with hypercholesterolemia may provide a source of injury to the endothelial cells and may also convert what might otherwise be a limited tissue response to injury to the frank progressive lesions of atherosclerosis. This hypothesis has stimulated a great deal of experimental work that has led to an increase in our understanding of factors that determine the capacity of the endothelial cells to maintain themselves as an integral continuous functional cell layer; the hypothesis has also led to studies of those factors that control the normal function and growth of endothelium. Of equal importance, many studies have elucidated factors that modify the capacity of arterial smooth-muscle cells to form connective tissue proteins, to synthesize and metabolize lipids and lipoproteins, and to proliferate in response to different mitogenic factors. One of the most important observations that has resulted from the examination of this hypothesis is the discovery that platelets contain a potent mitogen, the platelet-derived growth factor.[37] It has been suggested that this factor may play an important role in inducing the intimal smooth-muscle proliferation seen in experimentally induced atherosclerosis and in atherosclerosis in human beings. This is discussed in greater detail below. A number of important questions have arisen about the factors that promote the proliferation of smooth-muscle and endothelial cells and about the mechanisms whereby the lesions of atherosclerosis may regress. More is becoming known about the factors responsible for the turnover of connective tissue matrix within the artery wall and about the mechanisms responsible for removing either this matrix or cholesterol from the lesions. A factor known as transforming growth factor-beta (TGFb) has been shown to be a potent stimulator of connective tissue formation and inhibitor of matrix degradation.[38 – 40] This factor can be made by all of the cells involved in the process of atherogenesis. The response-to-injury hypothesis has provided potential explanations for some of these phenomena. However, much remains to be learned, for example, with respect to the activity of endothelium, smooth muscle, and macrophages in their
Pathophysiology of Atherosclerosis
19
interactions with each other in the complex microenvironment of the lesions of atherosclerosis.
The Role of Lipids In many persons, both the initiation and the progression of atherosclerotic lesions appear somehow to be associated with markedly increased levels of plasma LDL. The accumulation of lipid within proliferated smooth-muscle cells, within macrophages in the lesions, and within the extracellular connective tissue matrix is a common finding, particularly in the lesions of atherosclerosis.[41] The presence of elevated levels of LDL suggests that cholesterol internalization and esterification by cells may be accelerated to such a degree that proliferated smooth-muscle cells and macrophages within the lesions become filled with cholesterol oleate. Many of the cells may go on to become necrotic and may release their lipid into the extracellular spaces. In the presence of excess plasma LDL, which is relatively rich in cholesterol linoleate, the debris may be a mixture of both types of cholesteryl esters. Some studies have suggested that in hyperlipemic animals there are changes in LDL that may promote endothelial injury, the proliferation of smooth-muscle cells, and the production of new connective tissue components by these cells.[42] Thus a sequence of events involving endothelial injury by chronic elevated levels of LDL, oxidation or other modifications of LDL, and the continuing progression of atherosclerotic lesions by exposure to modified LDL [and presumably to decreased levels of high-density lipoproteins (HDL)] could lead to the development of advanced atherosclerotic lesions. LDL can be modified not only by oxidation but by glycation (as occurs in many diabetics), by binding as a complex with proteoglycans, or by incorporation into immune complexes. This “modified” LDL is characteristically taken up by various scavenger receptors on the surfaces of macrophages and, thus, plays a major role in foam cell development and inducing the inflammatory response.[43 – 45]
Risk Factors A number of risk factors of atherosclerosis have become reasonably well established on the basis of their relationship in epidemiologic studies to the incidence of clinically manifest disease. Unfortunately, there is no basis for comparison between risk factors and the severity or extent of the lesions of atherosclerosis. Among many factors that are considered to be important are hyperlipidemia, hypertension, cigarette smoking, male sex, and diabetes mellitus. These have in general been associated with an increased incidence of fibrous plaques and their sequelae. The associations are relatively strong when they are made on a group basis, although all the studies have demonstrated a high degree of variability among individuals within even the most homogeneous groups.[46]
Hypercholesterolemia Dietary lipids are considered to be among the most important environmental agents responsible for severe
20
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atherosclerosis and for the high frequency of atherosclerotic disease in industrially developed parts of the world. Saturated fats became known to be associated with an increased incidence of atherosclerosis when it was found that they elevate the concentration of plasma cholesterol. The specific contributions of cholesterol, saturated fats, polyunsaturated fats, and total fats in atherosclerosis have become clarified. It has been possible to demonstrate an unequivocal association between dietary cholesterol or plasma cholesterol levels and the incidence and prevalence of coronary disease within population groups.[47] Unfortunately, there is a great deal of daily variation from individual to individual in terms of the dietary intake of fats and plasma cholesterol levels. There is also intrinsic variation in plasma cholesterol levels among individuals who consume the same diet and respond differently to it. This has increased the difficulty of relating this factor in individuals to the incidence of atherosclerosis, but it does not negate the clear association between hyperlipidemia and atherosclerosis that has been demonstrated by numerous epidemiologic studies. There is little question that dietary cholesterol directly affects the levels of plasma cholesterol.[48] However, only recently has it been suggested that dietary cholesterol may affect the incidence of atherosclerosis by altering the profile of plasma lipoproteins and possibly by changing the structural or functional properties of these lipoproteins.[49] Increased dietary cholesterol generally results in an increase in LDL cholesterol levels, with a lesser increase in HDL cholesterol levels. As the role of these two lipoproteins in atherogenesis becomes clearer, it can be stated that elevated HDL levels appear to be protective, whereas the reverse is true for elevated LDL levels. There are many differences in the ways in which animals and humans respond to dietary cholesterol, and there are limits to the extent to which information concerning responses to dietary intake in experimental animals can be applied to human beings. Nevertheless, the epidemiologic association between the increased incidence of atherosclerosis and the increased intake of saturated fat is very strong. The means by which these fats affect the incidence of atherosclerosis at the cellular and molecular levels is probably related to the formation of “modified” LDL, as discussed above.
Hypertension Hypertension has been established unequivocally as an associated risk factor in that persons with elevated blood pressure show accelerated atherogenesis, an increased incidence of coronary heart disease, and, in particular, an increased incidence of cerebrovascular disease. The effects of hypertension appear to be independent of other risk factors in an epidemiologic sense; however, it does not appear to be a primary cause of advanced atherosclerosis in those populations in which the incidence of clinically manifest atherosclerosis is less than average. The means by which hypertension induces atherogenesis are not clear, although there are many humoral mediators of blood pressure which may participate in this process. For example, renin and other hypertensive agents may induce cellular changes that lead to atherogenesis. Fry[33] and his
colleagues, as well as others, have suggested that the altered shear stress of the flow of blood, particularly in hypertensive persons, at selected anatomic sites within the arterial tree may result in focally altered endothelium and in the development of atherosclerotic lesions very much as suggested in the response-to-injury hypothesis discussed earlier. Angiotensin II (AII), the principal product of the reninangiotensin system, is a potent vasoconstrictor and may contribute to elevated blood pressure. Interestingly, AII can increase the activity of smooth-muscle lipoxygenases, which can participate in the oxidation of LDL and augment the inflammatory response.[50] Hypertension has a pro-inflammatory capacity; in hypertensive individuals there is an increase in the formation of hydrogen peroxide and other free radicals, such as superoxide anion.[51,52] These substances can negate the effects of nitric oxide on the endothelium and serve to augment the process of atherogenesis by pro-inflammatory means.
Cigarette Smoking Cigarette smoking provides perhaps the strongest and most consistent correlation with the increased incidence of atherosclerotic disease and appears to be a major contributor to the increased risk of disease, generally in combination with other risk factors. Unfortunately, there is relatively little information about how cigarette smoking exerts an impact at the cellular level. Free radicals that form in the plasma and interstitial fluid as a result of smoking may induce endothelial injury and participate in modifying LDL. Becker et al.[53] identified agents derived from cigarette smoke that may be injurious to the artery wall. They also suggested that the inhalation of cigarette smoke may result in the exposure of arterial cells to mutagens that transform the smooth-muscle cells, which are stimulated to proliferate. Apparently, the cessation of cigarette smoking decreases the risk for the development of the clinical sequelae of atherosclerosis and may augment the regression of lesions. Further research is clearly required to identify the factors in cigarette smoke that are responsible for its cardiovascular effects and to determine the mechanisms by which it alters cellular metabolism.
Male Sex Perhaps one of the best-documented and most consistent risk factors for coronary atherosclerosis is male sex. This differential is accentuated in nonwhite populations, and it has been suggested that women have a decreased incidence because estrogens exert a protective function. Paradoxically, large doses of estrogenic hormones appear to increase cardiovascular mortality in men who have had one myocardial infarct and in men under treatment for prostatic cancer. Consequently, the reasons for the sex differential are not yet understood.
Diabetes Another risk factor known to be associated with an increased incidence of atherosclerosis and myocardial infarction is diabetes mellitus. The mechanisms involved are poorly understood. There is, unfortunately, no consistency
Chapter 2.
in the evidence related to whether elevated concentrations of plasma cholesterol and lipoproteins occur in diabetics whose concentrations of blood and urine glucose are carefully regulated. There is some evidence suggesting a decreased concentration of HDL cholesterol in diabetics and a high prevalence of hypertension associated with hyperglycemia. The basic mechanisms associated with the proliferation of smooth-muscle-type cells in the mesangium of the kidney in the renal complication of diabetes and in the increased thickness of capillary basement membranes in diabetics with microvascular disease may bear some similarity to the mechanisms of smooth-muscle proliferation in atherogenesis. However, the alterations in the arterial tree that precede the lesions of atherosclerosis in diabetics are not well documented and are poorly understood. Although a great deal is known (see below) about endothelial cells, smooth-muscle cells, macrophages, platelets, and their interactions, the specific role of each of the risk factors associated with atherosclerosis remains, for the most part, to be investigated. This information is critical if we are to improve the means of diagnosis, prevention, and intervention in this disease process.
CELLULAR MODIFICATIONS IN ATHEROSCLEROSIS Endothelium Endothelial cells provide a selective permeability barrier, a blood-compatible interface, and a thromboresistant lining to the artery wall, and they are also metabolically active. A number of studies of endothelial permeability using various tracer molecules have demonstrated the presence of pinocytotic vesicles, transendothelial channels, and intracellular clefts in different kinds of endothelium. The junctional complexes between endothelial cells and the artery wall appear to be functionally dynamic structures that can respond to stimuli such as pharmacologic agents and changes in blood pressure. At the molecular level, the surface components of the endothelial cells appear to influence the selective permeability of the endothelium.[54,55] Endothelial cells have been shown by the Steins[56] to be capable of transporting plasma lipoproteins of certain sizes into the artery wall via vesicles. Thus molecules like HDL are transported, but larger lipoproteins the size of very-lowdensity lipoproteins (VLDL) or chylomicrons have difficulty crossing the endothelial barrier without some kind of alteration in these lipid-rich particles. In a number of experimental animals, the disruption of this barrier has been shown to permit interactions between platelets and the artery wall at the sites of endothelial injury; this interaction results in an intimal smooth-muscle proliferative response. Stemerman and Ross[13] observed that if endothelial cells are removed by abrasion with an intraarterial catheter, the sites of exposure of the subendothelial connective tissue are quickly coated with a “carpet” of degranulated platelets. At such sites of endothelial injury, the interaction of plasma constituents with products released from the platelets is followed by focal smooth-muscle migration
Pathophysiology of Atherosclerosis
21
and proliferation that eventually lead to the development of a fibromusculoelastic lesion. If this mechanical injury is accompanied by a high-fat, high-cholesterol diet, the hyperlipemic animals develop intimal proliferative lesions essentially identical to fibrous plaques. In the normocholesterolemic animals, such endothelial injury leads to fibromusculoelastic proliferative lesions that, over a period of 6 months, may undergo regression, whereas in hypercholesterolemic animals, the lesions become slowly progressive and show no signs of regression. Ross and Harker,[15] Faggioto et al.,[19,20] and Masuda and Ross[21,22] observed that monkeys that received no mechanical injury but were only fed a high-fat, high-cholesterol diet for a year or longer showed signs of endothelial injury as determined morphologically and by measurements of endothelial cell turnover at selected sites in the arterial tree (Fig. 2-2). The intimal smooth-muscle proliferation that accompanies the functional alteration in the endothelial cell barrier has been shown to be associated with the interaction between monocytes and endothelium and between platelets and the exposed subendothelium at such sites of injury. This is further discussed below.
Endothelial Cell Culture Arterial endothelial cells have been successfully cultured from a number of species, including the cow, rabbit, swine, nonhuman primate, and human being.[57,58] Endothelial cells from each of these species demonstrate a number of common characteristics. They grow, as they do in vivo, in a unique, continuous monolayer and, unlike other cells such as smoothmuscle cells or fibroblasts, appear to be truly contactinhibited. That is, the cells become quiescent when they become confluent and remain quiescent as long as they
Figure 2-2. A scanning electron micrograph demonstrating an area over a fatty streak in the iliac artery of a monkey that had been hypercholesterolemic (600 mg/dL) for 5 months. Several exposed macrophages are visible. One of them is covered by a mural collection of platelets (arrow ). A lesion such as this is found in the same anatomic site that 1 or 2 months later is occupied by a smooth-muscle proliferative lesion of atherosclerosis.
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Part One. Assessment of Vascular Disease
remain in contact. If the monolayer is disrupted, for example, by wounding, the cells are stimulated to synthesize new DNA, to migrate, and to proliferate and restore the continuity of the monolayer. Only those cells next to the margins of the wound appear to undergo DNA synthesis and proliferation, whereas those in the monolayer at a distance from the wound appear to remain relatively quiescent. This peculiar characteristic of the growth of endothelium is so strikingly different from that of smooth-muscle cells that it has been suggested that these two different cell types are under different sets of growth controls and that somehow cell-cell contact is important in determining the state of quiescence of endothelial cells. Endothelial cells grown in a culture have been shown to be capable of forming a number of connective tissue matrix macromolecules, including particular types of collagen;[59] of transporting lipids; of synthesizing PGI2,[34] factor VIII,[60] and angiotensin-converting enzyme;[61] and of maintaining many aspects of their differentiated phenotype through several passages.
Endothelial Responses Endothelial cells have been shown to be capable of forming mitogens, or growth factors, in culture. One of the earliest detectable responses of the endothelial cells to “injurious agents” such as hyperlipidemia or oxidized LDL is to increase the transport of lipoproteins through the endothelial cells, where they localize subendothelially. At the same time, the endothelial cells participate in a specialized type of chronic inflammatory response by developing specific cell-surface glycoproteins that are adhesive for monocytes and T lymphocytes. These adhesive glycoproteins, or endothelial leukocyte adhesion molecules (ELAM), bind to other glycoproteins on the surfaces of the monocytes and lymphocytes in receptor-ligand –type interactions.[62,63] Concurrently, monocyte chemotactic factors can be formed either by the endothelial cells or subendothelially by smooth muscle, and these can induce monocytes to migrate between endothelial cells and localize subendothelially. Activation of the endothelial cells can not only lead to the formation of new adhesive glycoproteins on their surfaces but may possibly stimulate the endothelial cells to make growthregulatory molecules including PDGF, TGFb, and possibly fibroblast growth factor (FGF).
Smooth Muscle Smooth-Muscle Proliferation Smooth-muscle cells have long been recognized to possess a number of features important to normal arterial function, including their capacity to contract, maintain arterial tone, and synthesize connective tissue proteins. Perhaps the most important phenomenon associated with the smooth-muscle cell is cell proliferation in atherogenesis. Since intimal smooth-muscle proliferation is an important early feature in atherogenesis, the factors responsible for this proliferative response are under intensive investigation in vivo and in vitro. In cell culture, it is well known that whole blood serum provides all the factors necessary for smooth-muscle proliferation. Arterial smooth-muscle cells from a large
number of species can be grown in culture and are able to maintain their differentiated phenotype under these conditions.[64,65] Ross and coworkers[37] together with several other research groups [66,67] demonstrated that the principal component that is present in whole-blood serum and missing in cell-free, plasma-derived serum and that is responsible for the proliferation of arterial smooth-muscle cells in culture is a mitogen derived from the platelet, the platelet-derived growth factor. The observation that smooth-muscle proliferation in culture is stimulated principally by this mitogen led to a series of studies to examine the role of this factor, PDGF, in smoothmuscle proliferation induced in vivo. As described above, several forms of endothelial injury result in the adherence of macrophages and platelets at the sites of injury. Platelet adherence is followed by degranulation and then material stored in the platelet granules is released into the artery wall. When activated, macrophages can also release PDGF. Together with plasma constituents, these platelet products have far-reaching effects upon the smooth-muscle cells of the artery wall. Harker et al.[16] demonstrated that in homocystinuria, a genetic disease of childhood commonly associated with a markedly increased incidence of arteriosclerosis, platelets appear to interact at sites where the endothelium has somehow been injured by increased levels of plasma homocysteine. Harker et al. demonstrated this association by measuring the survival of autologous 51Cr-labeled platelets in homocystinuric children and observed that the greater the levels of plasma homocysteine, the greater the decrease in platelet survival. As a result of these observations, they developed an animal model of homocystinuria by chronically infusing homocysteine in baboons. In this model they showed a similar correlation between elevated levels of plasma homocysteine and decreased rates of platelet survival (or increased rate of platelet utilization). When they maintained the baboons on a homocystinemic regimen for 3 months, they observed an increased incidence of missing endothelial cells by morphometric examination of whole-mount preparations of the aorta. Their studies established a correlation between the amount of injured endothelium, the rate of platelet survival, and the formation of proliferative smooth-muscle atherosclerotic lesions at the sites of endothelial injury. Harker and colleagues[16] went on to demonstrate that if they administered to the homocystinemic baboons a pharmacologic agent that could inhibit platelet interactions with the injured artery wall, they could prevent the intimal smoothmuscle proliferative lesions that could otherwise develop. One agent, dipyridamole, returned platelet survival rates to normal. This drug is known to have the capacity to inhibit platelet phosphodiesterase activity and to inhibit platelet adherence. Another agent, sulfinpyrazone, appears to somehow protect the endothelial cells, since the sulfinpyrazonetreated homocystinemic baboons demonstrated fewer areas of endothelial injury. In both approaches, platelet survival rates were normalized and the proliferative lesions of atherosclerosis were prevented. These were the first data to correlate a requirement for platelet function with experimentally induced atherosclerosis. Other approaches to examining these same phenomena were taken by Moore and colleagues[68] and by Friedman
Chapter 2.
et al.[69] In both their studies, atherosclerosis was induced in rabbits by injuring the endothelium with an intraarterial catheter. In each case, the investigators induced a thrombocytopenia by the administration of a specific antiplatelet antiserum. They found that the animals made thrombocytopenic in this manner had no proliferative atherosclerotic lesions, whereas the control animals had extensive lesions. Using a different approach, Fuster and colleagues[70] examined the incidence of atherosclerosis in the aortas of swine fed a high-fat, high-cholesterol diet. They were able to study the role of platelets by trying to induce atherosclerosis with a high-cholesterol diet in a group of swine that were homozygous for von Willebrand’s disease and then comparing them with a group of normal swine on the same diet. The swine with severe von Willebrand’s disease have essentially no factor VIII—von Willebrand factor—in their plasma. Normally this factor is required for platelet adherence and release. Fuster et al. showed that the control animals on the high-lipid diet developed extensive proliferative lesions of atherosclerosis, whereas the von Willebrand swine developed intimal infiltrates of lipid but no smooth-muscle proliferative lesions. In the absence of the von Willebrand factor, platelet interactions may be inhibited in the hypercholesterolemic von Willebrand swine. The ability of the smooth-muscle cell to migrate and proliferate gives it a central role in the development of the advanced lesions of atherosclerosis and, in particular, in the formation of the fibrous cap that covers the necrotic core. Recent data have demonstrated that the matrix with which the smooth muscle cells interact can play a critical role in determining whether the cells respond to mitogens, such as PDGF, as they do in the intima where the lesions develop, or are nonresponsive, as they are in the media of the artery.[71,72] Atherosclerosis is an inflammatory response, and activated macrophages can secrete metalloproteases that can profoundly affect both the smooth muscle cells and the form taken by the matrix surrounding them.[10] As we achieve a clearer understanding of the importance of these interactions, the process of lesion formation and progression may be modifiable in part by paying closer attention to the form and nature of the matrix formed by the smooth-muscle cells.
Lipid Metabolism Lipids are essential components of all cells; it is not surprising that they are involved in a number of cell functions and metabolic processes, as they represent the principal constituent of all cell membranes. Both the plasma membrane and the internal membranous compartments of all cells, including smooth muscle, are composed of phospholipids, proteins, and cholesterol, principally unesterified cholesterol. Esterified cholesterol is found in smooth muscle only under abnormal conditions. Accumulations of cholesteryl ester in smooth-muscle cells and macrophages lead to the development of foam cells, which are found in the lesions of atherosclerosis. Recent experiments have shown that smoothmuscle cells can acquire cholesterol both by de novo synthesis[73] and from an exogenous source of cholesterolcarrying lipoproteins.[74] Such a dual mechanism may help the cell to protect itself against possible deficits in cholesterol.
Pathophysiology of Atherosclerosis
23
Smooth-muscle cells and many other cells can also protect themselves against excess cholesterol. The mechanism that has evolved for this purpose is the surface-located, highaffinity LDL receptor.[75,76] These receptors bind LDL, and the cell then internalizes the bound LDL by endocytosis and transports it to lysosomes, where the LDL is degraded and free cholesterol is liberated for use by the cell. If the cell is exposed to excess LDL, there is a feedback-inhibitory pathway in the cell that inhibits the synthesis of LDL receptors. In addition, the presence of excess cholesterol within the cell inhibits cholesterol synthesis by the ratelimiting intracellular enzyme hydroxymethylglutaryl –coenzyme A reductase (HMG-CoA reductase). Under normal circumstances, sterol balance in the cell maintains a given level of receptor for LDL at the cell surface. In this way the requirements for extracellular cholesterol are met by concentrations of plasma LDL that are not atherogenic. Increased concentrations of plasma LDL may alter the endothelial barrier and bring large amounts of LDL, much of which may be modified (oxidized), in direct contact with the smooth-muscle cell, which may ingest much of the oxidized LDL by bulk-phase endocytosis and by special highaffinity receptors; this leads to the increased esterification and storage of cholesteryl esters and the development of foam cells (Fig. 2-3). The metabolism of lipoproteins is sufficiently complex that it will not be covered in this chapter. Nevertheless, recent data suggest that at least two alterations of lipoproteins may be important in the process of atherogenesis. The first of these, as referred to earlier, is the modification or oxidation of LDL. Low-density lipoprotein can be modified by the endothelium, by macrophages, or perhaps even by smoothmuscle cells. Such modified LDL can be taken up by macrophages via scavenger receptors on the cell surface and can lead to foam-cell formation. The oxidized forms of LDL, however, can also be quite toxic to the endothelial cells, to smooth muscle, and perhaps to the macrophages themselves. When Watanabe heritable hyperlipidemic (WHHL) rabbits or hypercholesterolemic monkeys were treated with antioxidants such as probucol, the lesions that formed in these animals were much smaller. This has led to an exciting series of experiments suggesting that antioxidants might perhaps be useful in the treatment and prevention of the process of atherogenesis. It is now widely appreciated that HMG-CoA reductase inhibitors (statins) have been enormously successful in preventing the clinical consequences of atherosclerosis, such as myocardial infarction.[77,78] They effectively lower LDL cholesterol by inhibiting the rate-limiting enzyme of cholesterol synthesis. Nevertheless, it has recently become apparent that these interesting pharmacologic agents have a broad array of effects in addition to lowering LDL cholesterol. Some of these effects may directly inhibit the inflammatory response that represents the earliest phase of the process of atherogenesis. The use of these agents and ones in development will have profound effects on the incidence of atherosclerosis and its clinical sequelae. Evidence is accumulating in favor of the notion that HDL, in contrast to LDL, is a negative factor in the development of atherosclerosis. Two hypotheses have been proposed to explain how HDL might be a deterrent against
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Part One. Assessment of Vascular Disease
Figure 2-3. A transmission electron micrograph of part of an atherosclerotic lesion from the iliac artery of an 8-month-old hypercholesterolemic monkey. The smooth-muscle cell in the center of this micrograph contains numerous lipid droplets and is surrounded by connective tissue.
atherosclerosis. The first suggests that HDL augments the removal of cholesterol from cells such as smooth-muscle cells. The second mechanism involves the apparent ability of HDL to influence the binding and absorption of LDL by cells such as smooth-muscle cells. However, neither of these mechanisms has been shown to be responsible for the control of cellular cholesterol levels.
The Macrophage Macrophages represent the principal cell in early lesions of atherosclerosis and are present in all stages including advanced lesions like the fibrous plaque. These cells could conceivably play several roles in lesion progression and possibly in regression as well. In tissue culture, macrophages have been shown to release into the culture medium a mitogen as potent as that derived from platelets.[79] Platelet-derived growth factor is the principal mitogen that can be released from activated macrophages. However, macrophages also make a large number of cytokines and growth factors, including interleukin 1 (IL-1), tumor necrosis factor-alpha (TNFa), TGFb, and numerous others. Thus the macrophage represents a potent source of growth-regulatory
molecules that can affect its surrounding neighbors. It can also form colony-stimulating factor, a mitogen for macrophages themselves. It has recently been shown that macrophage replication may be as important a component of cell proliferation in the lesions of atherosclerosis as is smooth-muscle proliferation. Replicating macrophages have been observed in experimental animals and recently in human lesions of atherosclerosis. Macrophages have long been known to be largely responsible for tissue debridement. There is increasing evidence in experimental studies and in human beings[32] that some lesions of atherosclerosis are capable of regression. The role of the macrophage in this phenomenon remains to be elucidated. Not only monocytes are ubiquitous in all of the lesions of atherogenesis, but so are subsets of T lymphocytes.[80] The monocyte-derived macrophage is not only a scavenger cell, it is also an antigen-presenting cell. The presence of monocytederived macrophages, together with T cells, suggests that some form of immune response may be responsible for the development of the lesions of atherosclerosis. Hansson and colleagues have shown that oxidized LDL can serve as such an antigen.[81] Also, some infectious organisms, such as herpesvirus or Chlamydia pneumoniae, may play such
Chapter 2.
a role.[82 – 84] There are increasing data suggesting that, in some cases, infection, together with other components associated with risk factors, may be involved in the process of atherogenesis. The macrophage as the hallmark of chronic inflammation, together with the lymphocytes, can not only be a phagocytic cell but can provide cytokines, chemokines, metalloproteases, and other hydrolytic enzymes, and the growth factors noted above in the process of atherogenesis. Macrophages also multiply and are potentially important as proliferating and replicating cells, as are smooth-muscle cells.[85]
Platelets Platelet-Derived Growth Factor Platelet-derived growth factor is a mitogen that is stored in the alpha granule of the platelets. The factor has been purified to homogenicity. It has a molecular weight of approximately 32,000 and is a highly cationic (pI 9.8), stable, disulfidebonded protein. This growth factor is extremely potent; it causes the proliferation of connective tissue cells such as smooth muscle in culture at levels of 5 ng/mL of culture medium (equivalent to the addition of 5% whole-blood serum). As discussed earlier, in whole-blood serum, PDGF is the principal mitogen to which cells characteristically respond by cell proliferation. When susceptible cells are exposed to this factor, the result is a sequence of events that includes the binding of the molecule to specific receptors on the surface of the cell. This causes the cell to undergo cell-cycle traverse leading to DNA synthesis and cell multiplication. Upon exposure to smooth-muscle cells, the plateletderived growth factor stimulates a number of phenomena in addition to DNA synthesis. It causes increases in pinocytosis, protein synthesis, RNA synthesis, and lipid metabolism. Chait et al.[74] have observed that the exposure of arterial smoothmuscle cells to this growth factor results in the increased binding of LDL to the cells because of the formation of an increased number of high-affinity receptors for LDL at the cell surface. This increased binding of LDL permits the cells to more effectively utilize exogenous sources of cholesterol for cell multiplication. Habenicht et al.[73] have demonstrated that this mitogen also simulates increased cholesterol synthesis by cells if an exogenous source of cholesterol is not available to them. Davies and Ross[86] observed that smooth-muscle cells exposed to the platelet-derived growth factor undergo a marked increase in the rate of endocytosis of tracer molecules. In other words, exposure to this mitogen results in an increase in a number of cellular activities, many of which are associated with cell proliferation and with new protein syntheis, and therefore with connective tissue formation.[87] Thus exposure to this factor could trigger the initiation of all the components of a proliferative lesion. The role of functional platelets in inducing experimental atherosclerosis in vivo is unquestioned. The role of the platelet-derived growth factor in stimulating mitogenesis in cell culture is also clear. The question remains whether this factor is active in vivo (Fig. 2-4). Since activated platelets can play a role not only in the genesis of the lesions of atherosclerosis but also in
Pathophysiology of Atherosclerosis
25
thrombosis, one of the principal clinical sequelae of the advanced lesions, thrombus formation and its prevention have become integral to approaches to treatment and prevention of lesions of atherosclerosis. Activated platelets express on their surfaces a glycoprotein, the IIbIIIa receptor, which is a member of the integrin superfamily of adhesion molecules that plays a key role in thrombosis. These receptors normally serve an important hemostatic function. Clinical antagonists have been developed into pharmacologic agents, which are used to prevent thrombus formation, particularly in individuals who have had myocardial infarction.[88]
Other Factors Possibly Involved in Atherogenesis During the past several years, a host of new factors has been uncovered which may play roles that either aggravate the process of atherogenesis or are important in its inhibition. Endothelial cells have been shown to form vasodilatory factors called endothelial-derived relaxing factors (EDRF), which represent a thiolated form of nitric oxide. This factor is very important in maintaining the arteries in a dilated state and thus maintaining patent arterial lumina. In addition, all three cell types associated with the lesions of atherosclerosis—endothelium, smooth muscle, and macrophages—are capable of converting the fatty acid arachidonic acid into prostaglandin endoperoxides. Studies of these endoperoxides identified a number of unstable intermediates in the metabolic pathway of arachidonic acid that leads to the formation of two important end products: thromboxane A2 (formed by platelets) and PGI2 (formed by endothelium and smooth muscle). Understanding these two end products has greatly expanded our view of the role played by platelets in thrombosis and by endothelium and smooth muscle in the prevention of thrombosis and atherosclerosis. Arachidonic acid is derived either from linoleic acid, an essential fatty acid in the membranes of cells, or from the diet. Thromboxane A2 is a powerful vasoconstrictor and is capable of stimulating smooth-muscle contraction and platelet aggregation. It has a short half-life (30 s) and breaks down spontaneously into a stable substance, thromboxane B2. A number of inhibitors of thromboxane synthesis markedly reduce platelet aggregation. These include aspirin and indomethacin.[89,90] PGI2 is the principal product of cyclooxygenase activity in the walls of arteries and veins. Endothelium and smooth muscle synthesize PGI2 from arachidonic acid may also be able to synthesize this prostaglandin derivative from endoperoxides released from platelets. PGI2 is unstable and is an extremely potent vasodilator, as well as an inhibitor of platelet aggregation. It is possible that an imbalance in the relative amounts of thromboxane A2 and PGI2 may partly explain the involvement of platelets in cardiovascular diseases. Since platelets contain thromboxane synthetase, the enzyme responsible for the synthesis of thromboxane A2, and since the inhibition of the activity of this enzyme does not interfere with cyclooxygenase activity, it has been speculated that thromboxane synthetase –inhibited platelets could donate endoperoxides to endothelial cells, which could then use them as substrates for PGI2 production. Therefore, attempts are
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Part One. Assessment of Vascular Disease
Figure 2-4. A diagram illustrating the proposal that smooth-muscle cells are susceptible to at least two potential growth factors: PDGF, which can stimulate smooth muscle proliferation, and TGFb, which can inhibit proliferation and increase connective tissue formation and LDL. The particular importance of each of these as a cause of smooth-muscle proliferation in the genesis of the lesions of atherosclerosis must be better defined for each special set of circumstances; this provides important opportunities for further research.
being made to develop specific inhibitors of thromboxane synthesis that do not affect PGI2 production by cells of the blood vessel wall. Prostaglandin biosynthesis may be important not only in thrombosis (in terms of platelet adherence and aggregation) but also in the prevention of atherogenesis (by the formation of PGI2). This had led to the speculation that alterations in the contents of the fatty acids in the diet might offer some protection against the development of atherosclerosis. Populations that consume diets principally composed of marine animals often replace arachidonic acid, the normal substrate for prostaglandin synthesis, with eicosapentaenoic acid. This fatty acid is not completely metabolized by platelets and instead produces a relatively inert form of thromboxane, thromboxane A3. Eicosapentaenoic acid appears to inhibit the capacity of platelets to metabolize arachidonic acid. When eicosapentaenoic acid is exposed to cells of the blood vessel, they form an analogue of PGI2, PGI3. PGI3 appears to be as effective as PGI2 in preventing platelet aggregation and in inducing vasodilation. Thus further studies of the role of this fatty acid derived from marine animals could be important in terms of protecting persons who
consume a marine diet against atherogenesis. Clearly, there is much to be learned about prostaglandin metabolism before the agents that have thus far been discovered, and those that are yet undiscovered, can be understood in relation to both atherogenesis and protection against this disease process.
FUTURE DIRECTIONS The fields of atherosclerosis research has changed dramatically within the last decade. The emphasis has shifted to probing the fundamental roles of the cells of the artery wall as well as the roles of those in the blood, particularly the platelet and the monocyte. The developments of cell and molecular biology, experimental pathology, and immunology have provided tools that will lead to new approaches to diagnosis, intervention, and prevention. Since it is now apparent that the process of atherogenesis is an inflammatory process and the lesions of atherosclerosis are lesions of an inflammatory disease,[10] it may be possible to
Chapter 2.
treat and prevent the disease with anti-inflammatory agents that are specific for the response sin the artery wall. If, for example, it can be demonstrated unequivocally that PDGF plays a role either in the initiation of the lesions of atherosclerosis or in their progression or in both, the development of specific inhibitors of this factor and the development of specific diagnostic tests to measure increased activity would greatly alter present approaches to diagnosis, treatment, and prevention. Future research at the cellular and molecular levels could provide important diagnostic tools that may be of use clinically.
Pathophysiology of Atherosclerosis
27
The process of atherogenesis is highly complex, involving many cellular interactions as well as interactions between cells and constituents in the fluid phase of the blood, the plasma. The importance of these interactions is undoubtedly modified by the genetic makeup of each individual. Consequently, from individual to individual, the differences in susceptibility to each of the risk factors, and at the cellular level to the various components considered to be important in atherogenesis, will have to be understood if we are to make further progress not only in diagnosis and treatment but ultimately also in prevention.
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30. Duguid, J.B. Thrombosis as a Factor in the Pathogenesis of Coronary Atherosclerosis. J. Pathol. Bacteriol. 1948, 58, 207. 31. French, J.E. Atherosclerosis in Relation to the Structure and Function of the Arterial Intima, with Special Reference to the Endothelium. Int. Rev. Exp. Pathol. 1966, 5, 253. 32. Ross, R.; Glomset, J. Atherosclerosis and the Arterial Smooth Muscle Cell. Science 1973, 180, 1332. (32 References). 33. Fry, D.L. Cerebrovascular Disease; Raven Press: New York, 1976; 77. 34. Moncada, S.; Higgs, E.A.; Vane, J.R. Human Arterial and Venous Tissue Generate Prostacyclin, a Potent Inhibitor of Platelet Aggregation. Lancet 1977, 2, 18. 35. Vanhoutte, P.M.; Boulanger, C.M. Endothelium-Dependent Responses in Hypertension. Hypertension Res. 1995, 18, 87. 36. Brown, B.G.; Albers, J.J.; Fisher, L.D.; et al. Treatment Study: A Randomized Trial Demonstrating Coronary Disease Regression and Clinical Benefit from Lipid Altering Therapy Among Men with High Apolipoprotein B. N. Engl. J. Med. 1990, 323, 1289. 37. Ross, R.; Glomset, J.; Kariya, B.; Harker, L.A. A PlateletDependent Serum Factor That Stimulates the Proliferation of Arterial Smooth Muscle Cells In Vitro. Proc. Natl Acad. Sci. USA 1974, 71, 1207. 38. Ignotz, R.A. Massague´: Transforming Growth Factor-b Stimulates the Expression of Fibronectin and Collagen and Their Incorporation into the Extracellular Matrix. J. Biol. Chem. 1986, 261, 4337. 39. Roberts, A.B.; Sporn, M.B.; Assoian, R.K.; et al. Transforming Growth Factor Type b: Rapid Induction of Fibrosis and Angiogenesis In Vivo and Stimulation of Collagen Formation In Vitro. Proc. Natl Acad. Sci. USA 1986, 83, 4167. 40. Laiho, M.; Saksela, O.; Andreasen, P.A.; Keski-Oja, J. Enhanced Production and Extracellular Deposition of the Endothelial-Type Plasminogen Activator Inhibitor in Cultured Human Lung Fibroblasts by Transforming Growth Factor-b. J. Cell. Biol. 1986, 103, 2403. 41. Geer, J.C.; McGill, H.C., Jr.; Strong, J.P. The Fine Structure of Human Atherosclerotic Lesions. Am. J. Pathol. 1961, 38, 263. 42. Steinberg, D.; Parthasarathy, S.; Carew, T.E.; et al. Beyond Cholesterol: Modifications of Low-Density Lipoprotein That Increase Its Atherogenicity. N. Engl. J. Med. 1989, 320, 915. 43. Steinberg, D. Low Density Lipoprotein Oxidation and Its Pathobiological Significance. J. Biol. Chem. 1997, 272, 20963. 44. Khoo, J.C.; Miller, E.; McLoughlin, P.; Steinberg, D. Enhanced Macrophage Uptake of Low Density Lipoprotein After Self-Aggregation. Arteriosclerosis 1988, 8, 348. 45. Khoo, J.C.; Miller, E.; Pio, F.; Steinberg, D.; Witztum, J.L. Monoclonal Antibodies Against LDL Further Enhance Macrophage Uptake of LDL Aggregates. Arterioscler. Thromb. 1992, 12, 1258. 46. McGill, H.C. Risk Factors for Atherosclerosis. Adv. Exp. Med. Biol. 1977, 104, 273.
47. NHLBI Consensus Development Conference: Lowering Blood Cholesterol to Prevent Heart Disease. J. Am. Med. Assoc. 1985, 253, 2080. 48. Grundy, S.M. Nutrition, Lipids, and Coronary Heart Disease; Raven Press: New York, 1979; 89. 49. McGill, H.C., Jr. The Relationship of Dietary Cholesterol to Serum Cholesterol Concentration and to Atherosclerosis in Man. Am. J. Clin. Nutr. 1979, 32 (Suppl.), 2664. 50. Griendling, K.K.; Alexander, R.W. Oxidative Stress and Cardiovascular Disease. Circulation 1997, 96, 3264. 51. Lacy, F.; O’Connor, D.T.; Schmid-Scho¨nbein, G.W. Plasma Hydrogen Peroxide Production in Hypertensives and Normotensive Subjects at Genetic Risk of Hypertension. J. Hypertens. 1998, 16, 291. 52. Swei, A.; Lacy, F.; DeLano, F.A.; Schmid-Scho¨nbein, G.W. Oxidative Stress in the Dahl Hypertensive Rat. Hypertension 1997, 30, 1628. 53. Becker, C.G.; Dubin, T.; Wiedemann, H.P. Hypersensitivity to Tobacco Antigen. Proc. Natl Acad. Sci. 1976, 73, 1712. 54. Simionescu, N.; Simionescu, M.; Palade, G.E. Permeability of Muscle Capillaries to Small Hemepeptides. Evidence for the Existence of Patent Transendothelial Channels. J. Cell. Biol. 1975, 64, 586. 55. Renkin, E.M. Multiple Pathways of Capillary Permeability. Circ. Res. 1977, 41, 735. 56. Stein, Y.; Stein, O. Biochemistry of Atherosclerosis; Marcel Dekker: New York, 1979; Vol. 7, 313. 57. Gimbrone, M.A., Jr. Progress in Hemostasis and Thrombosis; Grune & Stratton: New York, 1976; Vol. 3, 1. 58. Jaffe, E.A.; Nachman, R.L.; Becker, C.G.; Minick, C.R. Culture of Human Endothelial Cells Derived from Umbilical Veins. J. Clin. Investig. 1973, 52, 2745. 59. Jaffe, E.A.; Adelman, B.; Minick, C.R. Synthesis of Basement Membrane by Cultured Human Endothelial Cells. Circulation 1975, 51 (Suppl. 2), 11. 60. Jaffe, E.A.; Hoyer, L.W.; Nachman, R.L. Synthesis of Antihemophilic Factor Antigen by Cultured Human Endothelial Cells. J. Clin. Investig. 1973, 52, 2757. 61. Gimbrone, M.A., Jr.; Alexander, R.W. Angiotension II Stimulation of Prostaglandin Production in Cultured Human Vascular Endothelium (Abstract). Science 1975, 189, 219. 62. Springer, T.A. Adhesion Receptors of the Immune System. Nature 1990, 346, 425. 63. Bevilacqua, M.P.; Stengelin, S.; Gimbrone, M.A., Jr.; Seed, B. Endothelial Leukocyte Adhesion Molecule 1: An Inducible Receptor for Neutrophils Related to Complement Regulatory Proteins and Lectins. Science 1989, 243, 1160. 64. Ross, R.; Kariya, B. Handbook of Physiology—Circulation, Vascular Smooth Muscle; American Physiological Society: Bethesda, MD, 1980; 69. 65. Chamley-Campbell, J.; Campbell, G.R.; Ross, R. The Smooth Muscle Cell in Culture. Physiol. Rev. 1979, 59, 1. 66. Kohler, N.; Lipton, A. Platelets as a Source of Fibroblast Growth-Promoting Activity. Exp. Cell. Res. 1974, 87, 297. 67. Heldin, C.-H.; Wasteson, A.; Westermark, B. Partial Purification and Characterization of Platelet Factors Stimulating the Multiplication of Normal Human Glial Cells. Exp. Cell. Res. 1974, 87, 297.
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Hypercholesterolemia. N. Engl. J. Med. 1995, 333, 1301. Leibovich, S.J.; Ross, R. A Macrophage-Dependent Factor That Stimulates the Proliferation of Fibroblasts In Vitro. Am. J. Pathol. 1976, 84, 501. Hansson, G.K.; Libby, P. Atherosclerosis and Coronary Artery Disease; Lippincott-Raven: Philadelphia, 1996; 557. Stemme, S.; Faber, B.; Holm, J.; Wiklund, O.; Witztum, J.L.; Hansson, G.K. T Lymphocytes from Human Atherosclerotic Plaques Recognize Oxidized Low Density Lipoprotein. Proc. Natl Acad. Sci. USA 1995, 92, 3893. Libby, P.; Egan, D.; Skarlatos, S. Roles of Infectious Agents in Atherosclerosis and Restenosis. An Assessment of the Evidence and Need for Future Research. Circulation 1997, 96, 4095– 4103. Hajjar, D.P.; Fabricant, C.G.; Minick, C.R.; Fabricant, J. Virus-Induced Atherosclerosis. Herpesvirus Infection Alters Aortic Cholesterol Metabolism and Accumulation. Am. J. Pathol. 1986, 122, 62. Thom, D.H.; Wang, S.P.; Grayston, J.T.; et al. Chlamydia pneumoniae Strain Twar Antibody and Angiographically Demonstrated Coronary Artery Disease. Arterioscler. Thromb. 1991, 11, 547. Rosenfeld, M.E.; Ross, R. Macrophage and Smooth Muscle Cell Proliferation in Atherosclerotic Lesions of WHHL and Comparably Hypercholesterolemic Fat-Fed Rabbits. Arteriosclerosis 1990, 10, 680. Davies, P.F.; Ross, R. Mediation of Pinocytosis in Cultured Arterial Smooth Muscle and Endothelial Cells by PlateletDerived Growth Factor. J. Cell. Biol. 1978, 79, 663. Burke, J.; Ross, R. International Review of Connective Tissue Research; Academic Press: New York, 1979; Vol. 8, 119. Badimon, J.J.; Meyer, B.; Feigen, L.P.; et al. Thrombosis Triggered by Severe Arterial Lesions Is Inhibited by Oral Administration of a Glycoprotein IIb/IIIa Antagonist. Eur. J. Clin. Investig. 1997, 27, 568. Moncada, S.; Vane, J.R. Arachidonic Acid Metabolites and the Interactions Between Platelets and Blood Walls. N. Engl. J. Med. 1979, 300, 1142. Moncada, S.; Vane, J.R. Mode of Action of Aspirin-Like Drugs. Adv. Intern. Med. 1979, 24, 1.
CHAPTER 3
Pathophysiology of Human Atherosclerosis Christopher K. Zarins Seymour Glagov determine human lesion composition, rate of lesion enlargement, lesion organization, and lesion disruption remain to be elucidated. In this chapter we discuss both the structural features of the artery wall and the hemodynamic factors which may relate to the pathogenesis, localization, and disruption of plaques, and we review the principal features of human lesion composition and configuration. These considerations should help to provide insight into the clinical consequences of differences in plaque localization and composition and serve as a basis for the critical evaluation of currently available methods for the quantitative assessment of human lesions.
Atherosclerosis is a degenerative process of the major human elastic and muscular arteries. It is characterized by the formation of intimal plaques consisting of lipid accumulations, smooth-muscle and inflammatory cells, connective tissue fibers, and calcium deposits. Morbidity associated with atherosclerosis arises from plaque enlargement or degeneration. Plaque enlargement may obstruct the lumen, resulting in stenosis and impairment of blood flow. Sudden obstruction of the lumen may result from the dissection of blood from the lumen into or under the plaque or hemorrhage within the plaque from vasa vasorum. Plaque ulceration may result in embolization of plaque elements or thrombus formation on the disrupted intima. Thrombosis may also occlude atherosclerotic vessels without obvious plaque disruption due to local modifications of flow. Finally, atrophy of the media, often associated with atherosclerotic disease, may result in weakening of the artery wall with aneurysmal dilatation, mural thrombosis, and rupture. Atherosclerosis is a generalized disorder of the arterial tree associated with a number of recognized predisposing risk factors, including altered serum lipid and lipoprotein profiles, hypertension, cigarette smoking, diabetes mellitus, and lifestyle. However, the clinical expression of atherosclerosis tends to be focal, with clinical symptoms caused by localized interference with circulation occurring in several critical sites. In addition, the morphologic features underlying morbidity and mortality vary somewhat depending on location. In the coronary arteries, for example, stenosis and thrombosis tend to reduce flow or cause sudden catastrophic occlusion, principally at the site of lesion formation, while at the carotid bifurcation, plaque ulceration and thrombosis often cause characteristic symptoms by embolization to distal cerebral vessels. Extensive disease, often with multiple focal occlusive stenoses, is characteristic of peripheral vascular disease of the lower extremities, while aneurysm formation is a major feature of abdominal aortic disease. While there is a large body of descriptive clinical and experimental knowledge with regard to the general appearance of atherosclerotic lesions, the precise initiating and perpetuating pathogenic mechanisms in human beings remain obscure, and the factors which
STRUCTURE OF THE ARTERY WALL The artery wall consists of three concentric layers or zones. From the lumen outward, these are the intima, the media, and the adventitia (Fig. 3-1).
Intima The intima extends from the luminal endothelial lining to the internal elastic lamina. The endothelium is formed by a continuous monolayer of flat, usually elongated polygonal cells, which tend to be aligned in the direction of blood flow. In areas of slow, reversing, or nonlaminar flow, endothelial cells tend to assume a less clearly oriented configuration.[1] Edges of adjacent endothelial cells overlap, with the downstream edges of most endothelial cells overriding their immediate downstream neighbors much like the shingles on a roof. Cytoplasmic bridges, surface ridges, and microvillus projections as well as interendothelial gaps, stomata, or open junctions between endothelial cells have been described. These features are, however, largely absent from vessels which have been fixed while distended and which have not been manipulated prior to fixation.[2] A protein coating, the glycocalyx, overlies the luminal surface. Immediately beneath the endothelium is a closely associated fibrillar
Hobson/Wilson/Veith: Vascular Surgery: Principles and Practice, Third Edition, Revised and Expanded DOI: 10.1081/0819-9-120024886 Copyright q 2004 by Marcel Dekker, Inc.
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Figure 3-1. Transverse section of a normal human superficial femoral artery. Note intima (I), media (M), and adventitia (A). The intima and media are separated by the internal elastic lamella (IEL).
layer, the basal lamina. This structure is thought to form a continuous bond between the endothelial cells and the subendothelial connective tissue matrix. Numerous focal attachments are also present between endothelial cells and the underlying internal elastic lamina,[3] while less prominent focal attachments are also formed with other fibers in the intima. The extensive basal lamina provides a supple, pliable junction well adapted to permit bending and changes in diameter or configuration associated with pulse pressure without disruption or detachment of the endothelium. The focal, tight, relatively rigid junctions may prevent downstream slippage or telescoping, which could result from the shear stresses imposed by blood flow. Between the basal lamina and the internal elastic lamina, the intima in most locations normally contains a few scattered macrophages, smooth-muscle cells, and connective tissue fibers. Since the endothelial cell layer is the immediate interface between the bloodstream and the underlying arterial wall, it is subjected to normal forces exerted by blood pressure and to shearing or drag forces resulting from blood flow. Experimentally imposed shearing stresses in excess of 400 dyn/cm2 in canine aortas have resulted in morphologic evidence of endothelial injury or disruption and in increased endothelial permeability.[4] Other observations have failed to reveal evidence of endothelial injury in areas normally subjected to comparable or higher levels of shear stress,[5] suggesting that endothelial cells may withstand relatively high shearing stresses without ill effect in some locations (Fig. 3-2). The endothelial layer has been considered to function as a thrombosis-resistant surface as well as a selective interface for diffusion, convection, and active transport of circulating
Figure 3-2. Scanning electron micrograph of a monkey aortic ostial flow divider (FD). The flow divider is an area subjected to high shear stress. The endothelial cells are intact and elongated in the direction of flow with no disruption. Arrows indicate direction of blood flow.
Chapter 3. Pathophysiology of Human Atherosclerosis
substances into the underlying artery wall. Endothelial cells play a critical role in the physiology and pathophysiology of vascular disorders.[6] They respond to hemodynamic stresses and may transduce an atheroprotective force[7] by regulating the ingress, egress, and metabolism of lipoproteins and other agents that may participate in intimal plaque initiation and progression.[8,9] Endothelial cells have been shown to participate in an array of metabolic and biosynthetic functions related to thrombosis, prostaglandin formation, and smoothmuscle contraction.[10] Detachment of endothelial cells with persistence of the basal lamina does not necessarily result in occlusive thrombus formation. Although a layer of thrombocytes appears to deposit on the denuded basal lamina, large aggregates and fibrin deposits may require the exposure of collagen fibers and other deeper mural components.
Media The media extends from the internal elastic lamina to the adventitia. Although an external elastic lamina demarcates the boundary between media and adventitia in many vessels, a distinct external elastic lamina may not be present, particularly in vessels with a thick and fibrous adventitial layer. The outer limit of the media can nevertheless be distinguished in nearly all intact arteries, for in contrast to the adventitia, the media consists of closely packed layers of smooth-muscle cells in close association with elastin and collagen fibers. Elastic fibers of the media are predominantly wavy or undulating on cross sections of collapsed arteries but appear as relatively straight bands or lamellae in fully distended vessels (Fig. 3-3). The smooth-muscle cell layers are composed of groups of similarly oriented cells, each
Figure 3-3. Tracing of elastic fibers in transverse sections of rabbit aortic media. (A ) A transverse section of a collapsed aorta demonstrating wavy elastic lamellae and increased thickness of each lamellar unit and increased total thickness of the media. (B ) A rabbit aorta fixed while distended. Note the straight elastic fibers and thickness of the media.
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surrounded by a common basal lamina and a closely associated interlacing basketwork of collagen fibrils, which tighten about the cell groups as the media is brought under tension.[11] This configuration tends to hold the groups of cells together and prevents excessive stretching or slippage. In addition, each cellular subgroup or fascicle is encompassed by a system of similarly oriented elastic fibers. Focal tight attachment sites between smooth-muscle cells and elastic fibers are normally abundant. In the aorta, the juxtaposition of similarly oriented musculoelastic fascicles results in the appearance on transverse sections of layers of continuous elastic lamellae and intervening smooth-muscle layers. In addition to the pericellular network of fine collagen fibrils, thicker, crimped collagen bundles weave between adjacent lamellae. The elastic fibers are relatively extensible and allow for some degree of compliance; they recoil during the cardiac cycle and tend to distribute mural tensile stresses uniformly. The thick collagen fiber bundles provide much of the tensile strength of the media and, because of their high elastic modules, limit distension and prevent disruption (Fig. 3-4). The aortic elastin lamella and its corresponding smoothmuscle layer has been termed a lamellar unit. With increasing mammalian species size, the adult aortic radius increases, with a corresponding increase in medial thickness and in the number of transmural lamellar units (Fig. 3-5).[12] The total tangential tension exerted on the wall is closely approximated by the product of the distending pressure and the radius (law of Laplace). Since aortic pressure is similar for most adult mammals and individual medial layers tend to be of similar thickness regardless of species, there is a very nearly linear relationship between adult aortic radius and the number of medial fibrocellular lamellar units. On the average, the tangential tension per aortic lamellar unit is close to 2000 dyn/cm. Smaller muscular arteries contain relatively less collagen and elastin and more smooth-muscle cells than the aorta and the proximal, larger elastic arteries. The musculoelastic fascicles, which are very prominent in elastic arteries, are also present in muscular arteries and are generally aligned in the direction of the tensile forces (Fig. 3-6). However, because of the preponderance of smooth-muscle cells, they are less clearly demarcated and the layering of the media is less distinct.[13] Medial thickness and the number of layers is nevertheless closely related to the radius, and the average tension per layer tends to be constant for homologous vessels in mammals.[14] In addition, the relative proportion of collagen and elastin varies between muscular and elastic arteries. The media of the proximal aorta and that of the major brachiocephalic elastic arteries contain a larger proportion of elastin and a lower proportion of collagen than the abdominal aorta or the distal peripheral vessels.[15] The proximal major vessels are therefore more compliant than the abdominal aorta but also are more friable and prone to tear with suturing. Medial smooth muscle cells, in addition to synthesizing the collagen and elastin fibers, which determine the mechanical properties of the aortic wall, are actively engaged in metabolic processes that contribute to wall tone and may be related to suceptibility to plaque formation.[16] Under conditions of increased pulse pressure, increased wall motion, and increased wall tension, such as exist proximal to
34
Part One. Assessment of Vascular Disease
Figure 3-4. Diagrammatic representation of the microarchitecture of the media of the aortic wall. The long axes of the smooth muscle cells (C) are oriented circumferentially or perpendicular to the long axis of the artery. Each cell is surrounded by a matrix (M) consisting of basal lamina and a fine meshwork of collagen fibrils. Groups or layers of smooth-muscle cells are surrounded by circumferentially oriented elastic fibers (E), which appear as almost continuous sheets on transverse section of the artery. Wavy collagen bundles (F) course between the successive facing elastic fiber layers. (Adapted from Clark JM, Glagov S: Transmural organization of the arterial media: The lamellar unit revisited. Arteriosclerosis 5:19, 1985. With permission.[11])
an aortic coarctation, medical smooth muscle cell metabolism is increased, as is plaque formation.[17] Conversely, when wall motion, pulse pressure, and smooth-muscle cell metabolism are decreased, as in areas distal to a severe arterial stenosis, intimal plaque formation is inhibited, despite the continued presence of strong atherogenic stimuli such as marked hyperlipidemia.[18] In vitro studies have revealed that cyclic stretching of smooth-muscle cells grown on elastin membranes results in increased biosynthetic activity,[19] and acute arterial injury experiments have revealed that an intact, metabolically active media may be required for intimal plaque formation.[20] The composition and microarchitecture of the media are designed to ensure stability, whereas the metabolic state of the media appears to be an important factor in the pathogenesis of atherosclerotic lesions.
Adventitia Although the boundary between media and adventitia is usually distinct, even in the absence of a well-defined external elastic lamina, the outer limit of the adventitia may be difficult to identify, for it is often continuous with the surrounding perivascular connective tissues. Although the aorta and pulmonary trunk are normally invested by relatively little adventitial fibrous connective tissue and are closely associated with mediastinal or retroperitoneal adipose tissue and lymph nodes, the adventitia of some of the major arteries, such as the renal and mesenteric branches, are composed of prominent layers of elastic and collagen fibers and may be thicker than the associated media. Compared to the media, cells in the adventitia are relatively sparse and most are fibroblasts. For the normal aorta, removal of the adventitia has
Chapter 3. Pathophysiology of Human Atherosclerosis
35
Figure 3-5. Aortic lamellar architecture in three mammals. With increasing species size, the aortic radius increases. There is a corresponding increase in medial thickness due to an increase in the number of medial lamellar units. (A ) Higher-power view of transverse section of media demonstrating lamellar architecture.
little effect on static pressure-volume relationships. In muscular arteries, however, where connective issue fibers are relatively sparse in the media and smooth muscle contraction may regulate vessel diameter and play a role in maintaining circumferential tensile support, a thick, structured adventitia may serve to provide significant tethering and axial tensile support, prevent excessive dilatation, and dampen the cyclic changes in tangential tension associated with the pulse pressure wave. In instances where a large, intimal atherosclerotic plaque overlies an atrophic media, a thickened adventitia may be the principal mural structural component of the artery wall (see Fig. 3-7). During carotid or femoral endarterectomy, the entire intima and extensive portions of remaining media may be removed, leaving only the adventitia to provide support. The adventitia is also the primary source of vasa vasorum and may play a prominent role in arteritis and periaortitis[21] as well as in the inflammatory component of atherosclerosis.[22] Adventitial responses may also be important in the artery wall response to balloon injury and angioplasty.[23,24]
ARTERY WALL NUTRITION The adventitia of all of the major elastic and muscular arteries contains vasa vasorum—i.e., small arteries, arterioles,
capillaries, and venous channels—which are presumed to participate in nutrition of the artery wall. Except for the aorta, however, precise relationships among vasa supply, vessel location, diameter, wall thickness, and architecture have not been established. The aortic media is nourished directly from the lumen and may also be perfused by means of vasa vasorum from the adventitial side. Passage through the lining endothelium is apparently sufficient to nourish the inner 0.5 mm of the adult mammalian aortic media, which corresponds to approximately 30 medial fibrocellular layers.[25] Thus, the aortic media of a small mammal such as the rat or rabbit, which is less than 0.5 mm thick and has fewer than 30 medial lamellar layers, contains no medial vasa vasorum and is nourished largely from the intimal side. Large mammals such as pigs, sheep, and horses have an aortic media with more than 30 medial lamellar layers. The inner 30 aortic layers in such species are avascular, but the remaining outer medial lamellar units contain vasa vasorum (Fig. 3-8). Aortic vasa vasorum arise from major arterial branches close to their origins and usually enter the media at right angles. Within the media, the vasa tend to be oriented axially in several branching levels. The average tension per medial lamellar unit for aortas that contain medial vasa tends to be somewhat higher than for aortas without vasa, suggesting that the presence of nutritive vessels within the media permits each lamellar unit to function at a somewhat higher level of tensile stress. The human abdominal aorta appears to be exceptional
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Part One. Assessment of Vascular Disease
Figure 3-6. Diagrammatic representation of microarchitecture of the wall of a muscular artery. The long axes of the smooth muscle cells (C) of the media are oriented circumferentially or perpendicular to the long axis of the artery. Cells are surrounded by a matrix (M) of basal lamina and collagen fibrils. Elastin fiber systems (E) are less prominent. Collagen bundles (F) are interspersed. Compared to elastic arteries (see Fig. 3-4), muscular arteries have a greater number of smooth-muscle cells and relatively fewer collagen and elastin fibers. (Adapted from Clark JM, Glagov S: Transmural organization of the arterial media: The lamellar unit revisited. Arteriosclerosis 5:19, 1985. With permission.[11])
when compared to aortas of other mammals, since it is more than 0.5 mm thick but contains fewer than 30 layers.[26] It is not furnished with medial vasa vasorum, although the estimated tensile stress per layer is in the range of those aortas with medial vasa (Fig. 3-9). The implication of this situation with respect to atherosclerosis and aneurysm formation are discussed below. Although mural stresses and deformations associated with hypertension may impair medial vasal flow,[27] the details of aortic media microarchitecture, which permit intramural vasa vasorum to remain open under normal conditions despite the cyclic compressive and shearing stresses within the artery wall, have not been clarified. Vasa vasorum have been identified in atherosclerotic arteries and, in particular, within atherosclerotic plaques. Although vasa vasorum in atherosclerotic plaques have been supposed to underlie disruptive lesion hemorrhages,[28] relationships
among lesion size, composition, and complications and the presence of vasa vasorum are not clear.
AGE-RELATED CHANGES IN THE ARTERY WALL Focal intimal thickenings, including cushions or pads at or near branch points, have been observed in infants and fetuses. Many of these tend to be modified and incorporated into the media during growth, and most are therefore likely to represent local changes in vessel wall organization related to redistributions of tensile stress associated with developmental changes in diameter, length, and geometric configuration.
Chapter 3. Pathophysiology of Human Atherosclerosis
37
thickened intima or in plaques may result in the accumulation of many layers of elastic fibers in the intima. In general, arteries tend to increase in diameter, elongate, and become tortuous with age. This diffuse, apparently irreversible enlargement, when marked, is called ectasia. The common form of diffuse and extensive ectasia of the aorta and large arteries parallels a relative overall increase in matrix fiber accumulation,[32] including an increase in collagen content, a decrease in elastin content, a calcification of the elastic fibers, and a decrease in compliance of the wall. While elongation and tortuosity of the vessel may be quite marked, the diffuse and extensive form of moderate ectasia is not necessarily associated with serious consequences. When complications occur, they are generally attributable to associated atherosclerosis and/or the formation of aneurysms.
STRUCTURE OF ATHEROSCLEROTIC LESIONS
Figure 3-7. Transverse section of superficial femoral artery. Note prominent adventitial (A) thickening and vasa vasorum (arrow ) penetrating through media (M) into plaque (P).
Progresssive fibrocellular diffuse intimal thickening, on the other hand, proceeds from infancy to old age, differing considerably in both extent and degree in different locations in the arterial tree.[29,30] This process tends to be more or less uniform about the vessel circumference and is not limited to areas about branch ostia, bifurcations, or the inner aspects of curves. Although the component cells tend to be oriented axially in straight portions of arteries, the organization and composition of thickened intima resemble to some extent that of the underlying media (Fig. 3-10). The lumen may not, however, be significantly narrowed by this process, for while the condition may produce an artery wall with an intima thicker than the media, the process tends to be concentric, accumulation of lipid is not a prominent feature, there is no focal stenosis, and the vessel lumen may actually be larger than normal. Diffuse intimal thickening is, nevertheless, especially evident in those vessels that tend to be susceptible to clinically significant atherosclerotic disease.[31] There is, however, little evidence to indicate that diffuse intimal thickening is necessarily a precursor of the formation of atherosclerotic lesions. With advancing age, the internal elastic lamina of the aorta and of the large arteries may show gaps, splits, and fragmentation as well as calcium salt deposits. In addition, neoformation of elastin within the
Atherosclerotic lesions may begin in childhood or adolescence and enlarge progressively over years or decades without associated symptoms. Although intimal plaques are evident in arteries of nearly all adults coming to autopsy in much of the world, little is known concerning the factors which determine individual differences in plaque morphology or govern the gradual or sudden transition from asymptomatic plaques to those which enlarge sufficiently to cause obstruction to flow, ulcerate, or induce occlusive thrombosis or aneurysm formation. On the basis of morphologic appearance and composition, human lesions are usually classified as fatty streaks or fibrous “raised” plaques. Transitional forms have also been identified. While fatty streaks are not associated with symptoms, raised plaques are more complex and are associated with the alterations which underlie circulatory compromise.
Fatty Streaks Fatty streaks are relatively flat, fairly well-demarcated patches or minute yellow foci which may appear soon after birth and are seen on the luminal surface of most aortas of individuals over the age of 3 years (Fig. 3-11).[33] Fatty streaks are found with increasing frequency between the ages of 8 and 18, becoming most numerous around puberty. These formations are not, however, limited to young persons and may be seen at any age adjacent to or even superimposed upon fibrous plaques. Fatty streaks consist largely of intimal lipid-laden cells (foam cells) and variable quantities of matrix materials beneath an intact endothelium. The extent to which fatty streaks are precursors of subsequent complex, fibrous, progressive atherosclerotic lesions remains unresolved.[34] There is evidence that many human fatty streaks may be evanescent, for the distribution of fatty streaks seen in young individuals does not coincide entirely with the distribution of fibrous plaques seen later in life. It has also been found that cells in human fatty streaks are not monotypic with respect to isoenzyme content, [35] but that advanced lesions are composed of cells which contain extensive regions of cellular
38
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Figure 3-8. Relationship between aortic medial lamellar architecture and vasa vasorum blood supply to outer portion of the media in different species. (From Glagov S: Hemodynamic risk factors: Mechanical stress, mural architecture, medial nutrition and the vulnerability of arteries to atherosclerosis. In Wissler RW Geer, JC (eds): The Pathogenesis of Atherosclerosis. Baltimore, Williams & Wilkins, 1972, pp 166 – 199. Reproduced by permission.[14])
Figure 3-9. The human thoracic aorta has medial vasa vasorum in the outer lamellae, and each lamellar unit supports approximately 2095 dyn/cm. The human abdominal aorta, however, has 28 lamellar units, has no medial vasa, and each lamellar unit supports about 3180 dyn/cm. This architectural difference may be important in the vulnerability of the abdominal aorta to atherosclerosis and aneurysm formation. (From Glagov S: Hemodynamic risk factors: Mechanical stress, mural architecture, medial nutrition and the vulnerability of arteries to atherosclerosis. In Wissler RW. Geer JC (eds): The Pathogenesis of Atherosclerosis. Baltimore, Williams & Wilkins, 1972, pp 166– 199. Reproduced by permission.[14])
Chapter 3. Pathophysiology of Human Atherosclerosis
Figure 3-10. Transverse section of coronary artery of 18-yearold accident victim demonstrating diffuse intimal thickening (I). Note that the organization and composition of the thickened intima resembles the underlying media (M). IEL represents the internal elastic lamina.
[36]
monotypia. These findings have suggested that focal events occurring in some fatty streaks may result in cellular proliferation with the persistence of lesions and the subsequent formation of the more complex fibrous plaques, while other fatty streaks resolve. Intimal thickening can reflect an adaptive response to diminish lumen caliber under conditions of reduced flow or can be a response designed to augment wall thickness when tensile stress increases.[37,38] Focal intimal thickenings have been observed in infants and fetuses at or near branch points and probably represent local remodeling of vessel wall organization related to growth and the associated redistribution of tensile stress.[39] Diffuse fibrocellular intimal thickening can occur as a more generalized phenomenon without a clear relationship to branches or curves and may result in a diffusely thickened intima that is considerably thicker than the media. Lipid accumulation is not a prominent feature in such intimal thickening, and the lumen remains regular and normal or slightly larger than normal in diameter.[40] Although there is little direct evidence that diffuse intimal thickening is a precursor of lipid-containing atherosclerotic plaques, both intimal thickening and plaques tend to occur in similar locations, and intimal thickening is
39
Figure 3-11. Fatty streaks in aorta of 45-year-old patient.
most evident in vessels that are especially susceptible to atherosclerosis.[41,42] Evidence has also been presented that diffuse forms of intimal thickening do not develop uniformly and that foci of relatively rapid thickening undergo dystrophic changes, which give rise to necrosis and other features characteristic of plaques.[43] The relationship of these findings to usual atherosclerosis remains to be defined.
Fibrous Plaques Fibrous plaques do not usually appear until the second decade of life and may not become the predominant lesion type until the fourth decade. The endothelial lining appears to be intact over most uncomplicated lesions, i.e., lesions without evidence of disruption, ulceration, hemorrhage, or thrombus formation. Although plaque composition varies considerably with respect to the relative proportions of the usual lesion components, a predominant mode of composition and organization can be discerned. There is frequently a relatively compact zone of connective tissue fibers and smooth-muscle cells immediately beneath the endothelium known as the fibrous cap (Fig. 3-12). Deeper in the central portion of the plaque and beneath the fibrous cap is a zone of variable composition and consistency known as the necrotic core or
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Part One. Assessment of Vascular Disease
Figure 3-12. (A ) Transverse section of superficial femoral arteries demonstrating fibrous plaque with prominent fibrous cap (F). Note thinning of media below the thickest portion of the plaque. Note the formation of a new elastic lamina (arrow ) near the lumen. (B ) Plaque with prominent necrotic center (N) medial thinning, and thickened adventitia (A). Note vasa vasorum (arrow ) penetrating into plaque and fibrous cap.
center. It contains amorphous debris, lipid-containing cells with morphologic and functional characteristics of either smooth-muscle cells or macrophages,[44] extracellular lipids including droplets and cholesterol crystals, calcium salts, and myxoid deposits. In addition, matrix fibers, including elastin, collagen, finer fibrillar material, and structures resembling basal lamina as well as amorphous ground substance, are evident. The fibrous cap may become quite thick and form a well-organized fibrocellular, layered structure, which may even include a subendothelial elastic lamina. Thrombi formed on lesions as well as librin deposits are also incorporated into lesions. Vasa vasorum penetrate from the adventitia or from the lumen to supply the plaque[45] and fibrous cap (Fig. 3-7) and to organize thrombotic deposits. There may be thinning and attenuation of the media below the intimal lesion such that the atheromatous deposit and the media bulge outward toward the adventitia. Some advanced lesions, particularly those associated with aneurysms, may appear to be atrophic and relatively acellular, consisting of dense fibrous tissue, prominent calcific deposits, and only minimal evidence of a necrotic center. Calcification is a prominent feature of advanced plaques and may be quite extensive, involving both the superficial and deeper reaches of the plaques. Although there is no consistent relationship between plaque size or complexity and the degree of calcification, calcific deposits are most prominent in plaques of older individuals and in areas, such as the abdominal aortic segment and coronary
arteries, where plaques form earliest.[46] Advanced lesions are called fibrocalcific, lipid rich, fibrocellular, necrotic, myxomatous, etc., depending on their morphologic features. The presence of large quantities of lipid, necrotic material, and cells would tend to make a lesion soft and friable, in contrast to the hard or brittle consistency of a mainly fibrocalcific lesion with an intact and prominent fibrous cap.
Lesion Complications Although it tends to isolate the advanced lesion from the lumen, the fibrous cap may be very thin or virtually absent. It may also be interrupted or disrupted focally, exposing underlying lesion contents to the bloodstream and favoring the formation of thrombi or the penetration of blood from the lumen into the lesion. Since advanced atherosclerotic lesions often contain vasa vasorum, these vessels may rupture and result in hemorrhage into the lesion and degeneration of plaque contents. Degeneration and ulceration of plaques is most common at the sites at greatest risk of advanced lesion formation. Thus, the consequences to the circulation of lesions in those areas derive not only from the tendency to progressive stenosis but also from the effects of lesion complications, leading to rapid or sudden local occlusion or to distal embolization of thrombi or atheromatous fragments. Direct relationships among lesion composition, age of the
Chapter 3. Pathophysiology of Human Atherosclerosis
lesion, lesion complication, and the presence of particular risk factors remain to be demonstrated. Excision of lesions obtained during surgical procedures and at autopsy have revealed complications which may be related spatially and temporally to documented clinical manifestations.[47] It should also be noted, however, that lesions studied at autopsy and not associated with known clinical manifestations may show evidence of earlier complications, including hemosiderin deposits from hemorrhages, partially organized thrombi, and inflammatory cells such as macrophages, lymphocytes, plasma cells, and giant cells.[48,49] These findings indicate that lesions may progress through stages potentially severe enough to induce clinical morbidity but that local tissue reactions may be adequate, at least temporarily, to contain the injury.
CONFIGURATION OF LESIONS The perception that advanced atherosclerotic lesions protrude or bulge into the arterial lumen is suggested by angiographic or ultrasonic views of arteries in longitudinal projections which reveal narrowing of the lumen. En face observations of the luminal surface of arteries opened at operation or autopsy also reveal plaques as projecting elevations, and transverse sections of unopened but undistended atherosclerotic arteries may show narrow, crescentic or slitlike arterial lumens. These perceptions may be somewhat misleading, for the absence of distending pressure results in partial collapse of the arterial lumen and corresponding deformation of both the artery wall and the plaque. Progressive distension of the normal aorta from zero to diastolic pressure results in a nearly twofold
41
increase in aortic radius, a fourfold increase in lumen crosssectional area, and a 50% reduction in wall thickness (see Fig. 3-3).[50] Similar findings are evident for other arteries. Beyond diastolic pressure there is little change in artery wall configuration or lumen diameter in keeping with the mechanical properties related to the connective tissue fiber content and organization of the media as outlined above. Examination of atherosclerotic arteries fixed while distended reveals that the lumen on transverse section is almost always round or oval and only rarely irregular, triangular, or slitlike.[51] Sequential transverse sections through distended vessels with narrowings on axial projections reveal that the lumen is round even in areas of marked stenosis. In addition, plaques are most often eccentric with respect to the cross section of the artery wall and, under conditions of normal distension, do not usually protrude into the lumen as moundlike projections but tend instead to bulge outward from the lumen. The luminal surface of the fibrous cap is therefore usually concave on transverse section, corresponding to the curvature of the adjacent uninvolved artery wall. As a consequence, the external or outer contour of the artery tends to become oval while the corresponding lumen remains circular (Fig. 3-13). As long as the fibrous cap is intact, the necrotic center is effectively sequestered from the lumen and the circular configuration of the lumen is preserved. Thus, while plaques may appear as focal projections into the lumen on angiographic images, cross-sectional views reveal rounded lumen contours and a concave luminal profile of the plaque.[52] Circular lumen profiles may also be evident in excised undistended and unopened rigid atherosclerotic arteries when plaques are completely encircling and largely fibrocalcific. Irregular transverse lumen contours on sonograms or distended arteries examined in cross section
Figure 3-13. Multiple transverse sections at 0.5-cm intervals through a 10-cm segment of superficial femoral artery. Despite the presence of large intimal plaques, the lumen remains rounded. The external vessel contour becomes oval as the artery locally dilates to accommodate the enlarging lesion.
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Part One. Assessment of Vascular Disease
generally correspond to recent or resolving plaque disruptions ulcerations, or thrombus deposition.
ENLARGEMENT OF ATHEROSCLEROTIC ARTERIES The formation of intimal plaque does not necessarily lead to stenosis and obstruction of the arterial lumen. Atherosclerotic arteries may compensate for increasing plaque deposits by enlarging, and such enlargement can maintain a normal or near-normal lumen caliber when the cross-sectional area of the intimal plaque does not exceed approximately 40% of the area encompassed by the internal elastic lumina.[53] Larger plaques tend to be completely encircling and result in lumen stenosis. Compensatory arterial enlargement has been demonstrated in human coronary arteries,[53 – 57] carotid arteries,[58,59] superficial femoral arteries,[60,61] and abdominal aortas.[62,63] Enlargement has also been demonstrated in experimental atherosclerosis in primates in the coronary,[64,65] carotid,[66] and superficial femoral arteries and in the coronary artery of pigs.[67,68] However, different segments of the arterial tree respond differently to increasing intimal plaque.[69] In the distal left anterior descending coronary artery, arterial enlargement occurs more rapidly than intimal plaque deposition. This may result in a net increase in lumen area rather than lumen stenosis in the most severely diseased arteries.[70] Individual variation has also been demonstrated in the superficial femoral artery.[71] Thus, it appears that the development of lumen stenosis, the maintenance of a normal lumen cross-sectional area, or the development of an increase in lumen diameter is determined by the relative rates of plaque growth and artery enlargement.[72] Reduction in artery size can also result in the development of lumen stenosis, and this phenomenon has been demonstrated in vivo with intravascular ultrasound.[73] Further study of this phenomenon of artery enlargement, or reduction in size, particularly in regions associated with great morbidity related to plaque deposition, is needed in order to fully understand the processes involved in the development of atherosclerotic stenoses and aneurysms. Although plaques may occur in straight vessels away from branch points, they are usually located at bifurcations or bends, where variations in hemodynamic conditions are especially likely to occur.[74] The mechanism by which this enlargement occurs is not clear. Possible explanations include the effects of altered blood flow on the segment of artery wall which is free of plaque formation or direct effects of the plaque on the subjacent artery wall. Normal arteries respond to changes in wall shear stress[75,76] with increase[77] or decrease[78,79] in lumen diameter. This response appears to be dependent on the presence of an intact endothelial surface[80] and may be mediated through endothelial-derived vasoactive agents.[81] Whether enlargement of atherosclerotic arteries in response to increasing intimal plaque occurs by a similar mechanism is unknown. Focal narrowing of the lumen caused by intimal plaque may result in a local increase in wall shear stress, which may stimulate endothelial-dependent arterial
dilation.[82] Since most atherosclerotic plaques are eccentric, the relatively uninvolved sections of artery wall may respond normally to shear stress stimuli despite an extensive lesion on the opposite wall. Under these circumstances, enlargement of the free wall would act to promote the further development of eccentricity. Adaptive enlargement may fail if the plaque becomes concentric and rigid with no responsive free wall. Alternatively, atherosclerotic artery enlargement may develop as a result of plaque-induced involutional changes in the underlying media. Thinning of the media is commonly seen beneath atherosclerotic plaques, and dissolution of the support structure of the artery wall may result in outward bulging of the plaque.[83] Under these circumstances, direct effects of the plaque on the underlying wall promote enlargement. The observation of apparent overcompensation with excess enlargement in the distal left anterior descending coronary artery in humans[54] is consistent with a direct effect of the plaque on the artery wall, as are morphologic evidences of outward plaque bulging. The balance between plaque deposition and artery enlargement is likely to be an important determinant whether lumen caliber remains normal or whether lumen stenosis or ectasia develops. In experimentally produced arteriovenous fistulae, the afferent artery has been shown to enlarge just enough to restore shear stress to baseline levels.[84] Wall shear stress thus appears to act as a regulating signal to determine artery size, and this response in dependent on the presence of an intact endothelial surface.[85 – 88] The response is mediated by the release of endothelial-derived relaxing factor or nitric oxide.[89,90] Thus the endothelium functions as a mechanically sensitive signal-transduction interface between the blood and the artery wall.[91,92] Nitric oxide (NO) plays an important role in both the acute and chronic increase in vessel caliber in response to increased flow.[93,94] Inhibition of NO synthesis by means of long-term oral administration of LNAME can inhibit flow induced arterial enlargement.[95,96] Atherosclerotic arteries are also capable of enlarging in response to increases in blood flow and increase in wall shear stress, but this process may be limited.[97] Atherosclerotic artery enlargement is further discussed later in this chapter. The nature and mechanisms of the artery wall –adaptive processes which allow arteries to adjust lumen diameter are currently being actively investigated. Understanding the mechanism and limits of the adaptive process and identification of the consequences for the vessel wall of shear stress that is persistently higher or lower than normal will be of value in clinical efforts to maintain normal lumen caliber.
LOCALIZATION OF ATHEROSCLEROTIC LESIONS Several major arterial sites are particularly prone to the development of advanced atherosclerotic lesions, while others are relatively resistant. The coronary arteries, carotid bifurcation, infrarenal abdominal aorta, and iliofemoral vessels are particularly susceptible, while the mesenteric, renal, intercostals, and mammary arteries tend to be spared.[98]
Chapter 3. Pathophysiology of Human Atherosclerosis
The apparently selective localization of plaques which evolve to cause clinical symptoms has been attributed to local differences in vessel wall metabolism, structure, and permeability and to differences in local hemodynamic patterns. Since many plaques tend to form in relation to branch points and bends where flow profiles have been shown to undergo deviations from unidirectional laminar flow, various flow features related to these changes have been implicated in plaque localization. These include elevated shear stress,[4] turbulence,[99,100] flow separation,[101] and low shear stress.[102,103] Elevated shear stress has been thought to contribute to plaque initiation by causing endothelial injury. The resulting exposure of intimal connective tissue to the bloodstream would favor platelet deposition and release of platelet growth factor, thereby including focal intimal thickening by stimulating smooth-muscle cell proliferation.[104] Variations in shear stress direction associated with pulsatile flow may favor increased endothelial permeability by direct mechanical effects on cell junctions, whereas relatively high unidirectional shear stresses may not be injurious[105] and may even favor endothelial mechanical integrity.[106] Endothelial cells are normally aligned in the direction of flow[107] in an overlapping arrangement.[108] Cyclic shifts in the relationship between shear stress direction and the orientation of intercellular overlapping borders may disturb the relationships between ingress and egress of particles through junctions. This hypothesis agrees well with reports of increased permeability of cultured, confluent endothelial cells subjected to changes in shear stress[109] as well as increased permeability to Evans blue dye in relation to differences in endothelial cell orientation,[110] which may be associated with different flow patterns. Oscillatory shear stress has also been shown to influence endothelium and nitric oxide synthase expression[111] as well as stimulate adhesion molecule expression in cultured human endothelial cells.[112] Heart rate has been implicated as an independent risk factor in coronary atherosclerosis and is discussed further in the section dealing with the coronary arteries. Reduction in heart rate in experimental atherosclerosis has been shown to retard carotid plaque progression.[113,114] Turbulence may, however, develop in association with stenoses and irregularities of the flow surface caused by atherosclerotic plaques, but turbulence is located distal to the lesion, not at the lesion. Experimentally produced stenoses reveal that turbulence is greatest two to four vessel diameters distal to the stenosis in an area that frequently develops poststenotic dilatation but does not readily develop diet-induced plaques.[115 – 117] Thus, turbulence per se has not been shown to be an initiating factor in atherogenesis. Nevertheless, turbulence may play a role in plaque disruption or thrombogenesis. Further investigation is needed to establish these relationships. Evidence that these are major initiating or sustaining mechanisms in human or experimental plaque formation has not been forthcoming. Experimental observations reveal no evidence of endothelial damage or disruption over early developing experimental foam cell lesions,[118] suggesting that endothelial denudation is not an important initiating factor in plaque pathogenesis.
43
Clinical observations suggest that plaques localize first in areas of low shear stress, such as on the upstream rather than downstream rim of aortic ostia (Fig. 3-14). Quantitative correlative studies of flow profiles and early plaque formation in the human carotid bifurcation suggest that flow separation, reduced flow rate, reduced shear stress, and departures from unidirectional laminar flow may be the important hemodynamic factors in plaque pathogenesis.[119] At the carotid bifurcation, for example, plaques do not begin in the vicinity of the flow divider where flow velocity is high, laminar, and unidirectional throughout the cardiac cycle. Plaques are formed earliest and are most advanced opposite the flow divider, where flow velocity and shear stress are low (Fig. 315). Under conditions of pulsatile flow, flow reversal occurs in the same area, particularly during the downstroke of systole with oscillation in wall shear stress direction.[120] These flowfield disturbances may be associated with prolonged residence time of atherogenic particles such as lipids or mitogens at sites which are prone to plaque formation. Although reduced velocity and shear stress, departures from unidirectional laminar flow, and flow reversal appear to favor plaque
Figure 3-14. Celiac (CEL) and superior mesenteric (SMA) ostia of human aorta. Note prominent plaque formation at upstream rim of the ostia with no plaque formation on the flow divider (arrows ), which is exposed to high shear stress.
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Part One. Assessment of Vascular Disease
mortality on both men and women.[124] The combined protective effects of increased flow velocity and reduced heart rate are consistent with the known protective effects of regular exercise against coronary artery disease in humans.
CAROTID BIFURCATION PLAQUES
Figure 3-15. Blood flow patterns in the human carotid bifurcation. There is a large area of show flow, flow separation, low shear stress, and disordered flow patterns in the internal carotid sinus opposite the bifurcation flow divider. Plaques localize in this area. The area of high shear stress at the flow divider is relatively spared of plaque formation. (From Zarins CK, Giddens DP, Glagov S: Atherosclerotic plaque distribution and flow velocity profiles in the carotid bifurcation. In Bergan JJ. Yao JST (eds): Cerebrovascular Insufficiency. New York, Grune & Stratton, 1983, pp 19 – 30. Reproduced by permission.)
formation, turbulence as such does not appear to be a factor. Areas of high turbulence such as occur immediately distal to experimental stenoses are not sites of preferential lesion formation.[121] Such findings also suggest that an increase in flow velocity and shear in a developing atherosclerotic stenosis could tend to retard further plaque formation. Since the development of complex flow patterns and shear stress reversal occurs during systole, an elevated heart rate may be expected to be associated with the acceleration of plaque formation at sites of predilection, for increased heart rate would prolong the relative time spent in systole. This effect would be expected to be particularly important in the coronary arteries, where systolic flow is biphasic. Experimental studies reveal that lowered heart rate has a profound effect on retarding the development of diet-induced coronary artery[122] and carotid artery[66,123] plaques. Clinical epidemiologic studies have revealed heart rate to be a primary independent risk factor for coronary and cardiovascular
Intimal thickening is found in the carotid sinus or carotid bulb early in life, and atherosclerotic lesions are common at this site in adults. Although extensive, complex, and complicated plaques may be present in the carotid bifurcation, particularly within the sinus, there is little plaque formation in the immediately proximal common carotid artery or the internal carotid artery immediately distal to the sinus. Within the bony canal in the base of the skull, lesions are unusual, but the basilar artery as well as the proximal segments of the cerebral arteries about the circle of Willis are commonly involved. The distribution of lesions about the bifurcation is probably associated with hemodynamic conditions which derive from the special geometry at this site.[119] The internal carotid sinus is a localized region which has a cross-sectional area twice that of the immediately distal internal carotid segment. This configuration in combination with the branching angle results in a flow profile in which a large area of flow separation is formed along the outer wall of the sinus (Fig. 3-15). Secondary and tertiary flow patterns, vortex formation, and oscillations in the angle of the flow vector occur at the side walls of the sinus.[120] Intimal plaques are deposited early in life in this region. As plaques enlarge at the outer wall, the geometric configuration of the lumen is modified so that other flow patterns may develop which favor plaque formation on the side and inner walls. In its most advanced and stenotic form the disease may involve the entire circumference of the sinus, including the region of the flow divider, but plaques are commonly largest and most complicated at the outer and side walls of the carotid bifurcation (Fig. 3-16). The hemodynamic conditions which exist at the carotid bifurcation may also influence the surface characteristics of existing carotid plaques and contribute to their tendency to ulcerate and embolize. Carotid plaques producing high-grade stenosis exhibit features of intraplaque hemorrhage, ulceration, thrombosis, lumen surface irregularity, and calcification.[125] These microanatomic features are present in plaques removed from symptomatic and asymptomatic patients and appear to be related to plaque size. Ulceration and surface thrombi that may lead to cerebral embolization are prominent features in markedly stenotic plaques even when symptoms are absent. These observations indicate that the disruptive processes that underlie plaque instability appear to be closely associated with plaque size rather than plaque composition.[126] Quantitative morphologic studies of human carotid bifurcations have demonstrated increased intimal thickness in association with lumen enlargement with resultant preservation of normal tangential mural tension.[127,128] The factors that differentiate a normal adaptive intimal thickening from an inappropriate intimal hyperplastic response resulting in lumen stenosis at a vascular anastomosis are not well understood. Techniques to precisely measure stresses in the
Chapter 3. Pathophysiology of Human Atherosclerosis
Figure 3-16. Longitudinal section of carotid endarterectomy specimen. Note marked plaque formation (P) on outer wall of internal carotid (IC) sinus. This corresponds to the area which is exposed to low flow velocity and low shear stress. The inner wall (arrow ) has minimal intimal thickening. External carotid (EC), common carotid (CC).
artery wall are now available and will help define the role of mechanical forces in artery wall response.[129,130]
AORTIC ATHEROSCLEROSIS Plaques are regularly found in the adult human thoracic aorta, but they are often less abundant, more discrete, less complicated, and less calcific than in the abdominal aortic segment of the same individual. Although plaques tend to deposit about intercostal branch ostia, significant occlusive lesions of the thoracic aorta do not develop and thoracic aorta aneurysms are unusual. The infrarenal abdominal aortic segment, on the other hand, is particularly prone to the early occurrence of plaques and occlusive disease as well as to the development of marked medial atrophy, calcification, and aneurysmal dilation with mural thrombus formation.
45
The differing susceptibilities of the thoracic and abdominal aorta to atherosclerosis and to aneurysmal dilation may be due to differences in architecture, composition, and nutrition of the artery wall as well as to differences in the distribution of mechanical stresses. As noted previously, the thoracic aorta is thicker and has a greater number of medial lamellar units than the abdominal aorta, in keeping with its greater diameter and tangential wall tension.[131] The thoracic aorta contains a greater relative proportion of elastin and a lower proportion of collagen than the abdominal aorta.[132] The increased stiffness of the abdominal aorta is associated with an elevated pulse pressure that could result in altered medial smooth muscle metabolism and increased susceptibility to plaque deposition.[133,134] In addition, differences exist with respect to wall nutrition that could result in different propensities to atherogenesis and to different responses of the media to mechanical stress.[135] The outer two thirds of the thoracic aortic media is well perfused by intramural vasa vasorum, whereas the inner 30 lamellar units are nourished by diffusion from the lumen. The abdominal aorta, however, is nourished only from the lumen and lacks medial vasa vasorum; moreover, the tension per layer is much larger than for the thoracic segment.[2] These factors may place the medial smooth muscle cells of the abdominal aorta at a relatively higher risk for ischemic injury. Intimal plaque formation may increase the diffusion distance from the lumen and induce reparative and healing processes, which may promote lipid uptake and further plaque formation. Penetration of vasa vasorum into atherosclerotic plaque has been demonstrated and may further promote a proliferative response in the artery. Thus, the composition and microarchitecture of the media and the metabolic state of the media smooth muscle cells may be important factors in determining differential susceptibilities of the aorta to atherosclerosis.[133] Flow conditions in the aorta may also predispose it to plaque formation. The thoracic aorta is exposed to relatively high rates of flow, with obligatory flow to the cerebral, upperextremity, and visceral arterial beds, including the renal arteries, which deliver one quarter of the cardiac output at rest. By contrast, blood flow in the infrarenal aorta may be highly variable, with volume flow largely dependent on muscular activity of the lower extremities. Under modern conditions of motorized transport and an increasingly sedentary lifestyle, the abdominal aortic segment is likely to be subjected to relatively reduced blood flow velocities over the long term. The abdominal aorta would therefore be exposed to the adverse hemodynamic forces of low flow velocity, low wall shear stress, prolonged particle residence time, and oscillation of wall shear.[136,137] Each of these factors would act to favor plaque formation.[138] Experimental flow studies in models of the human abdominal aorta reveal that these adverse hemodynamic conditions can be eliminated or minimized by hemodynamic conditions that prevail during exercise.[139]
ANEURYSM FORMATION The association between atherosclerosis and abdominal aortic aneurysm formation has long been recognized in humans. However, the mechanisms by which the atherosclerotic
46
Part One. Assessment of Vascular Disease
process may be associated with aneurysmal dilation are not well defined. A number of other etiologic factors have been proposed, including increased proteolytic enzyme activity[140 – 142] and genetic abnormalities leading to deficiencies in connective tissue structure and function.[143] Although some investigators have questioned a role for atherosclerosis in aneurysm formation, evidence for its importance is increasing. Most aneurysms are localized to the infrarenal abdominal aortic segment, where aortic atherosclerosis is usually most advanced. Plaque formation in this region may further impair diffusion of nutrients to the aortic wall, resulting in atrophy of the underlying aortic wall. Plaque deposition is accompanied by compensatory enlargement of the aorta, as described
earlier in this chapter. Under these circumstances, the plaque may provide structural support to the aortic wall. Subsequent plaque atrophy may leave an enlarged aorta with a thinned wall unable to support wall tension as aneurysmal enlargement progresses. Ingrowth of vasa vasorum into the media and plaque occurs commonly in occlusive aortic atherosclerosis (Figs. 3-17 and 3-18). However, under conditions where vasa vasorum are absent, impaired nutrition of plaque and media may result in atrophy of both the plaque and the artery wall with aneurysmal enlargement.[144] Experimental studies confirm the importance of the medial lamellar architecture in the pathogenesis of aneurysms[145] and reveal that diet-induced atherosclerosis may result in destruction of the media and in aneurysm formation.[146,147]
Figure 3-17. (A ) Transverse section of abdominal aorta demonstrating intimal plaque (P) with preservation of underlying media (M) with its lamellar architecture. Vasa vasorum (arrow ) are present in the media. (B ) Aneurysm with marked medial atrophy (M), delineated by arrows, fibrous plaque (P), and large mural thrombus (T).
Chapter 3. Pathophysiology of Human Atherosclerosis
47
SUPERFICIAL FEMORAL ARTERY STENOSIS
Figure 3-18. Obstructing plaques in the abdominal aorta are characterized by ingrowth of vasa vasorum to nourish the media and plaque. Aneurysms are relatively devoid of vasa with atrophy of the aortic wall. A deficiency of medial nutrition may be a factor in aneurysm pathogenesis. (From Zarins CK, Glagov S: Aneurysms and obstructive plaques: Differing local responses to atherosclerosis, in Bergan JJ, Yao JST (eds): Aneurysms: Diagnosis and Treatment. New York, Grune & Stratton, 1982, pp 61– 82. Reproduced by permission.[144])
A controlled trial of cholesterol-lowering therapy in monkeys revealed plaque regression, thinning of the media, and aneurysmal dilation of the abdominal aorta.[148] These observations suggest that the formation of abdominal aortic aneurysms may complicate the atherosclerotic process under special experimental and human clinical conditions. Aneurysms appear at a relatively late phase of plaque evolution, when plaque regression and medial atrophy predominate, rather than at earlier phases when cell proliferation, fibrogenesis, and lipid accumulation characterize plaque progression. Macrophages and proteolytic enzymes during this phase of atherosclerotic artery wall degeneration may provide the mechanisms whereby dissolution of the aortic wall occurs. Individual differences in plaque evolution reflecting differences in both the rate and duration of plaque formation and plaque regression and in tissue and cell responses to the atherogenic process are likely to be major determinants of individual susceptibility to aneurysm formation. Microarchitectural differences in artery wall structure as well as local mechanical conditions related to geometry, blood flow, and blood pressure are likely to be major determinants of aneurysm localization.[149] These factors may be modulated by genetic predisposition and by local injurious,[150] hemodynamic,[151] metabolic, and tensile stresses.
The arteries of the lower extremities are frequently affected by atherosclerotic plaques, while vessels of similar size in the upper extremities are spared. In addition to differences in hydrostatic pressure, the arteries of the lower extremities are subjected to more marked variations in flow rate, depending on the level of physical activity. Similar to the situation that prevails in the abdominal aorta, sedentary lifestyles would tend to favor low flow rates and lead to increased plaque deposition in vessels of the lower extremities. Cigarette smoking and diabetes mellitus are the risk factors most closely associated with atherosclerotic disease of the lower extremities.[152] The manner in which these factors and the special hemodynamic conditions are mutually enhancing in the vessels of the lower extremities remains to be elucidated. Of the arteries of the lower extremity, the superficial femoral artery is most commonly the site of multiple stenotic lesions, while the profunda femoris tends to be spared. The superficial femoral artery is a major conduit with relatively few proximal branches, and flow velocity is likely to be relatively slow on the average, varying in relation to activity of the calf muscles during walking or running. The profunda femoris is a smaller, muscular vessel with many branches to lower extremity muscles; flow velocity is likely to be relatively high under normal conditions. Plaques in the superficial femoral artery have not been shown to occur preferentially at branching sites, but stenotic lesions tend to appear earliest at the adductor hiatus, where the vessel is straight and branches are few (Fig. 3-19). Repeated mechanical trauma, limitations on vessel compliance, or alterations in the adaptive enlargement process associated with the closely applied adductor magnus tendon[60] may contribute to the selective localization of occlusive disease in this position.
CORONARY ARTERY ATHEROSCLEROSIS The coronary arteries are particularly prone to develop atherosclerosis.[153] The special hemodynamic features of the coronary circulation, including the marked excursions in flow rate during the cardiac cycle, the geometric configuration of the vessels and their branches, the mechanical torsion and flexions of the vessels associated with cardiac motion, and the special reactivity of coronary artery smooth muscle to vasoactive substances and nervous impulses, have been suggested as predisposing factors that could underlie individual differences in lesion distribution. The selective involvement of the left coronary artery opposite the flow divider at the bifurcation of the left circumflex indicates that hemodynamic relationships similar to those that prevail at the carotid bifurcation also occur in the coronary arteries. In addition, compared to other vessels, there are two pulses of flow during systole. Since the oscillatory changes in fluid shear are related to the downstroke phase of the systolic pulse,[120] an increase in heart rate may exert a greater effect
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Part One. Assessment of Vascular Disease
but related aspects of involvement.[155] These include the extent of the disease process, i.e., the degree to which a given artery segment or arterial bed is involved by the disease and/or the number of distinguishable lesions present in a vessel or group of vessels (Fig. 3-20). Irregularities and strictures of lumen contour on angiograms as well as on ultrasonic and axial tomographic images and the presence of calcifications have been considered to be major indicators of extent of disease. A second quantifiable feature that bears directly on the consequences to the circulation is the severity of the disease, as reflected in the degree of luminal stenosis. Usual estimates are expressed as percent stenosis, based on comparisons between lumen diameter at a definite narrowing and an immediately adjacent segment which appears to be uninvolved. Another discernible index of the atherosclerotic process, independent of both extent of involvement and severity of stenosis, is lesion complication. This includes ulceration, necrosis, thrombosis, and plaque hemorrhage. Finally, quantitative information concerning lesion composition may be obtained. This includes calcification, frequently revealed by clinical visualization methods, and estimates of
Figure 3-19. Focal stenosis of superficial femoral artery at adductor hiatus.
on atherogenesis in the coronary arteries than elsewhere in the arterial tree. Recent studies suggest that reduced heart rate retards the development of experimental, diet-induced plaques.[66,122,123,154] These observations are consistent with clinical observations of a reduced risk of cardiovascular mortality in men and women with a lower heart rate.[124]
QUANTITATIVE EVALUATION OF ATHEROSCLEROSIS Quantitative clinical assessment of atherosclerosis by modern diagnostic methods may include evaluation of several distint
Figure 3-20. Quantifiable aspects of atherosclerotic lesions. In light of developing techniques for assessing plaque size, configuration, and composition in vivo, use of more precise terms for the description of lesions could improve validation and clinical pathologic correlative studies. Extent implies degree of involvement of a particular vessel or arterial bed, while severity implies interference with flow and reduction of perfusion. Both stenosis (narrowing of the lumen) and complication (plaque disruption, hemorrhage, or thrombosis) determine severity regardless of the extent of disease. Lesion composition may be important in predisposing to complication.
Chapter 3. Pathophysiology of Human Atherosclerosis
lipid, cell, and matrix fiber content, usually estimated from histological sections. Most often, quantitative descriptions of atherosclerosis deal with the severity of disease, or percent stenosis, of a lesion imaged by angiography. Since angiography can only demonstrate the opacified artery lumen, the degree of stenosis is calculated by comparing lumen diameter at the narrowest point to an apparently “disease-free” area in the same vessel. In addition to errors in projection, resolution, and magnification, errors may arise if the apparently normal zone is involved by advanced intimal plaques. In comparing sequential angiograms, further errors may result if arteries dilate as atherosclerosis progresses. Such a response to progressing disease has been demonstrated in experimental[156] and human atherosclerosis.[52] Ultrasonic imaging of arteries has the capability of visualizing not only the lumen of the vessel but also the artery wall.[157] Other imaging techniques such as computed tomography and nuclear magnetic resonance have similar potential to visualize the plaque. It is important, however, to recognize the difference in definition of percent stenosis by these imaging techniques compared to angiography (Fig. 321) when assessing validation studies. Gross morphologic and histologic examinations of atherosclerotic arteries have the advantage of direct visualization and inspection of the lumen, plaque, and artery wall. However, redistension of the collapsed artery wall during fixation is necessary in order to restore in vivo configuration.[52] Failure to do so has led to a misperception that angiography “underestimates” the degree of stenosis when compared to postmortem examination.[158] Calculation of percent stenosis from histologic cross sections of arteries is usually performed by comparing the lumen cross-sectional area to the area encompassed by the internal elastic lamina, the presumed lumen size before the plaque developed (Fig. 321). This difference in definition of percent stenosis may make comparison to other methods difficult. In addition, if vessel enlargement occurred during plaque enlargement, the internal elastic lamina landmark may not accurately represent the “true lumen.” Furthermore, accurate quantitative correlation of plaque cross-sectional area as measured on histologic sections with in vivo clinical measurements requires corrections to account for tissue shrinkage during fixation and processing.[52] Although plaques may vary a good deal in composition, methods for assessing the distribution of plaque components in vivo are not yet sufficiently sensitive or specific to permit the establishment of criteria for predicting which lesions are likely to enlarge or ulcerate and which lesions will remain relatively stable. Methods that provide direct information about actual plaque size and composition are developing rapidly and are likely to gain increased application. These include real-time ultrasound imaging, reconstructions from computerized tomography, and nuclear magnetic reasonance and positron imaging. Thus, more accurate assessments of the extent of disease may be available in the future,
49
Figure 3-21. Different methods of measuring and defining percent stenosis.
including more quantitative in vivo measurements of lumen diameter, plaque and artery wall thickness, plaque composition, plaque disruption, and thrombosis. For the present, attempts to quantitate atherosclerotic disease in the living patient or from histologic sections in order to evaluate treatment programs dealing with prevention, regression, or early detection must take appropriate account of the features of plaque and vessel morphology outlined above. In particular, the outward sequestration effect, the persistence of a circular lumen which may approximate normal dimensions despite the presence of a large plaque, the association of plaque formation with enlargement of the vessel, and the need for fixation under pressure must be considered.
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Part One. Assessment of Vascular Disease Growth, and Compensatory Vessel Enlargement in Coronary Arteries of Miniature Pigs. Arterioscler. Thromb. Vasc. Biol. 1998, 18 (3), 415. Birnbaum, Y.; Fishbein, M.C.; Luo, H.; Nishioka, T.; et al. Regional Remodeling of Atherosclerotic Arteries: A Major Determinant of Clinical Manifestations of Disease. J. Am. Coll. Cardiol. 1997, 30 (5), 1149. Zarins, C.K.; Weisenberg, E.; Kolettis, G.; et al. Differential Enlargement of Artery Segments in Response to Enlarging Atherosclerotic Plaques. J. Vasc. Surg. 1988, 7, 386. Wong, C.B. Atherosclierotic Arterial Remodeling in the Superficial Femoral Artery: Individual Variation in Local Compensatory Enlargement Response. Circulation 1997, 95 (1), 279. Keren, G. Compensatory Enlargement, Remodeling, and Restenosis. Adv. Exp. Med. Biol. 1997, 430, 187. Smits, P.C.; Bos, L.; Quarles van Ufford, M.A.; Eefting, F.D.; et al. Shrinkage of Human Coronary Arteries Is an Important Determinant of De Novo Atherosclerotic Luminal Stenosis: An In Vivo Intravascular Ultrasound Study. Heart 1998, 79 (2), 143. Ravensbergen, J.; Ravensbergen, J.W.; Krijger, J.K.; Hillen, B.; et al. Localizing Role of Hemodynamics in Atherosclerosis in Several Human Vertebrobasilar Junction Geometries. Arterioscler. Thromb. Vasc. Biol. 1998, 18 (5), 693. Zarins, C.K.; Zatina, M.A.; Giddens, D.P.; et al. Shear Stress Regulation of Artery Lumen Diameter in Experimental Atherogenesis. J. Vasc. Surg. 1987, 5, 413. Kamiya, A.; Togawa, T. Adaptive Regulation of Wall Shear Stress to Flow Change in the Canine Carotid Artery. Am. J. Physiol. 1980, 239, H14. Masuda, H.; Bassiouny, H.S.; Glagov, S.; Zarins, C.K. Artery Wall Restructuring in Response to Increased Flow. Surg. Forum 1989, 40, 285. Guyton, J.R.; Hortley, C.J. Flow Restriction of One Carotid Artery in Juvenile Rats Inhibits Growth of Arterial Diameter. Am. J. Physiol. 1985, 248, H540. Singh, T.M.; Zhuang, Y.J.; Masuda, H.; Zarins, C.K. Intimal Hyperplasia in Response to Reduction of Wall Shear Stress. Surg. Forum 1997, 48, 445. Langille, B.L.; O’Donnell, F. Reductions in Arterial Diameter Produced by Chronic Decreases in Blood Flow Are Endothelium-Dependent. Science 1986, 231, 405. Furchgott, R.F. Role of Endothelium in Responses of Vascular Smooth Muscle. Circ. Res. 1983, 53, 557. Zarins, C.K. Adaptive Responses of Arteries. J. Vasc. Surg. 1989, 9, 382. Glagov, S.; Zarins, C.K.; Giddens, D.P.; Ku, D.N. Hemodynamics and Atherosclerosis: Insights and Perspectives Gained from Studies of Human Arteries. Arch. Pathol. Lab. Med. 1988, 112, 1018. Masuda, H.; Bassiouny, H.S.; Glagov, S.; Zarins, C.K. Artery Wall Restructuring in Response to Increased Flow. Surg. Forum 1989, 40, 285. Langille, B.L.; O’Donnell, F. Reductions in Arterial Diameter Produced by Chronic Decreases in Blood Flow Are Endothelium-Dependent. Science 1986, 231, 405. Pohl, U.; Holtz, J.; Busse, R.; Bassenge, E. Crucial Role of Endothelium in the Vasodilator Response to Increased Flow In Vivo. Hypertension 1986, 8, 37.
87. Hull, S.S.J.; Kaiser, L.; Jaffe, M.D.; Sparks, H.V.J. Endothelium-Dependent Flow-Induced Dilatation of Canine Femoral and Saphenous Arteries. Blood Vessels 1986, 23, 183. 88. Rubanyi, G.M.; Romero, C.J.; Vanhoutte, P.M. Flow Induced Release of Endothelium-Derived Relaxing Factor. Am. J. Physiol. 1986, 250, H1145. 89. Furchgott, R.F. Role of Endothelium in Responses of Vascular Smooth Muscle. Circ. Res. 1983, 53, 557. 90. Koller, S.; Sun, D.; Huang, A.; Kaley, G. Corelease of Nitric Oxide and Rotaglandins Mediates Flow-Dependent Dilatation of Rat Gracilis Muscle Arterioles. Am. J. Physiol. 1994, 267, H326. 91. Davies, P.F. Flow-Mediated Endothelial Mechanotransduction. Physiol. Rev. 1995, 75, 519. 92. Cooke, J.P.; Rossitch, E.J.; Andon, N.A.; Localzo, J.; Dzau, V.J. Flow Activates an Endothelial Potassium Channel to Release an Endogenous Nitrovasodilator. J. Clin. Investig. 1991, 88, 1663. 93. Holtz, J.; Fostermann, U.; Pohl, U.; Giesler, M.; Bassenge, E. Flow-Dependent, Endothelium-Mediated Dilatation of Epicardial Coronary Arteries in Conscious Dogs: Effects of Cyclooxygenase Inhibition. J. Cardiovasc. Pharmacol. 1984, 6, 1161. 94. Miller, V.M.; Burnett, J.C.J. Modulation of NO and Endothelin by Chronic Increases in Blood Flow in Canine Femoral Arteries. Am. J. Physiol. 1992, 263, H103. 95. Tronc, F.; Wassef, M.; Esposito, B.; Henrion, D.; Glagov, S.; Tedgui, A. Role of NO in Flow-Induced Remodeling of the Rabbit Common Carotid Artery. Arterioscler. Thromb. Vasc. Biol. 1996, 16 (10), 1256. 96. Guzman, R.J.; Abe, K.; Zarins, C.K. Flow-Induced Arterial Enlargement Is Uninhibited by Suppression of Nitric Oxide Synthase Activity In Vivo. Surgery 1997, 122, 273. 97. Glagov, S.; Weisenberg, E.; Zarins, C.K.; et al. Compensatory Enlargement of Human Atherosclerotic Coronary Arteries. N. Engl. J. Med. 1987, 316, 1371. 98. Roberts, J.C., Jr.; Moses, C.; Wilkins, R.H. Autopsy Studies in Atherosclerosis: I Distribution and Severity of Atherosclerosis in Patients Dying Without Morphologic Evidence of Atherosclerotic Catastrophe; II. Distribution and Severity of Atherosclerosis in Patients Dying with Morphologic Evidence of Atherosclerotic Catastrophe. Circulation 1959, 29, 511, 520. 99. Stehbens, W.E. The Role of Hemodynamics in the Pathogenesis of Atherosclerosis. Prog. Candiovasc. Dis. 1975, 18, 89. 100. Bharadvaj, B.K.; Mabon, R.F.; Giddens, D.P. Steady Flow in a Model of the Human Carotid Bifurcation. Part II. Laser Doppler Anemometer Measurements. J. Biomech. Eng. 1982, 15, 363. 101. Scharfstein, H.; Gutstein, W.H.; Lewis, L. Changes of Boundary Layer Flow in Model Systems, Implications for Initiation of Endothelial Injury. Circ. Res. 1963, 18, 580. 102. Caro, C.G.; Fitz-Gerald, J.M.; Schroter, R.D. Atheroma and Arterial Wall Shear: Observation, Correlation and Proposal of a Shear Dependent Mass Transfer Mechanism for Atherogenesis. Proc. R. Soc. Lond. [Biol.] 1971, 117, 109.
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Ku, D.N.; Giddens, D.P. Pulsatile Flow in a Model Carotid Bifurcation. Arteriosclerosis 1983, 3, 31. Bomberger, R.A.; Zarins, C.K.; Taylor, K.E.; Glagov, S. Effect of Hypotension on Atherogenesis and Aortic Wall Composition. J. Surg. Res. 1980, 28, 402. Beere, P.; Glagov, S.; Zarins, C.K. Retarding Effect of Lowered Heart Rate on Coronary Atherosclerosis. Science 1984, 226, 180. Bassiouny, H.S.; Zarins, C.K.; Hovanessian, A.; Glagov, S. Heart Rate and Experimental Carotid Atherosclerosis. Surg. Forum 1992, XLIII, 373. Kannel, W.B.; Kannel, C.; Paffenbarger, R.S., Jr.; et al. Heart Rate and Cardiovascular Mortality: The Framingham Study. Am. Heart J. 1987, 113, 1434. Glagov, S.; Zarins, C.K. What Are the Determinants of Plaque Instability and Its Consequences? J. Vasc. Surg. 1989, 9, 389. Bassiouny, H.S.; Davis, H.S.; Masawa, N.; et al. Critical Carotid Stenoses: Morphologic and Biochemical Similarity of Symptomatic and Asymptomatic Plaques. J. Vasc. Surg. 1989, 9, 202. Masawa, N.; Glagov, S.; Zarins, C.K. Quantitative Morphologic Study of Intimal Thickening at the Human Carotid Bifurcation: I. Axial and Circumferential Distribution of Maximum Intimal Thickening in Asymptomatic Uncomplicated Plaques. Atherosclerosis 1994, 107, 137. Masawa, N.; Glagov, S.; Zarins, C.K. Quantitative Morphologic Study of Intimal Thickening at the Human Carotid Bifurcation: II. The Compensatory Enlargement Response and the Role of the Intima in Tensile Support. Atherosclerosis 1994, 107, 147. Vito, R.P.; Choi, H.S.; Seitferth, T.A.; Zarins, C.K.; Glagov, S.; Bassiouny, H.S. Measurement of Strain in Soft Biological Tissue. Dev. Theor. Appl. Mech. 1990, 536. Vito, R.P.; Whang, M.C.; Giddens, D.P.; Zarins, C.K.; Glagov, S. Stress Analysis of the Diseased Arterial CrossSection. Adv. Bio-Eng. ASME 1990, 4, 273. Clark, J.M.; Glagov, S. Transluminal Organization of the Arterial Wall: The Lamellar Unit Revised. Arteriosclerosis 1985, 5, 19. Clark, J.M.; Glagov, S. Structural Integration of the Arterial Wall: I Relationships and Attachments of Medial Smooth Muscle Cells in Normally Distended and Hyperdistended Aortas. Lab. Investig. 1979, 40, 587. Stehbens, W.E. Hemodynamics and the Blood Vessel Wall; Charles C Thomas: Springfield, Illinois, 1979. Cozzi, P.J.; Lyon, R.T.; Davis, H.R.; et al. Aortic Wall Metabolism in Relation to Susceptibility and Resistance to Experimental Atherosclerosis. J. Vasc. Surg. 1988, 7, 706. Lyon, R.T.; Runyon-Hass, A.; Davis, H.R.; et al. Protection from Atherosclerotic Lesion Formation by Reduction of Artery Wall Motion. J. Vasc. Surg. 1987, 5, 59. Klocke, F.J.; Mates, R.E.; Canty, J.M.; et al. Coronary Pressure-Flow Relationships. Controversial Issues and Probable Implications. Circ. Res. 1985, 56, 310. Granata, L.; Olsson, R.A.; Huvos, A.; et al. Coronary Inflow and Oxygen Usage Following Cardiac Sympathetic Nerve Stimulation in Unanesthetized Dogs. Circ. Res. 1965, 16, 114.
54 138.
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Part One. Assessment of Vascular Disease Zarins, C.K.; Glagov, S.; Giddens, D.P.; Ku, D.N. Hemodynamic Factors and Atherosclerotic Change in the Aorta. In Aortic Surgery; Bergan, J.J., Yao, J.S.T., Eds.; Saunders: Philadelphia, 1988; 17 –25. Ku, D.N.; Glagov, S.; Moore, J.E., Jr.; Zarins, C.K. Flow Patterns in the Abdominal Aorta Under Simulated Postprandial and Exercise Conditions: An Experimental Study. J. Vasc. Surg. 1989, 9, 309. Dobrin, P.B.; Baker, W.H.; Gley, W.C. Elastolytic and Collagenolytic Studies of Arteries: Implications for the Mechanical Properties of Aneurysms. Arch. Surg. 1984, 119, 405. Menashi, S.; Campa, J.S.; Greenhalgh, R.M.; Powell, J.T. Collagen in Abdominal Aortic Aneurysm: Typing, Content, and Degradation. J. Vasc. Surg. 1987, 6, 578. Cohen, J.R.; Mandell, C.; Margolis, I.; et al. Altered Aortic Protease and Antiprotease Activity in Patients with Ruptured Abdominal Aortic Aneurysm. Surg. Gynecol. Obstet. 1987, 164, 355. Tilson, M.D. A Perspective on Research in Abdominal Aortic Aneurysm Disease with Unifying Hypothesis. In Aortic Surgery; Bergan, J.J., Yao, J.S.T., Eds.; Saunders: Philadelphia, 1989; 1st ed., 355 – 358. Zarins, C.K.; Glagov, S. Aneurysms and Obstructive Plaques: Differing Local Responses to Atherosclerosis. In Aneurysms: Diagnosis and Treatment; Bergan, J.J., Yao, J.S.T., Eds.; Grune & Stratton: New York, 1982; 61 – 82. Zatina, M.A.; Zarins, C.K.; Gewertz, B.L.; Glagov, S. Role of Medial Lamellar Architecture in the Pathogenesis of Aortic Aneurysms. J. Vasc. Surg. 1984, 1, 442. Zarins, C.K.; Glagov, S.; Wissler, R.W.; Vesselinovitch, D. Aneurysm Formation in Experimental Atherosclerosis: Relationship to Plaque Evolution. J. Vasc. Surg. 1990, 12, 246. Strickland, H.L.; Bond, M.G. Aneurysms in Large Colony of Squirrel Monkeys (Saimiri sciureus ). Lab. Anim. Sci. 1983, 33, 589.
148. Zarins, C.K.; Xu, C-P.; Glagov, S. Aneurysmal Enlargement of the Aorta During Regression of Experimental Atherosclerosis. J. Vasc. Surg. 1992, 15, 90. 149. Glagov, S.; Zarins, C.K. Pathophysiology of Aneurysm of Formation. In Aneurysms; Kerstein, M., Moulder, P.V., Webb, W.R., Eds.; Williams & Wilkins: Baltimore, 1983; 1 – 18. 150. Bomberger, R.A.; Zarins, C.K.; Glagov, S. Medial Injury and Hyperlipidemia in Development of Aneurysms or Atherosclerotic Plaques. Surg. Forum 1980, 31, 338. 151. Zarins, C.K.; Runyon-Hass, A.; Zatina, M.A.; et al. Increased Collagenase Activity in Early Aneurysmal Dilatation. J. Vasc. Surg. 1986, 3, 238. 152. Gordon, T.; Kannel, W.B. Predisposition to Atherosclerosis in the Head, Heart and Legs: The Framingham Study. J. Am. Med. Assoc. 1972, 221, 661. 153. Glagov, S.; Rowley, D.A.; Kohut, R. Atherosclerosis of Human Aorta and Its Coronary and Renal Arteries. AMA Arch. Pathol. 1961, 72, 558. 154. Beere, P.A.; Glagov, S.; Zarins, C.K. Retarding Effect of Lowered Heart Rate on Coronary Atherosclerosis. Science 1984, 226, 180. 155. Strandness, D.E.; et al. Workshop Overview. In Clinical Diagnosis of Atherosclerosis; Bond, M.G., Insull, W., Jr., Glagov, S., Eds.; Springer-Verlag: New York, 1983; 1 – 9. 156. Bond, M.G.; Adams, M.R.; Bullock, B.C. Complicating Factors in Evaluating Coronary Artery Atherosclerosis. Artery 1981, 9, 21. 157. Greene, E.R.; Eldridge, M.W.; Voyles, W.F.; et al. Quantitative Evaluation of Atherosclerosis Using Doppler Ultrasound. In Clinical Diagnosis of Atherosclerosis; Bond, M.G., Insull, W., Jr., Glagov, S., Eds.; SpringerVerlag: New York, 1983; 8 – 168. 158. Isner, J.M.; Kishel, J.; Kent, K.M.; et al. Accuracy of Angiographic Determination of Left Main Coronary Arterial Narrowing. Circulation 1981, 63, 1056.
CHAPTER 4
Epidemiology of Atherosclerosis and Its Modification Allen W. Averbook Samuel E. Wilson findings. The International Atherosclerosis Project (IAP), 1960–1965, confirmed findings from previous reports that the occurrence of raised arterial lesions ranged from a high of 18% for the white population in New Orleans to a low of 6% in African blacks.[12 – 14] Populations with a higher incidence of raised arterial lesions also showed a higher incidence of extensive coronary atheroma. Comparisons among geographic locations suggest that the extent of atherosclerotic lesions on postmortem examination reflects CHD mortality in the respective populations. The severity of atherosclerosis therefore is closely related to the frequency of clinically apparent CHD.[6] These early population studies also hinted at the varying influences of different risk factors that, at the time, were not well defined. The expression of atherosclerotic vascular disease is influenced by underlying racial differences as well as by the specific risk-factor differences between these groups.[15,16] Results comparing atherosclerotic lesions in 25- to 44-yearold men from Tokyo and New Orleans support the findings of earlier studies.[17,18] The coronary arteries and abdominal aorta of both black and white men from New Orleans showed significantly more raised, atherosclerotic lesions than did those of men from Tokyo. These results parallel the reported differences in mortality from CHD between the two countries. Other studies indicate that atherosclerosis is relatively milder in the Japanese living in Japan than among those living in Hawaii or among western whites.[14,19 – 21] These differences in severity of atherosclerosis between men in different geographic locations but of the same racial stock demonstrate the important contributions that environmental factors make in the development and expression of the disease between and within populations. The strong role that socioeconomic status plays in the development and progression of atherosclerotic vascular disease and the fact that this effect appears mediated through known atherosclerotic risk factors has been well documented.[22,23] Importantly, lower socioeconomic status can impact on the manifestations of atherosclerotic vascular disease early in its natural history. Genetics also plays a significant role in determining the degree, time course, severity, and anatomic pattern of the
INTRODUCTION Atherosclerosis has a predilection for the critical arterial beds: coronary, cerebral, renal, and aortoiliac. Its complications are the major cause of death in North America as well as in other economically developed societies.[1] Coronary heart disease (CHD) and cerebrovascular disease join cancer as the three leading causes of death in the United States.[2,3] The development of atherosclerotic lesions follows a variable course dependent on multiple influences. In the past decade much has been learned about these factors through study of the epidemiology, pathophysiology, clinical progression, and therapy of the disease in humans. An early study by Strong and McGill[4] demonstrated that atherosclerosis is the significant determinant of CHD in a population, a crucial underlying assumption of many studies that have used the severity of clinically manifested CHD as representative of the severity and extent of atherosclerotic disease. Risk factors for the development of the arterial lesions of atherosclerosis have been shown to be similar to those for clinically overt CHD, peripheral vascular disease and cerebrovascular disease.[5 – 11] The implication then is that many of the risk factors for these clinically diagnosed disease states are shared concomitants of atherosclerosis. More so, the outcomes derived from measurements of CHD have been considered applicable to other manifestations of atherosclerotic vascular disease in many studies. Although there is some variation of magnitude and role between the different risk factors identified and the various arterial beds affected by atherosclerotic changes, these associations have provided a useful tool for assessing risk factors and their potential modification.
SEXUAL AND RACIAL PREDISPOSITION Extensive studies of geographic differences in the prevalence of atherosclerotic lesions support Strong and McGill’s early
Hobson/Wilson/Veith: Vascular Surgery: Principles and Practice, Third Edition, Revised and Expanded DOI: 10.1081/0819-9-120024887 Copyright q 2004 by Marcel Dekker, Inc.
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atherosclerotic process.[24] The extent to which environmental and genetic factors each influence the development and expression of atherosclerotic disease is unclear; an interaction of both, though, is certain, as is demonstrated in studies of endothelial function and the different physiologic responses between races to various stimuli.[25,26]
RISK FACTORS AND ATHEROSCLEROSIS While never denying the role that genetic factors must play, epidemiologic studies have indicated the role of diet, lifestyle, and personal habits as being strongly influential in the pathogenesis and progression of vascular disease. As early as 1980, a decreasing incidence of coronary atherosclerosis in association with declines in mortality rates from CHD became evident.[27 – 29] Between 1968 and 1976, CHD mortality decreased by over 20% in adults aged 30 –74 in the United States.[30] The Minnesota Heart Survey[31,32] suggested that both preventive efforts and improved medical care had an impact on reducing CHD mortality in the Minneapolis – St. Paul area between 1970 and 1990 (Fig. 4-1). The downward trend in CHD mortality may be related to the concomittant improvement seen in multiple cardiovascular risk factors,[33] but a recent computer simulation analysis of the U.S. population between the ages of 35 and 84 years suggests that the decline in CHD-related mortality from 1980 to 1990 was only 25% related to primary prevention, whereas improvements in the treatment of patients with CHD contributed significantly more to this trend.[34] These statistics raise questions about the nature of risk factors and which ones are important influences on the development of atherosclerosis, as well as what are the most cost-effective methods to manage and prevent the development of vascular disease. Despite these encouraging trends, the death rate from complications of atherosclerosis in the United States is still very high. Risk factors may be independent causal agents, intervening variables, or indicators of other, more fundamental associations. The Pooling Project[35] described three principal risk factors: hypercholesterolemia, hypertension, and cigarette smoking. Other important risk factors have emerged, including diabetes mellitus, male sex, age, obesity, physical inactivity, specific behavioral patterns, familial history, hypertriglyceridemia, amount of alcohol consumption, hyperhomocystinemia, prothrombotic factors, and plasma fibrinogen. In evaluating an individual’s risk for atherosclerotic disease, the presence of risk factor clusters correlates with a particularly high risk of CHD. In the Pooling Project, the presence of more than one risk factor for CHD in men aged 30 –59 was found to have a synergistic effect (Table 4-l).[36,37]
Age There is a close relationship between age and the incidence and severity of atherosclerosis in both sexes.[12,38,39] This association is evident in all arterial beds affected by atherosclerosis.[40 – 42] Lower extremity arterial disease is associated with a 4–5 relative risk for all-cause mortality and
Figure 4-1. Age-adjusted death rates (per 100,000) for coronary heart disease in the population 30 – 74 years old. (From Gillum et al.[31] Reproduced by permission.)
progresses over time.[43] In a recent population study, the development of the fibrous plaque of the aorta was seen to be associated with advancing age.[44] In another study, the effects of aging on aortic morphology in populations with high and low prevalence of hypertension and atherosclerosis was performed via postmortem exam.[45] It was apparent that aging itself had a marked effect on aortic morphology (aortic circumference and intimal thickness) separate from but modified by both hypertension and the presence of atherosclerotic changes. This study also suggested that a decrease in tensile strength with advancing age rather than atherosclerosis alone contributes to the formation of abdominal aortic aneurysm. In contrast to aortic aneurysmal, femoropopliteal, and combined segmental disease, studies have demonstrated that atherosclerotic aortoiliac disease occurs more often in a younger population.[46] Death rates from CHD rise with each decade of life up to age 85. The death rate from CHD among white males aged 25 –34 is about 10 per 100,000; by ages 55 –64, it has increased 10-fold to nearly 1,000 per 100,000. It is interesting that death due to acute myocardial infarction (MI) seems to decline slightly after age 75. The relationship between the prevalence of atherosclerosis and age may be due to the time required for
Table 4-1. Ten-Year Age-Adjusted CAD Mortality Rates in Men Aged 30–59 at Entry by Number of Risk Factors Presenta—The National Cooperative Pooling Project No. of risk factors 0 1 2 3
Predicted additive rate/1000
Observed rate/1000
– – 33 43
13 23 44 82
Risk factors were any use of cigarettes, serum cholesterol $ 250 mg/dL, and diastolic blood pressure $ 90 mmHg. CAD = coronary artery disease. Source: From Criqui et al.[37] Reproduced by permission.
a
Chapter 4. Epidemiology of Atherosclerosis and Its Modification
the lesions to develop, but the duration of exposure to risk factors possibly accelerates atherogenesis.[12]
57
Ischemic Heart Disease Death Ratesa in the United States
Table 4-2.
Male
Female
Male Sex In a study of the populations of six different countries, variations across cultures were compared and the sex difference in high-density lipoprotein (HDL) cholesterol levels usually assumed to be related to biologic factors seemed related to environmental factors.[47] Nonetheless, the association between sex and risk for atherosclerosis is not a trivial one (Table 4-2). Fabris et. al.[48] studied 457 patients and found that the prevalence of carotid atherosclerosis was greater in men than in women in all age groups, as was the number of plaques and the severity of vascular narrowing. There was a high prevalence of asymptomatic carotid atherosclerosis in the general population, especially among the very old. One of the few prospective studies of a general population that evaluated cardiovascular disease in female as well as male subjects was the Framingham Study.[49] On the average, symptomatic coronary artery disease appeared 10 years later in U.S. women than in men. When this comparison was made on the basis of proven myocardial infarction (MI), the difference between the sexes increased to approximately 20 years. Also, the factors that influence the development of raised atherosclerotic lesions seem to act differently in the coronary arteries and in the aorta as well as in the two sexes.[38,39,50] While the incidence of CHD is much lower in women than in men for each of the four leading risk factors considered in the Framingham Study, the relationship of these risks to incidence of CHD is at least as strong for women as for men.[51] Interestingly, the sex differential is less apparent in nonwhites.[49,50] Sex differences in the extent of atherosclerotic lesions are striking in the white race and minimal in the black race. These differences are probably related to the influence of other ethnic or racially related risk factors. Myocardial infarction is uncommon in premenopausal women, but the rate of CHD is increased in women with a history of heavy cigarette smoking and diabetes, indicating the influence and complex interactions of other risk factors on the relative risk of CHD. Multiple studies evaluating estrogen use in postmenopausal women have suggested less of a risk for developing CHD than is seen in those who do not use hormone therapy. A recent clinical trial however, has challenged this hypothesis by showing an increase in cardiovascular events with a specific hormone replacement regimen. Indeed, large doses of estrogens also appear to increase cardiovascular mortality in men who have had one myocardial infarction as well as in men being treated for prostatic cancer with exogenous estrogens. Also, some investigators contend that oral contraceptives increase a female’s risk for cardiovascular disease. A large prospective study,[52] though, demonstrates that the use of oral contraceptive agents in the past does not raise a woman’s risk of subsequent cardiovascular disease. As we write in 2002, much needs to be discovered in this important area.
Hypertension Elevated blood pressure (BP), systolic or diastolic, is related to an increased incidence of CHD as well as to other
Age group
1960
1985
1960
1985
44– 54 55– 64 65– 74 75– 84 .85
347 885 1863 3637 6931
170 475 1111 2545 2659
72 296 915 2503 6009
43 163 514 1548 4643
a
Per 100,000 population. Source: Adapted from Levy, R. I. and Feinleib, M: Risk factors for coronary artery disease and their management, in Braunwald, E. (ed): Heart Disease: A Textbook of Cardiovascular Medicine. Philadelphia, Saunders, 1984, p 1205.
manifestations of atherosclerotic disease.[21,53 – 56] The Framingham Study suggested that hypertension is the principal vascular risk for all the complications of atherosclerosis, including arterial disease of the lower limbs.[57] It is an independent risk factor for claudication, approximately doubling the risk, and has been strongly associated with CHD after stratifying for other risk factors.[54,58] In the Framingham Study,[53] men aged 45 –62 with BP exceeding 160/95 had more than five times the incidence of CHD than did normotensive men (BP 140/90 or less). Also, the relationship between BP and the risk of developing CHD was found to be as strong in women as it is in men. Hypertension is a consistent and powerful contributor to coronary disease, with casual BP readings at any age being potent predictors of CHD.[35,49] The risk of cardiovascular death increases stepwise with the level of BP, beginning at quite low levels. There is a smooth, direct, linear relationship between the levels of BP and the risk of morbidity and mortality from cardiovascular disease (as well as from other atherosclerotic diseases) over the entire range of values measured under casual conditions; there is no specific critical value above which the risk of atherosclerotic disease increases and below which it decreases (Fig. 4-2).[51] It is noteworthy, then, that in the VA Cooperative Study,[59] antihypertensive therapy for diastolic BP exceeding 104 mmHg was shown to reduce the incidence of strokes and possibly also of CHD. But the benefits, measured as decreased morbidity and mortality, of treating mild hypertension (defined as a diastolic BP between 90 and 104 mmHg) were not demonstrated.[60,61] Whether or not lowering BP in those with mild hypertension will reduce mortality from MI and coronary disease in general remains unclear. However, in the Tecumseh study,[62] it was demonstrated that borderline hypertension is clearly associated with other risk factors for cardiovascular disease and with structural changes of the heart and blood vessels. The controversy persists as to whether, individually systolic or diastolic BP is more influential. The traditional teaching that the diastolic measurement is the more important component may no longer be valid (Table 4-3).[56,59,63,64] One study identified systolic hypertension as a risk factor of early
Part One. Assessment of Vascular Disease
58
significance. For example, obesity and alcohol intake both cause a significant increase in BP, while regular exercise in men of age 20 or above is associated with a decrease in BP.[41] The means by which hypertension induces atherogenesis is unclear. Various mechanisms have been hypothesized. Humoral mediators of BP may induce cellular changes or the shear stress of the flow of blood at selected anatomic sites within the arterial tree may result in focally altered endothelium and in the development of atherosclerotic lesions.
Cigarette Smoking
Figure 4-2. Actual and smoothed probability of cardiovascular disease (CVD) according to BP level: men and women aged 45– 64 years, Framingham Study. (From Kannel et al.[49] Reproduced by permission.)
atherosclerosis in the carotid artery by measuring intimalmedial thickness with ultrasonography.[65] As an individual predictor, BP has been found to be more reliable than cholesterolemia or cigarette smoking, especially after the age of 45. Other risk factors associated with CHD, though, also affect BP and its prognostic
The risk of cardiovascular death is high in the smoking population (Fig. 4-3), correlating with a strong and independent link to CHD.[55,56,66] The association of tobacco use with the extent and character of atherosclerotic peripheral arterial occlusive disease, aortic disease, and cerebrovascular disease is also well documented. When smoking is combined with other risk factors, there is a notable synergy yielding increased mortality from CHD.[67] The association between passive exposure to cigarette smoke and CHD mortality and morbidity is also becoming increasingly apparent.[68] Recent large trials have demonstrated the significant association of passive smoke exposure to CHD risk and the strong association between active smoking and acceleration of coronary disease along with new arterial lesion formation.[69,70] In the Framingham Study’s 30-year follow-up,[71] men who smoked one or more packs of cigarettes per day had a two to three times greater risk of having a first-time major
Table 4-3. Risk Factors: Systolic BP Versus Diastolic BP Study Veterans Administration Cooperative Study Group on Antihypertensive Agents[35]
Findings Persons with diastolic BP $ 115 mmHg have greater risk of developing organic complications associated with atherosclerosis
Subjects: male veterans Duration: varied The Western Collaborative Group Study[34]
Risk of CHD more strongly associated with systolic than diastolic BP
Subjects: 3154 males Duration: 8.5 years The Framingham Study[31] Subjects: 5209 male/female Duration: 20 years The Framingham Study of the Evolution of Atherothrombotic Brain Infarction[37]
Declining importance of diastolic BP relative to systolic BP with advancing age
Risk of stroke and CHD most closely linked to systolic BP or mean arterial pressure
Subjects/duration: as above The Pooling Project[23]
Risk for developing CHD proportional to BP over twofold range for both systolic and diastolic BP individually
Chapter 4. Epidemiology of Atherosclerosis and Its Modification
Figure 4-3. Age-adjusted mortality rates/thousand in men after 6 years for coronary artery disease (CAD) and cardiovascular disease (CVD) by smoking status. (From Criqui et al.[37] Reproduced by permission.)
coronary event than did nonsmokers, especially younger men (Table 4-4). As stated earlier, atherosclerotic aortoiliac disease occurs more often in a younger population as compared to other potentially involved segments. This may be due to the critical role that tobacco use plays in its development in the younger population (,60 years old).[72] The effect of smoking on peripheral vascular disease is also well documented.[73] There is an increased risk of developing intermittent claudication among smokers, and the risk is higher in diabetic smokers. The risk of peripheral arterial occlusive disease is increased two- to threefold among smokers and smoking correlates more closely with the
59
development of intermittent claudication than any other cardiovascular risk factor.[58] Importantly, smoking cessation is associated with an improvement in the symptoms of claudication.[73] In both peripheral arterial occlusive disease and CHD, the current number of cigarettes smoked each day is directly related to the risk of development and progression of the disease. Smoking tobacco is also significantly and independently related to the development and progression of carotid atherosclerosis and stroke.[74,75] The 1986 Honolulu Heart Program[76] study firmly demonstrated a strong relationship between cigarette smoking and stroke in men. It was not until the publication of two subsequent studies, however, that a significant causal role for cigarette smoking in stroke in middle-aged women was demonstrated. The relative risk for fatal stroke was found to be consistent in magnitude with that reported for men.[77] As in peripheral arterial occlusive disease and CHD, a graded dose-response relationship between smoking and cerebrovascular disease in both sexes independent of age and hypertensive status has been well established.[78] Those smoking more than 40 cigarettes per day have nearly twice the risk of stroke as those smoking fewer than 10 cigarettes per day. The risk of stroke is still high among ex-smokers as compared to nonsmokers, especially in the first 2 years after stopping, although it is lower than that for current smokers (Fig. 4-4). By 2 years after quitting, the risk decreases significantly; within 5 years after stopping, the risk reverts to the lower levels seen in nonsmokers, sooner than that noted in CHD.[78] These relationships between the development of carotid atherosclerosis and tobacco use and the significance of the number of pack-years smoked have been corroborated by studies utilizing carotid duplex in large samples.[41,79] It has also been demonstrated through B-mode ultrasonography that the development of carotid atherosclerosis may progress more slowly in people who have quit smoking as compared to those who continue to smoke, even after taking into account the effect of other risk factors.[80] Cessation of smoking will also dramatically reduce the rate of cardiovascular death in persons of all ages.[81 – 84]
Table 4-4. Risk of Cardiovascular Diseasea by Cigarette Smoking: 30-Year Follow-Up of the Framingham Study Men Age 35– 64 Years No. of cigarettes per day None 1 – 10 11– 20 21– 40 41– 90 All a
Women Age 65 – 94 Years
Age 35 – 64 Years
No. of events
Age-adjusted rate/1000b
No. of events
Age-adjusted rate/1000b
No. of events
Age-adjusted rate/1000c
No. of events
Age-adjusted rate/1000c
236 47 212 143 27 665
12 13 23 21 27 17
237 32 43 26 3 341
38 36 39 33 81 38
276 60 86 33 3 458
8 8 10 11 26 9
326 35 40 5 0 406
26 25 34 12 – 26
Cardiovascular disease: coronary heart disease, stroke, cardiac failure, peripheral arterial disease. p , 0:001: c Not significant. Source: Kannel et al.[71] Reproduced by permission. b
Age 65 – 94 Years
60
Part One. Assessment of Vascular Disease
Figure 4-4. Survival free of stroke in male and female cigarette smokers (dotted line ), nonsmokers (solid line ), and former smokers (dashed line ) aged 60 years, using Cox proportional hazard regression model. (From Wolf et al.[78] Reproduced by permission.)
There is consistent evidence that within 1 year of quitting tobacco, the risk of CHD attributable to smoking drops to about half that of those who continue to smoke. However, this reduced risk only approximates but never quite equals that of lifelong nonsmokers, and then only after a decade or more, according to most studies.[67,85] The cardiovascular risk declines more rapidly than that of lung cancer or emphysema.[67] The effect of cigarette smoking on both stroke and cardiovascular disease previously appeared to be due predominantly if not entirely to current or very recent smoking.[77] In the large population –based ARIC Study,[86] environmental tobacco smoke and active smoking were both found to increase the rate of progression of atherosclerosis by 20% and 50%, respectively. This may be a direct manifestation of cigarettes’ effect on blood coagulation by increasing levels of fibrinogen or other clotting factors or by enhancing platelet aggregability, as suggested by the observed relationship between cigarette smoking and acceleration of atherosclerosis via an effect on platelets.[87] Nonetheless, the ARIC Study demonstrated that the number of years smoking and that past smoking were less important than the total number of pack-years, suggesting that the adverse affects of smoking are cumulative and some progression of atherosclerotic disease appears irreversible.[86] The development of an abdominal aortic aneurysm (AAA) is also strongly associated with tobacco use, with an eightfold increased risk in heavy smokers as compared to nonsmokers. The findings of Witteman et al.[88] in a female population – based cohort regarding the association between smoking and AAA were supported and expanded by Lederle et al.’s ADAM Study.[89] In this large ongoing screening program designed to assess the appropriate management of moderatesized AAA, 1031 patients with AAA . 4.0 cm were identified. Smoking was the risk factor most strongly associated with the presence of AAA. This association increased significantly with the number of years of smoking and decreased significantly with the number of years after quitting. In Witteman’s study, a residual effect of smoking on atherosclerosis appeared to be present for at least 10 years following the cessation of smoking.[88]
Contrary to popular belief, cigarettes that are low in tar and nicotine have not been shown to lessen the cardiovascular morbidity and mortality associated with smoking.[90] In fact, in the Framingham Study, smokers who used filtered cigarettes possibly had an even higher incidence of CHD than did smokers of nonfiltered cigarettes. This was probably related to deeper and larger inhalations, thus compensating for the lower level of nicotine and negating the advantage of the filter. Also, the delivery of carbon monoxide has not been shown to be reduced by filters. A definite relationship between cigarette smoking and fibrinogen has been established.[91] Age-adjusted fibrinogen values in the Framingham Study were significantly higher in cigarette smokers than in nonsmokers, and they increased with the amount of tobacco smoked in each sex.[71] The risk of CHD increased with increasing fibrinogen values in both smokers and nonsmokers. There was no evidence of a greater impact in smokers than in nonsmokers (Table 4-5). Interestingly, multivariate analysis indicates that fibrinogen makes a stronger independent contribution than cigarettes to the occurrence of cardiovascular disease. A direct reversible relationship, though, was suggested, in that fibrinogen values increased in proportion to the amount smoked. The relationship of cigarette smoking to the occurrence of atherosclerotic cardiovascular disease must be attributable to some extent to the effect of smoking on fibrinogen levels, which in turn enhances thrombotic tendencies leading to occlusive clinical events. Cigarette smoking exerts a long-term effect (possibly via an atherogenic mechanism)[92] as well as a short-term triggering effect; it appears to exert this short-term effect by its influence on the incidence of lethal events that trigger sudden death in those who already have a compromised coronary circulation. This may occur through a thrombotic or hypoxic mechanism.[85] Nonetheless, cigarette smoking should still be considered an independent risk factor in the development of atherosclerosis. The epidemiologic data reviewed thus far is very compelling, and direct effects of tobacco’s by-products on the tissue of the heart, the vascular tree, and the blood have been demonstrated.[85,93 – 97] A dose-related and potentially revers-
Chapter 4. Epidemiology of Atherosclerosis and Its Modification
61
Risk of Cardiovascular Disease by Fibrinogen Level and Smoking Status: 14-Year Follow-Up of the Framingham Study (Subjects 48–80 Years of Age)
Table 4-5.
14-Year Age-Adjusted Rate/1000 Men Fibrinogen (mg/dL) 126– 264 265– 310 312– 696
Women
Nonsmokersa
Cigarette smokersb
Nonsmokersb
Cigarette smokersb
318 295 397
230 421 486
176 209 297
213 165 343
a
Trend not significant. Trend significant at p , 0:05: Source: Kannel et al.[71] Reproduced by permission. b
ible impairment of endothelium-dependent arterial dilation in asymptomatic young adults, consistent with endothelial dysfunction, was seen using noninvasive assessment of 200 subjects aged 15 –57 years old.[98] This phenomenon has also been demonstrated in a smaller sample of subjects in association with passive smoking.[99] The effect of long-term cigarette smoking on impairment of endothelium-dependent coronary vasodilatation is well documented. [100] The mechanism by which cigarette smoking stimulates atherogenesis is, however, controversial. High-density lipoprotein levels, which are associated with a decreased risk of atherosclerosis, are reduced in cigarette smokers in a doseresponse manner, but evidence suggests that cigarette smoking mainly influences the HDL3 subfraction, which is considered to be unrelated to CHD.[85,101,102] The Lipid Research Clinics Follow-Up Study[103] supported these findings by demonstrating via multivariate analysis that cigarettes are strongly linked to coronary artery disease and cardiovascular mortality while being independent of an HDL mechanism.
not been supported by studies of population groups.[109] The level of plasma cholesterol is measurably influenced by the dietary intake of total calories of cholesterol, saturated fat, and polyunsaturated fat. There are five major groups of cholesterol-bound lipoproteins, each with a different prognostic significance. The three that are of most concern are as follows:
Hyperlipidemia
The development, progression, and regression of atherosclerosis is closely related to the plasma cholesterol level. There is a direct relationship between diet, hyperlipidemia, and the development of CHD.[111] Dietary cholesterol intake from 0 to 600 mg/day correlates closely with plasma cholesterol levels. A high consumption of saturated fat is directly related to an increase in coronary artery disease; dietary saturated fatty acids elevate plasma cholesterol levels and detrimentally affect other coronary risk factors, whereas polyunsaturated and, more recently, monounsaturated fatty acids have been found to reduce them.[112 – 114] Proteins and carbohydrates are preferred substitutes for fat calories, being associated with a significantly decreased risk of new atherosclerosis lesions as compared to poly- and monounsaturated fat when total saturated fat intake is reduced.[115] Interestingly, emigrants from populations having low plasma cholesterol levels attain higher cholesterol levels, presumably because of the new diet, and an associated increase in the incidence of coronary disease comparable to those of their host populations within a few years of their emigration, as is been seen in Japanese e´migre´s to the United States.[116] It is still unclear whether beans, oat bran, and other forms of
Multiple prospective population studies have supported the thesis that elevated serum lipid concentrations contribute to the development of atherosclerosis.[55,56,104,105] Elevated total serum cholesterol level is an independent risk factor for the development of stroke as well as CHD.[106] Populations with relatively high levels of cholesterol have a higher mortality from CHD, and the probability of developing a myocardial infarction increases in proportion to the plasma cholesterol level. In the Honolulu (Hawaii) Heart Program,[107] 1480 men aged 65 years and older and free of coronary heart disease were followed up for an average of 12 years. In this study, serum cholesterol level was shown to be an independent predictor of coronary heart disease among men older than 65 years, disputing other reports that there is a diminished association between serum cholesterol level and coronary heart disease in the elderly. High serum total cholesterol levels have been identified as a risk factor for the development of atherosclerosis in the carotid, coronary, and peripheral arteries.[41,108] The theory that genetic factors are the predominant determinants of plasma lipid metabolism has
1.
2. 3.
LDL (low-density lipoprotein), which is about 70% total cholesterol and, when elevated, has the strongest association with CHD in both men and women.[110] Patients with increased LDL-C levels, and particularly increased LDL apolipoprotein B, have the greatest risk of premature atherosclerosis and present the greatest therapeutic challenge.[111] VLDL (very-low-density lipoprotein), which is strongly correlated with triglyceride levels. HDL (high-density lipoprotein), which is about 30% cholesterol and plays a role in transporting cholesterol away from the peripheral tissues—an action opposite that of LDL.
62
Part One. Assessment of Vascular Disease
soluble fiber lower total cholesterol or lipoprotein subfractions; only short-term data are available, and the results are inconclusive.[117 – 122] The North American population’s intake of cholesterol has declined since 1970 as a result of increased public awareness, and the polyunsaturate/saturate ratio in dietary fat has been increasing. Concurrently, there has been a definite downward trend in the plasma cholesterol levels of adult Americans. These trends have all coincided with a significant reduction (25–27%) in CHD mortality among persons 36 –74 years of age, further supporting the possibility of a causal relationship.[123 – 125] Dietary therapy can play a major role in reducing CHD events and decreasing progression of coronary atherosclerosis. Dietary modification studies have demonstrated that sustained decreases in serum cholesterol levels of 10–20% can be achieved by diet manipulation alone in dissimilar study groups.[104,126,127] Increased dietary cholesterol usually results in an increase in LDL cholesterol levels, with a lesser increase in HDL cholesterol levels. Serum levels of HDL are inversely related to the risk of coronary disease—the higher the level, the lower the risk of death from heart disease (Table 4-6).[110,128 – 130] In the Framingham Study, HDL cholesterol was a more important predictor of CHD than either total or LDL cholesterol. This was true for both men and women, where for each 1% rise in HDL there was a 2% reduction in the incidence of coronary artery disease.[110] More recently, findings have suggested that total LDL and HDL cholesterol levels in men 40 – 69 years of age with and without preexisting cardiovascular disease predict subsequent mortality.[131] The hypothesis that increased triglycerides is an independent cause of CHD remains controversial. While some studies did not initially support this relationship, more recent prospective studies do—the difference between the studies being related more to methodological concerns and statistical interpretations.[110,132 – 140] Triglycerides have also been shown to be an independent risk factor for stroke and coronary arterial disease in a Taiwanese population.[141] Elevated LDL cholesterol and triglyceride levels as well as low HDL levels are also strongly correlated with the development and progression of peripheral atherosclerosis. Elevated LDL cholesterol and triglyceride levels as well as low HDL levels are strongly correlated with development and progression of peripheral atherosclerosis.[142 – 145] The epidemiologic association between increased incidence of atherosclerosis and the increased intake of fat with concomitant changes in plasma LDL and HDL levels is very strong. Aside from dietary influences on HDL, alcohol consumption, cigarette smoking, obesity, and exercise may influence the serum level of HDL.[94] The HDL2 subfraction of the HDL lipoprotein is considered to be the protective subfraction.[128,146] It is this subfraction of HDL that is markedly elevated in women undergoing postmenopausal estrogen therapy, suggesting the mechanism by which estrogen exerts its documented cardioprotective effect in the postmenopausal female.[147 – 151] The cardiovascular death rates in the Lipid Research Clinics Follow-Up Study[152] were significantly lower for women taking postmenopausal estrogen; the protective effect appeared to be mediated by HDL (Table 4-7). However, lowered levels of plasma
Coronary Artery Disease Incidence per 1000 after 4 Years in Men and Women by Level of HDL Cholesterol— The Framingham Study
Table 4-6.
HDL, mg/dL
Men
Women
,25 25– 34 35– 44 45– 54 55– 64 65– 74 $75 All levels
176.5 100.0 104.5 51.0 59.7 25.0 0.0 77.1
0.0 164.2 54.5 49.2 39.7 13.9 20.1 43.6
Source: From Criqui.[37] Reproduced by permission.
cholesterol, triglycerides, LDL, and VLDL are also associated with postmenopausal estrogen use, suggesting a more complicated relationship.[150] The clinical utility of these findings is limited at this time, given the controversial association between postmenopausal estrogen use and endometrial cancer as well as the contradictory results denying any protective effect of estrogens on the incidence of CHD in men and in menopausal female smokers.[153 – 155] Population studies have also shown that HDL levels are increased by alcohol consumption in a dose-response manner, and alcoholics often have very high HDL levels (Table 4-8).[156,157] This may explain the protective effect for CHD observed in some studies with moderate alcohol consumption (Table 4-9). It is not clear, however, which HDL subfraction is most affected by alcohol; while some studies report an effect on HDL2, others find alcohol intake to affect only the HDL3 subfraction.[102,158] One prospective study suggests that with moderate alcohol consumption in middleaged women, the risks of CHD and ischemic stroke are decreased but the risk of subarachnoid hemorrhage is increased.[159] This does not imply that it is healthy to drink heavily. Coronary heart disease and related cardiovascular deaths as well as stroke and hypertension are more commonly observed with excessive alcohol consumption than with moderate drinking, probably indicating a complex interaction
Age-Specific and Age-Adjusted Cardiovascular Death Rates per 10,000 Person-Years by Estrogen Use at Baseline
Table 4-7.
Estrogen
Age, years 40– 49 50– 59 60– 69 70– 79 Crude rate, all ages Age-adjusted rate, all ages
Nonusers, n ¼ 1676
Users, n ¼ 593
0.0 19.0 46.3 159.6 30.9 41.8
0.0 5.5 8.1 67.8 10.1 12.4
Source: From Criqui et al.[37] Reproduced by permission.
Chapter 4. Epidemiology of Atherosclerosis and Its Modification 4-8. Mean High-Density and Low-Density Lipoprotein Cholesterol Levels According to Alcohol Consumption
Table
Alcohol, oz/week 0 1–3 4–9 10– 19 20+
No. of men
HDL-C,a mg/dL
LDL-C,b mg/dL
849 320 354 166 24
42.2 44.8 48.3 52.2 56.7
147.0 148.5 138.6 125.8 97.7
63
reduction in cholesterol was observed, correlating with a 39% decrease in coronary disease (Fig. 4-5). The reduction in cardiovascular risk was greatest in those patients with the greatest decreases in total cholesterol levels.[162] Some aspects of this study lead to questions about its full significance, since total mortality was similar in the two groups and the actual difference in CHD incidence after 7 years was only 7% in the treatment group compared with 8.6% in the placebo group. This amounts to an absolute difference in endpoints of only 1.7%—a very modest difference, despite the initial appearance of a major decrease in CHD incidence in the treatment group early in the study. Also, strict application of the results is limited to middle-aged men with type II hyperlipidemia. Despite some methodological concerns, this study strongly demonstrated the relationship between serum cholesterol and CHD. The results of this and other clinical trials were in agreement with predictions from some much longer running epidemiologic studies such as the Framingham Study. In the World Health Organization Cooperative Trial,[163] a reduction of total cholesterol was associated with a significant reduction in nonfatal myocardial infarction after 5 years. Despite the reduction in cardiovascular events, though, there was a significant increase in noncardiovascular morbidity and mortality with clofibrate therapy. In the Coronary Drug Project (CDP),[164] an excessive cancer and cardiovascular mortality was noted with the use of either estrogen or dextrothyroxine. Clofibrate and niacin were also evaluated in this study. Unlike the WHO Cooperative Trial, the short-term and long-term studies of clofibrate showed no beneficial effects on mortality or other cardiovascular events, although clofibrate therapy was associated with a reduction in total cholesterol levels similar to that seen in the WHO Cooperative Trial. Despite poor patient compliance with the niacin regimen (3 g/day), this therapy was associated with a significant reduction in total cholesterol levels and a significant reduction in nonfatal MI, although nearly identical death rates were noted for the niacin- and placebo-treated groups in the initial report. After a mean follow-up of 15 years,[165] almost 9 years after termination of the trial and possibly of niacin therapy, mortality from all causes was 11% lower in the niacin-treated patients than in the placebo group. These results may suggest a potential long-term benefit from a relatively short course of niacin therapy, with a significant
a
HDL-C = high-density lipoprotein cholesterol. LDL-C = low-density lipoprotein cholesterol. Source: From Kagan et al.[160] Reproduced by permission. b
of mechanisms and multiple risk factors, especially hypertension.[160] The full extent of the effect of alcohol consumption on cholesterol levels remains to be elucidated in a study designed specifically to address the role of alcohol in CHD. Many intervention trials have been conducted to determine whether reducing total cholesterol and, specifically, LDL, with diet and/or drug therapy can lower the incidence of CHD. In showing that this can be done, such studies further strengthen the thesis that there is a relationship between hypercholesterolemia and CHD (Table 4-10). A multicenter controlled study, the Lipid Research Clinics Coronary Primary Prevention Trial (LRC-CPPT),[161] evaluated the efficacy of the bile acid sequestrant cholestyramine (an agent effective in reducing cholesterol) on morbidity and mortality from CHD in middle-aged hypercholesterolemic men. All participants were placed on a cholesterol-lowering diet that reduced plasma total cholesterol by 3 –5%. A random half of the men were then given cholestyramine, while the remainder received placebos. Initially, with cholestyramine use after optimizing diet control, a reduction of plasma LDL and total cholesterol was seen as compared with the control group. Significant reductions in risk for fatal CHD or nonfatal MI were seen. A graded effect was observed. In those individuals who did not take the medication and had no reduction in cholesterol, there was no reduction in coronary risk. In the subgroup able to take the full dose of medication, a 19%
Table 4-9. Alcohol Consumption and Incidence of Coronary Heart Disease 6-Year CHD incidence, age-adjusted rate/1000 Alcohol consumption, oz/month 0 1–6 7 – 15 16– 39 40+ a
No. of men at risk
Total CHDa
CHD death and MIb
Acute CIc and angina
3565 1034 962 1024 1006
46.0 41.2 30.7 26.7 21.2
28.0 28.3 18.2 19.6 7.2
18.0 12.9 12.5 7.1 14.0
CHD = coronary heart disease. MI = myocardial infarction. c CI = coronary insufficiency. Source: From Kagan et al.[160] Reproduced by permission. b
64
Part One. Assessment of Vascular Disease
Table 4-10.
Intervention Trials
Trial
No. of subjects Duration (yr)
Drug used
Mean cholesterol reduction (%)
Reduction in CHD (%), endpoint
9 6 Clofibrate 10 Niacin 9
20 (nonfatal MI) 27 (nonfatal MI)
WHO CDP
15,745 3908
5 5
LRC-CCPT
3806
7.4
Clofibrate Niacin, estrogens, clofibrate Cholestyramine
Helsinki Heart Study
4081
5
Gemfibrozil
8
NHLBI Type II CIS
116
5
Cholestyramine
15
CLAS
162
2
CARE
4159
5
4S
4444
5.4
Colestipol þ niacin 26 (57% reduction in LDL/HDL ratio) Pravastatin 20% (mean LDL lowered by 28% and triglyceride by 14%; mean HDL increased by 5%) Simvastatin 25% (LDL lowered by 35%, triglyceride by 8%, HDL increased by 8%)
19 (nonfatal MI) 24 (CHD death) 37 (nonfatal MI) 34 (CHD events) 26 (CHD death) Outcomes determined by coronary angiogram only (see text)
WHO = World Health Organization Cooperative Trial;[163] CDP = Coronary Drug Project;[164] LRC-CCPT = Lipid Research Clinics Coronary Primary Prevention Trial;[161,162] Helsinki Heart Study;[168,182] NHLBI Type II CIS = National Heart, Lung, and Blood Institute Type II Coronary Intervention Study;[166,167] CLAS = Cholesterol-Lowering Atherosclerosis Study;[178] CARE = the Cholesterol and Recurrent Events Trial;[173] 4S = Scandinavian Simvastatin Survival Study.[172,309]
reduction in mortality evident years after discontinuation of therapy. The National Heart, Lung, and Blood Institute (NHLBI) Type II Coronary Intervention Study[166] was the first major report to indicate that pharmacologic intervention directed at lipids and an increase in the HDL/LDL ratio is associated with a decreased progression of coronary artery atherosclerosis. As demonstrated by serial angiograms, coronary artery disease progressed in 49% of placebo-treated patients as compared with 32% of cholestyramine-treated patients. Independent of the specific treatment group, progression of coronary disease was inversely associated with an increase in HDL-C and a decrease in LDL-C levels.[167] In the Helsinki Heart Study,[168] gemfibrozil therapy was extremely well tolerated; side effects were no more likely than with placebo therapy. The level of HDL-C increased by 10% and total cholesterol, LDL-C, and triglyceride levels decreased 8, 8, and 35%, respectively. Total deaths and cancer rates were no different in the two groups, but gemfibrozil was associated with a strongly significant reduction in CHD events. Similar to the LRC-CPPT results, total mortality during the study period was not reduced by gemfibrozil therapy, with only a 1.4% absolute difference in endpoints between study groups. Most of the early treatment studies were conducted using a population of middle-aged hypercholesterolemic men, and although epidemiologic data has always supported the role of hypercholesterolemia in CHD in most patient subgroups, the vigorous management of lipids for the prevention of CHD in women or in elderly persons was not supported by these intervention trials. More recent trials have included an older population and both sexes.[169 – 171]
The Scandinavian Simvastatin Survival Study (4S) evaluated a large cohort of patients with coronary artery disease for the effects of cholesterol reduction with simvastatin on mortality and morbidity.[172] The participants were started on lipid-lowering diets and randomized to receive either simvastatin or placebo. Another large secondary prevention trial, the Cholesterol and Recurrent Events (CARE) trial,[173] enrolled 2081 patients, including patients with usual cholesterol levels rather than elevated levels as was done in the other studies. The results of these studies further supported and elucidated those of their predecessors in that the reduction of cardiovascular risk was greatest in those patients with the greatest decreases in total cholesterol levels in a graded fashion. In the more recent trials this risk reduction was shown to apply even to a population of both sexes over the age of 59 years. These results strengthened the earlier findings of The Honolulu Heart Program [107] that elevated total cholesterol level is a risk factor for coronary artery disease in the elderly population, a conclusion that has been further substantiated by a recent population-based prospective study.[174] Of great importance, these statin drug trials demonstrated a reduction in total mortality with lipidlowering therapy, something that the earlier studies could not demonstrate.[169,173] Long-term results of coronary artery bypass operations are hampered by progression of disease in the native coronary circulation and by closure of saphenous vein grafts. Data from the Montreal Heart Institute[175] demonstrated a saphenous vein graft closure rate of 2% annually for the first 5 years and then 5.3% annually between years 5 and 10; at 10 years, the patency of saphenous vein grafts is only about 50%.[176] In a
Chapter 4. Epidemiology of Atherosclerosis and Its Modification
Figure 4-5. Relationship of reduction in low-density lipoprotein cholesterol (LDL-C) levels to reduction in coronary heart disease (CHD) risk (logarithmic scale). Risk reduction was estimated by comparing distribution of percent change in LDL-C levels among CHD cases to that among all participants in same treatment group. Dashed line represents reduction in CHD risk predicted by proportional hazards model for given decrease in LDL-C level in cholestyramine group. Estimates of percent reduction in CHD risk for men in cholestyramine group (solid circles ) and placebo (open circles ) group with differing degrees of LDL-C level reduction are compared with this line. Each point (except those at either extreme) is plotted at center of 5% interval of percent change in LDL-C levels that it represents. Points for open-ended strata at extremes are plotted at their approximate median values of percent change in LDL-C levels. (From Lipid Research Clinics Program.[161] Reproduced by permission.)
study of 82 patients 10 years after a bypass procedure, plasma levels of LDL, apolipoprotein B, HDL-C, LDL-C, and triglycerides were found to be strong predictors of both saphenous vein graft patency and progression of disease in the native circulation.[177] A subsequent study, the CholesterolLowering Atherosclerosis Study (CLAS),[178] evaluated whether aggressive lowering of LDL-C with a concomitant increase in HDL-C would affect the growth of atherosclerotic lesions in the native coronary arteries as well as in saphenous vein grafts. Through the use of diet, colestipol, and niacin in the treatment group, total cholesterol was reduced by 26%, LDL-C decreased 43%, and HDL-C increased 37%—in conjunction with a 57% reduction in the LDL/HDL ratio. By serial coronary angiography, the treatment group had a statistically significant reduction in progressive lesions in the native coronary arteries and saphenous vein grafts. Deterioration in overall coronary status was less in the drug-treated patients, and a significant regression in coronary atherosclerosis was also noted. The results of the statin trials are also now being correlated with angiographically proven slowing and in some cases prevention of development of coronary atherosclerosis in both native coronary vessels and saphenous vein bypass grafts.[179] Aggressive management of lipids in the secondary prevention of ischemic heart disease is thus
65
justified. A double-blind, randomized clinical trial with progression of early extracranial carotid atherosclerosis as an outcome variable was performed using 151 patients with coronary disease being randomized to placebo or pravastatin. B-mode ultrasound quantification of carotid artery intimalmedial thickness (IMT) was followed. Total cholesterol and LDL cholesterol plasma levels were both decreased in the pravastatin-treated patients while HDL2 cholesterol levels were higher. A nonsignificant 12% reduction in progression of the mean-maximum IMT and a statistically significant 35% reduction in IMT progression in the common carotid artery was seen along with a significant reduction in nonfatal and fatal coronary events.[180] In the Asymptomatic Carotid Artery Progression Study (ACAPS),[181] reduction of LDL cholesterol levels with lovastatin was seen in 919 men and women with asymptomatic corotid artery disease. This was a randomized, double-blind, placebo-controlled, factorially designed study in which the LDL cholesterol levels were reduced by 28% in the lovastatin group as compared to the placebo-controlled group. Concomitantly, a significant reduction in the progression of mean maximum IMT of the carotid arteries along with a decreased incidence of cardiovascular events was observed. Results of the major clinical trials of cholesterol lowering are consistent in showing that the greater the degree of cholesterol lowering, the greater the reduction in CHD risk. The results of these studies can be fitted to a regression line relating cholesterol reduction to decreased CHD risk. As a rough rule of thumb, a 1% reduction in cholesterol reduces the risk of developing CHD by 2%. Interestingly, in the Helsinki Heart Study,[182] there was a 4% fall in coronary artery disease for every 1% fall in cholesterol. This correlated with a 10% rise in HDL levels and an 8% fall in LDL. Therefore, in men with elevated LDL levels who were at high risk for coronary heart disease, a reduction of total cholesterol through a decrease in LDL levels diminished morbidity and mortality from CHD. Many early dietary studies gave suggestive but inconclusive results. Changes in recent diet habits that do not represent lifetime patterns may have little overall impact. Development of atherosclerosis occurs over a decade, diluting the significance of many studies that analyze diet and other factors over brief intervals. Some authors believe that the early prospective intervention studies failed to demonstrate statistically significant associations between diet and CHD risk. They felt that reduced mortality from CHD might have been due to a reduction in a variety of risk factors not accounted for, such as cigarette smoking.[183] The more current intervention studies are not without flaws, but the results are powerful. Old lipid-lowering drugs (fibrates, resins, niacin) have proven morbidity benefits, but the statins are efficacious and safe with proven mortality benefits. For these reasons, it has become apparent that lipid profiling as well as assessment of total cholesterol levels is very important. All but a few of the intervention trials looked at patients with significantly elevated plasma cholesterol levels. They demonstrated that a reduction of plasma cholesterol level is beneficial in a high-risk population. Most of the attributable cases of CHD, though, arise from people whose cholesterol values are average, not from the few in whom the
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concentration is conspicuously high. The CARE trial[173] and the Air Force/Texas Coronary Atherosclerosis Prevention Study[184] both demonstrate the significance of average total cholesterol levels in patients with coronary arterial atherosclerotic disease and describe the risk benefits of cholesterollowering therapy in these patients. These results supported and extended the findings of earlier epidemiologic studies that found the incidence of coronary atherosclerosis in a specific population to vary directly with the mean serum cholesterol level, regardless of the population examined.[185] Early in the Framingham Study, serum cholesterol levels of 265 mg/dL or above in men and women 35–44 years of age were associated with a five times higher risk of developing coronary artery disease than in those with levels below 220 mg/dL.[186] The Pooling Project[35] supported these findings and suggested that rates of CHD are relatively constant for cholesterol levels up to 200 –220 mg/dL, but above this threshold range the risk for CHD increases as cholesterol concentrations rise. These findings have been qualified by the Multiple Risk Factor Intervention Trial (MRFIT),[187] which studied a large male sample. The results showed unequivocally that the relationship between serum cholesterol and CHD is not a threshold one but rather a continuously graded one in which the risk of fatal CHD increases with serum cholesterol levels of about 180 mg/dL and above in a gradual manner; the threshold of 220 mg/dL is no longer accurate (Fig. 4-6). Importantly, in a recently published mortality follow-up of the MRFIT, 16 years after randomization, a continued mortality benefit of the multifactor intervention program, which included serum cholesterol reduction, was confirmed.[188]
Fish Consumption and Omega-3 Fatty Acids Another dietary concern is the relationship of omega-3 fatty acids, or fish oils, to the prevention of heart disease. Much of the interest in these fish oils began with the observation that despite their high-fat, high-cholesterol, low-carbohydrate diet, Greenland Eskimos, who eat cold-water fish, have a low incidence of cardiovascular disease, low plasma triglyceride and total cholesterol levels, and high concentrations of HDL cholesterol.[189,190] The fat found in cold-water fish is rich in long-chain, highly unsaturated omega-3 fatty acids. It has also been reported that Eskimos have decreased platelet aggregation and reactivity and a lower thrombotic tendency than do Danes, who eat a dairy- and meat-rich diet.[191] In addition to their lipid-lowering, antiaggregating, and viscosity effects, omega-3 fatty acids also decrease blood pressure, the magnitude of the change being dependent upon the dose given.[192,193] Thus, ingestion of omega-3 fatty acids shifts the physiologic balance in the direction of vasodilation and antiaggregation. Omega-3 fatty acids may also exert antiinflammatory effects via their inhibition of production of some leukotrienes as well as other immunomodulators, such as interleukin-1 and tumor necrosis factor.[194] The effects of these fish oils on lipid levels have been examined in a few studies with varying results. The hypolipidemic effect
Figure 4-6. Actual and smoothed probability of cardiovascular disease (CVD) according to serum cholesterol level: men and women aged 45 –64 years, Framingham Study. (From Kannel et al.[49] Reproduced by permission.)
observed varies with the dosage used. The evidence that cardiovascular disease can be prevented by the ingestion of fish oils taken in regular doses, however, has not been borne out. Reports in the literature are inconsistent regarding fish consumption and the risk of CHD. The effects of fish consumption on the development of myocardial lesions separate from the extent of atherosclerosis were assessed in a recent autopsy study. The protective effects of fish consumption appeared to extend to individuals relatively free of coronary atherosclerosis, possibly through hemostatic mechanisms.[195] Another recent study[196] demonstrated an inverse association between fish consumption and death from CHD. This observed relationship may not be due to omega-3 fatty acids since other studies have not demonstrated any evidence of omega-3 fatty acids affecting the progression of coronary atherosclerosis.[197] Components other than omega3 fatty acids may be contributing to the CHD risk reduction seen with fish consumption. The Honolulu Heart Program[198] questioned the discrepancy seen in the strength of cigarette smoking as a risk factor for CHD observed between populations. In looking at a cohort of Japanese men, a population with strong smoking habits but relatively fewer CHD risks as compared to some other smoking populations, a significant interaction of cigarette smoking/day and fish intake on CHD mortality was identified. The manner in which fish consumption may impact on cigarette smoking to lessen its risk for promoting atherosclerosis is unknown, but may be related to a diminution of tobacco’s prothrombotic effects.
Diabetes Mellitus More peripheral arterial, coronary, and cerebrovascular disease develops in diabetics than in nondiabetics. There is a twofold increase in the incidence of MI among diabetics as compared with nondiabetics as well as an increased tendency toward cerebral thrombosis. There is a two- to fourfold increased risk of developing intermittent claudication as compared to nondiabetics and an 8- to 150-fold increased frequency of gangrene of the lower extremity.[199] The association between diabetes mellitus (DM) and an increased incidence of myocardial infarction, atherothrombotic brain infarction, and intermittent claudication is well
Chapter 4. Epidemiology of Atherosclerosis and Its Modification
documented.[51,199,200] The Framingham Study showed that the risk of cardiovascular disease and death was greater in diabetic women than in men.[201] It appears that risk is mediated in part by the association of DM with hypertension and hyperlipidemia. Nonetheless, DM is also an independent risk factor for CHD and stroke.[201,202] Along with cigarette smoking, diabetes is one of the strongest risk factors for peripheral arterial disease.[203,204] The degree of glycemic control is not well correlated with the presence or severity of peripheral arterial disease,[205] but the associated risk factors of smoking and hyperlipidemia correlate strongly with disease severity.[205,206] The mechanism by which DM contributes to atherogenesis is poorly understood. Some prospective population studies on nondiabetic subjects have suggested that high plasma insulin levels are associated with an increased risk of CHD; other studies have suggested a relationship between the level of plasma insulin in patients with impaired glucose tolerance or NIDDM and atherosclerotic vascular disease.[207 – 211] Through ultrasonographic measurements of carotid intimal-medial wall thickness (an accepted and reproducible indicator of atherosclerosis), the ARIC study[212] demonstrated a positive association with diabetes (abnormal glucose metabolism). The nature of this relationship, whether hyperinsulinemia is an independent risk factor or dependent upon other factors such as hypertriglyceridemia in promoting the development and progression of atherosclerotic vascular disease, remains unanswered. It has been known for some time that there is a relationship between plasma insulin and triglyceride concentrations.[213] There appears to be an increased risk of CHD in persons with hyperinsulinemia associated with elevated plasma triglycerides, low plasma HDL, and elevated blood pressure.[214,215] Plasma insulin level has been shown to be a strong predictor of the HDL2 cholesterol level in specific populations, suggesting a causal relationship, although this may be more related to the obese rather than the diabetic state.[216] In support of an association between known coronary artery risk factors and non – insulin-dependent diabetes mellitus (NIDDM), a recent case-control study found that patients with a predominance of LDL subclass phenotype B, a known risk factor for coronary heart disease, had an increased risk for the future development of NIDDM.[217] This association was independent of age, sex, glucose intolerance, but not fasting triglyceride or insulin levels. Lipoprotein(a) [Lp(a)] levels appear to be independently associated with the development of coronary artery atherosclerosis in NIDDM.[218] Overall, there is no consistency in the studies evaluating whether elevated concentrations of plasma cholesterol and lipoproteins occur in diabetics whose concentrations of blood and urine glucose are carefully regulated. Also, some evidence suggests a decreased concentration of HDL levels in diabetics and a high prevalence of hypertension associated with hyperglycemia. This obviously raises doubts as to the independent influence that the hyperglycemia of diabetes has on the progression of atherosclerosis. It is even less clear whether borderline hyperglycemia is a risk factor, as evidenced by the equivocal results in numerous studies.[219,220] Some studies indicate that the fasting plasma glucose level, when measured as a continuous variable in nondiabetic patients, appears to be an independent risk factor
67
for cardiovascular mortality in men, but not in women.[220] No controlled clinical trials have been conducted to assess the effect of risk factor modification on the regression of vascular disease in the diabetic person, and much remains to be learned about the relationship between hyperglycemia, hyperinsulinemia, and the progression of atherosclerosis.
Obesity and Physical Inactivity Obesity is correlated with an increased risk of dying from the clinical complications of atherosclerosis. Obese individuals tend to have severe hyperlipidemia, with decreased HDL levels, sedentary lifestyles, hypertension, and DM.[128,221] The Framingham Study, though, suggests that obesity is a risk factor independent of such associations—a finding that has been inconsistently supported in the literature.[222,223] Prospective studies have demonstrated the influence of obesity on the development of CHD in women. After controlling for multiple risk factors, even mild to moderate overweight increased the risk of coronary disease in middleaged women.[224] The ARIC study looked at the association between body mass, waist-to-hip circumference ratio, and physical inactivity and asymptomatic carotid artery wall thickness.[212] It found that physical inactivity and abdominal adiposity were both positively associated with carotid intimal-medial wall thickness, suggesting a contribution by these factors to the atherogenic process. Of note, it is upperbody obesity rather than total body weight alone that is associated with an increased risk of CHD, possibly through an HDL2 mechanism.[216] There is little doubt that obese persons have an increased risk for CHD, but obesity is not as consistently predictive of ischemic heart disease in white men as would be expected if it were an independent risk factor.[225] A significant gain in weight may indirectly affect the atherosclerotic process by worsening one or more of the many atherogenic traits with which it has been associated, this effect being more pronounced in whites than in blacks.[226] Also, the debate continues as to whether obesity paradoxically has a protective effect against cardiovascular disease in persons with hypertension.[227,228] The loss of substantial body fat through either dieting or exercising alters plasma lipoprotein concentrations favorably, decreases triglyceride levels, and raises HDL and HDL2 cholesterol levels.[229] This has great significance, given the findings of the Helsinki Heart Study. Even without any associated weight loss, the beneficial effect of fitness, if not moderate exercise alone, in decreasing the mortality rate from heart disease was demonstrated.[230,231] In the Framingham Study,[232] the most sedentary men had about three times the risk for cardiovascular disease as compared to 15% of the most physically active. There was a trend of improved overall cardiovascular and coronary mortality with increased levels of physical activity among those of all ages, including the elderly. Properly prescribed physical activity can affect atherosclerosis and its sequelae. More energy expenditure seems to be associated with greater benefits in achieving regression of coronary atherosclerosis, but any activity is good. The benefits of exercise, though, are much less apparent
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if modification of other coronary risk factors is not also achieved.[233] Elevation of serum HDL—specifically the protective HDL2 subfraction—is seen with both weight loss and exercise.[102,146,221,234] This may account for the frequent observation in population studies that higher activity levels appear to be protective against CHD.[235] It is also known that other consequences of physical activity may protect from the effects of ischemic change, including increases in heart volume and mass, development of collaterals, and a decrease in heart rate.
Other Potential Risk Factors In addition to the major risk factors already discussed, studies have identified others, including elevated levels of apolipoprotein B and lipoprotein(a), homocysteine and fibrinogen, low antioxidant ingestion, periodontal disease, infectious agents, stress and behavior patterns, and blood viscosity.[236 – 238] Many of the associations of these factors with the development and progression of atherosclerotic disease appear to be mediated either independently or through their impact on different systems, such as lipid metabolism or the coagulation cascade.
Stress and Behavior Patterns The specific coronary-prone behavior profiles and the physiologic mechanisms linking behavior to CHD are still unclear. Stress, behavior patterns, and personality traits have received considerable attention for their possible roles in atherosclerosis. Statistical evidence appears to validate the commonly held belief that stressful life events influence the risk of coronary disease.[239] Several epidemiologic studies have described men with a type A personality (characterized by a chronic sense of urgency, competitiveness, ambitiousness, and hostility) as having a higher rate of CHD than men judged to be of the less competitive type B behavior pattern.[240 – 243] In these studies, a synergistic relationship between type A behavior and other coronary risk factors is postulated in the development of CHD. Other studies have not confirmed an association between this behavioral type and the incidence of CHD and cardiovascular death.[244,245] In a large study looking at the prevalence, incidence, and risk factors for intermittent claudication, stress and psychosocial coping factors were found along with more traditional risk factors to be associated with the development of intermittent claudication and therefore presumably peripheral vascular arterial disease.[246]
Hyperhomocystinemia Individuals with homozygous homocystinuria have abnormally elevated homocysteine levels and suffer from multiple medical problems including an accelerated form of atherosclerosis. In recent years it has become increasingly evident that a large percentage of patients with premature atherosclerosis have less dramatic elevations in plasma homocysteine levels that may arise from nutritional deficiencies and subtle genetic abnormalities.[247] Enzymes involved in the metabolism of homocysteine are dependent
upon the availability of vitamin B6 (pyridoxal phosphate) or B12 and folate. Deficiencies of any of these factors can induce homocystinemia and are probably the most common and easily corrected causes of homocystinemia. A strong association has been noted between increases in plasma homocysteine concentration and the risk of developing peripheral arterial disease.[248] A study that analyzed the possible association between homocysteine and the risk of ischemic stroke was inconclusive.[249] Noninvasive examination of the endothelium-dependent, flow-mediated dilation of the brachial artery have shown that hyperhomocystinemia is an independent risk factor for arterial endothelial dysfunction in healthy middle-aged adults.[250,251] Whether or not this is a mechanism by which premature atherosclerosis develops has not been defined, although as stated earlier, endothelial dysfunction has been hypothesized as one mechanism by which atherosclerosis develops and progressess. Hyperhomocystinemia is associated with smoking and low levels of vitamin B12 and folate.[252] A higher level of homocysteine is seen in patients with multilevel disease as compared to suprainguinal or infrainguinal disease.[252] In two large studies, the independent association of elevated plasma homocysteine levels with manifestations of vascular disease in the various arterial beds and the potential prevention of CHD in women by folate and vitamin B6 intake in doses greater than the current recommended daily allowances was significantly demonstrated.[253,254] Also, plasma homocysteine levels have been shown to strongly predict mortality in patients with angiographically confirmed coronary artery disease, even after adjusting for other significant cardiovascular risk factors.[255] Hyperhomocystinemia appears to be an independent risk factor for premature vascular disease in the coronary, cerebral, and peripheral arteries.
Antioxidant Vitamins Vitamin antioxidants include vitamins A, C, E, and b-carotene. The results from different studies have not been conclusive and the role of each of these antioxidants alone or in combination is unclear when looking at all the studies. The evidence strongly suggests a role for them in the development of atherosclerosis when their plasma levels are low. Some epidemiologic studies have demonstrated an inverse relation between coronary artery disease and especially vitamin E supplementation.[256,257] For example, the Prospective Basel Study[258] suggested that low plasma antioxidant levels contribute to an increased risk for developing ischemic heart disease and cerebrovascular disease. The variety of roles by which antioxidants might prevent clinical manifestations of CHD is still unclear, but a tendency to thrombosis, plaque stability, vasomotor function/endothelial dysfunction, and a reduced oxidation of LDL are all mechanisms that have been proposed by which antioxidants may play a protective role.[259] Elevated levels of LDL cholesterol is a major risk factor for atherosclerosis. The oxidative susceptibility of LDL and its proatherogenic role has been demonstrated in recent studies and is enhanced by known cardiovascular risk factors including diabetes,
Chapter 4. Epidemiology of Atherosclerosis and Its Modification
smoking, and hypercholesterolemia.[260] Antioxidant therapy may confer a benefit by decreasing LDL oxidation.[261] Randomized trial data are not yet sufficient to fully assess the risk-to-benefit ratios for antioxidant supplements. The possible role of antioxidants such as vitamins C and E and b-carotene in the primary prevention of cardiovascular disease is supported by basic research and various clinical studies, but results from several large-scale randomized trials are not consistent, and there is no definitive answer as to the value of antioxidant therapy in modifying atherosclerotic risk. Of the different antioxidant vitamins, vitamin E currently seems to hold the most promise.[256,262,263]
Miscellaneous Factors Controversy exists as to the possible association between total body iron stores (TBIS) measured as serum ferritin levels and the development and progression of atherosclerosis. In some studies, a declining ferritin level is associated with improvements in atherosclerotic disease, while a rising ferritin level is associated with disease progression.[264] Increased TBIS appeared associated with an increased risk for CHD and stroke.[265] The level of TBIS seemed to be a predictor of carotid atherosclerosis and has also been proposed to account for gender differences in the expression of atherosclerotic vascular disease.[266,267] The reduced risk of CHD in premenopausal women may be related to lower levels of TBIS rather to variations in sex hormones.[268,269] The ARIC[270] study investigated this possible relationship between body total iron stores and cardiovascular disease indirectly by sonographically looking at carotid arterial intima-media thickening as described earlier in this chapter. Using a matched case-control design with major cardiovascular risk factors, it concluded that increased body iron stores did not increase the risk of atherosclerotic cardiovascular disease. Infectious etiologies of atherosclerotic vascular disease development and progression have also been proposed including both viral and bacterial agents.[271,272] A relationship between cytomegalovirus (CMV) and other infectious agents in the development and progression of atherosclerosis has been demonstrated, but the nature of this association remains to be elucidated.[273 – 275] Immunologic mechanisms modulating atherosclerosis may relate to the infectious causes identified in some studies as contributing to the development and progression of atherosclerosis.[276,277] The identification of a relationship between dental caries, periodontal disease, and atherosclerosis also suggests possible mediation by infectious pathways.[278 – 280] Whether or not infectious/ inflammatory changes affect atherosclerosis via fibrinogen as an acute phase reactant or by other means is unclear.[281]
Thrombosis A thrombotic tendency may also be associated with the development of atherosclerosis, as already alluded to in this chapter. A relationship between fibrinogen and cardiovascular disease development and progression has been established.[209,282] The Framingham Study strongly supports the finding that elevated fibrinogen level is a predictor of the same magnitude as other well-accepted risk factors for cardiovascular
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disease and stroke.[283] The findings of the ARIC[284] study also support the role that thrombosis and defective fibrinolysis play in the progression of atherosclerotic lesions. Moderate alcohol consumption may affect the clotting system, and exercise may stimulate fibrinolysis.[285] Certain fish oils may reduce platelet aggregation and exert favorable effects on lipoprotein levels. The omega-3 fatty acids competitively inhibit synthesis of thromboxane A2 (a vasoconstrictor that promotes platelet aggregation) in the membrane of platelets.[286,287] The net effect is decreased platelet reactivity and documented increased bleeding times, as is seen in Eskimos. In one large population study comparing Japenese men and women to American men and women of mixed races, there was a statistically significant difference in plasma fibrinogen levels, with the Americans having higher plasma levels.[288] In this study, women’s plasma fibrinogen level was positively associated with menopause and inversely associated with the use of hormone replacement therapy.[288] Also, total fish intake was inversely associated with plasma fibrinogen in all sex-race groups with a statistically significant association seen in Caucasian men.[288] The antiplatelet effects of fish oils appear to be dose-dependent, but the overall effect of the omega-3 fatty acids on hemostasis remains unclear. Growing evidence points to the interdependence between clotting factors and lipids. Increased blood viscosity and plasma fibrinogen, along with the major fibrinolytic inhibitor a2-antiplasmin, have been reported in type II hyperlipoproteinemia.[289] Fibrinogen levels have also been correlated with serum cholesterol.[290] Arachidonic acid, a stimulator of platelet aggregation, has been noted to be released in greater concentrations from platelets incubated with cholesterol-rich liposomes as opposed to cholesterol-poor platelets.[291] The relationships are far from clear. Another risk factor associated with premature atherosclerosis, atherothrombotic disease, and a greater tendency for restenosis after interventional procedures is lipoprotein(a) [Lp(a)].[292 – 295] The addition of apoprotein(a) to a molecule that is otherwise identical to LDL cholesterol confers a property of adhering to fibrinogen and inhibiting fibrinolysis. This is not surprising because apoprotein(a)’s structure is very similar to that of plasminogen. Lp(a) is very atherogenic, and high levels seem to be a stronger predictor of peripheral arterial disease than reduced levels of HDL cholesterol or elevated levels of LDL cholesterol. Estrogen given to postmenopausal women does seem to reduce Lp(a) levels, as do high doses of niacin.[292,293] Most of the antilipid agents and dietary intervention alone seem, however, to be ineffective in modifying Lp(a) levels. Gender difference exists in the expression of serum lipoprotein levels in patients with advanced coronary artery disease.[296] In patients studied who had a similar severity of coronary disease, 60% of the women and only 39% of the men had serum Lp(a) levels higher than 25 mg/dL. Based on these findings and the age of the sample population, Lp(a) level seemed to be a risk factor for coronary artery disease mostly in older (postmenopausal) women.[296] Lipoprotein(a) is a recently described lipoprotein fraction that is an independent risk factor for atherosclerosis in coronary and peripheral beds.[297 – 300] This association may be racially dependent in that the studies done have shown that
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elevated plasma concentration of Lp(a) is not an independent risk factor for coronary artery disease in African-Americans as it seems to be in the Caucasian populations.[301]
CONCLUSIONS Clinical research in atherosclerotic epidemiology has focused on cardiovascular disease, specifically CHD. The same risk factors, however, apply in general to cerebrovascular disease, aortoiliac disease, and other forms of peripheral vascular disease. The preponderance of data compiled to date has demonstrated a common set of precursors to all the major atherosclerotic diseases, whether manifest in the brain, the heart, or peripherally. In assessing risk for cardiovascular disease, consideration of only a single risk factor to detect persons at high risk may not be sufficient. Further, the relative importance of different risk factors varies according to the anatomic location and morphology of the lesion. Atherosclerotic changes appear in the coronary arteries years or decades before the age at which CHD becomes a clinically
recognized problem.[302] Atherosclerotic lesions in the coronary arteries, some causing narrowing or even occlusion, are found in young men in their 20s and 30s who have no symptoms of CHD. The lesions were commonly located at or near points of bifurcation. The occlusive process assumes distinctive characteristics in the four major arterial beds, and the development of these patterns is based on an interplay between genetics, environment, and physiologic forces.[303 – 308] Atherogenesis is a multifactorial process involving the interaction of blood lipids, metabolism of the arterial wall, and hemodynamic factors. The atherosclerotic process increases with age and is influenced by racial, geographic, and dietary factors. Risk factors, including hyperlipidemia, hypertension, diabetes mellitus, smoking, and obesity, determine to what extent the disease will manifest clinically. Anatomic distribution of the lesions follows reproducible patterns in most patients, with changes in plaque morphology contributing to the development of complications and symptoms. Current management concepts favor prevention, by minimizing risk factors, even for patients treated successfully by operation, since regression of the disease is unusual in the continuing presence of these readily identifiable risk factors.
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Venous Occlusion in Healthy Adults. N. Engl. J. Med. 1980, 302, 987. Thorngren, M.; Gustafson, A. Effects of 11-Week Increases in Dietary Eicosapentaenoic Acid on Bleeding Time, Lipids, and Platelet Aggregation. Lancet 1981, ii, 1190–1193. Knapp, H.R.; Reilly, I.A.; Allessandrini, P.; FitzGerald, G.A. In Vivo Indexes of Platelet and Vascular Function During Fish-Oil Administration in Patients with Atherosclerosis. N. Engl. J. Med. 1986, 314, 937–942. Iso, H.; Folsom, A.R.; et al. Plasma Fibrinogen and Its Correlates in Japanese and U.S. Population Samples. Arterioscler. Thromb. 1993, 13 (6), 783– 790. Lowe, G.D.O.; Stromberg, P.; Forbes, C.D.; et al. Increased Blood Viscosity and Fibrinolytic Inhibitor in Type II Hyperlipoproteinaemia. Lancet 1982, 1, 472. Korsan-Bengtsen, K.; Willhelmsen, L.; Tibblin, G. Blood Coagulation and Fibrinolysis in a Random Sample of 788 Men 54 Years Old. Thromb. Diath. Haemorrh. 1972, 28, 99. Stuart, M.J.; Gerrard, J.M.; White, J.G. Effect of Cholesterol on Production of Thromboxane B2 by Platelets In Vitro. N. Engl. J. Med. 1980, 302, 6. Hajjar, K.A.; Nachman, R.L. The Role of Lipoprotein(a) in Atherogenesis and Thrombosis. Annu. Rev. Med. 1996, 47, 423– 442. Maher, V.M.; Brown, B.G. Lipoprotein(a) and Coronary Heart Disease. Curr. Opin. Lipidol. 1995, 6, 229– 235. Liu, A.C.; Lawn, R.M. Vascular Interactions of Lipoprotein(a). Curr. Opin. Lipidol. 1994, 5, 269– 273. Kario, K.; Matsuo, T.; et al. Close Relation Between Lipoprotein(a) Levels and Atherothrombotic Disease in Japanese Subjects .75 Years of Age. Am. J. Cardiol. 1994, 73 (16), 1187– 1190. Stiel, G.M.; Reblin, T.; et al. Differences in Lipoprotein (a) and Apolipoprotein(a) Levels in Men and Women with Advanced Coronary Atherosclerosis. Coron. Artery Dis. 1995, 6 (4), 347– 350. Valentine, R.J.; Kaplan, H.S.; et al. Lipoprotein(a), Homocysteine, and Hypercoabulable States in Young Men with Premature Peripheral Atherosclerosis: A
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Prospective, Controlled Analysis. J. Vasc. Surg. 1996, 23 (1), 53 – 61. Takami, S.; Kubo, M.; et al. High Levels of Serum Lipoprotein(a) in Patients with Ischemic Heart Disease with Normal Coronary Angiogram and Thromboangiitis Obliterans. Atherosclerosis 1995, 112 (2), 253– 260. Budde, T.; Fechtrup, C.; et al. Plasma Lp(a) Levels Correlate with Number, Severity, and Length-Extension of Coronary Lesions in Male Patients Undergoing Coronary Arteriography for Clinically Suspected Coronary Atherosclerosis. Arterioscler. Thromb. 1994, 14 (11), 1730. Schreiner, P.J.; Morrisett, J.D.; et al. Lipoprotein[a] as a Risk Factor for Preclinical Atherosclerosis. Arteioscler. Thromb. 1993, 13 (6), 826– 833. Moliterno, D.J.; Jokinen, E.V.; et al. No Association Between Plasma Lipoprotein(a) Concentrations and the Presence or Absence of Coronary Atherosclerosis in African-Americans. Arterioscler. Thromb. Vasc. Biol. 1995, 15 (7), 850– 855. Enos, W.F.; Holmes, R.H.; Beyer, J. Coronary Disease Among United States Soldiers Killed in Action in Korea. J. Am. Med. Assoc. 1953, 152, 1090. Strong, J.P.; Restrepo, C. Coronary and Aortic Atherosclerosis in New Orleans. Lab. Investig. 1978, 39, 358. DeBakey, M.E.; Lawric, G.M.; Glaeser, D.H. Patterns of Atherosclerosis and Their Surgical Significance. Ann. Surg. 1985, 201, 115. The Progression of Atherosclerosis. Lancet 1985, i, 791. Montenegro, M.R.; Eggen, D.A. Topography of Atherosclerosis in the Coronary Arteries. Lab. Investig. 1968, 18, 586. Solberg, L.A.; Eggen, D.A. Localization and Sequence of Development of Atherosclerotic Lesions in the Carotid and Vertebral Arteries. Circulation 1971, 43, 711. Haimovici, H. Atherogenesis: Recent Biological Concepts and Clinical Implications. Am. J. Surg. 1977, 134, 174. Scandinavian Simvastatin Survival Study Group; Baseline Serum Cholesterol and Treatment Effect in the Scandinavian Simvastatin Survival Study (4s). Lancet 1995, 345, 1274– 1275.
CHAPTER 5
Hemodynamics of Abnormal Blood Flow David S. Sumner kinetic energy and vice versa with each change in velocity and direction. All along the way—but in some regions more than others—energy is converted into heat and is thus “lost.” By the time the blood returns to the right atrium, it has given up most of its potential energy but still retains some kinetic energy. Arterial obstruction accelerates the dissipation of energy and interferes with the smooth operation of this system by creating discontinuities in the energy gradient (Fig. 5-1).
To remain viable and to maintain proper function, all living cells depend on an adequate supply of nutrients and the efficient removal of metabolic products. In all except the most primitive organisms, blood is the vehicle for transporting these substances and the blood vessels are the conduits. Lesions within the human arterial tree produce symptoms and signs only when the integrity of the vessel wall is violated, allowing blood to escape, or when transportation is impaired sufficiently to compromise the viability or function of the tissues. A level of blood flow that suffices under resting conditions may be inadequate under conditions of stress, such as exercise, trauma, or infection. Thus, while the physical dimensions of an obstructing lesion place limitations on the ability of the arteries to transport blood and the strength of the arterial wall determines its resistance to leakage, the needs of the recipient organs ultimately dictate the threshold for the appearance of symptoms. Like all hydraulic systems, the motion of blood and the behavior of the arterial wall adhere to the laws of physics.[1 – 6] A basic knowledge of the principles of fluid transportation and vessel wall mechanics is, therefore, fundamental to the understanding of arterial disease and to the formulation of a rational approach to treatment.
Potential Energy In addition to the dynamic pressure PD produced by the heart, blood is subjected to pressure due to the elastic recoil of the vascular walls and to the effect of gravity (Fig. 5-2). Both of these pressures are present even when the circulation is completely static. While they are not ultimately responsible for the motion of blood, they are pertinent to our understanding of vascular physiology. Although elastic recoil is an important mechanism for storing energy produced during systole for discharge during diastole, the static filling pressure is ordinarily quite small, around 7 mmHg, and can be neglected for most practical purposes. On the other hand, hydrostatic pressure—which represents the weight of a column of blood extending from the right atrium to the point of measurement—may be appreciable. Hydrostatic pressure PH depends on the density of blood r, about 1.056 g/cm3; the acceleration due to gravity g, 980 cm/s2; and the distance h from the right atrium:
BASIC HEMODYNAMICS Because blood vessels are not ideal conduits and blood is not a frictionless fluid, the motion of blood from one site to another in the vascular tree involves the dissipation of energy. Consequently, to maintain blood flow, energy must be supplied continuously. Most of this requirement is met by the heart, which transforms chemical energy into mechanical energy. To a lesser degree, some energy is also contributed by the muscles of respiration and locomotion, but for the most part it is sufficient to focus on the heart as the major source. Blood leaving the left ventricle is given a potential energy boost in the form of hydraulic pressure and a kinetic energy boost in the form of increased velocity (Fig. 5-1). As the blood traverses the intricate network of tubes that make up the circulatory system, potential energy is transformed into
PH ¼ 2rgh
ð5-1Þ
At a point 100 cm below the heart, PH would be 103,488 dyn/cm2. Since 1.0 mmHg is equal to 1333 dyn/cm2, the pressure in more familiar terms would be 77.6 mmHg. In general, therefore, hydrostatic pressure in millimeters of mercury can be predicted by multiplying the vertical distance in centimeters from the heart by 20.78. Distances above the heart are given a plus sign, those below, a minus sign. As shown in Fig. 5-3, the total pressure at any point in the arterial tree is the sum of the dynamic and hydrostatic pressures. Below the heart, these pressures are additive, while above the heart, the hydrostatic component acts to reduce the
Hobson/Wilson/Veith: Vascular Surgery: Principles and Practice, Third Edition, Revised and Expanded DOI: 10.1081/0819-9-120024888 Copyright q 2004 by Marcel Dekker, Inc.
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Figure 5-1. Potential energy (pressure) gradient from the left ventricle to the right atrium. Normally, the greatest pressure drop is across the arterioles. Note that discontinuities produced by arterial obstructions at the iliac and superficial femoral levels are largely rectified by a reduced gradient across the arterioles.
total pressure. In collapsible structures, such as veins or capillaries, intraluminal pressure cannot fall below that of the surrounding tissue (, 1 to 5 mmHg); otherwise the lumen would be obliterated and no blood would flow.[7] In a standing subject, blood flows from a lower pressure in the aortic arch to a higher pressure at the ankle (Fig. 5-3). To explain this apparently paradoxical situation requires consideration of gravitational potential energy. Gravitational potential energy is not manifest as pressure but represents the energy that any particle of matter (such as blood) acquires merely because of its distance from the center of the earth (Fig. 5-2). A useful artificial convention is to designate the left atrium as the reference point, calling this the point of “zero” gravitational potential energy. Using this convention, the formula for gravitational potential energy EG is identical with that for hydrostatic pressure but has the opposite sign: EG ¼ þrgh
Therefore, hydrostatic pressure and gravitational potential energy tend to cancel, explaining how blood may move against a pressure gradient but not against an energy gradient.
Kinetic Energy Like any other matter in motion, blood flowing in the vascular tree possesses kinetic energy (Fig. 5-4). In fluid systems, kinetic energy EK is proportional to the density of the fluid and the square of its velocity v (in centimeters per second): 1 EK ¼ rv 2 2
ð5-3Þ
ð5-2Þ
Total Fluid Energy At any point in the vascular system, the total fluid energy E, in ergs per milliliter of blood, is the sum of the potential and kinetic energy: E ¼ P D þ PH þ E G þ E K 1 ¼ PD 2 rgh þ rgh þ rv 2 2
Figure 5-2. Forms of potential energy acting on blood. Dynamic pressure is produced by cardiac contraction and is ultimately responsible for the blood circulation. Note that hydrostatic pressure and gravitational potential energy have opposite signs.
ð5-4Þ
Neglecting hydrostatic pressure and gravitational potential energy, most of the energy at the aortic arch is manifested in the form of dynamic pressure, with only a small fraction being kinetic, while in the thoracic venae cavae, most of the energy may be kinetic. According to Bernoulli’s principle, the total energy at one point in a closed system is equal to that at another under ideal conditions of steady flow and no frictional losses. In reality, blood always flows down an energy gradient, since energy is
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Figure 5-3. Effect of hydrostatic pressure on total arterial and venous pressure at various anatomic levels in the standing position. [From Sumner, D.S.: Hemodynamics and pathophysiology of venous disease. In Rutherford, R.B. (ed): Vascular Surgery, 4th ed. Philadelphia, Pennsylvania, Saunders, 1995, pp 1673 –1695. With permission.]
continuously dissipated in the form of heat: E1 ¼ E2 þ heat P1 þ rgh1 þ 12 rv1 ¼ P2 þ rgh2 þ 12 rv2 þ heat
ð5-5Þ
Because the mechanical equivalent of heat is so great, only about 16 cal would be generated per minute in moving 5 L of blood from the left ventricle to the right atrium when the mean pressure differential between these two sites is 100 mmHg. If there were no heat loss to the environment, this would raise the temperature of a 70 kg person only 2:6 £ 1024 8C=min: Figure 5-5 illustrates the interchange between one form of energy and another. Fluid flows from a reservoir (1) with a low pressure but high gravitational potential energy to a horizontal tube (2) where the pressure is higher but the gravitational potential energy is lower. In the aneurysmal area (3), velocity is decreased, since flow Q is the product of velocity v and cross-sectional area A: Q ¼ nA
Conversely, in the stenotic area (4), velocity increases. When velocity decreases, pressure tends to rise as kinetic energy is transformed into potential energy; but when velocity increases, the reverse change occurs—pressure falls as potential energy is converted into kinetic energy. Thus, at several points in the system, fluid may flow against a pressure gradient but never against an energy gradient. For most practical purposes, total fluid energy can be considered to be roughly equivalent to the dynamic pressure. Neglecting kinetic energy introduces an error that seldom
ð5-6Þ
Figure 5-4. Blood, like other fluids, gases, or solid bodies in motion, possesses kinetic energy.
Figure 5-5. Hydraulic model illustrating Bernoulli’s principle (Eq. 5-5): P, pressure; K, kinetic energy; E, total fluid energy. Although there is a sequential decline in total fluid energy from point 1 to point 5, fluid flows against a pressure gradient in several areas owing to an interchange between pressure and gravitational potential energy or between pressure and kinetic energy.
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exceeds 2 mmHg and is ordinarily much less; hydrostatic pressure and gravitational potential energy cancel each other out. Bernoulli’s principle has been used to estimate pressure drops (DP ) across stenoses. When the patient is horizontal in a supine position, the rgh terms on both sides of Eq. 5-5 are equal and can be eliminated. If energy losses (heat) are neglected, Eq. 5-5 can be rearranged to obtain: 1 DP ¼ P1 2 P2 ¼ rðv22 2 v21 Þ 2 Velocity of blood flow proximal (v1) and distal (v2) to a stenosis can be measured transcutaneously with a Doppler instrument. Predictions of pressure drops are fairly accurate across cardiac valves, because v1 in the cardiac chamber is low and can be neglected and because viscous losses are minimal, owing to the short length of the stenosis (see below).[8] Attempts to use the formula in other areas have met with little success.[9] Pressure gradients across low-grade stenoses tend to be overestimated, especially when the distal velocity (v2) is relatively low and when velocity above the stenosis (v1) is not measured.[10] Moreover, pressure below the stenosis may be recovered downstream as v2 decreases and kinetic energy is transformed into pressure. On the other hand, when viscous and kinetic energy losses (heat) are high (as they frequently are in relatively long arterial stenoses), the formula underestimates the pressure gradient.[10] It is evident, therefore, that this simplified formula is not adequate when applied to the relatively complex lesions that predominate in the peripheral circulation.
Energy Losses Viscosity, or the friction between contiguous layers of fluid, accounts for much of the transformation of energy into heat. In an idealized situation (steady, nonpulsatile, laminar flow in a straight cylindrical tube with rigid walls), the energy losses due to viscosity are described by Poiseuille’s equation: DP ¼ v
8Lh 8Lh ¼ Q 4 r2 pr
ð5-7Þ
where v ¼ mean flow velocity, cm/s, across a tube with inside radius r, cm Q ¼ flow, cm3/s DP ¼ pressure drop, dyn/cm2, over a length of tube L, cm h ¼ coefficient of viscosity P (poise ¼ dyn · s/cm2) That DP is directly related to flow, length, and viscosity comes as no surprise, but the inverse relationship to the fourth power of the radius is less intuitively evident. As shown in Fig. 5-6, diminishing radius has little effect on DP until a critical point is reached; thereafter, even small reductions in radius cause a major increase in DP. With increasing flow, the point of inflexion occurs at a greater radius, and at any given radius, DP is proportional to flow. Large vessels, such as the iliac arteries with diameters of 7 mm, can sustain massive flows of 3000 cm3/min (50 cm3/s) over a 10 cm segment with only a 2 mmHg DP due to viscous losses (h ¼ 0:035 P ). In contrast, the DP across a similar length of a 2-mm vessel, such
Figure 5-6. Curves depicting viscous energy losses DP across a 1.0-cm-long tube at various radii and flow rates (Eq. 5-7). Viscosity is assumed to be 0.035 P.
as the posterior tibial artery, would exceed 3 mmHg at a flow of only 30 cm3/min (0.5 cm3/s). Diameters of normal vessels are, therefore, consistent with the loads they are expected to carry. Viscous losses, however, may be overshadowed by those due to inertia. Velocity is a vector quantity; consequently, inertial losses occur any time the speed or direction of blood flow is altered. Because of the pulsatile nature of blood flow, velocity is continuously changing throughout the cardiac cycle and across the vascular lumen (Fig. 5-7). Direction changes occur at all branches or bifurcations, in areas of curvature, at the entrance and exit of stenoses or aneurysms, and even during systole and diastole as the vessel wall expands and contracts (Fig. 5-8). Turbulence, which creates a multitude of velocity vectors, is a major source of energy loss.* Inertial losses are proportional to the density of blood r and to the square of the change in velocity Dv: 1 DP ¼ k rðDvÞ2 2
ð5-8Þ
The constant k varies depending upon the nature and rapidity of the velocity change. For example, at the exit from a stenosis, k approaches 1.0 when the orifice is abrupt but is less than 0.2 when the orifice expands gradually at a 68 angle.[11] It should be emphasized that Dv may imply a change in *Frictional losses due to flow in directions other than the long axis of the tube are neglected in Eq. 5-7, but are incorporated in a general way in the constant k in Eq. 5-8. Thus, “inertial energy loss” is a term of convenience; it should be understood that all these losses are ultimately due to molecular interaction.
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Figure 5-7. (A ) Femoral arterial flow pulse. (B ) Velocity profiles across the vascular lumen at various phases of the pulse cycle (indicated by lowercase letters). At the wall, velocities are zero. During peak systole b, the profile is nearly parabolic; at other times it is quite blunt. When the overall direction of flow is changing rapidly, forward and reverse flow may occur simultaneously. [From Sumner, D.S.: Essential Hemodynamic Principles. In Rutherford RB (ed): Vascular Surgery, 4th ed. Philadelphia, Pennsylvania, Saunders Co., 1995, pp 18 – 44. With permission.]
“direction” of a blood particle without necessarily a change in its “speed.” As a result of inertial losses, the relationship of pressure gradients and flow in the arterial system never adheres to Poiseuille’s law. For a given flow, pressure gradients are always larger than those predicted; likewise, for a given
pressure gradient, flows are always less (Fig. 5-9). Instead of a linear relationship between pressure gradient and flow, the curve is concave toward the pressure axis and is best described by equations in which flow appears as a squared term. This, of course, would be anticipated from Eq. 5-8, since velocity and flow are interdependent. A curve depicting the inertial energy losses for the artery shown in Fig. 5-9 could be obtained by subtracting the line representing Poiseuille’s equation from the experimentally determined values. The resulting equation ðP ¼ 144Q þ 11Q 2 Þ emphasizes the relationship between inertial losses and flow. Reynolds number (Re) defines the ratio between destabilizing inertial forces and stabilizing viscous forces acting on a fluid: Re ¼
Figure 5-8. Factors responsible for energy “losses” due to inertia. All affect either the speed or direction of blood flow. The energy given up by a baseball bouncing off a hard surface provides a rough analogy.
2rvr h
ð5-9Þ
Although laminar flow disintegrates into turbulent flow when Reynolds number exceeds 2000, numbers of this magnitude seldom occur in the circulation under normal circumstances. Yet the pattern of blood flow in a large part of the arterial tree can be characterized as disturbed for the reasons mentioned above.[12]
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Figure 5-9. Flow versus pressure drop across a 9.45 cm length of canine femoral artery. The dashed line represents the pressureflow curve predicted from Poiseuille’s law (Eq. 5-7). Note that the formula for the curve that best approximates the experimental data has both a linear and a squared term. [From Sumner, D.S.: Essential Hemodynamic Principles. In Rutherford, R.B. (ed): Vascular Surgery, 4th ed. Philadelphia, Pennsylvania, Saunders. 1995, pp 18– 44. With permission.]
Indeed, energy losses calculated with turbulent friction factors more closely approximate those observed experimentally than they do when Poiseuille’s equation is employed.[13]
Arterial Stenoses Energy losses caused by stenoses in the arterial system are due to both viscous and inertial factors.[14,15] Viscous losses depend on the length of the stenosis and the fourth power of its diameter. According to Poiseuille’s law, a reduction in luminal diameter of 50% would increase the pressure gradient by a factor of 16, and a reduction of 75% would increase DP by a factor of 256—provided flow remained constant (Eq. 57). The diameter of the stenosis, therefore, is far more important than its length.[14,16,17] Energy losses due to inertia occur at the entrance to a stenosis and also at its exit.[3,15,16,18,19] Less flow disturbance occurs at the entrance than at the exit, where much of the excess kinetic energy resulting from the increased fluid velocity within the stenosis is dissipated in a turbulent jet. Just beyond the stenosis, areas of flow separation develop near the arterial wall. In these areas, flow may actually reverse. That inertial losses ordinarily exceed those due to viscous factors is illustrated in Fig. 5-10. Viscous factors predominate only at low flow rates or in relatively long stenoses. Because flow disturbances are concentrated at the ends of a stenosis, doubling the length of a stenosis—which affects only the viscous factors—will not double the energy loss. Based on Poiseuille’s law (Eq. 5-7) and Eq. 5-8, one would predict that narrowing of the arterial lumen would have little
Figure 5-10. Calculated energy losses experienced by nonpulsatile blood flow through a 60% stenosis. Flow velocity before and after the stenosis is 50 cm/s. Inertial losses are based on Eq. 5-8. At the entrance, k is 0.5, and at the exit, 1.0. [From Sumner, D.S.: Essential Hemodynamic Principles. In Rutherford, R.B. (ed): Vascular Surgery, 4th ed. Philadelphia, Pennsylvania, Saunders, 1995, pp 18 – 44. With permission.]
effect on the pressure gradient across or the flow through a stenosis until the cross-sectional area is reduced by about 75%. These predictions have been substantiated by numerous experimental studies.[20,21] As shown in Fig. 5-11, in an isolated system with a fixed peripheral resistance and no collateral input, changes in DP and flow are mirror images of each other. Flow decreases are commensurate with increases in the pressure gradient. When the peripheral resistance is low and initial flow rates are high, the curves are shifted to the left; in other words, changes in pressure and flow are perceived a lesser degree of narrowing when initial flow rates are high.[20,21] In part, this explains why a lesion that does not appear particularly severe on arteriography may cause no symptoms at rest but causes significant disability during exercise.[22] When the lesion responsible for a stenosis is axisymmetric, a 75% area reduction corresponds to a 50% diameter reduction. Stenoses of this magnitude seen on arteriography are frequently labeled “critical” or “hemodynamically significant.” While this is a clinically useful concept, permitting the surgeon to predict physiological changes from the arteriographic picture, it must be used cautiously. Because many lesions are not axisymmetric, the anteriographic picture may overestimate or underestimate the degree of stenosis. Moreover, as pointed out above, a lesion may or may not be critical, depending upon the rate of flow.
Hemodynamic Resistance Hemodynamic resistance (R ) is defined as the ratio of the energy gradient between two points along the vessel to the
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Figure 5-12. Electrical analogue showing effect on total resistance R of isolated resistances R1, R2, and R3 arranged in series and in parallel.
CIRCULATORY EFFECTS OF ARTERIAL OBSTRUCTIVE LESIONS
Figure 5-11. Effect of increasing stenosis on pressure and flow in isolated segment of canine femoral artery. Peripheral resistance was modified by means of an arteriovenous communication. [From Sumner, D.S.: Essential Hemodynamic Principles. In Rutherford, R.B. (ed): Vascular Surgery, 4th ed. Philadelphia, Pennsylvania, Saunders, 1995, pp 18–44. With permission.]
mean blood flow through the vessel: R¼
E 1 2 E2 P1 2 P2 ð<Þ Q Q
ð5-10Þ
Stenotic or obstructed arteries are part of a complex hemodynamic circuit that includes the involved artery, a parallel system of collateral arteries, and the peripheral runoff bed (Fig. 5-13).[3,25] The parallel resistances of the collaterals Rc and the involved artery Rs constitute a “segmental” resistance Rseg, which is in series with the resistance of the runoff bed Rp. Therefore, the total blood flow QT to the peripheral tissues is determined by the central arterial pressure Pa, the venous pressure Pv, and the sum of the segmental and runoff resistances: QT ¼
Pa 2 Pv Pa < Rseg þ Rp Rseg þ Rp
ð5-12Þ
For most purposes, R can be roughly approximated by the ratio of DP to Q. It must be recognized that the resistance of any vascular segment is not fixed and is not determined exclusively by the diameter of the segment. Because of inertial factors, resistance increases as flow increases. The minimum possible resistance is given by Poiseuille’s law*: Rmin ¼
8Lh pr 4
ð5-11Þ
Analogous to electrical circuitry, resistances in series are roughly additive (Fig. 5-12).[23,24] Arranged in parallel, the reciprocal of the total resistance is equal to the sum of the reciprocals of the resistance of each component part (Fig. 512). The total resistance of vessels in parallel must, therefore, be less than that of the vessel with the least resistance.
*Since blood is a non-Newtonian fluid, its viscosity (h ) decreases as its shear rate increases. (Shear rates are directly proportional to velocity and inversely proportional to the vessel diameter.) At very low velocities, when blood is practically stagnant, viscosity may be several times higher than that at normal flow velocities, but throughout the wide range of velocities normally present in human arteries, viscosity is nearly constant.[3] Therefore, the minimal resistance calculated from Eq. 5-11 varies little with changes in flow rate.
Figure 5-13. Diagram illustrating components of a hemodynamic circuit containing an arterial occlusion or stenosis. Shown below is an electrical analogue, in which the battery represents the left ventricle and ground potential represents the right atrium.
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(Because the venous pressure is ordinarily quite low, it can be neglected for the purpose of the following discussion.) To maintain adequate tissue perfusion in the face of a developing stenosis, the body has three options: reduce the segmental resistance, reduce the runoff resistance, or reduce both. The success in accomplishing this task and the mechanisms involved depend not only on the extent and severity of the lesion, but also on its location and the rapidity with which it develops. Collateral arteries are preexisting pathways consisting of intercommunications between terminal branches of distributing arteries that originate both above and below the obstructing lesion.[26] Their recruitment and subsequent enlargement are stimulated by an increased pressure gradient across the involved segment and an increased demand to carry blood flow.[27 – 29] This response is probably mediated by the release of nitric oxide (endothelium-derived relaxing factor).[30] In some areas of the body, the collaterals are sufficiently developed to sustain tissue viability even in the event of an acute obstruction, provided the obstruction does not block the inflow or reentry vessels. In most cases, however, preexisting collaterals are inadequate to prevent ischemia. As a rule, collateral development occurs over a prolonged period; even when they have attained their maximum dimensions, their resistance almost always exceeds that of the major artery whose function they are called upon to supplement or replace. For example, 256 collaterals, each with a diameter of 2.5 mm, or 10,000 collaterals with a diameter of 1.0 mm would be required to reduce the segmental resistance to that of a major vessel with a diameter of 10 mm (Eq. 5-11 and Fig. 5-12). Although the resistance of the collateral bed is relatively fixed, that of the runoff bed is quite variable and acutely responsive to various exigencies.[25,31,32] Most of the resistance is concentrated in the terminal arterioles and precapillary sphincters, which, because of their small diameter and muscular walls, are ideally suited for regulatory functions (Fig. 5-1). Their tone is controlled by the sympathetic nervous system, circulating catecholamines, local products of metabolism, and myogenic influences. These vessels have the remarkable ability to autoregulate, dilating in response to a fall in blood pressure and constricting in response to a rise.[33,34] By this mechanism, blood flow is maintained within tolerable limits despite wide variations in perfusion pressure. In skeletal muscles, autoregulation ceases when perfusion pressure drops below about 20 – 30 mmHg.[34,35] Beyond this point, flow becomes pressuredependent. When flow drops to the point that ischemia results, metabolic products accumulate. These substances are powerful vasodilators, their influence overcoming the vasoconstrictive effects of sympathetic nerve impulses.[36,37] As the segmental resistance rises, the resistance of the runoff bed falls. At first, the fall in resistance is due to autoregulation, but once blood flow to the periphery is compromised, the products of ischemia play a role. Peripheral vasodilatation, therefore, is immediately available to compensate for an acute elevation of the segmental resistance. With persistence of the obstruction, the collateral arteries dilate, allowing the peripheral resistance to rise. However, peripheral resistance never returns to normal levels as long as arterial obstruction persists.
Pressure-Flow Relationships At Rest The pressure distal to an arterial obstruction Pd depends on the central arterial pressure Pa and the product of the segmental resistance and the total blood flow (Fig. 5-13): Pd ¼ Pa 2 QT Rseg
ð5-13Þ
In subjects without arterial disease, Rseg is so low that the mean Pd is only a few millimeters of mercury below Pa. Because pulse waves are reflected from the periphery, the systolic pressure distal to the segment may actually be higher than the central systolic pressure; the diastolic pressure, however, will be less.[3,38] (This accounts for the observation that systolic blood pressure at the ankle normally exceeds that in the arm.[39]) Segmental resistance becomes appreciable only when the stenosis in the major artery becomes “critical,” and, even then, well-developed collaterals may provide adequate compensation. As the segmental resistance rises, arterioles in the runoff bed dilate, thereby maintaining total blood flow QT constant. Because Rseg is elevated, the product QTRseg increases, and the distal pressure Pd falls (Fig. 5-14). Thus, a fall in distal pressure is the earliest objective evidence of arterial obstruction. This explains why blood flow in a limb with well-advanced arterial obstruction is usually normal but the peripheral pressure is reduced.[3,39 – 42]
Figure 5-14. Relationship between increasing segmental resistance, distal pressure, and distal blood flow. Although flow is maintained at normal levels until maximal peripheral vasodilatation is reached, pressure begins to drop immediately. [From Sumner, D.S.: Correlation of lesion configuration with functional significance. In Bond, M.C., Insull, W. Jr., Glagov, S., Chandler, A.B., Cornhill, J.F. (eds): Clinical Diagnosis of Atherosclerosis: Quantitative Methods of Evaluation. New York, Springer-Verlag, 1983. With permission.]
Chapter 5.
With increasing disease, poor collateral development, lesions that block collateral inflow or outflow, or multilevel involvement, Rseg becomes quite high and the peripheral pressure Pd drops below the limits where autoregulation is possible. Total limb resistance rises; total blood flow QT falls, and the peripheral tissues become ischemic at rest (Eq. 512).[43] Despite the fact that QT is decreased, the product QTRseg continues to rise, and the peripheral pressure Pd continues to fall, albeit at a slower rate (Eq. 5-13 and Fig. 514). Noninvasive studies suggest that ischemic signs and symptoms—such as rest pain, ulcers, gangrene, and poor healing—usually become manifest only when the pressure drops below 30 mmHg.[44 – 47] It is important to recognize that a level of blood flow adequate to maintain tissue viability under normal conditions may not be sufficient to supply the additional nutrients and other blood-borne factors required to heal traumatic wounds or ulcers, especially in the presence of diabetes and infection. Therefore, it is impossible to state precisely what the critical level of tissue perfusion might be in a particular situation. In most patients with ischemic feet, elevating the legs increases rest pain and impedes healing, while placing the feet in a dependent position often provides relief from pain and may encourage healing. These effects are the result of changes in hydrostatic pressure. Consider a patient who, when lying supine, has an arterial pressure of 25 mmHg and a venous pressure of 10 mmHg in the toes. In this position, the pressure gradient determining blood flow across the arterioles, capillaries, and venules is 15 mmHg. A 20 cm elevation of the feet would decrease the hydrostatic pressure 16 mmHg (Eq. 5-1), causing the arterial pressure to fall to 9 mmHg. Since the venous pressure cannot fall below tissue pressure ( t 1–5 mmHg), the gradient across the capillary bed decreases from 15 to 4–8 mmHg; nutritive flow suffers by a like amount; and the patient develops paresthesias or pain in the elevated foot.[48] On the other hand, if the patient were to sit up, allowing the feet to rest on the floor, the vertical distance from the heart to the toes would increase by perhaps 80 cm, and the hydrostatic pressure would rise by 62 mmHg. Although both the arterial and the venous pressures increase by the same amount and perfusion pressure across the capillaries remains unchanged (87 mmHg – 72 mmHg – 15 mmHg), the capillary bed dilates in response to the increased intraluminal pressure. This reduces the resistance of the capillaries and venules, thereby augmenting tissue perfusion despite the fact that the transcapillary pressure gradient has not changed.[49,50] If the patient contracts the calf muscles and if the venous valves are intact, the venous pressure in the foot will fall from 72 mmHg to some lower value (often to 5– 10 mmHg). Since arterial pressure is unaffected by calf motion, the pressure gradient across the capillaries will be augmented proportionate to the drop in venous pressure, and tissue perfusion will be similarly enhanced. This explains the somewhat paradoxical observation that ischemic rest pain may be relieved by walking a few steps. Last, in considering the mechanism of ischemic rest pain, one must not forget that the central pressure Pa also plays a role in determining tissue perfusion (Eq. 5-12). Rest pain occurs primarily at night, when the cardiac output falls and arterial pressure decreases. The stimulation of sitting up or
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moving about usually raises the mean blood pressure, thus augmenting tissue perfusion.
Pressure-Flow Relationships During Exercise During exercise, the terminal arterioles supplying the involved muscles dilate, reducing the peripheral resistance Rp. In normal limbs which have a high resting peripheral resistance, exercise produces a marked decrease in total limb resistance and a similarly marked augmentation of limb blood flow (Eq. 5-12). Blood flow to the muscles increases commensurate with the vigor of the exercise, often by a factor of 5 or more.[3,42,51,52] Despite the marked increase in blood flow, the product QTRseg remains low, and there is little drop in peripheral pressure Pd (Eq. 5-13). These relationships are illustrated in Fig. 5-15. In limbs with arterial obstruction, the terminal arterioles— already partially dilated to compensate for the increased segmental resistance—dilate further in response to exercise, but, because of the elevated segmental resistance, the total limb resistance remains relatively high (Fig. 5-15). Although exercise induces an increase in blood flow to the muscles, the increase may be inadequate to meet metabolic demands.[3,42,50 – 53] Consequently, the by-products of metabolism accumulate, provoking the symptoms of intermittent claudication. Because blood flow through the elevated segmental resistance increases, peripheral pressure falls (Eq. 5-13). This drop in peripheral pressure, usually measured at the ankle level, is one of the most sensitive methods for detecting obstruction of the arteries supplying blood to the legs.[39,42,54 – 56] Even when the resting ankle pressure is imperceptibly reduced, exercise may induce an unequivocal pressure drop, thus establishing the diagnosis.[57] The effects of exercise for a given degree of arterial stenosis are often more severe when the obstruction is located in the proximal arterial segments. A stenosis of the terminal aorta or common iliac artery may impair walking tolerance to a greater degree than a similar stenosis of the superficial femoral artery. Since the iliac artery supplies a much larger muscle mass than that supplied by the superficial femoral artery, the metabolic demands for increased blood flow are correspondingly greater. The central blood pressure Pa frequently rises during exercise, especially in patients with peripheral vascular disease. This seldom provides much relief from claudication but may disguise small drops in peripheral pressure (Eq. 513). Consequently, to detect subtle falls in ankle pressure during exercise, one must measure the brachial and ankle pressure simultaneously. When obstructions involve more than one arterial segment, the hemodynamic situation becomes far more complex (Fig. 5-16).[58,59] An arterial segment is composed of a major artery and its collaterals, which supply a more or less well-defined peripheral vascular bed. The major artery of a given segment may also constitute the primary inflow source for another more distally located segment. For example, the iliac segment consists of the common and external iliac arteries, which function as major arteries, and the internal iliac system, which make up the collateral
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Figure 5-15. Relationship between total resistance RT, segmental resistance Rseg, peripheral resistance Rp, blood flow QT, and distal blood pressure Pd in normal limbs and limbs with single-level arterial obstruction. Central arterial pressure Pa is 100 mmHg. PRU = mmHg/mL/min. (Theoretical curves based on Fig. 5-13 and experimental observations.)
channels. These vessels supply not only the buttock and thigh muscles but also provide inflow to the superficial femoral artery, which in turn—with its collaterals— supplies the calf muscle via the popliteal artery. Thus, the leg may be divided into iliac, femoral, calf, and pedal segments. Walking exercises buttock, thigh, and calf muscles and thus simultaneously involves the iliac, femoral, and calf segments. In a limb with both iliac and superficial femoral disease, exercise provokes increased pressure drops across both segments (Fig. 5-17). Because blood flow to the thigh and buttocks increases due to arteriolar vasodilatation, the femoral arterial pressure drops; and the superficial femoral artery and its collaterals will be perfused—not by the central arterial pressure, but by a reduced pressure. Although dilation of the arterioles in the calf muscle decreases the peripheral resistance, the reduction in pressure at the upper end of the femoral segment will further restrict the increase in calf blood flow. Therefore, claudication occurs with less exercise when there is multiple segment disease than when disease is limited to a single segment. In severe cases, the
foot and toes, which are at the end of the line, may have virtually no blood flow.[39,52,55,60] Thus, in limbs with multilevel obstruction, the proximal segments “steal” blood from those more distally located. This explains why multilevel disease is far more physiologically devastating than disease confined to a single segment. Even with a single obstruction at the iliac level, the proximal muscle compartments may steal blood from the calf, since the superficial femoral artery, though widely patent, is perfused by a reduced common femoral pressure. Return of blood to the heart is facilitated during walking by the venous pump mechanism. As mentioned earlier, in normal limbs with functioning venous valves, contraction of the calf muscles forces blood cephalad, reduces the effective length of the hydrostatic column, and decreases venous pressure. Since the hydrostatic component of arterial pressure is not affected, the pressure gradient across the capillaries of the exercising muscles is increased and blood flow is augmented. Therefore, one might expect that claudication would occur earlier in limbs with arterial obstruction when chronic venous insufficiency is also present.
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91
Figure 5-16. Components of a hemodynamic circuit with two levels of obstruction (Rseg1, Rseg2) and two runoff beds (Rp1, Rp2). Electrical analogue is shown below.
Pressure-Flow Relationships After Exercise Following exercise, the greatly increased blood flow in normal limbs rapidly replenishes any nutritional deficiencies that might have developed during muscular contraction and rapidly removes any accumulated products of metabolism. As a result, the dilated arterioles constrict to their resting diameter and blood flow falls to preexercise levels within a few minutes (see Fig. 5-15).[3,25,40] Limbs with arterial obstruction, on the other hand, develop a much larger “flow debt” during exercise, the extent of which is roughly proportional to the severity of the obstruction and the duration and magnitude of the muscular work. A prolonged period, therefore, is required to restore the metabolic state to that existing prior to exercise. As a result, postexercise blood flow remains elevated and peripheral pressure remains decreased until the arterioles once again return to their preexercise state (see Fig. 5-15).[25,39,40,54 – 56,58] In limbs with multilevel disease, repayment of the flow debt of the distal muscular compartments may be delayed until that of the more proximal compartment is satisfied.[55,58] For example, in a limb with combined iliac and superficial femoral arterial obstruction, hyperemia of the thigh and buttock muscles must decrease before the femoral pressure can rise (Fig. 5-17). As the femoral pressure rises, blood flow to the calf will initially increase and then gradually decrease as the flow debt of the calf muscle is eradicated. Peripheral pressure remains low until calf blood flow begins to fall, returning to preexercise levels only after the hyperemia has subsided. Recording the ankle pressure after exercise, therefore, provides an excellent method for assessing the severity of
arterial obstruction and for predicting the changes occurring in blood flow to the calf and thigh.[55] Given an equivalent amount of exercise, one can assume that the greater the decrease in ankle pressure and the longer it remains below preexercise levels, the more severe the obstructive process. An ankle pressure that remains low or undetectable for a prolonged period implies multilevel disease and a diversion of blood flow into the more proximal muscular compartment (Fig. 5-17).
PRESSURE AND FLOW PULSES The periodic discharge of blood from the left ventricle into the arterial system during the systolic phase of the cardiac cycle is basically responsible for the pulsatile nature of blood flow. Energy developed during systole is stored within the arterial wall. During diastole, the elastic recoil of the expanded arteries continues to propel blood into the various vascular beds; otherwise, flow would be intermittent and pressure would fall to zero. Many factors affect the contour of flow and pressure pulses. Among these are resistance to outflow, inertia and viscosity of blood, stiffness of the arterial wall, pulse rate, and wave reflections—all of which are incorporated into the concept of input impedance.[3,61] The effect of resistance and wave reflections is perhaps the most easily understood (Fig. 518). In the normal arterial system, the major site of resistance is in the arterioles. When the surge of blood constituting the flow pulse meets this high resistance, part of the blood is
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Figure 5-17. Relationships between pressure in the common femoral and popliteal arteries and flow in the thigh and calf in a limb with severe occlusive disease of the iliac and superficial femoral segments. Central arterial pressure is 100 mmHg. Note that calf blood flow may drop during exercise and that popliteal pressure remains low for 10 min: ankle pressure would be undetectable during this time. (Theoretical curves based on Fig. 5-16 and experimental observations.)
transmitted into the capillaries and part is reflected back up the arterial tree.[3,62] The relative magnitude of the reflected wave is therefore a function of the peripheral resistance, being accentuated by vasoconstriction and attenuated by vasodilatation.[63] The reflected wave explains the characteristic appearance of the normal flow pulse, which has a large forward flow component in systole, followed by a reverse flow component (representing the reflected wave) in early diastole (Fig. 5-18). Finally, another—but much smaller—forward flow wave is often present in late diastole. When the arterioles are dilated, as in exercise, there may be no perceptible reflected wave, and flow is antegrade throughout the cardiac cycle. This configuration is also typical of the pulse in arteries (such as the internal carotid) that supply low resistance vascular beds. The normal pressure pulse has a sharp upslope and a dicrotic wave on the downslope (Fig. 5-18). This wave is produced by the return of potential energy reflected from the periphery. Plethysmographic pulses (which represent the interaction of arterial pressure and vessel wall compliance) have contours that are roughly the same as that of the pressure pulse.[64,65] Distal to a critical stenosis, pulse waves are attenuated due to energy losses incurred in the vicinity of the lesion and within the high-resistance collateral pathways
Figure 5-18. Effect of reflected waves on the contour of flow and pressure pulses. Reflected waves subtract from forward flow waves but add to pressure waves. Vasoconstriction accentuates the reflected wave, producing flow reversal in diastole and a prominent dicrotic notch in the pressure tracing. Vasodilatation minimizes pulse wave reflection.
(Fig. 5-19).[66,67] The combination of high resistance and arterial compliance functions as a low-pass filter. While the lower frequency harmonics are passed with relatively little change, the energy in the higher frequency harmonics is markedly diminished. This produces a characteristic damping of the pulses. The pressure pulse becomes rounded, develops a slow upslope and a downslope that bows away from the baseline, and loses the dicrotic wave. Similarly, the flow pulse displays a slow upslope, a rounded peak, a gradual decline during diastole, and no reverse flow. Palpation of the peripheral pulse is an essential part of the physical examination in patients with suspected arterial disease. Reduction or absence of palpable arterial pulses distal to an obstruction is the result of both the decrease in mean pressure and the attenuation of the pressure pulse. While gross changes in the flow pulse can be easily recognized with an electromagnetic or Doppler flowmeter, various mathematical manipulations have been introduced to enhance diagnostic accuracy. The simplest of these is the pulsatility index, which is defined as the ratio of the maximum excursion of the velocity pulse wave (from peak systole to the lowest diastolic point) and the mean velocity.[68,69] Reduction of the pulsatility index below established normal values indicates proximal stenosis.[70,71] Since the accuracy of this test may be compromised by distal obstruction—which also affects the contour of the wave—other more complicated methods, including the use of Laplace transforms, have been
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93
Figure 5-19. The combination of a hemodynamically significant stenosis and compliant vessels functions as a “low-pass” filter, attenuating high-frequency components of pulse waves. Arterioles are represented by the faucet and the variable resistance. Mean pressure (dashed line ) is reduced, but mean flow (dashed line ) remains unchanged distal to a stenosis. [From Sumner, D.S.: Correlation of lesion configuration with functional significance. In Bond, M.C., Insull, W. Jr., Glagov, S., Chandler, A.B., Cornhill, J.F. (eds): Clinical Diagnosis of Atherosclerosis: Quantitative Methods of Evaluation. New York, Springer-Verlag, 1983. With permission.]
devised.[72] The relative merits of these calculations have as yet not been established. Although changes in the envelope of the pulse waves do not become evident until the stenosis reaches critical dimensions, even minor lesions generate turbulent eddies and areas of flow separation.[73,74] These disturbances produce a variety of velocity vectors that “broaden” the Doppler frequency spectrum, providing a sensitive method for detecting low-grade stenoses.
applicability and subjects the patient to additional hazards.[75] On the other hand, restoring blood pressure to normal levels by improving the cardiac output of hypotensive patients with pump failure and extensive arterial disease may reverse severe ischemia of the feet and toes. In most cases, however, eliminating the cause of increased resistance is the only rational approach.
Direct Arterial Surgery THERAPY Improvement of peripheral perfusion is the objective of all methods for treating obstructive arterial disease. When the obstruction is severe and the goal is to eliminate ischemia at rest, a small increase in blood flow may suffice, but when the obstruction is less severe and the goal is to secure relief from claudication, it is necessary to provide a large increase in blood flow during exercise. To increase blood flow, two basic mechanisms are possible: elevation of perfusion pressure Pa and reduction of hemodynamic resistance (Eq. 5-12). While temporary relief of severe ischemia can sometimes be achieved by inducing systemic hypertension, this approach has limited
Since the site of increased resistance is the diseased arterial segment and not the peripheral runoff bed (which almost invariably has a decreased resistance), restoration of normal hemodynamics requires removing or bypassing the obstruction. Depending on the nature, extent, and location of the obstructing lesion, it can be removed by embolectomy, thrombectomy, endarterectomy, atherectomy, angioplasty, replacement grafting, or lytic therapy. Bypass grafting is preferred when the lesions are quite extensive or difficult to remove, or when preservation of collateral channels might be jeopardized by attempts to disobliterate the involved artery. When the obstruction is confined to one arterial segment, it is often possible to return inflow resistance to normal levels and completely restore normal function.[76] Peripheral pressures at rest and during and following exercise return to
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normal levels, and blood flow under the same conditions becomes normal. The same results can be achieved in multisegmental disease when all diseased segments are bypassed. Restricting the operation to one or more segments (usually the more proximal segments), but leaving residual disease, will effect only partial restoration of hemodynamic function. The degree of improvement will depend on the relative reduction in resistance.[77] Although peripheral pressures are improved, they continue to be abnormal at rest and to fall during exercise; however, the postexercise decrease in pressure is reduced and recovery time is lessened. Likewise, partial repair is often sufficient to return blood flow to normal levels at rest and to provide sufficient blood flow to prevent claudication during moderate exercise. In cases being operated on for ischemia, it is only necessary to raise the peripheral perfusion pressure to a level that permits autoregulation to occur—about 40 mmHg at the ankle or 30 mmHg at the toe. In cases being operated on for claudication, this degree of improvement would not provide much relief; peripheral pressures need to reach levels that allow some constriction of the intramuscular arterioles at rest. Only then can the arterioles dilate under the influence of exercise to provide the additional flow required to ameliorate claudication. Even when disease is confined to one segment, the operative procedure may not completely return the resistance of that segment to normal levels. For example, stenosis can occur during closure of an endarterectomy site or at the proximal or distal ends of a bypass graft. Aside from these technical errors, the buildup of pseudointima within a prosthetic graft or the development of fibrodysplastic thickening at the ends of an autogenous graft or within the recipient vessels can narrow the lumen. While these changes may not be clinically evident, they can often be recognized by a less than perfect result in terms of objective hemodynamic data.[78,79] Peripheral pressures may not return to normal or, if normal at rest, will show reduction following exercise, and flow disturbances may be detected with a Doppler survey or by the presence of a bruit. To provide sufficient blood flow at a minimal pressure drop, the diameter of the graft must be selected with its proposed function in mind. Like other blood conduits, the resistance of a graft is directly related to its length and inversely related to the fourth power of its diameter. Thus the minimal resistance of a graft can be estimated from Poiseuille’s law (Eq. 5-11). This, of course, neglects the inertial energy losses that occur at the graft-host artery junctions—losses that can be appreciable. Table 5-1 lists the minimal pressure gradients that would occur across grafts of various diameters at various flow rates. At flow rates normally observed at rest in a femoropopliteal bypass (about 60 – 150 mL/min), a graft diameter of less than 4 mm would be associated with an appreciable pressure drop; the gradient during exercise, when flow rates of 300–500 mL/min are required, would be unacceptably high. While a 3-mm femoropopliteal graft might relieve ischemic symptoms, it would provide little benefit in claudicating limbs. A 7-mm aortofemoral graft having a length of 20 cm would be capable of carrying flows of 3000 mL/min with a pressure drop of only 4.5 mmHg. Due to additional inertial losses, the actual experimental values are considerably
Table 5-1.
Minimal Pressure Gradient Across Grafts,
mmHga Flow, mL/min Aortofemoral, length = 20 cm Diameter, mm 10 7 6 5
300
500
1500
3000
0.1 0.5 0.8 1.7
0.2 0.7 1.4 2.9
0.5 2.2 4.1 8.6
1.1 4.5 8.3 17.1
Flow, mL/min Femoropopliteal, length = 40 cm Diameter, mm
50
150
300
500
6 5 4 3
0.3 0.6 1.4 4.4
0.8 1.7 4.2 13.2
1.7 3.4 8.4 26.4
2.8 5.7 13.9 44.0
Flow, mL/min Femorotibial, length = 80 cm Diameter, mmb 6– 4 5– 3 4– 2 a b
50
100
150
200
1.3 3.5 13.0
2.6 6.9 26.0
3.9 10.4 39.0
5.2 13.8 52.0
Based on Eq. 5-7, h ¼ 0:035 P. Evenly tapered grafts, largest diameter to smallest.
higher, about 7–20 mmHg at flows of 1200 mL/min.[80,81] Nonetheless, grafts of this size should suffice in most circumstances. A 5 mm graft, however, would develop a rather large gradient during exercise and could restrict flow. Long grafts (80 cm) from the femoral to the tibial regions are ordinarily employed for the treatment of ischemic symptoms. Resting flow rates are not high, and pressure drops of 10 mmHg or more may be acceptable. Still, long segments of such grafts with small diameters (, 3 mm) are inefficient blood conduits. After implantation, prosthetic grafts develop a pseudointima. A thin (0.5 mm) fibrinous layer applied circumferentially to the interior of the graft would reduce the diameter by 1 mm, a reduction that could be of hemodynamic significance if a graft of borderline dimensions had been chosen. On the other hand, if the diameter of the graft is too large, clots tend to form on the inner walls as the flow stream tries to mold itself to the diameter of the recipient vessel. As in the case of aneurysms, this lining has little tensile strength, is loosely attached, and may embolize, causing the graft to fail. A highflow velocity is conducive to the formation of a thin, tightly adherent pseudointima. Because mean flow velocities are directly related to the flow rate and inversely related to the square of the radius, the velocity in a 7 mm graft would be 1.3 times that in an 8 mm graft and 2.0 times that in a 10 mm graft (Eq. 5-6). To reduce inertial losses, it is important to make the transition from graft to host vessel as smooth as possible. End-to-end anastomoses, therefore, cause the least flow
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disturbances.[3] End-to-side anastomoses are usually tailored to enter the recipient artery or leave the donor artery at an acute angle. While this diminishes flow disturbances at the entrance to the graft and in the antegrade recipient limb, it accentuates disturbances in the retrograde recipient limb, where the flow vectors are almost completely reversed. No matter what construction is used, there will always be regions of flow separation that contribute to energy losses and, more importantly, to the development of initial thickening or thrombus formation (Fig. 5-20).[82,83] Thus, grafts of all sorts always introduce new hemodynamic problems while they decrease others.
Vasodilators and Sympathectomy Vasodilators and sympathectomy have little effect on collateral arteries and, therefore, can do little to reduce an elevated segmental resistance. Their function is to dilate the peripheral arterioles, principally in the skin of the more distal parts of the extremity. Since these arterioles are already maximally dilated in ischemic tissues, administration of vasodilators does not enhance blood flow to the critical areas. By dilating arterioles in nonischemic tissues distal to a proximal arterial obstruction, these drugs may actually cause a steal, which, at least theoretically, could be detrimental. Sympathectomy has the advantage of exerting its effect in a more limited area, thus minimizing the likelihood of a steal. Some surgeons feel that sympathectomy hastens demarcation of ischemic tissues, encourages healing of minor skin lesions, and decreases rest pain. The evidence, however, that sympathectomy has a beneficial effect is scant.[84 – 87] In patients with claudication, sympathectomy and vasodilator drugs do increase blood flow at rest in the nonischemic peripheral tissues. Since resting blood flow is already adequate in these limbs, the only potentially beneficial effect would be to increase the rate of flow through an arterial reconstruction, reducing the chance of thrombosis in the early postoperative period. Exercise itself is the most powerful dilator of intramuscular arterioles.[36,85,88,89] Because further dilatation is not possible, these measures are not helpful in the treatment of intermittent claudication (Fig. 5-21).[85,90,91]
Reducing Viscosity Blood with a hematocrit of 50% is about twice as viscous as that with a hematocrit of 30%; consequently, it is possible to augment blood flow somewhat by hemodilution.[92 – 94] Lowmolecular-weight dextran, which expands blood volume, raises cardiac output, decreases hematocrit, and reduces erythrocyte aggregation, has been used for this purpose. The effects, however, are unpredictable, difficult to control, and do not offer a long-term solution to the problems associated with chronic arterial obstructive disease. Pentoxifylline, a drug that increases erythrocyte flexibility and decreases plasma fibrinogen and platelet aggregation, has been shown to increase walking tolerance in claudicants, but again the results are variable.[95]
Figure 5-20. Flow patterns at end-to-side and side-to-end anastomoses. Note that blood may reverse and travel circumferentially to reach the recipient conduit. Areas where the mainstream flow is separated from that at the wall are prone to neointimal hyperplasia. (Based on studies by LoGerfo, F.W. et al.[82] and Crawshaw, H.M. et al.[83] With permission.)
Collateral Dilatation Collateral development can be stimulated by exercise therapy, thus reducing segmental resistance. Not only are walking times increased appreciably when the patient adheres to an exercise program, but there may also be some improvement in the postexercise ankle pressure response.[75,94 – 98] Most of the beneficial effects, however, are probably metabolic and not hemodynamic in origin. But this mode of therapy is not applicable to patients with rest pain, and the beneficial effects are variable and are lost when the program is discontinued.
ARTERIOVENOUS FISTULAS The components of a typical vascular circuit containing an arteriovenous fistula are illustrated in Fig. 5-22. With appropriate modifications, all arteriovenous fistulas, regardless of their complexity, conform to this basic model. Collateral arteries connect the proximal and distal arteries,
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Figure 5-21. Contrasting effects of sympathectomy and bypass grafting on blood flow during exercise. Peripheral resistance (represented by the faucet) is maximally decreased during exercise, and sympathectomy cannot further reduce resistance. Grafts, bypassing the obstruction, reduce segmental resistance and permit increased blood flow even when there is less peripheral vasodilation. [From Sumner, D.S.: Pathophysiology of arterial occlusive disease. In Hershey, F.B., Barnes, R.W., Sumner, D.S. (eds): Noninvasive Diagnosis of Vascular Disease. Pasadena, California, Appleton Davies, 1984, pp. 2 – 15. With permission.]
bypassing the abnormal communication. Similarly, on the venous side, collaterals connect the proximal and distal veins. The critical component of the circuit is the fistula itself, which can be classified as “large” or “small,” depending on its resistance relative to that of the contributing vessels. Fistulas with a narrow diameter or those that are quite long (e.g., a graft between the radial artery and brachial vein) have a high resistance, whereas those with a diameter approaching or exceeding that of the donor artery have a low resistance.[3,99] Blood always traverses the fistula from its arterial to its venous end, the rate of flow being determined by the resistance of the fistula and the arteriovenous pressure gradient (Fig. 5-22). Although flow is always directed distally in the proximal artery and proximally in the proximal vein, flow direction varies in the distal artery and vein, depending on the relative resistance of the components of the circuit.[3,99 – 102] When the fistula is “small,” a portion of the blood from the proximal artery continues past the fistula, flowing in the normal distal direction in the distal artery, where it joins the collateral inflow to supply the peripheral vascular bed. When the fistula is “large,” part of the collateral inflow is diverted into the distal artery, flowing retrograde up the artery to enter the fistula. In this event, the peripheral tissues are nourished only by input from the collateral arteries.
Figure 5-22. Diagram of typical H-type or side-to-side arteriovenous fistula.
In other words, the fistula “steals” blood from the peripheral vascular bed. The situation is duplicated on the venous side. Normal flow direction persists in the distal vein when the fistula is small, but the volume of flow is reduced.[99] When the fistula is large, there may be no reverse flow in the distal vein if the communication is acute and the valves remain competent. When, however, the fistula is chronic, the distal veins tend to expand, the valves become incompetent, and blood flows retrograde in the distal veins, returning to the central veins via collateral channels.[103,104] Peripheral arterial pressures (point 3 in Fig. 5-22) are always reduced in the presence of an arteriovenous communication, the extent of the pressure reduction increasing as the resistance of the fistula decreases.[3,99,105,106] When flow is reversed in the distal artery, the peripheral pressure (point 3) exceeds the pressure at the arterial end of the fistula (point 2).[100] Peripheral venous pressures (point 4) are always elevated, especially when there is reversed flow in the distal veins. The pressure at the venous end of the fistula (point 5) exceeds that at the periphery (point 4) when venous flow is retrograde; otherwise, the normal gradient is maintained.[100,105 – 107] In summary, all fistulas, regardless of size, tend to impair peripheral perfusion, decrease peripheral arterial pressure, and elevate peripheral venous pressure. Steals associated with “large” fistulas can seriously compromise blood flow to the distal tissues, producing ischemia and venous congestion.
Therapy Surgical obliteration of the abnormal communication restores normal hemodynamics and is the optimum form
Chapter 5.
of treatment. Ligation of the proximal artery, a procedure sometimes attempted in the past, is the worst approach.[3] This operation ensures that all flow through the fistula will be derived from the collateral arteries; thus an increasing proportion of the collateral input is diverted into the distal artery, further depriving the peripheral tissues of nutrition. On the other hand, quadruple ligation (ligation of all proximal and distal arteries and veins) may be an acceptable compromise. Although this procedure blocks the major inflow arteries and the major outflow veins, it eliminates the devastating effects of the steal. If the fistula is chronic, the collateral arteries and veins are usually well developed and are capable of sustaining peripheral perfusion. In fact, quadruple ligation usually increases peripheral arterial pressure and reduces peripheral venous pressure.[3] These parameters, however, seldom return to normal levels, unless the collateral supply is truly excellent (as it may be when the ulnar artery represents the collateral supply for a radial artery – cephalic vein fistula). When a significant steal accompanies a side-to-side arteriovenous fistula constructed for vascular access, relief can often be obtained by ligating the distal artery, provided the collateral arteries are well developed.[108] This operation maintains adequate flow through the fistula and ensures that the collateral input will be totally devoted to peripheral perfusion.
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shown that expansion of the coronary arterial wall may partially compensate for a reduction in the radius of the lumen produced by arteriosclerotic plaques.[112] Low shear rates, on the other hand, promote the development of atherosclerotic plaques and fibromuscular dysplasia.[113] This may explain the tendency for atherosclerotic plaques to develop in the carotid bulb, where expansion of the lumen results in flow separation, flow reversal, decreased velocity, and a low wall shear rate.[114] Similar flow disturbances leading to a reduction in shear rate occur in the vicinity of atherosclerotic plaques and at arterial graft anastomoses, again predisposing to dysplastic wall thickening.[82,83,115,116]
ANEURYSMS The circumferential stress t developed within an arterial wall is directly proportional to the transmural pressure P.[3,4] Transmural pressure is the difference between the blood pressure within the artery and the surrounding tissue pressure. Wall stress is also directly related to the inside radius ri of the artery and is inversely proportional to its wall thickness d:
t¼P
ri d
This explains why large aneurysms are more apt to rupture than small ones and why the risk of rupture is increased in hypertensive patients (Fig. 5-23). Rupture is more likely to
EFFECT OF SHEAR ON THE ARTERIAL WALL When flow is laminar, the velocity profile in a cylindrical vessel is parabolic, being maximal at the center and decreasing to zero at the wall. The ratio of the incremental decrease in velocity (2 dv ) to the incremental increase in radius (dr ), as measured from the center of the flow stream, is known as the shear rate (D ): D¼2
dv dr
ð5-14Þ
Shear stress (t ), which represents the force required to overcome the friction between contiguous layers of fluid, is the product of shear rate and viscosity (h ). At the arterial wall, shear rate (I )w) and shear stress (tw) are given by Dw ¼
4v ri
ð5-15Þ
tw ¼
4hv ri
ð5-16Þ
where v¯ represents the mean velocity across the flow stream and ri is the radius of the arterial lumen. Endothelium is capable of sensing shear. When shear is increased by an increasing velocity or by a decreasing radius, nitric oxide is released from the endothelium, promoting relaxation of the arterial wall.[109,110] This results in an increased radius, which tends to normalize shear. Thus, arteries proximal to an arteriovenous fistula dilate to compensate for an increased flow rate.[111] It has also been
Figure 5-23. Effect of increasing arterial diameter on tangential stress t. Original diameter (2.0 cm) and wall thickness (0.2 cm) correspond to that of a terminal aorta. Solid line assumes that cross-sectional area of the wall remains constant as the artery expands (wall thickness decreases). Broken line assumes constant wall thickness. Aneurysmal rupture occurs when stress exceeds tensile strength.
98
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occur when the wall is thin. Although most aneurysms have thicker walls than normal arteries, the collagen content, which is primarily responsible for tensile strength, may be diminished[117] or degraded.[118] In other words, the functional thickness of an aneurysmal wall may be less than that of a normal artery. According to recently reported computer simulations, the thick layer of clot that develops in most aneurysms may reduce wall stress by as much as 50% and provide some protection against rupture.[119 – 121] While collagen degradation weakens the aneurysm wall and is responsible for rupture, expansion is most likely a function of decreased elastin content.[117,118,122]
CONCLUSION A basic knowledge of hemodynamic principles is necessary to understand the adverse effects that obstructive arterial disease has on the circulation to the multiple organs of the body. Although the factors governing pressure-flow relationships, velocity profiles, blood flow patterns, arterial wall properties, and metabolic interactions are exceedingly complicated and remain a fertile area for investigation, one can work with the knowledge currently on hand to enhance diagnostic accuracy and therapeutic capabilities.
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CHAPTER 6
Clinical Examination of the Vascular System Joshua A. Beckman Mark A. Creager than those supplying the upper extremities. Approximately 9% of the population over the age of 55 have evidence of peripheral arterial disease as assessed by noninvasive testing, but only 2.5% of them are symptomatic.[1,2] The subclinical presence of atherosclerosis is important to discern for it conveys information about the probability of co-existing coronary artery disease and prognostic information about the patient’s survival. There are two cardinal symptoms: claudication and rest pain. The word claudication derives from the Latin and French, claudicatio and claudico, respectively, and was commonly used to describe a lame horse. Claudication is exertion-induced discomfort described as pain in the extremity that is exacerbated with further exercise and relieved with rest. As such, it occurs intermittently, hence the term intermittent claudication. The discomfort is commonly described as a cramping, burning, aching, or fatigue. Both lower and upper extremities may develop these symptoms. The discomfort recurs in the same area with each provocation. Typically, specific activities like walking or brushing one’s hair will cause discomfort at the same level of exertion each time in the legs and arms, respectively. The location of discomfort is a clue to the site of greatest stenosis. Symptoms generally occur in the most proximal muscle area with inadequate perfusion. Thus, severe iliac stenoses often will cause discomfort in the buttock or thigh, while superficial femoral and infrapopliteal arterial disease cause calf and pedal symptoms, respectively. Symptoms may develop in more than one area, like the thigh and calf, depending on the location and severity of the stenoses. Patients with chronic occlusive disease may occasionally be unaware of a specific limitation or progression in their symptoms. Subconsciously, patients may accommodate their lifestyle to the limitations imposed by the limited blood flow. Specific questioning about the discomfort should exact a reliable amount of exercise required. Certain activities can act as benchmarks to follow disease progression. Examples include flights of stairs climbed or blocks walked prior to onset of pain. Each of these may be compromised, however, by a slowing of pace. Thus, while questioning the patient
INTRODUCTION Vascular diseases comprise disorders of the arteries, veins, and lymphatics. This chapter will review the salient features of the history and physical examination of common circulatory diseases such as peripheral arterial disease, chronic venous insufficiency, and lymphedema. Complete examination of the patient with vascular disease requires an appreciation of the whole patient with focus on specific findings. As will be apparent later in the chapter, multi-system diseases can easily be missed with a limited perspective. Adequate synthesis of signs and symptoms necessitates generating a broad differential diagnosis. The confines of this chapter preclude a full discussion of the comprehensive history and physical exam, but accurate diagnosis and treatment depend on it.
ARTERIAL DISEASES Arterial disease can be classified as occlusive or aneurysmal. Arterial occlusive disease can be caused by atherosclerosis, inflammation (vasculitis), external compression (e.g., popliteal artery entrapment), or thrombo-embolism. There may be similarities among the complaints upon presentation, but each has specific historical and clinical features that enable the examiner to focus in on the correct diagnosis. The arterial vascular examination should be performed consistently with special examinations performed as dictated by the history. This chapter will describe the historical features of the disease processes and then the physical exam to match the physicianpatient encounter.
Peripheral Arterial Disease Peripheral arterial disease (PAD) is a term generally applied to atherosclerosis of the limb vasculature. The arteries supplying the lower extremities are affected more frequently
Hobson/Wilson/Veith: Vascular Surgery: Principles and Practice, Third Edition, Revised and Expanded DOI: 10.1081/0819-9-120024889 Copyright q 2004 by Marcel Dekker, Inc.
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about the activities that provoke discomfort, the physician should try to formulate an understanding about the patient’s activity level in general and whether it is changing. Relief from discomfort with a discrete period of rest is a hallmark of claudication. Just as the pain should develop with a predictable amount of exertion, relief should require a consistent period on each occasion. Whether that relief comes with sitting, standing, or reclining, the patient will be able to quantify it. Pain that is relieved immediately upon cessation of activity is not claudication and not related to inadequate perfusion. Pain that results from specific positional changes, occurs while lying, or can be relieved by activity is not a consequence of peripheral arterial disease and may be neuropathic or musculoskeletal in origin. Age of onset and disease progression can also provide clues to the cause of the arterial occlusive disease. The presence of arterial occlusive disease in younger patients should prompt examination for etiologies that can exacerbate the development and progression of atherosclerosis like hyperhomocysteinemia and familial hypercholesterolemia and for other causes like vasculitis or arterial entrapment. Atherosclerosis is usually a disease of slow progression. The time course for disease evolution is over years. The initial symptoms generally occur during periods of extreme exertion and may remain undiagnosed. As the disease progresses, the process of plaque rupture and thrombosis may lead to periods of waxing and waning symptom progression. Disease processes that proceed more rapidly may indicate the presence of exacerbating factors like diabetes mellitus. A thorough history that acquires a complete set symptoms is usually the most sensitive means to diagnose a condition. Several questionnaires have been devised and evaluated for the diagnosis of claudication. The Rose questionnaire was the first device created to assess claudication.[3] Its low diagnostic sensitivity has decreased its use. These devices provide a written standard to accompany exercise testing for changes in the disease. The Walking Impairment Questionnaire evaluates both the extent of walking impairment and its etiology. Six questions characterize the patient’s difficulty in walking a defined distance and four the walking speed. Specific symptoms are also evaluated to infer the source of walking limitation including aching in the calf or thigh (claudication), joint pain or stiffness (arthritis), leg weakness (neurologic), and chest discomfort and shortness of breath (cardiovascular). The disease-specific Walking Impairment questionnaire has been validated and can be used to assess baseline functioning and changes after therapy.[4] The San Diego questionnaire is another valid assessment device.[5] Rest pain occurs when the perfusion pressure during inactivity is inadequate to meet basal requirements. The lack of blood flow may affect all of the structures of the extremity including cutaneous, muscular, nervous, and bony. The pain affects the most acral part of the limb, usually the toes or foot. The most severe pain occurs at the site of tissue breakdown. Other complaints include sensitivity to cold, weakness, joint stiffness, and hypesthesia. When perfusion pressure drops low enough to cause rest pain, gravity plays an important role in blood supply. Patients will report more pain at night when the leg is elevated and mitigation of pain with leg dependency, as occurs when dangling from the bed.
Vasculitis Inflammation of the blood vessel wall can cause the development of stenotic lesions, aneurysmal dilation, and constitutional symptoms. Important clinical entities that affect large and medium sized arteries include Takayasu’s arteritis, giant cell (temporal) arteritis, and Buerger’s disease (thromboangiitis obliterans). Takayasu’s arteritis (TA), also known as pulseless disease, was first described by and named for a Japanese ophthalmologist. At one time thought to be a disease primarily of the East Asian rim, TA has been described worldwide. This large vessel vasculitis affects elastic arteries, specifically the aorta and its branches. Women are more commonly affected than men. This is a disease of younger adults. The most common age of onset is the third to fifth decades of life, although it has been diagnosed beyond this range. Early in the course of the disease, patients may report nonspecific constitutional symptoms like fever, weight loss, malaise, arthralgias, and myalgias. These may last months and occasionally years. The continuing arterial inflammation causes progressive stenosis yielding upper more commonly than lower extremity claudication, strokes, renal artery stenosis, and myocardial infarction. The ostial portion of the coronary and renal arteries, as an extension of aortic disease, is the most likely affected area. Any secondary or tertiary branch from the aorta may develop a stenotic or aneurysmal lesion. The presentation of upper extremity symptoms out of proportion to lower extremity complaints should prompt an investigation into large vessel vasculitis. Giant cell (temporal) arteritis (GCA) is another elastic artery vasculitis that tends to involve the secondary and tertiary branches of the thoracic aorta, but may present with abdominal aortic disease. GCA is a disease of the elderly. The incidence climbs from 1.5 per 100,000 age 50 –59 years to nearly 30 per 100,000 age 70–79 years.[6] Women are more likely to be affected than men. Up to 15% of patients with GCA may have their most significant stenosis or aneurysm in the aorta, arch vessels, coronary arteries, or even lower extremities. Presenting complaints may include arm or leg claudication. More commonly patients report visual changes like amaurosis fugax, headaches, and jaw claudication. However, it is not unusual that the primary complaints concern constitutional changes like fever and malaise. About half of patients will have symptoms of polymyalgia rheumatica, including proximal muscle stiffness and pain on active motion. In contrast to the two previous vasculitides, thromboangiitis obliterans (Buerger’s disease) is a bland inflammation of the extremities that occurs in the distal, small to medium arteries. Larger vessel involvement has been reported, but occurs rarely in the absence of small vessel disease. Symptoms of ischemia are the most common complaint. Patients describe hand or foot claudication. As the disease progresses, claudication may develop proximally and finger or toe ulceration may occur. Patients may complain of cold sensitivity, painful red nodules (i.e., superficial phlebitis), or report symptoms compatible with Raynaud’s phenomenon. The typical patient is a young male heavy smoker.
Chapter 6.
Acute Arterial Occlusion Sudden occlusion of an artery of the lower extremity may result from local thrombus formation or from an embolism originating at a more proximal site. Plaque rupture and its resultant thrombosis may occlude an atherosclerotic vessel. In patients with hypercoagulable states, thrombus formation may occlude an otherwise normal artery. Aortic dissection may occlude the vessels of the lower extremities because of the intimal flap from aortic dissection or propagation of the dissection into the limb. Trauma may damage the vessel directly and incite thrombosis in situ or cause a hematoma or compartment syndrome and occlude the vessel from external compression. The heart may be the source of emboli from dysrhythmias like atrial fibrillation, valvular abnormalities like mitral stenosis or prosthetic valves, and structural abnormalities like atrial myxoma. Patients with congestive heart failure are at greater risk for left ventricular thrombus which may embolize. Patients with lower extremity bypass grafts may develop graft occlusion at anastomotic sites and within the conduit. The usual time course for symptom development and progression in a patient with an acute arterial occlusion is hours. Sudden and dramatic decreases in perfusion cause symptoms that are related to ischemia of skin, musculature, and nerves. The range in clinical outcome, however, remains broad. New thrombosis may cause the asymptomatic loss of a pulse, a decreased threshold for claudication, or the sudden onset of severe pain at rest. The pain does not change locations, however, certain patients may present several days after the signal event with symptomatic progression and exacerbation caused by thrombus propagation. The decrease in blood flow can impair nerve function creating paresthesias and then numbness. In addition, paralysis may develop. The severity of the blood flow decrement dictates the symptoms appreciated. Sudden but moderate changes may not cause rest pain acutely but only decrease the exercise required for claudication. Severe changes may be associated with a sudden loss of limb strength and induce a fall. The presence of nervous complaints like paresthesias and muscular symptoms, like weakness or paralysis, indicate a greater severity of disease. The symptomatology of the presentation does not necessarily discriminate among etiologies.
Atheroembolism Atheroembolism arises from the atherosclerotic plaques of the aorta and its branches and is derived from the components of the plaques. These atheromatous emboli, variably composed of cholesterol crystals and fibrin and platelets, may occlude arteries and arterioles, often lodging in distal arteries, such as the plantar arch and digital arteries. The most common causes of atheroemboli are catheterization, aortic manipulation in surgery, and idiopathic. Nearly half of the presentations for atheroemboli have an unknown cause. Warfarin anticoagulation has been posited to cause atheroembolism at the case report level, but not proved. Thrombolytic agents do not necessarily increase the incidence of cholesterol embolization.[7] Patients will present with painful blue-violet spots on their toes (blue toe syndrome) and pain in their calves
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representing focal areas of ischemia. Depending on the site of origin, distal or proximal to the bifurcation of the aorta, symptoms may develop on one side or bilaterally, respectively. The symptoms are usually sudden in onset, may recur, and are slow to heal. The skin around the affected area may feel cool and demonstrate livedo reticularis.
Miscellaneous Thoracic Outlet Syndrome The patient that presents with upper extremity complaints reminiscent of claudication or vascular insufficiency, but reports that it is positional, may have thoracic outlet syndrome. In this syndrome, the axillo-subclavian artery is compressed, usually by a cervical rib, abnormal insertion of the scalene anticus muscle, or apposition of the clavicle and first rib during arm lifting, arm extension, or head turning. Patients may complain of weakness, fatigue, or heaviness with activities performed above the shoulder. Common complaints include difficulty with hair washing or brushing and cleaning high places. This complex of symptoms may be mimicked by nerve compression instead of diminished arterial flow. The physical exam can discern between these two processes. Repetitive stress on the artery may damage the intimal lining of the artery and lead to aneurysm formation and its sequelae.
Popliteal Artery Entrapment Intermittent claudication is unusual among patients under the age of 50. One cause among this population is popliteal artery entrapment. The artery may be displaced or compressed by the medial head of the gastrocnemius muscle. The popliteal artery usually courses along the popliteal veins in between the medial and lateral heads of the gastrocnemius vein. Less common sources of entrapment include fibrous bands or the popliteus muscle. In addition to intermittent claudication, patients may complain about tingling and pain at rest, depending on the severity of compression.
Reflex Sympathetic Dystrophy Reflex sympathetic dystrophy (RSD), or causalgia, is a progressive painful disorder that usually stems from an injury to the soft tissue or neural tissue of an extremity, although there are nontraumatic etiologies, including malignancy and myocardial infarction. After the precipitant, the patient develops complaints consistent with autonomic nervous dysfunction including color changes, alterations in limb temperature, and edema. Three stages have been described in the disease. Each stage may last from weeks to years, but 3 –6 months is the common duration of each stage. Initially, in the acute or hyperemic stage, the area of injury is warm, erythematous, and swollen. In the second or dystrophic (ischemic) stage, the skin may be cool, pale or cyanotic, and clammy. The nails may develop ridges and become brittle while the hair on the extremities coarsens. During the third or atrophic stage, patients may report wasting in the entire extremity including the muscles, skin, and subcutaneous tissues. Attendant to this wasting is marked weakness, a cold sensation, and limited
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motion of the joints. The changes may become permanent during this stage. Pain is commonly the most prominent and enduring element in each stage of RSD. The pain is described as burning that is worse distally, diffuse, and occurs with little or no provocation. It tends to be palmar or plantar, and the subsequent symptoms are usually out of proportion to the severity of the initial injury. Small stimuli such as touch may provoke symptoms. Patients may report either hypersensitivity or diminished sensitivity to touch. Tissue ulceration may occur.
Raynaud’s Phenomenon Episodic vasospasm of the digital arteries in response to cold or emotional stress is the hallmark of Raynaud’s phenomenon. The classic description of the phenomenon includes three phases: digital pallor associated with arterial spasm and ischemia, cyanosis from the deoxygenated blood collecting in the dilated arterioles and venules, and rubor from rewarming and the subsequent hyperemia. Patients may report a sensation of cold or numbness during the first two phases and throbbing with hyperemia. All three phases do not need to be present to confer a diagnosis; some patients develop only pallor and/or cyanosis. Reproduction of the color response is usually difficult to induce in the office, and the diagnosis is usually made on the basis of historical information. These changes occur additionally in the toes in 40% of the patients, and rarely in the nose, earlobes, and tongue. The range of severity is wide from intermittent, mild attacks to the prolonged vasospasm with development of ulceration and gangrene. The primary form of Raynaud’s disease is typically benign with a rate of , 1% of tissue loss. The diagnostic criteria for the idiopathic form include intermittent attacks of ischemic discoloration of the extremities, absence of an arterial occlusion, a bilateral distribution, trophic changes limited to the skin, the absence of any symptoms or signs of a systemic disease that may cause Raynaud’s phenomenon, and the presence of symptoms for more than 2 years. Women comprise 70–80% of patients. The onset of symptoms may occur between menarche and menopause, but typically occurs before the age of 40. The secondary form of the phenomenon should be suspected in patients that present with symptoms that do not occur evenly in all digits, have prolonged vasospasm despite rewarming, or develop tissue loss. The secondary causes of Raynaud’s phenomenon include vasculitides like scleroderma, arterial occlusive disease including atherosclerosis, neurologic disorders, blood dyscrasias, trauma, and drug reaction. The development of symptoms unilaterally or after the age of 45 should prompt an investigation for a primary cause.
review. The patient should be in a comfortable position to avoid muscle tensing. The examiner should use the fingertips of the hand and avoid the thumb. The thumb pulse may be large enough to transmit sensation great enough to cause a misperception of the patient’s pulse. Palpation should begin lightly and increase in pressure gradually. Pulses may be palpated in the neck, arms, legs, and trunk. Subtle changes in pulse contour may be defined by comparing each pulse bilaterally. In the neck, the carotid pulse may be palpated between the trachea and the sternocleidomastoid muscles. It may be examined from the base of the neck to the angle of the jaw. In addition to impulse strength, pulse contour can impart information concerning proximal stenosis, valvular heart disease, and ventricular abnormalities. Palpation should be performed lightly at first, especially in older patients, for the carotid body may be sensitive and promote bradycardia and hypotension. The subclavian pulse may be palpated in two locations: in the supraclavicular fossa and between the lateral clavicle and pectoralis muscle. Upper extremity pulses typically examined include the brachial, radial, and ulnar pulses. The brachial pulse is found in the medial third of the antecubital fossa. The pulse is superficial and requires only a mild pressure. It may be traced back along the inferior border of the biceps muscle. The radial pulse is palpated in the wrist at the base of the first digit (Fig. 6-1). It is a superficial, usually brisk pulse and easy to appreciate. The ulnar pulse, in contrast, courses deeper and may be obscured by muscle. It requires deeper palpation and may be difficult to detect. Detection of both pulses in the wrist may be improved by supporting the subject’s hand to relax the muscles in the wrist with one hand while palpating the pulses with the other. Pulses may be examined at three levels in the lower extremities. The common femoral artery pulse can be examined just below or above the inguinal ligament. It lies medial to the quadriceps muscle. Obesity may obscure local landmarks. Lateral rotation of the leg, retraction of the overhanging pannus, and palpation using four fingers across can aid in detection. The common femoral artery can be palpated several centimeters proximal to the inguinal ligament in thin patients. The popliteal artery pulse is more
ARTERIAL PHYSICAL EXAM Pulse Examination of the arteries begins with the pulse examination. The pulse examination should be performed in a consistent manner by the examiner to ensure a complete
Figure 6-1.
Palpation of the radial pulse.
Chapter 6.
difficult to palpate. Generally located between the medial and lateral third of the popliteal fossa, the pulse is commonly obscured by the overlying muscle. The patient’s leg should be mildly flexed and relaxed. The examiner should use four fingers from both hands to palpate in the fossa while applying a moderate counter pressure via the thumbs on the knee cap. The pulse is a transmitted impulse and generally not discrete. The posterior tibial pulse can be found below the medial malleolus (Fig. 6-2). Gentle pressure with three or four fingers from above usually allows adequate palpation. Increased application of pressure may be counterproductive in patients with poor arterial perfusion, for examiners may confuse their own pulse for the patients. Relaxation and dorsiflexion of the foot improve detection. The dorsalis pedis pulse is found on dorsum of the foot between the second and third digital ligaments. It is usually 3–4 cm above the digits. In some cases, it may be found more laterally. Laying the fingers from both hands across the dorsum of the foot can help in the detection of difficult pulses. Because it is absent congenitally in approximately 10% of patients, its absence may not be pathological.[8] Certain clinical conditions require the palpation of additional pulses. The temporal arteries, which extend anteriorly and superiorly from the ear, can be palpated with gentle pressure applied by three fingers. Induration, warmth, erythema, and tenderness of this pulse may indicate temporal arteritis. The occipital arteries may be palpated approximately 2 cm laterally from the midline at the base of the occiput and should be examined for the same abnormalities as the temporal arteries. Coarction of the aorta causes excess blood flow through the costal arteries. Pulses, generally not appreciable, may be palpated at the base of the scapula and subcostally in the upper ribs.
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extrinsic compression, aneurysmal dilation, or arteriovenous connection. The proximal location of a bruit defines the location of turbulent flow, but auscultation of the bruit may propagate for an additional five centimeters. The transmitted sound is reflective of the originating vessel and the severity of the stenosis. Larger vessels like the femoral, carotid (Fig. 6-3), and subclavian arteries will usually transmit lower-pitched bruits in smaller vessels in the abdomen will be higher. As the severity of stenosis progresses, the pitch of bruits increases. Thus, severely stenotic large arteries may convey a high-pitched sound. As a stenosis progresses to near occlusion, the intensity of the bruit may decrease and then disappear. The span of the bruit also carries significance. Continuation into diastole implies an advanced stenosis. Continuous bruits traverse both systole and diastole and are pathognomonic for arterio-venous connections. These may be found in the fistulas of Osler-Weber-Rendu disease and at the sites of percutaneous catheter interventions.
Aneurysms
Auscultation of the normal vessel should reveal no sound. The presence of a bruit, sounds caused by turbulence of blood flow, represent alteration in flow because of arterial stenosis,
The abnormal increase in size of a blood vessel can augment its pulse. Abnormal enlargement is called ectasia, while expansion greater than 150% of a proximal segment is defined as an aneurysm. Most aneuryms of the chest and abdomen are discovered via incidental radiographic imaging. Abdominal aortic aneuryms may be detected on physical examination. Examination of the abdominal aorta requires cooperation of the patient. The examiner should gradually increase pressure in the midline using all eight fingers. Attempts should be made to relax the patient and the abdominal musculature. Both sides of the aneurysm are generally pulsatile. Once the pulse is identified, the lateral borders should be approximated using both hands and the diameter estimated. Detection is directly related to aneurysm size and inversely related to patient abdominal girth. Pulsatile expansion detected below the umbilicus indicates extension into the iliac arteries. Significant discomfort during the exam is unusual and may represent recent expansion, an inflammatory aneurysm, or a
Figure 6-2. Palpation of the posterior tibial pulse with three fingers from above applying mild to moderate pressure with counterpressure from the thumb.
Figure 6-3. Auscultation of bruits should be performed using the bell of the stethoscope to ensure an adequate skin seal and amplify their lower pitch.
Bruit
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contained rupture. A seroma may obscure the pulse on one side. Abdominal ultrasound is usually required to differentiate among the varying causes. The next two most common locations for aneurysms, the femoral and popliteal arteries, are readily palpable. Popliteal aneurysms are commonly bilateral and frequently are associated with abdominal aortic aneurysms. Both of these lesions commonly embolize and may present with claudicatory symptoms or blue toe syndrome. Femoral aneurysms are commonly detected by patients. As the aneurysms grow, they may compress first the adjacent vein to produce edema and then cause neuropathy. The carotid pulse is also readily palpable, allowing for aneurysm detection. Carotid artery tortuosity is a more common cause of an increased pulse than aneurysm, and ultrasound differentiation is usually required.
FURTHER EXAMINATIONS
arterial occlusive disease and allow for quantification of exercise tolerance. As the patient exercises, there is an incremental drop in perfusion pressure and ankle-brachial index across the lesion as energy is lost into the lesion and resistance vessels relax. Patients may be exercised on a treadmill using any standard protocol. Ankle pulse pressure should be obtained in both foot locations prior to exertion. Upon discontinuation of exercise, the patient should immediately lie supine on a stretcher and the ankle pulses palpated and ankle pressures examined by Doppler ultrasound (Fig. 6-4). In patients with peripheral arterial diseases, assessment following exercise cessation should reveal a decreased or near absent pulse and a decrease in anklebrachial index by more than 20%. As the severity of the lesion progresses, the time to return to baseline levels increases. To demonstrate the same phenomenon in the office, the examiner can have the patient stand on his toes repeatedly until symptoms develop and remeasure the distal pulses.
The Allen Test
Examination of the Skin
The circulation of the hand is supplied by the radial and ulnar arteries. These arteries, in most people, form two ends of the palmar arches. Thus adequate hand blood supply can arise from either vessel. Five to 10% of the population has a congenitally incomplete arch. Rheumatologic diseases like the CREST variant of scleroderma, vasculitides like thromboangiitis obliterans, and emboli from subclavian artery aneurysms preferentially affect the distal vessels. The Allen test can demonstrate the presence of an incomplete palmar arch. Occlusive pressure is applied over the radial and ulnar pulses. The patient is asked to open and close the fist several times and create palmar pallor. The examiner then releases one pulse. Normal skin color should return within seconds. The other branch of the arch is then tested in the same manner. Slowly resolving or persistent palmar pallor reveal an incomplete arch or occluded artery distal to the pulse.
Variations in the skin may render clues to the underlying vascular pathology. The patient with chronic occlusive disease may demonstrate absence of hair, thickened toe nails, mild pallor, and cool limbs. Chronic hypoperfusion may result in loss of muscle size and subcutaneous atrophy. Skin temperature is best assessed with the back of the hand. The examiner sequentially places a hand on each arm or leg. Even subtle differences in temperature, as low as 0.58C, may be appreciated. Arterial occlusive disease or embolic phenomena may lead to the formation of ischemic ulcers. The ulcers tend to be small, annular, pale, and desiccated because of inadequate perfusion (Fig. 6-5). They are usually located in the acral areas of the limbs, specifically the toes, heel, and finger tips, but may be found more proximally particularly at sites of trauma. Ischemic ulcers may be as small as 3 mm in diameter.
Leg Elevation Elicited changes in skin color can aid in the determination of perfusion. The patient should lie supine on the examining table. Lower extremity pallor while horizontal is indicative of markedly low perfusion and critical ischemia. If pallor is not evident in the horizontal position, the patient’s leg is elevated to 608 for one minute. Severe occlusive disease is suggested if pallor develops within 15 seconds. At one minute, the leg is lowered and the patient sits up. The pedal veins are examined for refill time. Normal patients have pedal venous refill in less than 15 seconds. Arterial occlusive disease subserved by collateral vessels is suspected if refill requires 30– 45 seconds, while severe disease with poor collateral development is likely present if venous filling time is longer than one minute.
Exercise Testing On occasion, a patient will present with complaints typical of arterial occlusive disease yet have a normal physical examination. Exercise can bring out signs consistent with
Figure 6-4. Systolic pressures may be obtained in either the dorsalis pedis or posterior tibial positions. A blood pressure cuff is inflated to suprasystolic pressure and slowly released. The systolic pressure is considered to be the first appreciable Doppler ultrasound signal.
Chapter 6.
Figure 6-5. Arterial ulcers are small, annular, and pale, usually occurring in the acral region of the lower extremity.
The ulcers show postural changes in hue. Ischemic ulcers are painful in contrast to the painless neurotrophic ulcers of diabetes. Diabetic ulcers, which frequently occur in the setting of lower extremity arterial occlusive disease, occur in the area of callus formation, bony prominence, or areas exposed to trauma such as those caused by ill-fitting shoes. Progression of ulceration leads to tissue necrosis and gangrene. Gangrene represents an area of dead tissue that blackens, mummifies, and sloughs. Prolonged leg dependency for pain amelioration may cause foot and ankle swelling in patients with critical limb ischemia. Skin hue can provide clues to the type and severity of disease. Livedo reticularis is a discoloration of the skin in a lace-like pattern. The “laces” vary from red to blue and surround a central clear area. It is usually found in the extremities, is associated with cool skin, and may be painful. The color changes are augmented by cold exposure. Both primary and secondary forms may occur and may be complicated by ulceration. The benign form is more common in women. The secondary forms may be seen accompanying vasculitis, atheroemboli, hyperviscosity syndromes, endocrine abnormalities, and infections. In the secondary form the lesions are more diffuse. Patients may develop purpuric lesions and cutaneous nodules that progress to ulceration in response to cold. The microcirculation frequently provides clues in the skin for diagnosis. Punctate violaceous lesions, splinter hemorrhages, and focal areas of cyanosis are indicative of microemboli. Lesions may be single or multiple, involve single or multiple territories, and may be associated with new onset unilateral Raynaud’s phenomenon. The lesions are usually approximately 1 mm in diameter and painful. Microcirculatory infarcts may lead to digital pitting. Whether the cause is persistent vasospasm in Raynaud’s disease or microemboli, the microinfarcts present as punctate areas of skin loss that resemble pits in the skin of the distal digit.
Thoracic Outlet Maneuvers The thoracic outlet is the site of possible interruption of any component of the neurovascular bundle as they exit
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the chest to each arm. Paresthesias and numbness of the arm in the absence of edema or a diminished pulse point to a neuropathic origin, and electromyographic testing may be necessary for diagnosis. Compression of the subclavian artery may be detected by several bedside maneuvers. Palpation of the supraclavicular fossa or neck may reveal the presence of a seventh cervical rib. To demonstrate the positional interruption of arterial flow, the examiner should hold the radial pulse in one hand and maneuver the arm with the other. The subclavian artery should be auscultated in the supraclavicular fossa. The presence of thoracic outlet syndrome is suspected by the development of a subclavian bruit and loss of the radial pulse during these maneuvers. The right and left sides should be examined in sequence. The hyperabduction maneuver calls for the arm to be raised above the head without rotation of the shoulder while the patient is seated and looking forward (Fig. 6-6). The Adson maneuver has the patient maneuver the neck. While seated with hands in the lap, the patient is asked to rotate the head toward the symptomatic side and extend the neck, thus looking up and over the shoulder, and simultaneously to perform exaggerated respiration. For the costoclavicular maneuvers, the patient both actively and passively thrusts his shoulders back and inferiorly. The maneuvers may be combined in the evaluation of specific symptoms. However, general application of these examinations are not warranted for they may be positive in up to 50% of the population and therefore carry significance only in symptomatic patients.
THE VENOUS SYSTEM In contrast to the stark signs and symptoms of arterial insufficiency, venous disease is more passive and demonstrates fewer signs. The complaints are less common, and the physical exam is more subtle. Objective testing is commonly required for diagnosis.
Figure 6-6. The hyperabduction maneuver is considered positive if, during arm raise, either a new bruit is appreciated in the subclavian fossa or the radial pulse disappears.
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History Varicose Veins Varicose veins are dilated and tortuous segments of superficial veins. They occur in up to 20% of the population. The inciting event may be an incompetent venous valve, structural abnormality of the venous wall, or elevated intraluminal venous pressures. Varicose veins may be primary or secondary. The primary form is more common in women, and approximately half of the patients will report a family history. The presence of a genetic component implies an inherited abnormality of the venous wall. Varicose vein development is incremental. An initial dilation may cause valvular incompetence, thus increasing intraluminal pressure. The superficial venous ectasia progresses as valvular incompetence increases the orthostatic pressure exerted on the distal valves. Secondary varicose veins occur as a result of deep vein thrombosis or insufficiency in concert with perforator vein incompetence. Initially competent collateral channels, the superficial veins are subjected to increased flow and pressure and progressively dilate. The dilation causes insufficiency, increased intraluminal pressures, and yields varicose veins. Obesity, pregnancy, and prolonged standing exacerbate both primary and secondary forms of the disease. Common complaints include pruritus, burning, and aching. Relief can usually obtained with leg elevation. Women may report premenstrual exacerbation of symptoms. The greater saphenous veins are involved in about 80% of patients. Sequelae include dermatitis, ulceration, superficial phlebitis, and rupture with hemorrhage. The hemorrhage may be dangerous for it is usually painless, although it is rarely fatal. Superficial thrombophlebitis is not uncommon in these vessels. The poor cosmetic appearance provokes most office visits.
Chronic Venous Insufficiency The presence of persistent venous thrombosis or valvular insufficiency results in the development of chronic edema and characterizes chronic venous insufficiency. The most common cause of chronic venous insufficiency is deep vein thrombosis, although a primary abnormality of the venous valves may also cause the syndrome. Approximately 30% of all patients with deep vein thrombosis have symptoms, signs, or laboratory evidence of venous insufficiency within 5 years.[9] The inciting deep vein thrombosis may be asymptomatic, thus making a definitive diagnosis difficult. Increased proximal pressure in the venous system results in chronic hypertension, edema, and hyperpigmentation from hemosiderin deposition in the skin. The deposition of hemosiderin arises from red blood cell lysis and is preferentially deposited around the malleloli and pretibial regions. Swelling of the extremity is the most common complaint. Patients will report that the edema nadirs in the morning after a night of elevation and progresses with time spent upright with the extremity in a dependent position. Muscular contraction can exacerbate venous hypertension by augment-
ing venous reflux. Walking may cause a reproducible deep pressure or bursting sensation in the calf that is relieved with rest. Venous insufficiency related to valvular incompetence may cause burning, itching, eczema, or pain. Superficial varicosities in the medial aspect of the calf and ankle may develop as perforator veins become incompetent. The persistent presence of edema decreases perfusion pressure to the skin and may result in ulceration, typically at the level of the malleolus.
Thrombosis Superficial Vein Thrombosis Superficial vein thrombosis may present with a warm, erythematous, tender streak or cord that courses along the path of a superficial vein. The symptoms are a result of the local inflammation associated with the venous thrombosis (i.e., phlebitis). In contrast to the secondary signs of infection present in lymphangitis, such as including fever, chill, and regional lymphadenopathy, local complaints predominate in phlebitis. Superficial vein thrombosis often complicates venous varicosities. The most common cause of superficial thrombophlebitis is iatrogenic, specifically indwelling catheters. Several syndromes are associated with recurrent or migrating superficial thrombophlebitis. Trousseau’s syndrome or migratory superficial phlebitis is seen in pancreatic cancer. Venulitis is common to two rheumatologic diseases, Bechet’s and Buerger’s disease (thromboangiitis obliterans). The latter commonly presents as an annular lesion, instead of as an erythematous streak.
Deep Vein Thrombosis Lower extremity deep vein thrombosis (DVT) may be asymptomatic. The most common complaints include swelling, pain, pressure, or fullness in the affected extremity, although each and all of these may be absent. Patients may complain of pain with walking, specifically with pressure on the ball of the foot. Leg elevation ameliorates the symptoms. Most lower extremity deep vein thromboses are secondary and occur in the setting of immobilization, malignancy, or trauma. The most common cause of primary deep vein thrombosis is the resistance to breakdown of factor Va by activated protein C. This point mutation in the factor V Leiden is found in 30–40% of patients with primary deep vein thrombosis. Other causes include endogenous factor deficiencies like protein C or S, anticardiolipin antibody syndrome, and hyperhomocysteinemia. Other diagnoses whose presentation may be similar to deep vein thrombosis include ruptured Baker’s cyst, hematoma, muscle tear, or cellulitis. One variant of deep vein thrombosis that always manifests symptoms is phlegmasia. In phlegmasia cerulea dolens and phlegmasia cerulea alba, the great extent of thrombosis and its attendant inflammation cause enough edema and an increase in compartmental pressure in the leg to impair blood flow. A leg with phlegmasia cerulea dolens is cyanotic, painful, markedly swollen, and tender. Phlegmasia cerulea alba is further along the spectrum. Arterial inflow is severely limited and the leg is pallid from
Chapter 6.
ischemia. This condition is not uncommonly confused with acute arterial occlusion, but may be differentiated by the physical exam. Effort-induced axillo-subclavian thrombosis, the PagetSchroetter syndrome, presents in a different population than classic lower extremity DVTs. The patient is usually young, athletic, and muscular. These patients complain of activityinduced swelling, heaviness, and early fatigue in the affected arm. The thrombosis is associated with repeated upper extremity physical exertion and presents with recurrent complaints of repeated swelling with effort. As venous collaterals develop, the extent of edema with activity will diminish, but the feelings of early fatigue and arm heaviness do not. The syndrome results from compression of the axillosubclavian vein, usually from a scalene tendon or a bony hyperostosis.
PHYSICAL EXAM Varicose Veins Superficial varicosities appear as dilated, tortuous, superficial veins. In some cases, multiple venous varicosities may feel and appear like a cluster of grapes. Dependent position increases their size with blood reflux. Once filled, the veins may demonstrate a fluid wave with balloting. “Spider veins” or venous telangiectasias are commonly confused for superficial venous varicose veins. The spider veins are small, cutaneous veins that manifest in a caput medusa pattern. Also known as spider hemangiomas, they may occur individually or in clusters.
Venous Insufficiency Superficial venous varicosities may result from superficial venous incompetence or from deep venous thrombosis or insufficiency. The examiner can distinguish superficial from deep/perforator venous incompetence at the bedside using the Brodie-Trendelenburg test. With the patient supine, the leg is elevated and a tourniquet applied after the veins have drained. Upon standing, veins below the tourniquet will fill slowly. Venous refill in less than half a minute is evidence of an incompetent deep and perforator system. If refill is slower, the superficial system should be examined after tourniquet release. Rapid retrograde superficial venous filling indicates superficial venous incompetence. The Perthes test can evaluate the cause of deep vein incompetence. A tourniquet is applied at mid-thigh or the proximal calf. The patient then walks. If the varicosities become visible, perforator and deep vein insufficiency are the cause. If there is proximal obstruction to flow, the patient develops claudication because the superficial return is eliminated. With chronic venous insufficiency, the physical examination may demonstrate fibrosis, tenderness, excoriation, skin induration from hyperkeratosis, cellulitis, and ulceration. The chronic inflammation causes fibrosis and induration of the skin. Hemosiderin deposition results in a brownish pigmentation. These yield the characterization of
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the limb as “brawny.” The ulcers, in contrast to the welldefined, pallid arterial ulcers, are large with irregular borders, erythematous, and moist. They are usually located near the medial or lateral malleolus. The base of the ulcer is composed of granulation tissue. The skin around the ulcer may be shiny.
Thrombosis The patient with superficial vein thrombosis may present with venous distension, a palpable venous cord, erythema, warmth, or tenderness, findings that are usually sufficient to make the diagnosis. The bedside diagnosis of deep vein thrombosis is more difficult. During the examination of a patient suspected of having a deep vein thrombosis, the examiner must scrutinize the extremities carefully in the supine and standing positions. Patients need to be examined both lying and standing since venous distension will be exacerbated in the upright position. The routinely associated physical exam maneuver, the Homan’s sign of pain with passive foot dorsiflexion, misses the diagnosis as commonly as it makes it. The most common physical findings of deep vein thrombosis include unilateral leg swelling, warmth, and erythema. The patient may have tenderness over the involved vein, and a cord may be palpable. Cords are most frequently palpated in the common femoral vein just below the inguinal ligament and in the superficial femoral vein along the anteromedial aspect of the thigh. The examiner may be able to detect unilateral superficial engorgement, alteration of the contours of the thigh, calf, or ankle, and compressive masses in the popliteal space or groin. The leg may be frankly edematous or the calf or thigh muscles may feel boggy and engorged. There may be palpable temperature difference between the warmer affected and normal lower extremity. Superficial venous prominence is more likely to be demonstrated in the standing position. The patient with phlegmasia cerulea dolens will have a painful, edematous, cyanotic limb. The development of this severe form of deep vein thrombosis requires an overwhelming thrombotic burden to impair venous return and cause stasis of deoxygenated blood. The casual examiner may mistake phlegmasia cerulea alba for an acute arterial occlusion. The extreme edema and inflammation of phlegmasia cerulea alba results from impedance of arteriolar and capillary flow causing pallor. The leg, however, will be edematous, turgid, and improved with elevation unlike a limb with arterial occlusive disease.
LYMPHATIC DISEASE History Lymphedema Lymphedema results from production of interstitial fluid that exceeds the drainage capacity of the lymphatics. Thus lymphedema may result from excess interstitial fluid sequestration from the veins and impaired lymphatic return.
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The former is commonly related to venous insufficiency. The latter is described as lymphedema and may result from lymphatic absence, underdevelopment, or obstruction. There are three types of primary lymphedema: congenital lymphedema appears near or at birth; lymphedema praecox develops around puberty; and lymphedema tarda begins after age 35. Primary lymphedema is also associated with Turner’s and Noonan’s syndrome. Secondary lymphedema may be acquired from a variety of conditions including recurrent bacterial lymphangitis, malignant obstruction of the lymphatics, nodal and lymphatic resection in cancer surgery, filariasis, contact dermatitis, tuberculosis, and pregnancy. Early in the course of lymphedema, the extravasated interstitial fluid is similar to venous insufficiency, feeling soft and improving with elevation. With time, the leg begins to feel wooden and stiff. The persistence of the edema allows for the development of cellulitis, lymphangitis, and proximal progression of the swelling.
Lymphangitis Infection of the lymphatic vessels results from extension from an infected or necrotic lesion. Patients may develop erythematous patches or a streak that extends proximally from the lesion. The infected vessel is associated with both pain and tenderness. Patients will usually have a high fever and shaking chills associated with bacterial infections. The chills commonly occur in the absence of other precipitating factors and recur frequently. The small red streak commonly expands to involve the entire limb. Injuries or fungal foot infections are common portals of entry. Recurrent attacks of lymphangitis result in lymphedema.
Physical Examination The patient with lymphedema will demonstrate edema similar to venous insufficiency early in the course. The edema is pitting and soft. At this stage, the “square toe” sign may aid in differentiating lymphedema from venous edema. In contrast to edema in venous insufficiency, lymphedema in the lower limbs
Figure 6-7. The “square-toe” sign and diffuse, nonpitting edema of lymphedema.
tends to extend to the boundary of the toes (Fig. 6-7). Over the course of years, the limb becomes wooden with progressive induration and fibrosis of the affected tissues. The skin becomes thickened with increased production of subcutaneous and adipose tissue. The edema at this stage is no longer pitting. The limb is clearly enlarged. The skin may appear verrucous at the toes. Examination of the patient with lymphangitis reveals a red streak that extends proximally from an inciting lesion. Later in the course, the entire limb may be erythematous, enlarged, and warm. There should not be evidence of venous congestion nor impairment of arterial flow. Usually there is induration of the regional lymph nodes.
REFERENCES 1. Murabito, J.M.; D’Agostino, R.B.; Silbershatz, H.; Wilson, W.F. Intermittent Claudication. A Risk Profile from The Framingham Heart Study. Circulation 1997, 96 (1), 44– 49. 2. Fowkes, F.G.; Housley, E.; Cawood, E.H.; Macintyre, C.C.; Ruckley, C.V.; Prescott, R.J. Edinburgh Artery Study: Prevalence of Asymptomatic and Symptomatic Peripheral Arterial Disease in the General Population. Int. J. Epidemiol. 1991, 20 (2), 384– 392. 3. Rose, G. The Diagnosis of Ischemic Heart Pain and Intermittent Claudication in Field Surveys. Bull. WHO 1962, 27, 645–658. 4. Regensteiner, J.; Steiner, J.; Panzer, R.; Hiatt, W. Evaluation of Walking Impairment Questionnaire in Patients with Peripheral Arterial Disease. J. Vasc. Med. Biol. 1990, 2, 142– 156.
5. Criqui, M.; Denenberg, J.; Bird, C.; Fronek, A.; Klauber, M.; Langer, R. The Correlation Between Symptoms and Noninvasive Test Results in Patients Referred for Peripheral Arterial Disease Testing. Vasc. Med. 1996, 1 (1), 65 – 71. 6. Huston, K.; Hunder, G.; Lie, J.; Kennedy, R.; Elveback, L. Temporal Arteritis: A 25 Year Epidemiologic, Clinical, and Pathologic Study. Ann. Int. Med. 1978, 88, 162– 167. 7. Blankenship, J.C.; Butler, M.; Garbes, A. Prospective Assessment of Cholesterol Embolization in Patients with Acute Myocardial Infarction Treated with Thrombolytic vs Conservative Therapy. Chest 1995, 107 (3), 662– 668. 8. Barnhosrt, D.; Barner, H. Prevalence of Congenitally Absent Pedal Pulses. N. Engl J. Med. 1968, 278, 264– 265. 9. Prandoni, P.; Lensing, A.; Prins, M. Long-Term Outcomes After Deep Venous Thrombosis of the Lower Extremities. Vasc. Med. 1998, 3 (1), 57– 60.
CHAPTER 7
Noninvasive Studies of Peripheral Vascular Disease James S. T. Yao the blood velocity. This is expressed mathematically as follows:
During the past two decades, noninvasive tests have emerged as routine laboratory procedures to provide diagnostic information and follow patients after reconstructive arterial surgery. In most hospitals, a noninvasive vascular laboratory is now an integral part of the diagnostic service. The purpose of this chapter is to describe the noninvasive techniques currently available for the evaluation of patients with peripheral arterial occlusive disease.
Change in frequency ðDoppler shiftÞ ¼ 2 fv cos u=C where f = frequency of incident sound beam, v = velocity, u = angle of incident sound beam to the vessel being examined (60 degrees), and C = velocity of sound in tissue. Since sound beam frequency, the angle of incidence, and the velocity of the sound in tissue are considered constant, the frequency shift is proportional to the blood flow velocity. It is important to note that the shift is directly related to the velocity of red blood cells and the cosine of the angle between the direction of blood flow and the ultrasound beam. When the Doppler angle approaches 90 degrees (cosine 908 = 0), the detection of the Doppler shift is jeopardized. The ideal Doppler angle is 0 degrees (cosine 08 = 1), but this angle can rarely be achieved. In practice, Doppler angles between 45 and 60 degrees produce satisfactory clinical results. The instrument provides audible and recordable information and can be used in the office, at the bedside, and in the vascular laboratory. Basic arterial testing by Doppler includes flow velocity recording and segmental pressure measurement. The vessels examined in the lower extremity are the femoral, popliteal, posterior tibial, and dorsalis pedis arteries, or, alternatively, the lateral tarsal and digital arteries. For the recording of lower limb pressure, the bladder cuff should be 20% wider than the diameter of the limb. Examination of the upper extremity involves the subclavian, axillary, brachial, radial, and ulnar arteries and the digital vessels. Positional changes (military position, abduction and external rotation, hyperabduction) are utilized to determine the presence of thoracic outlet syndrome. In the normal artery, the audible signals consist of three sounds. The first sound is louder and of longer duration than the second and third components. Flow signals detected distal to an occlusion where collateral flow is present consist of a single sound and are low-pitched in character. When the flow probe is placed over a stenosis where high velocity is present, again, the second and third sounds are absent, and the sound is high-pitched with a hissing character. In the presence of turbulent flow, such as arteriovenous communication, the
INSTRUMENTATION Although plethysmography has played a role in noninvasive testing, ultrasound technology appears to dominate the field. Most vascular laboratories are now equipped with ultrasound equipment ranging from the simple transcutaneous Doppler to a duplex scanner or color flow imager.
Transcutaneous Doppler The transcutaneous Doppler flow velocity detector is the most commonly used instrument for arterial examination. A piezoelectric crystal will vibrate under the influence of an electric current, radiating energy in the form of sound waves. Such a crystal will also change dimension when hit by a moving sound wave, developing a voltage across the crystal. These properties allow the crystal to generate and also to detect sound waves. The waves emanating from the crystal are in the low-frequency ultrasound spectrum (1 –10 mHz) and do not harm living tissue. Lower frequency provides better tissue penetration and is best suited for the examination of deep arteries. Doppler instruments are based on the Doppler effect and on the properties of the piezoelectric crystal. Generated ultrasound waves penetrate the tissue and are backscattered by moving red blood cells. The Doppler shift in frequency between the transmitted and reflected sound is proportional to
Supported in part by the Alyce F. Salerno Foundation.
Hobson/Wilson/Veith: Vascular Surgery: Principles and Practice, Third Edition, Revised and Expanded DOI: 10.1081/0819-9-120024890 Copyright q 2004 by Marcel Dekker, Inc.
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sound is mixed, with high and low pitches, and is continuous in nature. In analog display, the flow velocity waveforms of the normal artery, like the audible sounds with three components, should be triphasic with a diastolic reverse flow (Fig. 7-1A). Once arteriosclerotic changes occur, the first change is turbulence during systole (Fig. 7-1B), followed by the loss of reverse flow (Fig. 71C through E). The systolic flow is progressively lost from stenosis to complete occlusion. In the presence of severe ischemia, the systolic flow waveforms flatten and become broader and nonpulsatile (Fig. 7-1F through H). The use of the Doppler flow probe has greatly facilitated the measurement of lower limb pressure. With this technique, recording of penile pressure with a small cuff (2.5 cm) is now also feasible.
Figure 7-1. Different patterns of flow velocity waveforms. (A ) Normal. (B ) Atherosclerotic changes of artery causing turbulence during systole (high frequency). (C and D ) Loss of reverse flow due to progression of degree of stenosis. (E to H ) With increasing arterial stenosis, the flow velocity waveform becomes progressively damped. [From Johnston, K.W.; Maruzzo, B.C.; Kassam, M. et al.: Methods of obtaining, processing and quantifying Doppler blood velocity waveforms. In Nicolaides, A.N.; Yao, J.S.T. (Eds): Investigation of Vascular Disorders. London, Churchill Livingstone, 1981, p 543. Reproduced by permission.]
Ankle pressures are slightly higher than arm pressures. On comparing lower extremity pressures with brachial pressures, the ratio (ankle/brachial) should be greater than or equal to 1 in normal patients; less than this suggests stenotic disease. Diabetic or other patients with calcified vessels are an exception because these vessels are not compressible; therefore, the ratios are not useful for interpretation. Claudicants generally have a pressure index (ankle-brachial) of 0.5–0.7. Patients with rest pain or other severe ischemic symptoms generally have a ratio of 0.3 or less. In diabetics with calcified arteries, inspection of flow velocity waveform recording from the pedal arteries in conjunction with toe pressure measurement will help to determine the degree of ischemia. The normal toe/brachial pressure ratio is 0.85 or greater. A penile/brachial ratio of less than 0.6 is consistent with vasculogenic impotence. The absolute pressure can be helpful in determining segmental occlusions both in the upper and lower extremities, as suggested above. A pressure level less than 40 mmHg is often associated with limb-threatening ischemia. As one observes pressures from low thigh to ankle, a 30 mmHg pressure drop indicates a severe stenotic or occlusive process. Therefore, if one observes a 30 mmHg pressure drop from the low thigh to the calf and a flattening of the waveform with lack of reverse flow, a popliteal occlusion is highly probable. Study of the upper extremity has shown that a 15 mmHg segmental drop is significant. Ischemic indices are greater than or equal to 0.9 for normal patients, average 0.6 for exertional pain patients, and are 0.3 for those with severe ischemia. It has been shown that a greater than 29 mm/s delay in the onset of stenotic flow is present in unilateral subclavian artery stenosis when brachial arteries are monitored. Distal fingertip ischemia is suggested by a 30 mmHg wrist-to-digit difference or a 15 mmHg finger-to-finger differentiation. Stress testing by treadmill exercise is done by having the patient walk on a treadmill at 4 km/h on a 12% grade or at 2.5 km/h for 5 min or until the patient must stop due to leg pain. The patient then resumes the supine position and brachial and ankle pressures are taken every minute or until they reach baseline level (10– 15 min). If treadmill exercise testing is not possible, an alternative stress test is by reactive hyperemia. The blood pressure cuff is inflated to 50 mmHg above the systolic pressure for 5 min, and ankle and brachial pressures are then recorded at 1-min intervals after deflation of the cuff until baseline is reached. Table 7-1 shows the normal values of lower limb pressure measurement at various levels.
Duplex and Color-Encoded Technology Recent development of duplex Doppler technology has made it possible to evaluate not only anatomic features of vessels but also physiologic aspects of blood flow in vessels in a variety of locations, including the renal, mesenteric, penile, and peripheral arteries. Duplex technology combines conventional B-mode imaging with range-gated pulsedwave Doppler analysis. The method enables the examiner to obtain precise Doppler information from any vessel identifiable on the cross-sectional image and thereby to determine the presence, direction, and velocity of flow in that
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Table 7-1. Normal Values of Systolic Pressure of the Lower Extremity Pressure measurement Ankle systolic pressure Ankle pressure index (ankle/brachial ratio) Thigh systolic pressure High (narrow cuff) Low (wide cuff) Pressure gradients Toe pressure index
Treadmill exercise test (2 mph, 12% grade)
vessel. The color-encoded technology combines real-time ultrasound imaging with semiquantitative color encoding of the Doppler shift. The color assignment depends on the mean velocity and direction of flow. Whenever flow is detected, it is color-encoded and superimposed on the gray-scale real-time image. In general, arterial flow is usually displayed in red and venous flow in blue (Fig. 7-2; see also color plate). The hue or color saturation also reflects the relative blood velocity—slow flow has a deeper hue or saturation and fast flow has a lighter tone. Color flow imaging makes it easier to find and follow the vessel of interest and identifies regions with disturbed or turbulent flow, which facilitates placement of the sample volume for spectral analysis. Artery tortuosity can be recognized readily, and minor wall irregularities not affecting center-stream flow are detected instantly by a color flow imager. Spectral analysis is now a standard procedure to grade the degree of stenosis. Duplex instruments provide both audible and computed frequency information related to the velocity of moving red blood cells. An atherosclerotic plaque may change the pattern of blood flow velocities to produce
Normal values .brachial systolic pressure .1.0 30 – 40 mmHg . brachial systolic pressure 20 – 30 mmHg . brachial systolic pressure ,30 mmHg between adjacent sites 0:7 ^ 0:19 0.35 ^ 0.15 = claudication 0.11 ^ 0.10 = rest pain Elevated or no decrease of ankle pressure after 5 min walking time
frequency spectral broadening, defined as an increase in the range of frequencies present in the Doppler signal. In the normal artery, most of the energy during systole parallels the frequency envelope, with a narrow spectrum of frequencies and a clear “window” (Fig. 7-3A and B). In the presence of stenosis, the resulting flow disturbance causes disruption of the narrow spectrum; thus, the clear window no longer is seen. The flow spectrum becomes broadened, with the various frequencies filling in the window (Fig. 7-3C and D). Also, there is an increase of high-frequency components. Further narrowing is associated with increase in peak systolic velocities relative to the proximal arterial segment. When arterial stenosis exceeds 50% diameter reduction, the peak systolic velocity is increased by more than 100% relative to the proximal arterial segment, and there is spectral broadening throughout the pulse cycle. Lesions that decrease the luminal diameter by more than 75% are associated with increases in end-diastolic velocity (Fig. 7-4). Table 7-2 shows the diagnostic criteria for determining the degree of stenosis in peripheral artery segments.
Plethysmography Several types of plethysmographs are now available for clinical use in the evaluation of arterial occlusion. These are air-filled, strain-gauge, and photoelectric plethysmographs.
Air-Filled Plethysmograph
Figure 7-2. Color Doppler image of normal artery (red ) and adjacent vein (blue ). (See color plate.)
One of the popular instruments used in the vascular laboratory is the pulse volume recorder. In essence, this is an air-filled segmental plethysmograph designed to measure segmental pressure of the leg. The air-filled plethysmograph uses a pneumatic cuff placed around the part being examined, often at several levels. By injecting a known volume of air in the toe cuff bladder, instantaneous volume changes in the limb segment beneath the cuff can be calibrated and recorded with a sensitive pressure transducer to provide pulsatile flow tracings. Changes in the configuration of such pulse-volume tracings indicate proximal arterial occlusion. By visual inspection, the pulse waveforms can be related to different degrees of ischemia.The instrument can be used to record penile pulse waveforms.
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Figure 7-3. (A ) Normal laminar flow with parabolic curve. (B ) Normal spectral band with acoustic window present. (C ) Turbulent flow due to stenosis. (D ) Spectral display at the distal site. Frequencies are markedly elevated; there is total loss of acoustic window (spectral broadening) and an increase of end-diastolic velocity. [From Blackburn, D.R.; Peterson, L.K.: Noninvasive vascular testing. In Fahey, V.A. (ed.): Vascular Nursing. Philadelphia, Pennsylvania, Saunders, 1988, p 99. Reproduced by permission.]
Strain-gauge Plethysmograph Strain-gauge plethysmographs use fine-bore rubber tubes filled with mercury or a liquid-metal alloy that makes contact with copper electrodes at either end. The gauge is wrapped around the part being studied. As the part (calf or forearm) expands or contracts, the length of the gauge increases or decreases by a corresponding amount. The changes in the length of the gauge reflect changes in the circumference of the part and are interpreted as volume changes. Because the resistance of the liquid-metal column varies with its length, changes in voltage across the gauge, when amplified, can be calibrated to reflect changes in circumference (volume) of the circumscribed part. Changes in the strain-gauge length can be calibrated mechanically to reflect volume flow, or electrical calibration by a bridge circuit can be used to measure voltage drop across the gauge. The strain gauge can be used for recording pulse waveform of digits and to record systolic pressure of the extremity. In conjunction with the venous occlusion principle, the strain-gauge plethysmograph has been applied to record calf or skin blood flow expressed in mL/100 g/min. In the clinical practice of vascular surgery, the use of calf (muscle) or skin (foot) flow is of limited value. Flow measurement may be useful in the evaluation of the acute effect of various pharmacologic agents.
Photoelectric Plethysmograph Early instruments included the use of a photocell for pulse recording by means of alternating current (ac) signals. Recently, an infrared sensor has been used in the new generation of photoelectric plethysmographs. In this newer instrument, a direct current (dc) coupling technique is also provided. The dc signal is not related to the pulse, is slow to change, and depends on changes in the total blood volume in the skin. With refinement in probe design, the photoplethysmograph has become a standard instrument for the recording of pulse waveforms in most laboratories. The technique is of particular value in the evaluation of thoracic outlet compression. The use of dc mode to detect volume changes is helpful in recording finger or toe pressure.
CLINICAL APPLICATIONS Peripheral Arterial Occlusive Disease Diagnosis A thorough history taking combined with a careful and skillful physical examination will establish the diagnosis of
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Figure 7-4. Typical velocity spectra for four categories of stenosis: (A ) normal (no stenosis); (B ) 1 – 19% diameter reduction; (C ) 20–49% diameter reduction; (D ) 50– 99% diameter reduction. [From Kohler, T.R.; Nace, D.R.; Cramer, M.M.; et al. Duplex scanning for diagnosis of aortoiliac and femoropopliteal disease: A prospective study. Circulation 76: 1074, 1987. Reproduced by permission.]
peripheral arterial occlusive disease. The role of noninvasive testing in establishing a diagnosis lies in those cases where palpation of a pulse is in doubt or in those patients with intermittent claudication in the presence of a palpable pedal pulse. In these circumstances, the use of systolic pressure measurement allows instant confirmation of the presence of arterial occlusive disease. Intermittent claudication in patients with palpable pedal pulses is a well-known syndrome; it is frequently seen in patients with iliac artery stenosis. However, the ankle pressure is always abnormal, and this abnormality
will become more pronounced after treadmill exercise. Treadmill exercise is also useful to differentiate neurogenic pseudoclaudication from claudication of vascular origin.
Degree of Ischemia. Both the pressure index and the absolute ankle pressure are useful to grade the degree of ischemia, but the pressure index correlates well with presenting symptoms. In patients with claudication, the pressure index often ranges from 0.50 to 0.70, and a marked
Table 7-2. Duplex Criteria for Peripheral Arterial Stenosis Diameter reduction 19% or wall irregularity 20– 49% 50– 75% 76– 99% Occlusion
Velocity spectral characteristics No increase in peak systolic velocity relative to proximal arterial segment, but mild spectral broadening during systole Greater than 30% increase in peak systolic velocity relative to proximal arterial segment; spectral broadening throughout the pulse cycle Peak systolic velocity ratio at stenosis relative to segment proximal to stenosis . 2; uniform spectral broadening over the entire pulse cycle with simultaneous forward and reverse flow components Similar velocity rate as in 50 – 75% category but end-diastolic velocity greater than 100 cm/s No flow signal from visualized segment
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decrease in the pressure index, often to less than 0.30, is seen in patients with rest pain, ischemic ulcer, or gangrene. The absolute pressure alone, however, is more useful to determine limb viability. Chronic critical leg ischemia in both diabetic and nondiabetic patients has recently been defined by several working groups.[1 – 3] The criteria are an ankle systolic pressure less than or equal to 50 mmHg and/or a toe systolic pressure less than or equal to 30 mmHg, or ulceration or gangrene of the foot or toes with an ankle systolic pressure of less than 50 mmHg or a toe systolic pressure of less than 30 mmHg. There is a spectrum of ankle pressure in patients with skin ulcers and/or rest pain. However, to standardize the description of these patients, the level of 50 mmHg is recommended because this includes the majority of patients for whom rest pain or ulcers do not improve spontaneously without intervention. For diabetics, the toe systolic pressure measurements should be performed because a falsely high ankle systolic pressure is frequently found in these patients. A cutoff pressure of 30 mmHg is based on the fact that a majority of diabetic patients with a toe systolic pressure of less than 30 mmHg have a very poor prognosis.[4]
color flow imaging as a surveillance program to follow in situ and other grafts.[5,6] Because the in situ graft is superficially situated, it is readily accessible for blood flow velocity measurement and waveform recording. Transformation of the triphasic graft velocity waveform to a biphasic or monophasic configuration coupled with a decrease in peak velocity to less than 45 cm/s has been found to be highly suggestive of a remote occlusive lesion.[5,6] The major advantage of color Doppler is the reduction of examination time required to completely map a femorotibial bypass graft. The visual feedback afforded by the color flow imaging enables areas of flow abnormalities to be rapidly identified. To accurately determine the site of stenosis, velocities immediately proximal and distal to the site of disturbed color flow must be compared using pulsed-Doppler spectral analysis. A velocity ratio greater than 2.0 or peak systolic velocity in excess of 150 cm/s is evidence that a stenosis is present.[6] With a combination of ankle systolic pressure measurement and duplex scanning, stenosis of the graft can be detected and corrected surgically prior to thrombosis. This type of surveillance program is now a standard practice for the first 2 years after most infrainguinal vein grafts.
Immediate and Late Follow-Up After Arterial Reconstruction
Adequacy of Aortoiliac Inflow
The Doppler flow detector provides a simple way to monitor the patency of a bypass graft during the postoperative period in both the recovery room and intensive care unit. The degree of improvement in ankle pressure depends upon whether or not there is a residual occlusion distal to the site of reconstruction. If multiple occlusions are present, correction of the proximal lesion will significantly elevate the ankle pressure, often to double the preoperative level, but will not convert it to normal. Frequent monitoring of the ankle pressure is helpful to detect graft failure. For late follow-up, the ankle pressure remains the simplest method to detect graft failure. A decrease of pressure index of 0.15 is considered a significant change, and further investigation is necessary. The ankle pressure measurement is useful to detect hemodynamic failure of a bypass graft (a failing graft). Hemodynamic failure is defined as a graft that is patent by arteriography and yet fails to provide hemodynamic improvement. A hemodynamically failed graft, if recognized early, may be corrected by surgery prior to graft occlusion by thrombosis. Postoperative study can determine whether an additional reconstructive procedure is necessary in order to achieve the desired result. Need for a further bypass procedure is commonly seen in patients who have multiplelevel disease and in whom a proximal reconstruction is performed in the presence of a distal occlusion. If there is no improvement in the ankle pressure after aortoiliac or profunda femoris reconstruction, a distal bypass graft to relieve symptoms is often warranted. Although ankle systolic pressure is a simple test, several investigators have claimed that this test is less sensitive to detect graft stenosis, especially in patients with in situ saphenous vein grafts. To deal with this shortcoming, most vascular laboratories have added either duplex scan or
The correct assessment of aortoiliac occlusive disease is often a challenge, especially in multilevel occlusive disease, in which the decision to perform an inflow or outflow operation depends primarily on the hemodynamic significance of the proximal lesion. However, a careful physical examination aided by segmental pressure measurement and common femoral waveform recording will help to resolve the dilemma. A small percentage of cases will need further testing to evaluate the adequacy of aortoiliac inflow. This circumstance includes cases in which one must determine adequate inflow to support a femorofemoral bypass graft or cases in which one must decide whether the disease is located predominantly in the aortoiliac segment or in the femoropopliteal tract, when the results of clinical examination or segmental pressure measurement are ambiguous. In recent years, several techniques ranging from simple waveform inspection to sophisticated computer analysis have been proposed to aid in the assessment of the hemodynamic significance of an inflow tract lesion. The simplest method is waveform amplitude calculation[7] followed by a higher level of sophistication such as pulsatility index[8] to LaPlace transform damping and principal component analysis.[9 – 11] Because of the complicated nature of computer analysis technique, pulsatility index, LaPlace transform, and principal component analysis have not yet been adapted as routine tests in most vascular laboratories, and many vascular surgeons rely on femoral pressure measurements before and after papaverine or before and after the distal bypass is completed (see Chap. 32). Since most laboratories are now equipped with a color flow Doppler or duplex scanner, several investigators have advocated the use of velocity data to assess the degree of aortoiliac lesion in a fashion similar to the analysis of carotid stenoses. While resting Doppler frequency spectrum analysis may offer useful diagnostic information, some investigators have advocated
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the use of reactive hyperemia to increase the diagnostic accuracy.[12]
Vascular Pathology of the Popliteal Fossa Vascular problems in this anatomic region include popliteal aneurysm, cystic degeneration of the popliteal artery, and popliteal artery entrapment syndrome. Diagnosis can now readily be accomplished with duplex technology.[13] The technique is of particular use in the diagnosis of popliteal entrapment. The patient is placed in the prone position and the popliteal fossa is then scanned. Compression of the artery with decreased or absent flow signals when the leg is placed in hyperextension is diagnostic of popliteal entrapment syndrome. The technique is more accurate than the positional testing technique with the Doppler pulse detector. For aneurysm and cystic degeneration, the B-mode image of the duplex scan is also helpful to establish the diagnosis.[14]
Arteriovenous Fistula or Pseudoaneurysm With the proliferation of interventional procedures, arteriovenous fistula or pseudoaneurysm of the femoral artery is now a common vascular complication. The diagnosis can be readily made with duplex scan—in particular, a color flow imager. Unlike the gray-scale B-mode scan, the color imager identifies the jet stream from the puncture site and follows it into the lumen of the pseudoaneurysm. The flow pattern of the pseudoaneurysm is characterized by swirly flow mixed with red and blue color changes. This technique is of particular value if there is a broad-based defect in the artery. In using this technique to evaluate 27 patients with groin pulsatile masses, Schwartz and coworkers reported 100% sensitivity and specificity.[15] The color-encoded imager is useful in the detection of arteriovenous fistula. Diagnostic features for fistula detection include persistent intra-arterial flow throughout the cardiac cycle at the site of the fistula and disorganized color flow pattern as the high-velocity flow jet enters the more compliant venous system. The technique is not only diagnostic but may also be therapeutic, as some investigators have used the imager to identify the communication and to use manual compression to eliminate the aneurysm or fistula.[16] Although compression treatment may help in treating small, acute aneurysms, spontaneous thrombosis of these aneurysms or fistulas has also been reported.[17] The color flow imager appears to help to determine the natural course of these aneurysms.
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Renovascular Hypertension With continuous refinement of duplex technology, diagnosis of renal artery stenosis is now possible by this technique. Duplex technology represents a new screening test in patients suspected of having renovascular hypertension. The colorencoded technique permits a more rapid identification of renal artery origins and anatomic course to the kidney. The size of the kidney can be accurately determined. Normal renal artery flow signals are of low resistance and have continuous flow in diastole, similar to the internal carotid artery and the celiac artery. In addition, flow signals from interlobar arteries may help to determine renal parenchymal disease. When there is stenosis of the renal artery, the peak velocity is increased, and the peak frequency ratio (compared with the aorta) has been suggested as the diagnostic criterion for renal artery stenosis. In the presence of renal artery stenosis (60% or greater), the renal/aortic ratio is 3.5 or greater.[18] This degree of stenosis was chosen because it appears to be the point at which the renin-angiotensin system is activated.[18] This increased frequency is also associated with loss of the acoustic window and turbulent flow. Hansen et al.[19] found that the ratio is not accurate. Instead, they found focal renal artery peak systolic velocity of 2 m/s or more in combination with distal poststenotic turbulence to be a more accurate diagnostic criterion (Table 7-3). Using this criterion, they found a high correlation with the angiographic presence of a 60% or greater diameter-reducing stenosis of the renal artery. In 122 kidneys studied, they reported a sensitivity of 93% and a specificity of 98% with an overall accuracy of 96% when compared with angiography.
Mesenteric Ischemia As with renovascular hypertension, until the introduction of duplex technology, there was no convenient noninvasive test for the detection of mesenteric artery stenosis in patients suspected to have mesenteric ischemia. Over the years, the technique has evolved to be a reliable screening test for mesenteric ischemia (Fig. 7-5 see also color plate). In addition to resting measurement, the physiologic changes of blood flow in response to oral consumption of a standard test meal or pharmacologic stimulation have added more hemodynamic information to the understanding of mesenteric ischemia.[20 – 22] For resting measurement of mesenteric circulation, the hemodynamic (velocity) criteria to establish the degree of ischemia vary slightly among several investigators.[23,24] The variation is due to the use of the threshold of angiographic
Table 7-3. Doppler Velocity Criteria for Renal Artery Stenosis B-Mode defect , 60% diameter-reducing defect . 60% diameter-reducing defect Occlusion Inadequate study for interpretation Note: RA = renal artery; PSV = peak systolic velocity. Source: Adapted from Hansen et al.[19] Reproduced by permission.
Criteria RA-PSV from entire RA, 2.0 m/s or less Focal RA-PSV .2.0 m/s, distal turbulent velocity waveform No Doppler shift signal from B-mode image Failure to obtain Doppler samples from entire main renal artery
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Figure 7-5. Oblique view of the aorta and celiac axis. The flow signal from the celiac axis is one of low resistance with absence of reverse flow. (See color plate.) [From Blackburn, D.R.: Color duplex imaging of the mesenteric and renal arteries. J. Vasc. Technol. 15:140, 1991. Reproduced by permission.]
stenosis (50% or 70%) as the standard for comparison. In general, peak systolic velocity, end-diastolic velocity, color flow image, and presence of reverse flow in the hepatic artery are diagnostic of celiac axis and mesenteric artery stenosis. In a validation study of a cohort of 243 patients, Zwolak and colleagues found the following criteria in patients with angiographic evidence of 75% stenosis.[25] For superior mesenteric artery stenosis, an end-diastolic velocity (EDV) of $45 cm/s or the absence of flow signals has a sensitivity of 90%, specificity of 91%, positive predictive value of 90%, negative predictive value of 91%, and an overall accuracy of 91%. Peak systolic velocity (PSV) was less accurate than EDV: a threshold of $ 300 cm/s resulted in the highest attainable PSV accuracy of 81% with low sensitivity (60%) but high specificity (100%). Doppler velocity criteria were accurate in the diagnosis of celiac axis stenosis: for identification of $50% stenosis or occlusion, an EDV of .55 cm/s or the absence of flow signal resulted in a sensitivity of 93%, specificity of 100%, and overall accuracy of 95%. These velocity data are accurate in the identification of mesenteric ischemia. Color flow image is also helpful to identify anatomic variants that may influence the study interpretation. Also, retrograde common hepatic artery flow direction is diagnostic for severe celiac axis stenosis or occlusion. Duplex scan is a useful screening test and is ideal for follow-up study after mesenteric revascularization.[26]
Infrainguinal Bypass Graft Surveillance Duplex scan is now readily available for direct examination of the entire length of the graft, the proximal and distal anastomoses, and the adjacent inflow and outflow arteries. Graft surveillance helps to identify hemodynamically failing
graft, especially in in situ graft, prior to failure by total occlusion. Graft surveillance is of particular value in in situ vein graft. The advent of color-flow technology has greatly simplified the scanning of the bypass graft. Color-flow scanning, which superimposes a color-coded flow map on the B-mode image, greatly shortens the scanning time. With color-flow mapping, the proximal anastomoses are always indentified and distal anastomoses are visualized in about 90% of the studies. Arteriovenous fistulae, hematomas, fluid collections, false aneurysms, kinks, and other defects related to bypass grafting are readily identified. The B-mode image of normal segments of bypass graft has a smooth contoured appearance. Color saturation is determined by the Doppler frequency shift. Because stenoses are associated with increased flow velocities, a localized change in color (red to white or blue) is a sensitive indicator of the presence of a stenosis. Once the stenotic lesion is identified, it is necessary to evaluate the Doppler flow spectrum and to determine the degree of stenosis. Both peak systolic velocities (PSV) and velocity ratio are helpful to determine the degree of stenosis. Velocity ratio is calculated by dividing the PSV obtained at the stenotic site by the PSV in the adjacent “normal” segment. As recommended by Sumner and Mattos,[27] a velocity ratio greater than 2.0 is predictive of a 50% diameter-reducing lesion. Higher ratios are indicative of more severe diameter reduction. For peak systolic velocity, several investigators have suggested that a PSV greater than 150– 180 cm/s is also indicative of a greater than 50% diameter reduction.[28,29] High-grade stenoses (greater than 70% or 80% diameter reduction) are usually associated with PSV exceeding 170–300 cm/s and end-dissection velocities of 20– 100 cm/s or more. Additionally, Bandyk et al. reported an increase of graft occlusion when the PSV measured at the innermost segment of a graft (either the upper end of a reversed vein graft or the lower end of an in situ graft) was less than 45 cm/s.[28] Graft surveillance by duplex scan is now a recommended routine examination following bypass graft. Approximately 10–34% of infrainguinal grafts developed hemodynamically significant stenoses.[27] The duplex scan examination detects early hemodynamically failing graft (pseudo occlusion), and early correction of stenosis extends graft patency. An increase in secondary graft patency of approximately 10–25% can be achieved with duplex scan over that with routine clinical follow-up or ankle pressure alone. Routine graft surveillance is cost-effective and should be a standard follow-up test for infrainguinal bypass grafts.
Vein Mapping for Infrainguinal Bypass It is uniformly acknowledged that autogenous vein is the choice for bypass grafts. Unfortunately, an adequate long saphenous vein is present in only 67% of patients.[30] The availability of duplex scan has made vein mapping a valuable preoperative evaluation of the adequacy of long saphenous vein or for other potential venous conduits such as the cephalic vein or the short saphenous vein. In repetitive infrainguinal bypass, vein mapping is helpful to locate
Chapter 7.
residual veins or the short saphenous vein. This information helps to determine whether a composite-sequential graft may be used as a limb salvage procedure. Vein mapping is done in a warm room with the patient resting in the supine position with 10– 208 tilt in the reversed Trendelenburg position. With the extremity externally rotated, the long saphenous vein is examined from the groin to the ankle. For short saphenous vein scan, the patient is best examined in a prone position. Duplex mapping of the cephalic and basilic veins is performed with the patient in the supine position, the upper extremity externally rotated. A transverse and longitudinal view of the vein can be obtained and marked with permanent ink for identification. Vein mapping is indicated in patients with (1) previous history of infrainguinal bypasses in which a portion of long saphenous vein has been removed; (2) history of vein ligation or stripping; (3) history of superficial thrombophlebitis; (4) drug abuse; and (5) obesity. Although an absolute vein diameter to be used as a conduit remains unclear, most vascular surgeons would accept an internal diameter of 2 mm at resting condition as suitable for distal anastomosis of an infrainguinal bypass onto the infrapopliteal vessels. Vein mapping extends the usage of autogenous vein, and the technique is useful to detect anatomic variation, which is rather common with the venous system. Vein mapping by duplex scan is now an integrated
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preoperative assessment for patients who are candidates for infrainguinal bypass.
Sexual Impotence The status of pelvic blood flood can now be assessed by recording penile pressure in males. Such pressure recording helps to evaluate sexual potency in patients with aortoiliac occlusive disease. In general, with a pressure index below 0.60, vasculogenic impotence is suspected. Several authors using the current duplex technology have reported that the color flow imager and velocity measurement of the cavernosal arteries provide more diagnostic information. A peak systolic velocity of 25 – 30 cm/s can correctly distinguish patients with normal cavernosal arteries from those with severe arterial disease. The color Doppler imager can be used to evaluate the deep arteries of the corpora cavernosa in the flaccid state and after erection induced by direct injection of 60 mg of papaverine. The degree of arterial dilatation is evaluated, as well as the increase in peak systolic velocity after injection. A lack of arterial dilatation or minimal velocity increase is evidence of arterial insufficiency.[31,32] This approach is helpful in selecting patients for pudendal arteriography for further diagnosis and possible treatment.
REFERENCES 1.
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Bell, P.R.F.; Charlesworth, D.; DePalma, R.G.; et al. The Definition of Criteria Ischaemia of a Limb: Working Party of the International Vascular Symposium (Editorial). Br. J. Surg. 1982, 69 (suppl), S2. Rutherford, R.B.; Flanigan, D.P.; Gupta, S.K.; et al. Suggested Standards for Reports Dealing with Lower Extremity Ischemia. J. Vasc. Surg. 1986, 4, 80– 94. European Working Group on Critical Leg Ischaemia; Second European Consensus Document on Chronic Critical Leg Ischemia. Circulation 1991, 84 (suppl), IV1– IV2. Carter, S.A. The Definition of Critical Ischemia of the Lower Limb and Distal Systolic Pressure. Br. J. Surg. 1983, 70, 188– 189. Bandyk, D.F. Postoperative Surveillance of Infrainguinal Bypass. In Noninvasive Diagnosis of Vascular Disease; Yao J.S.T., Pearce W.H., Eds.; Surg. Clin. North. Am. 1990, 70, 71– 85. Blair, J.-F.; Bandyk, D.F. Real-Time Color Doppler in Arterial Imaging. In Technologies in Vascular Surgery; Yao, J.S.T., Pearce, W.I.I., Eds.; Saunders: Philadelphia, Pennsylvania, 1991; 129 – 149. Fronck, A.; Coel, M.; Bernstein, E.F. Quantitative Ultrasonographic Studies of Lower Extremity Flow Velocity in Health and Disease. Circulation 1976, 53, 957– 960. Johnston, K.W.; Kassam, M.; Gobbold, R.S.C. Relationship Between Doppler Pulsatile Index and Direct Femoral Pressure Measurements in the Diagnosis of Aortoiliac Occlusive Disease. Ultrasound Med. Biol. 1983, 9, 271–281.
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Macpherson, D.S.; Evans, D.H.; Bell, P.R.F. Common Femoral Artery Doppler Waveforms: A Comparison of Three Methods of Objective Analysis with Direct Pressure Measurements. Br. J. Surg. 1984, 71, 486– 493. Baker, J.H.D.; Machleder, M.I.; Skidmore, R. Analysis of Femoral Doppler Signals by LaPlace Transform Damping Method. J. Vasc. Surg. 1984, 1, 520–524. Baird, R.N.; Bird, D.R.; Cliffort, P.C.; et al. Upstream Stenosis: Its Diagnosis by Doppler Signals from the Femoral Artery. Arch. Surg. 1980, 115, 1316– 1322. Van Astern, W.N.J.; Beijneveld, W.J.; Pieters, B.R.; et al. Assessment of Aortoiliac Obstructive Disease by Doppler Spectrum Analysis of Blood Flow Velocities in the Common Femoral Artery at Rest and During Reactive Hyperemia. Surgery 1991, 109, 633– 639. Marzo, I.D.; Cavallaro, A.; Sciacca, V.; et al. Diagnosis of Popliteal Entrapment Syndrome: The Role of Duplex Scanning. J. Vasc. Surg. 1991, 13, 434– 438. Hoyne, R.F. Ultrasonographic Findings in a Case of Adventitial Cystic Disease of the Popliteal Artery, with a Review of the Literature. J. Cardiovasc. Technol. 1991, 10, 7987. Schwartz, R.A.; Kerns, D.B.; Mitchell, D.G. Color Doppler Ultrasound Imaging in Iatrogenic Arterial Injuries. Am. J. Surg. 1991, 162, 4 – 8. Fellmeth, B.D.; Roberts, A.C.; Bookstein, J.J.; et al. Postangiographic Femoral Artery Injuries: Nonsurgical Repair with US-Guided Compression. Radiology 1991, 178, 671– 675.
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17. Kresowik, T.F.; Khoury, M.D.; Miller, B.V.; et al. A Prospective Study of the Incidence and Natural History of Femoral Vascular Complications After Percutaneous Transluminal Coronary Angioplasty. J. Vasc. Surg. 1991, 13, 328–336. 18. Strandness, D.E. Duplex Scanning in Diagnosis of Renovascular Hypertension. In Noninvasive Diagnosis of Vascular Disease; Yao, J.S.T., Pearce, W.I.I., Eds; Surg. Clin. North Am. 1990, 70, 109– 117. 19. Hansen, K.J.; Reavis, S.W.; Dean, R.H. Use of Duplex Scanning in Renovascular Hypertension. In Technologies in Vascular Surgery; Yao, J.S.T., Pearce, W.H., Eds.; Saunders: Philadelphia, Pennsylvania, 1991; 174 – 184. 20. Flinn, W.R.; Sandager, G.P.; Lilly, M.; et al. Duplex Scan of Mesenteric and Celiac Arteries. Arterial Surgery: New Diagnostic and Operative Techniques; Grune and Stratton: Orlando, Florida, 1988; 367 – 375. 21. Jager, K.; Bollingber, A.; Valli, C.; et al. Measurement of Mesenteric Blood Flow by Duplex Scanning. J. Vasc. Surg. 1986, 3, 462– 469. 22. Lilly, M.P.; Harward, T.R.S.; Flinn, W.R.; et al. Duplex Ultrasound Measurement of Changes in Mesenteric Flow Velocities with Pharmacologic and Physiologic Alteration of Intestinal Blood Flow in Man. J. Vasc. Surg. 1989, 9, 18– 25. 23. Moneta, G.L.; Lee, R.W.; Yeager, R.A.; et al. Mesenteric Duplex Scanning: A Blinded Prospective Study. J. Vasc. Surg. 1993, 17, 79– 86. 24. Harward, T.R.S.; Smith, S.; Seeger, J.M. Detection of Celiac Axis and Superior Mesenteric Artery Occlusive
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Disease with Use of Abdominal Duplex Scanning. J. Vasc. Surg. 1993, 17, 738– 745. Zwolak, R.M.; Fillinger, M.F.; Walsh, D.B.; et al. Mesenteric and Celiac Duplex Scanning: A Validation Study. J. Vasc. Surg. 1998, 27, 1078– 1088. McMillan, W.D.; McCarthy, W.J.; Bresticker, M.R.; et al. Mesenteric Artery Bypass: Objective Patency Determination. J. Vasc. Surg. 1995, 21, 729– 741. Sumner, D.S.; Mattos, M.A. Influence of Surveillance Programs on Femoral-Distal Bypass Graft Patency. In The Ischemic Extremity: Advances in Treatment; Yao, J.S.T., Pearce, W.H., Eds.; Appleton & Lange: East Norwalk CT, 1995; 455–474. Bandyk, D.F.; Cato, R.F.; Towne, J.B. A Low Flow Velocity Predicts Failure of Femoropopliteal and Femorotibial Bypass Grafts. Surgery 1985, 98, 799– 809. Bandyk, D.F.; Schmitt, D.D.; Seabrook, G.R.; et al. Monitoring Functional Patency of In Situ Saphenous Vein Bypasses: The Impact of a Surveillance Protocol and Elective Revision. J. Vasc. Surg. 1989, 9, 284– 296. Mattos, M.A.; Sumner, D.S. Vein Mapping for Infrainguinal Bypasses. In Practical Vascular Surgery; Yao, J.S.T., Pearce, W.H., Eds.; Appleton & Lange: Stamford CT, 1999; 79 – 90. Paushter, D.M. Role of Duplex Sonography in the Evaluation of Sexual Impotence. Am. J. Roentgenol. 1989, 153, 1161– 1163. Schwartz, A.N.; Lowe, M.; Berger, R.E.; et al. Assessment of Normal and Abnormal Erectile Function: Color Doppler Flow Sonography Versus Conventional Techniques. Radiology 1991, 180, 105– 109.
CHAPTER 8
Noninvasive Cerebrovascular Diagnostic Techniques Thomas G. Lynch Robert W. Hobson II (Fig. 8-2A). In the presence of a hemodynamically significant internal carotid artery stenosis or occlusion, flow in the distal internal carotid artery is augmented by collateral circulation from the superficial temporal, facial, and infraorbital branches of the external carotid artery. Blood flow reaches the distal internal carotid artery through the nasal, frontal, and supraorbital branches of the ophthalmic artery (Fig. 8-2B). Early experience with a cerebrovascular Doppler examination was reported by Brisman et al.[1] They observed that stenosis or occlusion of the internal carotid artery was associated with a reduction in the amplitude and velocity of common carotid artery flow. Maroon et al.[2] employed a Doppler velocimeter to assess ophthalmic artery flow velocity transorbitally and were able to predict the presence of an internal carotid artery occlusion or a significant stenosis by evaluating the amplitude and velocity of ophthalmic artery flow (Fig. 8-3). Their accuracy, however, decreased when there was adequate collateral circulation through the branches of the external carotid artery. Evidence of this collateral circulation was demonstrated by Muller.[3] Using a directional Doppler velocimeter, he observed that an internal carotid artery stenosis or occlusion was associated with flow reversal in the frontal and ophthalmic arteries (Fig. 8-4). As subsequently refined by Bone and Barnes[4] and by Barnes et al.,[5,6] the cerebrovascular Doppler examination was performed using a 10 mHz directional Doppler. The supraorbital and/or frontal arteries were identified and the direction of flow determined, as well as the response to superficial temporal, facial, infraorbital, and common carotid artery compression. The study was abnormal if the direction of the flow was reversed in either or both arteries or if flow decreased with external carotid artery branch compression. The directional Doppler velocimeter used to perform the CDE was relatively inexpensive, and there were no contraindications to the technique. The accuracy, however, was variable and could be influenced by the skill of the examiner, the technique employed, the definition of hemodynamically significant disease, and the relative distribution of stenotic and occluded arteries in the study population. The technique is no longer commonly employed, but it remains valuable as
INTRODUCTION The hemodynamic changes associated with internal carotid artery stenosis and occlusion have provided the basis for a wide range of noninvasive diagnostic techniques. The cerebrovascular or periorbital Doppler examination (CDE), supraorbital photoplethysmography, oculoplethysmography, and ocular pneumoplethysmography (OPG) were sensitive to alterations in collateral circulation, ocular pulse delay, or decreased end-ophthalmic (distal internal carotid) artery pressure. They provided indirect evidence of hemodynamically significant carotid artery stenosis or occlusion. These indirect techniques, however, were unable to quantify the degree of stenosis, distinguish between stenosis and occlusion, or detect nonstenotic ulcerative disease. Techniques that directly assess the cervical carotid artery, such as real-time B-mode imaging and spectral analysis, provide additional information relative to the morphology of the plaque and the degree of obstruction. More recently, these techniques have also been employed to obtain information regarding the flow profile and its relationship to atherogenesis; the composition and morphology of atherosclerotic plaques and their relationship to symptomatic cerebrovascular disease; and the natural history of carotid atherosclerosis and atherogenesis.
HISTORICAL PERSPECTIVE Early noninvasive techniques developed from an understanding of the carotid circulation and its potential collateral pathways (Fig. 8-1). The ophthalmic artery is the first branch of the internal carotid artery. It divides into the frontal, supraorbital, and nasal arteries that communicate through collateral pathways with the superficial temporal, facial, and infraorbital branches of the external carotid artery. In the absence of obstruction, flow passes from the internal carotid artery through the ophthalmic artery and its branches
Hobson/Wilson/Veith: Vascular Surgery: Principles and Practice, Third Edition, Revised and Expanded DOI: 10.1081/0819-9-120024891 Copyright q 2004 by Marcel Dekker, Inc.
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The technique also yielded additional physiologic data. Gee et al.[10] calculated ocular blood flow from the pulse rate and amplitude of the ocular pulse wave, demonstrating a significant decrease in flow in those patients with hemodynamically significant obstruction. Further, the pulse wave morphology provides noninvasive correlation with intracranial pressure. Morphologically, the normal pulse wave obtained using the OPG lacks a dicrotic notch, reflecting the low resistance of the intracranial circulation and the damping effect of the carotid siphon. In a study of 81 head-injured patients,[11] Gee et al. observed a consistent relationship between increased intracranial pressure measurements and the presence of a dicrotic notch (Fig. 8-6). While no longer routinely employed as part of the noninvasive cerebrovascular evaluation, the technique does provide objective physiologic data regarding the
Figure 8-1. The common carotid artery and its bifurcation, demonstrating the branches of the internal and external carotid arteries.
a framework on which to discuss the anatomy and hemodynamics of the carotid circulation and the collateral pathways that are associated with stenosis or occlusion of the internal carotid artery. Ocular pneumoplethysmography employed a system of induced and controlled ocular hypertension to measure ophthalmic artery pressure. Ocular pulse volume changes were recorded using hemispherical cups (15 mm in diameter) applied to the sclera of each eye and held in place by a vacuum. As the vacuum was increased, the intraocular geometry was distorted and the intraocular pressure increased. The amount of vacuum applied correlated with the intraocular pressure, and thus it was possible to determine the pressure at which ophthalmic artery flow ceased—which corresponded to the ophthalmic artery systolic pressure (OAP). As initially conceived, measurement of ophthalmic artery pressure was combined with ipsilateral common carotid artery compression, as a means of measuring collateral cerebral blood flow.[7] In 1977, Gee and associates[8] first reported use of the OPG as a screening device to determine the presence of hemodynamically significant carotid disease (Fig. 8-5). While the OPG could neither distinguish between stenosis and occlusion nor quantitate the degree of stenosis, the sensitivity of the technique was a direct function of the percentage stenosis. As the OPG provided a measure of the extent of collateral circulation, it was also possible to document the increase in distal internal carotid artery pressure following carotid endarterectomy. In 14 of 15 patients[9] with a hemodynamically significant stenosis and a contralateral occlusion, endarterectomy of the stenotic artery resulted in hemodynamic improvement on the ipsilateral side, with an average increase in the OAP of 17 mmHg. In addition, 12 of 15 patients also demonstrated improvement on the contralateral side, with an average increase in the OAP of 12 mmHg.
Figure 8-2. The direction of flow is indicated in the absence (A) and presence (B) of a hemodynamically significant stenosis.
Chapter 8.
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Figure 8-3. Experimental data obtained from the monkey (Macaca speciosa) demonstrating the source of the transorbital Doppler signal. Illustrated is a continuous recording of the electrocardiogram (ECG) and mean amplitude (AMP) and frequency (FREQ) of the ophthalmic artery Doppler signal. There is a marked decrease in the amplitude and frequency of the Doppler signal with common carotid (A), internal carotid (C), and ophthalmic artery (D) compression. There were no changes with external carotid artery compression. (From Maroon JC, Pieroni DW, Campbell RL. Ophthalmosonometry: An ultrasonic method for assessing carotid blood flow. J Neurosurg 30:238 –246, 1969.)
hemodynamic significance of a stenosis and the extent of collateral circulation, which cannot be obtained with direct imaging techniques. In those patients with a high carotid bifurcation, which may prevent direct visualization of the distal internal carotid artery, indirect techniques may indicate the presence of distal obstructive disease.
DOPPLER ULTRASOUND Most early noninvasive techniques were dependent upon Doppler ultrasound. In theory, when transmitted ultrasound strikes a moving interface, the frequency of the reflected wave is shifted in proportion to the velocity of that interface. The Doppler velocimeter was the practical application of this principle. The Doppler transducer, a polarized, synthetic, ceramic crystal with piezoelectric properties, emits a high-frequency, ultrasonic pressure wave with the application of an electrical field.[12 – 14] When the transmitted ultrasonic waves are reflected from moving red blood cells, the frequency of the transmission is altered, or shifted, in proportion to the velocity
of the blood cells. The reflected ultrasonic wave then strikes the same, or a second, piezoelectric crystal, producing a voltage that is proportional to the frequency of the wave. The resulting frequency shift, relative to the transmitted frequency, may then be interpreted as an audible signal or an analogue recording. The Doppler effect is used to explain the frequency shift that occurs when transmitted ultrasound is reflected from a moving interface, such as red blood cells. The velocity of blood flow (V) can then be determined from the following relationship: V¼
DF m 2 cos Q f o
where DF is the frequency shift; m is the speed of sound through blood; Q is the probe angle relative to the longitudinal axis of the blood vessel; and fo is the transmitted frequency. If the above relationship is rewritten, it is evident that the magnitude of the frequency shift is related not only to the velocity of blood flow, but also to the transmitted frequency
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Figure 8-4. Normal ophthalmic artery Doppler tracing (A), demonstrating forward (+) flow. Common carotid artery compression (B) results in a decrease in forward flow, and intraoperative clamping of the internal carotid artery (C) results in flow reversal. (From Muller HR. The diagnosis of internal carotid artery occlusion by directional Doppler sonography of the ophthalmic artery. Neurology 22:816– 823, 1972.)
( fo) and the probe angle (Q): DF ¼
2 cos QV f o m
While the magnitude of the frequency shift is directly related to the transmitted frequency ( fo), absorption of the
ultrasound by tissue is proportional to the square of the transmitted frequency ð f 2o Þ: Thus greater tissue penetration is achieved at lower frequencies, but at the expense of a decrease in the magnitude of the frequency shift.[13,14] The optimum frequency ( fopt) is related to the depth (d) in centimeters, by the following relationship:[15] f opt ¼ 9=d The Doppler transducer can be modified to permit continuous or pulsed (gated) sampling of the reflected ultrasound. The continuous-wave transducer has two piezoelectric crystals, one of which transmits the ultrasound while the other continuously receives a reflected, Doppler-shifted sound wave. The ultrasound is reflected from red blood cells across the diameter of the vessel, so that the reflected and Doppler-shifted frequencies represent a range of red cell velocities within the plane of insonation. The pulsed Doppler
Figure 8-5. Study obtained using the OPG-G. The ophthalmic artery pressures are determined using the center scale, The left ophthalmic artery pressure (52 mmHg) is less than two-thirds of the brachial systolic pressure (L. arm, 134 mmHg £ 0:66 ¼ 88), indicating a hemodynamically significant obstruction of the left common or internal carotid artery.
Figure 8-6. Two tracings obtained with the OPG-G illustrating a normal pulse wave contour (A) and one with catacrotic or dicrotic notching (B, arrow).
Chapter 8.
transducer has a single crystal, which alternately transmits and receives ultrasound. The time during which reflected ultrasound is received, relative to the preceding transmission, determines the depth, or distance from the probe, at which the reflected ultrasound is sampled. This permits flow velocity measurements within a discrete sampling area, such as the midstream of an artery (Fig. 8-7). While the magnitude of the frequency shift is directly related to flow velocity, the direction of the frequency shift is a function of the direction of flow. Flow toward the transducer results in a Doppler-shifted frequency that is greater than the transmitted frequency, while flow away from the transducer results in a decrease relative to the transmitted frequency. A continuous-wave directional Doppler velocimeter was employed in the cerebrovascular Doppler examination to determine the direction and amplitude of periorbital blood flow. Both continuous-wave and pulsed Doppler velocimeters have also been used in an attempt to quantify, noninvasively, the degree of stenosis. Since flow (Q) is a function of velocity (V) and cross-sectional area (A), Q ¼ VA velocity is directly related to flow and indirectly related to cross-sectional area:
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visualization of the artery. Identification of the branches of the carotid artery is dependent upon the relationship of the transducer to the bifurcation. When the transducer can be positioned so that the scanning plane includes the internal and external carotid arteries, an image demonstrating the bifurcation and its branches is obtained (Fig. 8-8; see also color plate). In 70% of cases, however, the probe must be moved laterally from the bifurcation to visualize the internal carotid artery or medially to visualize the external carotid artery. The spatial relationship of the bifurcation to the external and internal carotid arteries is illustrated in Fig. 8-9. Early data published by Hobson and associates[16] demonstrated that real-time B-mode imaging had an 89% specificity for the absence of significant carotid disease. There was a 58% sensitivity to the presence of stenoses exceeding 50% and only an 18% sensitivity to carotid occlusion. In this early study, B-mode imaging was particularly useful in excluding disease in those patients with normal arteries and in characterizing hemodynamically insignificant stenoses. The real-time instrument provided images of high resolution that defined the relationship between the arterial wall and the atherosclerotic plaque, characterizing as well the size and ultrasonic morphology of the plaque. The presence of calcification and shadowing interfered with the characterizatican of high-grade stenoses or carotid occlusion.
V ¼ Q=A If flow is constant, then the velocity of flow must increase as the cross-sectional area of the artery is reduced by stenosis. The Doppler frequency shift is directly related to flow velocity. Velocity may be derived from the measured frequency shift if the insonant angle, relative to the axis of the artery, is known. Using spectral analysis, the arterial flow velocity profile can be characterized using the output of continuous-wave and pulsed Doppler velocimeters. Spectral data may be expressed as the Doppler shifted frequency or as velocity.
REAL-TIME B-MODE IMAGING Depending upon the signal processing algorithm, ultrasound may be used not only to determine the direction and velocity of a moving interface, but also to sense the depth and amplitude of signals reflected from a stationary interface, thus creating a visual image of subjacent structures. The amplitude of the reflected signal is proportional to the difference in density of two adjacent media. B-mode ultrasonic imaging employs time relationships to sense the depth of the interface and brightness variations to express differences in amplitude. If the changes in the reflected ultrasound can be displayed at a sufficient rate (greater than 15 frames per second) then a realtime image can be obtained. Real-time B-mode imaging of the cervical carotid artery is routinely performed with the patient in a supine position, with the neck slightly extended and the head rotated away from the side of examination. Longitudinal scans are obtained in planes anterior, lateral, or posterior to the carotid artery. The transducer is then rotated 90 degrees for cross-sectional
DUPLEX ULTRASONOGRAPHY Using a position sensing arm and a storage oscilloscope, continuous-wave or pulsed Doppler instruments could be used to generate a static, flow-dependent image of the carotid artery and its branches (Fig. 8-10). Hobson and associates[16] demonstrated that pulsed Doppler ultrasonic imaging had a 100% sensitivity to carotid occlusion in the same group of patients in which B-mode imaging alone had only an 18% sensitivity. These results can be explained by the differences in approach to vascular imaging. Pulsed Doppler imaging is based on the presence of flow and might reasonably be expected to demonstrate occlusion or absence of flow with a high degree of accuracy. Images produced by real-time Bmode ultrasonography, which demonstrate anatomical relationships rather than flow, might not be as accurate. Similarly, analysis of the Doppler spectral profile might provide a more quantitative assessment of high-grade stenoses, which morphologically can be associated with calcification, shadowing and varying degrees of organization. Duplex ultrasonography is the result of combining pulsed Doppler velocimetry (and spectral analysis) with real-time Bmode imaging. Spectral data may be expressed as the Doppler shifted frequency or as velocity. Both values increase in direct relationship to the percentage stenosis or reduction in cross sectional area. Theoretically some authors have concluded that spectral data, expressed as velocity, are of greater predictive value and more reproducible because they take into account and normalize for differences in probe angle which may effect frequency measurements. Beach,[17] however, has suggested that Doppler-derived velocity measurements are less significant at the carotid bifurcation because flow at
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changes in spectral distribution than is the continuous-wave Doppler. Spectra obtained using a continuous-wave Doppler reflect the velocity profile across the diameter of the artery. Because the normal, laminar flow profile is parabolic, lowvelocity flow at the periphery is insonated along with midstream high-velocity flow resulting in relative spectral broadening. The pulsed Doppler, on the other hand, reflects the velocity profile within a discrete sample area. Thus the midstream profile demonstrates a discrete spectral envelope without significant spectral broadening.
DOPPLER QUANTITATION OF CAROTID STENOSIS Figure 8-8. Longitudinal scan of the carotid bifurcation demonstrating the common carotid artery (Common), the proximal internal carotid artery (INT) and the external carotid artery (EXT). The scan was obtained with the probe imaging from top (superficial tissues) to bottom. (See also color plate.)
the bifurcation can be helical. The question of whether to use Doppler-shifted frequency or velocity as the measure of carotid stenosis remains unsettled. Of 54 duplex imaging devices evaluated at study sites prior to the Asymptomatic Carotid Atherosclerosis Study (ACAS),[18] the primary Doppler measure was reported as velocity, expressed in centimeters per second, from 24 devices and as frequency, expressed in hertz, from 30. The normal internal carotid artery has a prominent diastolic flow component. The velocity profile reflects the laminar flow pattern and is tightly distributed about the midstream velocity[19,20] (Fig. 8-11). This results in an open area, or “window,” beneath the peak systolic envelope. In addition to the increase in peak systolic velocity (frequency) that occurs with increasing stenosis, there is also poststenotic turbulence. This loss of the laminar flow profile results in disordered, low-velocity flow patterns. These are reflected in a shift in the spectral distribution, with increased low-velocity flow and an opacification of the “window” (Fig. 8-12). The shift, or abnormal spectral distribution, associated with increasing stenosis is also referred to as spectral broadening. When interpreting the spectral profile, differences between pulsed and continuous-wave Doppler instrumentation need to be considered. The pulsed Doppler is more sensitive to
Arteriography is the standard against which all noninvasive studies are commonly compared. While arteriography is the only practical standard at present, it is not a perfect standard. Since arteriography yields a two-dimensional image of a three-dimensional process, the extent of disease may be overor underestimated, depending upon which plane or planes of the artery are imaged. (Fig. 8-13). Sensitivity and specificity are used to express the accuracy of a technique relative to a standard, in this case arteriography. The sensitivity of a technique is defined as the percentage of those arteries with arteriographically demonstrated disease that are correctly identified noninvasively. Specificity is defined as the percentage of those arteries without arteriographically demonstrated disease that are correctly identified noninvasively (Table 8-1). Early noninvasive studies focused on the diagnosis of hemodynamically significant disease. May et al.[21] had shown experimentally that the cross-sectional area of the internal carotid artery must be reduced by 75% before flow is decreased distal to the obstruction. This is equivalent to a 50% reduction in diameter as visualized arteriographically. Initially, the peak systolic velocity (frequency), the relative distribution of velocities (frequencies) within the spectral profile, and the end-diastolic velocity (frequency) were used in an attempt to characterize the extent of disease. Using pulsed Doppler spectral analysis, Blackshear and associates from the University of Washington[22] first constructed a relationship between spectral broadening, peak systolic frequency, and the percentage stenosis. In the normal artery, the midstream spectral profile shows no opacification of the peak systolic window (Fig. 8-12, left). There were lesser degrees of spectral broadening, but no
Figure 8-7. The sampling range of the continuous-wave Doppler velocimeter (A, top) encompasses the entire diameter of the insonated vessel. The range of the pulsed Doppler velocimeter (B, top), however, is limited to a small sample volume, the relative position of which is dependent upon the time relationship between the transmitting and the receiving modes of the single piezoelectric crystal. In the example, an ultrasonic wave is emitted at time t ¼ 0; only at time t ¼ 18 msec does the crystal receive a wave, which was reflected from the midstream of the vessel. A parabolic profile characterizes laminar flow at peak systole. The midstream spectral profile obtained with a pulsed instrument (B, bottom) reflects the well-defined spectral envelope and window which are characteristic of midstream flow velocity. The spectral profile obtained with a continuous-wave instrument (A, bottom), however, is characterized by a relative spectral broadening. Because the continuous-wave velocimeter reflects the velocity profile across the entire diameter of the vessel, the spectral envelope is more divergent and the window less well defined.
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Figure 8-9. Spatial relationships are relevant to the appearance of real-time images. An artist’s conception of various anatomical examples. (From Hobson RW, Berry SM, Lynch TG. Applications of B-mode ultrasonography and ocular pneumoplethysmography in the diagnosis of carotid occlusive disease. In Bergan JJ, Yao JST (eds), Cerebrovascular Insufficiency. New York, Grune and Stratton, 1983, pp 165–177.)
increase in peak systolic frequency, when stenoses ranged from 10 to 49%. Total opacification of the spectral window and an increase in peak systolic frequency were associated with hemodynamically significant 50–99% stenoses (Fig. 8-12, right). Using these criteria, they correctly identified 88% ðn ¼ 8Þ of normal arteries, 78% ðn ¼ 23Þ of those arteries with 10–49% stenoses, and 100% ðn ¼ 22Þ of those with 50–99% stenoses. The University of Washington categories were subsequently modified[23] to classify disease as absent (normal artery), mild (1 –15% diameter reduction), moderate (16–49% diameter reduction), severe (50 – 99% diameter reduction), and occluded. In an attempt to characterize more
precisely those stenoses from 50 to 99%, Roederer et al.[24] used pulsed Doppler ultrasound and measured the enddiastolic frequency. Using 4.5 KHz as a cutoff they correctly identified 88% of stenoses less than 80% and 84% of those greater than 80%. While some authors attempted to further narrow the categories within which stenotic disease was classified, refinements in the classification initially appeared useful only in studies attempting to characterize the natural history of carotid disease. The duplex criteria as initially defined by the group at the University of Washington remained useful until publication of the results of the European Carotid Surgery
Figure 8-10. A continuous-wave Doppler ultrasonic image (right) of a normal carotid artery bifurcation. The image is relative and is not useful in quantitating the degree of stenosis. Diagnostic implications are drawn from an analysis of the spectral profile.
Chapter 8.
Figure 8-11. Spectral profile of laminar flow in a normal internal carotid artery obtained using a continuous-wave (left) and pulsed (right) Doppler probe. The profiles demonstrate a well-defined spectral envelope and window (see Fig. 8-7). (Right, from Zierler RE, Roederer GO, Strandness DE. The use of frequency spectral analysis in carotid surgery. In Bergan JJ, Yao JST (eds), Cerebrovascular Insufficiency. New York. Grune and Stratten, Inc., 1983, pp 137 – 163.)
Trial (ECST), the North American Symptomatic Carotid Endarterectomy Trial (NASCET), and the Asymptomatic Carotid Atherosclerosis Study. The ECST concluded that the risks of surgery were significantly outweighed by later benefits in those patients with a 70–99% stenosis of the carotid artery. The risk of surgical morbidity and mortality and subsequent stroke was 12.3% in the surgical arm of the study and 21.9% for the control group.[25] The NASCET demonstrated an early and significant benefit associated with carotid endarterectomy in symptomatic patients with an ipsilateral internal carotid artery stenosis greater than 70%. The cumulative risk of ipsilateral stroke at 2 years was 26% in the medically managed patients and 9% in the surgical group.[26] A second publication from the NASCET group demonstrated a benefit to carotid endarterectomy in symptomatic patients with a 50 –69%
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stenosis. Compared to those patients who had a 70 –99% stenosis, the benefits of surgery in this group required a longer period of follow-up to achieve significance. The 5-year rate of ipsilateral stroke was 15.7% in those patients treated surgically and 22.2% in those treated medically.[27] The ACAS concluded that asymptomatic patients with an internal carotid artery stenosis $ 60%, could benefit from carotid endarterectomy. The aggregate five-year risk of ipsilateral stroke and perioperative stroke and death was 5.1% for the surgical group and 11.0% for the medical group.[28] These three trials introduced clinically relevant criteria for the pharmacological and surgical management of symptomatic and asymptomatic carotid occlusive disease. The new criteria did not correspond to the categories initially defined by researchers at the University of Washington. To further complicate decision making, the three groups of trialists had not adopted a uniform method for the quantification of angiographically defined carotid occlusive disease (Fig. 8-14). Researchers working at the University of Washington had compared Doppler spectral parameters to angiographic stenosis determined relative to the estimated normal diameter of the carotid bulb. While this definition had been adopted in the ECST, it was not the definition that had been employed in the NASCET and ACAS trials. The latter two had determined angiographic stenosis by comparing the least transverse diameter of the carotid artery at the stenosis, with the diameter of the distal uninvolved internal carotid artery. This resulted in an underestimation of stenoses relative to the criterion initially proposed at the University of Washington and that adopted by the ECST. Yet a third methodology proposed that the percentage stenosis be determined relative to the diameter of the visible, disease-free distal common carotid artery.[29 – 33] Eliasziw et al.[31] found the relationship between the percentage stenosis calculated according to the NASCET protocol and that using the common carotid artery diameter to be linear. Rothwell et al.[33] found no significant difference between the three methods in their ability to predict ipsilateral ischemic stroke, but did find that the method employing a common carotid artery reference was consistently the most
Figure 8-12. Normal spectral profile characteristic of the pulsed Doppler velocimeter (left) and profiles demonstrating the changes that occur with progressive stenoses (right). (From Zierler RE, Roederer GO, Strandness DE. The use of frequency spectral analysis in carotid artery surgery. In Bergan JJ, Yao JST. (eds), Cerebrovascular Insufficiency. New York, Grune and Stratton, Inc., 1983, pp 137 – 163.)
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Statistical Calculations Used in the Evaluation of Noninvasive Cerebrovascular Diagnostic Techniques
Table 8-1.
Noninvasive examination Carotid arteriography
Abnormal
Normal
Positive (stenosis or occlusion) Negative Sensitivity Specificity Positive predictive value Negative predictive value Accuracy
A C B/A+B D/C+D A/A+C D/B+D A+D/A+B+C+D
B D
CURRENT CLINICAL APPLICATIONS OF DUPLEX IMAGING
Figure 8-13. (A) The assumed, or apparent, degrees of diameter and area stenosis when an asymmetrical lesion is visualized in different projections. (From Sumner DS, Russell JB, Miles RD. Pulsed Doppler arteriography and computer assisted imaging of the carotid bifurcation. In Bergan JJ, Yao JST (eds), Cerebrovascular Insufficiency. New York, Grune and Stratton, Inc., 1983, pp 115 – 135.) (B) The relationship between area stenosis and diameter stenosis when the artery is asymmetrically narrowed (upper and lower lines) and when it is symmetrically narrowed (middle line). Arrows indicate the direction of the x-ray beam in the projection that shows the greatest degree of narrowing. (From Sumner DS, Russell JB, Miles RD. Pulsed Doppler arteriography and computer assisted imaging of the carotid bifurcation. In Bergan JJ, Yao JST (eds), Cerebrovascular Insufficiency. New York, Grune and Stratton, Inc., 1983, pp 115 –135.)
reproducible. The Committee on Standards for Noninvasive Vascular Testing of the Joint Council of the Vascular Societies[34] recognized that any approach to estimating the angiographic degree of stenosis was a compromise and would have inherent limitations. Nonetheless, the committee recommended that% diameter reduction should be determined relative to the distal internal carotid artery.
Initially noninvasive studies were used to screen individuals for evidence of atherosclerotic involvement of the cervical carotid artery. Such patients included those with asymptomatic cervical bruits; those with symptoms of posterior circulation or vertebrobasilar insufficiency; candidates for major cardiac and vascular reconstructive procedures; those with associated risk factors predisposing to atherosclerotic occlusive disease; and those symptomatic patients with a history of transient ischemic events or stroke. Asymptomatic and symptomatic patients without evidence of significant disease could be treated on the basis of imaging studies alone, but those with evidence of significant disease required arteriographic confirmation of disease prior to surgery. While contrast arteriography has been a prerequisite to surgical intervention, the role of preoperative noninvasive imaging is being critically reevaluated based on criteria established by the ECST, NASCET, and ACAS groups. As a screening test, sensitivity to the presence of disease was of critical importance; as a preoperative study in lieu of arteriography it may of value to modify noninvasive diagnostic criteria based on the risk of surgery (and arteriography) and the expected benefits of the procedure. Thus the positive and negative predictive values of a criterion become important and Doppler criteria are frequently evaluated relative to receiver operator characteristic curves. The positive predictive value represents the percentage of noninvasively abnormal studies which are also abnormal by contrast arteriography, while the negative predictive value represents the percentage of negative noninvasive studies which are associated with normal arteriograms. Unlike sensitivity and specificity, which characterize the percentage of arteriographic studies that are correctly classified noninvasively, the positive and negative predictive values yield the percentage of noninvasive studies that are in agreement with arteriography. Thus the predictive value represents the probability that a given noninvasive test result will accurately reflect arteriographic findings. Receiver operator characteristic (ROC) curves are used to demonstrate the relationship of sensitivity, specificity, positive predictive value, negative predictive value, and accuracy across a spectrum of criteria used to classify the presence or absence of disease (Table 8-2, Fig. 8-15).
Chapter 8.
Noninvasive Cerebrovascular Diagnostic Techniques
Figure 8-14. Measurements used for calculation of the percentage stenosis employing the University of Washington/ ECST method, the NASCET method, and common carotid artery reference (CC).
Attempts to redefine Doppler criteria relative to the significant ranges of carotid disease defined by clinical trials have demonstrated that multiple factors can influence the resulting criteria, including parameters measured, manufacturer specific equipment, individual laboratories, and associated (contralateral) disease. Doppler measures correlated with angiographic stenosis have included the peak systolic velocity (PSV) and end-diastolic velocity (EDV) in the internal carotid artery and ratios of the PSV or EDV measured in the internal carotid artery (at the point of stenosis) and from the common carotid artery (i.e., ICA PSV/CCA PSV). Using ROC curves to compare sensitivity, specificity, PPV and NPV, Faught et al.[35] concluded that the combination of a PSV greater than 130 cm/s and an EDV greater than 100 cm/s
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provided the optimal criteria for diagnosis of a 70 –99% stenosis. Figure 8-15 and Table 8-2 illustrate the ROC curve, and the statistical measures of accuracy generated from the curve, for differentiating a less than 70% stenosis from one equal to or greater than 70%. These demonstrate that a PSV of 210 cm/s yields the highest overall accuracy (93%), but a poor PPV (75%). By combining PSV and EDV, the authors were able to achieve an overall accuracy of 95%, with a sensitivity of 81%, a specificity of 98%, a PPV of 89%, and a NPV of 96%. Using a similar approach, but arriving at a different criterion, Moneta et al.[36] concluded that an ICA PSV/CCA PSV ratio greater than 4.0 provided the best combination of sensitivity (91%), specificity (87%), PPV (76%), NPV (96%), and overall accuracy (88%) for the diagnosis of a 70 –99% stenosis. Yet a third set of criteria were proposed by Carpenter et al.[37] They suggested that a combination of PSV (. 210 cm/s), EDV (. 70 cm/s), ICA PSV/CCA PSV (. 3.0), and ICA EDV/CCA EDV (.3.3) provided optimal criteria for detection of a greater than 70% stenosis. Recent publications clearly demonstrate that Doppler criteria are equipment (manufacturer) and laboratory specific and may explain this variability in published criteria. Alexandrov et al.[38] compared two independent laboratories using similar equipment. Eighty-seven patients (174 bifurcations) underwent imaging in both laboratories, as well as intra-arterial digital subtraction angiography. Applying criteria from one laboratory to studies performed in the second resulted in a 43% reduction in sensitivity and a 15% reduction in PPV. Fillinger et al.[39] compared the duplex criteria for a 60% angiographic stenosis from two laboratories, employing four different scanners. Doppler criteria to obtain a PPV greater than 90% and an accuracy greater than 90% differed, with ICA PSV/CCA PSV ratios varying from 2.6 to 3.3 and PSV in the internal carotid artery varying from 190 to 240 cm/s. Ranke et al.[40] recorded peak systolic velocity in 21 patients using color-flow duplex systems from two different commercial manufactures.
Relationship Between Sensitivity, Specificity, PPV, NPV, and Accuracy of Varying ICA PSVs Differentiating 70% Stenosis from Stenosis $ 70%
Table 8-2.
ICA PSV . (cm/s) 140 150 160 170 180 190 200 210 220 230 240 250
Sensitivity
Specificity
PPV
NPV
Accuracy
96.2 96.2 94.7 94.7 94.0 94.0 91.0 88.7 82.7 75.2 63.9 53.4
84.6 85.9 87.4 89.0 90.6 90.9 92.6 93.9 94.4 95.5 96.4 97.3
56.6 58.7 61.2 64.3 67.6 68.3 72.0 75.2 75.3 77.5 78.7 80.7
99.1 99.1 98.8 98.8 98.6 98.6 98.0 97.6 96.3 94.9 92.8 90.9
86.6 87.7 88.7 90.9 91.2 91.4 92.3 93.0 92.3 92.0 90.8 89.7
(From Faught WE, Mattos MA, van Bemmelen PS, Hodgson KJ, Barkmeier LD, Ramsey DE, Sumner DS. Color-Flow Duplex Scanning of Carotid Arteries: New Velocity Criteria Based on Receiver Operator Characteristic Analysis for Threshold Stenosis Used in the Symptomatic and Asymptomatic Carotid Trials. J. Vasc. Surg. 1994, 19, 818 –828.)
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Figure 8-15. ROC curve of the peak systolic velocity (cm/s) for differentiating between a stenosis of less than 70% and one that is equal to or greater than 70%. The curve demonstrates the relationship between the sensitivity and specificity for the range of velocities from 290 cm/s to 110 cm/s. Table 8-2 expands the measures to show the relationship between peak systolic velocity and the sensitivity, specificity, positive predictive value, negative predictive value, and accuracy. (From Faught WE, Mattos MA, van Bemmelen PS, Hodgson KJ, Barkmeier LD, Ramsey DE, Sumner DS. Color-Flow Duplex Scanning of Carotid Arteries: New Velocity Criteria Based on Receiver Operator Characteristic Analysis for Threshold Stenosis Used in the Symptomatic and Asymptomatic Carotid Trials. J. Vasc. Surg. 1994, 19, 818– 828.)
The peak systolic velocity was significantly higher when measured with one unit compared to the other ð218 ^ 156 cm=s versus 169 ^ 114 cm=sÞ; resulting in a 10% difference in predicted stenosis. Contralateral disease has also been correlated with an increase in carotid volume flow and flow measures, resulting in an overestimation of the severity of disease. Van Everdingen et al.[41] measured mean volume flow in the internal carotid artery using magnetic resonance angiography flow quantification. They demonstrated that flow in an artery with less than 70% stenosis was increased, relative to controls, contralateral to an artery with a greater than 70% stenosis. Busuttil et al.[42] identified 146 patients in whom duplex criteria overestimated disease contralateral to a highgrade stenosis or occlusion. Following carotid endarterectomy, the average peak systolic frequency decreased by 1175 Hz and the end-diastolic frequency by 475 Hz in 44 (of 128) unoperated contralateral stenoses. This resulted in a reduction in the estimate of disease by at least one duplex category.
across the diameter of the artery. Color flow imaging employs a real-time color overlay, superimposed on the gray scale duplex image, which visually demonstrates changes in flow velocity and direction. The diagnostic significance of color-flow duplex imaging continues to be evaluated. It has been demonstrated that colorassisted duplex imaging increases the speed of examination. Polak and associates[43] reported that the determination of peak systolic velocities was 40% faster using color-flow imaging. The peak systolic velocity, measured with and without color assistance, was not significantly different. On average it took 54 seconds to determine velocities using color-assisted techniques compared to 90 seconds with nonassisted techniques. Steinke et al.[44] have suggested that the color-assisted visualization of hemodynamic disturbances increases sensitivity to lesser degress of disease. In comparison to conventional duplex imaging, color flow techniques identified 72 small plaques and 8 minor stenoses in 159 arteries considered normal by conventional techniques. While color imaging may provide the flow image necessary to identify echolucent or anechoic lesions (Fig. 8-16; see also color plate), further information needs to be derived regarding the relationship between the plaque morphology, surface characteristics, and hemodynamic alterations. Only 51% of smooth plaques and 36% of irregular plaques were associated with turbulence. Color-flow techniques have also increased the overall accuracy of duplex imaging in the diagnosis of internal carotid artery occlusion. Bornstein et al.[45] evaluated data from a pooled series representing 2095 arteries. The sensitivity of gray-scale duplex imaging to 248 occluded arteries was 85%; the specificity for 1847 arteries without occlusion was 98%. The positive predictive value of grayscale imaging was 89% and the negative predictive value was 99%. AbuRahma et al.[46] compared the results of color-flow imaging and arteriography for 520 arteries, 103 of which had
COLOR-FLOW DUPLEX IMAGING The development of duplex imaging provided the technology to image arteries in real time, as well as to assess the Doppler velocity (frequency) profile. Color duplex imaging permits the integration of morphologic and hemodynamic information
Figure 8-16. An echolucent plaque in the proximal internal carotid artery. The color-flow image accentuates the luminal reduction and demonstrates increased flow velocities (see color scale to the left) and turbulence distal to the plaque. (See also color plate.)
Chapter 8.
a duplex diagnosis of occlusion or suspected high-grade stenosis/occlusion. The diagnosis of occlusion was based on the absence of flow in the internal carotid artery for at least 1 inch beyond the bifurcation. Near-total or total occlusion was suspected if the internal carotid artery could not be seen beyond the difurcation and there was damping of the common carotid artery signal or internalization of flow in the external carotid artery. In optimal studies, the accuracy of imaging to carotid occlusion was 97%, with a sensitivity of 91%, a specificity of 99%, a positive predictive value of 96%, and a negative predictive value of 98%. Of 12 suspected neartotal/ total occlusions, there were 4 occluded arteries and 8 with stenosis. Mansour et al.[47] evaluated color-flow duplex images of 596 internal carotid arteries for which arteriographic correlation was available. Defining total occlusion as the absence of flow in the internal carotid artery and preocclusive lesions as demonstrating only a trickle of flow, they reported a 98% sensitivity to occlusion, with a negative predictive value of 99%. Eighty-seven percent of preocclusive lesions were correctly identified, with a positive predictive value of 84%. Using color-flow imaging techniques, it has also been possible to assess flow dynamics across the artery in a dynamic fashion. This allows visualization of flow separation within the bulb (Fig. 8-17; see also color plate) as well as identification of turbulent flow profiles distal to stenoses. Ku and associates[48] compared in vitro and in vivo flow studies of the carotid bifurcation using laser Doppler anemometry and Doppler velocity measurements obtained with a Duplex scanner. Within the carotid bulb or sinus it was possible to identify areas of high flow velocity near the inner wall approximating the flow divider. Using a three-dimensional representation of velocity in a model of the proximal internal carotid artery, it was also possible to identify flow reversal in the carotid sinus. The implications of these findings with respect to vessel wall injury and the subsequent development of atherosclerotic plaque remains uncertain, but atherosclerotic involvement of the carotid artery initially involves the posterior and lateral aspect of the bulb and appears to develop in those areas where there is transient flow reversal.
CAN DUPLEX IMAGING REPLACE CAROTID ARTERIOGRAPHY? The logical extension of the advances in technology associated with carotid imaging and spectral analysis is decreased reliance on contrast arteriography in the preoperative assessment and evaluation of patients with suspected carotid obstructive disease. While arteriography may seem to be a reasonable adjunct in this evaluation, issues of cost, the incidence of complications, and patient discomfort become significant considerations. Carotid arteriography has been estimated to cost between $1,000 and $4,000 and can represent approximately 15% of the total expense associated with carotid endarterectomy.[49 – 53] Complications may result from direct arterial injury, contrast reaction, dye-induced renal failure, and embolic events. The
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reported incidence of complications associated with carotid arteriography varies from 0.2 to 2%. The best-documented data come from the ACAS and NASCET trials. In the ACAS, the incidence of cerebral infarction associated with arteriography was 1.2%, representing almost half of the operative risk.[28] There were four strokes and one death among the 414 patients who underwent arteriography. There was a 0.65% stroke rate among 2320 patients undergoing angiography in the NASCET.[26] In order to determine the value of carotid arteriography, it is first necessary to consider the information provided by an arteriogram. Arteriography was the standard used to quantify the percentage stenosis in the three studies validating the role of carotid endarterectomy in the treatment of symptomatic and asymptomatic carotid obstructive disease. In addition to quantifying the extent of atherosclerotic disease involving the carotid bifurcation, bulb and proximal internal carotid artery, arteriography also provides evidence of associated disease involving the arch, the origin of the great vessels, and the intracranial circulation. Eliasziw and associates,[54] writing for the NASCET group, concluded that the accuracy of ultrasonography and spectral data was “moderate” in the quantification of carotid stenosis. They felt that arteriography remained an essential component of the assessment prior to carotid endarterectomy. The NASCET, however, had randomized patients based on arteriographic data, and Eliasziw and associates had assigned duplex criteria for the diagnosis of a 70% stenosis retrospectively based on a review of the literature. Sensitivity and specificity varied from 0.65 to 0.71 using peak systolic velocity, peak frequency shift, and the ratio of peak velocity or frequency change in the internal carotid and the common carotid arteries. The authors did not account for laboratory or machine specific differences. Howard and associates[55] came to a different conclusion based on the ACAS data. Prior to the study an attempt was made to establish machine-specific criteria for each of the instruments that might be used in the study. Criteria were set to provide a 90% positive predictive value of a 60% angiographic stenosis. Using those criteria, sensitivity varied from excellent (80+%) in 21% of instruments to marginal (50–80%) in 51%. In 14% of instruments the sensitivity was less than 50%, and in 14% criteria could not be established. Despite the variation in sensitivity, Doppler-defined stenoses of greater than 60% were confirmed in 92% of 395 patients coming to angiography. The authors concluded that using protocols for standardization, the results of duplex ultrasonography could be used as the sole basis for carotid endarterectomy. Published series reporting carotid endarterectomy without preoperative arteriography have generally been small and uncontrolled. The surgical indications cited have frequently provided a relative (potential) contraindication to arteriography, including contrast allergy, disease progression on serial imaging, preocclusive lesions, crescendo TIAs, concurrent and acute surgical problems, unstable angina, and aortoiliac disease. Validation of the practice has been based on perioperative morbidity and mortality and operative confirmation of preoperative imaging studies. Several retrospective studies, however, have compared the relative value of noninvasive imaging and arteriography prior to carotid endarterectomy. Ricotta et al.[56]
Figure 8-17. A color image of the carotid bifurcation during systole (A) demonstrating flow in the internal (I) and external (E) carotid arteries. Color assignments are arbitrary, with shades of red generally representing forward arterial flow and shades of blue representing venous flow. During late systole and early diastole (B), there is evidence of flow reversal (blue/white shaded area) in the carotid bulb. (See also color plate.)
Chapter 8.
reviewed the records of 111 consecutive patients undergoing evaluation who had noninvasive assessment and arteriography. Of those patients with hemispheric symptoms, angiography was necessary in 11%, useful in 20%, and unnecessary in 69%. In asymptomatic patients, arteriography was necessary in 7%, useful in 20%, and unnecessary in 73%. For patients with nonhemispheric symptoms, arteriography was necessary in 31%, useful in 50%, and unnecessary in 19%. The study by Ricotta and associates employed early noninvasive techniques including OPG and continuous-wave Doppler ultrasonography. Moore et al.[57] reported on a prospective study in which history, physical findings, and duplex imaging were used to develop a proposed anatomic diagnosis. The anatomic diagnosis demonstrated a 94% correlation with arteriography. Preoperative assessment was 100% predictive of carotid occlusion and hemodynamically significant disease, 96% predictive in asymptomatic patients, and 91% predictive in symptomatic patients. Preoperative assessment was least effective in patients with nonstenotic ulceration (64% predictive). Mattos et al.[58] compared color-flow duplex imaging and arteriography in 167 patients being evaluated for possible carotid endarterectomy. The two diagnostic methods agreed exactly in 82% of patients. Duplex diagnosis was within one category of the arteriographic standard in 99% of cases. More importantly, however, clinical management was altered by arteriography in only 4% of cases. Similarly, Dawson and associates[59] prospectively evaluated the clinical decisionmaking process in 103 patients. Of the 94 patients undergoing arteriography, duplex imaging was diagnostic in 93%. If technically inadequate scans were excluded, arteriography affected clinical management in only one case. Technically inadequate studies were associated with disease that extended distally beyond the proximal internal carotid artery, anatomic or pathologic features that interfered with carotid imaging, or an inability to distinguish internal carotid artery occlusion from high-grade stenosis. Since duplex imaging techniques could be used to quantify the extent of carotid disease present, what is the incidence and significance of associated atherosclerotic involvement of the arch and great vessels or of the intracranial arteries? Akers et al.[60] evaluated the arteriographic studies of 1000 patients who underwent arch and four-vessel arteriography for suspected carotid occlusive disease. Eighteen patients (1.8%) had involvement of the arch and great vessels. In 12 of the patients the presence of the obstruction could be suspected on the basis of unequal brachial pressures. Eighty-seven had absence or stenosis of one or both vertebral arteries. Kadwa et al.[61] prospectively evaluated 129 consecutive patients undergoing evaluation for carotid endarterectomy. Pulse and blood pressure were recorded in both upper extremities, supraclavicular bruits were noted, and duplex flow velocity was assessed in the common carotid arteries. Nineteen patients (14.7%) had aortic branch disease, including 6 with disease involving the common carotid artery, 3 with involvement of the innominate artery, and 10 with involvement of the subclavian artery. Involvement of the arch branches was identified on physical examination or with duplex imaging in all cases.
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The incidence of intracranial disease varies depending upon the definition employed. Akers et al.[62] reported a 6% incidence of siphon stenosis in a series of 784 patients. The stenoses ranged from 5 to 70%, and no stenosis greater than 75% was identified. Roederer et al.[63] reported an 84% incidence of siphon stenosis involving 282 sides in 141 patients. Only 9% of lesions exceeded 50%, and 10% of the arteries were occluded. Mackey et al.[64] identified complete angiographic data on 597 patients. Significant intracranial disease was classified as identifiable plaque (, 80% stenosis), stenosis (. 80% stenosis), and occlusion. Two hundred lesions were present in 134 patients. Sixty-six% of the lesions involved the siphon, 20% the posterior communicating artery, 6% the anterior communicating artery, 4% the middle cerebral artery, and 4% the basilar artery. While the incidence of significant intracranial disease (greater than 50%) is generally low, it is variable. The critical question, however, is not the incidence but the effect of concurrent disease on outcome. Schuler et al.[65] demonstrated increased morbidity and mortality in 35 patients (44 endarterectomies) with associated intracranial disease. There was a 4.5% incidence of intraoperative stroke, a 6.8% incidence of perioperative stroke, and a 9.1% mortality. There were no intraoperative or perioperative strokes and a 2.1% mortality in a group of 44 patients (47 endarterectomies) without associated intracranial disease. These differences were not significant, but the number of patients was small. In a larger series reported by Mackey et al.,[64] there were 134 patients with associated intracranial disease and 463 without evidence of intracranial disease. The authors demonstrated no significant difference in perioperative stroke or mortality associated with intracranial disease. The incidence of perioperative stroke and mortality in the group of patients with intracranial disease was 1.9% and 0.5%, respectively, and that associated with the absence of intracranial disease was 1.8% and 0.7%, respectively. The consideration of intracranial disease must also take into account the incidence of intracranial aneurysms. Akers et al.[62] reported a 2% incidence of intracranial aneurysms in 784 patients. Ladowski et al.[66] reported on the results of carotid endarterectomy in 19 patients, with a symptomatic carotid stenosis and an associated intracranial aneurysm, undergoing 20 operations. The aneurysm was ipsilateral to the symptomatic stenosis in 10 patients, contralateral in 9, and involved the basilar artery in one. There was no perioperative stroke or mortality and no perioperative complications associated with rupture of the intracranial aneurysm. The data would suggest that those patients with significant disease involving the proximal branches of the aortic arch can be identified on the basis of physical examination or noninvasive assessment. Such patients could undergo arteriography on a selective basis. While the incidence of intracranial disease is variable, the presence of an intracranial stenosis or aneurysm does not appear to significantly increase the morbidity and mortality associated with carotid endarterectomy. Thus it would appear that arteriography could be supplanted by duplex imaging if criteria for the quantification of disease involving the carotid bifurcation could be developed and validated. While criteria for the quantification of carotid stenosis are variable, suitable
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laboratory-specific criteria can be developed using ROC curves. This statistical technique, in addition, allows criteria to be tailored to the indication for evaluation and endarterectomy. Criteria for screening tests can be adjusted to achieve a high sensitivity and positive predictive value so as not to miss disease. Sensitivity can be sacrificed in favor of a high positive predictive value and specificity when validating the presence of operative disease in an asymptomatic patient who will not undergo arteriography. In those patients with symptomatic disease, sensitivity could be maximized at the expense of overall accuracy.
OPERATIVE AND POSTOPERATIVE IMAGING Postoperative surveillance has heightened awareness, and demonstrated an increased incidence, of recurrent stenosis. The reported incidence of restenosis is variable, dependent upon the technique employed for diagnosis and whether asymptomatic as well as symptomatic recurrences are involved. Stoney and String[67] reported a 1.9% incidence of recurrent disease based upon a recurrence of symptoms, while Nicholls et al.[68] and O’Donnell and Callow[69] have documented recurrence rates of 12 –22% based upon the results of noninvasive assessment. Technological improvements in noninvasive diagnostic methods have provided a safe and practical means of serial follow-up after carotid endarterectomy. The use of real-time B-mode imaging has permitted the identification of lesser, hemodynamically insignificant, degrees of restenosis. On the basis of serial noninvasive examinations, utilizing the OPG, spectral analysis, and real-time B-mode imaging, DeGroote et al.[70] identified 69 (28%) arteries with evidence of restenosis following 248 endarterectomies. Thirteen% had hemodynamically significant restenosis and 15% had hemodynamically insignificant recurrence. O’Donnell and Callow[69] employed a combination of Doppler ultrasound and real-time B-mode imaging, and reported a 29% recurrence rate, with a 12% incidence of hemodynamically significant restenosis and a 17% incidence of hemodynamically insignificant restenosis. Recent data from the ACAS trial[71] have demonstrated a 16% incidence of recurrent stenosis over 5 years of follow-up. Evidence of recurrence was based on instrument specific criteria adjusted to achieve a 90% positive predictive value of a stenosis equal to or exceeding 60%. Recurrence in those arteries closed primarily was 21%, but only 7% in those arteries closed using a patch angioplasty technique. The ACAS data demonstrated that there was a 5.7% incidence of recurrent stenosis in the first 3 months following endarterectomy, an 8.5% incidence from 3 to 18 months and a 3.2% incidence from 18 to 60 months. Ouriel and Green[72] reported an 8.9% incidence of recurrence following 281 carotid endarterectomies and a 4% incidence of occlusion. There was a 5% incidence of restenosis in the first year and a 2% incidence per year thereafter. In an effort to reduce the incidence of postoperative recurrence, Sigel and colleagues[73] recommended intrao-
perative B-mode imaging to evaluate the adequacy of carotid endarterectomy and to identify the presence of unsuspected technical errors. Wall surface abnormalities and intimal flaps can be localized using real-time B-mode imaging. Spectral abnormalities, including elevated peak systolic velocity and spectral broadening, can be used to identify carotid obstruction occlusion. It would appear that small intimal defects can be safely observed. Sawchuk et al.[74] evaluated 80 endarterectomy sites using intraoperative ultrasound. Eighteen arteries had a total of 21 minor defects. Nineteen of these were small, intimal flaps of less than 3 mm, and two were described as minor stenoses. Sixteen of the 19 intimal flaps were no longer apparent at the time of the first postoperative evaluation, a mean of 27 12 months after carotid endarterectomy. Both stenotic lesions resolved within a month. Dorffner et al.[75] studied 50 patients intraoperatively. Abnormalities were identified in 19 cases and were classified as residual plaque, stricture, or a flap. In nine cases the endarterectomy was revised. No flap was associated with the subsequent development of a stenosis, and the authors concluded that intimal flaps less than 10 mm in size could be safely observed. Residual plaque, however, was associated with postoperative thrombosis in one case and stenosis in three cases. One of the strictures was also associated with postobstructive thrombosis. Unlike minimal disease, stenotic lesions should be corrected. While Jackson and associates[76] did not employ intraoperative imaging, early postoperative imaging following 206 carotid endarterectomies identified abnormalities in 5.8%. Two of the patients with greater than 60% stenosis by velocity criteria had a perioperative stroke, and four underwent reoperation. Of four uncorrected defects representing less than 60% stenosis, three had resolved on subsequent imaging; of two defects resulting in greater than 60% stenosis, one had resolved at the time of subsequent imaging and one persisted. Schwartz and associates[77] evaluated 84 arteries in 76 patients following carotid endarterectomy. Eighty% of the arteries studied demonstrated no evidence of a technical defect. Eighteen abnormalities were identified in the 84 arteries studied. Nine involved the internal carotid artery, of which 7 were repaired. There was no evidence of a recurrent stenosis at the end of 4 months. Two patients had evidence of a 50% stenosis at the time of intraoperative evaluation. Neither was repaired, and both lesions persisted at the time of follow-up examination. In addition to the identification of technical defects, intraoperative imaging can be predictive of subsequent postoperative recurrence. Johnson et al.[78] found that the luminal cross-sectional area of arteries closed using a vein patch increased in the first three months post-operatively and patents with a mean cross-sectional area greater than 1.77 cm2 developed evidence of mural thrombus. They recommended tailoring patches to achieve a luminal diameter of less than 1 cm. Golledge et al.[79] imaged patients one day and one week following carotid endarterectomy. They found that restenosis (. 50%) was associated with decreased luminal diameter. The diameter of the distal internal carotid artery was 4.8 mm in those arteries without restenosis and 3.4 mm in those with restenosis ðp ¼ 0:03Þ.
Chapter 8.
Postoperative surveillance also has been used to assess disease in the contralateral internal carotid artery following endarterectomy. In 496 patients, Ricotta and DeWeese[80] reported a 30% incidence of a 50% or greater stenosis in the contralateral internal carotid artery at the time of initial endarterectomy. In those patients with an initial contralateral stenosis that was less than 50%, progression of disease to a greater than 50% stenosis occurred in 10% of the overall population. The rate of progression was 5% at 3 years, 18% at 5 years, and 30% at 7 years. Lafrati et al.[81] attempted to evaluate the cost-effectiveness of postoperative surveillance of the contralateral internal carotid artery following carotid endarterectomy. Duplex scans were obtained in 324 patients, with 19.5% of patients progressing to a critical (.75%) stenosis over 5 years. Patients over age 65 and those with initial stenoses greater than 50% progressed to a critical stenosis at rates of 27 and 39%, respectively. The cost of each stroke prevented was $392,562 if the initial stenosis was less than 25% and $143,522 if the initial stenosis was 50–74%. The cost was $148,320 for patients 65 years of age and older.
MORPHOLOGY/PATHOLOGY It is apparent that certain atherosclerotic patterns are associated with the occurrence of cerebrovascular events. Moore and associates[82] demonstrated a relationship between angiographically identified carotid ulceration and focal neurologic symptoms. It has also been suggested that the presence of intraplaque hemorrhage is associated with a high incidence of symptoms. Imparato et al.[83] reported a relationship between the presence of intraplaque hemorrhage and focal neurologic symptoms. In addition, they further noted that atherosclerotic morphology tended to be symmetrical, observing that the pathologic characteristics of one carotid bifurcation were not dissimilar to those of the contralateral bifurcation. Persson and colleagues[84] reported that 33 of 34 (97%) symptomatic patients had intraplaque hemorrhage, while asymptomatic patients demonstrated similar pathological findings in only 11 of 21 (52%) patients. Lusby et al.[85] subsequently published a prospective study of carotid endarterectomy specimens. Acute or recent intraplaque hemorrhage was present in 46 of 53 symptomatic patients. As a result of this correlation between pathological characteristics and symptomatic events, attempts have been made to identify ultrasonic characteristics that correlate with pathologic morphology. The sensitivity of duplex imaging techniques to carotid ulceration has been variable. O’Donnell and associates[86] have had the greatest success noninvasively identifying carotid ulcerations. In their study, ultrasonic imaging and selective four-vessel arteriography were compared with pathologic specimens. Compared with 89 endarterectomy specimens, angiography demonstrated a 59% sensitivity to the presence of ulceration, while B-mode imaging demonstrated an 89% sensitivity, identifying 24 of 27 ulcerations. Arteriography had a 73% specificity and B-mode imaging an 87% specificity. Ulceration was defined as the presence of an isolated crater, proximal and distal
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lipping, with sharp demarcation of the overhanging echogenic borders, and visualization in two of three planes of insonation. Katz et al.[87] were unable to consistently identify ulcerative plaques using real-time B-mode ultrasonography. These investigators reported a 33% sensitivity to ulcerations of less than 2 mm, while there was a 58% sensitivity for ulcerations greater than 2 mm. O’Leary and associates[88] evaluated images in 55 patients who had undergone carotid endarterectomy. Compared with the pathologic specimen, an ulceration was identified by ultrasound with an accuracy of 60%, a sensitivity of 39% and a specificity of 72%. Sitzer et al.[89] evaluated 43 consecutive patients who underwent carotid endarterectomy. Each patient had a highgrade ($ 70%) stenosis of the internal carotid artery and had been imaged preoperatively with color-flow duplex ultrasonography. Compared with the pathoanatomic characteristics recorded for each endarterectomy specimen, ultrasonography had a 33% sensitivity to carotid ulceration, with a 67% specificity and a 46% positive predictive value. The interobserver reliability for a duplex defined ulcer had a kappa value of 0.57. While surface characteristics can be described as smooth, irregular, and ulcerative, plaques can also be described as echogenic or echolucent. Fibrous plaques, with an increased collagen content, are highly echogenic and homogeneous in character. Calcification is also echogenic or echoreflective and is generally associated with evidence of shadowing (Fig. 8-18). Echolucency is associated with intraplaque hemorrhage, as well as increased lipid deposition (Fig. 8-19). Echolucency associated with lipid deposition tends to be more homogeneous in character, while that associated with intraplaque hemorrhage is often characterized by irregular borders and scattered echoreflectivity. In their study, O’Donnell and associates[86] were able to identify evidence of plaque hemorrhage with a 93% sensitivity. Gray-Weale et al.[90] classified plaque morphology into four categories: dominantly echolucent, with a thin echogenic cap; substantially echolucent, with small areas of echogenicity; dominantly echogenic, with small areas of echolucency (less than 25%); and uniformly echogenic. Two hundred and forty-four specimens, obtained at the time of endarterectomy, were pathologically examined and classified as exhibiting intraplaque hemorrhage only, ulceration only, intraplaque hemorrhage and ulceration, or fibrous changes. The majority of operations, 236 of 244, were performed for symptomatic disease. In this group of predominately symptomatic patients, the majority had a plaque showing evidence of ulceration and/or intraplaque hemorrhage. Of these, 73% were characterized as dominately or substantially echolucent. Evaluated in another fashion, of the 179 specimens which were classified as dominantly or substantially echolucent, 174 or 97% contained evidence of interplaque hemorrhage or ulceration. More recently, AbuRahma et al.[91] classified the ultrasonic morphology of 152 plaques by surface characteristics and echodensity. Intraplaque hemorrhage was present in 90% of the plaques with evidence of surface irregularity and 90% of those characterized as heterogeneous. Eighty-four% of the irregular plaques and 80% of the heterogeneous plaques were symptomatic. Polak et al.[92] investigated the relationship between first stroke and plaque echogenicity in a cohort of 4886
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Figure 8-18. An echoreflective plaque (single arrow) is seen on the near wall of the common carotid artery, proximal to the bifurcation. The associated shadowing (double arrow), which obscures the deep wall of the artery, suggests the presence of calcification.
individuals and found the relative risk of stroke was 1.72 ðp ¼ 0:015Þ for hypoechoic plaque and 2.32 ðp ¼ 0:004Þ for stenoses of at least 50%. Using the Gray-Weale classification system, Golledge et al.[93] categorized plaque morphology in 350 patients with
Figure 8-19.
60–99% stenosis of the internal carotid artery. Echolucent type I and II plaques were most common in symptomatic patients (83% versus 44%). Ulceration was seen in 23% of symptomatic patients and 14% of those without symptoms ðp ¼ 0:04Þ: Recently the reproducibility of morphologic classifications has been questioned in two publications. de Bray et al.[94] found interobserver and intraobserver reproducibility for echostructure and luminal surface classifications varied from 0.41 to 0.64. Arnold and associates[95] came to similar conclusions, observing that interobserver and intraobserver reproducibility were not consistently achievable. They evaluated the Gray-Weale classification as well as a simpler two-category classification (homogeneous and heterogeneous). They found reduced variability with the twocategory grading scheme. Studies evaluating the influence of plaque morphology on presentation or outcome will need to carefully evaluate the reproducibility of their models. Recent reports have begun to employ computer models, which may ultimately provide more reproducible results. El Barghouti et al.[96] used an image analysis program to classify 209 plaques by echogenicity and heterogeneity. Symptomatic plaques and those associated with computed tomography (CT) evidence of infarction were more echolucent and less heterogeneous.
NATURAL HISTORY In addition to defining the relationship between plaque pathology/morphology and clinical presentation, early studies
An area of central echolucency (arrow) within an atherosclerotic echoreflective plaque.
Chapter 8.
have suggested that real-time B-mode imaging could also be used to study the natural history of atherosclerosis and, by extension, could be used to follow the progression and regression of atherosclerotic disease in response to therapeutic interventions. Senin et al.[97] evaluated 118 atherosclerotic lesions in 70 patients. The patients were scanned and the plaques defined on the basis of echoreflectivity, surface characteristics, and the degree of stenosis. Echoreflectivity was defined as soft, intermediate, hard, and mixed. Soft lesions were homogeneous and echolucent, consistent with lipid deposition. Intermediate lesions were homogeneous and moderately reflective, corresponding to a fibrous plaque, while hard lesions were homogeneous and highly reflective with evidence of shadowing. Mixed lesions demonstrated a heterogeneous pattern with areas of high and low reflectivity, suggesting thrombus and/or hemorrhage. Surface aspects were characterized as regular or irregular. After 2 years, the authors observed that 68% of lesions remained unchanged while there was an increase in the degree of stenosis in 32%. Regression was not observed in any of the lesions. Factors associated with increasing stenosis were hard and mixed echogenic patterns, an irregular surface, and an initial stenosis of greater than 50%. Henerici and associates[98] evaluated ultrasonic characteristics and patterns, relative to pathologic findings, in 54 carotid arteries examined in vitro in a postmortem study. The normal carotid artery was characterized by parallel echoreflective lines, enveloping an echolucent core (Fig. 8-20). The distance between the echoreflective lines corresponded to the thickness of the media. The inner echoreflective contour represented the intima/lumen interface, while the outer corresponded to the media/adventia interface. The authors identified a progression of disease from flat plaques to soft plaques to hard plaques. The flat plaque was an eccentric fibrous thickening adjacent to the arterial lumen, with a soft friable center secondary to decreased cellularity. By ultrasound these lesions were characterized by the appearance of heterogeneous echoes within the normally echolucent media (Fig. 8-21). Pathologically, the atherosclerotic process increased by a layering of fibrous tissue, calcific deposits, thrombus, or hemorrhage. By ultrasound this progression was characterized by laminated echoes of different intensities which began to encroach on the lumen. With progression, echoreflective or hard plaques were produced by further compaction of fibrous materials or microcalcification. In a subsequent study, the senior author and others[99] evaluated 43 extracranial carotid plaques (less than 30% diameter stenosis) in 31 patients over 18 months. Regression was restricted to a volume reduction in soft plaques. Fibrous and hard plaques remained unchanged or progressed. Extending these observations, Poli and associates[100] ultrasonically evaluated the thickness of the intima/media complex of the common carotid artery in a group of hypercholesterolemic patients, comparing this with a group of controls. The thickness was significantly increased in those patients with hypercholesterolemia. In the control patients the thickness of the intima/media complex increased with age. In the hypercholesterolemic group, the thickness of this complex increased in male patients and smokers. Pignoli and associates[101] had previously
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evaluated the abdominal aorta and common carotid artery, removed at autopsy, in 18 male subjects. The specimens were evaluated by ultrasound as well as pathologic and histologic examination. The authors concluded that B-mode estimates of the intima-media thickness did not differ significantly from the thickness of the intima and media measured microscopically. Gnasso et al.[102] demonstrated a relationship between intima-media thickness and hyperlipidemia. Fifty hyperlipidemic and 50 control patients were evaluated using real-time B-mode imaging techniques. The intima-media thickness of the common carotid artery ranged from 0.52 to 1.24 mm in hyperlipidemic patients and 0.46 to 0.82 mm in controls. O’Leary et al.,[103] reporting for the Cardiovascular Health Study Collaborative Research Group, demonstrated that the risk of myocardial infarction or stroke increased with intimamedia thickness. The relative risk of a cardiovascular event increased by a factor of 3.87 when patients with the greatest thickness were compared to those with the least. The Cholesterol Lowering Atherosclerosis Study[104] demonstrated a reduction in coronary artery disease and carotid intima-media thickness at 2 and 4 years with colestipal/niacin therapy. A reduction in intima-media thickness was apparent after one year of therapy. Untreated controls showed increasing intima-media thickness at a rate of 0.018 mm/year.
Figure 8-20. A demonstration of the parallel echoreflective lines that characterize the wall of the carotid artery. These are best seen on the far wall of the artery and envelop an echolucent core, which corresponds to the media. The inner echo reflective strip represents the intima/lumen interface and the outer corresponds to the media/adventitia interface.
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Figure 21. An area of intimal thickening (single arrow) is characterized by heterogeneous echoes within the normally echolucent media. Pathologically, the atherosclerotic process progresses with a layering of fibrous tissue, calcific deposits, thrombus, or hemorrhage. By ultrasound this progression is characterized by laminated echoes of different intensities that begin to encroach on the lumen (double arrow).
The transcranial Doppler (TCD) technique has found varied clinical application because it is portable, noninvasive, and can be used for continuous monitoring. It can provide information regarding flow direction and normal and collateral intracranial flow patterns as well as flow velocity and intracranial obstructive disease. While significant experience is required to develop the proficiency necessary to evaluate all major intracranial arteries, identification of the middle cerebral artery is relatively simple. Insonnation of the middle cerebral artery has been used to assess the vasospasm associated with subarachnoid hemorrhage,[106,107] the changes in cerebral perfusion that occur in patients with closed head injuries,[108,109] for continuous intraoperative monitoring[110,111] (Fig. 8-22), and perioperative evaluation of patients undergoing carotid endarterectomy.[111 – 116] Continuous intraoperative monitoring of the middle cerebral artery can demonstrate changes in blood flow velocity with carotid artery clamping, which may indicate the need for shunting. A decrease in flow while shunted may indicate shunt occlusion. Additionally, it has been possible to identify periods of interaoperative embolization. This information can be used to modify operative technique and decrease the incidence of perioperative morbidity.[111] Postoperative evaluation following endarterectomy has demonstrated early hyperperfusion followed by a normalization of velocities. Araki and associates[117] evaluated anterior and middle cerebral artery flow velocity prior to and following carotid endarterectomy. They demonstrated a sustained increase in middle cerebral artery flow up to 3 weeks following surgery in those patients with evidence of a hemodynamically significant stenosis (greater than 75% by diameter or OPG positive).
FUTURE PERSPECTIVES Newer imaging techniques, as well as advancements in the use of ultrasound and image processing, are being evaluated in an effort to increase the diagnostic range and resolution of current noninvasive methodologies. These include the transcranial application of Doppler ultrasound, the use of intravenous echoenhancement agents and three-dimensional ultrasonic imaging techniques, and the extention of magnetic resonance and CT imaging technology. With advancements in the use of ultrasound it has become possible to directly insonnate the major intracranial arteries through the thin, bony windows of the frontal and temporal bones using a 2 MHz transducer, with the capacity to axially gate or focus the signal at specific increments from the transducer. The posterior circulation is accessible through the foramen magnum. Since the position of the major arteries is relatively constant and their distance from the probe fixed by the skull, the distal internal carotid, anterior and middle cerebral, anterior and posterior communicating, and the vertebral and basilar arteries can be identified and studied. Although the angle of insonnation cannot be precisely determined for the branches of the circle of Willis, it is limited by the bony windows of the frontal and temporal bones to between 0 and 30 degrees. Thus, minimal error is introduced (, 15%) by variation in this angle, allowing for accurate and reproducible determination of blood flow velocity.[105]
Figure 8-22. Doppler velocity profiles from the middle cerebral artery, ipsilateral to the side of carotid endarterectomy, prior to (A) and following (B) the application of vascular clamps, following the insertion of a shunt (C) and following the restoration of flow after endarterectomy (D) of a hemodynamically significant obstruction. Corresponding systolic and diastolic velocities are provided below each figure.
Chapter 8.
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Figure 8-23. Magnetic resonance angiogram (MRA, center) demonstrating minimal atherosclerotic disease in the area of the right carotid bulb (R) and occlusion of the left internal carotid artery (L). Corresponding selective carotid arteriograms appear to the right and left of the MRA.
Intravenous echoenhancement agents and three-dimensional imaging algorithms are being used in an effort to improve the resolution of current duplex imaging techniques. Sitzer et al.[118] found that qualitative measures of crosssectional area and plaque length were comparable before and after echoenhancement, but visualization of the stenotic flow lumen was significantly improved. The authors speculated that this improved visualization of the residual flow lumen might increase ultrasonic sensitivity to internal carotid artery occlusion. Abildgaard et al.,[119] however, observed that there was a relative increase in peak systolic and end-diastolic velocities associated with ultrasound contrast media. Spectral intensity was also accompanied by spectral broadening. The authors concluded that intravenous contrast agents may facilitate flow detection, but can also produce spectral and color artifacts. As plaque morphology becomes increasingly important in the natural history of carotid atherosclerosis and atherogenesis, three-dimensional imaging may provide greater correlation with pathoanatomic studies. Yao et al.[120] reported that three-dimensional ultrasound had excellent reproducibility and acceptable intraobserver and interobserver variability with respect to plaque length and volume measurements. In the future, magnetic resonance angiography (MRA) may provide noninvasive images of the extracranial (Fig. 823) and intracranial (Fig. 8-24) cerebral circulation that offer even greater resolution than echoenhanced or three-dimensional ultrasound. Spiral CT imaging is yet another technique that provides high-quality images, three-dimensional visualization, and the opportunity for digital manipulation, facilitating assessment of plaque morphology and luminal characteristics. Magnetic resonance angiography is an extension of magnetic resonance imaging and provides a means of visualizing the aortic arch and proximal great vessels as well as the carotid bifurcation and the intracranial internal carotid artery. Currently, two techniques are utilized. Phase contrast MRA is based on the movement of flowing blood along magnetic field gradients and the resulting phase shifts.
Equal and opposite gradients are applied to the imaging slice. Stationary tissue will produce no net phase shift, while moving blood will produce a positive phase shift. The magnitude of the shift correlates with the velocity of blood flow and a velocity map or phase contrast angiogram is produced. Time-of-flight MRA is based on the principle of “flow-related enhancement.” When tissue is “excited” by a radio frequency (RF) pulse, the tissue produces a weak RF echo, which is used to obtain an image. After emitting an echo, the tissue must relax before it can be reexcited to produce a signal. Tissue that is not fully relaxed or “saturated” does not produce a signal. Blood entering the imaging field, however, has not experienced prior RF pulses and is fully relaxed. Flowing blood will produce a high signal, while
Figure 8-24. Magnetic resonance arteriogram of the intracranial circulation, demonstrating the circle of Willis. (R, L, and P designate right, left, and posterior, respectively.)
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the stationary tissue will produce little signal. This phenomenon is called “flow-related enhancement” and is the basis for time-of-flight MRA. Regardless of the technique, images are computer generated based on maximum intensity projection (MIP) algorithms. The computer surveys all of the cross-sectional
Figure 8-25. MRA of the carotid bifurcation demonstrating the common carotid artery, the internal carotid artery (curved arrow), the external carotid artery (open arrow), and the vertebral artery (arrowhead). Cross-sectional data images (A) and the computer reconstructed MIP image of the carotid bifurcation in a lateral projection (B).
Figure 8-26. MRA of the aortic arch and origin of the great vessels. The upper image (A) was obtained using surface coils, and the lower image (B) was obtained using intravascular contrast agents.
Chapter 8.
images (Fig. 8-25A) and selects the brightest coordinates or pixels in each section. The cross-sectional images are then stacked, producing an angiographic-like display (Fig. 8-25B) that can be viewed in multiple projections. Studies[121,122] have demonstrated good correlation with conventional arteriography, suggesting the usefulness of this technique in the noninvasive evaluation of carotid atherosclerosis (Fig. 8-23). Published series evaluating magnetic resonance angiography have generally been small, evaluating the technique relative to duplex imaging or conventional angiography. Blakeley et al.[123] abstracted multiple articles comparing carotid noninvasive techniques and concluded that duplex ultrasonography and MRA had comparable sensitivities to carotid occlusion, varying from 0.82 to 0.86. The sensitivity of these techniques to high-grade stenoses ($ 70%) was 0.83 –0.86, with specificities of 0.89 –0.94. Pan et al.[124] compared ultrasonography, MRA, and conventional angiography with ex vivo measurement of plaque stenosis. The series included 28 patients and 31 endarterectomy specimens. The correlation with ex vivo measurements was 0.80 for ultrasound, 0.76 for MRA, and 0.56 for angiography. MRA offers some unique advantages in comparison to conventional arteriography. It is dependent on the intrinsic properties of blood flow. As such, it is noninvasive and does not utilize intravenous contrast for visualization. This is an important advantage in patients who may have a contrast allergy or renal dysfunction. Like conventional magnetic resonance imaging, magnetic field gradients are used to generate images so that the patient receives no ionizing radiation during this procedure. As the MRA is generated from many cross-sectional views, the image may be viewed in multiple projections following a single acquisition, rather
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than the single projection provided by standard angiographic techniques. There are also disadvantages compared to conventional arteriography. Patients with metallic implants, such as cardiac pacemakers, certain heart valves, and aneurysm clips, are prohibited from undergoing MR examination. Claustrophobic patients may be uncomfortable in the scanner, although usually this can be overcome with reassurance or sedation. Artifacts can result from patient motion, swallowing, and excessive arterial pulsation. These artifacts can generally be minimized through meticulous patient instruction and alterations in scanning methods. The intracranial circulation and the circle of Willis were the first areas to be explored with MRA. Considerable research has resulted in images of remarkable quality (Fig. 822). Less work has been done in the evaluation of the aortic arch and proximal great vessels.[125] Initial problems encountered in visualizing these arteries were related to the orientation of the arteries, making it difficult to maximize the arterial signal while minimizing signal from the venous return. Patient positioning, newer chest surface coils, and intravenous enhancement agents show promise in circumventing these problems, permitting good quality images (Fig. 8-26) to be obtained in selected patients. The spatial resolution of MRA is less than that of conventional arteriography, and high-grade stenosis and turbulence may produce artifacts, resulting in an overestimation of the degree of stenosis (Fig. 8-27). Because of these limitations, preliminary applications have employed MRA in combination with duplex ultrasonography. While the current resolution of MRA does not approach that of standard arteriography, it does provide a means of confirming the presence of an ultrasonically defined high-grade stenosis. In addition, it permits visualization of the aortic arch, proximal
Figure 8-27. MRA (center) of the right (R) and left (L) carotid arteries. The arrows demonstrate flow voids in the region of the bulb and proximal internal carotid artery, bilaterally. The corresponding arteriogram of the right internal carotid artery demonstrates only a minimal stenosis, indicating that the MRA has overestimated the degree of stenosis. The arteriogram demonstrates a high-grade stenosis (.75%) of the left internal carotid artery consistent with the high-grade stenosis predicted by the flow void on the MRA.
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Figure 8-28. Severe stenosis of the proximal left internal carotid artery (arrow) shown by conventional arteriography (center). A twodimensional (2-D) MRA demonstrates a void in the region of the bulb and proximal internal carotid artery, characteristic of a severe stenosis (left). This area is better defined in the three-dimensional (3-D) MRA (right).
great vessels, and the distal intracranial internal carotid artery. Newer three-dimensional imaging techniques excite or saturate a volume of tissue, rather than the linear slice saturated with earlier two-dimensional techniques. The threedimensional studies provide a greater number of crosssectional images and increased resolution (Fig. 8-28). Using a three-dimensional time-of-flight (TOF) technique, Patel et al.[126] found that MRA had a 94% sensitivity to 70 – 99% stenoses, with a specificity of 85% and an accuracy of 88% relative to contrast arteriography. Doppler ultrasound had a sensitivity of 94%, a specificity of 83% and an accuracy of 86%. MRA accurately differentiated 16 high-grade (90–99%) stenoses from 17 carotid occlusions. Recently spiral CT imaging techniques have permitted three-dimensional reconstruction of contrast enhanced CT images (Fig. 8-29). While this technique does require the use of a contrast agent, it may be administered intravenously and does not carry the risks associated with the introduction of arterial catheters. Spiral CT arteriography can accurately depict the degree of carotid stenosis in comparison to standard carotid arteriography, and three-dimensional reconstructions provide images that can be viewed in multiple projections.[127] This technique may offer an alternative to arteriography or MRA in those patients with ultrasonic evidence of minimal (, 50%) stenosis or ulceration. Data evaluating the results of CT angiography are sparse, but at least one reference has also suggested[128] that the technique has a higher positive predictive value for carotid occlusion than that of duplex imaging (95% versus 77%). With the exception of indirect techniques such as the OPG, none of the current noninvasive methods provide specific information regarding the hemodynamic consequences of extracranial or intracranial carotid occlusive disease. Xenon CT imaging (Fig. 8-30) may provide a means with which to assess flow (mL/100g tissue/min) in the anterior and posterior cerebral circulations. Venninan et al.[129] have also
evaluated MR phase-contrast flow quantification. The technique allows measurement of PSV and volumetric flow rate (VFR). In a series of 55 patients and 10 normal volunteers there was a significant correlation between PSV obtained using duplex ultrasound and MR flow quantification in those volunteers without disease (0.73) and in the study population (0.64). VFR was significantly reduced in arteries with stenoses equal to or greater than 70%. While early techniques evaluated the patency of the carotid circulation indirectly based upon the presence of abnormal collateral flow patterns or decreased end-ophthalmic artery pressures, newer technologies permit the direct assessment of the cervical carotid artery using real-time B-mode ultrasound, pulsed and continuous wave Doppler
Figure 8-29. An image of the carotid bifurcation, generated by spiral CT imaging, demonstrating the internal and external carotid arteries, with an area of stenosis just distal to the carotid bulb.
Chapter 8.
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Figure 8-30. Computer generating reproduction of a CT scan with superimposed flow profiles. The circles represent specific areas of interest and the corresponding table provides the flow wind cc per 100 grams of tissue per minute in the selected areas. Flow estimates can be obtained using the color comparison gradient on the right. Xenon-enhanced CT scan at the level of the occipital lobes (arrows). Cerebral blood flow (cc/100 g of tissue/min) can be calculated for a specific area (mean ^ SD) or displayed visually relative to a color code. The scan demonstrates decreased flow (, 15 mL/100 g tissue/min) in the posterior circular (areas 9, 10, 11, 21, 22).
spectra, and duplex imaging. Current technology now permits accurate quantification of carotid stenoses, and these estimates can be correlated with recent reports defining clinically significant asymptomatic and symptomatic carotid obstructive disease. Using protocols for standardization, the results of duplex ultrasonography can be used as the basis for carotid endarterectomy in selected cases. Recent innovations have resulted in the integration of realtime color flow velocity and B-mode images, the construction of three-dimensional ultrasonic images, and the use of intravascular echocontrast agents. In time these advances may provide greater information regarding atherogenic flow patterns and the flow velocity patterns and turbulence that
result from minimal wall surface irregularities as well as highgrade stenoses. Transcranial techniques have permitted the characterization of intracranial flow patterns, demonstrating increased poststenotic flow velocities, abnormal collateral flow profiles resulting from proximal obstructive disease, and abnormal velocity profiles consistent with decreased cerebral perfusion. In the future, magnetic resonance and CT angiography may provide high-resolution noninvasive images of the extracranial and intracranial cerebral circulation. At present, however, such techniques have technical limitations, and further evaluation will be necessary in order to determine their eventual role in the assessment of patients with atherosclerotic cerebrovascular disease.
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Study Using an Ultrasound Imaging System. Angiology 1988, 5, 429– 436. Hennerici, M.; Reifschneider, G.; Trockel, U.; Aulich, A. Detection of Early Atherosclerotic Lesions by Duplex Scanning of the Carotid Artery. JCU 1984, 12, 455– 463. Hennerici, M.; Rautenberg, W.; Trockel, U.; Kladetzky, R.G. Spontaneous Progression and Regression of Small Carotid Atheroma. Lancet 1985, 1, 1415– 1419. Poli, A.; Tremoli, E.; Colombo, A.; Sitori, M.; Pignoli, P.; Paoletti, R. Ultrasonic Measurement of the Common Carotid Artery Wall Thickness in Hypercholesterolemic Patients. A New Model for the Quantitation and FollowUp of Preclinical Atherosclerosis in Living Human Subjects. Atherosclerosis 1988, 70, 253–261. Pignoli, P.; Tremoli, E.; Poli, A.; et al. Intimal Plus Medial Thickness of the Arterial Wall: A Direct Measurement with Ultrasound Imaging. Circulation 1986, 74, 1399. Gnasso, A.; Pujia, A.; Irace, C.; Mattioii, P.L. Increased Carotid Arterial Wall Thickness in Common Hyperlipidemia. Coron. Artery Dis. 1995, 6, 57– 63. O’Leary, D.H; Polak, J.F; Kronmal, R.A; Manolio, T.A; Burke, G.L; Wolfson, S.K Carotid-Artery Intima and Media Thickness as a Risk Factor for Myocardial Infarction and Stroke in Older Adults. N. Engl. J. Med. 1999, 340, 14– 22. Mack, W.J.; Selzer, R.H.; Hodis, H.N.; Erickson, J.K.; Liu, C.; Lio, C.; Crawford, D.W.; Blankenhorn, D.H. OneYear Reduction and Longitudinal Analysis of Carotid Intima-Media Thickness Associated with Colestipol/Niacin Therapy. Stroke 1993, 24, 1779–1783. Aaslid, R. The Doppler Principle Applied to Measurement of Blood Flow Velocity in Cerebral Arteries. In Transcranial Doppler Sonography; Aaslid, R., Ed.; Springer-Verlag: New York, 1985; 22. Aaslid, R.; Markwalder, T.M.; Nornes, H. Noninvasive Transcranial Doppler Ultrasound Recording of Flow Velocity in Basal Cerebral Arteries. J. Neurosurg. 1982, 57, 769– 774. Aaslid, R.; Huber, P.; Nornes, H. Evaluation of Cerebrovascular Spasm with Transcranial Doppler Ultrasound. J. Neurosurg. 1984, 60, 37– 41. Powers, A.D.; Graeber, M.C.; Smith, R.R. Transcranial Doppler Ultrasonography in the Determination of Brain Death. Neurosurgery 1989, 24, 884– 889. Glasier, C.M.; Seibert, J.J.; Chadduck, W.M.; et al. Brain Death in Infants: Evaluation with Doppler US. Radiology 1989, 172, 377. Padayachee, T.S.; Gosling, R.G.; Bishop, C.C.; et al. Monitoring Middle Cerebral Artery Blood Velocity During Carotid Endarterectomy. Br. J. Surg. 1986, 73, 98– 100. Jansen, C.; Ackerstaff, R.G.A.; Eikelboom, B.C. The Use of Transcranial Doppler in Carotid Artery Disease. In Technologies in Vascular Surgery; Yao, J.S.T., Pearce, W.H., Eds.; WB Saunders Co.: London, 1991; 159 –165. Lindegaard, K.F.; Bakke, S.J.; Grolimund, P.; Aaslid, R.; Huber, P.; Normes, H. Assessment of Intracranial Hemodynamics in Carotid Artery Disease by Transcranial Doppler Ultrasound. J. Neurosurg. 1985, 63, 890– 898. Schneider, P.A.; Ringelstein, E.B.; Rossman, M.E.; Dilley, R.B.; Sobel, D.F.; Otis, S.M.; Bernstein, E.F.
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Artery Occlusion: A Prospective Study. Eur. J. Vasc. Endovasc. Surg. 1998, 16, 133– 136. 129. Vanninen, R.L.; Manninen, H.I.; Partanen, P.L.; Vainio, P.A.; Soimakallio, S. Carotid Artery Stenosis: Clinical Efficacy of MR Phase-Contrast Flow Quantification as an Adjunct to MR Angiography. Radiology 1995, 194, 459– 467.
CHAPTER 9
Noninvasive Diagnosis of Venous Disease J. Leonel Villavicencio David L. Gillespie Sandra Eifert
INTRODUCTION
CLINICAL MANIFESTATIONS OF DEEP VENOUS THROMBOSIS OF THE LOWER EXTREMITIES
It has been estimated that each year, nearly 200,000 people in the United States die from complications from venous thrombosis of the lower extremity.[1] The figures from Great Britain are no less impressive, with an estimated annual mortality rate of 21,000.[2] Lower extremity venous thrombosis frequently accompanies other disease processes, and several conditions predispose to its development (Table 9-1). Procedures such as transjugular and transsubclavian catheterization and infusion lines, transvenous pacemaker insertions, and intravenous hyperalimentation have led to a remarkable increase in the incidence of brachiocephalic and upper extremity venous thrombosis. This iatrogenic thrombosis is superimposed on a generally low, but potentially crippling incidence of upper extremity venous occlusion associated with thoracic outlet syndrome. While it was formerly believed that pulmonary embolism rarely occurred in patients with brachiocephalic or upper extremity venous thrombosis, an incidence of pulmonary embolism of 12% has now been documented.[3 – 5] Despite a great deal of experience with lower extremity venous thrombosis, uncertainty continues regarding the optimum treatment during the acute stages and optimum methods of long-term management. However, there has been significant progress over the last several years in the development of noninvasive techniques for diagnosing both venous obstruction and venous insufficiency. As will be discussed in subsequent sections, these techniques have significant advantages over the invasive counterparts, such as contrast phlebography, and they have been shown to have comparable cost-effectiveness.[6]
The most common symptom reported by patients with lower extremity deep venous thrombosis (DVT) is pain. The pain may be mild and insidious in patients with thrombosis of the calf veins, or it may be acute and excruciating in patients with iliofemoral thrombosis and extensive venous occlusion such as phlegmasia cerulea dolens. Most commonly, it is described as a dull ache, throbbing sensation, feeling of tightness, or a feeling that the leg is about to burst. These symptoms are present at rest and may be aggravated by walking. Unfortunately, many patients, particularly those who are postoperative or critically ill from other diseases, have no symptoms related to the leg and their first manifestation of venous thrombosis is an episode of pulmonary embolism. When signs of toxicity such as severe temperature elevation or tachycardia are present, one should suspect the presence of septic thrombophlebitis or massive iliofemoral venous thrombosis. The presence or absence of these signs of inflammation was previously thought to be quite important, and distinctions were made between phlebothrombosis, in which there was little or no inflammation of the vein and therefore few clinical manifestations, and thrombophlebitis, in which inflammation of the vein was prominent and the clinical signs and symptoms were quite evident.[7] Patients with phlebothrombosis were thought to be at much greater risk of pulmonary embolism than those with thrombophlebitis. While these distinctions may have enhanced the basic pathophysiological course of the disease,
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the categorizations are almost impossible to make on the basis of clinical findings. The term phlebothrombosis is rarely used nowadays, and all patients with venous thrombosis should be considered to be at significant risk of pulmonary embolism. Some patients seek medical care only after the onset of leg swelling. Leg swelling and edema may also be a subtle clue to the onset of venous thrombosis in bedridden patients. Edema fluid may collect behind the malleoli before it becomes more diffuse. This subtle finding of retromalleolar edema in bedridden patients should alert one to the possibility of deep venous thrombosis.[8] In searching for leg swelling and edema, one should remember that there is normally some discrepancy between the sizes of the two lower extremities. However, size discrepancies greater than 1 cm are considered significant.[9] In comparing sizes between the two extremities, it is necessary to use fixed landmarks as reference points and to make sequential measurements at the same distance from this fixed reference point (medial malleolus, anterior tibial spine, and anterior superior iliac spine). Local heat and erythema are common in superficial thrombophlebitis, but not in thrombosis of the deep veins. Superficial tenderness and the presence of a palpable cord are also common is superficial thrombophlebitis. It is important to recognize these signs, since it is not unusual for superficial thrombophlebitis to advance into the deep system and result in a deep venous thrombotic episode. The most important physical findings of deep venous thrombosis are leg swelling, dilatation of superficial veins, and tenderness. In iliofemoral thrombosis, the area of maximum tenderness is generally in the thigh or groin. At times, however, it may be in the lower abdominal quadrants, and it may mimic the tenderness elicited in conditions such as appendicitis and diverticulitis. This is especially true in the young female patient in whom an episode of acute iliac venous thrombosis may resemble acute appendicitis or adnexitis. When calf tenderness is present, one must try to determine whether it arises from the underlying muscles or veins. Tenderness due to a partial tear of the gastrocnemius muscle or rupture of the plantaris tendon is usually elicited by side-toside compression of the muscle bellies. Ecchymosis, either at the calf or retromalleolar, should be investigated. A history of recent participation in athletics provides a further clue to the diagnosis of these acute muscular disorders. Calf tenderness due to venous thrombosis is usually elicited by compression of the muscle bellies directly against the tibia. A common physical finding in cases of calf venous thrombosis is the tightening or induration in the area of the calf muscles. This should be investigated with the patient in the supine position with the knees slightly flexed and the calf muscles relaxed.
Pregnancy Previous deep venous thrombosis Sepsis Thrombocytosis Trauma Varicose veins
Gentle palpation of the calf muscles will detect localized induration or tightening of the areas involved in the thrombotic process and will elicit pain. The position adopted by the patient with acute deep venous thrombosis of the lower extremity is classic. The patient lies down with the thigh flexed over the hip and the knee flexed over the thigh. Any efforts to stretch the extremity will produce excruciating pain.
CLINICAL MANIFESTATIONS OF CHRONIC VENOUS INSUFFICIENCY The clinical manifestations of chronic venous insufficiency will vary depending on the pathophysiology of the problem. The clinical types of venous problems seen most often are summarized in Table 9-2. This is a useful classification that aids in the understanding of the pathophysiology of venous insufficiency and constitutes the basis for the selection of treatment.[10] The current classification of chronic venous insufficiency of the SVC/ICVS (CEAP classification) is described in another chapter of this book. Congenital, essential, familiar, or primary varicose veins are all terms used for the same problem, namely, varicose veins that appear early in life, sometimes in childhood, and that are usually present in one or more members of the family. Venous stars, spiders, telangiectases, venous lakes, and venules are all ordinary small veins in the skin that have a striking familial tendency. They appear especially in women on the medial, posterior, and lateral aspects of the thigh and less often on the lower leg and calf (Fig. 9-1). Secondary, acquired, or
Table 9-2. Clinical Classification of Varicose Veins Primary or familial varicose veins Greater saphenous incompetence Lesser saphenous incompetence Perforator vein incompetence Venous spiders Internal iliac venous insufficiency (pelvic varices) Secondary varicose veins Postphlebitic syndrome with severe varicosities Congenital venous malformations with or without AV fistulas (Klippel-Trenaunay and Parkes-Weber syndromes) Acquired arteriovenous fistulas (posttraumatic, spontaneous, etc.)
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Figure 9-1. Telangiectases or “spider veins,” as illustrated here, are a common manifestation of primary varicose veins. They are an unsightly, cosmetic nuisance that are usually asymptomatic. They appear either alone or in association with incompetence of the superficial venous trunks.
postphlebitic varicose veins are the late consequences of an episode of thrombophlebitis. The clinical manifestations of these sequelae are usually severe and vary widely, depending primarily on the extent and location of the initial damage to the valvular mechanism of the deep and/or superficial venous systems and the degree of incompetence of the perforating or communicating systems (Fig. 9-2). Congenital anomalies of the venous system with or without arteriovenous (AV) fistulas lead to another type of chronic venous insufficiency. The KlippelTrenaunay syndrome is the typical example of congenital venous anomalies without obvious AV fistulas (Fig. 9-3). Patients with this syndrome have varicose veins, a port wine stain, and hypertrophy of soft tissue and bone with overgrowth of the extremity. This type of venous malformation should not be confused with the Parkes-Weber syndrome, in which the major pathological difference seems to be the presence of AV Figure 9-3. A 35-year-old woman with bilateral Klippel – Trenaunay syndrome. Extensive congenital varicose veins and capillary hemangioma localized to the external aspect of the extremities are characteristic features of this syndrome. No AV fistulas were detectable by arteriography. This type of venous malformation should not be confused with the Parkes – Weber syndrome, wherein the major difference is the presence of multiple congenital AV fistulas.
fistulas. In the group of acquired, iatrogenic, or traumatic AV fistulas, varicose veins are secondary to the venous hypertension occurring on the venous side of an AV fistula. The hemodynamic effects on the venous system depend to a great extent on the location, size, and duration of the AV fistula.[11,12]
Figure 9-2. Secondary varicose veins, hyperpigmentation, eczema, induration, and ulceration are the devastating sequelae of an episode of deep venous thrombosis that occurred 10 years before in this 27-year-old woman. Incompetent perforators and deep venous reflux were indentified.
DIAGNOSIS OF VENOUS DISEASES In superficial thrombophlebitis, septic thrombophlebitis of the lower extremities, phlegmasia alba dolens, and phlegmasia
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cerulea dolens, diagnosis based solely on symptoms and physical findings should be relatively easy. The diagnosis of varicose veins is also straightforward, but additional studies are needed to define its pathophysiology. In superficial thrombophlebitis, in particular, the diagnosis can usually be made with a high degree of accuracy on clinical grounds and special diagnostic tests are not usually needed. However, conditions such as gout, bacterial cellulites, lymphangitis, fat necrosis, vasculitis, and underlying malignancy must be kept in mind and ruled out. Phlegmasia alba dolens refers to severe iliofemoral thrombosis in which there is marked pain and swelling of the involved extremity. Skin color ranges from white to bluish. Despite the ominous appearance, there is no immediate threat of limb loss. In phlegmasia cerulea dolens,
however, the entire venous outflow from the leg becomes blocked by the thrombotic process and the leg becomes massively swollen and violaceous (Fig. 9-4A). Arterial pulsations are initially present but are later either diminished or lost as the outflow resistance and intracompartmental pressure increases. Cutaneous blebs and bullae may develop. As the process worsens, cardiovascular collapse due to sequestration of fluids in the lower extremity may occur and gangrene will develop unless some degree of venous outflow can be established.[13] This is called venous gangrene (Fig. 94B). Because of the massive venous involvement, the diagnosis is seldom in question in either form of phlegmasia. In the less dramatic but more common variants of deep venous thrombosis, diagnosis is often difficult because of the vague signs and symptoms. Clinical diagnosis is in error in at
Figure 9-4. (A ) Phlegmasia cerulea dolens represents near total obstruction of venous outflow, resulting in massive swelling and violaceous discoloration Cutaneous blebs and bullae may develop. (B ) As shown, limb loss occurs if some degree of venous outflow cannot be established.
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least 50% of the cases.[9] Venous thrombosis should be suspected and ruled in or out in any patient with lower extremity pain if no other obvious cause is present. Even in the absence of pain or discomfort, it should also be suspected in bedridden patients who develop lower extremity edema. Although unilateral edema makes one more suspicious, the presence of bilateral edema does not rule out the diagnosis. The postthrombotic limb poses special problems for the clinician because of the possibility of combined venous obstruction and venous insufficiency. The limb is usually larger than its counterpart, but distinction must be made between primary and secondary varicosities. Chronic leg edema must be distinguished from that of lymphedema or, in the case of bilateral swelling, from that of congestive heart failure and/or anasarca from other causes. The diagnosis of congenital vascular malformations can usually be made by noninvasive techniques, including computed tomography (CT) and magnetic resonance imaging (MRI). Invasive studies such as phlebography or arteriography are usually indicated when there is a questionable diagnosis or when surgical intervention is contemplated. Continuous wave (CW) bidirectional Doppler study provides bedside information on the presence of deep or superficial venous reflux, including the abnormal lateral marginal vein collector and its large perforators. In patients with hemodynamically active arteriovenous malformations, CW Doppler recordings may identify increased arterial and venous flow signals along the involved vessels. Pulsatile venous signals are detected on the venous trunks of the superficial as well as the deep system, above the site of the malformation. Because of the high rate of inaccuracy of clinical diagnosis in both acute and chronic conditions, physicians initially turned to phlebography as the gold standard for diagnosis of venous thrombosis. Important aspects of phlebography will be discussed in the ensuing paragraphs.
Phlebography Several techniques of phlebography have been described.[14 – 17] Excellent phlebograms are obtained using the technique outlined by Rabinov and Paulin,[18] which is regarded as one of the preferred techniques. In this technique, the patient is in the semi-upright position. No tourniquet is used, and the extremity is not supporting weight. The more common radiographic signs of venous thrombosis are outlined in Table 9-3. Generally speaking, modern phlebography is a safe procedure that is usually done on an outpatient basis. The use of modern low osmolar, nonionic contrast material has made phlebography a very safe procedure with virtually no contraindications or compliTable 9-3.
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cations. Chemical thrombophlebitis, in reaction to the contrast medium that used to be present in roughly 2% of the cases, has been virtually eliminated with the use of lowosmolality contrast medium. Even accidental extravasation of the dye, which often led to tissue necrosis, now produces very few symptoms. The incidence of subclinical chemical phlebitis, which used to be as high as 33%,[19] has not occurred in centers using low osmolar contrast medium.[20,21] The contrast media currently recommended for phlebography are Iopamidol 300 or 370, Iohexol 300 or 350, Sodium –Meglumine Ioxaglate 320, or Iopromide.[22] Even though phlebography is now a much safer procedure, there has been a decline over the past several years in the number of phlebograms performed in major institutions due to the impressive developments of the noninvasive technology. Related techniques that require minor invasiveness and involve little discomfort or risk include several radioisotope techniques, which will be discussed in the next section. Ascending and descending phlebography, as well as select varicography, have been extensively utilized in our centers to outline the anatomy and extension of venous malformations. The phlebographic technique in patients with congenital vascular malformations of venous predominance (Klippel-Trenaunay syndrome) usually requires modification. The large superficial venous bed should be neutralized by the application of an elastic bandage. In this manner, the contrast material preferentially goes into the deep system. This information is of great value when considering the type of treatment and the prognosis of the patient,[2,8 – 11] since agenesia or hypoplasia of deep venous trunks is not an uncommon finding in congenital vascular malformations.
Radioisotope Techniques Radionuclide phlebography refers to a technique in which a radioactive substance is injected into a pedal vein. Dynamic imaging using a scintillation camera is then done over the extremity veins, iliac veins, and inferior vena cava. Some of the substances that have been used are 99mTechnetium (99mTc) macroaggregated albumin, 99mTc macroaggregated fibrinogen, and 99mTc human albumin microspheres (HAM). The basis for the test is that in the presence of venous thrombosis, a portion of intravenously injected macroaggregated albumin particles will become adherent to the thrombus. Thrombi are identified by recognition of delayed clearance of radioactivity from the extremity after intravenous injection of the radiolabeled particles. Compared with contrast phlebography, radioisotope imaging techniques have yielded accuracy rates ranging from 89 to 96%.[23,24] They have a great deal of appeal
Radiographic Signs of Deep Venous Thrombosis
Constant, well-delineated filling defects Abrupt termination of contrast medium at a constant site above or below obstruction Nonfilling of the entire deep system or portions thereof provided that proper technique was used Diversion of flow-through collaterals
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because of a high degree of patient acceptance and the ability to perform a lung scan using the same injection of radioactive substance.[25] However, they also have some drawbacks. In the early studies, the contralateral extremity was used as a reference. Thus, results were difficult to interpret when there was bilateral lower extremity involvement. Furthermore, sluggish blood flow through the popliteal space may lead to false-positive results. Further investigations of these types of imaging techniques are warranted in view of their low risk and potential applications. Another radioisotope technique involves trapping radiolabeled fibrinogen in developing thrombus. Serial counts are obtained over the extremity, but no images are obtained. These techniques were made possible by the recognition that radiolabeled fibrinogen could be incorporated into developing thrombi in sufficient quantity to make it detectable by scintillation counting.[26] 131I was used in the early studies, but a major shortcoming of the technique, related to the short half-life of this isotope,[26,27] was overcome when it was found that the more stable isotope, 125I, gave similar results.[28] Incorporation of 125I-labeled fibrinogen into a developing thrombus now forms the basis of the fibrinogen uptake test. Many of the early studies of the fibrinogen uptake test were done in surgical patients. It was found that in some cases in which venous thrombosis became apparent in the postoperative period, the clotting process actually began either during the operation or as early as the first postoperative day.[29] To perform the fibrinogen uptake test, thyroid uptake of iodine is blocked with 100 mg of sodium iodide, which can be given orally or intravenously, and a 100-Ci dose of 125Ilabeled fibrinogen is given intravenously. Radioactivity counts are then taken at various points over each extremity and expressed as a percentage of reference counts made over the precordium. Based on phlebographic comparisons, accuracy rates ranging from 80 to 93% have been reported.[2,28,30,31] However, the fibrinogen uptake test is not useful in traumatized or recently operated-upon extremities, and it has a low degree of accuracy in the iliofemoral venous segment. Its greatest usefulness has been as an investigation tool in trials comparing various methods for preventing postoperative venous thrombosis. Development of this test also contributed greatly to the identification of categories of patients who are at high risk of developing postoperative venous thrombosis. Thus far, neither phlebography nor radioisotope techniques have provided the degree of clinical usefulness needed for the rapid, safe, and accurate diagnosis of deep venous thrombosis. For this reason, noninvasive tests have gained in popularity and are now widely used as the first diagnostic tests in patients with suspected lower extremity venous thrombosis. The Doppler test, which is discussed further, can also be used to evaluate suspected upper extremity venous thrombosis.[32]
Noninvasive Techniques A number of totally noninvasive techniques for diagnosing venous obstruction and/or venous insufficiency are available. As these techniques have improved, they have begun to
replace contrast phlebography, which is now being used in several institutions only when the diagnosis remains in question after noninvasive testing. The most commonly used techniques will be discussed in the ensuing paragraphs.
Plethysmography There are several techniques of venous plethysmography, including air plethysmography (APG), strain gauge plethysmography (SPG), photoplethysmography (PPG), and foot volumetry (FV). Plethysmography may be used for the detection of venous outflow obstruction or venous reflux. Air plethysmography detects changes in limb volume by using an air-filled cuff from the knee to the ankle. Strain gauge plethysmography uses a mercury-filled silastic strain gauge to encircle the leg at a single point. It detects changes in leg volume following inflation of a thigh occlusion cuff. Foot volumetry is a technique used extensively in Scandanavian countries. This method uses a water-filled container in which the patient stands. Data on volumetric changes are recorded at rest and during exercise by a strip chart recorder. A final noninvasive method of measuring venous hemodynamics is photoplethysmography. This indirect method of measuring volumetry uses a transducer containing an infrared light – emitting diode and an adjacent phototransistor to receive back-scattered light reflected from the superficial layers of the skin. The amount of reflected light varies with the number of red blood cells in the microcirculation.
Venous Outflow Obstruction The investigation of venous outflow obstruction may be performed by APG, PPG, or SPG. In these techniques the patient is placed in the supine position with the leg elevated on a soft heel support and the knee slightly flexed. A proximal thigh occlusion cuff is inflated to a level between arterial and venous pressure (50 –60 mmHg). Limb volume increases and the baseline of the tracing rises. With cuff release, a rapid return toward baseline occurs in normal extremities. The rate of venous emptying in the presence of proximal venous obstruction is retarded. By dividing the fall occurring in the first 1–2 s after release by the total rise, a ratio can be established that will separate extremities with normal venous emptying from those with abnormal venous emptying (Fig. 9-5). In most normal extremities, 50% of venous emptying occurs during the first 2 s after cuff release.[33] Overall accuracy is in the range of 80%. False positives are not common for major obstructing thrombi and have been reported at less than 3.0%.[33] False-positive results are obtained in patients if the leg is improperly positioned. This method cannot detect calf venous thrombosis.[34]
Venous Reflux Competency of the deep system and the perforating veins can be tested using APG, SPG, PPG, and FV. In these tests venous reflux is examined by serially occluding the superficial system with tourniquets. To determine if the reflux comes from the superficial or the deep system, reflux from the superficial vein is eliminated with the use of a tourniquet. If the abnormal plethysmographic tracing is
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Figure 9-5. (A ) In segmental venous occlusion plethysmography, the baseline begins to rise when the occluding cuff is inflated to greater than venous pressure (arrow ). When the capacitance bed is filled, the tracing stabilizes at a higher level (Tf). When the cuff is released (arrow ), the tracing returns to baseline. Venous outflow is calculated by dividing the fall at 2 s (F2) by the total rise (Tr). (B ) Outflow tracing from the normal (left ) and abnormal (right ) lower extremities in a patient with acute deep venous thrombosis.
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corrected with the application of the tourniquet, the abnormality is located in the superficial venous system. On the other hand, if the tourniquet does not correct the abnormal tracing, the abnormality is due to deep venous insufficiency. The location of incompetent perforators can be carefully mapped in a manner similar to the Trendelenburg test by placing the tourniquet at different levels of the extremity. The venous refill time (VRT) is a measurement of venous reflux as measured by strain gauge plethysmography. In this measurement the strain gauge is placed at the ankle of the patient. A series of five plantar flexion/dorsiflexion maneuvers are performed. This empties the leg of blood and then refills over time. Normal refill time is usually longer than 20 s. Venous reflux is defined as a VRT of , 20 s. This method differs from air plethysmography in that it only measures volume changes in a single slice of the leg. In lower extremity venous malformations, SPG has been used to assess the importance and contribution of the large lateral collecting marginalis vein to the venous outflow of the extremity. SPG should be performed under basal conditions and then repeated with compression of the large lateral collector trunk shortly before thigh/cuff deflation. A pattern of venous obstruction is observed if the lateral collector plays an important role in the venous outflow. SPG, in cases of arteriovenous malformations, reveals an increased arterial inflow, a relatively low venous capacitance due to decreased resistance, and a normal venous outflow.[1] Air plethysmography has been shown to be a quantitative method of measuring venous reflux.[35] In this technique, the air-filled chamber is calibrated with the patient in the supine position with the leg elevated and the knee slightly bent. Continuous measurements are taken using a strip chart recorder of the leg volume as the patient moves to a standing position, weight bearing on the opposite leg. The leg volume will increase and plateau at a volume defined as the venous volume (vv). The venous filling index (VFI) is determined as the rate of venous reflux in cc/s. The residual volume fraction (RVF) is a measure of the leg volume after the patient has performed 10 tiptoe maneuvers. Christopoulos et al. have shown this measurement to have a high correlation with invasive measurements of ambulatory venous pressure. The technique of APG has also been shown to be a valuable adjunct to monitor the results of venous surgery[36 – 38] and to assess venous outflow obstruction of the upper extremity. Using foot volume plethysmography, Norgren et al. showed good correlation between venous insufficiency and the ratio of refilling flow to the expelled volume.[39] In this technique the patient starts in a standing position with each foot placed in its own water-filled container. After initial calibration the patient is asked to perform a standard exercise of 20 deep knee bends at a metronomed pace. The PPG examination is performed with the patient in the sitting position with both feet on the floor. The transducer is fixed to the skin above the medial malleolus, using doublefaced clear adhesive tape. Comparison tracings are obtained by examining both extremities at the same time. The examination is performed similarly to the SPG technique of repetitive foot dorsal and plantar flexion. Since the PPG output cannot be calibrated, the quantitative endpoints for this study are related to the recovery time of the baseline skin blood content after active leg muscle exercise. Recovery time
is recorded as the total number of seconds required for the recording to return to the preexercise baseline level or to one half of the preexercise baseline level (t1/2), as shown in Fig. 9-6. Normally, skin blood content decreases in response to active or passive calf muscle exercise due to venous emptying. The recovery time is usually greater than 20 s, and it is not affected by application of a tourniquet.[40,41]
Ultrasound Techniques Doppler ultrasound techniques have been used extensively to detect both venous obstruction and venous insufficiency. The detection of venous obstruction is based on impedance of forward flow and a consequent reduction in transmitted venous flow sounds. Using a bidirectional flow probe, forward flow is recorded as flow away from the probe (Fig. 9-7). Certain maneuvers used to investigate valvular incompetence will augment flow toward the bidirectional probe. For simplicity and ease of application, however, both obstruction and insufficiency can be also detected using a unidirectional probe. With a trained ear, one can rapidly assess the lower extremity veins using the Doppler. Recording of tracings is not entirely necessary but is highly useful for documentation of findings, for physician interpretation of technician’s findings, and for providing a permanent record. Representative tracings are shown in Fig. 9-8. In performing the Doppler ultrasound examination, one needs to assess five elements of the venous Doppler signal: spontaneity, phasicity, augmentation, competence, and pulsatility. Each is discussed in greater detail below. Excellent descriptions are also available in basic texts.[42] Spontaneity: Normally, spontaneous venous flow sounds can be recorded from all the major veins. In vasoconstricted extremities, these sounds may be greatly attenuated or absent over the posterior tibial veins or superficial veins but are still present over the deep veins in the popliteal space and femoral region in the thigh. Absence of spontaneous venous flow signals thus represents an abnormal finding and is one of the early signs of venous obstruction. Phasicity: This refers to the normal waxing and waning of the venous flow signals with respiration. During descent of the diaphragm during inspiration, venous flow is greatly diminished or totally interrupted due to increased intraabdominal pressure. The flow signal then increases maximally during expiration. In the presence of proximal venous obstruction, the venous flow signal becomes high pitched and continuous, and respiratory variations become markedly diminished or absent. The presence of a continuous high-pitched venous flow signal is highly suggestive of venous obstruction and is typical of collateral circulation. Augmentation: The venous flow signal is normally increased by compression of the limb distal to the probe or by release of compression proximal to the probe. Such augmentation is diminished or absent in presence of venous obstruction. Competence: Competent venous valves prevent reflux flow. In cases of congenitally incompetent or absent valves (avalvulia) and in cases of postthrombotic valvular destruction, there will be retrograde flow during compression of the limb proximal to the flow probe. When the venous valves are competent, a Valsalva maneuver causes prompt cessation of
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Figure 9-6. Photoplethysmography is not strictly quantitative, but measurement of the recovery half-time allows one to distinguish between extremities with normal hemodynamics and those with venous insufficiency with a high degree of accuracy. (From Barnes and Yao.[41] Reproduced by permission.)
flow. Contrarily, in the face of valvular incompetence, the Valsalva maneuver augments retrograde flow. Pulsatility: Venous signals are normally nonpulsatile and vary in intensity with respiration but not with the heart beat. When venous pressure is elevated, such as in congestive heart failure, venous sounds may be difficult to distinguish from
arterial sounds. However, limb compression maneuvers and the Valsalva maneuver continue to alter venous flow sounds. These maneuvers have no effect on arterial flow sounds. To perform the Doppler examination, the patient should be positioned supine in a comfortable position with the head of the bed or examining table slightly elevated to increase
Figure 9-7. With the bidirectional probe at a 45-degree angle to the skin and directed toward the heart, forward flow is recorded as flow away from the probe. If reflux occurs with a Valsalva maneuver, there is augmentation of flow toward the probe. This photograph shows the proper orientation of the probe.
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Figure 9-8. Normally, venous flow is nonpulsatile and phasic, as shown in (C ), and valvular competence prevents a venous flow signal during proximal compression, as shown in (E ). When venous obstruction is present, the venous flow signal may be continuous due to flow through collaterals (D ), and proximal limb compression causes an augmented retrograde flow signal due to valvular incompetence (F ). The venous flow signal may also take on a pulsatile arterial quality when venous pressure is elevated as shown in (H ). (From Barnes.[42] Reproduced by permission.)
venous pooling. The legs should be in a comfortable, relaxed position with the hips externally rotated and the knees slightly flexed. Examination of the popliteal veins is best accomplished with the patient in the prone position and the knee slightly flexed. One should routinely examine the posterior tibial, the popliteal, the superficial femoral, and the common femoral veins. Close attention should be paid to the presence of spontaneous venous flow sounds and to the influence of proximal and distal compression. The superficial venous system, especially the greater saphenous vein, can also be tested for incompetence using the Doppler instrument. In this case, the patient should be standing. As mentioned earlier, the Doppler can also be used to detect upper extremity venous obstruction.[32] The accuracy of the venous Doppler examination is observer-dependent, and the test requires time, experience, and practice to learn. However, a competent observer should be able to obtain an accuracy on the order of 90%. Sources of
error, in addition to observer experience, include nonobstructive thrombi, thrombi in parallel veins (duplicated veins), and thrombi in veins that are not in the axial stream. Examples include thrombi in muscular veins, veins of the soleal plexus, and the profunda femoris veins. All the previously mentioned noninvasive tests are subject to the same limitations. The combination of the continuous wave Doppler ultrasound and a B-mode imaging of the veins (Duplex scanning) allows for visualization of both acute and chronic thrombi.[43] It will be described at length in the following sections.
Duplex Scanning Duplex scanning has become the most widely used noninvasive method for the diagnosis of both arterial and venous diseases. As reported by Sumner et al.,[44] a recent survey conducted by the American Registry of Diagnostic
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Medical Sonographers revealed that 94% of registered vascular technologists use Duplex scanning in their investigations. No other method was used by more than 57% of the respondents. The widespread acceptance of this method is due to its versatility, noninvasiveness, and well-established accuracy. Duplex scanning incorporates two modalities of noninvasive techniques: real-time B-mode scanning and analysis of the Doppler flow signals. The B-mode component scans the echoes reflected from acoustic interfaces in the underlying tissues. At the same time, sound energy is received from a linear array of crystals, thus avoiding the moving parts required by sector scans. At the present time, Duplex imaging offers the most accurate information available for the diagnosis of venous disease including upper and lower extremity venous thrombosis, venous reflux, venous aneurysms, and venous malformations.[45] Each segment of deep venous system from the lower calf to the external iliac vein can be evaluated with the B-mode ultrasonographic imaging. This mode of evaluation provides a three-dimensional assessment of the deep venous system below the external iliac vein. For accurate imaging of the iliac system and the deep venous system, a 3.0 or 4.0 MHz transducer is suggested. For veins below the inguinal ligament, a 7.5 or 8.0 MHz transducer is adequate.
Scanning Technique The patient is placed in the supine position with the shoulders raised approximately 30 degrees. The patient’s knee is slightly flexed, and the entire lower extremity should be rotated externally. A generous amount of transmitting gel is applied over the areas to be scanned. The Duplex probe is placed at the level of the femoral triangle, and the common femoral and superficial femoral veins are visualized along its long axis. In a normal venous segment, gentle pressure applied with the transducers produces approximation of the venous walls. Partial compressibility or incompressibility in both the longitudinal and transverse projections is considered suggestive of thrombosis. The absence of Doppler signals and incompressibility, both in the longitudinal and transverse axis, is strong evidence of thrombosis. Partial compressibility in the longitudinal as well as in the transverse axis, accompanied by weak Doppler signals, suggests the presence of nonocclusive thrombus, partial recanalization, or chronic thrombosis. Duplex scanning of the femoral triangle often reveals the presence of normal valve motion. Valsalva maneuvers can be used to evaluate the changes in venous diameter as well as the presence of venous reflux. In each extremity tested, the entire common and superficial femoral veins are examined. As the scanning is continued to the medial aspect of the thigh, visualization of the superficial femoral vein may be obscured at the level of the Hunter’s canal due to the adductor fascial planes. The popliteal vein is assessed with the patient in the prone position and the knee slightly flexed to reduce tension of ligaments and tendons. In the obese or severely ill patient, the prone position may be difficult. In this situation, flexing the knees and external rotation of the hips usually allows visualization of the popliteal vein. Sitting the patient with the legs dangling at the edge of the examining table is also an acceptable way to investigate the popliteal vein. The popliteal
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vein is examined by moving the probe proximally towards the adductor canal and distally to the popliteal confluence. To assess the personeal veins, the patient should remain in the prone position and the scanning probe placed 1 – 2 cm medial to the edge of the fibula. The anterior and posterior tibial veins can usually be visualized in the proximal and mid-calf. Visualization of the peroneal veins is more difficult because of their anatomical location. One of the drawbacks of the Duplex scanning examination is the impossibility to move the patient from the supine to the prone position to gain optimal access to the popliteal and peroneal veins. In these cases, even though it is not optimal, it is possible to examine the calf veins with the patient in the supine position by elevating the leg and placing support under the heel, allowing the calf muscles to hang away from the bones.[46] The echogenicity of the flowing blood, compared with the thrombus, is quite different. This allows for easy differentiation using Duplex imaging. Fresh thrombus may give the appearance of flowing blood unless motion is detected. Old thrombi are more echogenic and less compressible than fresh thrombus. Because of the difficulty of identifying thrombus by compression in certain anatomic locations, such as the deep femoral vein, the femoral canal, and the personeal veins, compressibility alone should not be used as the single criterium for diagnosis of deep venous thrombosis (DVT) in the absence of other abnormalities. Despite its drawbacks, Duplex scanning has been shown to be highly accurate for the diagnosis of DVT, both in the outpatient population as well as in the screening of high-risk symptomatic or asymptomatic hospitalized patients. In a prospective analysis utilizing Duplex scanning, Lensing et al. studied 220 patients with suspicion of DVT.[47] The sole criterion used for the diagnosis of deep venous thrombosis with Duplex ultrasound was vein compressibility. All patients had contrast phlebography performed 2 hours after the Duplex examination; patients who underwent phlebography were unaware of the Duplex results. These authors found 100% sensitivity and 99% specificity for proximal deep venous thrombosis when using Duplex scanning as compared with phlebography. The sensitivity of Duplex scanning for detecting both proximal and calf venous thrombosis was 91%. In a study of 707 veins examined both by Duplex ultrasonography and phlebography, Montefusco found that Duplex ultrasonography yielded information about the specific thrombus location, extent, and configuration that was similar in detail to the results provided by contrast phlebography. In this study, Duplex ultrasonography had 100% sensitivity and 98.9% specificity. The overall accuracy of duplex ultrasonography in the detection of venous thrombosis, as compared with phlebography, was 97.7%.[46] Because the diagnostic accuracy of traditional noninvasive studies has been shown to be significantly less than that of phlebography for screening asymptomatic, high-risk individuals as compared with screening symptomatic patients, Barnes et al. performed routine preoperative and postoperative Duplex screening and phlebography on 78 patients undergoing total hip or knee arthroplasty with routine anticoagulation for prophylaxis.[48] Of 309 extremity examinations, Duplex scanning had an overall sensitivity of 85.7% and a specificity of 97.3% when compared with
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phlebography. In two instances, Duplex scanning detected thrombi initially overlooked by phlebography. These findings indicate that Duplex scanning is a reliable method for screening perioperative high-risk patients. Duplex scanning has become the preferred examination in many centers for the diagnosis of DVT. However, Hobson et al.[49] currently utilize an algorithm in which IPG is initially performed. In this author’s experience, IPG and serial followup has been sufficiently accurate for the diagnosis of aboveknee thrombi to justify anticoagulant therapy and to avoid treatment in patients with negative studies. As stated by Hobson et al., the final role of B-mode ultrasonography in replacing plethysmographic testing will await further clinical trials. However, there is evidence at the present time that Duplex scanning has enhanced sensitivity and specificity as compared with IPG. The availability of a competent and skilled ultrasonographer is essential to obtain results of comparable accuracy. Kahn and Barnes consider that if acute or recurrent deep venous thrombosis is suspected, Duplex scanning is the diagnostic method of choice.[50] If the Duplex scan is normal, a search for another cause of the patient’s symptoms is begun. If the scanning is clearly abnormal, the findings may be as follows: Thickened, less compressive walls: This is usually a finding in postthrombotic syndrome. Noncompressible vein: If this is found, therapy for DVT should be instituted. Superficial flow and the presence of a floating thrombus: In this situation, therapy should be instituted. If there are any questions in regard to the interpretation of the scanning, a phlebogram should be performed. Color flow Duplex (CFD) imaging of the tibial veins has become increasingly utilized for the detection of infrapopliteal venous thrombi. With the advent of newer, more sensitive Duplex machines, this technique is now possible in the majority of vascular laboratories. Centers have reported the sensitivity and specificity of CFD to detect tibial venous thrombi to be 91% and 93%, respectively.[51,52] Using CFD, Mattos et al. were able to identify acute tibial vein DVT in 110 of 655 (17%) symptomatic limbs.[53] The significance of isolated calf vein thrombus and its relationship to pulmonary embolism has been a subject of debate. Using this newer technology, however, studies have shown that tibial thrombus not only can be identified accurately but also has been shown to propagate.[54]
Venous Reflux Detection with Duplex Scanning and Color Flow Imaging Duplex scanning has provided the ability to quantify reflux in individual veins. This has been demonstrated by several authors. The method of examination to detect venous reflux with duplex scanning requires the use of a pneumatic cuff placed in the calf with standard compression pressure of 70 mmHg and sudden release. The gate of the sample volume is adjusted so that insonation of the vein under examination is from wall to wall. The Doppler spectrum is recorded on video during compression and release. The mean velocity at peak reflux in centimeters per second (cm/s) is determined. The
diameter of the vein is calculated, and this serves to determine the cross-sectional area in square centimeters. The flow in milliliters per second (mL/s) at peak reflux is obtained by multiplying the cross-sectional area by the average flow velocity at peak reflux. The results in 47 limbs of patients who were affected with chronic venous insufficiency problems, studied by Nicolaides et al.,[55] demonstrated that skin changes and ulceration do not occur when the sum of peak reflux in all the veins is less than 10 mL/s. However, the incidence of skin changes and/or ulceration is high when peak reflux exceeds 15 mL/s, whether such reflux is in the superficial or the deep veins. The introduction of color flow imaging (CFI) has simplified the previously tedious procedure of interrogating most vessels by B-mode real-time ultrasound, which used to take approximately 30 minutes per limb. Color flow imaging provides instant visualization of blood flow and its direction. These characteristics are very important for venous assessment. The direction and magnitude of the Doppler frequency shift determine the hue and intensity of the color, respectively. Conventionally, blue indicates flow toward the heart and red, flow away from the heart. The higher the velocity, the paler the color becomes. Previous studies on the arterial system have demonstrated that flow can be quantified using CFI and that flow patterns in specific areas such as the carotid bulb can be visualized accurately. The examination of the venous system for reflux is performed following the same protocol as for duplex scanning, with the patient in the standing position. The veins are initially identified using the gray scale. When the color is switched on, the pulsatile flow in the arteries becomes obvious (red) and distal compression results in augmentation of venous flow and increased Doppler shift frequency, which is assigned a color (blue) for flow toward the heart. In this manner, any shift direction of the venous flow away from the heart would represent reflux, and it will be shown with a different color (red) indicating flow away from the heart. With the introduction of color flow imaging, the detection of reflux in any anatomic position in the superficial or deep system has been simplified and can be seen immediately. The demonstration of venous reflux can be done very quickly and the measurement of reflux (in mL/min) at the time that reflux is occurring is easy to quantify with the available computerized software. Color flow imaging has also made the demonstration of incompetence in the thigh or calf perforators an objective and simple procedure.[56] The examination of tibial, peroneal, and calf-perforating veins is performed with the patient sitting at the end of a table with the legs placed on a low stool. The flow variations during muscle contractions can be studied with CFI. New physiological information has become available as a result of the introduction of this new technology. There is no doubt that color flow imaging is a powerful diagnostic and research tool that will allow us better insight into the hemodynamics and natural history of chronic venous insufficiency. Demonstration of venous valvular reflux has been shown to be a useful adjunct to investigations of patients with severe venous disease. As described by van Bemmelen et al.,[57] a duplex probe is placed over the popliteal, common, or superficial femoral vein with the patient in the standing
Chapter 9.
position. Reverse flow in the popliteal vein is then generated using a rapid cuff inflator placed at a level a few centimeters below the probe. The cuff is inflated to 80 mmHg and then rapidly deflated. Continuous Duplex monitoring reveals a forward jet of venous flow followed by rapid closure of a competent valve. Normal reflux flow duration is less than 0.5 s. Valve closure times (VCT) greater than 2 s are consistent with valvular incompetence.
Congenital Vascular Malformations Duplex scanning of vascular malformations enables us to document the severity of the venous disease and the staging of the malformation.[58 – 61] Even in low-flow venous malformations, duplex may demonstrate an increased venous outflow in comparison to the contralateral extremity. The large venous volume flowing through collateral superficial veins can be traced by duplex scan.[60 – 63] In arteriovenous malformations, there is a
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spectral broadening and continuation of color in diastole in the color flow Duplex scanner. Systolic and diastolic flow velocities, as well as venous flow volume, are also increased above the malformation. Computed tomography and MRI have been extensively utilized in the assessment of the extent and nature of congenital vascular malformations. The combination of MRI and magnetic resonance angiography (MRA) enables the investigator to evaluate the deep and superficial venous channels. MRI and MRA provide basic information regarding the prognosis and treatment of the vascular malformation. Magnetic resonance angiography is usually performed with commercially available pulse sequences, including the time of flight and phase contrast techniques. MRA and MRI are useful, noninvasive, easily repeatable diagnostic and screening methods for the study of peripheral and central venous malformations and have been shown to have excellent correlation with conventional angiography.[64 – 68]
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Bernstein, E.F., Ed.; CV Mosby Co.: St. Louis., MO, 1982; 452– 457. Flanagan, L.D.; Sullivan, E.D.; Cranley, J.J. Venous Imaging of the Extremities Using Real Time B-Mode Ultrasound. In Surgery of the Veins; Bergan, J.J., Yao, J.S.T., Eds.; Grune and Stratton: New York, 1985; 89– 98. Sumner, D.S.; Spadone, D.E.; Colgan, M.P. Duplex Scanning and Spectral Analysis of Carotid Artery Occlusive Disease. In Current Therapy in Vascular Surgery; 2nd Ed. Ernst, C.B., Stanley, J.C., Eds.; B. C. Decker, Inc.: Philadelphia, 1991. Gillespie, D.L.; Villavicencio, J.L.; Gallagher, C.; Chang, A.; Hamelink, J.K.; Fiala, L.A.; O’Donnell, S.D.; Jackson, M.R.; Pikoulis, E.; Rich, N.M. The Presentation and Management of Venous Aneurysms. J. Vasc. Surg. 1997, 26, 845 – 852. Montefusco, C.M.; Bakal, C.W.; Sprayregan, S.; Rhodes, B.; Veith, F.J. Duplex Ultrasonographic Venography: The Definitive Diagnostic Tool for Thrombophlebitis. In Current Critical Problems in Vascular Surgery; Veith, F.J., Ed.; Quality Medical Publishing, Inc.: St. Louis, MO, 1989; 145– 150. Lensing, W.A.; Prandoni, P.; Brandjes, D. Detection of Deep Venous Thrombosis by Real Time B-Mode Ultrasonography. N. Engl. J. Med. 1989, 320, 342. Barnes, R.; Nix, M.; Ferris, E. Perioperative Asymptomatic Venous Thrombosis: Role of Duplex Scanning Versus Venography. J. Vasc. Surg. 1989, 9, 251. Hobson, R.W.; Lynch, T.G.; Jamil, Z. Role of the Vascular Laboratory in the Diagnosis of Venous Disease. In Operative Surgery; DeWeese, J.A., Ed.; Butterworth: London, 1985; 253 – 263. Kahn, M.B.; Barnes, R.W. Noninvasive Methods of Diagnosing Venous Disease. In Current Therapy in Vascular Surgery; 2nd Ed. Ernst, C.B., Stanley, J.C., Eds.; B. C. Decker, Inc.: Philadelphia, 1991; 943 – 949. Prandoni, P.; Lensing, A.W. New Developments in Noninvasive Diagnosis of Deep Vein Thrombosis of the Lower Limbs. Ric. Clin. Lab. 1990, 20, 11. Habsheid, W.; Hohmann, M.; Wilhelm, T.; Epping, J. Real Time Ultrasound in the Diagnosis of Acute Deep Venous Thrombosis of the Lower Extremity. Angiology 1990, 41, 559. Mattos, M.A.; Melendres, G.; Sumner, D.S.; Hood, D.B.; Barkmeier, L.D.; Hodgson, K. et al. Prevalence and Distribution of Calf Vein Thrombosis in Patients with Symptomatic Venous Thrombosis: A Color Flow Duplex Study. Lohr, J.M.; Kerr, T.M.; Lutter, K.S.; Cranley, R.D.; Spirtoff, K.; Cranley, J.J. Lower Extremity Calf Thrombosis: To Treat or Not to Treat? J. Vasc. Surg. 1991, 14, 618. Nicolaides, A.N.; Vasdekis, S. Detection and Quantification of Venous Reflux Using Doppler Ultrasound: The Impact of Color Flow Imaging. In Current Critical Problems in Vascular Surgery; Veith, F.J., Ed.; Quality Medical Publ. Inc.: St. Louis, MO, 1990; 2, 127 – 136. Hanrahan, L.M.; Araki, C.T.; Fisher, J.B.; Rodriguez, A.A.; Walker, G.; Woodson, J.; LaMorte, W.W.; Menzoian, J.O. Evaluation of the Perforating Veins of the Lower Extremity
Chapter 9.
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Using High Resolution Duplex Imaging J. Cardiovasc. Surg. 1991, 32 (1), 87. van Bemmelen, P.S.; Bedford, G.; Beach, K.; Strandness, D.E. Quantitative Segmental Evaluation of Venous Valvular Reflex with Duplex Ultrasound Scanning. J. Vasc. Surg. 1989, 10, 425– 431. Rudofsky, L. Kompaktwissen Angiologie; 2nd Ed. Perimed Verlag: Erlangen, Germany, 1988; 131 – 144. Villavicencio, J.L. Treatment of Varicose Veins Associated with Common Congenital Vascular Malformations. In Complex Problems Involving Varicose Veins. Part IV; Bergan, J.J., Goldman, M.P., Eds.; Quality Medical Publ.: St. Louis, MO, 1993; 329 – 342. Lobato, R.; Martinez, L.; Leal, N.; Diaz, M.; Diez-Pascual, R.; Velasco, B.; Ros, Z.; Lopez-Gutierrez, J.C. Hemangiomas and Vascular Malformations. Review and Update. Circ. Pediatr. (Spain) 1997, 19 (3), 119. Vaghi, M. Apparative Diagnostik der Angeborenen Gefassfehler. In Angeborene Gefassmisbildungen; Loose, D.A.; Weber, J.: Eds. Period. Angiol. 1997, 21, 122. Eifert, S. Clinical and Ultrasonic Diagnosis of Combined Angiodysplasias (Klinische and Sonographische Diagnos-
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tik Kombinierter Angiodysplasien); 29– 34 Univ. Med. Fab. Diss.: Halle, Germany, 1996; 14 – 18. Loose, D.A.; Funk, J. Angeborene Venenfehler—Diagnostische und Therapeutische Mo¨glichkeiten. Akt. Chir. (Germany) 1995, 30 (6), 329. Laor, T.; Burrows, P.E.; Hoffer, F.A. Magnetic Resonance Venography of Congenital Vascular Malformations of the Extremities. Pediatr. Radiol. (Germany) 1996, 26 (6), 371. Allison, J.W.; Glasier, C.M.; Stark, J.E.; James, C.A.; Angtuaco, E.J. Head and Neck MR Angiography in Pediatric Patients: A Pictorial Essay. Radiographics 1994, 14 (4), 795. Villavicencio, J.L.; Papendieck, C. et al. Venous Disorders in Childhood. In Pediatric Surgery; 5th Ed. O’Neill, J.A., Jr., Ed.; Mosby Yearbook Inc.: St. Louis, MO, 1998; 1945–1972. Invasive Diagnostik Angeborener Gefa¨ssfehler. In Angeborene Gefa¨ssmisbildungen; Loose, D.A.; Weber, J.: Eds.; Period. Angiol. 1997, 21, 122–127. Mulliken, J.B.; Fishman, S.; et al. Vascular Anomalies: Hemangiomas and Malformations. In Pediatric Surgery; 5th Ed. O’Neill, R., Ed.; Mosby Yearbook Inc.: St Louis, MO, 1998; 1039– 1052.
CHAPTER 10
Angiography Timothy M. Koci Frances Chiang C. Mark Mehringer monomeric, nonionic monomeric, ionic dimeric (lowosmolality), and nonionic dimeric media. Ionic monomeric compounds are the standard triiodobenzoic acid salts, which dissociate in solution into an iodinated anionic component (diatrizoate or iothalamate) and a cationic component (sodium or meglumine). Agents with a higher proportion of sodium are less viscous (but more toxic), as sodium is a smaller cation. At concentrations necessary for diagnostic angiography, these agents are hypertonic, approximately five to seven times the osmolarity of normal plasma. This high osmolarity accounts for some of the toxicity of these media. Nonionic monomeric agents (iopamidol, iohexol) also feature a triiodinated benzene ring, but the sodium or meglumine cation has been replaced by a nondissociating side chain. Their osmolarity is only two to three times that of blood. An ionic dimeric medium (ioxaglate) is a dimer of two benzene rings (with a total of six iodine atoms) but only a single cation, which results in an osmolarity half that of a standard ionic agent of equal iodine content. The nonionic dimers such as iodixanol (283 mOsm/kg) have nearly the same osmolality as plasma. Properties of several representative agents are summarized in Table 10-1.[6] The adverse effects of intravascular contrast injection are well known. Local sensations of pain and burning as well as flushing (vasodilation) are considered physiologic irritant or chemotoxic effects and are related to high osmolarity. In sensitive areas such as the external carotid territory and peripheral extremities, these local effects can be significantly reduced by the use of low-osmolarity agents.[7 – 9] The addition of local anesthetics to contrast media does not appear to be effective in reducing patient discomfort during aortofemoral angiography.[10] Minor systemic reactions such as nausea and vomiting are not infrequent in arteriography and are common in intravenous contrast injection. Nonphysiologic anaphylactoid or idiosyncratic reactions can manifest as symptoms ranging from urticaria to bronchospasm, laryngospasm, and cardiovascular collapse. The mortality rate in one large series of 300,000 patients was 1:75,000.[11] Pretesting for allergy is of no predictive value and should be abandoned.[12] Patients with a history of previous severe reaction have approximately a 15% change of
INTRODUCTION The history of angiography began only a few months after the discovery of x-rays in 1895 by Roentgen, when contrast agents too toxic for human use were being injected into cadavers, severed limbs, and animals. The next major developments came in the late 1920s, when percutaneous translumbar aortography and cerebral angiography were described by the Portuguese surgeons Dos Santos and Moniz, respectively. Contrast agents were now less toxic, and clinically useful angiography was a reality. In 1953, Seldinger described his technique for percutaneous vascular catheterization,[1] which formed the basis of many catheterization techniques to follow. In the 1970s the development of less invasive methods such as computed tomography (CT) and ultrasound decreased the indications for diagnostic angiography. Vascular imaging progressed rapidly in the 1990s with the addition of color Doppler ultrasound and magnetic resonance imaging (MRI). Magnetic resonance angiography (MRA) is now producing images of striking clarity and resolution. Nonetheless, angiography remains the most important way to demonstrate vascular diseases graphically. The relative decrease in routine diagnostic angiographic procedures has been offset by a proliferation of interventional techniques requiring angiographic guidance, including embolization therapy, angioplasty, thrombolytic therapy, atherectomy, intravascular stenting, intraarterial chemotherapy, caval filter placement, and even hybrid techniques such as intraarterial contrast-enhanced CT angiography.[2] We hope to provide an overview of major areas of angiographic utilization and diagnosis. Interventional techniques will be addressed in other chapters. The basic techniques of arterial puncture and catheterization have been well described elsewhere.[3 – 5]
CONTRAST AGENTS Iodinated radiopaque contrast agents currently used for angiography can be classified into four groups: ionic
Hobson/Wilson/Veith: Vascular Surgery: Principles and Practice, Third Edition, Revised and Expanded DOI: 10.1081/0819-9-120024893 Copyright q 2004 by Marcel Dekker, Inc.
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170 Table 10-1.
Part One. Assessment of Vascular Disease
Contrast Agents
Trade name Ionic monomeric agents Hypaque 50% (Nycomed) Conray-60 (Mallinckrodt) Renografin-60 (Bracco) Renografin-76 (Bracco) Nonionic monomeric agents Isovue (Bracco) Isovue (Bracco) Omnipaque (Nycomed) Omnipaque (Nycomed) Ionic dimeric (low osmolality) Hexabrix (Mallinckrodt)
Generic name
Concentration, %
Cation
Iodine, mg/mL
Osmolarity, mOsm/kg
Viscosity (cP), 378C
Diatrizoate
Sodium
50
300
1550
2.5
Iothalamate
Meglumine
60
282
1400
4.1
Diatrizoate
Meglumine 52% Sodium 8% Meglumine 66% Sodium 10%
60
288
1420
3.9
76
370
1940
9.1
Iopamidol
61.0
300
616
4.7
Iopamidol
76.0
370
796
9.4
Iohexol
64.7
300
709
6.8
Iohexol
75.5
350
862
11.2
Ioxaglate Meglumine 39.3% Sodium 19.6%
58.9
320
600
7.5
Diatrizoate
Source: Ref. 6.
having another reaction. Corticosteroid premedication reduces the frequency of repeat reactions;[13] additional protection may be afforded by the antihistamines Benadryl (diphenhydramine HCl, an Ht antagonist) and Tagamet (cimetidine HCl, an H2 antagonist). Anesthesia standby should be employed. There has been much recent debate and study regarding the safety, toxicity, expense, and indications for use of the new nonionic contrast agents. The two largest series[14,15] compared reactions to intravenous contrast injection for ionic versus nonionic media. The frequency of severe reaction for nonionic versus ionic were 0.02% versus 0.09%[14] and 0.04% versus 0.22%.[15] To complicate matters, some authors[16] have reported that corticosteroids given 12– 24 h in advance of ionic contrast injection can provide protection against contrast toxicity such that reactions are no greater than those for patients receiving nonionics. Central nervous system complications include seizure, transient cortical blindness (vertebral angiography), and transient global amnesia. “Spinal seizure” can rarely be seen during spinal or aortic angiography.[17] Among the ionic media, pure meglumine salts (no sodium) are tolerated best for cerebral angiography.[18] In a series of 2509 cerebral arteriograms, Skalpe[19] recorded complication rates of 2.0% for ionic contrast and 1.3% for nonionic iohexol. The difference was not statistically significant. Cardiac, coronary, and aortic root injections of contrast can precipitate arrhythmias. If ionic media are used in cardiac
work, agents with a physiologic sodium level should be employed.[20] Myocardial depression and transient blood pressure depression can also occur. The nonionics have fewer cardiac effects[21] and are now in wide use in cardiaccoronary catheterization. Contrast agents are cleared by glomerular filtration, and minor contributions to excretion are made by the liver and small bowel. A few patients may develop impaired renal function following contrast administration, especially those with multiple myeloma or diabetes.[22] Patients of advanced age, those with preexisting renal or cardiac disease, and those receiving large volumes of contrast also appear to be at higher risk for renal compromise.[23] This is usually a self-limited state similar to acute tubular necrosis, but in some cases permanent renal impairment can occur. Contrast may cause sickling in some patients with hemoglobin S. Limiting the contrast dose as much as possible and keeping the patient well hydrated are the best forms of prevention. Animal studies[24] have shown reduced nephrotoxicity for the nonionic iohexol. In a group of high-risk patients, 10% of the ionic group and 5.5% of the nonionic group developed acute renal dysfunction after angiography; however, the difference was not statistically significant.[25] Nonionics, while less toxic, are also less anticoagulant than ionic contrast. Reports of clot formation in angiographic syringes[26] raised a concern that thrombotic complications would increase with nonionics. Attention to meticulous technique has been emphasized, and some authors[27] find no evidence of increased thromboembolic phenomena, while others advocate the addition of
Chapter 10. Angiography
heparin (5 IU/mL contrast) to ensure an anticoagulant medium.[28] Gadolinium chelates (gadopenetate dimeglumine and gadodiamide) are finding increasing use in catheter angiography for patients with renal insufficiency or allergy to iodinated contrast media.[29 – 31] Finally, carbon dioxide is an important radiolucent contrast agent[32] that can provide excellent diagnostic arteriograms when used with digital subtraction technique (Fig. 10-1). It can be used safely “below the diaphragm” in patients with hypersensitivity to iodinated contrast or with renal insufficiency. It has the advantages of low cost, no toxicity, and very low viscosity; moreover, it is resorbed from blood in 1–3 min.
ANGIOGRAPHIC CATHETERS Angiographic catheters are most commonly made of polyethylene, polyurethane, Teflon, or woven Dacron. These can be formed in hot water or steam to a desired shape, but most angiographers now use preformed catheters. Teflon can hold higher injection pressures and therefore deliver higher flow rates, but it takes extreme heat to modify its shape. It is also stiffer than the other materials. The torque control of a catheter is a function of its stiffness, which, in turn, relates to size, wall thickness, and composition. Some “torque control” catheters are braided with a wire mesh being incorporated into the catheter wall. Stiffer catheters are easier to manipulate, but more readily dislodge plaques or injure the vessel wall. It has been said that the stiffness and size of the catheters used are inversely related to the skill of the angiographer. The trend in recent years has been to smaller (usually 4 or 5 French), thinner-walled catheters,[33,34] which
Figure 10-1. CO2 abdominal aortogram (50 cm3 injection CO2) in a patient with renal insufficiency being evaluated for possible renal artery stenosis. The main renal arteries (arrows) are clearly seen and show normal caliber and contour. (Courtesy of Mark Allgood, M.D., Washoe Medical Center, Reno, Nevada.)
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can deliver high rates of flow. The refinement of coaxial systems (usually 2 –4 French selective catheters with 5 –7.5 French guiding catheters) has facilitated superselective catheterizations and the steady advancement of therapeutic interventional techniques. Furthermore, the development of hydrophilic coated catheters and wires has greatly facilitated selective catheterization.
THORACIC AORTOGRAPHY Percutaneous femoral puncture is the most commonly used approach to the aorta and its branches. This technique is most comfortable for the patient, is associated with the lowest rate of puncture complications, and allows the easiest manipulation of the catheter into the desired position, including small aortic branches. Mani et al.[35] cite a rate of 0.1% of damage to the femoral artery in a large series. A prospective sonographic study showed a higher-than-expected incidence of pseudoaneurysm detected by color flow duplex ultrasound following transfemoral catheterization.[36] The study group included patients undergoing diagnostic angiography alone, angioplasty, stenting, or thrombolysis. Initially, pseudoaneurysm incidence ranged from 1.2% for angiography up to 27% for thrombolysis with angioplasty, but in the second part of the study pseudoaneurysms were reduced to 0% for angiography and 8% for thrombolysis combined with angioplasty. This reduction was accomplished merely by prolonging manual compression for an additional 5 minutes beyond visible hemostasis. Obesity and heparinization after sheath removal correlated with higher risk for pseudoaneurysm. All pseudoaneurysms thrombosed with ultrasound compression technique, and none required surgery. In a similar study, a 6.25% incidence of pseudoaneurysm was detected by color flow ultrasound following transfemoral puncture and sheath placement.[37] In addition to pseudoaneurysm formation, dissection of the intima or laceration of the whole arterial wall may cause thrombosis, embolism, or uncontrollable hemorrhage. This results from extraluminal placement of the needle, guidewire, or catheter and may be detected on test injections. An arteriovenous fistula may also develop if the vein is concomitantly punctured. The incidence of these complications clearly increases with the size of the catheter used[35,38] and is higher with an inexperienced angiographer. Thoracic aortography requires a high-flow catheter to achieve a contrast flow rate approaching 40 mL/s, which is needed to opacify this large vessel. Other very uncommon risks are infection at the puncture site and breakage of the catheter or guidewire, requiring snare retrieval or possibly surgical removal. If the femoral artery is not available, we select the axillary artery, which is smaller and deeper and therefore carries a higher risk of local damage than a comparable femoral catheter placement.[35,39] In addition, the musculature in the axilla makes postangiographic hemostasis more difficult, and axillary hematoma may damage the brachial plexus. This may be avoided by careful postangiogram observation and urgent surgical evacuation of any significant hematoma. A recent large study of surgical complications of transaxillary arteriography cited a 2.3% complication rate, of which the
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Part One. Assessment of Vascular Disease
majority were nerve injuries followed by hematomas or pseudoaneurysms.[40] Because the brachial artery is even smaller, we do not advocate its use on a routine basis. Selected, limited cases may be performed using catheters of 4 or 5 French outer diameters or smaller. However, the smaller catheters may not deliver sufficient flow rates for thoracic aortography except with digital subtraction techniques. The most common local complications are loss of the radial pulse from either vasospasm or thrombosis and transient hand paresthesias.[41,42] Damage to the brachial artery with this approach is not uncommon but usually insignificant clinically. If neither axillary nor femoral sites are available, an aortogram can be performed using an intravenous catheter within the superior vena cava and digital subtraction techniques. There is a visible loss of image quality; however, a diagnostic exam can be obtained in most patients with good cardiac output.[43] When a prosthetic graft is in place, puncture is easily accomplished by routine transfemoral technique without a significant increase in complications, in our experience, as long as the graft is mature enough to have a firm neointima. The safety of this procedure has been confirmed in some reports[44] and denied in others.[45] Risks other than those associated with the arterial puncture are uncommon but include cerebral embolus and seizures, since injection is proximal to the brachiocephalic vessels. Dissections may occur with improper positioning of the catheter, as into a coronary artery orifice, under an atheromatous plaque, or with injection recoil into a carotid artery. Arrhythmias, hypotension, and contrast agent – induced renal failure also occur. An exact incidence of complications from thoracic aortography is uncertain, but data from a large series of angiography complications, which included a high proportion of aortograms, cited a mortality rate of 0.032% and a complications rate of 1.7–3.3%, depending on the puncture site.[39]
will identify other causes of mediastinal masses. Early reports on magnetic resonance imaging show similar accuracy as CT, with added flexibility in imaging planes.[48] Traumatic false aneurysms are the second most common type of thoracic aneurysm and have a characteristic angiographic appearance (Fig. 10-2). Although large autopsy series[49] show that only 45% of these aneurysms occur at the site of the ligamentum arteriosum, 95% of radiologically demonstrated aneurysms occur here. As many as 22% of aortic ruptures described on postmortem examination are in the ascending aorta, but they are infrequently diagnosed by angiography because of the much higher mortality rate from aortic root ruptures, associated cardiac injury, or pericardial hemorrhage with tamponade.[50] Fifteen to 20% of isthmus injuries survive hours to days, allowing diagnosis.[49] Chest radiograph findings suggesting aortic rupture include a widened mediastinum, present in the majority of cases of aortic rupture (but also present in 25% of other matched patients),[51] depression of the left main stem bronchus, tracheal and nasogastric tube deviation to the right, pleural fluid, and obliteration of the normal contour of the aortic knob. Widening of the right paratracheal stripe exceeding 5 mm is a sign of mediastinal hemorrhage.[52] In the past, some have advocated routine aortography in all patients with fractures of the first rib because of presumed correlation with aortic and brachiocephalic injuries. [53] Subsequent series[54,55] have demonstrated a low correlation of rib fractures and vascular injuries, which concurs with our experience.[56] Thoracic CT has become a valuable screening test in the evaluation of traumatic aortic injury (TAI) with the advent of high-speed helical/spiral scanners. Chest CT has shown a sensitivity of 100% for TAI [57,58] by virtue of detection of mediastinal hemorrhage. Helical CT was
ANEURYSMS The most common etiology of thoracic aneurysms is arteriosclerosis; 81.6% of aneurysms in DeBakey’s surgical series of 500 descending aortic aneurysms were arteriosclerotic.[46] These aneurysms are usually fusiform but may be saccular and even multiple. They may extend into the brachiocephalic vessels or the abdominal aorta; they are frequently calcified. Other etiologies of thoracic aneurysms are syphilis, bacterial infection, medial degeneration associated with Marfan syndrome or similar disorders, trauma, and aneurysms associated with congenital malformations. Luetic and mycotic aneurysms are usually saccular and more commonly found in the ascending aorta; mycotic aneurysms rarely calcify.[47] Since arteriosclerotic aneurysms may mimic these patterns, the precise etiology of the aneurysm often cannot be determined on the aortogram. Aneurysms create mediastinal masses on chest radiographs and have a diagnostic appearance on CT, which provides the true diameter of an aneurysm, including the amount of thrombosis, but may not demonstrate involvement of branch vessels. It
Figure 10-2. Traumatic false aneurysm (arrows) of the thoracic aorta occurring in its classic location at the level of the ligamentum arteriosum.
Chapter 10. Angiography
more sensitive than aortography (100% vs. 94.4%) but less specific (81.79 vs. 96.3%) in the detection of aortic injuries.[57]
DISSECTING ANEURYSM Aortic dissections arise in the thorax unless they are secondary to trauma or surgery. The chest film, along with the typical history of chest pain and findings of pulse deficits, provides important diagnostic information. Progressive mediastinal widening and haziness or a knobby appearance of the aortic arch or descending aorta is suggestive of dissection. A more specific sign is separation of a calcified intimal plaque from the outer wall of the aorta by 6 mm or more. However, this sign is present in a minority of cases.
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Furthermore, separation of up to 10 mm has been seen in arteriosclerosis without dissection.[59] In patients with suspected dissection, we approach the aortogram from the femoral route because we have found that entry into the false lumen is just as likely from the axilla. A guide wire with a very flexible tip is carefully advanced ahead of the catheter, and small test injections are used to avoid high-pressure injections into the false lumen. In this way we have been able to demonstrate both true and false lumens without extending the dissection (Fig. 10-3). Signs of dissection on an aortogram include narrowing and distortion of the intraluminal contrast with a parallel linear soft tissue density, which is the unopacified lumen, nonfilling of aortic branches, and associated aortic insufficiency. In other cases, the true and false lumens may fill and empty at slightly different times. If the tear is widely patent and the
Figure 10-3. Type III aortic dissection with retrograde extension. (A) Transfemoral aortogram. The catheter is in the true lumen, which fills the left subclavian artery. There is early filling of the false lumen (arrows) at the site of the tear. (B) Catheterization is now via the left subclavian artery and the false lumen is opacified. The dissection extends retrograde into the ascending aorta and right carotid artery (white open arrows). The true lumen appears as a filling defect (curved arrows) at the arch and descending aorta.
174
Part One. Assessment of Vascular Disease
lumens fill and empty simultaneously, the wall between them may be seen as a thin, linear filling defect in the column of contrast (Fig. 10-3). This dissected wall may be difficult to demonstrate because not only does it assume a spiral configuration, but it also may flap with the heartbeat, changing its appearance or even disappearing on sequential films. Dissections arising at the aortic root within a few centimeters of the valve and extending into the descending aorta (DeBakey type I) or limited to the ascending aorta (DeBakey type II) were most common in autopsy series.[60] In clinical series[61] DeBakey type III dissections have been more frequent; that is, tears arise just distal to the left subclavian artery origin, dissect distally, and often extend proximally as well. Whenever possible, the angiogram will identify the site of the tear by sequential opacification of first the true, then the false lumens (Fig. 10-3). In some cases the tear will not be demonstrated because of rapidity of flow across the tear or multiple reentry sites. A series reported by Abrams[59] demonstrated the tear in only 50% of cases. Intramural hematoma of the thoracic aorta, also known as “noncommunicating aortic dissection” or “aortic dissection without intimal disruption,” may explain many cases of dissection without demonstrable tear on aortography. This important entity can progress to communicating aortic dissection.[62 – 64] High-resolution CT is a valuable tool for diagnosis of dissection. Although demonstration of the tear and reentry or extension into branch vessels or the aortic valve may necessitate angiography, CT is accurate in diagnosing or excluding a dissection and in following up chronic dissections or postsurgical repair.[65] Similarly, transesophageal echocardiography may also demonstrate an intimal flap and false lumen as well as associated pericardial effusions and aortic insufficiency. The position of the trachea may limit evaluation of the aortic arch by ultrasound. Extension into branch vessels or the abdominal aorta is still better assessed with angiography.[66] For the stable and cooperative patient, MRI may provide the greatest anatomic detail, with a reported diagnostic accuracy of 90%.[67] Penetrating atherosclerotic ulcers of the aorta may present similarly to aortic dissections. However, these patients are elderly, with severe underlying atherosclerosis. The ulcerated plaque penetrates the internal elastic lamina, forming a hematoma within the media, which can develop a false aneurysm or rupture. The most common location is in the middle or distal descending thoracic or upper lumbar aorta. The lesion can be demonstrated by either angiography or CT[68] (Fig. l0-4). Occlusive disease of the aorta and brachiocephalic vessels—such as arteriosclerosis, arteritis, and congenital coarctation—is a common indication for arch aortography. Arteriosclerotic plaques of the carotid bifurcation are best demonstrated by selective injection; aortography demonstrates proximal stenoses, collateral vessels, or retrograde flow. The most common example of the latter is so-called subclavian steal: filling the subclavian artery distal to an occluded segment by retrograde flow down the vertebral artery (Fig. 10-5). Retrograde filling of the right carotid may similarly fill an occluded right subclavian artery. Takayasu’s arteritis (Fig. 10-6) occurs typically in premenopausal females who have pulse deficits and
Figure 10-4. Penetrating atheromatous ulcer. CT (not shown) demonstrated periaortic or intramural hemorrhage consistent with aortic dissection. Angiography of the aortic arch and proximal descending thoracic aorta was unremarkable. Penetrating atheromatous ulcer (arrows ) in the distal descending thoracic aorta.
angiographically show long or short segments of smooth stenosis in the aorta itself or any of its branches. Less commonly, there is dilatation of the ascending aorta or arch, or aneurysms in the descending aorta. In advanced cases, superimposed arteriosclerosis may mask the diagnosis of aortitis.[69] Most other types of arteritis cause dilatation and irregularity of the aorta and do not have a diagnostic radiologic picture. These include giant cell arteritis, which may also cause stenosis, and arteritis associated with syphilis, rheumatic fever, rheumatoid arthritis, ankylosing spondylitis, and Reiter’s syndrome.[70] Congenital coarctation appears in one of three patterns: (1) a short-segment stenosis in the high thoracic aorta near the origin of the left subclavian artery (Fig. 10-7), which is most common; (2) distal thoracic segmental narrowing, which is
Chapter 10. Angiography
175
Figure 10-5. Subclavian “steal.” (A) Arch aortogram showing nonfilling of the right subclavian and right vertebral arteries as well as stenoses at the origins of all the other brachioccphalic vessels. (B) Delayed film shows retrograde filling of the right vertebral artery (arrows), which fills the right subclavian artery (open arrows).
probably a form of Takayasu’s arteritis; and (3) complete interruption of the aortic arch or hypoplasia over a long segment involving the brachiocephalic origins.
PULMONARY ANGIOGRAPHY The two most common approaches to the pulmonary artery are percutaneous femoral or antecubital vein (preferably basilic vein) puncture, although axillary, subclavian, or internal jugular routes can also be used. Because the right heart and pulmonary arteries are relatively thin-walled and delicate, we almost exclusively use catheters with a pigtail shape to minimize the risk of cardiac or vessel perforation. Multiple side holes and large caliber (7 or 8 French) help prevent recoil on injection and allow high injection rates, up to 30 – 40 mL/s. The Grollman reversed-curve pigtail catheter[71] used from the transfemoral approach often passes easily through the heart and into the pulmonary artery, although a tip-deflecting wire may be needed to traverse the tricuspid valve in some cases. If pulmonary artery pressure is acceptable (see discussion below), a pulmonary arteriogram can be obtained with the catheter in the main pulmonary artery, or the right or left pulmonary artery can be selected, depending on which side shows the most suspicious findings on the ventilation/perfusion lung scan. Alternative catheters include the Van Aman right-angled pigtail,[72] which easily
crosses the tricuspid valve and is then passed over a wire into the pulmonary artery. The Ledor downward-turned pigtail catheter[73] may be helpful in lower lobe catheterization. Multiple-side-hole balloon-tipped Berman catheters (Arrow, Reading, Pennsylvania) can be flow-directed into the pulmonary arteries, and flow rates up to 27– 30 mL/s can be achieved. Two major risks complicate pulmonary arteriography. The first is arrhythmia induced by passage of the catheter into the right ventricle. ECG monitoring is mandatory during the procedure. Patients with preexisting left bundle branch block (LBBB) should have placement of a temporary pacemaker before pulmonary angiography. Fortunately, arrhythmias usually resolve when the catheter is withdrawn into the right atrium. In Mills et al.’s series of 1350 pulmonary angiograms,[74] 11 serious arrhythmias and 5 cardiac arrests occurred. The second danger is that of acute cor pulmonale. In patients with pulmonary hypertension where right ventricular end-diastolic pressure (RVEDP) reaches 20 mmHg or higher, acute right heart failure can follow even small contrast injections in the pulmonary arteries. Of 10 deaths reported in a series of 4000 pulmonary angiograms, most manifested acute cor pulmonale.[75] In a series of 388 patients with pulmonary hypertension and/or elevated RVEDP, 6 complications and 2 deaths occurred following pulmonary angiography.[76] Pulmonary artery pressures (PAP) and/or RVEDP must be obtained before contrast injection. In Mills et al.’s series,[74] all 3 deaths occurred in patients with PAP
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The most common indication for pulmonary arteriography is documentation of pulmonary emboli. The results from the Prospective Investigation of Pulmonary Embolism Diagnosis (PIOPED) cooperative study[85] set a perspective for the value of the ventilation/perfusion (V/Q) scan and the role of pulmonary angiography. Of patients with high-probability V/Q scans, 88% had positive pulmonary angiographs: of those with intermediate V/Q scans, 33% had positive angiograms; of those with low-probability V/Q scans, 12% had positive angiograms; those with normal or near normal V/Q scans had an estimated 4 –9% incidence of pulmonary emboli. Of all patients with confirmed pulmonary emboli, only 41% had a high-probability V/Q scan. If clinical criteria were considered, patients with low-probability or normal V/Q scans where clinical impression also indicated embolism to be unlikely had only a remote possibility of pulmonary embolism. Patients with intermediate or indeterminate scans where matching areas of ventilation and perfusion defects are seen require angiography for definitive diagnosis. Undue delay may result in missing the diagnosis because lysis of clots has been documented in 2 days, although most persist longer.[86] The diagnosis is made by
Figure 10-6. Takayasu’s arteritis in 21-year-old woman with absent pulses in both upper extremities. Arch aortogram shows a long smooth stenosis in the right subclavian artery (arrowheads), severe diffuse left subclavian narrowing (curved arrows), and a moderate left common carotid stenosis (small arrows).
greater than 75/28 mmHg or RVEDP greater than 20 mmHg, and the 2 deaths reported by Perlmutt et al.[76] had systolic PAP greater than 70 mmHg. Nonionic contrast agents have less hemodynamic effect on PAP,[77 – 79] and we now use nonionic contrast media for all pulmonary angiograms. Ioxaglate also produces less cough stimulation and thereby reduces patient motion.[80] Our guidelines are that a systolic PAP above 60 mmHg is a contraindication to continuing the study. If the pressure is between 40 and 60 mmHg, we proceed carefully with subselective injections in the areas of highest suspicion, continuing if the first injections are well tolerated. Two recent large studies[81,82] document improved safety of pulmonary angiography with low osmolar contrast. There were no deaths attributed to the procedure in either series. Since straight catheters are no longer used for pulmonary angiography, the complications of subintimal injection, cardiac perforation, and tamponade previously reported[74] have disappeared. It is wise to bear in mind the theoretical danger of dislodging emboli while advancing the catheter or from the proximal pulmonary arteries during injection. We minimize this risk by careful test injections and gentle catheter manipulation. We now use digital subtraction angiography (DSA) for most pulmonary angiograms. Although cut film angiography (CFA) has higher spatial resolution, DSA studies can be viewed subtracted or unsubtracted and reviewed in a “live” cine mode. DSA studies can be performed more quickly, require less contrast media, and have diagnostic accuracy comparable to CFA pulmonary angiograms.[83,84]
Figure 10-7. Congenital aortic coarctation. Arch aortogram showing a focal coarctation (white arrow) distal to the left subclavian artery. Note also the hypertrophied supreme intercostal collaterals (white arrowheads).
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demonstrating an intraluminal filling defect in one of the pulmonary arteries (Fig. 10-8). Amputated vessels and avascular areas may be seen, but these also occur in chronic pulmonary embolism, pneumonia, emphysematous bullae, tumors, and other conditions. Superselective injections or oblique projections may be necessary to distinguish emboli from these other types of occlusions. Congenital or acquired arteriovenous (AV) fistulas (Figs. 10-9 and 10-10) are an indication for pulmonary arteriography. Posttraumatic AV fistula or false aneurysms (Fig. 1011) or “Rasmussen” aneurysms[87] associated with tuberculosis (Fig. 10-12) are also diagnosed by pulmonary angiography. Arteriovenous fistulas may be closed with detachable balloon embolization[88] or coils.[89] Balloon placement in large fistulas (greater than 6–8 mm) incurs the risk of balloon escape into the systemic arteries. The Amplatz “spider” occluding device resembles a miniature caval umbrella filter and can be used to anchor the balloon or balloons. Other anomalies of the pulmonary vasculature that may be demonstrated on angiogram include pulmonary artery atresia or stenosis, anomalous pulmonary drainage, or venous obstruction by tumor or mediastinitis. Displacement and encasement of pulmonary arteries may be caused by tumor, but tumor vascularity of both primary and metastatic lung cancers is supplied by systemic vessels.[90] The bronchial arteries are variable in number and configuration, but most commonly there are one right and two left bronchial arteries arising from the descending thoracic aorta. Bronchial arteriography is indicated in lifethreatening hemoptysis.[91,92] Bronchoscopy assists in localizing the side of hemorrhage. Actual extravasation of
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contrast is uncommonly seen angiographically, and embolization is performed empirically provided that no vascular supply to the spinal cord is identified on the arteriogram. We routinely use polyvinyl alcohol sponge particles and occasionally coil emboli. At our institution, massive hemoptysis is most commonly due to tuberculosis or lung carcinoma. Other causes for bronchial bleeding include bronchiectasis, cystic fibrosis, sarcoidosis, pneumoconiosis, and other inflammatory or neoplastic processes.
PORTAL AND MESENTERIC VENOGRAPHY Angiographic methods remain the most reliable means of demonstrating the portal venous system, but the noninvasive imaging techniques of ultrasound/color flow Doppler, CT, MRI, and MRA provide important and often complementary data and can be expected to have an increasing role in the evaluation of patients with portal hypertension.[93 – 100] The development of transjugular intrahepatic portosystemic shunting (TIPS) and proliferation of liver transplantation has driven new innovations in angiographic imaging and intervention in the portal circulation.
ARTERIAL PORTOGRAPHY The portal vein and its tributaries are usually well visualized 8–12 s after selective injection of either the celiac or superior mesenteric artery (Fig. 10-13). An injection of 50 mL over 6 – 7 s is our routine dose, but we have safely used injections or up to 100 mL in large arteries to increase the venous contrast; this is particularly useful in cases of gross splenomegaly for dense opacification of the splenic vein. Venous contrast can be further enhanced by injecting 25– 50 mg of tolazoline (Priscoline) through the catheter immediately prior to the contrast injection. We no longer perform arterial portography to assess patency or provide localization of the portal vein prior to TIPS. In celiac and mesenteric angiography for suspected bowel ischemia or gastrointestinal bleeding, careful attention is given to the portal and venous mesenteric phase images because unsuspected varices or venous occlusive disease may be discovered.
TRANSJUGULAR INTRAHEPATIC PORTAL CATHETERIZATION AND TIPS
Figure 10-8. Pulmonary embolism. Pulmonary angiogram during main pulmonary artery injection shows a large saddle embolus at the bifurcation of the right main pulmonary artery (arrowheads). Filling defects representing emboli are also seen in left lower lobe segmental arteries (small arrowheads and white arrow).
A transjugular intrahepatic approach to portal venography was first described in animal studies in 1969[101] and was first reported in humans as a method of creating an intrahepatic portosystemic shunt in 1982.[102] Initially, portocaval shunts were created by a combined transjugular and transhepatic approach.[103] Transjugular intrahepatic portosystemic shunting has become a safe and effective method of reducing
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Figure 10-9. Right (A) and left (B) pulmonary arteriograms show multiple arteriovenous fistulas. This patient with Osler-Weber-Rendu syndrome presented at the age of 19 years with a brain abscess.
portal venous pressure and arresting variceal hemorrhage, and in some cases it is a successful treatment for intractable ascites.[104] The procedure typically begins with percutaneous puncture of the right internal jugular vein, placement of a long 9-11 French sheath and catheterization of the right hepatic vein (or middle hepatic vein). A wedged hepatic venogram can be performed through a standard catheter or balloon occlusion catheter and can facilitate retrograde opacification of the portal venous system. Carbon dioxide has been an effective contrast agent for this application when used with DSA.[105] This provides a portal vein target. Other techniques to target the portal vein before or during TIPS include arterial portography, ultrasound, and transhepatic placement of a metallic marker or wire adjacent to the portal vein bifurcation (extravascular), within the hepatic artery, or in the portal vein itself.[106] Subsequently, a 55-cm-long curved 16-gauge
Colapinto needle is passed out of the hepatic vein caudad and into the portal vein, targeting the right main portal vein near the portal bifurcation. Over a wire, the portal vein is catheterized, portal and systemic pressures measured, and a portal venogram obtained. An intrahepatic tract is balloondilated and stented, creating the portosystemic shunt (Fig. 1014). A final portosystemic pressure gradient is measured. If a high gradient persists, the stent can be dilated to a larger size or a second parallel shunt constructed (Fig. 10-14a). In cases of active variceal bleeding when angiographic filling of varices persists, sclerosant or coil embolization of varices can be performed at the same session.[107] Several randomized trials comparing TIPS versus endoscopic sclerotherapy/band ligation for variceal bleeding have been published with mixed results.[108 – 111] Three of four studies found significantly lower rates of rebleeding in the
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Figure 10-10. Osler-Weber-Rendu syndrome. The patient has hypoxemia and previous surgical resection of a left lower lobe arteriovenous fistula 9 years eazrlier. (A) Left pulmonary arteriogram. A large left upper lobe arteriovenous fistula is demonstrated. Two major feeding arteries (white arrows) and a large draining vein (white arrowheads) are identified. (B) Two detachable balloons were placed in the medial feeding artery and anchored by an Amplatz “spider” (black arrowhead) to prevent balloon migration. The proximal arterial trunk remains patent, sparing branches to the lateral portion of the left upper lobe.
TIPS group (23%, 12%, and 15% vs. 52%, 48%, and 45%). In one study, rebleeding was equal at 25% for both groups. Since TIPS achieves immediate portal venous decompression, the patients in the endoscopic therapy group are in theory at risk for rebleeding over a longer time since multiple treatments are given over a period of months. Not surprisingly, portosystemic encephalopathy was higher in the TIPS group in three of four studies (33%, 30%, 36% vs. 13%, 12%, 18%), but in one study encephalopathy rates were similar.[110] Overall, the studies showed a lack of significant survival differences between the two therapies.
INTERPRETATION OF MESENTERIC VENOGRAPHY Indications for mesenteric venography include most cases of portal hypertension being considered for surgical or embolic therapy. As well as giving the surgeon a “road map” of the veins available and their calibers, it will demonstrate the venous dynamics; hepatofugal flow in advanced cirrhoses is shown by retrograde flow down a portal tributary toward an
organ whose artery was not injected—that is, superior mesenteric or inferior mesenteric vein filling on a celiac injection or splenic or inferior mesenteric vein filling from the superior mesenteric arteriogram. Also, varices at unsuspected sites such as the ileum (Fig. 10-15) or colon (Fig. 10-16) will be seen; these may be sites of gastrointestinal bleeding not visible on barium studies or endoscopy. Portal vein thrombosis, sometimes an unsuspected etiology of variceal bleeding, will be revealed (Fig. 10-17). In addition, patients with previous surgical portal-systemic shunts may be evaluated for shunt patency (Fig. 10-18). Dynamic CT and MRI can be effective means of noninvasive assessment of shunt patency.[112 – 114] Finally, invasion of the portal vein by hepatic tumors, a grave prognostic sign and usually a contraindication to resection, is well shown by portography.
HEPATIC VENOGRAPHY Hemodynamic information about the portal system can also be obtained by hepatic venography. A wedge pressure may be taken by advancing a catheter from the inferior vena
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Figure 10-11. Subtraction left pulmonary arteriogram showing a posttraumatic false aneurysm at the site of a gunshot wound a year before. Contrast jet into the left atrium (arrows) indicates that an AV fistula is also present.
Figure 10-12. Right pulmonary arteriogram shows a “Rasmussen” aneurysm (arrow) in a patient with tuberculosis and hemoptysis refractory to bronchial artery embolization.
Figure 10-13. Arterial portography in portal hypertension. (A) Splenic artery injection, venous phase. There is splenomegaly. There is good opacification of the splenic and portal veins. Hepatofugal flow is present in a recanalized umbilical vein (arrowheads) with an aneurysmal varix (white arrows). (B) Superior mesenteric artery injection, venous phase. The superior mesenteric vein is well opacified (open arrow). Hepatofugal flow is seen in the inferior mesenteric vein (curved arrow) and again in the umbilical vein (arrowheads).
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Figure 10-14. Transjugular intrahepatic portosystemic shunting (TIPS). (A) A transjugular catheter has been directed into a hepatic vein, traversed liver parenchyma, entered the portal vein, and advanced into the superior mesenteric vein. A venogram shows an enlarged coronary vein (open arrow) and gastroesophageal varices (curved arrows). (B) Superior mesenteric venogram after balloon dilatation of the portosystemic tract and deployment of balloon-expandable stainless steel stents (arrows). Streaming of contrast into the inferior vena cava (IVC) and right atrium is seen (arrowheads). (C) Injection within the stent (arrows) shows rapid flow of contrast into the IVC and right atrium (arrowheads).
cava far into a hepatic vein until it blocks a small hepatic branch. Pressure measurements then accurately reflect the sinusoidal pressure and also the portal pressure in cases of postsinusoidal portal hypertension, as in most cases of alcoholic cirrhosis. Normal portal venous pressure is about 5–10 mmHg. Corrected sinusoidal pressure (wedged hepatic venous pressure minus free hepatic vein pressure) is normally 6 mmHg or less. Injection of contrast will demonstrate distorted hepatic venules in cases of cirrhosis
and even portal radicle filling if cirrhosis has advanced to stage III, where the flow in the portal vein is reversed (hepatofugal). In eases of presinusoidal portal hypertension, such as portal vein thrombosis or schistosomiasis, the wedge study will be normal. However, in Budd-Chiari syndrome or hepatic vein thrombosis, if a hepatic vein can be catheterized, contrast injection reveals a typical “spiderweb” pattern of hepatic vein collaterals (Fig. 10-19). A more detailed discussion of all
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transhepatic and transjugular method was used. Transhepatic puncture into or adjacent to the portal vein is sometimes used to localize the portal vein for TIPS[119] and may facilitate TIPS in cases with anatomy unfavorable for the transjugular approach.[120] Umbilical vein catheterization can also facilitate access to the portal venous system and was described in 1959 in children.[121] Surgical cutdown[122] and percutaneous ultrasound guided punctures have also been used to enter the umbilical vein and localize the portal vein for TIPS.[123] Mesenteric venous catheterization via minilaparotomy has also been used to cannulate the portal venous system for variceal embolization[124] and to facilitate TIPS.[125]
TRAUMA
Figure 10-14a. Two parallel TIPS shunts. Initial placement of TIPS between the right hepatic vein and portal vein achieved little clinical response in this patient with intractable ascites. A second TIPS via the middle hepatic vein resulted in resolution of ascites without encephalopathy.
CT has replaced arteriography in evaluation of blunt trauma to the liver or spleen except in cases where therapeutic embolization is anticipated. Angiographic signs of vascular injury are similar in the liver and spleen and include areas of extravasation or puddling of contrast agent; filling of false aneurysms (Fig. 10-21); avascular clefts; arteriovenous shunting; and displacement of the parenchymal blush away from the body wall, which is a sign of subscapular hematoma. Care must be taken in interpreting the splenic angiogram because congenital lobulations and accessory spleens occur
forms of mesenteric venous pathology may be found in Reuter et al.’s text.[115]
CELIAC AND MESENTERIC ARTERIOGRAPHY The celiac and mesenteric vessels may be approached by the femoral or axillary routes for selective catheterization. Stenosis of the origins of these vessels is best appreciated on the lateral aortogram. Risks of mesenteric arteriography are small; vessel injuries are uncommon with the use of smaller, softer catheters.
TRANSHEPATIC AND OTHER PORTAL VENOUS ACCESS The portal vein can be entered directly via a transhepatic puncture. This approach is now seldom used because the transjugular intrahepatic approach to the portal venous system is preferred. Variceal embolizations (Fig. 10-20), blood sampling in portal vein tributaries for localization of secreting pancreatic tumors (gastrinomas and insulinomas),[116,117] and diagnostic portal venograms have been performed via this route. This has been discussed in further detail in an earlier edition of this text.[118] Direct portal venous puncture was also used early in the development of TIPS when a combined
Figure 10-15. Ileal varix demonstrated on venous phase of superior mesenteric arteriogram. The superior mesenteric vein fills retrograde (open arrows) down to the varix (large white arrow) and up the right ovarian vein (small white arrows) to the interior vena cava.
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commonly and may simulate splenic rupture. Most accessory spleens lie near the hilus, but those below the lower pole can be confusing. CT scans are highly accurate in diagnosing splenic trauma,[126]permitting correct identification of splenic injury in 54 of 55 surgically proved cases. CT is also a reliable indicator of hepatic trauma, playing an important role in patient management.[127,128]
TUMORS Hepatic Tumors Angiography continues to be a valuable modality in the diagnosis, preoperative planning, and therapy of hepatic tumors. Malignant hepatic tumors (primarily hepatocellular carcinoma and cholangiocarcinoma) typically show arterial neovascularity. Angiography can localize tumors with respect to vascular territory within the liver and help determine the possibility and extent of resectability. A hybrid technique of liver CT performed during arterial portography is helpful in preoperative localization of focal lesions to specific liver segments.[129] Portal vein invasion may also be detected. A road map of vascular anatomy and detection of variant vessels (such as origin of the right hepatic artery from the superior mesenteric artery) is a valuable guide to the surgeon. Angiography continues to be of value in presurgical planning for resection of both malignant and benign tumors in children.[130] A new technique of digital subtraction angiography, using the partially opacified late hepatic portogram as the subtraction mask, has shown improved detection of faintly enhanced small hypervascular tumors, including hepatomas and metastases.[131] Finally, hepatic arteriography is necessary to guide effective chemotherapeutic infusion catheter placement for treatment of metastatic and primary liver tumors.[132]
Pancreatic Tumors
Figure 10-16. (A) Transhepatic injection of the splenic vein showing retrograde (hepatofugal) flow down the superior mesenteric vein (arrowheads). (B) Later film of transhepatic splenic venogram showing filling of colonic varix and drainage into the inferior vena cava (arrowheads). (Courtesy of Dr. Robert Conroy, Long Beach Veterans Administration Hospital.)
Angiography is now seldom used to diagnose pancreatic adenocarcinoma, which would usually appear as a hypodense mass within a background of normal parenchymal blush. Currently, angiography is indicated in determining the extent and resectability of tumor particularly as this relates to the encasement and invasion of adjacent vascular structures (Fig. 10-22). Conversely, pancreatic islet cell tumors such as insulinoma (Fig. 10-23) typically manifest themselves as focal highly vascular masses at angiography.[133] Other modalities can be superior to angiography for localization (portal venous sampling, CT, and intraoperative ultrasound),[134] but these tumors can be difficult to identify. In our experience, correlation of several imaging studies including angiography may be necessary to reach a confident diagnosis.
Alimentary Tract Tumors Angiography plays little role in the diagnosis of bowel tumors, as barium studies and endoscopy are highly effective in mass detection. However, bowel tumors are occasionally
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Figure 10-17. Portal vein thrombosis with “cavernous transformation” of the portal vein (curved arrows) demonstrated on the venous phase of a splenic artery injection. The splenic vein (arrow) and coronary vein (open arrow) are normal, but retrograde filling of mesenteric collaterals (arrowheads) indicates portal hypertension.
Figure 10-18. Patent Warren shunt demonstrated on venous phase of high-volume splenic arteriogram. Straight arrows outline the renal vein. Curved arrows show the inferior vena cava.
Figure 10-19. Wedged hepatic venogram in patient with BuddChiari syndrome, showing typical pattern of tortuous hepatic venous collaterals.
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Figure 10-20. (A) Transhepatic portogram showing large esophageal varices. (B) Selective catheterization of the coronary vein for variceal embolization. (C) Postembolization portogram showing occluded coronary vein (arrow). (Courtesy of Dr. Robert Conroy, Long Beach Veterans Administration Hospital.)
noted in the evaluation of gastrointestinal bleeding, identified by virtue of active bleeding, vessel displacement or invasion, tumor vascularity, or early venous drainage. For the interested reader, the text by Reuter, Redman, and Cho[115] contains a complete discussion of angiographic findings for specific bowel tumors.
GASTROINTESTINAL BLEEDING Bleeding into the gut is reliably demonstrated by selective mesenteric arteriography if the patient is bleeding at a rate of at least 0.5– 1.0 mL/min at the moment of contrast
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Figure 10-21. (A) Selective proper hepatic arteriogram showing large hepatic false aneurysm secondary to shotgun wound. (B) Close-up of right hepatic branch after particulate embolization shows stump of occluded vessel at the site of the aneurysm (arrow).
injection.[135] The diagnosis is made by demonstration of extravasation or puddling of contrast agent, which persists beyond the phase of venous emptying (Fig. 10-24). The major problem with arteriographic diagnosis is that bleeding is often intermittent and may have stopped at the time of the injection. In patients with recurrent life-threatening bleeding where standard techniques have failed, provocation of bleeding with intraarterial vasodilators such as tolazoline
(Priscoline), heparinization,[136] or urokinase infusion at the time of angiography may allow localization of the bleeding site.[137] A recent prospective study of provocative intravenous urokinase administration combined with systemic heparin anticoagulation enabled determination of the bleeding source in only 2 of 10 patients with recurrent gastrointestinal bleeding.[138] Within this study group, intraoperative endoscopy subsequently was diagnostic in 2 of 3 patients. Other previous studies utilizing intraarterial thrombolytics have shown a higher diagnostic yield angiographically.[137,139] Endoscopy immediately prior to the angiogram helps to localize the site and limits the number of vessels to be injected. This avoids the long catheter time and high contrast agent load often required to select all possible gut vessels. Recent barium studies preclude arteriography, because the residual barium masks extravasation. Several intravenous isotope studies are available which are more sensitive than the arteriogram to slow or intermittent bleeding. Extravasation at 0.1 mL/min may be visible on scan after injection of 99mTc-labeled sulfur colloid[140] or 99m Tc-labeled red blood cells.[141] For the sulfur colloid scans, bleeding must be active at the moment of injection and bleeding adjacent to the liver is obscured. In areas where upper and lower bowel are superimposed, it may be difficult to tell which segment is bleeding. Gastrointestinal bleeding can be controlled in a high percentage of patients by transcatheter therapy with vasopressin (Pitressin) infusion or embolization. In general, vasopressin infusion is easier because catheter placement is less critical and the risk of bowel infarction is negligible; however, the prolonged presence of the catheter in the femoral artery carries a risk of thrombus formation and embolization in the leg. In the stomach, embolization is an attractive choice, since the left gastric artery can usually be catheterized without difficulty and the risk of stomach infarction is exceedingly low. Control of gastric bleeding by vasopressin has been reported at approximately 80% in multiple series.[142] Pyloroduodenal bleeding is more difficult because of the double blood supply from the pancreaticoduodenal arcade, and the success of vasopressin is correspondingly lower at 40% or less.[142] For better control, selection of the gastroduodenal artery for embolization is desirable. Even after gastroduodenal embolization, bleeding may persist from superior mesenteric artery collaterals. Selective embolization can control bleeding in 65 – 70% of cases.[142] Selective small bowel embolization can be performed safely[143] in cases that cannot be controlled with vasoconstrictive therapy, but cases of bowel infarction have been reported. Colon infarcts after embolization are known to occur in approximately 12% of patients,[144] so that in the lower bowel infusion is the treatment of choice, achieving success in 80–90% of cases (Fig. 10-24).[145] Although intraarterial infusion of vasopressin into the superior mesenteric artery (SMA) reduces splanchnic blood flow, it has been demonstrated that intravenous infusion is just as effective at controlling variccal bleeding;[146] we have therefore abandoned intraarterial therapy in these cases.
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Figure 10-22. Poorly differentiated adenocarcinoma of the pancreas with vessel encasement. (A) Celiac arteriogram demonstrates irregular narrowing of the celiac trunk (straight arrow) and common hepatic artery (curved arrow) consistent with tumor encasement. (B) Superior mesenteric arteriogram shows SMA narrowing (curved arrows) and markedly irregular contour of the gastroduodenal artery (arrowheads) representing encasement. A biliary stent is in place.
MESENTERIC ISCHEMIA Chronic Ischemia Angiography is not a precise diagnostic tool in many cases of suspected chronic mesenteric ischemia because stenoses and occlusions correlate very poorly with ischemic symptoms of bowel infarcts in radiological or pathological series. It is not rare to see proximal stenoses or occlusions of all three mesenteric vessels in asymptornatic patients.[147] The rich
collateral supply of the gut often compensates adequately in slowly progressive stenoses. Proximal occlusions are seen best on the lateral aortogram, while the anterior projection demonstrates the anatomy of collaterals. Collateral flow between the SMA and the inferior mesenteric artery (IMA) develops along the left colic to middle colic anastomoses, along the marginal artery of Drummond (the “functional artery” of the colon), in the mesenteric edge of the descending colon, and along the arc of Riolan between the proximal IMA and SMA. Enlarged pancreaticoduodenal arteries are the most commonly seen
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Figure 10-23. Pancreatic insulinoma. A common hepatic arteriogram (subtraction film) shows the insulinoma in the pancreatic head as an area of blush or “stain” (arrowheads).
collaterals between the SMA and the celiac artery, although routes around the stomach are available. Atherosclerosis is the most common etiology for stenoses; the most frequently affected vessel is the IMA. Other etiologies include Takayasu’s arteritis, dissecting aneurysm, fibromuscular dysplasia, and the controversial median arcuate ligament syndrome wherein the celiac trunk is compressed by this diaphragmatic ligament (Fig. 10-25). Patients with the clinical syndrome of intestinal angina have been successfully treated with balloon angioplasty of the celiac and superior mesenteric arteries.[148]
configuration. The constriction may be precipitated by a variety of insults including hypotension, transient SMA occlusion, pressor agents, digoxin toxicity, or decreased cardiac output, but it may persist after correction of the initial event. Infusion of vasodilators, either papaverine or tolazoline,[150,151] has been successful in relieving symptoms and avoiding bowel resection. Papaverine has been used successfully after demonstrating a clot[151] in a few patients. Acute venous thrombosis is an infrequent cause of bowel infarction and often is not visible on angiography. Nonvisualization of the portal vein or tributaries and delayed washout of the small vessels and mucosal blush are seen with an extensive thrombosis.
Acute Mesenteric Ischemia Angiography is indicated in cases of acute mesenteric ischemia to delineate an obstructive lesion and differentiate obstruction from nonocclusive ischemia; in some cases of nonocclusive ischemia, transcatheter therapy is indicated. Obstructive ischemia is usually caused by either thrombus or embolus or occasionally by an acute aortic dissection (Fig. 10-26). Emboli appear as rounded filling defects in the artery; thrombi are usually associated with atherosclerotic stenoses that are often evident in other vessels as well. Radiologic differentiation between thrombi and emboli may not be possible. Occlusions of the celiac and superior mesenteric arteries have been treated successfully with thrombolytic agents.[149] Nonocclusive ischemia is causes by mesenteric vasoconstriction, which appears on the angiogram as diffusely decreased caliber of the mesenteric arteries, impaired filling of distal branches—giving a “pruned” appearance—and a series of segmental stenoses forming a “string of sausages”
RENAL ARTERIOGRAPHY Either selective renal artery injections or abdominal aortography can be used to evaluate the renal vasculature. The best images result from selective injections; however, when disease is suspected at the renal artery origin, aortography may be used first in lieu of renal artery catheterization. A slight right posterior oblique projection shows the renal artery orifice optimally in most patients (Fig. 10-27). Aortography may also be preferred in cases of renal trauma, for large renal tumors with parasitized blood supply, and for evaluating renal donors. Aortography provides an anatomic overview, which is useful in demonstrating multiplicity of renal arteries, present in 20 – 30% of cases.[152] The left kidney is preferred as a donor kidney because of its longer renal vein, but multiple arteries or early
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branches (renal parenchymal or ureteral) less than 1 cm from the origin would dictate harvest of the right kidney.[153] Renal angiography has been replaced by CT as the preferred method of evaluating acute renal trauma.[154] Even nonvisualization of a kidney on intravenous urogram may not be an indication for arteriography; some feel it merely delays
Figure 10-24. (A) Inferior mesenteric arteriogram showing extravasation of contrast (curved arrow), indicating an active bleeding site in the descending colon. (B) Repeat injection of the interior mesenteric artery after a trial of pitressin infusion. The caliber of all the branches is reduced, and the extravasation is no longer seen.
Figure 10-25. (A) Lateral aortogram in expiration showing narrowing (open arrow) at the origin of the celiac axis typical of median arcuate ligament syndrome. (B) Aortogram in inspiration. The stenosis has disappeared (curved arrow).
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Chapter 10. Angiography
emergent surgical repair.[155] Renal angiography is more apt to be utilized in cases of penetrating injury (as opposed to blunt trauma) or where embolization is anticipated. Selective catheterization of the renal artery is usually straightforward; however, an acute takeoff from the aorta may make a recurved catheter shape or an approach from the axillary artery necessary. Injection of epinephrine into the renal artery immediately prior to filming has been recommended in cases of suspected renal tumor.[156] Normal vessels respond by constricting. Neovascularity does not respond as much and is thereby rendered more prominent. This form of pharmacoangiography does enhance visualization of tumor vessels but has, in our experience, seldom made a diagnosis which was not already possible from routine films. In our practice, the greatest usage of renal angiography currently is for vascular lesions, such as renal artery stenosis, renal arteriovenous fistula or malformation, renal artery aneurysm, fibromuscular dysplasia, and arteritis. When lesions are not primarily vascular in nature, less invasive tests such as intravenous urography, ultrasound, CT, and isotope studies almost always precede angiography. If less invasive procedures are not diagnostic, angiography may demonstrate an etiology in some cases of oliguria, hypertension, hematuria, or hydronephrosis. Arteriography may elucidate the extent of tumor spread in cases of renal cell carcinoma. Venous phase films may reveal tumor thrombus in the renal vein. Inferior venacavography may also be indicated in staging of renal cell carcinoma, but selective renal vein catheterization should be avoided, if possible, as friable tumor could be dislodged. We have found MRI particularly helpful in assessing renal vein or caval tumor invasion. Preoperative ablation of renal tumors with intraarterial absolute ethanol can be effective in reducing blood loss at the time of radical nephrectomy.[157,158] Atherosclerotic narrowing is the most common renal vascular lesion. Atherosclerosis usually involves the proximal third of the renal artery and is seldom present without associated abdominal aortic disease. Since only a small percentage of hypertension is renovascular and patients with renal artery stenosis may be normotensive, the presence of renal artery narrowing alone is rarely appropriate as the sole determinant for angioplasty. If selective renal vein renin samples show a ratio of l.5:1 or greater for the ipsilateral side, it has been considered likely that the renal artery stenosis is the cause of hypertension; however, a prospective study concludes that renal vein renins are unreliable in predicting which patients will respond to revascularization and are not specific enough to exclude patients who do not have renovascular hypertension.[159] Based on arteriography alone, a narrowing of 80% or more is usually significant.[160] Renal artery aneurysms have been incriminated as a cause of pain, hematoma, and hypertension. They may rupture, and an increased incidence of rupture during pregnancy has been
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described.[161] Selected patients can be treated by embolization (Fig. 10-28). Renal arteriovenous fistulas are usually associated with congenital arteriovenous malformations or penetrating trauma or are iatrogenically induced. The most common cause overall is percutaneous needle biopsy. Most postbiopsy fistulas resolve with time, but a few go on to severe hypertension or heart failure. Arteriovenous fistulas and malformations may also be treated by embolization techniques (Fig. 10-29).[162] Renal artery dysplasia or fibromuscular dysplasia occurs most frequently in women in the middle decades of life (Fig. 10-30). Other visceral and cerebral vessels may be involved. Renal artery dysplasia can be associated with spontaneous renal artery dissection, aneurysms, and hypertension. The proximal third of the main renal artery is usually spared, which is not the case with atherosclerotic involvement. A number of classification systems based on location and type of arterial involvement have been described.[163] In some instances, dysplasia may be difficult to differentiate from arteritis. Arteritis of the renal vasculature causes changes that are not specific for the different etiologies. Vessel irregularities, stenoses, occlusions, and aneurysms may be seen. Small aneurysms of medium- and smaller-sized renal artery branches are suggestive of polyarteritis nodosa (Fig. 10-31) and are usually associated with clinically florid disease.[164] Other necrotizing vasculitides may cause similar aneurysms.
ABDOMINAL AORTIC AND LOWER EXTREMITY ARTERIOGRAPHY We routinely use the femoral approach to arteriography of the abdominal aorta and lower extremity. The femoral artery on the least symptomatic side is usually punctured. In patients with absent femoral pulses and iliac occlusion, common femoral artery puncture (with or without ultrasound guidance) may result in successful catheterization of the aorta, as even chronically occluded iliac segments can often be traversed with careful technique and use of steerable hydrophilic wires. In the author’s experience, axillary puncture can be avoided in many of these cases, and in some, thrombolysis or primary stent angioplasty can restore iliac patency. Other safe alternatives include the “high” proximal brachial approach,[165,166] and we occasionally use a percutaneous antecubital brachial approach in cases where a nonselective arteriogram will be performed and a 4 French catheter can be used.[41,167] The translumbar aortic approach can also be employed, and some angiographers prefer this route.[168] The translumbar technique, originally described by Dos Santos et al.[169] in 1929, has been modified by the use of
Figure 10-26. (A) Extension of a thoracic aortic dissection causing acute mesenteric ischemia shown on lateral aortogram. The septum is indicated by arrowheads. There is a tight stenosis of the superior mesenteric artery (open arrow) and no celiac filling. (B) Subtraction of true lumen arteriogram showing superior mesenteric artery stenosis (arrow) and hepatic artery filling via collaterals. (C) Lower portion of severely narrowed true lumen giving rise to normal lumbar arteries.
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Figure 10-27. (A) The proximal right renal artery origin is partially obscured in the straight AP projection (arrow). (B) A right posterior oblique projection more clearly demonstrates the proximal renal artery stenosis (curved open arrow).
Figure 10-28. Traumatic renal artery aneurysm arising from the lower pole artery. (A) Preembolization. (B) Postembolization.
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Figure 10-29. (A) Traumatic renal AV fistula unsuccessfully treated by surgery. White arrow indicates the renal artery, and black arrow shows venous shunting into the left renal vein. (B) A single detachable balloon (white arrow) occludes the fistula with cessation of pain and hypertension.
guidewires and replacement of the needle with a Teflon sheath or catheter after the aortic puncture. Severe hypertension or coagulopathy are firmer contraindications to the use of translumbar aortography than to angiography using peripheral access sites, because the inability to compress the puncture site following catheter withdrawal or to visualize the site makes bleeding more problematic. Thousands of aortograms have been performed using the translumbar approach, with a surprisingly low complication rate, but the approach is lacking in flexibility in that selective catheterizations and interventional techniques such as angioplasty or thrombolytic therapy are not easily performed by this route. The authors have not performed translumbar aortography in many years and currently utilize gadolinium-enhanced magnetic resonance angiography when arterial access difficulties are extreme. It is possible to catheterize mature grafts with a low complication rate, but the tough scar and graft material may make catheter passage difficult. The amounts, rate, and location of contrast agent injection and the sequence and centering of filming vary depending upon the suspected pathology. For example, an arteriovenous fistula would require rapid injection and filming, while the slowed, turbulent flow of an aneurysm would be better demonstrated by slower rates of injection and filming. Atherosclerotic occlusive disease of the lower extremity is one of the most common indications for angiography in our practice; following a cut film abdominal aortogram, the study
is completed by placing the 4 or 5 French catheter in the distal abdominal aorta. Nitroglycerin (200 mg intraarterially) injected through the catheter immediately before contrast injection can improve visualization of distal vessels. Other vasodilators have been shown to be less effective in this regard.[170] Reactive hyperemia following temporary tourniquet application prior to contrast injection is another effective technique for enhancing visualization of distal vessels, but a case of prosthetic graft occlusion immediately following this method has been reported.[171] In cases where exquisite detail of the small runoff vessels, including the plantar arch and foot vessels, is necessary, as in patients being evaluated for distal in situ saphenous vein bypass grafting, a technique of balloon occlusion femoral angiography has been advocated.[172] Contrast (4 mL/s for total 60 mL) is injected via the balloon catheter while the ipsilateral external iliac artery is occluded by the balloon, which is inflated with carbon dioxide (Fig. 10-32). Supplemental selective DSA angiograms may also be very helpful in visualizing small runoff vessels beyond the trifurcations. For our standard aortogram with runoff, contrast agent is injected at a rate of 8 mL/s for 10 s (80 mL total), and films are exposed at intervals for up to 40 s from the beginning of the injection. Because of the generalized nature of atherosclerosis, an abdominal aortogram is included in the study even when symptoms and noninvasive studies suggest disease limited to the lower extremity. Films extend at least down to
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Figure 10-30. Renal artery fibromuscular dysplasia in a 35year-old woman with renovascular hypertension. Characteristic beaded stenosis is seen in the right mid-main renal artery (arrow). The right kidney is small.
the ankle. Long films that cover the entire lower extremity or a programmed moving tabletop are valuable for obtaining films that show all vessels maximally opacified and for minimizing the need for repeat injections. We routinely obtain films with a long-leg changer in both oblique projections. This is particularly helpful in demonstrating the common iliac bifurcations and origins of the superficial femoral and profunda femoris arteries. It is desirable to keep the contrast agent load within limits so as not to impair renal function. Injection of contrast is also uncomfortable for the patient, but nonionic and ionic dimeric low-osmolality agents have considerably decreased the pain effects in peripheral arteriography.[173,174] Ioxaglate (Hexabrix) seems to cause the least pain and heat sensation in angiography of the lower extremity.[175] Conflicting reports regarding pain reduction when local anesthetics are added to contrast media have appeared in previous years,[176,177] but a more recent study[178] concludes that this is an ineffective technique. When aortography is performed to examine the abdominal aorta alone, smaller amounts of contrast agent are adequate; 25 –40 mL injected over 2 s is usually sufficient. Diagnostic quality aortofemoral angiography can also be obtained using carbon dioxide with DSA along with limited selective injections of iodinated contrast. Atherosclerotic occlusive disease is seldom a diagnostic dilemma per se, because the vessel irregularities, stenoses, and occlusions are easily diagnosed. Performance of the examination may be the most challenging aspect of the study. Vascular access may be limited, and plaques that compromise
Figure 10-31. Polyarteritis nodosa. Multiple small aneurysms are evident in (A) the right kidney and (B) the left kidney. (C) Superior mesenteric artery injection in the same patient also reveals several small aneurysms (white and black arrows).
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Figure 10-32. Balloon occlusion femoral arteriography (BOFA), lateral projection. Distal runoff was inadequately demonstrated on conventional aortofemoral arteriogram. There is occlusion (white arrow) of the distal superficial femoral artery, which “continues” via a geniculate collateral. The popliteal artery is occluded, and all three trifurcation vessels are occluded proximally. Well-filled collaterals reconstitute all three runoff vessels in the lower calf. The posterior tibialis artery is occluded at the ankle (curved white arrow). The dorsalis pedis artery is patent and affects filling of plantar vessels.
Figure 10-33. (A) Collateral circulation to the lower extremities in infrarenal aortic occlusion. A prominent inferior mesenteric artery (black arrow) and superior hemorrhoidal branches (white arrows) are seen. (B) A network of perirectal and perineal collaterals gives rise to retrograde filling of pudendal and obturator branches of the hypogastric artery (arrowheads), which reconstitutes the common and external iliac and femoral arteries (black arrows). Note also the left L1 lumbar to iliolumbar collateral (white arrows) contributing to the hypogastric artery.
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the lumen increase the chance of subintimal passage of the guidewire. Distal emboli in the form of dislodged plaque fragments or showers of cholesterol emboli may complicate the procedure. For these reasons we prefer small, soft catheters and soft guide wires such as the 0.032-in. Bentson guide (Cook, Inc., Bloomington, Indiana) as our standard equipment. Certain patterns of atherosclerotic occlusion occur with predictable frequency. The area most often involved is the distal superficial femoral artery at the adductor canal, presumably because of repeated trauma as the artery enters the canal. The calf vessels and popliteal artery are involved in order of decreasing frequency after the superficial femoral artery. Profunda femoris occlusion is uncommon, although there may be stenoses at its origin. This is fortunate, because it is the collateral pathway for superficial femoral disease. The patterns of occlusive disease have been well described for the lower extremity[179,180] as well as for the abdominal aorta and pelvic vessels.[181 – 183] Pathways of collateralization in chronic distal aortic and iliac disease are testimony to the body’s ability to adapt to adversity (Figs. 10-33 and 10-34). If unsuspected or incompletely defined, they can lead to unpleasant surprises.
Figure 10-35. Aortogram with runoff. In situ saphenous vein graft (large white arrow) with multiple persistent “perforators,” which now function as arteriovenous communications (small white arrows), shunting between the arterialized saphenous graft and the superficial femoral vein (black arrowheads), which appears abnormally early on the arteriogram.
Figure 10-34. Collaterals in external iliac occlusion. Iliolumbar branch (arrows) from the hypogastric artery anastomoses with a circumflex iliac artery (arrowheads), which reconstitutes the common femoral artery. Note also the collateralization from the superior gluteal artery (short curved arrows) to the lateral circumflex femoral artery (arrow with tail).
When the aorta is occluded, both parietal and visceral collateral networks may form. The visceral network involves connections between branches of the superior mesenteric to inferior mesenteric to internal iliac to profunda femoris systems. The level of obstruction will determine which portion of the network develops. The parietal network involves aortic branches such as the intercostal, subcostal, lumbar, and middle sacral arteries, anastomosing with external iliac, internal iliac, and profunda femoris branches. The epigastric arteries may be important collaterals in the
Chapter 10. Angiography
form of the Winslow pathway, which is a superior epigastric to inferior epigastric connection linking the internal mammary and intercostal arteries to the internal iliac artery. This pathway should be remembered because it is not evaluated by standard injections in the abdominal aorta. In patients who have had vascular grafts, angiography is indicated when acute symptoms of limb ischemia occur, because these usually indicate graft occlusion. Less abrupt clinical deterioration can represent progression of atherosclerotic disease in native vessels, development of anastomotic site stenoses, or graft occlusion. Selection of puncture site may be influenced by therapeutic options such as thrombolysis, but we prefer to avoid graft puncture. Urokinase infusion directly into graft thrombus can be very effective, as grafts have no side branches or collaterals by which the drug could diffuse away. Following clot lysis, anastomotic stenoses amenable to angioplasty are often revealed. A unique feature of in situ saphenous grafts that may be responsible for graft failure is the persistence of arteriovenous communications (Fig. 10-35).[184] If the small tributaries between the superficial and deep venous systems are not all ligated, shunting may occur when the vein becomes arterialized. This shunting can lead to ischemic symptoms or thrombosis of the distal graft. We have also found color Doppler ultrasound helpful in identifying these AV fistulas. A localizing skin mark can be made preoperatively, guiding the surgeon to the site for ligation. Vascular trauma is the second most frequent indication for lower extremity angiography. The indications for angiography in extremity trauma have been the matter of some debate. Positive findings on physical exam of decreased or absent pulse or blood pressure, cold limb, bruit or murmur, uncontrolled bleeding or expanding hematoma, or neurologic deficit are accepted criteria for emergent arteriography. In patients with negative physical exam where arteriography was performed only because of proximity of the wound to vessels, arteriograms were consistently negative.[185] It has been suggested that patients without signs or symptoms of arterial injury be observed and have elective arteriograms.[186] The injury patterns include vasospasm (arterial narrowing), intimal flap, occlusion, laceration, complete transection, arteriovenous fistula, pseudoaneurysm, and combinations of these. When a pseudoaneurysm, AV fistula, or frank extravasation is seen, diagnosis is straightforward, but an angiogram may not be able to differentiate the others.[187] It is possible to have a complete arterial transection with intact flow. Rose and Moore[188] correlated angiograms, operative findings, and clinical outcome in arterial trauma. Intraluminal defects “typical” for intimal flaps can be misleading and result in false-positive or false-negative angiographic interpretation. Focal luminal widening usually represents partial-thickness injury to the arterial wall. Smooth arterial narrowing was a finding generally associated with a benign clinical course; when combined with slowed arterial flow, however, it indicates compartment syndrome. An irregular beaded pattern of arterial narrowing corresponds to severe vascular injury.[188] Angiography generally underestimates the severity of injury. Penetrating wounds cause the majority of injuries and more commonly cause lacerations and transections. Blunt trauma is more commonly associated with intimal
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flaps.[189,190] Intravascular embolization therapy is useful in arteriovenous fistula, hemorrhage, and some false aneurysms. It is especially useful in traumatic pelvic bleeding, which may be difficult to control surgically. Pelvic and lumbar fractures may also lead to retroperitoneal hemorrhage due to injury to lumbar arteries,[191] so aortography (not merely selective iliac or hypogastric injections) should be performed in these patients. Embolization therapy for pelvic hemorrhage during the postpartum period and from pelvic malignancy can also be effective.[192,193] Abdominal aortic aneurysms are usually atherosclerotic in origin. Thoracic aortic dissection may extend into the abdomen, but a dissecting aneurysm originating in the abdominal aorta is rare. Traumatic, arteritic, and mycotic aneurysms are also rare. Most abdominal aortic aneurysms are fusiform (Fig. 10-36); some are saccular. Ultrasound is an effective method for the detection and serial measurement of abdominal aortic aneurysms.[194] Computed tomography is very accurate in the assessment of abdominal aortic aneurysms with respect to size, extent, and presence of mural thrombus as well as in distinguishing between simple mural thrombus calcification in an aneurysm versus displaced intimal calcification in aortic dissection.[195] CT is also helpful in identifying leaking aneurysms,[196] but it is not sufficiently accurate in defining the origins of the renal arteries relative to the aneurysm.[197] Angiography allows precise definition of which branches are involved. Extension into renal or iliac arteries can be demonstrated. Angiography may fail to demonstrate the full diameter of the aneurysm because of thrombus in the lumen (Fig. 10-37).
LOWER EXTREMITY VENOGRAPHY Many techniques for performing lower extremity venography have been described. The choice depends on the equipment available, the patient’s clinical status, and the personal preference of the radiologist. We routinely perform venography of the lower extremity using the following technique. A superficial vein on the dorsum of the foot is cannulated with a plastic cannula or butterfly needle. Tourniquets are placed at the ankle, below the knee, and above the knee to force flow into the deep venous system. Then 50 mL of nonionic contrast is injected by hand, with careful attention to any signs of extravasation over the dorsum of the foot. Films arc obtained over a longleg film changer at the end of injection, and tourniquets are removed just before final films to better demonstrate the superficial, soleal, and gastrocnemius veins. Placement of a sandbag or manual compression at the groin can help pool the contrast in the lower extremity. Subsequent release of compression, coupled with elevation of the leg prior to final films, can enhance visualization of the iliac vein and inferior vena cava. Immediately after filming, we flush the veins with normal saline. We occasionally use an alternative technique wherein the venous system is filled with 100 mL of contrast (diluted to half concentration) while the patient is semiupright and non–weight-bearing on the leg that is being studied. A tilting fluoroscopic table is used, and spot films are obtained as the table is lowered and contrast advances cephalad.
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Figure 10-36. Fusiform infrarenal abdominal aortic aneurysm. (A) Anteroposterior view. Note the displacement of the superior mesenteric artery. (B) Steep LPO oblique view. (C) Pelvic arteriogram confirms absence of extension into the iliac arteries.
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pool.[204] The reported sensitivity of this technique ranges from 68[205] to 90%.[206] Radionuclide blood pool venography can be helpful in detecting iliac vein thrombosis,[207] which is a difficult area to evaluate with ultrasound. The labeled fibrinogen test may be sensitive for acute thrombi in the calf, but it is not widely available, takes up to 48 h to complete, and is of less use in chronic thrombosis. Results of MRI in the diagnosis of lower extremity and pelvic vein thrombosis using flow-sensitive gradient echo techniques have been impressive. A recent study with venography correlation reported a sensitivity of 100% and specificity of 92.9% for MRI.[208] Contrast venography also plays a role in the evaluation of the patient with chronic venous stasis syndrome. Chronic venous insufficiency occurs when there is valve dysfunction or obstruction of the deep venous system and/or incompetent perforator valves. The ascending venogram performed with a calf tourniquet in place drives contrast into the deep system. Opacified blood flowing from the deep venous system through
Figure 10-37. Saccular abdominal aortic aneurysm. Most of the aneurysm is filled with thrombus.
Major complications of the procedure include contrastagent reaction, contrast-material –induced thrombophlebitis, and skin slough secondary to extravasation at the injection site. Skin slough is rare and usually occurs when skin viability is already compromised by chronic venous or arterial disease. Thrombophlebitis related to the procedure is usually a mild, self-limited phenomenon. The risk of dislodging emboli by venography is negligible. Overall, the risks of lower extremity venography are quite low.[198] The most accurate venographic sign of acute thrombosis is direct demonstration of thrombus as an intraluminal filling defect with a thin layer of contrast agent surrounding the clot (Fig. 10-38). Visualization of collaterals and nonfilling of veins are indirect signs suggesting thrombosis. In cases of chronic venous occlusive disease, collateral pathways, irregular vessel walls, and loss of valvular detail may be seen. Contrast venography is the most invasive of the techniques employed in the diagnosis of deep vein thrombosis, but it is 95% accurate and remains the standard by which other methods are judged. At our institution, the initial evaluation far suspected lower extremity deep venous thrombosis is performed with ultrasound using real-time venous compression technique.[199,200] For detection of thrombus above the knee, sensitivity has been reported at 89, 91, and 96%.[199,201,202] Color flow Doppler can facilitate visualization of the venous anatomy, especially in the calf, and may assist in identification of eccentric thrombus and partially recanalized thrombus.[203] Venography is performed when the ultrasound study is equivocal or suboptimal (usually due to massive edema or obesity) or if there is a high clinical suspicion for thrombosis limited to calf veins. Radionuclide venography can be performed by injection of isotope into a vein on the dorsum of the foot or 99mTc-labeled red blood cells can be injected in any peripheral vein and the venous system imaged “at equilibrium” as the circulating blood
Figure 10-38. Clot causing a serpentine intraluminal filling defect in the femoral vein of a patient with thrombophlebitis.
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effects are most often manifest by signs of ischemia if there is vessel occlusion, an enlarging mass in cases of false aneurysm (Fig. 10-39), and a thrill or bruit in an acquired arteriovenous fistula. An arteriovenous fistula may also cause local ischemia, cardiac failure, and swelling related to venous engorgement. Congenital arteriovenous malformations of the upper extremity may become very large and present with pain, ulceration, and hemorrhage. If they become too large to resect with limb salvage, embolization therapy may palliate symptoms or make surgery possible. Diagnostic evaluation of vasospastic and vasoocclusive diseases in the hand is difficult: the specific etiology may be elusive. Vasospasm may be a component of occlusive disease, may cause thrombosis, or may occur during angiography. Intraarterial administration of vasodilators may help distinguish vasospastic from occlusive disease. An overview of
Figure 10-39. Posttraumatic false aneurysm arising at the origin of the radial artery from the brachial artery (white arrow). This presented as an enlarging pulsatile mass following a stab wound to the antecubital fossa.
perforators to the superficial veins indicates incompetent perforators. The descending venogram is performed by puncture of the common femoral vein and placement of a 5 French catheter at the junction of the common femoral and external iliac veins. Injection of contrast material is made during a Valsalva maneuver, and valvular competence is graded from 0 to 4, with grade 0 indicating no reflux below the common femoral vein and grade 4 representing severe reflux into the calf veins or to the ankle.[209,210]
UPPER EXTREMITY ARTERIOGRAPHY Arteriography of the upper extremity is performed in most cases via retrograde catheterization from the femoral artery. Antegrade puncture of the brachial artery may be utilized when embolization therapy of lesions in the forearm or hand is performed. Upper extremity angiography is most often performed for evaluation of traumatic injuries, arteriovenous malformations or fistulas, vasospastic or vasoocclusive phenomena, and thoracic outlet syndrome. Acute traumatic injuries show a gamut of findings similar to vascular injuries elsewhere. Delayed or chronic traumatic
Figure 10-40. Thoracic outlet syndrome. Vascular compression related to an anomalous 1st rib with a pseudoarthrosis. (A) There is a slight poststenotic dilatation with the arm in neutral position. (B) There is marked compression when the arm is elevated.
Chapter 10. Angiography
the manifold causes of upper extremity and digital ischemia has been presented by Yao et al.[211] Thoracic outlet syndrome may be due to neural compression or vascular compromise, either arterial or venous. Arteriography is probably best limited to patients with a pulse deficit or bruit in the neutral position or in patients in whom a subclavian artery aneurysm or peripheral emboli are suspected. Demonstration of a vascular compression does not prove that it is the cause of symptoms. Many normal, asymptomatic patients will show compression in certain stress positions, and patients with severe outlet syndrome may have normal arteriograms. In our evaluation for thoracic outlet syndrome, whenever possible, we inject the subclavian artery in both the neutral position as well as in the position that recreates symptoms (Fig. 10-40). A more extensive technique has been described by Lang,[212] who also recommends radionuclide flow studies to decrease falsepositive results.
VENOGRAPHY OF THE UPPER EXTREMITY AND SUPERIOR VENA CAVA The technique of upper extremity venography is simple. A vein distal to the suspected site of occlusion is cannulated with a butterfly needle and 50 mL of contrast agent is injected by hand. Tourniquets are not used during injection. Elevation of the arm prior to the final film may give better opacification of the subclavian vein and superior vena cava.
Figure 10-41.
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Manual compression of the jugular vein during filming may improve opacification of the subclavian vein by decreasing filling defects from inflow of unopacified jugular venous return. If examination of the superior vena cava is desired, both upper extremities are injected simultaneously. Alternatively, the superior vena cava and subclavian veins can be visualized by retrograde or antegrade catheterization; however, this is seldom necessary. If a study performed for evaluation of the axillary and subclavian veins in the neutral position is negative, a second injection should be performed with the arm above the head to evaluate for positional compression by muscle, fibrous bands, or the first rib. Color Doppler ultrasonography provides accurate assessment of the axillary vein, but imaging of the adjacent proximal subclavian vein is dependent on body habitus. Patency of the subclavian vein or superior vena cava is evaluated indirectly by response to respiratory maneuvers.[213] Computed tomography with contrast agent infusion is a useful adjunct to image masses responsible for venous occlusion in some patients with superior vena cava or arm vein obstruction. It may also show collateral veins but generally does not demonstrate intraluminal clot as well as does venography. Upper extremity venous thrombosis is usually less symptomatic and more self-limited than venous thrombosis of the lower extremity. Etiologic factors include exertion, penetrating trauma, intravenous drug abuse, congenital venous web, central venous catheter placement, and hypercoagulable states (Fig. 10-41). Significant pulmonary embolism is not common from the upper extremity but is known to occur.[214,215]
Exertional thrombosis of the axillary vein in a young manual laborer.
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Figure 10-41a. Segmental carotid occlusion with collateral reconstitution. Ultrasound (not shown) demonstrated left common carotid occlusion. (A) Selective angiogram shows distal left common carotid occlusion. Prolonged filming showed no “string sign.” Note the carotid bulb calcification (arrow). (B) RAO right common carotid angiogram showing right external carotid collaterals (curved arrow) and left superior thyroid collateralization (open curved arrows) reconstituting the left internal carotid (arrowheads). (C) AP right common carotid angiogram (later phase than B) showing reconstituted left internal carotid (arrowheads). Note the carotid bulb calcification (arrow). Successful surgical endarterectomy repaired this short segment occlusion.
CAROTID-CEREBRAL ANGIOGRAPHY Angiography remains the most graphic method of demonstrating extracranial occlusive disease of the carotid and vertebral arteries as well as intracranial vascular abnormalities. The evaluation of extracranial occlusive disease usually begins with carotid duplex sonography (often with guidance from color Doppler imaging). This is an accurate screening technique for estimating carotid bifurcation stenosis,[216,217] but shadowing from calcified plaques can obscure areas of narrowing, and the carotid origins are not well imaged. The vertebral arteries are partially obscured by their bony canal. Magnetic resonance angiography of the carotid bifurcation has shown very good correlation with digital subtraction angiography[218] and is coming into increasing clinical use. The indications for angiography in carotid bifurcation disease, the interpretation of findings, and patient selection criteria for surgical carotid endartectomy (CEA) continue to be the subjects of debate. CEA remains the standard procedure for carotid stenosis, but many clinical trials of carotid stent-angioplasty are in progress. There is a trend to perform CEA based solely on results of carotid duplex imaging. Proponents of this approach argue that the major multicenter trials have differed in their methods for measuring carotid stenosis, that angiography may underestimate the degree of stenosis,
and that angiography seldom altered management even when intrathoracic and intracranial lesions were identified. The authors conclude that catheter angiography should be reserved for cases with atypical symptoms, suboptimal duplex imaging, or “uncommon vascular abnormalities.”[219] In practice, we frequently perform carotid angiography in such “atypical” cases (Fig. 10-41a). Some familiar examples would include patients with amaurosis fugax with ipsilateral internal carotid occlusion by duplex ultrasound, cerebral hemispheric symptoms contralateral to the “significant” carotid stenosis, or cases of suspected carotid dissection. Advocates of routine preoperative catheter angiography for carotid bifurcation disease cite a prospective study of 100 patients showing incidental concomitant nonatherosclerotic vascular pathology in 14 patients including 9 aneurysms, 2 arteriovenous malformations, 2 cases of subclavian steal, and 1 case of internal carotid fibromuscular dysplasia. In addition, 15 patients had “severe” intracranial atherosclerosis.[220] Another study advocating angiography found satisfactory concordance of ultrasound with angiography in vessels with mild stenoses (0–29%), but in vessels with 70– 99% stenosis, ultrasound was more likely to underestimate stenosis, identifying only 52% of patients with stenosis greater than 70% by angiography.[221] Intuitively, complex irregular or ulcerated lesions would be expected to be associated with a higher risk of stroke.
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However, in one blinded control-matched study, there was no significant difference in stroke risk by the various angiographic characteristics other than the degree of stenosis.[222] Ultrasound can classify carotid plaques as homogeneous, heterogeneous (complex), smooth, irregular, or ulcerated. These sonographic findings have been used as criteria for further imaging studies, either MRA or catheter angiography.[223,224] Carotid-cerebral angiography is almost exclusively performed via the femoral approach, with occasional need for the axillary or transbrachial route. Routinely, we begin with placement of a 5 French multiple-side-hole catheter at the aortic root and obtain an arch aortogram in the right posterior oblique projection. This is usually satisfactory for evaluation of the great vessel origins. Occasionally, a left posterior oblique view is necessary if the right common carotid and right subclavian origins are superimposed. We then proceed with selective catheterization of the common carotid arteries with a soft 5 French polyethylene end-hole catheter with a simple “hockey-stick” configuration. Tortuous vessels may require use of more complex or stiffer catheters such as recurved Simmons types or torqueable “headhunter” designs. Visualization of at least the proximal intracranial vessels is desirable when evaluating the extracranial occlusive disease. The presence of unsuspected distal lesions (e.g., at carotid siphon) may alter a treatment plan. Our technique includes three views of the neck with a field of view from above the supraclinoid carotid to below the carotid bifurcation while injecting in the common carotid artery. The results of the four major multicenter trials—the North American Symptomatic Carotid Surgery Trial (NASCET), the European Carotid Surgery Trial (ECST) and the two trials of asymptomatic patients, the Veterans Asymptomatic Carotid Trial (VACT) and the Asymptomatic Carotid Artery Surgery Trial (ACAS)—are discussed in depth elsewhere in this text. In summary, the degree of stenosis correlating with clinical benefit for CEA in each trial is as follows: NASCET, 70%; ECST, 70%; VACT, 50%; ACAS, 60%.[223]
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It is worth mention that the ECST method calculated stenoses at the carotid bulb using estimated full bulb diameter as the reference, while NASCET, VACT, and ACAS used the distal cervical internal carotid as the “normal” reference artery. If more of the intracranial vasculature or superficial temporal artery must be demonstrated, a second series of films can be obtained centered over the head. Although the efficacy of extracranial-intracranial bypass has been controversial,[225] important developments in cerebral revascularization techniques have enabled successful treatment of some cerebrovascular conditions, including vertebrobasilar insufficiency.[226] Specific techniques are discussed in other chapters, and a well-referenced review[227] outlines methods of cerebral revascularization. Vascular trauma is being recognized with increasing frequency as angiography is utilized more often to evaluate trauma patients. The usefulness of angiography in trauma is shown by one study where 42% of patients with clinical evidence of carotid injury had normal arteriograms and 20% of those with no clinical signs subsequently had positive studies.[228] Cranial CT is useful to rule out intraaxial and extraaxial hematomas as a cause of neurologic findings but cannot exclude associated vascular injury, and CT seldom demonstrates infarcts in the first several hours. Injury patterns in the head and neck are the same as elsewhere, but clinical presentations may differ. Blunt trauma to the neck may result in delayed carotid occlusion with a lucid interval of 1 –24 h before symptoms develop. The postulated mechanism is stretching of the vessel, with intimal injury or disruption of a preexistent atheromatous plaque. A wall hematoma or intimal flap then forms, with resultant occlusion or stenosis.[229] The carotid bifurcation and proximal internal carotid are most frequently involved. The vertebral artery is less commonly involved in trauma than the carotid, presumably because it is enclosed in a bony canal for most of its course. Arteriovenous fistulas in the head and neck offer a challenge to the interventional radiologist, especially when they are located in surgically difficult areas such as the cavernous sinus, vertebral canal, and high cervical carotid regions.[230]
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CHAPTER 11
Design of Clinical Trials for Evaluation of New Treatments and Methodology James M. Cook Robert W. Barnes Well-designed clinical trials have become the “gold standard” for the assessment of new treatments and comparison of alternate therapies in medicine. They have evolved as a joint discipline involving both medical and statistical science, and their rigorous methodology greatly strengthens the scientific foundation of clinical practice. This chapter is designed to review the background and rationale for clinical trials and to discuss principles of sound trial design, including analysis, interpretation, and presentation of results. Also, ethical issues are explored, costs and limitations are considered, and finally, some future trends in clinical trials and their applications are suggested.
medical practice and, in particular, reimbursement for physicians’ services.
TYPES OF CLINICAL TRIALS Clinical trials are only one form of research involving human subjects. Table 11-1 lists the conventional types of clinical studies. Clinical investigation may be classified as either observational or experimental.[4] In observational studies, the investigator does not control major variables but observes relationships among variables and possible causal relationships. Observational studies tend to be “hypothesis seeking,” and, although they often identify potential causal relationships or therapeutic efficacy,[5] the validation of such relationships often requires verification by experimental studies. Clinical trials may be defined as experiments utilizing human subjects in which two or more types of therapy are prospectively compared. They may be uncontrolled or controlled, and the latter may be either nonrandomized or randomized. Controlled trials compare the outcome of one treatment group (“experimental group,” usually a novel drug or procedure) with that of a second group given either traditional therapy or no treatment (control). Random assignment of patients to experimental and control groups assures that potentially important clinical variables (covariates), such as demographic characteristics and comorbidity, are similar between groups. Uncontrolled studies often rely on data from previous research to make assumptions about the value of the procedure or drug in question. In some cases, such use of historical controls may limit the validity of the study, since patients in prior times may not have shared similar diagnostic criteria or treatment regimens with contemporary patients.[4] However, ethical considerations may preclude a true control (i.e., no
RATIONALE Most physicians deliver health care based on practices reflecting their own uncontrolled clinical experience (induction) or on recommendations of authoritative figures (seduction).[1] Only a small proportion of medical practice is based on deduction derived from human experiments (clinical trials). Salzman[2] has indicated that only 10 –20% of health care technologies have been validated by prospective controlled studies. The objective appraisal of burgeoning medical technology, as well as certain traditional medical and surgical practices, is increasingly important in our current fiscal and legal climate. In addition, patients and third-party papers are increasingly concerned about prognosis and outcomes of health care, especially after interventional or surgical procedures.[3] However, as is discussed in the following sections, the bias of physicians and patients alike often leads to perpetuation of therapies that have minimal, if any, efficacy. Despite the complexity, ethical issues, and costs associated with clinical trials, such studies are becoming more commonplace and will probably be the basis for future
Hobson/Wilson/Veith: Vascular Surgery: Principles and Practice, Third Edition, Revised and Expanded DOI: 10.1081/0819-9-120024894 Copyright q 2004 by Marcel Dekker, Inc.
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Part One. Assessment of Vascular Disease Table 11-1. Types of Clinical Studies Observational studies Epidemiologic studies Cross-sectional studies Retrospective studies (case control) Prospective studies (cohort) Experimental studies Prospective studies (clinical trials) Uncontrolled studies Controlled studies Nonrandomized Randomized Source: Barnes RW.[18] Used by permission.
treatment) group in certain situations, so that some unrandomized or uncontrolled research must continue to be performed in medicine. It is the prospective, randomized clinical trial that represents the most rigorous clinical design to document the efficacy and risk of medical therapies. By controlling major variables and minimizing bias, the clinical trial fulfills the criteria of an experimental study, which permits “hypothesis testing” versus the “hypothesis searching” characteristic of observational studies. The combination of the size of a clinical trial and the degree to which confounding factors are controlled in a study determines, respectively, the precision and internal validity of the trial. These factors have led to an organizational strategy for clinical research termed population-adjusted clinical epidemiology (PACE), which is a mechanism for designing and implementing multicenter observational studies and randomized clinical trials.[6] Clinical trials may be classified as preventative or therapeutic. The former are further categorized as primary or secondary prophylaxis, depending upon whether the intent is to prevent disease occurrence or recurrence. The latter examine the course of active disease when modified by a particular drug or procedure. Therapeutic drug trials are frequently classified in three phases. Phase I trials are designed to study a relatively small number of patients to determine tolerated doses and side effects or risks of new agents (is it dangerous?). These trials may also reveal some potential therapeutic effects. Phase II trials are designed to estimate the efficacy of the new therapy compared with conventional treatment (does it work?). Phase III trials, which are randomized clinical trials, establish the effectiveness or therapeutic value of the new agent compared with controlled or conventional therapy (how well does it work compared with standard treatment?). Both the efficacy and effectiveness of potential therapies may be evaluated. Efficacy refers to the maximal potential or effect of a therapy and is often evaluated in so-called explanatory trials.[7] Effectiveness refers to the general effect or net benefit (risk/benefit) of a therapy and may be evaluated in a management trial.
TRIAL DESIGN AND ANALYSIS The design, performance, analysis, and reporting of a clinical trial should follow the principles of rigorous scientific methodology. These precepts have been well outlined by Salter.[8] First, the investigator should recognize an unsolved clinical problem and take time to think and reflect on it. Next, the scientific literature on the subject should be reviewed. Although such a review is usually integrated in a qualitative or narrative form, consideration should be given to a quantitative research integration by the method of metaanalysis, as reviewed by Thacker.[9] After this background work, one may ask an intelligent question and formulate a hypothesis. A research protocol is then developed with appropriate collaboration, particularly with a biostatistician. The investigator must then apply for and secure funding for the study. After approval by an appropriate institutional review board and/or human use committee, the formal investigation is conducted and data are collected, analyzed, and interpreted. Valid conclusions should be drawn that answer the original questions. Finally, the results are presented and published. The goal of clinical investigation should be the application of new knowledge to the care of patients. The time and effort devoted to planning and securing funding for a clinical trial is considerable. Powell et al.[10] have recommended the following steps to facilitate approval and funding of randomized clinical trials: (1) trials should address an important clinical problem; (2) potential trialists should be surveyed to establish the need for a trial; (3) a multidisciplinary team should be established early in the development phase; (4) professional bodies should endorse the trial; (5) measurement techniques should be validated before trial design is finalized; (6) the costs of multicenter trials should be spread across different funding bodies; (7) funding bodies should provide guidance to preparation of the application, including the need for socioeconomic evolution, the availability of funds, and the review process; and (8) nationally based ethical committees or review boards should be established to minimize the need for multiple local applications. Failure to properly design and analyze the results of a clinical trial will hinder its application to clinical practice. Hall et al.[11] reviewed the nature and methodologic standards of 364 trials reported in 10 prestigious journals between 1988 and 1994. They found that less than 50% of the trials reported unbiased assessment of outcome, provided a description of the randomization technique, or prospectively estimated the required sample size. Economic analyses were carried out in only 6.5% of the studies. Finally, only 2% of the trials measured outcome effects such as quality of life.
Design As previously noted, clinical trials are usually designed to compare two or more groups of patients subjected to a new medical or surgical procedure with groups receiving conventional therapy or no treatment (control or placebo). Such trials usually test the null hypothesis that there is no
Chapter 11.
Design of Clinical Trials for Evaluation of New Treatments and Methodology
significant difference between the two groups. The comparison of outcomes of treatment and control groups usually follows one of three standard design methods: parallel, crossover, or self-controlled. In parallel studies,[12] each patient receives one method of treatment; results are analyzed by comparison between treatment groups. In crossover studies,[13] each patient receives two (or more) treatments, and outcomes are analyzed by within-patient comparisons. In self-controlled studies,[13] each patient receives one treatment, and results are analyzed by within-patient comparison before and after administration of the therapy. An advantage of the latter two designs is that a separate control group need not be recruited, thus decreasing study size requirements. Also, since each patient is his or her own control, there are no covariate differences between experimental and control groups. If the null hypothesis is rejected, a significant difference is said to exist between the treatments. Such a difference may be the result of one of the following four circumstances: (1) a true effect of the new procedure, (2) differences between the treatment and control groups in some important covariate, (3) differences in handling and evaluating the treatment and control groups during the investigation, or (4) sampling variation or chance. The goal of sound trial design is to eliminate all but the first of these possible explanations. The other situations result in a type I error (false-positive study). The second and third circumstances are a result of bias in selection or management of patients in the trials. The fourth situation occurs as a result of random chance that the groups selected for comparison differed significantly but the larger populations from which they were chosen did not differ. The probability of this latter occurrence is set by the investigator by his choice of alpha, as discussed later. Bias refers to systematic error introduced into sampling that selects or encourages one outcome over others. Sackett has described a large number of sampling and measurement biases that must be controlled in designing a clinical trial.[14] Selection or sampling bias includes differences in prognostic factors or covariates of patients in treatment and control groups and is generally controlled by the process of randomization, as discussed below. Measurement bias is minimized by blinding or masking both subjects and observers in the study whose conscious or often unconscious bias may otherwise affect the interpretation of the outcome variables in the study (particularly subjective, decisionrelated endpoints). The combination of randomization and masking leads to internal validity or believability of the study. Careful, unbiased patient selection and treatment compliance improves the external validity or generalizability of the study (clinical relevance and utility). A clinical trial may accept the null hypothesis that there is no significant difference between the treatment and control groups. Although such an outcome may be true, a “falsenegative” trial (type II error) may result from an insignificant sample size. The importance of designing a trial with an adequate sample size to prevent such errors will be discussed below. Some clinical trials are designed to demonstrate the equivalence of two treatments. An equivalence trial may be of value if the standard treatment has been documented to be
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efficacious and the innovative treatment is easier to use, is associated with fewer side effects, or is less costly.[15]
Patient Selection The patient sample, as well as the larger population from which the sample is selected, must be carefully defined. Only by clarifying the characteristics of the patient sample can one extrapolate the results of the study to the larger patient population. Patient selection criteria as well as exclusion criteria must be stated clearly. A register of patients screened and rejected from the study should be maintained to permit subsequent documentation that selection bias has been minimized or eliminated. The period of patient recruitment or enrollment should be stated clearly, and withdrawals prompted by either the investigator or the patient should be described and followed if at all possible. Safeguards for the patient, including informed consent, the right to withdraw, and assurance of privacy, must be delineated.[16] If the study involves an unusual disease or large numbers of patients are required to detect small but important differences in therapeutic efficacy, patients may be recruited from multiple centers. Although this increases the logistical complexity and potential for selection and measurement bias, the results of a carefully performed multicenter study may often be more readily applied to the general population than those of a study from a single institution. Several alternative trial formats have been proposed to enhance patient recruitment and to minimize patient dropouts by taking into account the strong preferences of patients eligible for enrolment.[17] These alternatives include partly randomized trials in which patients without strong preferences are randomized and opinionated patients are assigned the treatment of their choice, with separate analysis of the latter group as a prospective cohort study. Other options include varying the randomizing ratio depending upon patient attitudes as influenced by evidence accumulating during the trial. Finally, patients may be allowed to participate in the randomizing process, such as picking a sealed envelope. A final feature of successful patient recruitment is the ability to “market” clinical trials to clinicians, as emphasized by Macbeth and Stephens.[18] Key features of making a trial attractive to clinicians include (1) addressing an important or interesting clinical question, (2) facilitating patient entry, and (3) simplifying data collection. Strategies must be developed to reduce demands on the clinician, such as time, effort, or increased resources necessary to carry out a study. Finally, rewards for clinician participation in clinical trials should be developed, which may include tangible rewards (financial, resources, travel), academic or professional esteem, group membership, or satisfaction of intellectual curiosity (usually valued in that order).
Therapeutic Regimens The treatment and control groups must be well defined. If “conventional” treatment is used as a control, the exact characteristics of such therapy should be stated. The strategy of dealing with changes in conventional treatment or cointerventions should be anticipated. Ancillary treatments
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or management should be clarified. Placebo treatment, if used, must be described. Finally, the timing of treatments and drug washout periods (in crossover studies) should be stated.[19]
Randomization To avoid bias in treatment assignment and balance covariates between groups, patients are randomly allocated to treatment and control groups.[20] Although fixed randomization (i.e., allocation of patients in a strict order determined precisely by chance alone) is ideal, adjustment procedures are often employed to ensure balance of certain critical prognostic factors. Such adjustments, when carried out before randomization, usually take the form of stratification of important covariates within both treatment and control groups. Blocking to ensure roughly equal numbers of patients in each of these stratified subgroups may also be used. For multicenter trials, it is often wise to stratify by institution to prevent unbalancing if a given institution must be dropped for any reason. The number of stratified groups should be kept to a minimum (usually no more than two to five) to avoid problems with statistical analysis of groups with inadequate sample size. Finally, allocation concealment from both investigator and patient is imperative, because of the bias that may be introduced if deciphering of assignment sequences occurs before ramdomization (a not infrequent occurrence). As Schulz[21] has stated, “randomized controlled trials appear to annoy human nature—if properly conducted, indeed they should.”
Blinding It is clear that randomization alone will not prevent observer bias. This is minimized by masking or blinding participants in the study so that the treatment received by an individual patient is not known. In a review of 145 publications of treatment of acute myocardial infarction, Chalmers et al.[22] demonstrated that positive study results were found in 58.1% of 43 reports of nonrandomized studies, 24.4% of unblinded randomized studies, and only 8.8% of blinded randomized trials. Masking may be single-blind (the patient), double-blind (the patient and physician), or triple-blind (the patient, physician, and those evaluating outcomes, including statisticians). The randomization process should also be masked (quadruple blinding). Although blinding of patients and investigators may not be possible in some studies, particularly in comparison of medical and surgical therapy, observer and statistical blinding may still be appropriate.
Statistical Design Statistical design refers to a series of measurements that should be undertaken before and during a study to ensure statistical validity at the conclusion of the investigation. Because many statistical tests are performed after data have been generated, many clinicians falsely assume that such statistical interventions are most applicable at the conclusion of a study.
One of the most important design considerations is an estimation of the required sample size to achieve the objective of the study.[23] Certain steps are important in calculating sample size. First, the null hypothesis to be tested should be specified clearly, including a precise definition of the outcomes or endpoints of interest. Second, the investigator should decide what statistical tests will be used to accept or reject the null hypothesis and with what probability a positive result might be due to chance (alpha level of a false-positive, type I error). Commonly the level chosen is 0.05. The probability of accepting the null hypothesis (detecting no difference when none exists) is I-alpha and is analogous to the specificity of a diagnostic test. Third, the investigator should specify an alternative hypothesis representing a clinically important difference between treatments that, if the hypothesis is valid, should be detected. The probability of the study not detecting such a difference (beta or type II error) is often accepted at a level of 0.20, but for large trials or studies in which detection of a difference is very important, a level of 0.10 may be chosen. The probability of detecting a difference when one exists (a true positive, or I-beta) is termed the power of a study and is analogous to the sensitivity of a diagnostic test. The sample size of the study should be calculated to ensure adequate power, usually . 0.80. Thus the factors influencing beta and power include the alpha level chosen, the size of difference that treatment makes, the rate events among control patients, and, most important, the number of patients in the trial.[23] The importance of adequate sample size was illustrated by Freiman et al.,[24] who reviewed 71 negative randomized clinical trials. Of these, 67 had a risk of greater than 10% of missing a 25% therapeutic benefit, and 50 had a similar risk of missing a 50% therapeutic benefit. In general the investigator should anticipate screening at least twice the number of patients required for the projected sample size.[25] The number will depend on the entry requirements for the study. Relatively restrictive entry requirements may lead to a more homogeneous study population and, potentially, a greater probability for a positive outcome of a study of a given size. However, such rigid criteria may lead to a large number of screened patients and a limited generalizability to the general patient population. As a group, randomized clinical trials tend to be fairly specific (a low incidence of false-positive results), largely because of the choice of alpha level. They are thus useful to document efficacy of therapy (hypothesis testing). On the other hand, clinical trials often are relatively insensitive (high probability of false-negative results), largely because of inadequate sample size or power. Retrospective or historical control trials are inherently more sensitive than prospective, randomized, controlled trials and are thus useful for screening (hypothesis seeking).[26] However, because of their relatively low specificity, the results of such retrospective studies should be validated when possible by a prospective, randomized controlled trial. Other items of importance in statistical design[16] include a tabular listing of known prognostic factors (covariates ) and their distribution between treatment and control groups. Tests of blinding of both physicians and patients are advisable to determine whether either participant recognized the therapy
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employed. Tests of patient compliance should be specified, such as pill counts, blood or urine levels, or other tests of biologic equivalence. Despite the importance of the aforementioned statistical design of clinical trials, there are certain elements in the statistical analysis of the data generated by a trial that are a reflection of quality control.[16] The statistical significance of differences in major endpoints should present both the test statistic and the observed probability level so that others may verify the statistical conclusion. For negative study results, a discussion of the probability of a type II error should be made, which may include estimating a posterior beta (i.e., determining the statistical power of the study). Statistical inference should be based on appropriate use of confidence limits, life-table or time-series analysis, regression analysis, or correlations. It must be clear how withdrawals or dropouts are handled. It is usually preferable to analyze them in the group to which they were originally assigned (intent-totreat analysis).[27] Ignoring or eliminating such withdrawals is not acceptable. Considering crossover patients in the new treatment arm of the study may not be statistically valid, although it seems logically appealing.[27] Retrospective subgroup analysis (post hoc) should be performed with caution. Such “data dredging” or hypothesisseeking approaches are associated with bias, and the probability of finding significant differences by chance alone increases considerably.[28] Such analysis may be useful to identify possible causal relationships for future study, but inferences should not be drawn or confused with the original aims of the study.[29] Techniques to blind the statistician as well as the data monitoring committee should be encouraged.[16] Finally, repeated significance testing (“multiple looks”) prior to study termination increases the probability that a falsely significant difference will be found.[30] Techniques of sequential design or other methods to reduce the risk of premature termination of a trial should be stated. An excellent summary of common statistical problems and recommendations for avoiding distortions in clinical trials have been reported by Pocock et al.[31]
Presentation of Results The reporting of results of a study should relate to and reflect the original specific objectives of the study.[16] All endpoints should be tabulated, and the timing of outcomes and withdrawals should be presented so that others can reconstruct survival curves for independent validation of the statistical conclusions. Side effects should be reported, analyzed, and discussed. The completeness of reporting trial results will influence the willingness of physicians to incorporate the recommendations into their practice, e.g., from knowledge of relative risk reduction as opposed to absolute risk reduction.[32] Proper design and analysis of a clinical trial should establish[32a] its internal validity or believability and its external validity or clinical applicability (generalizability). Sackett[1] has suggested that a sound clinical trial should answer the following questions in the affirmative: (1) Is patient assignment randomized? (2) Are all outcomes
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reported? (3) Are the patients recognizably similar to one’s own? (4) Are both clinical and statistical significance considered? (5) Is the therapeutic maneuver feasible? (6) Are all patients accounted for? Table 11-2 lists the important elements of design and analysis that should be incorporated into a sound randomized clinical trial.[16] DerSimonian et al.[33] have reviewed 67 articles in leading scientific journals and found that in only 56% were design and analysis methodology clearly reported. In another 10% such design features were ambiguously reported, and in 34% such methodology was lacking. In order to assure greater rigor and uniformity of design, analysis, and reporting of randomized clinical trials, several
Table 11-2.
Design for Clinical Trials
Patient sample/data set Population sampled Selection criteria Exclusion criteria Rejection log Enrollment period Withdrawals, dropouts Patient safeguards (informed consent, privacy) Therapeutic regimens Treatment regimens Control, placebo Cointervention Ancillary management Randomization Complete (fixed) method Stratification/blocking Adaptive allocation Covariate adjustment Sequential design Masking (blinding) Randomization Patients/subject Physician Results (statistical blinding) Statistical design (testing, quality control) Sample size: a, b, power Pretreatment (confounding, covariate) variables Tests of blinding Compliance Biologic equivalent Statistical analysis Significance of major endpoints, adverse effects Posterior b estimates (negative trials) Statistical inference Withdrawals (intent to treat, endpoint) Retrospective (subgroup) analysis Multiple analysis, sequential designs, stopping rules Presentation of results Dates of study Prerandomization data analysis Tabulation of endpoints Timing of events Source: Chalmers TC, et al.[16] Used with permission.
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recommendations for standardized reporting practices have been published recently.[34 – 38] The reader is referred to these reports for current standards of reporting clinical trial results.
ETHICS Research involving human subjects inevitably raises ethical questions that profoundly influence the design and conduct of clinical trials.[39] A number of moral questions of clinical research include those relating to experimental design, funding sources, subject recruitment and selection, informed consent, experimental procedures, patient compensation, and subject injury or harm. The latter concern of subject risk is the central moral problem of clinical research. Clinical trials require a sacrifice of individualized treatment, although recent innovations in research design permit randomized trials in individual patients (“n of 1” trials),[40 – 42] and some novel designs allow a choice of treatment by patient or physician. Also, certain adaptive procedures may be useful to maximize the number of patients allocated to superior treatment.[43] The freedom to withdraw from a study must be ensured, but premature withdrawal from or termination of a study raises ethical questions, and consent should be obtained for such decisions. The role of informed consent for the conduct of human investigation has led to a wide spectrum of ethical opinions.[44] The concept of consent arises from an ethical principle: volenti non fit injuria (he who consents cannot receive an injury).[45] Kanoti[46] has defined the following ideal ethical imperatives of clinical research: freedom (patient and investigator), beneficence (benefit to patient or society), nonmalfeasance (no physical, social, psychologic, or spiritual risk), justice (no financial ruin), and confidentiality (no public scrutiny). Ethical issues in clinical trials are best addressed if the principles of research responsibility are followed as emphasized by Little:[47] realism with avoidance of undue protocol rigidity, accountability by the investigator as well as the review bodies, and purposiveness with research directed to a common good. Unfortunately, the ethical principles embodied in the doctor-patient relationship constitute the leading reason for resistance on the part to physicians to entering patients in clinical trials.[48] Despite the desire of most physicians to provide ethical care based on their own experience, Miller and Perry[49] have made the plea that “the obligation to replace ignorance with knowledge must have priority over the obligation to administer a suspected therapy.” Physicians participating in clinical trials enter into an ethical dilemma in their role as scientists during the investigation.[50] The physician is expected to be a practicing, empathetic professional whose primary concern is the patient. The scientist is concerned with answering questions that may be of benefit to humanity in general. Thus, the physicianscientist encounters conflicting demands between rightsbased and utilitarian moral theories. Passamani[51] responds to this ethical dilemma by noting that “proved therapies involve a consensus of the competent medical community that the
data in hand justify using a treatment in a given disorder. It is this consensus that defies an ethical boundary.” In addition to participating physician and patients, those who govern clinical trials also face ethical dilemmas. Sniderman[52] has recommended that the governance of clinical trials should be modified to permit a greater role of continuing monitoring of the local ethics committee (Institutional Review Board) not only to approve the protocol but also to assure patient safety, to inform patients of successes or failure of similar trials, to be informed of the whole trial, and to communicate with other safety-monitoring committees. A final ethical dilemma has emerged in applying the results of population-based clinical trials to the care of individual patients. This current era of “evidence-based medicine”[53] emphasizes the role of the physician in objectively interpreting the results of a hierarchy of published studies, often randomized clinical trials. There is an ethical danger of choosing care options based upon statistical significance or clinical significance, while overlooking the personal significance of the other partner in the decision making—the patient. Sweeney et al.[54] have emphasized that the practitioner’s role should be to evaluate the research evidence, to explore the patient’s philosophy of health, and to deliver an opinion based on a synthesis of this information. The patient’s role should be to participate actively in his or her health care decisions based upon personal, family, social, and demographic factors. As McCormack[55] has stated: “It is as important to know the patient who has the disease as it is the disease which the patient has.”
COSTS AND LIMITATIONS One of the most frequently quoted reasons for not carrying out a major clinical trial is the cost of such research. Many individuals fail to consider the cost of treating disease, particularly with therapy that has not been validated by appropriate clinical investigation.[56] The cost of clinical trials will vary depending on the type of trial. Although multicenter trials are usually more expensive than single-center trials, Meinert[57] has shown that the median cost per patient studied may actually be lower in multicenter trials. Treatment trials have the merits of providing the greatest initial benefit and are usually better accepted by patient and physician alike.[58] However, such trials suffer the limitations of potential changes in or obsolescence of treatment and the greater cost of treating disease. Prevention trials have the disadvantage of following relatively high-risk patients over a long latent period and often require a change in habits for possibly marginal benefits. However, preventive trials, despite great expense, ultimately offer the greatest reduction in the cost of disease. The sources of funding for clinical trials include the government through grants and contracts, industry, foundations or public funds, academic research institutions, and third-party sources.[57] The National Institutes of Health (NIH) remain the principal source of support for major clinical trials in this country. Despite increasing fiscal restraints, NIH support has increased steadily over the years.
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Design of Clinical Trials for Evaluation of New Treatments and Methodology
Not all medical therapy requires validation by randomized controlled trial. Clinical trials are inappropriate for treatment that favorably influences an otherwise rapidly fatal disease, a rare disease, or a disease that otherwise has a uniform outcome (no variance).[18] Although Spodick[59] has urged that surgical therapy be subjected to randomized clinical trials at the outset of their development, such procedures require a period of technical evolution for their perfection, unlike drugs.[60] Furthermore, operations are subject to variability of skill of different surgeons, which complicates the outcome of surgical trials. Finally, most operations are irreversible, unlike medical therapies, thus precluding crossover or self-controlled studies. Nevertheless, surgical procedures are being subjected increasingly to randomized controlled trials.[61 – 64]
ECONOMIC ANALYSIS Public, governmental, and professional concerns about escalating costs of health care have led to widespread efforts to carry out a variety of economic analyses of medical practice.[65] Economic analysis is based on the principle that choices must be made between alternative uses of resources, and these choices must consider both cost and outcome, in as much as there are insufficient resources to provide all possible medical care that is available or desired by patients. Economic analysis includes different types of analysis, different points of view, and different types of cost.[65] From the perspective of types of analysis, three commonly reported methods include cost-identification, cost-effectiveness, and cost-benefit analysis. Cost-identification analysis is most commonly used by physicians and describes the cost for services provided. Frequently, the true cost of services is difficult to identify, because charges are more readily available to physicians, patients, and third parties. Costidentification analysis, also called minimization analysis, assumes that outcomes are equivalent, because the method does not evaluate what the expenditures bring in terms of health care outcomes. This method applies only to services that provide lower cost and better or equal outcomes. Costbenefit analysis involves making explicit decisions about whether the cost is worth the benefit by measuring both in the same units, such as units of currency. This analysis may calculate the net benefit or net cost by subtracting cost from benefit or, alternatively, determining the ratio of benefits to cost. Cost-benefit analysis requires societal decisions as to what would be done with monies saved by choosing the more cost-beneficial treatment. Cost-effectiveness analysis has been the method most frequently used by health care economists. This technique measures the net cost of providing service (the expenditures minus the savings) as well as the outcomes achieved. Outcomes are reported as a single unit of measurement, such as year of life saved, or as several outcomes on a common scale (utility analysis). The latter often involves calculation of quality-adjusted life-years (QALYs), and such calculations may be termed cost-utility analysis. Economic analysis may be viewed from a number of perspectives, including the payer, the provider, the patient,
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and society at large. Payer costs are the charges for health care allowed by the payer. Provider costs involve the true costs of providing the service and, as mentioned previously, are difficult to establish without detailed analysis, because charges are more frequently evident. Charges measure cost only to those who pay those charges. Charges do not differentiate between fixed and variable costs. Patient costs include the amount paid for service that is not covered by insurance plus other costs incurred by the illness or treatment, such as time missed from work. Societal costs involve the net cost of all different societal components including the patient’s lost productivity and the expenses incurred in providing and receiving the medical care. Societal costs may be viewed as “opportunity costs” resulting from giving up the opportunity to use the resources for other purposes. Medical costs include fixed and variable costs. Fixed costs are those that would not be affected by a change in number of services provided (building maintenance), whereas variable costs are those affected by the volume of services (supplies). Costs may be defined as the consumption of a resource that otherwise could have been used for another purpose, i.e., opportunity cost. Costs may be direct, indirect, or intangible. Direct costs are those transactions or expenditures for medical or nonmedical products and services. Direct medical costs include hospitalization, drugs, physician fees, laboratory tests, radiological procedures, rehabilitation, durable medical equipment, and long-term care. Direct nonmedical costs include food, transportation, lodging, family care, home aides, and clothing for the patient as well as transportation and lodging expenditures by the family. Costs must be corrected for inflation and be discounted to the present in order to consider the effect of time. Future outcomes are often discounted at the same rate as the interest rate, which may be termed the “social rate of time preference.” Indirect costs are those that occur because of loss of life or livelihood (mortality and morbidity). Indirect costs may be calculated by the “human capital approach” or the “willingness-to-pay approach.” The human capital approach refers to the future earnings, in today’s value, that could have been realized had the individual not become prematurely disabled or died. The approach is beset with problems of devaluing individuals with lower income and sensitivity to the rate at which future dollars are handled. The willingness-to-pay approach applies market economy to the value of human life, or what someone would pay to avoid an adverse event. This approach suffers from difficulty in estimating willingness to pay for hypothetical outcomes, sensitivity to the ability to pay, the likelihood of the event, and the likelihood that payment will influence the outcome. Intangible costs include the costs of pain, suffering, grief, and other nonfinancial outcomes of illness and health care. These costs are often incorporated into outcome measures such as QALYs. Cost-effectiveness analysis is often calculated in terms of marginal or incremental effects. Marginal cost-effectiveness refers to the additional cost and effectiveness that can be obtained from one additional unit of service, such as an extra day in the hospital. Incremental cost-effectiveness reflects the additional cost and effectiveness resulting when one option is compared to the next most intensive or expensive alternative,
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such as outpatient surgery versus short-stay surgery (extra units of outcomes per extra dollar spent). Economic analyses also involve sensitivity analysis and decision analysis. Sensitivity analysis identifies the degree to which uncertainty or bias influences the economic results of clinical decisions. These results are calculated separately for different values of the various components of a study. Decision analysis is a method of determining the sensitivity of a decision to the probabilities of various outcomes, their economic effects, and the cost of health care interventions. Cost-effectiveness analysis has become an influential factor in health care policy decisions,[66 – 68] in assessing of the value of clinical trials,[69] and in the evaluation of the effectiveness of surgery,[70] including the cost-effectiveness of various vascular surgical procedures.[71 – 73] However, there are a number of limitations to economic analyses that must be recognized by all parties involved in health care delivery. First, there are a number of misconceptions about the implications of terminology:[74] cost-effective does not necessarily mean cost saving or more effective therapy. Rather, it implies an additional benefit that is worth the possible additional cost, assuming these caveats: (1) less costly and at least as effective; (2) more effective and more costly, with the additional benefit worth the cost; or (3) less effective and less costly, the added benefit not worth the extra cost. Second, clinical trials often fail to substantiate the costs, particularly start-up costs and general overhead.[75] Third, the assessment of outcomes of cost-effectiveness studies often fail to take into account the reasons for given outcomes, such as risk adjustment[76] of patient characteristics that influence the results of health interventions. Fourth, controversy exists about whether clinical trials with concurrent economic analyses should be blinded.[77] Fifth, both professionals and
the lay public often place a greater importance on equity than on cost-effectiveness analysis when making choices about health care priorities in the setting of budget constraints.[78] Finally, and perhaps most important, economic analyses applied at the bedside may disrupt the traditional physicianpatient fiduciary relationship.[79]
FUTURE TRENDS The aforementioned review suggests that clinical trials are serving an increasing role in validating medical and surgical therapies. Nevertheless, considerable resistance to clinical trials exists on the part of physicians and patients alike. Bias, ethics, and costs contribute to this problem. However, education of all parties—physicians, patients, public, and media—will be instrumental in increasing their awareness and acceptance of the value of clinical trials in improving medical practice. Increased participation by physicians in clinical trials is likely, in both academic centers and individual practices. Facilitation of such participation may arise from innovation in trial design, such as increasing use of self-controlled studies or randomized trials in the individual patient. Finally, there may be increasing pressure by various funding agencies to pursue clinical trials in order to validate costly medical and surgical therapies and technologies in an attempt to control spiraling health care costs. Indeed, the future of physician reimbursement may well rest on practicing “validated” medicine. Only by becoming knowledgeable about the rationale and principles of sound clinical trial design can physicians and patients participate meaningfully in this process.
REFERENCES 1. Sackett, D.L. Rational Therapy in the Neurosciences: The Role of the Randomized Trial. Stroke 1986, 17, 1323. 2. Salzman, E.W. Is Surgery Worthwhile? Arch. Surg. 1985, 120, 771. 3. Mahoney, J.E.; Wright, J.G.; McLeod, R.S.; Lossing, A. Prognosis in Surgery: Why They Are Determined, Strategies for Making Them, and Study Design. Surgery 1996, 120, 563. 4. Bourke, G.J.; Daly, L.E.; McGilvray, J., (Eds.) Interpretation and Uses of Medical Statistics; 3rd Ed. Blackwell Scientific Publications: Oxford, 1985. 5. Hu, X.; Wright, J.G.; McLeod, R.S.; Lossing, A.; Walters, B.C. Observational Studies as Alternatives to Randomized Clinical Trials in Surgical Clinical Research. Surgery 1996, 119, 473. 6. Engles, E.A.; Spitz, M.R. PACE-Setting Research. Lancet 1997, 350, 677. 7. Sackett, D.L.; Gent, M. Controversy in Counting and Attributing Events in Clinical Trials. N. Engl. J. Med. 1979, 301, 1410. 8. Salter, R.B. The Philosophy and Nature of Surgical Research. Can. J. Surg. 1980, 23, 349.
9. Thacker, S.B. Meta-Analysis. J. Am. Med. Assoc. 1988, 259, 1685. 10. Powell, J.T.; Greenhalgh, R.M.; Ruckley, C.V.; Fowkes, F.G.R. Prologue to a Surgical Trial. Lancet 1993, 342, 1473. 11. Hall, J.C.; Mills, B.; Nguyen, H.; Hall, J.L. Methodologic Standards in Surgical Trials. Surgery 1996, 119, 466. 12. Lavori, P.W.; Louis, T.A.; Bailar, J.C.; Polansky, M. Designs for Experiments: Parallel Comparisons of Treatment. N. Engl. J. Med. 1983, 309, 1291. 13. Louis, T.A.; Lavori, P.W.; Bailar, J.C.; Polansky, M. Crossover and Self-controlled Designs in Clinical Research. N. Engl. J. Med. 1984, 310, 24. 14. Sackett, D.L. Bias in Analytic Research. J. Chronic. Dis. 1979, 32, 51. 15. Ware, J.H.; Antman, E.M. Equivalence Trials. N. Engl. J. Med. 1997, 337, 1159. 16. Chalmers, T.C.; Smith, H.; Blackburn, B. et al. A Method for Assessing the Quality of a Randomized Controlled Trial. Control. Clin Trials 1981, 2, 31. 17. Silverman, W.A. Patients’ Preferences and Randomized Trials. Lancet 1994, 343, 1586.
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Design of Clinical Trials for Evaluation of New Treatments and Methodology
Macbeth, F.; Stephens, R. Marketing Clinical Trials. Lancet 1996, 348, 111. Barnes, R.W. Understanding Investigative Clinical Trials. J. Vasc. Surg. 1989, 9, 609. Byar, D.P.; Simon, R.M.; Friedwald, W.T. et al. Randomized Clinical Trials. N. Engl. J. Med. 1976, 295, 74. Schulz, K.F. Subverting Randomization in Controlled Trials. J. Am. Med. Assoc. 1995, 274, 1456. Chalmers, T.C.; Celano, P.; Sacks, H.S.; Smith, H. Bias Treatment Assignment in Controlled Clinical Trials. N. Engl. J. Med. 1983, 309, 1358. Colton, T. Statistics in Medicine; 1st Ed. Little, Brown: Boston, 1974. Freiman, J.; Chalmers, T.C.; Smith, H.; Kuebler, R.R. The Importance of Beta, the Type II Error and Sample Size in the Design and Interpretation of the Randomized Controlled Trial. N. Engl. J. Med. 1978, 299, 690. Charlson, M.E.; Horwitz, R.I. Applying Results of Randomized Trials to Clinical Practice: Impact of Losses Before Randomization. Br. Med. J. 1984, 289, 1281. Sacks, H.S.; Chalmers, T.C.; Smith, H. Sensitivity and Specificity of Clinical Trials. Arch. Intern. Med. 1983, 143, 753. Feinstein, A.R. Problems, Pitfalls, and Opportunities in Long-Term Randomized Trials. Arzneim.-Forsch./Drug Res. 1989, 39, 980. Smith, D.G.; Clemens, J.; Crede, W. et al. Impact of Multiple Comparisons in Randomized Clinical Trials. Am. J. Med. 1987, 83, 545. Yusuf, S.; Wittes, J.; Probstfield, J.; Tyroler, H.A. Analysis and Interpretation of Treatment Effects in Subgroups of Patients in Randomized Clinical Trials. J. Am. Med. Assoc. 1991, 266, 93. De Klerk, N.H. Repeated Warnings Re Repeated Measures. Aust. N Z. J. Med. 1986, 16, 637. Pocock, S.J.; Hughes, M.D.; Lee, R.J. Statistical Problems in the Reporting of Clinical Trials. N. Engl. J. Med. 1987, 317, 426. Bobbio, M.; Demichelis, B.; Giustetto, G. Completeness of Reporting Trials Results: Effect on Physicians’ Willingness to Prescribe. Lancet 1994, 343, 1209. Rothwell, P.M. Can Overall Results of Clinical Trials Be Applied to All Patients? Lancet 1995, 345, 1616. DerSimonian, R.; Charette, J.; McPeek, B.; Mosteller, F. Reporting on Methods in Clinical Trials. N. Engl. J. Med. 1982, 306, 1332. The Standards of Reporting Trials Group; A Proposal for Structured Reporting of Randomized Controlled Trials. J. Am. Med. Assoc. 1994, 272, 1926. Begg, C.; Cho, M.; Eastwood, S.; Horton, R.; Moher, D.; Olkin, I.; Pitkin, R.; Rennie, D.; Schulz, K.F.; Simel, D.; Stroup, D.F. Improving the Quality of Reporting of Randomized Controlled Trials. The CONSORT Statement. J. Am. Med. Assoc. 1996, 276, 637. Schulz, K.F. Randomized Trials, Human Nature, and Reporting Guidelines. Lancet 1996, 348, 596. Working Group on Recommendations for Reporting of Clinical Trials in the Biomedical Literature; Call for Comments on a Proposal to Improve Reporting of Clinical Trials in the Biomedical Literature. Ann. Intern. Med. 1994, 121, 894.
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63. McLeod, R.S.; Wright, J.G.; Solomon, J.M.; Hu, X.; Walters, B.C. Randomized Controlled Trials in Surgery: Issues and Problems. Surgery 1996, 119, 483. 64. Howard, G.; Chambless, L.E.; Kronmal, R.A. Assessing Differences in Clinical Trials Comparing Surgical vs Nonsurgical Therapy. Using Common (Statistical) Sense. J. Am. Med. Assoc. 1997, 278, 1432. 65. Eisenberg, J.M. Clinical Economics. A Guide to the Economic Analysis of Clinical Practices. J. Am. Med. Assoc. 1989, 262, 2879. 66. Russell, L.B.; Gold, M.R.; Siegel, J.E.; Daniels, N.; Weinstein, M.C. The Role of Cost-Effectiveness Analysis in Health and Medicine. J. Am. Med. Assoc. 1996, 276, 1172. 67. Weinstein, M.C.; Siegel, J.E.; Gold, M.R.; Kamlet, M.S.; Russell, L.B. Recommendations of the Panel on CostEffectiveness in Health and Medicine. J. Am. Med. Assoc. 1996, 276, 1253. 68. Siegel, J.E.; Weinstein, M.C.; Russell, L.B.; Gold, M.R. Recommendations for Reporting Cost-Effectiveness Analyses. J. Am. Med. Assoc. 1996, 276, 1339. 69. Detsky, A.S. Are Clinical Trials a Cost-Effective Investment? J. Am. Med. Assoc. 1989, 262, 1795. 70. Finlayson, S.R.G.; Birkmeyer, J.D. Cost-Effectiveness Analysis in Surgery. Surgery 1998, 123, 151. 71. Katz, D.A.; Cronenwett, J.L. The Cost-Effectiveness of Early Surgery Versus Watchful Waiting in the Management of Small Abdominal Aortic Aneurysms. J. Vasc. Surg. 1994, 19, 980.
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CHAPTER 12
Outcomes Assessment for the Vascular Surgeon John V. White “If the function of a hospital were to kill the sick, statistical comparisons of this nature would be (sufficient).” Florence Nightingale, 1863
The value of these interventions, then, lies in the improvement in overall well-being and productivity derived by the patient. Clinical outcomes parameters do not adequately describe patient benefit from vascular intervention.
The ultimate objective of health care is improvement in the quality of a patient’s life. Though simple in concept, the achievement of this goal is often difficult to substantiate. Despite health care costs exceeding $988 billion in 1996, the United States ranks only 9th in life expectancy and even lower for infant mortality and other health parameters.[1,2] There is little information available regarding the improvement in quality of life. Reflexively, the government has taken steps to assess the quality of health care in the United States. Congress, in 1989, created the Agency for Health Care Policy and Research and charged it with the responsibility to conduct research to identify effective health care and develop clinical guidelines based upon the findings. The government emphasizes that the outcomes of health care should be evaluated on the basis of factors which directly affect the patient, such as pain and functional ability, rather than on intermediate clinical measures, such as laboratory tests.[3] Ultimately, the rising cost of health care in the United States will mandate that therapies which fail to directly increase the well-being and productivity of patients be restricted or eliminated, regardless of technical outcome. This mandate will have a major impact upon the treatment of patients with vascular disease. The vast majority of vascular interventions are performed for palliation or a reduction in immediate mortality. These therapeutic endeavors do not clearly prolong life, and few are directed toward achieving a cure of the underlying cause of disease. Aneurysm resection does not alter the metabolic processes which destroy the structural integrity of the aortic wall. This has been demonstrated for both open surgery and in recent aortic stent-graft trials in which the proximal neck has continued to grow despite aneurysm resection.[4,5] Similarly, endarterectomy and bypass procedures do little to directly control the progression of atherosclerosis. The patient remains susceptible to recurrent disease after vascular surgery.[6,7] Life expectancy of patients with lower extremity ischemia is severely reduced despite revascularization.[8,9]
THE IMPACT OF THE DISEASE AND ITS TREATMENT Evaluation of the effects of vascular surgical intervention requires an understanding of (1) the characteristics of the specific condition, (2) the effect of the specific condition upon the patient’s life and level of functioning, and (3) the impact of therapy upon the patient. Each of these areas provides complementary information about the course of vascular disease and its treatment. Together, these pieces of information permit more reliable interpretation of the data, whether it is clinical or patient-based. Most vascular diseases have been well characterized by physical examination and laboratory testing, providing insight into the clinical characteristics of various vascular diseases. Based solely upon the information gathered during the performance of a complete history and physical examination plus noninvasive laboratory studies, a diagnosis can be made. However, a physician cannot accurately assess the overall impact of vascular disease upon the patient. Moreover, physiologic parameters do not correlate well with patient disability. Evaluating 555 patients with lower extremity ischemia by ankle-brachial index ¼ /(ABI) and patient-reported outcomes measures, Feinglass and colleagues noted only a modest correlation between the anklebrachial index and the patient’s self-reported level of physical functioning and walking ability.[10] Many patients with only slight reductions in ABI to 0.8–0.9 reported significant impairment in physical function. Conversely, many patients with significant reductions in ABI to 0.4–0.6 maintained high levels of physical function and walking ability. Thus, clinical descriptors of vascular disease do not provide a useful guide to the manifestations of the disease experienced by the patient.
Hobson/Wilson/Veith: Vascular Surgery: Principles and Practice, Third Edition, Revised and Expanded DOI: 10.1081/0819-9-120024895 Copyright q 2004 by Marcel Dekker, Inc.
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Similarly, the impact of the disease upon the patient’s life and level of functioning may be quite variable among patients. A clear understanding of this effect is essential for the appropriate management of the patient. It is as important for patients to completely describe their perception of the impact of the disease upon their life and level of functioning as it is for the physician to characterize the severity of vascular disease by physical examination and laboratory evaluation. This was nicely demonstrated by Pell, who had 201 claudicants rate their quality of life prior to their first visit with a vascular surgeon.[11] After the visit, the surgeon was asked to rate the patient’s quality of life based upon an understanding of the patient’s symptoms and examination. The correlation between these two estimates was poor and the vascular specialist often held an exaggerated concept of the impact of vascular disease on a given patient. Assessing 157 claudicants with treadmill walking distance, ankle-brachial index, and the Euroqol generic quality of life survey, Chetter and colleagues noted a poor correlation between the clinical parameters of treadmill walking distance and ankle-brachial index and the measured quality of life.[12] Barletta and associates evaluated treadmill performance and the quality of life with the McMaster Health Index Questionnaire in 251 patients and 89 age-matched controls.[13] These investigators documented a reduction in physical, emotional, and social function in claudicants compared with controls, but the reduction in these quality of life parameters did not correlate well with treadmill performance. Thus, it is imperative that the vascular specialist assess the impact of vascular disease through patient-based reporting. Once the manifestations of vascular disease and their impact upon the patient’s level of functioning have been documented, the beneficial and adverse effects of treatment can be determined. An optimal technical result represents a step toward the achievement of an improved patient wellbeing, but it is not itself sufficient to enhance a patient’s quality of life. This concept is familiar to most vascular surgeons who, for example, have puzzled over patients with a patent lower extremity revascularization who remain unable to walk because of persistent pain. Currie and associates studied 186 patients treated with an unsupervised exercise program, angioplasty, or surgery for claudication.[14] As might be expected, these investigators documented that angioplasty and surgery reduced the symptoms of claudication and improved functional status and quality of life scores. Strikingly, however, these improvements did not correlate directly with changes in the ankle-brachial index. Schneider and colleagues evaluated the functional status and well-being of 60 patients more than 6 months after aorto-bifemoral bypass grafting.[15] Although complete healing and postoperative recovery had occurred, patients with patent bypass grafts were found to have physical function, role function, and perceived health scores that were worse and bodily pain scores that were greater than those without symptomatic arterial occlusive disease. A similar study has documented greater anxieties and less satisfaction among patients requiring repeat vascular surgical interventions compared to those undergoing their first procedure.[16] These findings indicate that clinical measures, such as ankle-brachial index, patency, and limb salvage, effectively assess the physiologic impact of vascular intervention but do not adequately describe
overall patient benefit or adverse effect. This lack of correlation again underscores the need to use both clinical and patient-based parameters to adequately determine the impact of vascular disease and its treatment on the claudicant. Gibbons and colleagues evaluated the activities of daily living, mental well-being, and symptoms of vascular disease in 156 patients.[17] Though limb salvage was 97% at 6 months, only 45% of patients reported feeling “back to normal.” Nicoloff and colleagues evaluated 112 patients who had undergone infrainguinal bypass 5 – 7 years previously.[18] These investigators found that 30% of patients who were ambulatory preoperatively were not ambulatory at the time of evaluation postoperatively. Only 14.3% of the patients experienced an ideal surgical result of an uncomplicated operation with longterm symptom relief, maintenance of functional status, and no repeat or recurrent operations. Similarly, Abou-Zamzam and associates in a study of 513 patients undergoing lower extremity revascularization for limb salvage noted a primary assisted graft patency of 92%.[9] Despite this impressive success, 79% of patients who underwent revascularization because of inability to ambulate could not ambulate postoperatively although a patent bypass was present. The benefits and adverse effects of vascular surgical interventions, then, must be clearly defined by their ability to improve upon the patient’s quality and quantity of life, not simply by clinical parameters.
PATIENT-BASED OUTCOMES ASSESSMENT PARAMETERS The current approach to patient-based assessment has grown out of the National Health Interview Survey which was established in the late 1950s to characterize the national health.[19] In this survey, people were asked for the first time to rate their health, identify health problems, and describe the impact of the problem on their level of daily activity. In the 1970s the National Center for Health Services Research established a program to develop a survey instrument to measure the effect of illness on people’s lives. From this effort was created The Sickness Impact Profile.[20] During this same period of time, the Health Insurance Experiment developed a 20-question survey tool for patient-based assessment of health status.[21] This broadly applied tool became the foundation for the Medical Outcomes Study undertaken a decade ago to evaluate physician practice patterns and patient outcome after treatment.[22] Through the questioning of many thousands of individuals, these efforts delineated four integral components to the assessment of health-related quality of life: functional ability, perceived health, psychological well-being, and role functioning. Assessment of functional status provides information about how well the patient can perform tasks commonly required in daily life, such as climbing stairs, walking across a room, reading a newspaper, or holding a pen. These activities are basic and generic in nature and are independent of gender and occupation. They reflect the ability of the patient to perform common activities of daily living. Perceived health
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evaluation describes how healthy a person believes he/she is and those aspects of ill health which most limit the patient. The presence of chronic medical conditions which lead to the development of atherosclerosis can have a profound impact upon a patient’s perceived health. The Medical Outcomes Study documented that diabetes, hypertension, and angina are all associated with a significant reduction in perceived health.[23] Additionally, a patient’s perception of his/her health may be adversely affected by disease even after treatment. Though claudication is not a directly life- or limbthreatening disorder, numerous investigators have documented greater perceived health problems regarding energy, pain, and emotional reactions among claudicants compared to a nonclaudicating control group (Fig. 12-1).[24] In a study of 24 claudicants 1 year after angioplasty, Cook and Galland noted continued improvement in walking distance and quality of life but a deterioration in perceived health because of the development of co-morbid conditions.[25] Duggan and colleagues evaluated 17 patients who had successful lower extremity bypass procedures and found that, at a mean of 18 months after surgery, there was a decline in perceived health despite a patent bypass.[26] Each of these studies documents the complex nature of vascular disease and the challenge which vascular surgeons face in aiding their patients. Assessment of the psychological well-being of a patient yields insight into how worried, anxious, or depressed a patient is about his/her illnesses and treatment. Using carotid artery intimal-medial thickness as an indicator of progression of atherosclerosis, Agewall and colleagues found more rapid progression of disease in patients with poor psychological well-being even after correcting for serum cholesterol and cardiovascular disease.[27] Thompson and colleagues evaluated anxiety and depression in 112 patients with limbthreatening ischemia.[28] They found no difference in anxiety between those who had primary amputation and those who underwent an attempt at revascularization. Primary amputees, however, experienced greater depression. Role functioning evaluation is directed toward the assessment of the impact of a patient’s illness on his/her ability to work and perform obligatory duties. This dimension may provide important information for physicians regarding the goals of treatment. The desired improvement in walking ability is generally greater in younger patients with job-threatening claudication than in more sedentary elderly individuals. For the elderly, the goal of intervention is frequently maintenance of sufficient ambulatory ability to live at home. Nehler and associates studied the impact of lower extremity revascularization for limb-threatening ischemia in 88 patients 80 or more years of age.[29] These investigators found that 80% of those with a patent graft were ambulatory and living at home whereas 67% of those who sustained graft occlusion required amputation and transfer to a nursing home. The assessment of functional status, perceived health, psychological well-being, and rolefunctioning provide invaluable insight for the physician into the specific manifestations of the patient’s vascular disease and the impact of this disease and therapy upon the patient’s life and level of functioning. Other tools have been developed for the evaluation of patient choices, the impact of these choices on overall health, and the costs involved. Used largely for research, three wellestablished tools include the standard gamble,[30] the time
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Figure 12-1. General health status in patients with claudication (dark bars) and without claudication (light bars) as measured by the RAND-36. Note that although the major symptom of claudication is simply calf discomfort with walking some distance, this vascular problem has a pervasive effect upon the overall health status. (From Bosch and Hunink.[24])
tradeoff,[31] and the rating scale.[32] The standard gamble asks patients to choose between an assured intermediate outcome and a gamble between a bad outcome and a good outcome. The time tradeoff requests that a patient choose between a period of time at his/her current health state and an improved health state for fewer years. The rating scale asks the patient to rate his/her health status on a scale of 0 (death) to 100 (perfect health). Quality-adjusted life years is an outcome measure that combines both quantity of life and quality of life values into a single number.[33] Such a patient-based assessment generally uses a 0 (death) – 1 (perfect health) scale from which the patient identifies his/her health state. It is possible to track the patient’s changes in health state over the years subsequent to treatment to determine quality-adjusted life years as depicted in Fig. 12-2. These valuational tools are useful for tracking overall patient health states, the impact of clinical decision making, and the economic burden of treatments. Few are applicable to the assessment of a specific patient.
GENERIC OUTCOMES ASSESSMENT TOOLS There are currently several survey instruments developed in the United States and elsewhere which are capable of assessing functional ability, perceived health, psychological well-being, and role functioning (Table 12-1). Each of these broadly applied instruments has demonstrated both reliability and validity, which are essential properties for the acquisition of meaningful information. Reliability refers to the consistency of measurement of each question within the survey tool. In simplest terms, a reliable question will be answered in
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Figure 12-2. Outcome assessment in claudication.
the same way by most individuals who have the same overall health condition. Answers should be consistent if no changes in the patient’s health condition occur. A reliability measure of 1.0 indicates complete consistency. Many of the current tools, such as the SF-36, have a reliability measure of 0.85 or more.[34] Validity implies that each question actually measures what is intended and that the answers to similar questions are consistent. In the absence of a change in the patient’s condition, answers to specific questions in surveys administered over time should be the same. Assessment of validity is increased through the use of multiple questions on the same topic. The SF-36 is the most commonly used health assessment tool in the United States and has demonstrated excellent reliability and validity in the study of broad populations of patients. This generic quality of life instrument encompasses eight health dimensions (Table 12-2). Each of these dimensions can be interpreted separately. These measures are significantly affected by symptomatic vascular disease, such as claudication (Fig. 12-1). Because the design of the instrument is generic, it does not directly assess the specific impact of vascular disease but of all the co-morbid conditions that accompany it. For example, the successful treatment of claudication in the setting of worsening cardiac function may yield evidence of deterioration of general health status. As with other generic health assessment tools, the SF-36 scores may be affected by patient age.[35] Disease-specific instruments, therefore, are required to specifically identify the impact of therapy.
DISEASE-SPECIFIC INSTRUMENTS There are few disease-specific instruments for the measurement of vascular disease and its treatment. Those that have been constructed and validated involve the assessment of claudication. The most widely utilized is the Walking Impairment Questionnaire (WIQ), which has been designed to elicit information regarding the severity of discomfort experienced while walking, the reason for difficulty walking, walking distance and speed, and stair climbing.[36] The usefulness of this instrument for the assessment of treatment of claudication has been demonstrated in studies of exercise therapy for claudication in which the WIQ scores for walking distances and speed have improved in conjunction with increased treadmill walking distances. Evaluating severe claudicants before and after participation in a supervised exercise training program, Regensteiner and colleagues noted that after 24 weeks WIQ scores improved commensurate with increased treadmill walking distance.[37] There are no validated disease-specific instruments to evaluate the impact of limb-threatening ischemia and its treatment. Also lacking are disease-specific instruments for the evaluation of treatment of critical, asymptomatic vascular disease, such as carotid artery stenosis or abdominal aortic Medical Outcomes Study 36-Item Health Survey (SF-36)
Table 12-2.
Areas of assessment Table 12-1. Generic Quality of Life Instruments Nottingham health profile[38] EuroQol[39] Sickness impact profile[20] Medical outcomes study SF-36[22] Quality of well-being scale[40]
Perception of health Psychological well-being Role limitations due to physical health problems Role limitations due to mental health problems Physical function Social relations Pain Fatigue
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aneurysm. The development of instruments capable of identifying the benefits and adverse effects of treatment on these asymptomatic vascular problems is essential to vascular surgery.
APPLICATION OF OUTCOMES ASSESSMENT IN VASCULAR SURGERY At this time, practical application of outcomes assessment tools for the vascular surgeon is limited to the claudicant. Because the effect of treatment on the overall status of the patient does not directly correlate with improvement in clinical parameters, a more complete set of endpoints must be used (Table 12-3). The clinical results of any intervention for intermittent claudication should be documented through postrevascularization ankle-brachial indices and imaging studies which detail the area of intervention. A reduction in anklebrachial index should be correlated with the images of the treated segment to determine whether a reduction in index has been caused by problems within the treated segment or by progressive disease proximal or distal to the segment. Additionally, success of an intervention should be associated with an improvement in walking ability, an increase in WIQ score, and improvement in SF-36 scores. Only in this way can the benefit of palliative vascular surgical intervention for the treatment of patients with lower extremity ischemia be clearly demonstrated.
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Recommended Parameters for the Evaluation of Lower Extremity Ischemia and Its Treatment
Table 12-3.
Standard clinical parameters Technical success Morbidity Mortality Vascular examination Ankle-brachial indices Patency of treated arterial segment Changes in walking distance as measured by a treadmill protocol Changes in symptom severity by Rutherford classification Walking impairment questionnaire scores prior to and after treatment SF-36 quality of life scores prior to and after treatment
CONCLUSION Vascular surgical intervention is directed toward improvement in the patient’s quality of life. There are now wellestablished instruments for the assessment of quality of life. Utilization of such tools by physicians is simple and important for the analysis of all forms of palliative treatments of vascular disease. Only in this way can the benefits and adverse effects of intervention on patient quality of life and functional status be adequately documented.
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18. Nicoloff, A.D.; Taylor, L.M.; McLafferty, R.B. et al. Patient Recovery After Infrainguinal Bypass Grafting for Limb Salvage. J. Vasc. Surg. 1998, 27, 256– 263. 19. Fowler, F.J. Using Patients’ Reports to Evaluate Medical Outcomes. U.S. Congress Office of Technology Assessment, Tools for Evaluating Health Technologies: Five Background Papers; BP-H-142, U.S. Government Printing Office: Washington, DC, 1995;. 20. Bergner, M.; Bobbitt, R.A.; Carter, W.B. et al. The Sickness Impact Profile: Development and Final Revision of a Health Status Measure. Med. Care 1981, 19, 787– 805. 21. Brook, R.H.; Ware, J.E.; Davies-Avery, A. et al. Conceptualization and Measurement of Health for Adults in the Health Insurance Study: Vol. VIII—Overview; Publication No. R-1987/8-HEW, RAND Corp.: Santa Monica, CA, 1987;. 22. Ware, J.E.; Sherbourne, C.D. The MOS 36-Item ShortForm Health Survey SF-36-I: Conceptual Framework and Item Selection. Med. Care 1992, 30, 473– 483. 23. Stewart, A.L.; Greenfield, S.; Hays, R.D. et al. Functional Status and Well-Being of Patients with Chronic Conditions. J. Am. Med. Assoc. 1989, 262, 907– 913. 24. Bosch, J.L.; Hunink, M.G.M. The Relationship Between Descriptive and Valuational Quality-of-Life Measures in Patients with Intermittent Claudication. Med. Decis. Making 1996, 16, 217– 225. 25. Cook, T.A.; Galland, R.B. Quality of Life Changes After Angioplasty for Claudication: Medium-Term Results Affected by Co-morbid Conditions. Cardiovasc. Surg. 1997, 5, 424– 426. 26. Duggan, M.M.; Woodson, J.; Scott, T.E. et al. Functional Outcomes in Limb Salvage Vascular Surgery. Am. J. Surg. 1994, 168, 188– 191. 27. Agewall, S.; Fagerberg, B.; Dahlof, C.; Wikstrand, J. Negative Feelings (Discontent) Predict Progress of IntimaMedia Thickness of the Common Carotid Artery in Treated Hypertensive Men at High Cardiovascular Risk. Am. J. Hypertens. 1996, 9, 545– 550. 28. Thompson, M.M.; Sayers, R.D.; Reid, M. et al. Quality of Life Following Infragenicular Bypass and Lower Limb
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Amputation. Eur. J. Vasc. Endovasc. Surg. 1995, 9, 310– 313. Nehler, M.R.; Moneta, G.L.; Edwards, J.M. et al. Surgery for Chronic Lower Extremity Ischemia in Patients Eighty or More Years of Age: Operative Results and Assessment of Postoperative Independence. J. Vasc. Surg. 1993, 18, 618– 624. Torrance, G.W. Measurement of Health State Utilities for Economic Appraisal. J. Health Econ. 1986, 5, 1 – 30. Torrance, G.W. A Utility Maximization Model for Evaluation of Health Care Programs. Health Serv. Res. 1972, 7, 118– 133. Froberg, D.G.; Kane, R.L. Methodology for Measuring Health-State Preferences—II: Scaling Methods. J. Clin. Epidemiol. 1989, 42, 459– 471. Gold, M.R.; Siegel, J.E.; Russel, L.B.; Weinstein, M.C. Cost-Effectiveness in Health and Medicine; Oxford University Press: New York, 1996. Andrews, F.M.; Withey, S.B. Social Indicators of WellBeing: Americans’ Perceptions of Life Quality; Plenum Press: New York, 1976. Bartment, B.A.; Revicki, D.A.; Hochberg, M. et al. Relationship Between Health Status and Utility Measures in Older Claudicants. Qual. Life Res. 1998, 7, 67– 73. Regensteiner, J.G.; Steiner, J.F.; Panzer, R.J.; Hiatt, W.R. Evaluation of Walking Impairment by Questionnaire in Patients with Peripheral Arterial Disease. J. Vasc. Med. Biol. 1990, 2, 142– 152. Regensteiner, J.G.; Steiner, J.F.; Hiatt, W.R. Exercise Training Improves Functional Status in Patients with Peripheral Arterial Disease. J. Vasc. Surg. 1996, 23, 104– 115. Hunt, S.M.; McEwen, J.; McKenna, S.P., (Eds.) Measuring Health Status; Croom Helm: Dover, NH, 1986. EuroQol Group; EuroQol—A New Facility for the Measurement of Health-Related Quality of Life. Health Policy 1990, 16, 199– 208. Kaplan, R.M.; Bush, J.W. Health-Related Quality of Life Measurement for Evaluation and Research and Policy Analysis. Health Psych. 1982, 1, 61– 71.
CHAPTER 13
Computers and Vascular Surgery Richard F. Kempczinski frame computers utilizing the UNIX operating system and “dumb” terminals, most users rely on PCs incorporating the Intel Pentium IV processor running Windows XP (WinTel). A small but devoted minority prefer the Apple Macintosh, which incorporates the Motorola Power PCe chip and is able to run both Apple and IBM software. Since the author has no personal experience with this type of system, the subsequent discussion will focus on the most common WinTel system mentioned above. Hardware is usually the first hurdle the novice computer user must overcome when getting started. However, a good piece of advice that still applies even today is “to first decide what you want to do with your computer and then buy the hardware that best serves that purpose.” Every PC has a “mother board” containing the main processor (the Pentium IV chip), the computer’s volatile, random access memory (RAM), and a variable number of accessory boards depending on the peripheral devices attached to the machine. This integrated system is known as the central processing unit (CPU). There will also be devices for inputting data into the computer, typically a keyboard and a mouse or track-ball. Finally, a monitor is required to visualize the computer’s activity. Additional peripherals attached to most PCs include a printer, speakers, a fax/modem, a scanner, and a microphone. The cost of a complete system keeps coming down. It is generally quite easy to find a powerful system from a reputable manufacturer for less than $2,000. Such a system would typically include the Pentium IV chip running at 2 GHz Gigahertz with at least 512 megabytes (MB) of RAM. Given the size of most major software programs today, 20 gigabytes (GB) of hard disk storage space should be available. The choice of a suitable monitor is a balance between screen size and cost. Given the amount of time you will spend staring at the screen, I would recommend nothing smaller than 15 inches. A 17- or even 21-inch screen may be a worthwhile investment for users facing presbyopia but wishing to avoid the necessity for eyeglasses while using the computer. An internal fax/modem is usually part of most PCs, and current, top-of-the-line machines are being delivered with 56 kilobits (Kbps) modems. These devices are indeed capable of transferring data across the Internet at the rate of 56 Kbps
INTRODUCTION After the International Business Machine Co. (IBM) introduced their “personal computer” (PC) in 1981, computers began sporadically appearing in the offices of some vascular surgeons, where they were generally used for wordprocessing and to a much lesser extent, database management, spreadsheets and communication. This trend received an added boost several years later with the introduction of the graphical user interface called Windowse. However, it was not until 1992 with the emergence of the Internet that the real potential of computers in vascular surgery became apparent and they began appearing in the homes and offices of even the most confirmed computer phobics. In response to this interest and recognizing the potential opportunity to improve communications between vascular surgeons around the world, the Joint Council of the Society for Vascular Surgery and the American Association for Vascular Surgery decided in 1996 to create a home page on the World Wide Web (WWW). By combining the rosters of these two societies with those of all the major regional vascular societies and other affiliated national organizations, a large relational database of vascular surgeons was created as the nucleus for the “page.” Each society was then assigned its own “subpage” and encouraged to be as creative as its needs required. Two years later, the Association of Program Directors in Vascular Surgery mandated regular access of the home page [www.vascularweb.org] by its trainees to ensure that the next generation of vascular surgeons would be cognizant of and comfortable with the potential benefits of computers in their practice. This chapter will review the current status of PCs and will suggest how vascular surgeons might best use this new technology. We will also examine the most popular applications, with a particular emphasis on the Internet.
COMPUTER BASICS Although some academic vascular surgeons and members of large, multispecialty practices might have access to main-
Hobson/Wilson/Veith: Vascular Surgery: Principles and Practice, Third Edition, Revised and Expanded DOI: 10.1081/0819-9-120024896 Copyright q 2004 by Marcel Dekker, Inc.
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(kilobits per second). However, due to FCC rules that limit power output, current download (receiving information from the Internet) speeds are restricted to 53 Kbps and upload (sending information to the Internet) speeds are limited to 33.6 Kbps. In addition, actual speed may differ significantly depending on the local phone line and Internet traffic. As Internet access becomes increasingly part of the cable service users receive in their homes, line speed will no longer be the limiting factor and the modem can truly perform up to its potential. Some type of backup system is essential for every computer. It’s not a question of whether your system will ever “crash,” but when! A number of manufacturers offer tape systems capable of backing up more than 2 GB on a single tape. Although this operation might take 10– 15 hours, it only needs to be performed periodically, depending on how often major changes are made in your software, and can easily be run overnight. Most PC’s offer inexpensive, optional Iomega built-in zip drives which can back up 250 MB (Megabytes) of data on a single cartridge rapidly and conveniently. These are usually more than adequate to back up individual, and important programs on a daily basis and are highly recommended. The first time your hard drive crashes and you have to restore your computer without a backup, you will be kicking yourself for failing to take this simple precaution. As an alternative to tape which is slow, there are now writable CD drives which feature “removable media” that can be stored away from your computer and used to restore your files following a system crash. Software is the set of instructions that tells the computer how to perform its various functions. First, you will need an operating system, such as Windows XP, which tells the computer how to interact with each of its peripheral devices and with the different programs it will be running. Then, a specific application program will be required for each task the computer is expected to perform, e.g., wordprocessing, database management, spreadsheets/financial management, graphics and communications. The last of these, i.e., communications, is particularly challenging because it brings together computers and peripheral devices, such as modems, cable or telephone connections, usually from different manufacturers and attempts to make them work smoothly together while abiding by certain rules, or protocols, established by a third party, the “line provider.” Because today’s PCs are so powerful and the software programs are generally so well integrated under the operating system, it is possible to run several programs simultaneously. This ability, called multitasking, is limited by the amount of available RAM. Thus, it is generally advisable to have no less than 256 MB of RAM in your machine, but to paraphrase Gloria Vanderbilt’s famous aphorism, “you can never be too thin or too rich,” you can never have too much RAM!
APPLICATIONS Generally, each specific application, or task, requires its own software. However, certain “integrated” programs such as Microsoft Officew or Corel Office Suitew bundle together several programs, typically a wordprocessor, spreadsheet,
graphics program and database manager, into a coherent package that features a consistent interface and easier movement of data between programs. Computer software develops so quickly that it would be impractical and unfair of me to recommend specific programs within each category, especially since I have not personally worked with all of the programs currently on the market. However, I intend to describe the types of software which might be of interest to vascular surgeons and mention the most popular programs in each category. Although even the most complex programs now come with excellent online help, the quality of technical support each developer provides can be quite variable, and it is usually a good idea for novice users to choose programs for which local help is available. There’s nothing more frustrating than settling down in front of your home computer after a long day and then having your program stubbornly refuse to perform some simple task.
Wordprocessing This is probably the most widely used computer application. From simple tasks, such as the composition of individual letters or documents, to more complicated projects like the creation of multipage documents with tables, footnotes and references, every aspect of text processing is facilitated by these programs. When it comes to form letters, merge documents, newsletters, etc., there is simply no practical way to perform these tasks without computers. Although most vascular surgeons have a computer on their secretary’s desk running one of these programs, few have any personal experience working with them. With all the recent interest in the Internet, most of the current wordprocessing programs include the ability to prepare documents in hypertext markup language (HTML) for posting directly online. The most popular programs in this category are Microsoft Wordw and Corel WordPerfectw. For individuals who are not facile typists, voice activated programs such as Dragon System’s Naturally Speaking are capable of transcribing spoken text directly into most word processing programs at greater then 150 words per minute with an accuracy exceeding 90% and greatly facilitate data entry into such programs.
Database Management This is another very important computer application for the vascular surgeon. Even vascular surgeons in private practice who have no intention of reviewing their clinical experience for publication must keep track of their cases and results in order to honestly develop their own set of personal indications and to satisfy the demands of hospital credentialing committees and various certifying boards. Using any of the current database programs, such as Microsoft Accessw, it is easy to store all the relevant information on each case and to retrieve it in a usable fashion, when necessary. Similarly, one could also store references to the vascular literature[1] or organize the retrieval and reporting of vascular laboratory data.[2]
Chapter 13. Computers and Vascular Surgery
Spreadsheets Spreadsheets, such as Microsoft Excelw or Lotus 1-2-3w, are primarily intended for the storage and manipulation on numeric data, such as budgets or research data. In fact, it was the development of Lotus 1-2-3 that is credited with transforming PCs from mere toys intended primarily for playing games into serious business machines. Although you could develop and manage your personal finances with one of these programs, the same task is much more easily accomplished with specific financial management software, such as Microsoft Moneyw or Quickenw. Because so much financial information is available on the Internet and because many banks now permit their depositors to access their accounts online and to download account balances directly into their home computers, it is important to choose a program that automates these operations and works smoothly with the software supplied by your Internet provider.
Communications This software falls into two broad categories. One group of programs allows your computer to scan and fax information over the phone lines or, if your computer is equipped with an appropriate microphone, to actually use your computer as a alternative telephone. A second group is specifically designed for accessing the Internet. Included in this category would be software programs supplied by the Internet provider you select. This software must include a program to connect your computer via the modem with the Internet provider’s server, which, in turn, is physically linked, or hard-wired, to the Internet. If your computer is already so linked, you do not need either a modem or this type of software. However, if you are going to search for and download information or receive email via the Internet, you must have an Internet “browser,” such as Microsoft Internet Explorerw or Netscape Navigatorw. These programs have the ability to store your most frequently visited Internet sites as “bookmarks,” to develop and maintain an address book of email addresses and to download, organize and store your email. Usually, one of the two programs mentioned above will be included with the software you receive from your Internet provider, and although it is usually possible to substitute one for the other, it is generally a good idea to go with the program supplied by your Internet provider, unless you have a strong preference for the competing program. Although there are separate programs, such as Microsoft Outlook or Outlook Expresse, that are specifically designed to manage your email, the simple program included in your Web browser will usually be more than adequate.
Miscellaneous For surgeons who really want to immerse themselves in the digital revolution, there are pocket-sized, digital “assistants,” such as the Palm Pilot, which can store 128 kilobytes (KB) or more of information, such as telephone numbers, daily schedules, reminders, etc. They can be linked to the computer on your secretary’s desk via a small cable and updated at the end of each day with the following day’s activities. Many of
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them are small enough to fit in a shirt pocket and are equipped with small, internal alarms that sound to remind you of imminent meetings or important dates.
THE INTERNET Basic Considerations The Internet began more than a quarter of a century ago as a network of Defense Department computers which was designed to maintain critical communication links, even in the face of a possible nuclear war. Of all its component parts, none has captured the public’s interest more than the World Wide Web, which facilitated the posting and retrieving of information from around the world. Although it was originally conceived as a way for scientists to share data, it now contains information on virtually every imaginable subject. In 1992, the WWW was pushed into the spotlight when the National Center for Supercomputing Applications at the University of Illinois developed Mosaic, a software application that recognized graphics elements and dynamic links embedded directly within Web documents. This software program was the prototype for Netscape Navigator, the Web browser which opened the “information highway” to the general computing public. The power and unique appeal of the Internet derives from several important features. First, hypertext markup language, the language of the Internet, can be understood by most computers currently on the market, thus opening the Web to virtually every machine currently in use. Second, the ability to embed hypertext links within text documents on the Web allows the developers of each site to enrich them with virtually transparent links it to other “pages” within that site or anywhere on the Internet! These links usually appear within the document in a different colored font and are underlined. This gives each site on the Internet a potential richness and complexity usually lacking in two-dimensional documents. Finally, the incorporation of graphic elements (photographs, video clips, audio, animation, etc.) within documents can make them so visually appealing that it has released a creative energy within the Internet that is unmatched in a medium with such immediacy. Because there is so much information available on the Internet, some type of search “engine” is essential if you are going to find what you are looking for. Fortunately, a number of excellent search engines, such as Yahoow, Excitew, Googlew, Infoseekw, Alta Vistaw, and Lykosw, are all available, free of charge, and compete for your business, so there’s usually no problem finding what you are looking for. In fact, the opposite is usually the case, namely you find so many sites that fit your search criteria that winnowing through them becomes the challenge. As you refine your search techniques, your “net browsing” will become much more efficient. Before you venture too far, bear in mind that there is no one charged with the responsibility of policing the Internet or assuring the accuracy of any of the information contained on
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it, so Websurfer beware! There are several general standards you should hold up against data you need to trust. First, the source, or author, of that data should be clearly identified. Second, the date the information was posted should be listed, and finally, if matters of fact are stated, their source should be referenced. The unit of the Internet is a “page.” Since each page that contains information or graphic elements is a discrete, digital file, it has an “address” or uniform resource locator (URL) that precisely pinpoints its place on the Internet. Therefore, it is possible to interconnect all the documents that relate to a particular subject by embedding their URLs within the HTML coding of that document. One might compare this to the myriad, cellular interconnections that occur within the cerebral cortex in response to stimuli and which gives the brain its richness and complexity. To better understand URLs, let’s take a closer look at the Internet address for the vascular home page: http://www.vascweb.org Although this might, at first, seem like gibberish, it follows a precise protocol that is easily decipherable. “http” stands for hypertext transfer protocol and indicates the rules, that we will be expected to follow. “www” stands, as you know, for the World Wide Web and defines that portion of the Internet we will be using. “vascweb” is the unique, registered name for our site. Finally, the extender “org” describes the nature of the site, namely an organization. Some other common extensions that you might see here are: “com” for commercial sites; “edu” for educational sites; and “gov” for governmental sites. To go to any location on the Internet, you merely enter the URL for that site into a “location” box on your Internet browser and hit the , ENTER . key on your computer. If you identify a site that you might want to visit in the future, you can store its URL as a “bookmark” in your browser software. From within the Internet, other related sites can be accessed by merely clicking on the imbedded hypertext links, which are indicated by the change (from an arrow to a hand) in the shape of your mouse cursor when it passes over the word. For someone who has never visited the Internet and especially for someone who is a computer novice and may be a little intimidated by the strange computer jargon and technology, the immediate question that must come to mind is “why should I go to all this trouble to visit a place that I didn’t even know existed until a year or two ago and without which I got along perfectly well all my life?” The answer to that question will differ for each potential Websurfer, but for a vascular surgeon, I would suggest the following reply: “to communicate quickly and efficiently with your colleagues around the world and to get information that is largely unavailable any other way.” Email allows virtually instantaneous communication with your colleagues anywhere in the world. Most Web browsers have email components that automatically insert return addresses and allow mail to be saved, forwarded, etc. With digital address books, storing, retrieving and using a colleague’s email address is far simpler than conventional mail and you can post your communication
any time of the day, 7 days a week. Similarly, retrieving and reading your email can be performed at your convenience. Although each email address is unique, they follow a recognized convention, similar to that used for URLs. Let’s examine my email address as an example. E-mail:
[email protected] The “@” separates the address into two parts: to its left we have the “user name or user ID” and to its right we have the “domain” which identifies the file server where that individual receives his/her email. In my case, it’s the local phone company which calls their Internet service “fuse.” The terminal extender “net” identifies this server as a network. These are identical to the terms we used in categorizing URLs, thus “com” stands for a commercial server, “edu” signifies an educational computer, etc. Depending on the naming convention observed on that server, the user name is typically some contraction of the individual’s name, usually in a lowercase font, with quotation marks used to separate words rather than spaces, which are not allowed. If individuals use common sense in choosing their user name, their email address is usually quite simple and descriptive. The ability to attach digital files to an email is a great way to share larger documents and graphic images with colleagues around the world. When a document or manuscript is being prepared by several colleagues in different locations, the electronic wordprocessing file can be passed back and forth, revised and finalized without ever generating a hard copy. For vascular surgeons who are uncomfortable using a keyboard to type their email, there are several “voice recognition” programs which, after a brief training period, can recognize your voice and type your continuous speech directly into your email editor. They do require that your computer be equipped with an appropriate microphone and that your sound card be able to receive input, but the hidden benefit they bring to the process is synchronous spell checking! Because text is entered as whole words, these programs never misspell words already programmed into their extensive vocabularies, although they still have problems with homonyms. Furthermore, new words can be spelled into their vocabularies and memorized so that the next time they are used, they appear automatically. They also accept macros which allow you to store several steps or longer phrases as single word commands thus expediting the whole process of using computers. For example, this chapter was completely prepared, without any manual typing, using a program called Dragon-Dictate for Windowsw.
Communicating with the Vascular Societies’ Administrative Office In the very near future, it will be possible to submit abstracts for consideration by the Program Committee, to register for the annual meeting or to pay your membership dues online. Of course, email communication is always available, night or day. In the reverse direction, if individuals keep their personal listings in the roster database up to date, it will be possible for the Association Offices to send a “broadcast” email to every
Chapter 13. Computers and Vascular Surgery
vascular surgeon in the registry with a few clicks of the mouse. This potentially could be very important in alerting members to unfavorable legislative actions being considered or mobilizing a response from the vascular surgical community, when needed.
Searching for Data Regardless of whether you are looking for a reference in Medline, the contents of an abstract that is going to be presented at an upcoming meeting, the exact dates of a future vascular meeting or the membership requirements for the Western Vascular Society, a wealth of information can now be at your fingertips, night or day! The individual physician database which lies at the heart of Vascular Societies’ home page contains the names, addresses, phone & fax numbers, email addresses, photos and CVs of every member of all the affiliated societies. Since these data are arranged as a relational database, it is searchable by name, location, society, etc. This potentially represents the most comprehensive listing of vascular surgeons in the world and is a valuable demographic resource for our profession. As more and more vascular organizations develop their own Web pages, hypertext links on our home page can quickly take you to other sites of interest such as the Endovascular Forum or the home page for the Inter Societal Commission for the Accreditation of Vascular Laboratories.
Vascular Home Page In June 1996, the Joint Council of the Society for Vascular Surgery (SVS) and the North American Chapter of the International Society for Cardiovascular Surgery (NAISCVS)
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approved the creation of a home page on the World Wide Web that would bring together all the affiliated vascular societies and facilitate communication by vascular surgeons amongst themselves and with the Societies’ administrative offices. Demographic information from the membership rosters of all affiliated vascular societies was combined into a single, searchable, relational database. Subsequently, similar information was collected from the vascular residents in all approved and freestanding training programs in the United States and Canada and a registration form was designed to allow “Guest Physicians” from around the world to add their demographic information to the database. A standardized interface was created for each of the related vascular societies which were encouraged to populate their home page with up-to-date information on their history, officers, organizational structure, membership requirements, annual scientific meeting, etc. A full-text version of the Journal of Vascular Surgery (JVS) was linked to the site and a search engine was developed so all members could interrogate the Medline database as well as the JVS. Hypertext links were created to a large number of related sites which might be of potential interest to vascular surgeons. Although the exact appearance will differ slightly depending on your Web browser and the resolution of your monitor, most users will see an opening screen that looks something like Fig. 13-1 when they first logon. Let’s explore the website in greater detail and demonstrate how it might be used by a busy vascular surgeon. There are three distinct “areas” to the opening screen: a raised “power bar” across the top; a “button bar” down the left side; and the large central area of the screen. The power bar contains links to major vascular sites not directly controlled by the vascular societies themselves. The button bar features links to the major subdivisions of the vascular societies
Figure 13-1. Opening screen of vascular home page.
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Affiliated Vascular Societies That Have Linked Pages on the Vascular
Website American Venous Forum Canadian Society for Vascular Surgery Peripheral Vascular Surgery Society Society for Clinical Vascular Surgery Western Vascular Society
themselves, such as the Joint Council, the Lifeline Foundation, etc. The central area prominently features each of the two sponsoring societies and a link to a directory through which each of the affiliated societies can be reached (Table 13-1). What’s New is a great place to start each visit to the vascular website. It lists all new features that have been added to the page in the past month and contains hypertext links directly to those sites. In addition, whenever a site is significantly updated, a notice is posted here. By visiting this location first you will be certain not to miss any of the new and exciting features that are constantly being added.
Power Bar Currently, there are four power bars that take the user to other areas which should be of significant interest to most vascular surgeons. The first of these is the Journal of Vascular Surgery site. This site offers to subscribers the full text of the Journal online as well as a search engine that allows you to look for any text string and to focus your search on the title, the abstract or the entire text. Although the full text version is
Eastern Vascular Society Midwestern Vascular Surgical Society New England Society for Vascular Surgery Southern Association for Vascular Surgery
only available beginning with 1997, the abstracts for previous years are online. The Association of Program Directors in Vascular Surgery site offers a complete listing of all programs currently approved by the Residency Review Committee for Surgery to provide training in vascular surgery and permits downloading of several extensive documents which would be useful to individual vascular program directors, such as the “Vascular Laboratory Syllabus” (Fig. 13-2). Notice in the upper, left corner of every page “below” the opening screen a Home button. This is intended to facilitate navigation within the website and will take the visitor back to the opening screen with a single click of the mouse button. The Physician Database link provides access to the search engine which allows you to look into the entire database or to focus your member search on a single society (Table 13-2). You can then search for an individual by name or look for all members residing in a particular city, state, etc. In addition, each member, after entering the appropriate user ID and password, can access the individual “page” and update the demographic information in their own records. If members regularly update their records, as necessary, the roster information can be much more accurate than presently possible using conventional techniques.
Figure 13-2. Home page for Association of Program Directors in Vascular Surgery.
Chapter 13. Computers and Vascular Surgery Table 13-2. Categories of “Related Links”
Available Through the Vascular Home Page Other vascular societies Departments and divisions of vascular surgery Journals Evolving vascular technology Major vascular concerns Additional vascular surgery links Government sites Medical decision support Patient support groups General medical information
The Medline link will be described in greater detail below.
Button Bar The Welcome button is a good choice for first-time visitors to the website. It describes the rationale behind the site and directs laypeople to those areas specifically designed for them. The Joint Council page contains an up-to-date, complete list of the current members with hypertext links to their email address thus expediting communication with any member of the Council. It also contains a comprehensive list of all position papers commissioned by the Council and its “Issues & Answers” forum usually posts items of topical interest to vascular surgery. The Annual Meeting brings together on one page links to the annual scientific meeting of the SVS/AAVS. In addition to the current meeting, the dates and location for further meetings are available. Abstracts, posters and the research forum for the meeting are posted as soon as they are chosen by the program committee, which is usually several months prior to their availability through any other means. A complete section was devoted to Research Forum because of its importance to the future of vascular surgery. The complete program of the Research Initiatives Forum is posted each year. There is also a comprehensive section for young researchers giving advice on how to secure research grants with a detailed listing of potential funding sources and the latest deadlines for posting applications. The Lifeline Foundation page lists the current composition of the board and posts the annual recipients who have been chosen to receive research support from the foundation. A comprehensive list of all recent donors is available online and plans are being made to permit online contributions. The Clinical Case Forum features the “Case of the Month” which will be prepared monthly by one of the approved vascular training programs. In addition to a challenging clinical problem, there will be interactive questions through which visitors can compare their management of the case with that of the submitting service and receive feedback on how other respondents would have proceeded. The submitting service will prepare a referenced discussion of each case and the completed cases will be catalogued in a “Teaching Collection” for use by future vascular trainees. We are also planning a mechanism whereby physicians could post
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challenging clinical problems from their own practices and request consultation from colleagues around the world. This could be an extremely popular and unique “consulting service” for uncommon or complicated vascular problems. Frequently Asked Questions are intended for laypeople visiting our website and contains answers to the questions most often asked by our patients in terms they can understand. The list of questions is flexible and visitors are invited to post additional, new questions for future discussion, as long as they are likely to be of widespread interest. Finally, a link is provided for Feedback to the Webmaster in the form of a link to his/her email. Comments on the website, corrections of errors and suggestions for future additions to the page are all welcome.
Future Enhancements The website is a dynamic place that is constantly updating and changing. Hopefully, by the time this chapter is published, we will have added a Calendar of Meetings on which will be posted a complete listing of all meetings around the country offering Continuing Medical Education credits. Each listing will be hypertext linked to individual subpages describing the location, faculty and content of that meeting. We are also planning a Job Opportunity page on which will be posted all vascular job offerings advertised in the Journal of Vascular Surgery. These will be in the form of a searchable relational database which will allow interested job seekers to search by location, type of job (academic vs. private practice), etc. Since this chapter was written the “look of” the vascular website has been redesigned, although all the previously described features are still available. A great advantage of the internet is the ability to continuously modify and update our website to meet the needs of vascular surgeons.
Searching the Medical Literature During the past 30 years, there has been an explosion in the volume of published medical information. The development of the Internet as a highway for worldwide communication, and the emergence of the WWW as a common vehicle for communication have made instantaneous access to much of the entire body of medical information an exciting possibility. The National Library of Medicine (NLM) maintains MEDLINE, a comprehensive, cross-referenced database of citations to the medical literature covering 1966 to the present. Unfortunately, MEDLINE currently contains only abstracts of the medical literature, not the complete text of the articles. In 1996, the NLM began providing free, unlimited access to MEDLINE to all Americans over the World Wide Web. As the volume of cost-free medical information has increased, so has the need for efficient methods for searching the data.[3] Presently, MEDLINE is manually indexed with NLM’s Medical Subject Heading (MeSH) vocabulary. MEDLINE searches use AND/OR/NOT logical searching for “keywords” that have been assigned to each article and for “textwords” included in article abstracts. Using MeSH, a searcher can potentially create powerful and unambiguous
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MEDLINE queries. However, in order to get maximum productivity from your searches, you should be familiar with the MeSH vocabulary. Lowe and Barnett reviewed the structure and use of MeSH, directed toward the nonexpert, and outlined how MeSH may help resolve a number of common difficulties encountered when searching MEDLINE.[4] Recently, the complete text of some scientific journals, including figures and tables, has become accessible electronically. The vascular home page offers two methods for searching MEDLINE. The first is through PubMed, a free, simple search engine created by the National Library of Medicine that can quickly search the 9 million citations it indexes. The second is a search engine developed by Community of Science, the Baltimore-based Internet development company that has been hired by the Joint Council to support the development and maintenance of their website. Both are accessed through the “MEDLINE” link on the Power Bar. Grateful Med is a computer software package developed by the National Library of Medicine which provides access to MEDLINE and other medical databases.[5] The program is available for both IBM and Macintosh computers, is inexpensive, easy to install and has excellent documentation. Health professional in all areas find Grateful Med to be a userfriendly, cost-effective way to search current, worldwide medical literature. The full text of Journal of Vascular Surgery recently became available on CD-ROM. Once several years are available, this will be an alternate way to quickly search the medical literature on vascular topics since most of the important articles on vascular disease are contained in this publication. The advantages of this type of search are its speed and simplicity. However, its effectiveness will depend on the quality of the search engine provided by Mosby. In a study comparing the effectiveness and speed of searching the medical literature via CD-ROM versus the Internet, Smith et al. found a CD-ROM MEDLINE literature search took 60 minutes to find 31 articles (43% of the possible articles) compared with an online search to the Bibliographic Retrieval Services database in Chicago, which produced the same articles when MEDLINE was searched (but took only 16 minutes).[6] When Excerpta Medica was searched, they found 47 articles (with an overlap of only seven). They estimated that the combined MEDLINE and Excerpta Medica search detected 93% of all known relevant articles, based upon an assumed gold standard.
Eventually, conceptual searching in which the computer searches for related ideas, without having to be given all the related keywords, may become a reality. This will free the user from having to learn specific rules about searching, allowing energies to be focused on results of the search, not the search itself.
CONCLUSIONS Following the introduction of powerful, inexpensive personal computers and the development of an user-friendly, graphic interface, computers have become an inevitable part of everyday life and are present in the offices of most vascular surgeons. Because of the ever-growing demands on their time and all proliferation of labor-intensive record keeping, it is essential that all vascular surgeons become familiar with this new technology and take maximum advantage of its laborsaving potential. The Internet has opened up a highway on which vascular surgeons can easily and quickly communicate with their colleagues around the world and have access to medical information not easily obtained in any other way. In 1996, the Joint Council of the two major, national vascular societies created a home page on the World Wide Web. A larger relational database was formed by combining demographic information from the rosters of all affiliated vascular societies, and separate subpages were created for each of the societies on which they could post their annual scientific meetings, poster sessions, etc. Related hypertext links were created to most other major vascular sites on other servers, thus bringing the vascular medical “universe” together under one tent. Using tools provided on the vascular home page, it is now easy for vascular surgeons to access the medical literature quickly and efficiently 24 hours a day, 365 days a year. In addition, the availability of full-text Journal of Vascular Surgery online now makes it possible to search not just key words chosen by some medical librarian but every word that appears in the journal. The responsibility to learn how to use these powerful, new tools to improve the quality of care we provide our patients is no less real than would be our obligation to learn a new procedure for revascularizing the ischemic leg.
REFERENCES 1. Kempczinski, R.F. A Microcomputer-Based System for the Management of Vascular Surgical References. J. Vasc. Surg. 1987, 6, 542– 547. 2. Kempczinski, R.F. Computerized Data Management in the Vascular Non-invasive Laboratory. In The Noninvasive Vascular Laboratory: Current Issues and Clinical Developments; Auer, A.I., Neumyer, M.M., Eds.; Appleton Davies, Inc.: Norwalk, 2002; in press. 3. Kastin, S.; Wexler, J. Bioinformatics: Searching the Net. Semin. Nucl. Med. 1998, 28, 177– 187.
4. Lowe, H.J.; Barnett, G.O. Understanding and Using the Medical Subject Headings (MeSH) Vocabulary to Perform Literature Searches. J. Am. Med. Assoc. 1994, 271, 1103– 1108. 5. Horak, B.B.; Hamasu, C.C. Grateful Med: Gateway to World-Wide Literature. Hawaii Med. J. 1991, 50, 419–420. 6. Smith, B.J.; Darzins, P.J.; Quinn, M.; Heller, R.F. Modern Methods of Searching the Medical Literature. Med. J. Aust. 1992, 157, 603– 611.
CHAPTER 14
Medical Management of Atherosclerotic Vascular Disease Ralph G. DePalma Donna L. Kowallek† as well. Choices among alternatives for individual patients might appear to be superficially clear-cut, but instead are complex and require comprehensive knowledge of the natural history of particular lesions, surgical and endovascular options, and possible efficacy of nonoperative approaches.
Atherosclerosis is the disease most commonly treated by vascular surgeons. It is also the most common cause of morbidity and mortality in modern Western society, in spite of a decreasing cardiovascular mortality in the United States. Forty years ago, arteriosclerosis was believed to be an inevitable consequence of aging. Physicians considered it to be an inexorable arterial degeneration offering little hope for treatment. That atherosclerosis was segmental in nature and that diseased arteries could be treated by bypassing or removing lesions were uniquely surgical insights.[1] Surgical intervention is the most effective means of limiting the lethal consequences of aortic aneurysms, coronary artery disease, and carotid bifurcation plaques. However, atherosclerosis is also a systemic disease remaining dormant in arteries until a complication signals its presence. Operations on the cardiovascular system restore circulation, saving lives previously lost to aneurysmal rupture and limbs once lost to gangrene. With growing technical expertise, it is clear that life expectancy increases after surgical repair of aortic aneurysms and selected coronary lesions. However, a strictly surgical approach to treatment does not prevent disease progression. Life expectancy remains shortened, and many patients need additional vascular operations; about 12% will require another vascular procedure for the same problem that prompted the first operation.[2] Not only does atherosclerosis progress in native arteries, it also tends to occur in newly placed grafts.[3] This chapter discusses medical management of atherosclerotic disease. Surgeons are often required to choose among medical and surgical alternatives. Indeed, often a choice exists about recommending an operation or medical treatment. The surgeon plays a key role in postoperative recommendations
†
THE ATHEROSCLEROTIC PLAQUE Figure 14-1 depicts a typical fibrous plaque containing a central atheromatous core with a fibrous or fibromuscular cup, macrophage accumulation, and round-cell adventitial infiltration. The word atheroma is derived from a Greek word meaning porridge. Sclerosis means induration or hardening. These contrasting characteristics exist in varying degrees in distinct plaques, disease stages, and individuals. According to Haimovici et al.,[4] in 1755 Von Haller applied the term “atheroma” to the common type of plaque, which, on sectioning, exudes yellow pultaceous contents. DeBakey[5] provided a reference to show that such plaques were found in Egyptians as early as 1580 B.C. The plaques contain three components: cholesterol, mainly in the form of cholesterol esters; cells, mainly smooth muscle but also macrophages and other cell types; and fibrous proteins, mainly collagen, elastin, and proteoglycans. In advanced lesions, fibrin, blood components, and calcium also occur. Considerable lesion variability characterizes atherosclerosis. This variability is best illustrated in carotid atheromas.[6] Even in this limited and uniform site, plaques sometimes occur that exhibit mainly smooth-muscle cellular proliferation, collagen, and little fat. Such plaques contrast with commonly occurring carotid atheromas containing a core of friable lipid debris and blood elements. The variable compositional characteristics of atheromas in many sites probably account for difficulties in assessing the effects of treatment. Complicated plaques (i.e., fibrous plaques which
Deceased.
Hobson/Wilson/Veith: Vascular Surgery: Principles and Practice, Third Edition, Revised and Expanded DOI: 10.1081/0819-9-120024897 Copyright q 2004 by Marcel Dekker, Inc.
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are calcified, ulcerated, or necrotic) are unstable. Thus, there can be dissection from the arterial wall, causing sudden occlusion, expansion due to hemorrhage within the plaque, or overlying thrombosis due to cap rupture, such as often occurs in coronary atheromas. Ulcerated carotid plaques can embolize the porridgelike core material into the brain and retina. It is not yet known whether or not medical therapy might stabilize such intrinsically unstable lesions. The development and role of the atherosclerotic core and its relationship to the cap have been recognized as causing complications. A recent insight[7] is the finding that the “core” develops in early lesions, accumulating in the deep aspects of very early plaques before these become actual fibrous plaques.
It is probable that there are several pathways leading to the lesion depicted in Fig. 14-1. For example, one etiologic hypothesis suggested a role for cytomegalovirus[10] in atherogenesis to explain the onset of abnormal cellular proliferation. Immunologic or mechanical endothelial injury might result in exposure of underlying smooth muscle to a variety of plasma and cellular components which trigger smooth muscle proliferation and subsequently cause lipid accumulation. However, since the early lesion found in children and created experimentally in animals is usually fatty, the most commonly accepted theory of evolution focuses on the entry of low-density lipoprotein (LDL) cholesterol into the arterial wall.
FATTY STREAKS PLAQUE EVOLUTION After long latency periods, atherosclerotic plaques progress through early and more advanced asymptomatic stages to become complicated lesions causing clinical events. The ultimate pathology of advanced atherosclerotic plaques tells little of these early evolutionary events. Stary and colleagues[8] have provided a comprehensive report defining initial fatty streaks and intermediate lesions of atherosclerosis as well as the cellular alterations in early lesions. The advanced lesions of atherosclerosis have also recently been clarified.[9] Pragmatically, the value of hypotheses relating to pathogenesis must be judged by the ability to predict measures that would prevent or control this process. It seems probable that measures to prevent initial plaque formation might be quite different from those later used to control established disease, though in any individual several evolutionary stages of lesions coexist.
Fatty streaks are gross, minimally raised, yellow lesions found frequently in the aorta of infants and children. These lesions contain lipids deposited intracellularly in macrophages and in smooth muscle cells. Type I lesions in children are the earliest microscopic lesions, consisting of an increase in intimal macrophages with the appearance of foam cells. Type II lesions are grossly visible; in contrast to type I lesions, type II lesions stain with Sudan III or IV. Fatty streaks are characterized by foam cells and lipid droplets, also in intimal smooth muscle cells, and heterogeneous droplets of extracellular lipids. Type III lesions are considered intermediate lesions; they are usually the bridge between the fatty streak and the prototypical atheromatous fibrous plaque, the type IV plaque (Fig. 14-1). Type III lesions occur in plaque expression – prone localities in the arterial tree,[11] that is, sites exposed to forces that cause increased LDL influx, particularly low shear
Figure 14-1. Schematic of a typical atheroma. Note central lipid core, fibrous cap, accumulation of macrophages, and zone of synthetically active smooth muscle at the “shoulders” of the core. Note tendency of the media to bulge outward, adventitial neovascularization, and lymphocytic infiltration. (From DePalma, R.G.: Pathology of Atheromas. In Bell, P.R.F.; Jamieson, C.W.; Ruckley, C.V. (eds): Surgical Management of Vascular Disease. London, W.B. Saunders Co. Ltd, 1992, pp. 21 –34.)
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Medical Management of Atherosclerotic Vascular Disease
stress.[12] The fatty streak type II lipids are chemically similar to those of the plasma,[13] although the plasma lipids might enter the arterial wall in several ways. The plasma threshold level for LDL entry into the arterial wall is unknown. As described in a recent review of pathogenesis,[14] LDL accumulation may occur because of (1) alterations in the permeability of the intima, (2) increases in the interstitial space in the intima, (3) poor metabolism of LDL by vascular cells, (4) impeded transport of LDL from the intima to the media, (5) increased plasma LDL concentrations, or (6) specific binding of LDL to connective tissue components, particularly proteoglycans in the arterial intima. Experimental studies shows that LDL cholesterol accumulates in the intima even before lesions develop and in the presence of intact endothelium. These observations are quite similar to those of early lesion formation described by Aschoff[15] at the beginning of the twentieth century and Virchow[16] in the nineteenth century. A second event in early atherogenesis as shown in animal experiments is binding of monocytes to the endothelial lining, with their subsequent diapedesis into the subintimal layer to become tissue macrophages.[17 – 19] Experimentally, fatty streaks are populated mainly by monocyte-derived macrophages. These lipid-engorged scavenger cells mainly become the foam cells that characterize fatty streaks and other lesions. An important and key observation is that LDL must be altered in some manner,[20] such as by oxidation or acetylation, to be taken up by the macrophages to form foam cells. This concept has become central to thinking about pathogenesis and treatment, as will be seen in subsequent discussion. Oxidized LDL (OxLDL) is a powerful chemoattractant for monocytes. Another aspect of this concept suggests that the endothelium modifies LDL to promote foam cell formation. The interactions of plasma LDL levels with the arterial wall are the subject of intense interest. Low-density lipoproteins traverse the endothelium mostly through receptor-independent transport, but also through cell breaks.[21] Endothelial cells,[22] smooth cells,[23] and macrophages[24] are all capable of promoting oxidation of LDL. OxLDL, in turn, further attracts monocytes into the intima and promotes their transformation into macrophages. Macrophages produce cytokines including platelet-derived growth factor (PDGF), transforming growth factor beta (TGFb), and interleukin-1 (IL-1). The OxLDL also induces gene products ordinarily unexpressed in normal vascular tissue. A notable example is tissue factor (TF), the cellular initiator of the coagulation cascade that is expressed by atheroma monocytes and foam cells.[25] Expression of TF requires the presence of bacterial lipopolysaccharide, suggesting that hypercoagulability in atherosclerosis could be enhanced by endotoxemia.
GELATINOUS PLAQUES The intimal gelatinous lesion, also first described by Virchow in 1856,[16] is an interesting and overlooked lesion. Haust[26] believed that these plaques ranked among the important progenitors of advanced atherosclerosis. Smith[27] stressed their characterization; she and her associates have accumu-
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lated much valuable data about them.[28] It has been shown that virtually all plasma proteins, particularly hemostatic components, are capable of entering the intima. These plaques are not high in lipid content. Gelatinous lesions are translucent and neutral in color, with central grayish or opaque areas. This material separates easily from the underlying arterial wall without entering the usual endarterectomy plane. Gelatinous lesions are most commonly seen in the aorta. The gelatinous plaque is high in fluid and low in lipid content. In transitional stages, cellularity is increased and the plaques contain smooth-muscle cells. These lesions exhibit substantial amounts of cross-linked fibrin, possibly relating to increased plasma fibrinogen levels.
THE FIBROUS PLAQUE Figure 14-1 shows the more advanced atherosclerotic lesion capable of causing complications, the fibrous or type IV plaque. These are composed of large numbers of smoothmuscle cells and connective tissue forming a fibrous cap over an inner yellow atheromatous core. The soft core contains cholesterol esters, mainly cholesterol oleate, thought to be derived from disrupted form cells. A second type of particle contains both cholesterol and cholesterol lineates. The early case, described previously, is associated with lipids derived directly from LDL by enzymes capable of hydrolyzing LDL cholesterol esters.[14] Considerable emphasis has been placed on the composition and integrity of the cap as this structure stabilizes the atheroma, preventing intraluminal rupture of the soft core.[29,30] Chronologically, such lesions are detected after fatty streaks, often in the same anatomic locations, and characterize the clinically apparent stages of atherosclerosis. While other lesions can be precursors of fibrous plaques, the fatty streak is believed to be the most common pathway. Fibrous plaques can arise by conversion of a mural thrombosis into an atheroma.[31] While the fibrous plaque protrudes into the arterial lumen on fixed cut sections, abluminal bulges can also be seen when arteries are fixed at arterial pressures.[32] Such abluminal bulges have characterized early coronary and peripheral lesions in subhuman primates.[33,34] This prestenotic phase of atheroma development can make quantitating plaque evolution difficult, as luminal intrusion is not seen angiographically. Lipid arterial wall interactions are quite important for other reasons. The cholesterol esters in fatty streaks appear in the form of ordered arrays of intracellular lipid crystals. In fibrous plaques, the lipids assume isotropic forms and occur extracellularly.[35] Extracellular cholesterol esters and oxysterols cause severe inflammatory tissue reactions and are probably capable of eliciting the same responses in the arterial wall.[36] As illustrated, arteries with fibrous plaques often exhibit striking periarterial inflammation, fibrosis, and lymphocytic infiltration relating to disease severity.[37] Neovascularization from the adventitia also characterizes advancing intermediate and fibrous plaque lesions. Fibrous plaques protrude into the arterial lumen in fixed cut sections; however, when arteries are fixed at arterial pressure, they produce an albuminal or external bulge. For
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example, coronary plaques in vivo must occupy at least 40% of the arterial wall before angiographic detection is possible,[38] and atheroma growth can be compensated for by arterial enlargement within certain limits.[39] Remodeling of coronary arteries in subhuman primates and humans has been stressed.[40] However, with lesion growth, ulceration, rupture, or overlying thrombosis, the arterial lumen is ultimately compromised. When this occurs, distal ischemia develops. A unique adaptive response involving dilation, with atheromatous involvement of the entire arterial wall and participation of inflammatory cells and immunologically active T lymphocytes, may predispose to aneurysm formation. Atherosclerotic lesions contain immunoglobulin G (IgG) in large quantities along with other immunoglobulins and complement components. The contained IgG recognizes epitopes characteristic of oxidized LDL, indicating that immunologic processes characterize advanced plaques.[41] The process exhibits systemic effects; patients with carotid atherosclerosis have higher antibody levels of anti-oxLDL and IGM than comparable nonatherosclerotic controls.[42]
the younger the afflicted patient, the more likely one is to encounter a risk factor as it coincides with clinical events. Patients with extremity disease are often older than those with coronary disease, but, on careful inquiry, risk factors will be found in the past.[44] The clinical problem in treating patients is choice of modifications in lifestyle or medical interventions in individual stages or patterns of disease. The aim is to prevent progression of disease to lethal endpoints such as myocardial infarction, stroke, and peripheral ischemia. The choices that face the vascular surgeon occur both preoperatively and postoperatively and are somewhat different in each instance, depending upon the coexisting disease patterns.[47] The practical intervention that all vascular surgeons should insist upon is cessation of cigarette smoking. In this author’s opinion, control of this risk factor is paramount for immediate-term results along with control of LDL cholesterol level, an attempt to increase high-density lipoprotein (HDL) cholesterol, and control of diabetes, hypertension, or embolic phenomena in the long term.
LESION ARREST OR REGRESSION PROGRESSION TO COMPLICATED PLAQUES Late complications of fibrous plaques lead to clinical complications. Aneurysms might represent a unique genetic or immune response to atherosclerosis or alternatively be considered as nonspecific degenerative or purely mechanical responses. There clearly exists a high prevalence of risk factors for atherosclerosis in aneurysm patients.[43] The recent classification of advanced lesions[9] takes into account that extracellular lipid is the precursor of the core of the type IV fibrous plaque. Type V lesions contain a thick layer of fibrous tissue, whereas type VI lesions contain fissures, hematoma, or thrombus. Aneurysms are also included within the recent staging of advanced atherosclerosis.
APPROACH TO TREATMENT The complications of atherosclerosis relate to numerous interactive factors and inflammatory mechanisms occurring in complicated plaques. It is useful, but not scientifically rigorous, to view epidemiologically defined risk factors as etiologic factors. As this disease manifests itself as a spectrum of lesions, human atherosclerosis can be considered as a family of related vascular disorders. Interestingly, bodily patterns of involvement relate to particular risk factors and often are associated with distinctly differing rates of progression.[44,45] In an individual with atherosclerosis, it is almost always possible to elicit a past or present history of risk factors. Risk factors are epidemologically defined; their effects on vascular complications and changing disease prevalence have been reviewed.[46] These major risk factors are hyperlipidemia, primarily elevated levels of LDL cholesterol; cigarette smoking; hypertension; and diabetes mellitus. In general,
Regression of atherosclerosis in response to lowered serum cholesterol has been demonstrated in autopsy studies of starved humans,[15] in animals,[48,49] and in angiographic trials.[50] In experimental animals, plaque regression is clear, while in humans arrest is more commonly documented. As experimental plaques regress, bulk is reduced mainly by lipid egress in hypercholesterolemic dogs[51,52] and monkeys.[53,54] The authors and coworkers verified regression using serial direct observations of lessened bulk and lipid content of individual fibro-fatty plaques, which correlated with lessened plaque lipid and altered fibrous protein content.[54] An important operational aspect of this research was confirmation of regressive changes by immediate morphologic measurement and biopsy following angiography. While these observations are difficult to obtain in human atherosclerosis, lessening of luminal intrusion on segmental angiography does coincide with favorable lipid interventions. Experimentally, plaque fibrous protein content may increase in some instances during lipid egress,[53] which may limit regression, but this process also might convert a soft atheromatous plaque into a more stable entity. This process, in fact, has now been shown using pravastatin in an experimental model.[55] To produce consistent arrest or regression, serum cholesterol must be reduced to below 200 mg/dL; conversely, there also exist serum cholesterol levels above which lesions inevitably progress over time.[54,56] This threshold in humans might approximate a total serum cholesterol of 150 –170 mg/dL or an LDL level of 100 mg/dL or less, levels cited in world populations in which atherosclerosis is virtually absent.[57]
MEDICAL MANAGEMENT As can be seen from considerations of plaque evolution and complications, lipid dynamics play an important role in
Chapter 14. Table 14-1.
Medical Management of Atherosclerotic Vascular Disease
239
Diet Trials of Cholesterol Lowering
Trial
Type, years
Lipid change, %
LAVAMC
18 8
TC (14)
MRC Low Fat
28 3
TC (9)
MRC Soya Oil
28 4
TC (13)
OSLO Diet Heart
28 5
TC (15)
n
Fatal plus nonfatal CHD events
T = 424 C = 422 T = 123 C = 129 T = 199 C = 194 T = 206 C = 206
54 71 30 31 45 51 61 81
Note: 18 = primary; 28 = secondary; TC = total cholesterol; T = treated; C = control. Source: Rossouw, J.E.; Rifkin, B.M.[66] Used with permission.
atherogenesis. In late disease, the instability of fibrous plaques has now received increasing attention. As yet, however, among all the interventions intended to stabilize, arrest, or regress plaques, solely lipid interventions (i.e., decreasing LDL cholesterol or increasing HDL cholesterol) have been shown to promote favorable changes in the atheroma itself as well as increasing survival mainly in coronary atherosclerosis. These favorable changes require cessation of smoking. Many thousands of individuals have been studied by serial angiography in regression trials that use mostly lipid reduction,[58] most recently using pravastatin, which has evident effects in reducing cardiovascular events in older and younger patients, men and women, and patients with and without histories of prior infarctions, as well as in those with only modest elevation of serum cholesterol.[59,60] Vessel wall changes have also been measured in the carotid and femoral arteries using the statin drugs.[61] Epidemiologic and interventional studies support the view that it is desirable to keep total serum cholesterol (TC) values below 200 mg/dL, with LDL below 130 mg/dL, fasting triglycerides below 250 mg/dL, and HDL levels above 40 mg/dL;[62] these values may be true for older age groups as well.[63] When TC is greater than 200 mg/dL, calculations of LDL cholesterol are obtained according to the following formula: LDL cholesterol equals TC minus HDL cholesterol minus triglycerides divided by 5. When initial screening is positive—when TC is greater than 200 mg/dL—fasting blood for these determinations is required. This formula is valid only in fasted patients and when the triglycerides are below 400 mg/dL. Small differences in cholesterol concentrations over time have important effects; therefore, screens are repeated periodically in symptomatic patients. In patients in whom LDL cholesterol is above 130 mg/dL, cholesterol-lowering diets are prescribed, as outlined by Luepker[63] and Stone.[64] The Step I Diet recommends a total fat intake of less than 30% of the total caloric intake, with less than 10% of total calories derived from saturated fat and less than 300 mg of cholesterol a day. Total calories are calculated to achieve and maintain desirable weight. With high-risk patients—those whose LDL is above 160 mg/dL and who
have two other risk factors or clinical coronary disease— saturated fat is reduced to less than 7% of the total caloric intake and cholesterol intake to less than 200 mg/day. Dietary consultation and instruction will be needed to achieve these goals, and these have been long recommended by the author.[65] The effects of lipid-lowering diets on coronary heart disease (CHD) can be seen in Table 14-1, from a summary by Rossouw and Rifkin.[66] As the number of fatal CHD endpoints is too small in each trial to detect significant differences, the results for these data are tabulated as fatal plus nonfatal CHD events. Only the Oslo Heart Study demonstrated statistical significance.
DRUG THERAPY FOR HYPERLIPIDEMIAS When dietary therapy fails to achieve goals for lipid lowering (i.e., an LDL level below 130 mg/dL), drug therapy is used. The surgeon undertaking dietary recommendations must recognize that the time and effort required will often exceed that of operative interventions. Drug therapy does not substitute for a concerted and organized dietary approach for a minimum of 6 months or a search for familial dyslipoproteinemia. Drugs currently available include cholestyramine and cholestepol, which are bile acid sequestrants, nicotinic acid (a B-complex vitamin), Gemfibrozil, a fibric acid derivative that acts in the liver to elevate plasma HDL and lower triglycerides and LDL, and the statin drugs referred to previously.[59 – 61] The latter class of drugs are 3-hydroxy-3methylglutaryl coenzyme H – reducing agents and are currently in wide use in trials and clinically for primary and secondary coronary artery disease. This has led Roberts[67] to editorialize that statin drugs are to atherosclerosis what penicillin was to infectious disease. A cautionary note on the carcinogenicity of lipid-lowering drugs has been sounded by Newman and Hulley[68] in that all members of the statin and fibrin classes of drugs have exhibited cancer in rodents, in some cases at levels of animal exposure approaching those prescribed in humans. With regard to the statin drugs, an
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overview of all published trials by Herbert et al.[59] revealed no evidence of either noncardiovascular death increase or cancer incidence. The use of the statin drugs has been shown to be effective in primary prevention as well and likely will become more widespread for this purpose.[69] In addition, lowering LDL cholesterol reduces the cardiovascular risk of lipoprotein, a particle similar to LDL but containing apolipoprotein a, which causes it to promote thrombosis.[70] Niacin and the fibrate drugs are considered better agents for increasing HDL in certain circumstances, but the use of these agents in combination with other measures in various metabolic hyperlipidemic states is a complex issue. The reader is referred to a recent monograph by Grundy.[71] The drug probucol and the natural vitamins E and C are antioxidants which may impact the deleterious effects of oxidized LDL. Recent trials examining the use of vitamin E supplements were reported as yielding an associated 40% risk of coronary disease.[72] The role of antioxidants and correlation with plaque dynamics has emerged as an important new consideration, as these agents might be used as drugs.
ANTIOXIDANTS Oxidative damage to proteins, DNA, and macromolecules occurs with age and has been generally thought to be a major, but not the single factor in endogenous changes leading to aging and degenerative diseases, including atherosclerosis.[73] Experimentally, preservation of endogenous antioxidant activity and inhibition of lipid peroxidation are common mechanisms of antiatherosclerotic attributes of vitamin E as well as the drugs lovastatin and amlodipine based on superoxide dismutase measurements and extent of atherosclerosis.[74] A serial coronary angiographic study of men after bypass surgery indicated less coronary progression among men with supplementary vitamin E intake of 100 IU daily as compared to the use of vitamin C supplements exclusively or use of other multivitamins.[75] Randomized trials have shown questionable benefit in coronary events with vitamin E and not with vitamin A. These potentially new agents, along with the oxidative modification hypothesis of atherogenesis, have been exhaustively reviewed.[76]
CIGARETTE SMOKING This is the most prevalent and the most ominous risk factor in patients presenting with atherosclerotic disease. This habit is directly related to the progression of peripheral atherosclerosis to amputation,[77] high mortality from ischemic heart disease,[78] failure of aortic grafts,[79,80] and the failure of femoral-popliteal grafts,[81] added to the list of woes. For the practicing vascular surgeon, smoking cessation is the most important intervention required both pre- and postoperatively. The means by which cigarette smoking promotes atherosclerosis and graft thrombosis are incompletely understood. Carbon monoxidemia probably predisposes to arterial wall injury by producing increased plasma flux into the arterial
wall and entry of LDL and other proteins. Cigarette smoking causes increased platelet reactivity, promotes peripheral vasoconstriction, and is associated with reduced HDL levels.[82] It is interesting that in populations in whom LDL levels are exceedingly low, cigarette smoking may not be associated with a high incidence of atherosclerotic vascular disease. While it is well known that smoking is the most important factor in both rapid progression of atherosclerosis and graft failure and that cessation has an immediate potent and beneficial effect, a recent report suggested that pack-years of smoking, but not current versus past smoking, was associated with more rapid disease progression.[83] The progression in this study was a measure of intima-medial thickness of the carotid artery assessed by ultrasound and adjusted for demographic characteristics, cardiovascular risk factors, and lifestyle variables. This result from a clinical standpoint seems counterintuitive and should not exclude the vascular surgeon or physician from energetic management attempts at smoking cessation. Smoking cessation clinical practice guidelines have been recommended to identify and treat smokers with cessation and motivational intervention,[84] offer nicotine replacement, and scheduled follow-up contacts. Nicotine-replacement therapy is most effective when used as part of a program.[85] Following personal advice given by physicians to encourage smoking cessation at a single consultation, only an estimated 2% of all smokers stopped smoking with no relapse after one year.[86] With repeated visits, vascular surgeons should be able to improve this. Finally, bupropion therapy at higher dosages has improved results to 44.2% at 7 weeks as compared to placebo therapy with counseling, which yielded 19% at this short interval.[87]
HYPERTENSION Hypertension is a potent cardiovascular risk factor; its adequate control prolongs life. In experimental animals, atherosclerosis associated with hyperlipidemia is accelerated by chronic hypertension.[88] However, as with cigarette smoking, Asian and Caribbean populations exhibit hypertension with a low incidence of atherosclerotic disease in the absence of hyperlipidemia. Treatment of hypertension with thiazide diuretics was disadvantageous in a certain group of men, as shown in a previous trial. Traditionally, sodium reduction and weight loss have been regarded as an important recommendations; these measures in older people have been found to be feasible and safe in recent trial.[89] However, a recent meta-analysis addressing the controversy as to whether or not reduced sodium intake might decrease the blood pressure of a population did not support this general recommendation.[90] A recent issue is whether or not antihypertensive drugs, specifically calcium antagonists and angiotensin-converting enzyme (ACE) inhibitors, exert an antiatherosclerotic effect. Trials have been structured to test antiatherosclerotic actions of an ACE inhibitor versus diuretics in antihypertensive therapy as it affects carotid atherosclerosis.[91] ACE inhibitors may contribute to plaque stabilization by a variety of mechanisms, including inhibition of angiotensin II gener-
Chapter 14.
Medical Management of Atherosclerotic Vascular Disease
ation, antagonists of macrophage function and migration, and inhibition of thrombotic and sympathetic activity.[92] A number of trials using combined therapy to assess plaque stabilization, arrest, or regression are in progress.
DIABETES MELLITUS One of the most important risk or actual pathogenetic factors promoting atherosclerosis is diabetes. In its singular form, diabetes is associated with severe infracrural and coronary atherosclerosis. A current diabetes control trial[93] revealed favorable reduction in microvascular complications with “tight control” using insulin; unfortunately, this trial was not designed to study endpoints of macrovascular atherosclerotic complications. Diabetes as it affects atherogenesis has not been studied extensively in animal models of atherosclerosis. Causes of enhanced atherogenesis in diabetes include abnormalities in apoprotein and lipoprotein particle distributions, particularly elevated levels of lipoprotein(a),[94] an independent thromboatherosclerotic risk factor. In poorly controlled diabetes, a procoagulant state exists; insulin resistance and hyperinsulinemia also might contribute to smooth muscle proliferation. Not only do glycooxidation and oxidation contribute to LDL entry into macrophages, glycation of proteins and plasma in the arterial wall could contribute further to accelerated atherosclerosis in diabetics. Hormones, growth factors, cytokine-enhanced smoothmuscle cell proliferation, and increased foam cell formation are also postulated to be unique aspects of atherogenesis in diabetes mellitus.[95] However, it is not known which of these factors dominates atherogenesis in diabetes and why the distal vessels are more severely affected. In view of the utility of tight control in preventing microvascular and infectious complications, aggressive control of blood glucose on a consistent basis appears advisable. With any given level of LDL, coronary heart disease risk is tripled in patients with diabetes relative to those without,[96] an important consideration in overall management. In the diabetic, elevated triglyceride levels most commonly accompany severely elevated cholesterol levels; this particular combination greatly increases the risk of adverse coronary events.
OTHER RISK FACTORS Lack of exercise, obesity, and psychological factors are also to be considered. The classic retrospective study reported that sedentary London bus drivers had a higher incidence of coronary disease than a matched cohort of their more physically active bus conductors.[97] The Framingham Study[98] showed an inverse relationship of overall mortality, cardiovascular mortality, and CHD mortality as related to physical activity. This effect was small as compared to the major risk factors of smoking, hypertension, diabetes, and hyperlipidemia. Obesity remains a controversial risk factor.[99] Insurance statistics suggest that obesity promotes excess cardiovascular mortality,[100] and that life expectancy
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increases with weight reduction. Other data have been interpreted to suggest that obesity may be benign in the absence of other major risk factors.[101] Framingham prospective studies challenged these results.[102] Psychological studies associate coronary artery disease with type A behavior. These are also controversial.[103] Type A persons are said to exhibit enhanced competitiveness, ambitiousness, and a chronic sense of time urgency. The clinical impression that personality characteristics play a strong role in coronary artery disease was first stated in 1633. Fabrizio Bartoletti described patients with coronary disease to be “dissatisfied with themselves and others, very ill-humored, and easily angered or annoyed.” Clarkson[104] recently quoted Osler,[105] who noted the typical coronary patient to be “the robust, the vigorous in mind and body, the keen and ambitious man; whose engine is always at full-speed ahead.” Clarkson’s experiments[104] showed that highly aggressive monkeys who were kept in chronically unstable social conditions developed more extensive coronary atherosclerosis than dominant monkeys living in unstressed social conditions. These studies link the risk factor of stress to morphologically measured disease severity. It would not appear likely that surgeons would commonly employ psychological intervention, but they might consider behavior modification.
EXERCISE The effects of exercise on any treatment of atherosclerosis must be considered from two viewpoints: preventative or therapeutic for established disease. Epidemiologically, little doubt exists that habitual physical activity decreases the primary incidence of coronary heart disease.[106] The relative risk of physical inactivity is similar to the risk factors of hypertension, hyperlipidemia, and smoking. However, symptomatic improvement of established atherosclerosis, e.g., angina or claudication, appears to relate mainly to muscular tone and conditioning. A direct effect of exercise on the atherosclerotic plaque or on collateral arterial development has yet to be shown. Episodes of sudden death due to coronary atherosclerosis during exercise or emotional stress are believed to result from plaque disruption; this remains a matter of continuing concern[107,108] for clinicians. In evaluating exercise research studies, an operational definition of physical activity should be sought. Exercise is a complex behavior for which no standard measurement exists such as can be done for blood pressure or lipid profiles. Classic epidemiologic studies of CHD focused on occupation, e.g., London bus drivers versus conductors or longshoremen versus sedentary workers. Modern exercise research uses standard aerobic exercise programs. For example, recent research compared dietary weight loss to exercise by measuring enhanced VO2max induced by exercise to a predetermined amount.[109] This study suggested that weight loss by diet was preferred treatment to improve CHD risk factors in overweight middle-aged men, but these conclusions have been questioned.[110] Other studies using exercise combined with multiple
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interventions have shown favorable angiographic effects on rate of coronary plaque progression.[111] The quantitation of exercise in multiple intervention studies is often difficult to assess, as is its contribution to favorable effects observed. Regular exercise improves lipid profile and glucose and insulin metabolism, aids in weight reduction, and improves muscle tone and endurance. Exercise is undoubtedly beneficial in the treatment of claudication,[112 – 116] but direct effects of exercise on blood vessels and atherosclerosis remain to be determined. Experimentally, computer models of flow dynamics of human aortas show that with increased flow, shear stress is normalized, and thus atherosclerosis might be inhibited.[117] Favorable effects in clotting and platelet reactivity have also been shown in humans.[118] The role of exercise needs more study before specific prescriptions can be made for treatment. Recent pragmatic prescriptions suggest the prophylactic utility of moderate exercise such as brisk walking 30 minutes daily; others have warned of deleterious effects of intense exercise due to free radicals.[119] Highly trained athletes showed no ill effects on lipid levels or antioxidant activity after extreme exertion using the iron man triathlon as a model.[120]
ANTIPLATELET AND ANTICOAGULANT THERAPY To date, the only interventions shown to alter intrusive atherosclerotic plaques toward regression or arrest have employed the combination of both serum lipid reduction and cessation of smoking. Antiplatelet therapy has not yet been demonstrated to produce favorable effects on established lesions. In fact, the reverse has been described in some experimental studies.[121 – 123] The use of antiplatelet agents is based on the theory that these drugs might alter atheroma growth due to abnormal platelet kinetics or inhibit platelet-derived growth factors. Such hopes have not yet been fulfilled. The serial demonstration of beneficial effects on plaque morphology has been seen unequivocally in humans and animals only with lipid reduction. A voluminous literature regarding the optimal aspirin dose has been reviewed by Wecksler.[124] Smaller rather than larger doses of aspirin are now considered advantageous. Small doses of aspirin are recommended for certain patients (e.g., those with a asymptomatic carotid lesions or those who have had one transient ischemic attack). The data concerning intraplaque hemorrhage due to antiplatelet therapy are conflicting.[125,126] A number of patients needing vascular surgery have been found to exhibit hypercoagulable states, often manifested by postoperative graft thromboses. These patients may exhibit low antithrombin III levels and abnormalities of proteins C and S as well as plasminogen.[127] In properly selected patients, coumadin treatment will be useful postoperatively. Newer agents for patients at risk for ischemic events include antiplatelet agents such as ticlopidine and clopidogrel; the latter is believed to be safer as compared to aspirin 325 mg once daily[128] for the endpoints of stroke and myocardial infarction.
NEW HORIZONS Homocysteine and Folic Acid Supplementation Among the risk factors identified for cardiovascular disease, an elevated homocysteine level has surfaced.[129 – 131] Folic acid supplementation has been suggested for lowering homocysteine levels, but considerable controversy continues as to whether this should be done as a public health matter.[132] The addition of “either 140 or 350 mg of folic acid per 100 g of grain product”[133] or using folic acid supplements with mandatory addition of 1000 mg of vitamin B12 has been debated. Typical multivitamin supplements contain about 400 mg of folic acid.
Infection: Viral and Chlamydia pneumoniae Herpesviruses are widespread and often systemic in the general population. Antigens and nucleic sequences of herpesviruses have been found in atherosclerotic lesions; herpesvirus-induced atherosclerosis has been produced in animals; the herpesvirus family causes cholesterol ester accumulation in smooth muscle cells, induces growth factors and cytokines by vascular and inflammatory cells, and has procoagulant effects on endothelium.[134] The cytomegalovirus (CMV) relationship to atheroma is another observation previously mentioned.[10] Such circumstantial evidence of potential viral factors requires proof of a causal relationship. Another, perhaps more exciting, observation was the 1992 detection of Chlamydia pneumoniae by immunochemical staining and electron microscopy in coronary atheroma.[135] The organism has since been found in atherosclerotic lesions in the aorta and carotid and femoral arteries. In the peripheral arteries C. pneumoniae was detected in 48% (11/23) patients using several methods.[136] In another important study, coronary atherectomy specimens from 90 patients were definitely positive by direct immunofluorescence in 73% and equivocally positive in 6%, for a total of 79% showing evidence for the presence of these organisms.[137] This result compared with only one of 24 nonatherosclerotic coronaries showing evidence of Chlamydia. The evidence suggests that the first of Koch’s postulates has been fulfilled with regard to Chlamydia in atheromas. Animal studies as well as antibiotic trials are now in progress.
Gene Therapy Although not affecting the atheroma itself, this concept is based on the idea that new blood vessel growth might be induced by the use of direct application of growth factors.[138] These include fibroblast[139] and vascular endothelial growth factors (VEGF). The delivery of these growth factors includes direct gene application of DNA, by a viral vector using intravascular injection, by balloons or stents, and by direct application. Transfer of DNA coding for angiogenesis is a novel approach that will require considerable study to assess
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its value for revascularization. The reader is referred to a recent review.[140] Another aspect of gene therapy concerns the control of lipid metabolism. In transgenic mice in whom a rat apolipoprotein E (apo E) gene has been established, overexpression of apo E reduces plasma cholesterol and triglycerides, preventing atherosclerosis.[141] In another example, phenotypic correction of hyperlipidemia in rabbits was achieved by hepatic delivery of the rabbit LDL receptor gene.[142] These therapies are likely to assume importance in the treatment of familial hyperlipidemias.
CONCLUSIONS This chapter has considered the management of atherosclerosis as if it were a single entity. However, the clinical
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presentations of atherosclerosis are varied; a spectrum of lesions, some with differing modes of pathogenesis, exist, and the disease involves distinct patterns of distribution and progression rates. A simplistic approach to management will not suffice; the treating clinician will need to individualize medical and surgical management based on clinical presentations. In certain cases, peripheral vascular interventions in continued smokers will make matters ultimately worse. In coronary disease, interventions directed at lipid lowering appear to now show real primary and secondary benefit. This is of relevance to vascular surgeons since many of our patients succumb to coronary disease. The use of antioxidants promises benefits with little risk, as does dietary supplementation for homocystinemia. Finally, the unstable characteristics of certain atheromatous plaques, in particular arterial segments, have now been clearly recognized; visualization techniques permit quantitative evaluations of treatment of the arterial lesion itself.
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Part Two. Medical Treatment Grandl, V.A.; Galloe, A.M.; Garred, P. Effects of Sodium Restriction on Blood Pressure, Renin Aldosterone, Catecholamines, Cholesterols and Triglyceride. J. Am. Med. Assoc. 1998, 279, 1383. Zanchett, A. Antiatherosclerotic Effects of Antihypertensive Drugs: Recent Evidence and Ongoing Trials. Clin. Exp. Hypertens. 1996, 18, 489. Pepine, C.J. Ongoing Clinical Trials of AngiotensinConverting Enzymes Inhibitors for Treatment of Coronary Artery Disease in Patients with Preserved Left Ventricular Function. J. Am. Coll. Cardiol. 1996, 27, 1048. The Diabetes Control and Complication Trial Research Group; The Effect of Intensive Treatment of Diabetes on the Development and Progression of Long-Term Complications in Insulin-Dependent Diabetes Mellitus. N. Engl. J. Med. 1993, 329, 977. Loscalzo, J. Lipoprotein(a): A Unique Risk Factor for Atherothrombotic Disease. Arteriosclerosis 1990, 10, 672. Bierman, E.I. Atherogenesis in Diabetes. Arterioscler. Thromb. 1992, 12, 647. Stammler, J.; Vaccaro, O.; Nealon, J.D.; Westworth, D. Diabetes and Other Risk Factors and 12 Year Cardiovascular Mortality for Men Screened for MRFIT. Diabetes Care 1993, 16, 434. Morris, J.N.; Heady, J.A.; Raffle, P.A.B.; et al. Coronary Heart Disease and Physical Activity of Work. Lancet 1953, 2, 1053. Dawber, T.R. The Epidemiology of Atherosclerotic Disease: The Framingham Study; Harvard University Press: Cambridge, MA, 1980. Barrett-Connor, E.L. Obesity, Atherosclerosis and Coronary Artery Disease. Ann. Intern. Med. 1985, 102, 1010. Lew, E.A. Importance of Overweight in Life Insurance. 11th International Congress of COINTRA, 1969, p 277. Rosenman, R.; Brand, R.; Shaltz, R.; Friedman, M. Multivariable Prediction of Coronary Heart Disease. Am. J. Cardiol. 1976, 37, 903. Hubert, H.B. The Nature of the Relationship Between Obesity and Cardiovascular Disease. Int. J. Cardiol. 1984, 6, 268. Criqui, M.H. Epidemiology of Atherosclerosis: An Update and Overview. Am. J. Cardiol. 1980, 57, 186. Clarkson, T.B. Personality, Gender and Coronary Atherosclerosis of Monkeys. Arteriosclerosis 1987, 7, 1. Osler, W. The Lumeian Lectures on Angina Pectoris. Lancet 1910, 1, 839. Powell, K.E.; Thompson, P.D.; Casperson, C.J.; Kentrick, J.S. Physical Activity and the Incidence of Coronary Heart Disease. Ann. Rev. Public Health 1987, 8, 253. Curfman, G.D. Is Exercise Beneficial—or Hazardous—to Your Heart? N. Engl. J. Med. 1993, 329, 1730. Ciampricotti, R.; Deckers, J.W.; Tavern, R.; et al. Characteristics of Conditioned and Sedentary Men with Acute Coronary Syndromes. Am. J. Cardiol. 1994, 73, 219. Katzel, L.I.; Bleeker, E.R.; Colman, E.G.; et al. Effects of Weight Loss vs Aerobic Exercise Training on Risk Factors for Coronary Disease in Healthy, Obese, Middle Aged and Older Men. J. Am. Med. Assoc. 1995, 274, 1915. Civish, F.M. Letter. J. Am. Med. Assoc. 1996, 275, 1546.
111. Haskell, W.L.; Alderman, E.L.; Fair, J.M.; et al. Effects of Intensive Multiple Risk Factor Reduction on Coronary Arteriosclerosis. Circulation 1994, 89, 975. 112. Jonason, T.; Jonzon, B.; Ringquist, I.; Oman-Rydbert, A. Effects of Physical Training on Different Categories of Patients with Intermittent Claudication. Acta Med. Scand. 1979, 206, 253. 113. Hiatt, W.R.; Regensteiner, F.G.; Hargarten, M.E.; et al. Benefit of Exercise Conditioning for Patients with Peripheral Arterial Disease. Circulation 1990, 81, 602. 114. Creasy, T.S.; McMillan, P.J.; Fletcher, E.W.L.; et al. Is Percutaneous Transluminal Angioplasty Better Than Exercise for Claudication. Preliminary Results from a Prospective Randomized Trial. Eur. J. Vasc. Surg. 1990, 4, 135. 115. Gardner, A.W.; Poehlman, E.T. Exercise Rehabilitation for the Treatment of Claudication Pain: A Meta Analysis. J. Am. Med. Assoc. 1995, 274, 975. 116. Williams, L.R.; Ekers, M.A.; Collins, P.S.; Lee, J.F. Vascular Rehabilitation: Benefits of a Structured Exercise/Risk Modification Program. J. Vasc. Surg. 1991, 14, 320. 117. Taylor, C.A.; Tropea, B.I.; Hughes, T.J.R.; Zarins, C.K. Effects of Graded Exercise on Aortic Wall Shear Stress. Surg. Forum 1995, 46, 331. 118. Wang, J.; Fen, C.J.; Chen, H. Effects of Exercise Training and Reconditioning on Platelet Function in Men. Arterioscler. Thromb. Vasc. Biol. 1995, 15, 1668. 119. Kanter, M.M. Free Radicals, Exercise, and Antioxidant Supplementation. Int. J. Sport Nutr. 1994, 4, 205. 120. Ginsburg, G.S.; Agil, A.; O’Toole, M.; et al. Effects of a Single Bout of Ultra-Endurance Exercise on Lipid Levels and Susceptibility of Lipids to Peroxidation in Triathletes. J. Am. Med. Assoc. 1996, 276, 221. 121. DePalma, R.G.; Bellom, E.M.; Manalo, P.; Bomberger, R.A. Failure of Antiplatelet Treatment in Dietary Atherosclerosis: A Serial Intervention Study. In Cardiovascular Disease: Molecular and Cellular Mechanisms, Preventions, Treatment; Gall, L.L., Vahouny, G.V., Eds.; Plenum Press: New York, 1987; 407 – 426. 122. Hollander, W.; Kirkpatrick, B.; Paddock, J.; et al. Studies on the Progression and Regression of Coronary and Peripheral Atherosclerosis in the Cynomolgus Monkey: L Effects of Dipyridamole and Aspirin. Exp. Mol. Pathol. 1979, 30, 55. 123. Dembinska-Kiec, A.; Rucker, W.; Schonhofer, A. Effects of Dipyridamole in Experimental Atherosclerosis. Atherosclerosis 1979, 33, 315. 124. Wecksler, B.B. Arterial Thrombosis, Atherosclerosis and Platelet Activity: A Reassessment of Antiplatelet Therapy. In Atherosclerosis Reviews; Hegyeli, R.J., Ed.; Raven Press: New York, 1984; 39. 125. Lennihan, L.; Kuposky, W.J.; Mohr, J.P.; et al. Lack of Association Between Carotid Plaque Hematoma and Ischemic Cerebral Symptoms. Stroke 1987, 18, 879. 126. AbuRahma, A.F.; Boland, J.P.; Robinson, P.; DeCanio, R. Antiplatelet Therapy and Carotid Plaque Hemorrhage and Its Clinical Implications. J. Cardiol. Vasc. Surg. 1990, 31, 66. 127. Donaldson, M.C.; Weinberg, D.S.; Belkin, M.; et al. Screening for Hypercoagulable States: A Preliminary Study. J. Vasc. Surg. 1990, 11, 825.
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CAPRIE Steering; A Randomized Double Blinded Trial of Clopidogrel Versus Aspirin in Patients at Risk of Ischemic Events. Lancet 1996, 348, 1329. Boers, G.H.J.; Smals, A.G.H.; Trijbels, F.J.M. Heterozygosity for Homocystinuria in Premature Peripheral and Cerebral Occlusive Arterial Disease. N. Engl. J. Med. 1985, 313, 709. Brattstrom, L.E.; Hardebo, J.E.; Hultberg, B.L. Moderate Homocystinemia: A Possible Risk Factors or Arteriosclerotic Cerebrovascular Disease. Stroke 1984, 15, 1012. Taylor, L.M., Jr.; Porter, J.M. Elevated Plasma Homocysteine as a Risk Factor for Atherosclerosis. Semin. Vasc. Surg. 1993, 6, 36. Boston, A.G.; Mayer, J. Folic Acid Fortification of Food [letter]. J. Am. Med. Assoc. 1996, 275, 9. Boushey, C.J.; Beresford, S.A.A.; Omenn, G.S.; Motulsky, A.G. Quantitative Assessment of Plasma Homocysteine as a Risk Factor for Vascular Disease: Probable Benefits of Increasing Folic Acid Intakes. J. Am. Med. Assoc. 1995, 274, 1049. Nicholson, A.C.; Hajjar, D.P. Herpes Virus in Atherosclerosis and Thrombosis: Etiologic Agents or Ubiquitous Bystanders. Arterioscler. Thromb. Vasc. Biol. 1998, 18, 339. Shor, A.; Kuo, C.C.; Patton, D.L. Detection of Chlamydia pneumoniae in Coronary Fatty Steaks and Atherosclerotic Plaques. S. Afr. Med. J. 1992, 82, 158.
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Kuo, C.C.; Coulson, A.S.; Campbell, L.A. Detection of Chlamydia pneumoniae in Atherosclerotic Plaques of Lower Extremities from Patients Undergoing Bypass Operation for Arterial Obstruction. J. Vasc. Surg. 1997, 26, 29. Muhlestein, J.B.; Hammond, E.H.; Carlquist, J.F. Increased Incidence of Chlamydia Species Within the Coronary Arteries of Patients with Symptomatic Atherosclerotic Versus Other Forms of Cardiovascular Disease. J. Am. Coll. Cardiol. 1996, 27, 1555. Lewis, B.S.; Flugelman, M.Y.; Weisz, A. Angiogenesis by Gene Therapy: A New Horizon for Myocardial Revascularization. Cardiovasc. Res. 1997, 35, 490. Tabata, H.; Silver, M.; Isner, J.M. Arterial Gene Transfer of Acidic Fibroblast Growth Factor for Therapeutic Angiogenesis In Vivo: Critical Role of Secretion Signal in Use of Naked DNA. Cardiovasc. Res. 1997, 35, 470. Melillo, G.; Scoccianti, M.; Kovesdi, I.; et al. Gene Therapy for Collateral Vessel Development. Cardiovasc. Res. 1997, 35, 480. Harada, K.; Shimano, H.; Ishibashi, S.; Yamada, N. Transgenic Mouse and Gene Therapy. Diabetes 1996, 45 (Suppl. 3), S129. Li, J.; Fang, B.; Eisensmith, R.C.; et al. In Vivo Gene Therapy for Hyperlipidemia: Phenotypic Correction in Watanabe Rabbits by Hepatic Delivery of the Rabbit LDL Receptor Gene. J. Clin. Investig. 1995, 95, 768.
CHAPTER 15
Regression and Stabilization of Atherosclerosis by Medical Treatment Howard N. Hodis Wendy J. Mack Albert E. Yellin Anitschkow[4] observed that continued cholesterol feeding was necessary to sustain lesions produced in rabbits, the original animal model for atherosclerosis. Subsequently, reversal of atherosclerosis has been observed to occur after discontinuance of cholesterol feeding in all major species of animals used in atherosclerosis research: dogs,[5] rats,[6] pigs, [7] chickens,[8] pigeons, [9] and nonhuman primates.[2,3,10 – 36] Further, regression of atherosclerosis in the presence of continued cholesterol feeding has been observed to occur in animals treated with cholestyramine,[10 – 18] exercise,[19,20] diets high in polyunsaturated fats,[21] alfalfa meal,[22] clofibrate,[37] ileal bypass,[38] and calcium channel blockers.[39 – 41] Nonhuman primates, principally rhesus (Macaca mulatta ) and cynomolgus (Macaca fascicularis ) monkeys, are preferred animals for regression studies because of anatomic, physiologic, and metabolic similarities to human beings. For example, there are minimal differences between humans and macaques in lipoprotein patterns.[42] Hyperlipidemia of the rhesus monkey can be compared to human acquired type II hyperlipoproteinemia.[10] Although other animal models may not demonstrate the clinical features of advanced human disease, the severely atherosclerotic macaque has been shown to develop xanthomata,[43] myocardial infarction, and severe cerebral ischemia.[44,45] Hypercholesterolemia and atherosclerosis have been most commonly induced in monkeys by feeding 0.37 – 2% cholesterol diets with variable amounts of saturated fat (usually in the form of butter) for 2 –38 months. Total cholesterol levels typically are increased to 6.72 – 25.86 mmol/L (260–1000 mg/dL). Regression phases have ranged from 2 weeks to 48 months with cholesterol levels between 2.46 and 7.76 mmol/L (95 and 300 mg/dL), but mostly below 5.17 mmol/L (200 mg/dL). Typical observations of regression are based upon group comparisons of
This chapter presents evidence that the atherosclerotic process can be altered both in native vascular beds and in various bypass grafts. The rationale for risk-factor reduction is to prevent potential problems from disease progression in vascular grafts and to reduce lesion progression in other vascular beds. The surgeon should be aware of the high probability that if one vascular bed requires surgery, then substantial atherosclerosis is also present in other vascular beds.[1] Postoperative management of patients requiring vascular surgery should therefore include systematic evaluation of all vascular areas where risk of end-organ damage is high as well as immediate normalization of lipid abnormalities, reduction of elevated blood pressure, and smoking cessation.
ATHEROSCLEROSIS REGRESSION IN EXPERIMENTAL ANIMAL MODELS The strictest definition of atherosclerosis reversibility requires normalization of vessel wall anatomy and chemical composition, including (1) restoration of the integrity of the endothelium over plaques; (2) arrest of intimal cell proliferation; (3) decrease in the number of cells within lesions plus decreases in intra- and extracellular lipid; and (4) decrease in the extent of necrotic foci and calcification.[2] Controlled studies in animal models with quantitative histology indicate that regression meeting these criteria except for reduction in calcification can be achieved. A more liberal definition and one appropriate for surgical practice would accept as proof of reversibility any change except plaque rupture which reduces the size of intrusive lesions. Reduction in lesion size does not necessarily imply improvement in all cellular elements of the lesion.[3]
Hobson/Wilson/Veith: Vascular Surgery: Principles and Practice, Third Edition, Revised and Expanded DOI: 10.1081/0819-9-120024898 Copyright q 2004 by Marcel Dekker, Inc.
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animals sacrificed at different times for morphologic and histochemical exploration of atherosclerosis regression at a cellular level. Physiologic changes induced by regression have also been studied by pulse wave velocity[23] and arterial wall reactivity[24] and relaxation.[25] Absolute establishment of atherosclerotic lesion regression requires that evolution of individual atherosclerotic plaques be studied sequentially over time in the same subject. This has been accomplished in vivo by angiographic examination[18] as well as by serial arteriotomy for direct visualization of change in individual lesions.[5] Portman et al.[26] reported evidence of disease stabilization in squirrel monkeys achieved by returning the animals to regular chow following 3 months on a high-cholesterol diet. Animals returned to the nonatherogenic diet for 3 –5 months showed significantly fewer aortic lesions and less arterial wall lipid content than did those who remained on the atherogenic diet. In the early 1970s, Armstrong et al.[27] demonstrated unequivocal reduction in the size of advancing, stenosing coronary artery lesions in the rhesus monkey. A 17-month induction phase of a high-fat, high-cholesterol diet was followed by 40 months of a cholesterol-free diet, which allowed total cholesterol to return to a baseline level of 3.62 mmol/L (140 mg/dL). The lesions produced during dietary induction were found to average 60% obstruction in all main epicardial coronary arteries. After 40 months on regression diets, average coronary lumen obstructions had decreased to approximately 21%. Stary[28] observed normalization of cell kinetics in arterial lesions during regression after returning monkeys to a basal diet for 3 – 10 months. Reparative changes included a measurable decrease in intracellular lipid and a return to normal cellular proliferative patterns. Initial signs of disease reversibility were seen as soon as 4 weeks after the total cholesterol had returned to baseline levels. Foam-cell production stopped and normalization of smooth muscle cell morphology was observed. Tucker et al.[29] returned rhesus monkeys fed a high-cholesterol, high-fat diet for 2 months to a basal diet for 4 months and found a resulting decrease in the quantity of foam cells and intracellular lipid and an increase in extracellular lipid. Biochemical verification of lipid depletion has been demonstrated by Srinivasan et al.[30] in cynomologus monkeys and by Armstrong et al.[31] in rhesus monkeys. Armstrong et al.[31] observed that in arteries that had undergone regression, arterial wall cholesterol content decreased from 51 to 18 mg/g dry weight and that cholesteryl ester and free cholesterol decreased 69 and 53%, respectively. Regression of the atherosclerotic lesions was also accompanied by measurable reductions in the arterial wall collagen and elastin content.[32] Wissler’s group[11 – 16] has shown that experimental lesions in rhesus monkeys can be reversed by treatment with cholestyramine. Male rhesus monkeys were kept on an atherogenic diet for 1 year and then switched to a lowcholesterol, low-fat diet with or without the addition of cholestyramine. A third group of animals received cholestyramine while remaining on the atherogenic diet. The amount of aortic surface area affected with grossly visible lesions was significantly less at 1 and 2 years in all three treatment groups than among control animals who remained on the atherogenic diet (10–31% vs. 62–84%). Low-cholesterol, low-fat diet
with added cholestyramine produced the most favorable results, particularly in the coronary arteries, where there was 1–5% luminal narrowing versus 12 –36% narrowing among animals remaining on the atherogenic diet. Using female cynomolgus monkeys, Malinow et al.[17] also have shown coronary artery regression in monkeys fed an atherogenic diet for 6 months and then treated with cholestyramine for 18 months. Cholestyramine decreased the plasma cholesterol level to normal 4.24 mmol/L (164 mg/dL) and normalized lipoprotein patterns. Mendelsohn and Mendelsohn[21] studied the effect of polyunsaturated fat on regression of aortic and iliac vessel atherosclerosis. Vervet monkeys were initially placed on a “Western” diet containing 190 mg/day of cholesterol with a polyunsaturated/saturated fat (P/S) ratio of 0.28 for 24 months. One group continued on this diet, while the other had an adjustment of the P/S ratio to 1.5 and received an increase in daily cholesterol to maintain equivalence in the total sterol intake between the two groups. Both diets were continued for 20 additional months. Percentage of atheroma and arterial wall content of total cholesterol and cholesteryl ester were significantly higher than at baseline in the group that continued the Western diet ðP=S ¼ 0:28Þ versus the group with the increased P/S ratio (1.5). These results imply that dietary modification of the types and amounts of fats ingested as a cholesterol carrier can influence lesion regression. Kramsch et al.[19,20] studied the effects of exercise during induction of atherosclerosis. Regular moderate exercise in cynomolgus monkeys comparable to jogging in humans increased coronary vessel caliber and decreased lesion size. A control group fed regular chow for 36 months was compared to a group of monkeys on an atherogenic diet for 36 and 42 months. Half the latter group received regular treadmill exercising three times per week while the other half were sedentary. In the sedentary monkeys on the atherogenic diet, coronary artery mean involvement was 46–60%, compared to 15–20% in the exercising monkeys on the atherogenic diet. Whether there may be a threshold total cholesterol level at which atherosclerotic lesions undergo regression has been considered by several investigators. The threshold-forregression levels of total cholesterol tested in monkeys are well within ranges attainable in human beings. Clarkson et al.[33] induced cholesterol levels of approximately 15.51 mmol/L (600 mg/dL) in rhesus monkeys and then compared regression regimens with levels of 5.17 and 7.75 mmol/L (200 and 300 mg/dL). After 24 months, 13 of 19 animals in the 5.17 mmol/L group and 9 of 18 animals in the 7.75 mmol/L group showed coronary artery lesion regression, a nonsignificant difference between the two groups. At 48 months, 5.17 mmol/L prevented progression in practically all of the animals. The authors also reported an inverse relationship between high-density lipoprotein (HDL) cholesterol and coronary artery lesion progression. Only regression and no progression occurred at a total cholesterol/HDL cholesterol ratio of 2.5. No regression was seen in animals with a total cholesterol/HDL cholesterol ratio greater than 3.5. Changes seen in the abdominal aorta were comparable to those observed in the coronary arteries. Armstrong et al.[27] found that a serum cholesterol level of 3.62 mmol/L (140 mg/dL) resulted in regression of severe atherosclerotic lesions in the coronary artery and aorta in
Chapter 15. Regression and Stabilization of Atherosclerosis by Medical Treatment
rhesus monkeys. Vesselinovitch et al.[34] observed that returning rhesus monkeys to a low-cholesterol, low-fat diet for 18 months after 18 months of a high-cholesterol high-fat diet leads to regression of advanced coronary artery and aortic atherosclerotic lesions when total cholesterol levels are maintained at or below 4.52 mmol/L (175 mg/dL). DePalma et al.[18] found that regression of fatty-fibrous plaques in rhesus monkeys occurred at levels of total cholesterol below 5.17 mmol/L (200 g/dL). Several researchers have shown that atherosclerosis can be prevented if calcium channel blockers are administered concurrently with high-cholesterol diets to rabbits[39] and monkeys.[40] Thiery et al.[41] have shown that calcium channel blockers, without altering elevated plasma lipid levels, can lead to regression of established plaques in rabbits.
ATHEROSCLEROSIS REGRESSION AND STABILIZATION IN HUMANS
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Yokoyama et al.[50] demonstrated complete disappearance of a 90% stenotic renal artery lesion in a 5-year-old homozygous familial hypercholesterolemic patient after 6 years of low-density lipoprotein (LDL) apheresis. Prior to therapy, the patient’s total cholesterol was 18.62 mmol/L (720 mg/dL); during plasmapheresis, it averaged 7.76 mmol/L (300 mg/dL). Atherosclerotic lesions also regressed in the supravalvular region of the ascending aorta and stabilized in the coronary arteries.
Carotid Artery Among three brothers with severe familial hypercholesterolemia treated with plasmapheresis and followed with duplex ultrasound imaging, Keller and Spengel[51] observed regression and stabilization in two who had continuous plasmapheresis and progression in one who discontinued plasmapheresis.
Coronary Artery and Aorta
Uncontrolled Studies and Case Reports Femoral Artery The earliest human angiographic studies, of the femoral ¨ st and Ste´nson,[46] who treated 31 arteries, were reported by O hyperlipidemic men for intermittent claudication with 3 –6 g of nicotinic acid per day. After a mean treatment period of 42 months, 3 patients showed regression and 11 patients arrest of progression of femoral lesions. Barndt et al.[47] in a study conducted on 25 hyperlipidemic patients, reported 9 patients with regression and 3 with arrest in progression after an average of 13 months of treatment with lipid-lowering drugs, principally clofibrate and neomycin. Regression of disease was significantly correlated with reductions in total serum cholesterol levels, triglyceride levels, and systolic and diastolic blood pressures.
Popliteal Artery In one of the first angiographic case studies, DePalma et al.[48] showed plaque regression by serial arteriograms taken 9 months apart in the popliteal artery of a 57-year-old diabetic man who had reduced his total cholesterol from 8.46 to 4.91 mmol/L (327 to 190 mg/dL) after initiating dietary therapy, exercise, and cessation of cigarette smoking.
Renal Artery Basta et al.[49] reported a case of a 49-year-old hypertensive woman with renovascular hypertension due to a 90% occlusion of the right renal artery and a 75% narrowing of the left renal artery. After 3 years of therapy with cholestyramine and clofibrate, total cholesterol was reduced from 8.79 to 3.90 mmol/L (340 to 151 mg/dL) and total triglycerides from 1.77 to 1.37 mmol/L (157 to 121 mg/dL). A repeat arteriogram showed almost complete resolution of the right renal artery occlusion and some regression of the left renal artery lesion, with concomitant normalization of blood pressure and the peripheral vein plasma renin level.
Long-term (1 –2 years) plasma exchange for treatment of familial hypercholesterolemia was evaluated with serial aortograms and coronary angiograms 1 –2 years apart by Thompson et al.[52] Plasma exchange plus nicotinic acid in three homozygous patients produced a reduction in mean total cholesterol from 15.83 to 9.52 mmol/L (612 to 368 m/dL) and angiographic evidence of aortic supravalvular lesion stabilization. In two heterozygous patients, plasma exchange plus cholestyramine reduced mean total plasma cholesterol from 6.36 to 4.65 mmol/L (246 to 180 mg/dL), with coronary artery lesion regression in one patient and stabilization in the other. Stabilization of coronary atherosclerosis for 3 years with plasma exchange and lipid-lowering medication has also been demonstrated in homozygous familial hypercholesterolemia by Stein et al.[53] Rafflenbeul et al.,[54] in an angiographic study of coronary anatomy of 25 patients with unstable angina, noted regression in 5 patients treated after an average interval of 1 year with a low-saturated-fat diet and counseling for cigarette cessation. Lipid-lowering medications were not used. Roth and Kostuk[55] reported a symptomatic patient with a positive exercise thallium stress test and a 90% stenosis of the left anterior descending artery. Dietary modification and increased exercise reduced the total serum cholesterol level from 6.96 to 5.20 mmol/L (269 to 201 mg/dL) and the triglyceride level from 2.21 to 0.03 mmol/L (205 to 93 mg/dL). Repeat angiography 1 year later showed decreased stenosis in the left anterior descending artery and disappearance of retrograde collateral filling from the right coronary artery seen on a first angiogram. The patient was asymptomatic and repeat exercise thallium stress tests were normal. Kuo et al.[56] examined the effect of lipid lowering induced by dietary and colestipol therapy on coronary artery, brachiocephalic, and peripheral arterial lesions in familial type II hyperlipoproteinemia with a 3- to 4-year interval between angiograms. Average total cholesterol level decreased from 10.68 to 6.98 mmol/L (413 to 270 mg/dL) and the LDL cholesterol from 8.56 to 4.86 mmol/L (331 to
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188 mg/dL). Stabilization of lesions was demonstrated in all three vascular beds in 21 of 25 subjects. Nash et al.[57] reported 25 patients who received colestipol hydrochloride and 17 nonresponders to colestipol who were given placebo. All patients were on a low-cholesterol, low-fat diet, and all had baseline serum cholesterol levels greater than 6.46 mmol/L (250 mg/dL). Angiograms were repeated after 2 years, at which time the total cholesterol had decreased 21%, 7.24 to 5.74 mmol/L (280 to 222 mg/dL), with colestipol treatment and 2% 6.77 to 6.64 mmol/L (262 to 257 mg/dL), in the placebo group. In the drug-treated group, 22 of 25 patients had stable coronary artery lesions, in the placebo group, 9 of 17 were stable ðp ¼ 0:011Þ: Nikkila et al.[58] compared 28 patients on lipid-lowering diet and clofibrate and nicotinic acid therapy to 13 nonrandomized controls drawn from another study who were not on lipid-lowering diet or medication. In the dietdrug–treated group, total cholesterol, triglyceride, and LDL cholesterol decreased by an average of 18, 38, and 19%, respectively, and HDL cholesterol increased 10%. More patients showed coronary artery lesion stabilization upon repeat angiography at 2 years in the treated group than in the control group: 9 out of 28 (32%) versus 1 out of 13 (8%). The Leiden Intervention Trial,[59] a 2-year test of vegetarian diet with a P/S ratio greater than 2.0 and cholesterol intake less than 100 mg/day, included 39 patients with angiograms separated by 2 years. There was no control group. Eighteen patients showed no progression in coronary angiograms analyzed both by visual assessment and computerized image processing. Lesion progression was strongly related to the total cholesterol/HDL, cholesterol ratio, and no coronary lesion progression occurred in patients with a total cholesterol/HDL cholesterol ratio below 6.9 throughout the study or in those who had reduced a high ratio at baseline to less than 6.9. An important finding of the Leiden study was the indication that lesion progression can be arrested by dietary modification without weight loss. Atherosclerotic lesions have long been known to decrease with severe, war-related dietary deprivation[60] and wasting disease.[61]
Controlled Clinical Trials Femoral Artery In 1976, Terry et al.[62] reported atherosclerotic lesion stabilization in a randomized double-blind test of pyridinol carbamate versus placebo. After 2 years of treatment, 19 of 22 drug-treated patients showed no progression, while 15 of 16 placebo patients did show progression. This study provided early information on an appropriate treatment interval for angiographic trials because angiograms were obtained yearly and showed a difference in progression at 2 years. In a study of advanced femoral artery disease, Duffield et al.[63] described quantitative evidence of disease stabilization and regression. Twenty-four patients with stable intermittent claudication and baseline total cholesterol levels greater than 6.52 mmol/L (252 mg/dL) and/or triglyceride levels exceeding 1.78 mmol/L (158 mg/dL) were randomly assigned to a usual-care group or a drug treatment group,
which included dietary advice and cholestyramine, nicotinic acid, or clofibrate therapy. All patients received antismoking advice and a weight-reducing diet if indicated. Patients in the usual-care group showed no significant lipid changes. The treatment group exhibited mean plasma reductions in total cholesterol, total triglycerides, LDL cholesterol, and VLDL cholesterol of 25, 45, 28, and 57%, respectively, and a 26% increase in HDL cholesterol. Paired, matched femoral angiograms obtained an average of 19 months apart were analyzed visually and by computerized image processing. The treatment group had 60% fewer arterial segments showing progression than did the control group ðp , 0:01Þ: The mean increment in the arterial surface area covered by plaque (square millimeter per segment per year) among the treated patients was 33% less than that observed among the nontreated patients ðp , 0:01Þ: Regression was observed in 15 of 46 segments in the treatment group compared to 7 of 46 in the control group as determined by an edge irregularity index ðp , 0:05Þ: The Cholesterol-Lowering Atherosclerosis Study, described in more detail in the next section, was a randomized, placebo-plus-diet controlled clinical trial of aggressive colestipol-niacin plus dietary therapy to reduce LDL cholesterol and increase HDL cholesterol. Coronary, carotid, and femoral arterial beds were studied to provide a complete survey of atherosclerosis. These three vascular beds were visualized by angiographic and/or ultrasonographic methodology. The femoral arteries were visualized with angiography at baseline and after 2 years of treatment in 153 subjects. The annual rate of change in a computer-estimated measure of lumen abnormality was used to determine the persegment therapy effect between treatment groups.[64] A significant per-segment treatment effect was found in segments with moderately severe atherosclerosis ðp , 0:04Þ and in proximal segments ðp , 0:02Þ; but not in segments with mild or severe atherosclerosis.
Coronary Artery Lipid-Lowering Antiatherosclerosis Therapies. Cohn et al.,[65] who conducted the earliest controlled coronary angiographic trial, randomized 24 patients to clofibrate therapy and 16 patients to placebo. Total cholesterol and triglyceride levels were minimally reduced 3 and 14%, respectively, in the clofibrate group. No significant reduction in the progression of atherosclerosis was noted after 1 year. The National Heart, Lung, and Blood Institute Type II Coronary Intervention Study[66,67] (NHLBI type II) was a double-blind, randomized, placebo-controlled trial designed to test the effects of cholestyramine on the progression of coronary atherosclerosis. Average entry serum levels for total cholesterol, triglyceride, LDL cholesterol, and HDL cholesterol were 8.35, 1.85, 6.52, and 1.01 mmol/L (323, 164, 252, and 39 mg/dL), respectively. A prerandomization lowcholesterol, low-fat diet reduced LDL cholesterol 6% in both the treatment and control groups. After randomization, this level decreased another 5% in the control group and another 26% in the cholestyramine-treated group. At the end of the 5-year study period, there was a significant difference in total cholesterol, 7.47 versus 6.62 mmol/L (289 vs. 256 mg/dL), and LDL cholesterol, 5.66 versus 4.60 mmol/L
Chapter 15. Regression and Stabilization of Atherosclerosis by Medical Treatment
(219 vs. 178 mg/dL), between the cholestyramine and placebo groups. Triglyceride levels, 1.82 versus 2.18 mmol/L (161 vs. 193 mg/dL), and HDL cholesterol, 1.01 versus 1.06 mmol/L (39 vs. 41 mg/dL), were not significantly different between the two groups. Matched angiograms were evaluated in 116 patients, 57 placebo-treated and 59 cholestyramine-treated, after 5 years. Repeat angiograms were originally scheduled after 2 years, but only 9 out of 31 patients showed any lesion change, and the interval was therefore lengthened to 5 years. Definite progression of disease occurred in 35% (20 of 57) of the placebo-treated group compared to 25% (15 of 59) of the cholestyramine-treated group. Probable progression was found in 14% (8 of 57) of the placebo patients and in 7% (4 of 59) of the drug-treated patients. Definite and probable progression combined occurred in 49% (28 of 57) of the placebo-treated patients compared to 32% (19 of 59) of the cholestyramine-treated patients ðp , 0:05Þ: Definite regression was found in 2% (1 of 57) of the placebo-treated group compared to 3% (2 of 59) of the drug-treated group. After baseline demographic inequalities and lesion severity were taken into account, it was found that lesions with a 50% or more stenosis at baseline progressed more slowly in the cholestyramine-treated group than in the placebo-treated group, 12 versus 33% respectively ðp , 0:05Þ: Increases in ratios of HDL cholesterol/total cholesterol and HDL cholesterol/LDL cholesterol were found to be the best predictors of lesion stabilization.[67] The Cholesterol-Lowering Atherosclerosis Study (CLAS)[68] was the first angiographic trial to demonstrate lesion regression in humans. This was a single-blind, randomized, placebo-controlled angiographic trial consisting of 188 nonsmoking, nondiabetic, normotensive men aged 40– 59 years who all had coronary bypass surgery and entrance fasting cholesterol levels between 4.78 and 9.05 mmol/L (185 and 350 mg/dL). Coronary angiograms were obtained at baseline and repeated 2 years after therapy in 162 patients. The control group films were evaluated first by panels of expert angiographers with a global change score (GCS)[68] and later by quantitative coronary angiography (QCA) using automated computerized image processing.[69,70] The control group followed a diet that provided 26% of energy as fat (10% as polyunsaturated fat and 5% as saturated fat) and contained 250 mg of cholesterol per day. The treatment group received maximal dosage of colestipol (30 g/day) and nicotinic acid (3–12 g/day, average 4.3 g/day) as well as a diet that provided 22% energy as fat (10% polyunsaturated fat and 4% saturated fat) and contained 125 mg/day of cholesterol. After 2 years of intervention, the treatment group showed large decreases in total cholesterol (27%), from an average of 6.36 mmol/L (246 mg/dL) at baseline to 4.65 mmol/L (180 mg/dL); total triglycerides (27%), 1.70 to 1.24 mmol/L (151 to 110 mg/dL); LDL cholesterol (43%), 4.42 to 2.51 mmol/L (171 to 97 mg/dL); and the ratio of LDL cholesterol/HDL cholesterol (58%), 4.0 to 1.7. HDL cholesterol increased 36% from 1.15 to 1.57 mmol/L (44.6 to 60.8 mg/dL). In the placebo group, smaller, statistically significant decreases also occurred: total cholesterol (5%), 6.28 to 6.00 mmol/L (243 to 232 mg/dL); total triglycerides (8%), 1.74 to 1.59 mmol/L (154 to 141 mg/dL); LDL cholesterol (5%), 4.37 to 4.14 mmol/L
253
(169 to 160 mg/dL); and LDL cholesterol/HDL cholesterol (8%), 4.0 to 3.7. HDL cholesterol also increased 2%, from 1.13 to 1.15 mmol/L (43.7 to 44.4 mg/dL). All 162 patients had evaluable GCS end points; 156 of the 162 patients had evaluable end points by QCA. The distribution of angiographic change as determined by GCS (percentage of control group patients vs. percentage of treatment group patients) was regression (4% vs. 16%), progression (59% vs. 39%), and no change (37% vs. 45%) ðp , 0:001Þ: The percentage of patients in the treatment group with new lesion formation in native arteries was reduced compared to the control group (22% vs. 10%; p , 0:03).[68] Also compared to the control group, the drugtreated group showed a significant reduction in the percentage of patients with new lesion formation (30% vs. 12%; p , 0:04) and any adverse changes (39% vs. 24%; p , 0:03) in the venous bypass grafts.[68] The average ^ standard deviation change in percent diameter stenosis (% S) and minimum lumen diameter (MLD) for native arteries plus venous bypass grafts as determined by QCA (control group vs. treatment group) was 2:7 ^ 5:8% S versus 0:3 ^ 5:9% S ðp ¼ 0:02Þ and 20:09 ^ 0:26 mm versus 20:01 ^ 0:22 mm ðp ¼ 0:04Þ; respectively.[70] The evidence for angiographic benefit retained statistical significance after the cohort was divided according to baseline total cholesterol levels, ranging from 4.78 to 6.20 mmol/L (185 to 240 mg/dL) and from 6.23 to 9.05 mmol/L (241 to 350 mg/dL). This implicates the entire range of total cholesterol from 4.78 to 9.05 mmol/L (185 to 350 mg/dL) as a risk factor for arterial lesion progression. In a 2-year continuation study of the CLAS trial (CLAS II)[71] repeat coronary artery angiograms were obtained in 103 patients who continued colestipol –nicotinic acid therapy ðn ¼ 56Þ and placebo ðn ¼ 47Þ for an additional 2 years. Changes in lipid levels obtained in CLAS I were maintained in CLAS II. The repeat angiograms represented 4 years of colestipol–nicotinic acid therapy, which, when compared to the control group, showed a greater percentage of patients with regression (18% vs. 6%), a lesser percentage of patients with progression (48% vs. 88%), and a greater percentage of patients with stabilization (34% vs. 6%). Also compared to the control group, the treatment group showed a significant reduction in the percentage of patients with new lesions (40% vs. 13%) in native arteries. The drug-treated group also showed a significant reduction in the percentage of patients with new lesions in venous bypass grafts as compared to the control group (38% vs. 18%). Overall, the coronary artery lesion status of the drug- and placebo-treated groups grew more divergent over the additional 2 years, with the drugtreated group showing stability of lesions and the placebotreated group showing marked progression.[71] The power of CLAS to detect lesion change was greater than that of previous angiographic trials because more subjects completed sequential angiograms and maintained larger changes in LDL cholesterol (LDL-C) and HDL cholesterol (HDL-C) levels. The Familial Atherosclerosis Treatment Study (FATS) was the first coronary angiographic trial to report reduced cardiac morbidity with medical treatment.[72] One hundred and fortysix men less than 62 years of age with elevated apolipoprotein B levels ð. 125 mg=dLÞ and a family history of coronary artery disease were randomized to lovastatin-colestipol,
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Part Two. Medical Treatment
niacin-colestipol, or conventional care. Angiograms were separated in time by an average 2.5 years and analyzed by QCA. In the conventional care group, 46% of the subjects had lesion progression in at least one proximal coronary artery segment. Progression was less frequent in the subjects treated with lovastatin-colestipol (21%) and niacin-colestipol (25%). Regression was more frequent in the lovastatin-colestipol (32%) – and niacin-colestipol (39%) –treated subjects than those in conventional care group (11%). Multivariate analysis indicated reduction in apolipoprotein B (or LDL-C) and systolic blood pressure and an increase in HDL-C correlated with regression of coronary artery lesions. In the conventional care group, average change (mean ^ standard deviation) in % S was 2:0 ^ 3:7% S versus 20:3 ^ 5:0% S in the lovastatin-colestipol group and 21:1 ^ 3:7% S in the niacin-colestipol group ðp ¼ 0:0009Þ: Mean change in MLD in the conventional care group was 20:05 ^ 0:14 mm versus 20:002 ^ 0:14 mm in the lovastatin-colestipol group and 0:04 ^ 0:12 mm in the niacin-colestipol group ðp ¼ 0:003Þ: Clinical events (death, myocardial infarction, or revascularization) occurred in 19% of subjects in the conventional care group compared to 7% of subjects in the lovastatin-colestipol group and 4% of subjects in the niacin-colestipol group. The relative risk of a clinical coronary event during lipid-lowering therapy compared to conventional care was 0.27 (95% confidence interval, 0.10 –0.77). The University of California, San Francisco, Specialized Center of Research (UCSF SCOR) Intervention Trial was the first randomized, placebo-controlled trial to demonstrate statistically significant coronary angiographic lesion regression in women.[73] This trial was conducted in 72 subjects (41 women), 19 –72 years of age with heterozygous familial hypercholesterolemia in which only 3 subjects had objective evidence of coronary artery disease prior to the baseline angiogram. The treatment group received a combination of lipid-lowering agents up to 30 g of colestipol and 7.5 g of niacin daily. When lovastatin became available, 16 subjects were given 40 –60 mg daily in binary or ternary drug combinations. At first the control group was treated with diet alone. Later, 7 control men and 7 control women took 15 g of colestipol per day. The control group was thus comprised of those treated with diet alone and those with diet plus colestipol. After 2 years of treatment, angiograms were evaluated with per-patient averages in percent area stenosis determined by QCA. Mean change in percent area stenosis among controls was +0.80, indicating an average progression, while mean change for the treatment group was 2 1.53, indicating regression ðp ¼ 0:039Þ: When analyzed by gender, treatment group differences in lesion change among women was significant ðp ¼ 0:05Þ; whereas for men it was not ðp ¼ 0:42Þ: Treated women demonstrated a response of 2 2.06 in percent area stenosis, whereas men demonstrated a 2 0.88 change. Change in percent area stenosis was correlated with on-trial LDL-C levels. Because patients randomized to the UCSF SCOR study had heterozygous familial hypercholesterolemia, the baseline average LDL-C level was much higher than that in other serial coronary angiographic trials, 7.32 mmol/L (283 mg/dL) versus 3.52 mmol/L (136 mg/dL) to 5.07 mmol/L (196 mg/dL) (Table 15-1). Although the LDL-C reduction of 39% in the UCSF SCOR drug-treated group was
comparable to other serial coronary angiographic trials, the on-trial LDL-C level remained quite elevated relative to these other studies, 4.45 mmol/L (172 mg/dL) versus 2.46 mmol/L (95 mg/dL) to 3.36 mmol/L (130 mg/dL), respectively (Table 15-1). In fact, the on-trial LDL-C level in the UCSF SCOR drug-treated group was even higher than the on-trial LDL-C level in most of the placebo-treated groups of the other angiographic trials, which ranged from 3.10 mmol/L (120 mg/dL) to 4.65 mmol/L (180 mg/dL). It is often debated whether it is the absolute on-trial LDL-C level or percentage reduction of LDL-C that is important in the treatment of atherosclerosis. Data from the UCSF SCOR indicate that when on-trial LDL-C levels remain high after being reduced from an even greater level, progression of atherosclerosis can be stabilized. These data are also substantiated by the NHLBI type II study,[66,67] which had similar lipid level and angiographic outcome results as the UCSF SCOR study. The St. Thomas’ Atherosclerosis Regression Study (STARS) was a three-arm placebo-controlled study in which 90 men with coronary heart disease were randomized; 74 subjects completed the study with paired angiograms, 24 in the usual care group, 26 in the dietary intervention group, and 24 in the diet-cholestyramine group.[74] Paired angiograms were performed at baseline and after 39 months. Mean absolute arterial width, the primary end point, was measured by QCA. The proportion of subjects who showed overall progression of coronary narrowing was reduced by both interventions, 12% of subjects in the diet-cholestyramine group and 15% in the diet group compared to 46% in the usual care group (p , 0:02 for trend). Regression occurred in 33%, 38%, and 4% of subjects, respectively (p , 0:02 for trend). Per patient average width of coronary segments increased 0.103 mm with diet-cholestyramine and 0.003 mm with diet and decreased 0.201 mm in controls (p ¼ 0:012 for trend). Per patient change in % S did not show a significant effect (p ¼ 0:07 for trend). With segments rather than subjects as the experimental unit, treatment effects were found for mean arterial width, minimum width, % S, and vessel edge irregularity (p , 0:002 for trend in all measures). Improvement in mean absolute arterial width correlated with on-trial LDL-C levels and LDL-C/HDL-C ratios. Both dietcholestyramine and diet interventions reduced the frequency of total cardiovascular events (death, myocardial infarction, revascularization, or stroke). Fourteen subjects had clinical events: 10 (36%) control subjects, 1 (4%) diet-cholestyramine subject (p , 0:01 compared to control subjects), and 3 (11%) diet subjects (p , 0:05 compared to control subjects). The Stanford Coronary Risk Intervention Project (SCRIP) included 300 men and women (13% women) less than 75 years of age; 155 patients were randomized to usual care and 145 patients were randomized to multifactorial risk reduction, which included drug treatment principally with colestipolniacin, low-fat low-cholesterol dietary modification, smoking cessation, weight reduction, and exercise.[75] QCA arterial diameter measurements were made in nonbypassed coronary segments at baseline and 4 years later in 246 patients. The rate of change in MLD was 20:045 ^ 0:073 mm=y in the usualcare group and 20:024 ^ 0:066 mm=y in the risk-reduction group ðp , 0:02Þ: In women, the change was 20.046 mm/y for the usual-care group ðn ¼ 20Þ versus 2 0.016 mm/y for the
2
2.5
Pravastatin
REGRESS [83] Pravastatin
Fluvastatin
Pravastatin
PLAC I [82]
LCASe [84]
CARS [85]
2
4
247/270 (9%)b 37– 67 yrs (58 yrs) 299/331 (19%) 27– 70 yrs (54 yrs) 345/381 (10%) 30– 67 yrs (55 yrs) 320/408 (20%) (57 yrs)d 778/885 (0%) (56 yrs)d 261/319 (19%) 35– 75 yrs (58 yrs) 80/90 (23%) (64 yrs)d 232/159 153/43 250/194 173/41 244/170 169/43 231/166 164/41 233/157 166/36 213/165 137/43 189/126 123/41
156(2 32%)/120(2 22%) 93(2 38%)/46(+9%) 196(2 21%)/173(2 8%) 122(2 29%)/43(+7%) 191(2 23%)/149(2 18%) 117(2 31%)/46(+9%) 187(2 19%)/153(2 8%) 118(2 28%)/44(+7%) 189(2 20%)/129(2 7%) 125(2 29%)/39(+10%) 184(2 14%)/160(2 0.1%) 106(2 23%)/46(+9%) 166(2 11%)/114(7%) 99(2 18%)/45(+10%) CARS
LCAS
REGRESS
PLAC I
MAAS
CCAIT
MARS
b
Percentage of subjects. Percentage of women. c Mean ^ standard deviation, unless indicated. d Age range not reported. e 25% of subjects also received cholestyramine; data reported are based on subjects who received only fluvastatia. MARS = Monitored Atherosclerosis Regression Study. CCAIT = Canadian Coronary Atherosclerosis Intervention Trial. MAAS = Multicenter Anti-Atheroma Study. PLAC I = Pravastatin Limitation of Atherosclerosis in the Coronary Arteries. REGRESS = Regression Growth Evaluation Statin Study. LCAS = Lipoprotein and Coronary Atherosclerosis Study. CARS = Coronary Artery Regression Study. % S = Percent diameter stenosis. MLD = Minimum lumen diameter (mm). Control = Control group. Intervention = Lipid-lowering intervention group.
a
3
Simvastatin
MAAS [81]
2
Lovastatin
CCAIT [78]
2
Lovastatin
MARS [76]
Trial [Ref.]
Trial
Trial No. completed/ duration No. randomized Baseline TC/TG Intervention (y) age range (average) LDL-C/HDL-C (mg/dL)
On-trial TC/TG, LDL-C/HDL-C, mg/dL (% change)
Serial Coronary Angiographic Trials of HMG-CoA Reductase Inhibitor Monotherapy
Table 15-1.
41 29 50 33 32 23 38 26 28 22 36 29 39 18
Progressiona control intervention 12 23 7 10 12 19 14 14 5 8 8 14 2 3
na na na na 43 53 35 48 18 18 na na na na
Regressiona Stabilizationa control control intervention intervention na na 32 16 4 12 30 15 na na na na 12 15
New lesionsa control intervention
MLD change control intervention 2 0.06 ^ 0.21 2 0.03 ^ 0.21 2 0.09 ^ 0.16 2 0.05 ^ 0.13 2 0.13 ^ 0.27 2 0.04 ^ 0.25 2 0.05 mm/y 2 0.03 mm/y 2 0.09 2 0.03 2 0.09 2 0.02 na na
% S change control intervention 2.2 ^ 6.8c 1.6 ^ 6.7 2.89 ^ 5.9 1.66 ^ 4.5 3.6 ^ 9.03 1.0 ^ 7.90 1.12% S/y 0.69% S/y na na 2.5 ^ 9.19 0.5 ^ 9.09 na na
Chapter 15. Regression and Stabilization of Atherosclerosis by Medical Treatment 255
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Part Two. Medical Treatment
risk-reduction group ðn ¼ 10Þ ðp ¼ 0:27Þ: Progression occurred in 49.6% of patients in the usual-care group and 50.4% of the patients in the risk-reduction group; regression occurred in 10.3% of patients in the usual-care group and 20.2% of the patients in the risk-reduction group. In the first study year there were 17 cardiac events in the risk-reduction group and 9 events in the usual-care group ðp ¼ 0:09Þ: Over the next 3 years of the study, there were 8 additional cardiac events in the risk-reduction group and 35 in the usual-care group ðp , 0:003Þ: In more recent coronary angiographic trials, monotherapy with the newest lipid-lowering class of medications, the HMG-CoA reductase inhibitors, has been used. These medications offer certain advantages over the previous class of agents, including a low side effect profile and high tolerability. The Monitored Atherosclerosis Regression Study (MARS) was the first serial coronary angiographic trial of single-drug therapy with an HMG-CoA reductase inhibitor.[76] In this 2year coronary angiographic/carotid ultrasonographic trial, 270 smoking and nonsmoking men and women (9%), 37 –67 years of age, were randomized to lovastatin 40 mg twice daily or placebo. Both treatment groups had daily cholesterol intake targets of ,250 mg and daily fat intake of ,27% of calories, with saturated fat constituting , 7% of total calories and monounsaturated and polyunsaturated fats , 10% of calories each. Because of the minimal side effects of lovastatin, this was the first truly double-blind randomized clinical imaging trial. There were 247 subjects (123 lovastatin, 124 placebo) with baseline and 2-year coronary angiograms available for interpretation. Although mean change in % S by QCA for all lesions was not significant (an average increase of 1.6% S vs. 2.2% S in the lovastatin and placebo groups, respectively), there was a significant response to therapy according to baseline lesion severity. There was no statistical difference between treatment groups for change in lesions , 50% S at baseline (þ2.6% S in the lovastatin group and þ3.0% S in the placebo group). However, for lesions $ 50% S at baseline, there was a mean decrease of 24.1% S with lovastatin therapy compared to þ0.9% S with placebo ðp , 0:01Þ: Minimum lumen diameter (MLD), an absolute measure of lumen width, paralleled % S, providing this latter measure with an internal consistency since MLD is independent of the assumption that adjacent segments are normal. Mean change in MLD evaluated over all lesions was not significant (2 0.03 mm vs. 2 0.06 mm in the lovastatin and placebo groups, respectively). For lesions , 50% S at baseline, there was no statistical difference between treatment groups in change in MLD (2 0.05 mm for lovastatin vs. 20.07 mm for placebo). However, for lesions $ 50% S at baseline, lovastatin increased mean MLD þ0.13 mm compared to 2 0.04 mm with placebo ðp , 0:01Þ: Assessed by QCA, progression was less frequent in lovastatin subjects (29%) than placebo subjects (41%) ðp ¼ 0:07Þ: Regression was twice as frequent in lovastatin subjects (23%) than placebo subjects (12%) ðp ¼ 0:04Þ: Panel evaluation of angiographic change was consistent with the QCA angiographic results. Subgroup analyses of females in the MARS trial indicated two trends: women may have a better lesion response to lipid
lowering than men, and estrogen replacement may enhance lesion response to aggressive lipid-lowering therapy. The % S change after 2 years was þ2.0% S for men on lovastatin, þ0.8% S for women on lovastatin, and 2 2.1% S for women on lovastatin and estrogen. The observation in MARS that women may have a better lesion response to therapy than men has also been reported in the UCSF SCOR,[73] Lifestyle Heart Trial,[77] the Stanford Coronary Risk Intervention Project,[75] and the Canadian Coronary Atherosclerosis Intervention Trial.[78] It is also consistent with evidence indicating that lesions in women appear pathologically younger than those in men.[79] Compared to lesions in men, coronary artery lesions in women consist of more cellular fibrous tissue, found at earlier stages of plaque development, and less dense fibrous tissue, found at later stages of plaque development.[80] This difference in plaque composition suggests a pathological basis for expecting a greater potential for response to therapy in women. Since the MARS trial, there have been six additional published studies[78,81 – 85] examining the effects of HMGCoA reductase inhibitor monotherapy on the progression of atherosclerosis in coronary angiographic trials (Table 15-1). Results from these trials have demonstrated that lipid lowering with HMG-CoA reductase inhibitor monotherapy reduced coronary artery disease progression to a degree similar to the MARS trial (Table 15-1). Summary of Lipid-Lowering Coronary Angiographic Trials. The beneficial effect of slowing coronary artery atherosclerosis progression with LDL-C lowering is irrefutable. Figure 15-1 displays a review of the trials that have used the same angiographic outcome measure—the difference between treatment groups in the change in MLD. Figure 15-1 shows that the beneficial effect of LDL-C lowering is apparent across a broad range of baseline LDL-C levels, 3.36 mmol/L (130 mg/dL) to 5.17 mmol/L (200 mg/dL). Although it is unclear whether it is percentage reduction of LDL-C or the absolute on-trial LDL-C level that is most important in the slowing of coronary artery atherosclerosis, both factors most likely play a role depending on the cohort under study and the duration of intervention. In general, it appears that the longer the intervention, the greater the treatment effect. LDL-C reductions from baseline levels ranged from 20% to 45% and on-trial LDL-C levels from 2.46 mmol/L (95 mg/dL) to 3.36 mmol/L (130 mg/dL) with two exceptions—the Bezafibrate Coronary Angiographic Intervention Trial (BECAIT) and the Lopid Coronary Angiographic Trial (LOCAT). The BECAIT and LOCAT trials, reviewed later in the chapter, demonstrated very similar angiographic outcomes to these trials, although there was essentially no change of LDL-C from baseline, which averaged 4.47 mmol/L (173 mg/dL) and 3.39 mmol/L (130 mg/dL) on-trial, respectively (Fig. 15-1). The BECAIT and LOCAT trials were unique in that a reduction in the total triglyceride level rather than LDL-C was the primary goal. Normalization of all the trials to 2 years of intervention (Fig. 15-1b) reveals several important points. As shown in Fig. 15-1b, the treatment group difference in change in MLD resulting from LDL-C reduction falls into the range of 0.03– 0.06 mm with the majority of trials between 0.04 and 0.06 mm (a range of only 20 mm) with the exception of two trials.
Chapter 15. Regression and Stabilization of Atherosclerosis by Medical Treatment
257
Figure 15-1. Comparison of serial coronary angiographic trials reporting results as minimum lumen diameter measured by quantitative coronary angiography. Results are displayed as treatment group differences in change in minimum lumen diameter by baseline LDL-C levels. LOCAT reported for all native segments. (a) Each data point is labeled by the trial name, the therapeutic intervention, percentage of reduction in the on-trial LDL-C level from baseline, the absolute on-trial LDL-C level, the sample size, and the duration of the intervention. (b) Trials were normalized to a 2-year intervention. BECAIT = Bezafibrate Coronary Angiographic Intervention Trial; CCAIT = Canadian Coronary Atherosclerosis Intervention Trial; CLAS = Cholesterol-Lowering Atherosclerosis Study; FATS = Familial Atherosclerosis Treatment Study; LCAS = Lipoprotein and Coronary Atherosclerosis Study; LOCAT = Lopid Coronary Angiographic Trial; MAAS = Multicenter Anti-Atheroma Study; MARS = Monitored Atherosclerosis Regression Study; PLAC I = Pravastatin Limitation of Atherosclerosis in the Coronary Arteries; REGRESS = Regression Growth Evaluation Statin Study; SCRIP = Stanford Coronary Risk Intervention Project.
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Part Two. Medical Treatment
These data indicate that LDL-C lowering, regardless of the agent used, has a similar effect in reducing coronary artery atherosclerosis progression, but that LDL-C lowering itself may have a threshold or maximal effect on reducing progression of atherosclerosis. This point is demonstrated by the two exceptions to the narrow range of angiographic outcome to LDL-C lowering where colestipol/niacin lipidlowering intervention was used, CLAS and FATS. In addition to lowering LDL-C by 43% in CLAS and 32% in FATS, total triglyceride levels were reduced 27% in CLAS and 29% in FATS and HDL-C raised by 36% and 40%, respectively. These data indicate that further reduction of atherosclerosis progression may result from the lowering of total triglyceride levels and raising of HDL-C levels in addition to the lowering of LDL-C levels. This latter point is further demonstrated by the FATS trial where the angiographic outcome in the colestipol/lovastatin arm of the trial was half that of the colestipol/niacin arm. In the colestipol/lovastatin arm of the trial, LDL-C was reduced by 45%, whereas total triglyceride levels were reduced only 9% and HDL-C raised by 16%. Further, the angiographic outcome of BECAIT, where only the total triglyceride level was reduced, and LOCAT, where only the total triglyceride level was reduced and the HDL-C level raised, had similar angiographic outcomes as the trials in which LDL-C was reduced (Fig. 15-1). Lifestyle Modification. The Leiden Intervention Study,[59] discussed previously, was the earliest clinical trial to demonstrate that coronary artery disease progression in humans could be arrested with dietary modification alone. This study, however, did not have a control group. The STARS trial[74] design contained a dietary intervention treatment arm that demonstrated a reduction in the progression of coronary artery disease relative to a usualcare group. The Lifestyle Heart Trial was a randomized, controlled trial specifically designed to study lifestyle modification without lipid-lowering therapy on the progression of coronary artery disease.[77] Men and women (10%) between 35 and 75 years of age were recruited; 53 subjects were randomized to the risk-reduction group and 43 subjects to the usual-care control group with 28 and 20 subjects, respectively, taking part in the trial. The restrictive nature of the lifestyle intervention most likely accounted for the large drop-off in subject participation. Risk reduction included low-fat vegetarian diet, smoking cessation, stress management, and aerobic exercise. Treatment group dietary targets included cholesterol intake #5 mg/day, 10% of calories as fat, and allowed no animal products except egg white and 1 cup per day of nonfat milk or yogurt. Stress management included stretching exercises, breathing techniques, meditation, relaxation, and imagery. Dietary fat and cholesterol, which averaged 31% of calories and 213 mg/day on entry, were reduced to 7% of calories and 13 mg/day, respectively. Average weight on entry was reduced from 204 to 181 lb and average blood pressure reduced from 134/83 to 127/79 mmHg. At the end of the 1-year intervention, there were 22 treated and 19 control subjects with analyzable film pairs in which 105 coronary artery lesions in the treated group were compared with 90 lesions in the control group by QCA. Average % S was reduced from 40.0% S to 37.8% S in the
treated group and increased from 42.7% S to 46.1% S in the control group ðp ¼ 0:001Þ: Degree of adherence to lifestyle changes was directly correlated with extent of change in % S. The 5 women (all postmenopausal and not taking hormonereplacement therapy) in this study—1 in the intervention group and 4 in the control group—demonstrated regression with only moderate lifestyle changes. The Heidelberg Study was a randomized, controlled coronary angiographic trial designed to study the effects of dietary modification and exercise on the progression of coronary artery disease in subjects recruited after undergoing routine coronary angiography for angina pectoris.[86] A total of 113 patients 35 –68 years of age were randomized; 56 subjects were randomized to the intervention group which included a low-fat, low-cholesterol dietary intake and daily exercise at home on a cycle ergometer for a minimum of 30 minutes at 75% of the maximal heart rate. Daily total caloric intake included 15% protein, 65% carbohydrates, and , 20% fat; cholesterol , 200 mg daily with the polyunsaturated-tosaturated fatty acid ratio of , 1.57 subjects were randomized to the usual-care comparison group. Neither group received lipid-lowering medications. Coronary angiograms were obtained at baseline and repeated in 1 year in 40 patients in the intervention group and 52 patients in the usual-care control group. In the intervention group, body weight decreased by 5% from the baseline level of 176 pounds, total cholesterol decreased 10% from the baseline level of 234 mg/dL, LDL-C decreased 8% from the baseline level of 164 mg/dL, and triglycerides decreased 24% from the baseline level of 174 mg/dL (all p , 0:05). Based on MLD determined by QCA, coronary angiographic change between the usual-care control group versus the intervention group was significantly different; progression was seen in 48% of patients in the usual-care control group versus 23% in the intervention group; regression in 17% versus 32% of patients, respectively; and, stabilization in 35% versus 45% of patients, respectively. On a per-lesion basis, mean % S and MLD remained stable in the intervention group, 65 ^ 24% S at baseline to 64 ^ 23% S at 1 year; 0:92 ^ 72 mm at baseline to 0:91 ^ 0:67 mm at 1 year. In the usual-care control group, the per-lesion analysis showed significant progression of coronary artery lesions, 63 ^ 29% S at baseline at 66 ^ 28% S at 1 year and 1:00 ^ 0:87 mm at baseline to 0:87 ^ 0:79 mm at 1 year. The changes (progression) in the usualcare control group were significantly different from the intervention group ðp , 0:05Þ:
Calcium Channel Blockers In addition to lipid-lowering agents, other forms of medical therapy have been tested in coronary angiographic studies. Loaldi et al.[87] compared 2 years of therapy with nifedipine, a dihydropyridine calcium channel blocker (39 patients), propranolol (50 patients), and isosorbide dinitrate (38 patients). Baseline total cholesterol, LDL cholesterol, HDL cholesterol, and triglycerides averaged 5.17, 4.14, 0.90, and 1.58 mmol/L (200, 160, 35, and 140 mg/dL), respectively. The propranolol group showed a 28% increase in the level of triglycerides and a 25% decrease in the level of HDL cholesterol on trial, while the other two groups showed no lipid changes. The percentage of subjects with progression
Chapter 15. Regression and Stabilization of Atherosclerosis by Medical Treatment
was 31% in the nifedipine group compared to 53% in the propanolol group and 47% in the isosorbide dinitrate group ðp , 0:05Þ: Development of new lesions was also significantly lower in the nifedipine group, 10% of subjects, versus 34% and 29% of subjects in the propanolol and isosorbide groups, respectively ðp , 0:05Þ: The International Nifedipine Trial on Antiatherosclerotic Therapy (INTACT) was a randomized, double-blind, placebocontrolled, serial coronary angiographic trial of 425 patients 65 years old or less with coronary artery disease.[88] Patients were randomized to either placebo or nifedipine 80 mg per day. Coronary angiograms were done at baseline and repeated in 348 patients after 3 years; 282 patients (134 nifedipine and 148 placebo) received treatment throughout the study. At entry, 13% of the placebo-treated subjects and 6% of the nifedipine-treated subjects were taking lipid-lowering medications. These medications did not change throughout the study. There were no statistically significant differences in progression or regression of lesions between the placebotreated and the nifedipine-treated groups. However, 59% of nifedipine-treated subjects compared to 82% of placebotreated subjects developed new lesions over the 3-year treatment period ðp ¼ 0:034Þ: These data indicated that nifedipine had no effect on established lesions but significantly reduced the number of new lesions during treatment. The Montreal Study was a randomized, double-blind, placebo-controlled, serial coronary angiographic trial of 383 patients (17% women) 65 years old or less with coronary artery disease.[89] Patients were randomized to either placebo or nicardipine, a dihydropyridine calcium channel blocker, 30 mg three times per day. Coronary angiograms were done at baseline and repeated in 335 patients after 2 years. Patients did not receive lipid-lowering medication. Across all coronary artery lesions, there were no statistically significant differences in progression or regression of lesions between the placebo-treated and the nicardipine-treated groups. However, fewer nicardipine-treated subjects (12%) than placebo-treated subjects (24%) had progression of lesions #20% S at baseline ðp ¼ 0:035Þ: In general, the three coronary angiographic trials of calcium channel blockers[87 – 89] consistently indicated that these agents had no effect on the progression of established or advanced coronary artery lesions but that they significantly reduced development of new lesions and/or progression of mild lesions. LDL-Apheresis. LDL-apheresis entails simple venous access and selective extracorporeal removal of LDL-C by columns that selectively bind LDL particles based on the physical-chemical properties of the LDL particle. In general, HDL-C is conserved during LDL-apheresis. Except for the Familial Hypercholesterolemia Regression Study[90] and the LDL-Apheresis Atherosclerosis Regression Study (LAARS),[91] previous angiographic studies using LDLapheresis have been uncontrolled, as reviewed elsewhere.[92] The Familial Hypercholesterolemia Regression Study (FHRS) was a randomized, controlled, serial coronary angiographic trial of LDL-apheresis plus simvastatin versus simvastatin-plus-colestipol therapy in 49 patients with heterozygous familial hypercholesterolemia and baseline
259
LDL-C levels greater than 8.0 mmol/L (309 mg/dL).[90] Baseline and repeat coronary angiograms after 2 years of therapy were obtained in 20 patients randomizd to LDLapheresis once every 2 weeks plus simvastatin 40 mg every day and 19 patients randomized to combination drug therapy of simvastatin 40 mg plus colestipol 20 g daily. Changes in serum lipids were similar between the two treatment groups except for a greater reduction in LDL-C (124 mg/dL vs. 131 mg/dL; p ¼ 0:03) and Lp(a) (geometric means 14 mg/dL vs. 21 mg/dL; p ¼ 0:03) in the pheresis group. However, there were no significant differences between the apheresis and drug groups in the mean % S change either on a per-patient or per-lesion basis after 2 years of therapy. There were no significant differences between the two treatment groups in the number of patients who showed progression, regression, or stabilization. When analyzed on a per-segment or perlesion basis, mean MLD increased in the drug group (0.07 mm) and decreased in the pheresis group (2 0.004 mm) ðp , 0:046Þ: There was no angiographic benefit from lowering Lp(a) in patients whose LDL-C was concurrently lowered. The LDL-Apheresis Atherosclerosis Regression Study (LAARS) confirmed the results from FHRS. In LAARS, 42 men with baseline LDL-C of . 5.8 mmol/L (224 mg/dL) were randomized to LDL-apheresis once every 2 weeks plus simvastatin 40 mg every day (19 men) versus simvastatin 40 mg every day (19 men). Men in both groups received the highest tolerable dosage of a bile acid sequestrant if their total cholesterol level exceeded 8 mmol/L (309 mg/dL) for more than 2 consecutive months. The total cholesterol, LDL-C, and Lp(a) reductions were significantly greater in the drug/pheresis group than the drug only group ðp , 0:05Þ: On-trial plasma concentration of total cholesterol was 4.63 mmol/L (179 mg/dL) versus 5.95 mmol/L (230 mg/dL), and LDL-C levels were 2.95 mmol/L (114 mg/dL) versus 4.13 mmol/L (160 mg/dL) in the drug/pheresis group versus the drug-only group, respectively. The Lp(a) on-trial level was 45 mg/dL in both groups. Coronary angiography, repeated 2 years after the baseline angiogram, showed no treatment differences between the two interventions analyzed on either a perpatient or a per-segment basis. In the pheresis group, MLD on a per-patient and per-segment basis showed a change of 2 0.01 mm, whereas the drug-only group showed a change of 0.01 mm. Although LDL-apheresis can be used to effectively reduce LDL-C, it appears not to have any advantage over lipidlowering therapy in the routine management of atherosclerosis. However, LDL-apheresis provides a safe and effective alternative for reducing LDL-C in individuals with established atherosclerosis who cannot tolerate or do not respond to lipid-lowering medications.
Surgery Partial ileal bypass alone or in combination with lipidlowering drugs can be used to lower blood cholesterol. In 1953 Byers, Friedman, and Gunning[93] provided evidence that cholesterol absorption occurs in the small bowel of the rabbit and that the more distal the segment, the greater the absorption. Siperstien and coworkers[94] noted that the presence of bile was obligatory to the intestinal absorption
260
Part Two. Medical Treatment
of cholesterol. The first partial ileal bypass (PIB), specifically intended to manage hyperlipidemia in a human, was performed in May 1965.[95] The Program on Surgical Control of the Hyperlipidemias (POSCH), a multicenter trial initiated in 1975, randomized 421 postmyocardial infarction patients to PIB and 417 to diet control. Entry criteria required total cholesterol levels greater than 5.66 mmol/L (219 mg/dL) and LDL cholesterol greater than 6.18 mmol/L (239 mg/dL).[96] Compared to control patients, PIB produced a 30% reduction in total plasma cholesterol, 40% reduction in LDL cholesterol, and a slight increase in HDL cholesterol.[97] In July 1990, the mean trial follow-up interval was 9.7 years and PIB patients had a 23.3% lower total cholesterol ðp , 0:001Þ; 37.7% lower LDL cholesterol ðp , 0:0001Þ; and 4.3% higher HDL cholesterol ðp ¼ 0:02Þ compared to controls. Partial ileal bypass produced a 21.7% reduction in total mortality and a 28% reduction in coronary heart disease mortality; mortality was not statistically significantly different between treatment groups. However, total mortality in a subgroup of patients with a 50% or better ejection fraction was reduced 36.1% (39 of 292 control and 24 of 281 PIB patients; p ¼ 0:02). When atherosclerotic coronary heart disease mortality was combined with proven nonfatal myocardial infarction, there were 138 events in controls and 91 events in PIB patients ðp , 0:001Þ: For the combined end point of atherosclerotic coronary heart disease mortality, proven or suspected myocardial infarction, and unstable angina, there were 222 events in the control group and 160 events in the PIB group ðp , 0:0001Þ: The need for coronary artery bypass grafting, angioplasty, or heart transplantation was significantly reduced ðp , 0:0001Þ; and there was development of clinical peripheral vascular events ðp ¼ 0:038Þ in PIB versus control patients. At 5 years, 33.6% of control and 19% of PIB patients developed significant reductions in ankle brachial index by Doppler assessment ðp , 0:01Þ: Sequential coronary angiograms demonstrated continued progression of coronary artery disease at each follow-up interval in both treatment groups. However, the progression was consistently greater in control patients ðp , 0:001Þ: Progression occurred in 41.4% of control patients versus 28.1% of PIB patients at 3 years, 65.4% versus 37.5% of PIB patients at 5 years, 77.4% of control patients versus 46.5% of PIB patients at 7 years, and 85.7% PIB patients versus 53.8% PIB patients at 10 years.[98] A 5-year posttrial report of clinical events in the POSCH cohort was published in 1998.[99] Mean patient follow-up was 14.7 years (range, 12.2 –20 years) for this 5-year posttrial report. All POSCH patients were available for this follow-up. After a mean follow-up of 14.7 years, there was a 21% reduction in total mortality and 30% reduction in mortality from atherosclerotic coronary heart disease in the PIB patients compared to the control group ðp ¼ 0:049Þ: In the subgroup of patients with a 50% or better ejection fraction, there was a 37% reduction in total mortality ðp ¼ 0:01Þ and 38% reduction in mortality from atherosclerotic coronary heart disease ðp ¼ 0:05Þ in the PIB patients compared to the control group. In the PIB group versus the control group, there was a 33% reduction in mortality from atherosclerotic coronary heart disease and confirmed nonfatal myocardial infarction
ðp , 0:001Þ and an 18% reduction in mortality from atherosclerotic coronary heart disease, proven or suspected myocardial infarction, and unstable angina ðp , 0:001Þ: There was a 27% reduction in the onset of peripheral vascular disease ðp ¼ 0:02Þ and 47% reduction in coronary artery bypass surgery or angioplasty ðp ¼ 0:001Þ in the PIB patients compared to the control group. The results of POSCH offer strong long-term evidence that lipid lowering is effective in the management of atherosclerosis. Partial ileal bypass may prove to be a useful adjunct to cholesterol-lowering drugs in patients with extreme hypercholesterolemia and premature atherosclerotic coronary heart disease, especially in those who may require many years of expensive medication therapy. Additionally, partial ileal bypass could be considered for those patients who have failed various drug regimens or for those patients who cannot tolerate or have toxic effects from the various drugs. Clinical Outcome. Although not specifically designed to do so, the majority of the coronary angiographic trials have demonstrated a reduction in clinical coronary events in the lipid-lowering treatment groups relative to control groups. Long-term follow-up of the CLAS cohort indicated that measurement of progression of coronary artery disease at 2 years by both GCS and QCA was predictive of clinical coronary events over a subsequent 7-year period.[70] These data provide the mechanistic link between the reduction in progression of coronary artery disease and the reduction in clinical coronary events seen in morbidity/mortality studies designed to determine the effects of lipid lowering on clinical outcome.[100 – 106] Venous Bypasss Grafts. As discussed earlier, CLAS initially demonstrated that reduction of LDL-C to 97 mg/dL with colestipol-niacin reduced progression of atherosclerosis in coronary venous bypass grafts.[68] These initial results have now been confirmed in the Post Coronary Artery Bypass Graft Trial (Post CABG), which was specifically designed to address the question of whether aggressive lipid lowering or low-dose anticoagulation reduces progression of coronary venous bypass graft atherosclerosis.[107] A two-by-two factorial design was used to assign patients to aggressive treatment with lovastatin (LDL-C goal of 60–85 mg/dL) plus warfarin placebo or active warfarin (to maintain an international normalized ratio below 2) and to moderate treatment with lovastatin (LDL-C goal of 130 –140 mg/dL) plus warfarin placebo or active warfarin (to maintain an international normalized ratio below 2). Post CABG was conducted in 1351 patients (8% women), 21–74 years old (average age, 62 years), who had undergone saphenous-vein coronary artery bypass graft surgery 1 –11 years prior to the study entrance baseline coronary angiogram. Angiography was repeated an average of 4.3 years after the baseline coronary angiogram. Average baseline lipids were as follows: total cholesterol 226 mg/dL; triglycerides 160 mg/dL; LDL-C 155 mg/dL; and HDL-C 39 mg/dL. Ontrial, the mean LDL-C ranged from 93 to 97 mg/dL in the aggressive-treatment group versus 132 to 136 mg/dL in the moderate-treatment group ðp , 0:001Þ: The mean international normalized ratio was 1.4 in the active warfarin – treated group versus 1.1 in the warfarin placebo –treated
Chapter 15. Regression and Stabilization of Atherosclerosis by Medical Treatment
group ðp , 0:001Þ: The mean percentage of grafts that showed progression was 27% in the aggressive LDLtreatment group versus 39% in the moderate LDL-treatment group ðp , 0:001Þ: There was no significant difference in angiographic change between the active warfarin – and warfarin placebo –treated groups.
Carotid Artery Intima-Media Thickness Atherosclerosis research has moved from angiographic measurement of atherosclerosis progression and its response to therapy to noninvasive imaging assessment techniques. Because the earliest anatomic manifestations of atherosclerosis begin in the intimal layer of the arterial wall, noninvasive imaging by B-mode ultrasonography, particularly of the carotid artery wall, has become widely used in clinical trials of atherosclerosis intervention. This technique resulted from the observation that the two parallel echogenic lines seen on longitudinal view of the arterial wall represented the lumen intima and media adventitia interfaces, commonly referred to as the intima-media thickness (IMT) or complex.[108] It has become well established that carotid artery IMT represents the degree of subclinical or early preintrusive atherosclerosis.[109,110] As a measure of the degree of atherosclerosis, carotid artery IMT correlates with the standard cardiovascular risk factors seen with angiographic assessment of atherosclerosis.[111] In addition, carotid artery IMT correlates with extent, severity,[112] as well as progression of atherosclerosis.[113] Furthermore, progression of carotid artery IMT predicts future clinical coronary events as well as progression of coronary artery disease as assessed by coronary angiography.[114] In addition to demonstrating that lipid lowering reduced the progression of intrusive atherosclerotic lesions with coronary and femoral angiograms, CLAS was the first randomized, placebo-controlled, lipid-lowering trial to demonstrate a reduction in early preintrusive atherosclerosis using a noninvasive end point derived from B-mode images of the carotid artery wall.[115] Using automated computerized edge detection algorithms to measure average IMT in the distal centimeter of the common carotid artery,[116] 78 patients (39 placebo-treated, 39 colestipol-niacin treated) were studied over a 4-year period.[115] The placebo-treated group showed linear progression of carotid IMT over the 4year study period at a rate of IMT thickening of 0.018 mm/year. In contrast, the colestipol-niacin –treated group showed thinning of the common carotid IMT. The rate of IMT thinning was linear over the first 3.2 years of the study at a rate of 2 0.026 mm/y, which then plateaued during the remaining year of the study. In terms of absolute change in common carotid IMT from baseline, significant treatment group differences were seen as early as 1 year[117] and continued to be seen after 2 and 4 years of treatment.[115] MARS results confirmed CLAS results in a different cohort of 188 patients under different treatment conditions using the same IMT methodology;[116,118] 99 patients were randomized to lovastatin 80 mg per day and 89 patients were randomized to placebo. The patients underwent highresolution B-mode carotid ultrasonography for carotid wall thickness measurements every 6 months for 4 years. The annual rate of change in carotid IMT differed significantly
261
between the treatment groups at 2 and 4 years ðp , 0:001Þ: The placebo-treated group showed linear progression of carotid IMT over the 4-year study period at a rate of IMT thickening of 0.015 mm/y (0.019 mm/y at 2 years). The lovastatin-treated patients showed a consistent thinning in carotid IMT over the 4-year study period of 2 0.028 mm/y (2 0.038 mm/y at 2 years). Significant treatment group differences in absolute change in common carotid IMT was seen as early as 1 year. Several additional studies using carotid IMT as a primary end point have been published. These trials have taken advantage of the noninvasive nature of carotid ultrasonography to include both a direct measure of atherosclerosis (carotid IMT) as well as clinical coronary event end points in clinically asymptomatic[119] as well as symptomatic[120 – 123] individuals. Although several different image-acquisition methods and wall-measurement techniques were used in these trials, lipid-lowering therapy consistently reduced the rate of carotid IMT progression relative to the placebo treatment (Table 15-2). In addition, these trials have demonstrated a greater reduction in clinical coronary events in the lipidlowering treatment groups compared to the placebo-treated groups.
EVOLVING EVIDENCE FOR NEWER ANTIATHEROSCLEROSIS INTERVENTIONS AND FUTURE DIRECTIONS Triglyceride-Rich Lipoproteins and Atherosclerosis More than 3 decades of clinical research has suggested a relationship between triglycerides and coronary heart disease.[124] However, because of the complexity of what is truly measured by a plasma triglyceride determination, the relationship between triglycerides and coronary heart disease remains unsettled. Triglycerides are carried in all plasma lipoproteins, making triglyceride-rich lipoproteins highly heterogeneous. This heterogeneity is a major contributing factor to the complexity of the relationship between triglycerides and coronary heart disease. Accumulating evidence indicates that specific triglyceriderich lipoproteins such as very-low-density lipoproteins (VLDL), intermediate-density lipoproteins (IDL), lipoprotein B –containing particles, chylomicron remnants, markers of triglyceride-rich lipoprotein metabolism such as apo C-III, as well as lipoprotein particles of differing size and composition, are more related to progression of atherosclerosis than triglycerides per se.[125] A few observational studies have shown that an association exists between plasma triglyceride levels and the extent and severity of angiographically determined coronary artery disease after adjustment for HDL-C.[124] These observational studies have provided useful and important information about the relationships between the cross-sectional measurements of triglycerides and the severity of coronary artery disease. Serial coronary angiography has
54 58
62 na 57 55 61
CLAS [115] MARS [118]
ACAPS [119] PLAC II [120] KAPS [121] CAIUS [122] LIPID [123]
Asymptomatic Symptomatic 90% asymptomatic Asymptomatic Symptomatic
Symptomatic Symptomatic
Clinical status
231/231 (52) 75/76 (na) 212/212 (100) 151/154 (53) 273/249 (82)
39/39 (100) 99/89 (92) Lovastatin Pravastatin Pravastatin Pravastatin Pravastatin
Colestipol-Niacin Lovastatin
Intervention
HDL-C +33% +8% +5% 2 4% 2 2% +4% +5%
LDL-C 2 42% 2 45% 2 25% 2 28% 2 27% 2 22% 2 27% na 2 4% 2 8% 0% 2 13%
2 29% 2 24%
TG
PLAC-II ACAPS KAPS CAIUS LIPID
CLAS MARS
Trial 4 2 4 3 3 3 3 2 4
Trial duration (y)
Single maximum IMT measurement. Common = Wall thickness measurement obtained from common carotid artery. Aggregate = Wall thickness measurement obtained from the maximal thickness averaged over multiple carotid artery sites. na = Data not available. CLAS = Cholesterol-Lowering Atherosclerosis Study. MARS = Monitored Atherosclerosis Regression Study. ACAPS = Asymptomatic Carotid Atherosclerosis Prevention Study. PLAC II = Pravastatin Limitation of Atherosclerosis in the Coronary Arteries. KAPS = Kupio Atherosclerosis Prevention Study. CAIUS = Carotid Atherosclerosis Italian Ultrasound Study. LIPID = Long-term Intervention with Pravastatin in Ischemic Disease.
a
Mean age(y)
Sample size treatment/placebo (% males)
Randomized Control Trials with a Carotid Artery Wall Thickness Measurement End Point
Trial [Ref.]
Table 15-2.
0.010a 2 0.003a 0 2 0.0035
2 0.026 2 0.038 2 0.028 0.030a
Common
0.059 2 0.009 0.017 2 0.004
Aggregate
Active treatment
0.029a 0.008a 0.020 0.012
0.018 0.019 0.015 0.046a
Common
0.068 0.006 0.031 0.009
Aggregate
Placebo treatment
Progression rate (mm/y)
0.019a 0.011a 0.020 0.016
0.044 0.058 0.043 0.016a
Common
0.009 0.015 0.014 0.013
Aggregate
Treatment difference
262 Part Two. Medical Treatment
Chapter 15. Regression and Stabilization of Atherosclerosis by Medical Treatment
provided an opportunity to extend these cross-sectional associations to studies that permit the examination of the relationships between levels of triglyceride-rich lipoproteins and the progression of coronary artery disease. In a subset analysis of the analytical ultracentrifugational data from the NHLBI Type II Study, the 2-year change in IDL mass concentration (Sf 12 to 20) was significantly predictive of coronary artery disease progression at 5 years.[126] The 2year changes in LDL (Sf 0 to 12), VLDL (Sf 20 to 400), HDL2 (F1.20 3.5 to 9), and HDL3 (F1.20 0 to 3.5) mass concentrations were unrelated to progression of coronary artery disease at 5 years. This early finding demonstrated the atherogenic potential of the triglyceride-rich lipoprotein IDL in the progression of coronary artery disease. An unexpected finding in CLAS was the importance of triglyceride-rich lipoproteins in atherogenesis. This was discovered by analysis of the interrelations between apolipoprotein levels and angiographic change.[127] CLAS patients who progressed in the placebo group had significantly higher apolipoprotein B levels as well as apolipoprotein C-III levels in the LDL, VLDL, and HDL lipoproteins compared to placebo patients who did not progress. In the drug-treated group, a lower apolipoprotein CIII found in the HDL was associated with lesion progression. Multivariate analysis indicated that on-trial non-HDL-C and apo C-III heparin supernate (HS) (apo C-III found in HDL) were the single independent predictors of coronary artery disease progression in the placebo- and drug-treated groups, respectively. These data illustrated that after LDL-C was lowered below 100 mg/dL (i.e., removal of LDL-C as a risk factor for CAD progression), apo C-III-HS became the most significant risk factor for lesion progression. The association of plasma triglyceride and apo C-III levels with progression of coronary artery disease in CLAS strongly indicated the importance of triglyceride-rich lipoproteins in atherogenesis. The relationship between triglyceride-rich lipoproteins and atherogenesis is further substantiated by the association of apo C-III-HS, apo C-III-whole serum (WS), and the apo C-III ratio [apo C-III-HS/apo C-III-heparin precipitate (HP)] with the progression of early preintrusive atherosclerosis, as determined by measuring carotid IMT in a subset of the CLAS cohort.[115] In the MARS trial, multivariate analysis indicated absolute change in TC/HDL-C as the best predictor of lesion change in the placebo group for mild-moderate lesions (, 50% S) and severe lesions ($ 50% S). With LDL-C reduction below 85 mg/dL in the lovastatin group, on-trial LDL-C/HDL-C was the best predictor of lesion change for severe lesions. For mild-moderate lesions, on-trial apolipoprotein C-III levels in LDL-VLDL (apo C-III-HP), a marker of triglyceride-rich lipoprotein metabolism,[128] was the best predictor of lesion change.[129] These data indicated that triglyceride-rich lipoproteins play an important role in coronary artery lesion progression, their importance unmasked once LDL-C is aggressively lowered. These results are the first to indicate that lipoproteins have an important differential effect on lesion progression according to lesion severity. The results from MARS confirm those from CLAS. Thus, triglyceride-rich lipoproteins play an important role in the progression of CAD, their importance unmasked once LDL-C is lowered (,100 mg/dL in CLAS and ,85 mg/dL in MARS). In
263
addition, the finding of a differential effect of triglyceride-rich lipoproteins (apo C-III-HP) and cholesterol ester–rich lipoproteins (LDL-C:HDL-C ratio) on the progression of both mildmoderate and severe lesions, respectively, suggests that certain risk factors may act early and others late in the atherosclerotic process. This latter point is further illustrated by the significant association of on-trial plasma triglyceride and apo C-III levels with the progression of early nonintrusive atherosclerosis, determined by measuring carotid IMT in the entire MARS cohort.[118] The association of triglyceride-rich lipoproteins with the progression of early nonintrusive atherosclerosis in MARS confirmed the associations observed in the CLAS subgroup with the same IMT measurement methodology.[115] Taken together, these findings suggest that triglyceride-rich lipoproteins play an important role in the progression of early atherosclerosis. Further investigation of the relationship between triglyceride-rich lipoproteins and the progression of CAD was performed by analyzing the QCA and extensive analytical ultracentrifugational data of the lipoprotein subclasses from the MARS study.[130] In the placebotreated group, univariate risk factors for progression of lesions ,50% S were increases in small VLDL (Sf 20 to 60), intermediate VLDL (Sf 60 to 100), large VLDL (Sf 60 to 400), total VLDL (Sf 20 to 400), large IDL (Sf 14 to 20), and total IDL (Sf 12 to 20) mass. Multivariate analysis indicated the increase in small VLDL mass to be the single risk factor independently associated with progression of lesions , 50% S in the placebo-treated group. No lipoprotein mass was significantly associated with progression of lesions $ 50% S in the placebo-treated group. In the drug-treated group, multivariate analysis indicated lower on-trial peak LDL flotation rate to be the single risk factor independently associated (inversely) with progression of lesions , 50% S in the drug-treated group. The association between peak LDL flotation rate and progression of lesions , 50% S is consistent with an association between VLDL mass and progression of these lesions since the LDL peak flotation rate is inversely correlated to VLDL levels.[131] No lipoprotein mass was significantly associated with progression of lesions $ 50% S in the drug-treated group. With both treatment groups combined, univariate risk factors for progression of lesions ,50% S were on-trial levels of small VLDL, intermediate VLDL, total VLDL, and IDL total mass as well as a lower on-trial peak LDL flotation rate. Multivariate analysis indicated on trial small VLDL mass to be the single risk factor independently associated with progression of lesions ,50% S in the combined treatment group. No lipoprotein mass was significantly associated with progression of lesions $50% S in the combined treatment group. Thus, in the same cohort of MARS subjects, both apo CIII-HP and VLDL mass were correlated with progression of lesions , 50% S.[129,130] Apo C-III in VLDL is associated with denser, smaller VLDL subclasses believed to be particularly atherogenic.[132,133] In MARS, small VLDL, large VLDL, and total VLDL mass as well as apo CIII-HP were associated with progression of lesions , 50% S. The correlation between apo CIII-HP and total, small, and large VLDL was 0.71, 0.67, and 0.69, respectively, at baseline in the MARS cohort. Therefore, by two completely independent methods of identifying triglyceride-rich lipoproteins on the
264
Part Two. Medical Treatment
basis of different physiochemical properties, one based upon protein composition (electroimmunoassay for apo C-III) and the other based upon lipoprotein mass (analytical ultracentrifugation), the relationship between progression of lesions ,50% S and triglyceride-rich lipoproteins is confirmed. In addition, apo C-III-HP and apo C-III-WS were significantly correlated with progression of common carotid IMT in the MARS cohort;[118] these findings were consistent with those from CLAS.[115] Further compelling evidence for the relationship between triglyceride-rich lipoproteins and atherogenesis derive from the analytical ultracentrifugational lipoprotein subclass and carotid IMT data from the MARS cohort.[134] When the major apo B –containing lipoproteins were measured independently, IDL (Sf 0 to 12) but not VLDL (Sf 20 to 400) or LDL (Sf 0 to 12) was associated with the progression of carotid IMT.[134] Therefore, by two independent methods for measuring atherosclerosis progression, QCA for coronary artery atherosclerosis[130] and IMT for early carotid atherosclerosis,[134] the relationship between IDL and progression of atherosclerosis has been demonstrated. The lack of significant relationships between VLDL and LDL with carotid IMT progression may be indicative of a role of these lipoproteins in the more advanced intrusive lesions detected by coronary angiography but not in the progression of early preintrusive atherosclerosis detected by carotid IMT. The accumulated evidence for the role of triglyceride-rich lipoproteins in the progression of coronary artery disease indicates that apo B –containing lipoproteins other than those associated with cholesterol ester –rich lipoproteins may be involved in the progression of CAD. Data from the MARS study illustrate this newer concept of triglyceride-rich apo B – containing lipoprotein particle families and atherosclerosis. In a subset of 56 patients from the MARS study, lovastatin therapy significantly reduced LDL-C, apo B, and cholesterol ester –rich lipoprotein B(LP-B) levels without significantly affecting the apo B –containing triglyceride-rich LP (LP-Bc) particles, LP-B:C, LP-B:C:E, and LP-A-II:B:C:D:E.[135] Lipoprotein particles were isolated by column immunoaffinity techniques described by Alaupovic et al.[135] The differential effects of drug therapy on apo B –containing lipoproteins has provided the opportunity to determine the independent relationship of LP-B and specific LP-Bc particles on the progression of CAD.[136] In the placebo-treated group, significantly greater plasma triglyceride, apo C-III, and apo B levels were found in progressors versus nonprogressors. In the drug-treated group, significantly greater levels of LP-A-II:B:C:D:E and significantly lower levels of apo A-I were seen in progressors versus nonprogressors, but the LP-B:C or LP-B:C:E levels did not differ significantly. These data demonstrated that after lowering LP-B particles below 75 mg/dL in the drug-treated group, LP-A-II:B:C:D:E particles appeared to play a role in the progression of coronary artery disease. An increased residence time and exposure of the arterial wall to LP-AII:B:C:D:E due to its lower reactivity toward lipoprotein lipase may account for its greater atherogenicity compared to the other LP-Bc particles.[137] Apo C-III-HP, which was a significant predictor of coronary artery disease progression in both MARS and CLAS, is a constituent of intact or partially delipidized triglyceride-rich lipoprotein particles, including
the apo B –containing triglyceride-rich lipoprotein particles LP-B:C, LP-B:C:E, and LP-A-II:B:C:D:E. In the Nicardipine Study, progression of coronary artery disease and the occurrence of clinical coronary events were associated with the sum of a calculated IDL fraction and an estimated level of remnant VLDL-C.[138] These findings were consistent with those from MARS and CLAS, which demonstrate a significant association between apo C-III, as a marker of triglyceride-rich lipoprotein metabolism, and progression of coronary artery disease. Data from the control group of POSCH showed that triglyceride-rich lipoproteins at baseline and after 3 and 5 years were associated with serial coronary angiographic evidence of progression of lesions to 100% occlusion.[139] In a subgroup analysis of 333 control patients using baseline and 3-year angiographic data, the baseline plasma triglyceride and VLDL-C levels, as well as 3-year levels of triglycerides and VLDL-C, were greater in those subjects who demonstrated progression to total occlusion at 3 years versus those patients who did not. The baseline and 3-year total cholesterol, LDLC, and HDL-C levels did not differ between those patients with and without progression to total occlusion. In a subgroup analysis of 301 control patients using baseline and 5-year angiographic data, the baseline total cholesterol level and the 5-year level of plasma triglycerides were significantly greater in those patients who demonstrated progression to total occlusion at 5 years versus those subjects who did not. Not only did this trial fail to demonstrate an association between LDL-C with progression to total occlusion, but triglyceride levels were associated with new 3-year occlusions, even in the group of patients with higher HDL-C:TC ratios. Although the serial coronary angiographic evidence that links triglyceride-rich lipoproteins to the progression of coronary artery disease is compelling, the hypothesis that reducing triglyceride-rich lipoproteins will result in a reduction in the progression of atherosclerosis has only just begun to be studied. Except for 2 published trials (reviewed below), serial coronary angiographic trials have been designed to test the hypothesis that reducing LDL-C will result in a reduction in coronary artery disease progression, a hypothesis now well proven.[109,110] The Bezafibrate Coronary Angiographic Intervention Trial (BECAIT) was a double-blind, placebo-controlled serial coronary angiographic trial conducted in 92 survivors of a myocardial infarction under 45 years of age.[140] This trial was unique in that the intervention used was bezafibrate, a lipid-lowering medication that preferentially lowers plasma triglyceride levels without affecting LDL-C levels. Coronary angiography was done at baseline and after 2 and 5 years in intervention in 42 bezafibrate-treated and 39 placebo-treated patients. The efficacy analysis included the 81 patients who had a baseline and at least one posttreatment angiogram. The primary end point was change in MLD. In the bezafibrate-treated group, total cholesterol decreased from 7.73 mmol/L (226 mg/dL) to 5.92 mmol/L (229 mg/dL) (2 14%), and VLDL-C decreased from 1.11 mmol/L (43 mg/dL) to 0.72 mmol/L (28 mg/dL) (2 36%). In the placebo-treated group, total cholesterol decreased from 6.90 mmol/L (267 mg/dL) to 6.49 mmol/L (251 mg/dL) (2 6%), and VLDL-C remained unchanged at 0.85 mmol/L (33 mg/dL) (p , 0:001 between treatment
Chapter 15. Regression and Stabilization of Atherosclerosis by Medical Treatment
groups). In the bezafibrate-treated group, total triglycerides decreased from 2.44 mmol/L (216 mg/dL) to 1.81 mmol/L (160 mg/dL) (2 26%), and VLDL triglycerides decreased from 1.85 mmol/L (164 mg/dL) to 1.37 mmol/L (121 mg/dL) (226%). In the placebo-treated group, total triglycerides increased from 1.98 mmol/L (175 mg/dL) to 2.03 mmol/L (180 mg/dL) (3%), and VLDL triglycerides increased from 1.43 mmol/L (127 mg/dL) to 1.55 mmol/L (137 mg/dL) (8%) (p , 0:001 between treatment groups). HDL-C increased in the bezafibrate-treated group from 0.88 mmol/L (34 mg/dL) to 0.96 mmol/L (37 mg/dL) (þ9%), whereas HDL-C remained unchanged in the placebo-treated group at 1.01 mmol/L (39 mg/dL) (p ¼ 0:02 between treatment groups). LDL-C did not significantly change in either treatment group—from 180 mg/dL to 173 mg/dL (2 4%) in the bezafibrate-treated group and from 179 mg/dL to 175 mg/dL (2 2%) in the placebo-treated group ðp ¼ 0:55Þ: Therefore, the greatest on-trial lipid differences between the placebo-treated and the bezafibrate-treated groups were in total cholesterol 6.49 mmol/L (251 mg/dL) versus 5.92 mmol/L (229 mg/dL), VLDL-C 0.85 mmol/L (33 mg/dL) versus 0.72 mmol/L (28 mg/dL), total triglycerides 2.03 mmol/L (180 mg/dL) versus 1.81 mmol/L (160 mg/dL), and in VLDL triglycerides 1.55 mmol/L (137 mg/dL) versus 1.37 mmol/L (121 mg/dL), respectively. The differences between the placebo-treated and the bezafibrate-treated groups in HDL-C, 1.01 mmol/L (39 mg/dL) versus 0.95 (37 mg/dL) and LDL-C, 4.53 mmol/L (175 mg/dL) versus 4.47 mmol/L (173 mg/dL) levels were trivial. These are the expected lipid-altering effects of bezafibrate, which predominantly reduces the synthesis of VLDL particles resulting in a reduction in particle-associated cholesterol and triglycerides, which in turn results in a reduction in total cholesterol and total triglyceride levels. In addition to the lipid effects, the bezafibrate-treated group had a significantly greater treatment effect on apo A-I (þ7%), apo B (2 4%), and fibrinogen (213%) than the placebo-treated group — þ2%, þ2%, and no change, respectively. The median change in MLD in the placebo-treated group was 2 0.17 mm versus 20.06 mm in the bezafibrate-treated group ðp ¼ 0:049Þ: Compared to patients in the placebotreated group, fewer patients in the bezafibrate-treated group had progression of CAD (85% placebo vs. 74% bezafibrate) and more had regression of CAD (13% placebo vs. 21% bezafibrate). Clinical coronary events were significantly ðp ¼ 0:019Þ reduced in the bezafibrate-treated group after the 5year treatment period. In the placebo-treated group, 11 of the 45 patients (24%) had a clinical coronary event (3 myocardial infarctions, 1 myocardial infarction plus CABG, 4 CABG, and 3 PTCA). In the bezafibrate-treated group, 3 of the 47 patients (6%) had a clinical coronary event (1 myocardial infarction then death, 1 sudden death, 1 myocardial infarction plus CABG). BECAIT was an important study providing the first randomized serial coronary angiographic trial evidence for the reduction of coronary artery atherosclerosis progression and clinical coronary events with reduction in triglyceriderich lipoproteins, independent of a significant reduction in LDL-C. It is important to note that the angiographic results of BECAIT were similar to those from the serial coronary
265
angiographic trials that have tested the LDL-C –lowering hypothesis (Fig. 15-1). The angiographic results of BECAIT occurred even though the on-trial LDL-C remained high at an average level of 4.47 mmol/L (173 mg/dL) with essentially no change from baseline. In the LDL-C –lowering angiographic trials, on-trial LDL-C levels ranged from 2.46 mmol/L (95 mg/dL) to 3.36 mmol/L (130 mg/dL) with 20% to 45% reductions from baseline (Table 15-1; Fig. 15-1). BECAIT results are consistent with the accumulating evidence that triglyceride-rich lipoproteins play an important role in the progression of CAD. In particular, these data are consistent with those from the MARS trial in which triglyceride-rich lipoproteins were most important in the progression of lesions # 50% S, [129] the very lesions responsible for clinical coronary events.[70] The majority of lesions at baseline in the BECAIT study were in the range of 29–43% S. The Lopid Coronary Angiographic Trial (LOCAT) was a double-blind, placebo-controlled serial coronary angiographic trial conducted in 395 post –coronary artery bypass men #70 years of age.[141] The intervention used in LOCAT was gemfibrozil (slow-release 1200 mg/day), a fibric acid derivative similar to bezafibrate used in BECAIT. Coronary angiography was obtained at baseline and after an average of 32 months of intervention in 185 gemfibrozil-treated and 187 placebo-treated patients. In the gemfibrozil-treated group, total cholesterol decreased from 5.14 mmol/L (197 mg/dL) to 4.83 mmol/L (186 mg/dL) (2 6%), total triglycerides decreased from 1.65 mmol/L (149 mg/dL) to 1.02 mmol/L (92 mg/dL) (36%), LDL-C decreased from 3.58 mmol/L (137 mg/dL) to 3.39 mmol/L (130 mg/dL) (5%), and HDL-C increased from 0.81 mmol/L (31 mg/dL) to 0.98 mmol/L (38 mg/dL) (21%). In the placebo-treated group, total cholesterol increased from 5.21 mmol/L (201 mg/dL) to 5.48 mmol/L (211 mg/dL) (5%), total triglycerides increased from 1.63 mmol/L (149 mg/dL) to 1.69 mmol/L (154 mg/dL) (5%), LDL-C increased form 3.65 mmol/L (141 mg/dL) to 3.84 mmol/L (148 mg/dL) (5%), and HDL-C increased from 0.82 mmol/L (32 mg/dL) to 0.88 mmol /L (34 mg/dL) (7%). All percentage changes from baseline as well as the on-trial lipid levels were significantly different between treatment groups ðp , 0:001Þ: Although the primary study end point—segment unaffected by grafts and those distal to graft insertion—was negative, segments unaffected by grafts, graft-affected segments, and all native segments demonstrated a significant reduction in progression in the gemfibrozil-treated patients versus the placebo-treated subjects ðp , 0:05Þ: In segments unaffected by grafts, graft-affected segments, and all native segments, the differences in mean change in MLD between treatment groups were 0.06, 0.07, and 0.05 mm, respectively. In the aortocoronary bypass grafts, 23 patients (14%) randomized to placebo had new lesions in the follow-up angiogram compared with 4 patients (2%) in the bezafibratetreated group ðp , 0:001Þ: Thus, the LOCAT results confirmed those from BECAIT and, in addition, demonstrated that the reduction in total triglyceride levels in subjects with relatively low on-trial LDL-C levels [3.39 mmol/L (130 mg/dL)], with essentially no change from baseline results in coronary angiographic improvement in both native as well as aortocoronary bypass
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Part Two. Medical Treatment
grafts. The angiographic results of LOCAT were similar to those from the serial coronary angiographic trials that have tested the LDL-C –lowering hypothesis (Fig. 15-1).
Antioxidants Although there is a large body of experimental and epidemiologic data that indicate that supplementary antioxidant vitamins may reduce cardiovascular disease, there have been no double-blind, placebo-controlled arterial imaging studies published to date that have addressed the question of whether antioxidants affect progression of atherosclerosis. However, subgroup analyses from CLAS strongly indicate the potential of vitamin E for reducing the progression of atherosclerosis.[142,143] In the CLAS cohort of colestipol-niacin and placebotreated patients, men who had a supplementary vitamin E intake of 100 IU per day or more had significantly less coronary artery lesion progression than did men with a supplementary intake less than 100 IU per day ðp ¼ 0:04Þ:[142] When examined by treatment group, colestipol-niacin patients with high supplementary vitamin E intake had significantly less coronary artery lesion progression of all lesions ðp ¼ 0:02Þ and mild/moderate lesions ðp ¼ 0:01Þ: These data have important implications for the potential use of supplemental vitamin E as adjunctive antioxidant therapy with LDL-C reduction, especially in terms of slowing or halting the progression of mild/moderate lesions, which are the lesions predictive of clinical coronary events.[70] Further analysis of the CLAS cohort with IMT data indicated that men in the placebo-treated group with a supplementary vitamin E intake of $ 100 IU per day had less carotid IMT progression than those men with , 100 IU per day supplementary vitamin E intake (0.008 vs. 0.023 mm/year; p ¼ 0:03).[143] Although encouraging, these results must be cautiously interpreted, since patients in this study self-selected and self-reported their antioxidant vitamin intake. Consistent with the CLAS findings were two clinical trials that demonstrated that probucol, an antioxidant, slowed the rate of restenosis after coronary angioplasty. In the Multivitamins and Probucol (MVP ) trial, 317 subjects were randomized to placebo, probucol (500 mg), multivitamins (30,000 IU beta-carotene, 500 mg vitamin C, and 700 IU vitamin E), or probucol plus multivitamins, all given twice daily.[144] An extra 1000 mg of probucol, 2000 IU of vitamin E, both probucol and vitamin E, or placebo were administered to the subjects, according to their treatment assignment, 12 hours before they underwent angioplasty. All subjects were treated 4 weeks prior and 6 months after the angioplasty. The
baseline and follow-up angiographic changes at the angioplasty site were measured by QCA. Mean reduction in luminal diameter 6 months after angioplasty was 0.12 mm in the probucol group, 0.22 mm in the probucol-plus-multivitamin group, 0.33 mm in the multivitamin group, and 0.38 mm in the placebo group (p ¼ 0:006 for subjects receiving vs. those not receiving probucol). The Probucol Angioplasty Restenosis Trial (PART ) was a study of 101 subjects randomly assigned to probucol 1000 mg per day or to a control group of no lipid lowering 4 weeks prior to angioplasty.[145] Baseline and follow-up angiographic changes were measured by QCA 6 months after angioplasty. MLD at the angioplasty site was 1.49 mm in the probucol group and 1.13 mm in the control group ðp ¼ 0:02Þ: Restenosis occurred in 23% of the probucol-treated patients and in 58% of the control-treated patients ðp ¼ 0:001Þ: Double-blind, placebo-controlled studies with both QCA and carotid IMT imaging end points in individuals with and without cardiovascular symptoms are currently underway to study the question of whether antioxidants prevent the progression of atherosclerosis.
CONCLUSION Evidence for the achievement of lesion regression with LDLC reduction is derived from (1) observations in experimental animal models, including controlled, quantitative regression studies (nonhuman primate results have been reviewed in detail); (2) angiographic human case studies and noncontrolled trials; and (3) controlled clinical trials. Together, these reports provide evidence for the reversibility of atherosclerosis of sufficient strength that risk-factor control and LDL-C reduction should be an integral part of the long-term postsurgical management of the atherosclerotic patient. Growing evidence indicates that triglyceride-rich lipoproteins play an important role in atherosclerosis and need attention in the control of atherosclerosis progression. Another area of increasing interest is the role of antioxidants in the prevention of atherosclerosis progression. Rational decisions concerning the use of antioxidants for the control of atherosclerosis progression await results from ongoing trials. The role of the vascular surgeon, beyond that of providing the surgical care for patients with symptomatic atherosclerosis, is to ensure that patients receive optimal medical care. The rationale for this is to prevent potential problems from disease progression in vascular grafts and to reduce lesion progression in other vascular beds.
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Coronary Artery Disease in Hypercholesterolemic Men. Lancet 1987, 62. Blankenhorn, D.H.; Alaupovic, P.; Wickham, E. et al. Prediction of Angiographic Change in Native Human Coronary Arteries and Aortocoronary Bypass Grafts: Lipid and Nonlipid Factors. Circulation 1990, 81, 470. Alaupovic, P. David Rubinstein Memorial Lecture. The Biochemical and Clinical Significance of the Interrelationship Between Very Low Density and High Density Lipoproteins. Can. J. Biochem. 1981, 59, 565. Hodis, H.N.; Mack, W.J.; Azen, S.P.; Alaupovic, P.; Pogoda, J.M.; LaBree, L.; Hemphill, L.C.; Kramsch, D.M.; Blankenhorn, D.H. Triglyceride- and CholesterolRich Lipoproteins Have a Differential Effect on Mild/Moderate and Severe Lesion Progression as Assessed by Quantitative Coronary Angiography in a Controlled Trial of Lovastatin. Circulation 1994, 90, 42. Mack, W.J.; Krauss, R.M.; Hodis, H.N. Lipoprotein Subclasses in the Monitored Atherosclerosis Regression Study (MARS). Treatment Effects and Relation to Coronary Angiographic Progression. Arterioscler. Thromb. Vasc. Biol. 1996, 16, 697. Krauss, R.M.; Williams, P.T.; Lindgren, F.T.; Wood, P.D. Coordinate Changes in Levels of Human Serum Low and High-Density Lipoprotein Subclasses in Healthy Men. Arteriosclerosis 1988, 8, 155. Le, N.A.; Givson, J.C.; Ginsberg, H.N. Independent Regulation of Plasma Apolipoprotein C-II and C-III Concentrations in Very Low Density and High Density Lipoproteins. Implications for the Regulation of the Catabolism of These Lipoproteins. J. Lipid Res. 1988, 29, 669. Carlson, L.A.; Ballantyne, D. Changing Relative Proportions of Apolipoproteins C-II and C-III of Very Low Density Lipoproteins in Hypertriglyceridemia. Atherosclerosis 1976, 23, 563. Hodis, H.N.; Mack, W.J.; Dunn, M.; Liu, C.R.; Liu, C.H.; Selzer, R.H.; Krauss, R.M. Intermediate-Density Lipoproteins and Progression of Carotid Arterial Wall IntimaMedia Thickness. Circulation 1997, 95, 2022. Alaupovic, P.; Hodis, H.N.; Knight-Gibson, C.; Mack, W.J.; LaBree, L.; Cashin-Hemphill, L.; Corder, C.N.; Kramsch, D.M.; Blankenhorn, D.H. Effects of Lovastatin on ApoA- and ApoB-Containing Lipoproteins. Families in a Subpopulation of Patients Participating in the Monitored Atherosclerosis Regression Study (MARS). Arterioscler. Thromb. 1994, 14, 1906. Alaupovic, P.; Mack, W.J.; Knight-Gibson, C.; Hodis, H.N. The Role of Triglyceride-Rich Lipoprotein Families in the Progression of Atherosclerotic Lesions as Determined by Sequential Coronary Angiography from a Controlled Clinical Trial. Arterioscler. Thromb. Vasc. Biol. 1997, 17, 715. Alaupovic, P.; Knight-Gibson, C.; Wang, C.S.; Downs, D.; Koren, E.; Brewer, H.B.; Gregg, R.E. Isolation and Characterization of a Lipoprotein-Containing Lipoprotein (LP-A-II:B Complex) from Plasma Very Low Density Lipoproteins of Patients with Tangier Disease and Type V Hyperlipoproteinemia. J. Lipid Res. 1991, 32, 9.
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Phillips, N.R.; Waters, D.; Havel, R.J. Plasma Lipoproteins and Progression of Coronary Artery Disease Evaluated by Angiography and Clinical Events. Circulation 1993, 88, 2762. 139. POSCH Group; Bissett, J.K.; Wyeth, R.P.; Matts, J.P.; Johnson, J.W. Plasma Lipid Concentrations and Subsequent Coronary Occlusion After a First Myocardial Infarction. Am. J. Med. Sci. 1993, 305, 139. 140. Ericsson, C.G.; Hamsten, A.; Nilsson, J.; Grip, L.; Svane, B.; Faire, U. Angiographic Assessment of Effects of Bezafibrate on Progression of Coronary Artery Disease in Young Male Postinfarction Patients. Lancet 1996, 347, 849. 141. Lopid Coronary Angiography Trial (LOCAT) Study Group; Frick, M.H.; Syvanne, M.; Nieminen, M.S.; Kauma, H.; Majahalme, S.; Virtanen, V.; Kesaniemi, A.; Pasternack, A.; Taskinen, M.R. Prevention of the Angiographic Progression of Coronary and Veingraft Atherosclerosis by Gemfibrozil After Coronary Bypass Surgery in Men with Low Levels of HDL Cholesterol. Circulation 1997, 96, 2137. 142. Hodis, H.N.; Mack, W.J.; LaBree, L.; Cashin-Hemphill, L.; Sevanian, A.; Johnson, R.; Azen, S.P. Serial Coronary
Angiographic Evidence That Antioxidant Vitamin Intake Reduces Progression of Coronary Artery Atherosclerosis. J. Am. Med. Assoc. 1995, 273, 1849. 143. Azen, S.P.; Qian, D.; Mack, W.J.; Sevanian, A.; Selzer, R.H.; Liu, C.R.; Liu, C.H.; Hodis, H.N. Effect of Supplementary Antioxidant Vitamin Intake on Carotid Arterial Wall Intima-Media Thickness in a Controlled Clinical Trial of Cholesterol Lowering. Circulation 1996, 94, 2369. 144. Tardif, J.C.; Cote, G.; Lesperance, J.; Bourassa, M.; Lambert, J.; Doucet, S.; Bilodeau, L.; Nattel, S.; de Guise, P. Probucol and Multivitamins in the Prevention of Restenosis After Coronary Angioplasty. N. Engl. J. Med. 1997, 337, 365. 145. Yokoi, H.; Daida, H.; Kuwabara, Y.; Nishikawa, H.; Takatsu, F.; Tomihara, H.; Nakata, Y.; Kutsumi, Y.; Ohshima, S.; Nishiyama, S.; Seki, A.; Kato, K.; Nishimura, S.; Kanoh, T.; Yamaguchi, H. Effectiveness of an Antioxidant in Preventing Restenosis After Percutaneous Transluminal Coronary Angioplasty. The Probucol Angioplasty Restenosis Trial. J. Am. Coll. Cardiol. 1997, 30, 855.
CHAPTER 16
Hyperthrombotic States in Vascular Surgery Jonathan B. Towne
Hypercoagulable states as a cause of acute arterial or venous thrombosis pose a difficult clinical problem. There are essentially four clinical situations in which such states occur: three involving the arterial system and one the venous system. The first is a sudden unexplained thrombosis of medium- to large-size arteries of either the upper or the lower extremity, which on occasion can involve renal, mesenteric, and cerebral vessels. The second situation, which is of particular concern to vascular surgeons, is the acute thrombosis of an arterial repair in the perioperative period. These problems are usually evident in the operating room, and all occur in the first 12 hours following surgery. The third situation is thrombosis of arterial repair at a time remote from the vascular reconstruction, which is the most uncommon occurrence. Finally, there is the sudden, unexplained episode of venous thrombosis, which can affect any and all parts of the venous circulation but most typically involves the lower extremities and on occasion also the upper extremities and the mesenteric venous circulation. The ability of blood to remain fluid within the intravascular system and to form a thrombus when there is disruption or injury to the endothelial lining depends on complex interactions between the various components of the vascular system. These components include the endothelium, platelets, plasma, procoagulant factors, and fibrinolytic factors. Any abnormality of these factors can result in either hemorrhage or thrombosis. Since vascular surgeons deal primarily with ischemia, they generally have to deal with abnormalities on the thrombosis side of the blood coagulation equilibrium. Over the last several decades there has been an explosion of knowledge regarding the coagulation system, so that our understanding of its various components is much better. With this increased understanding, several clotting disorders have been identified that are secondary to either inherited or acquired deficiency of one of the components of the clotting cascade, resulting in unusual or previously unexplained thrombosis. Early on, the first hypercoagulable states identified were those that involved problems on the procoagulant side. However, within the last decade, problems involving the fibrinolytic systems or anticoagulant side of the clotting cascade have been identified. In order to treat these
unusual thrombotic episodes adequately, some knowledge of these thrombotic syndromes is necessary. Hypercoagulability as a cause of unexplained vascular thrombosis poses difficult clinical problems. Most graft failures in the perioperative period are presumed to result from technical errors in the construction of the anastomosis, problems with the conduit, or poor patient selection. The diagnosis of abnormal coagulability is often made only after all these other factors have been excluded. Although the failure of heparin to prevent clotting in the operative field or the immediate thrombosis of a vascular repair suggests abnormal coagulation, the diagnosis can only be confirmed by the blood coagulation laboratory. The clotting disorder must be detected early in the course of the disease if there is to be a favorable outcome. Abnormal thrombosis falls into five general categories: abnormalities in the antithrombin system, abnormalities of the fibrinolytic system, heparin-induced platelet aggregation, lupus anticoagulant, and a miscellaneous category consisting primarily of abnormal platelet aggregation deficiencies of protein C and protein S and activated protein C resistance.
GUIDELINES FOR IDENTIFYING HYPERCOAGULABILITY A good patient history remains the most important means of identifying patients with potential hypercoagulable disorders. Patients should be asked about previously unexplained thromboses in themselves or family members. Patients with hypercoagulability syndromes will often report episodes of thrombophlebitis that occurred in young adulthood. Of particular importance are those episodes of thrombophlebitis that do not have any contributing factors for their development—e.g., long leg fractures or prolonged immobilization or bed rest due to illness. Such a history becomes even more significant in patients with recurrent episodes of thrombophlebitis. Likewise, previous arterial thrombosis, especially if it occurred in early life, is an indicator of a coagulation disorder.[1] Eldrup-Jorgensen et al.[2] found a
Hobson/Wilson/Veith: Vascular Surgery: Principles and Practice, Third Edition, Revised and Expanded DOI: 10.1081/0819-9-120024899 Copyright q 2004 by Marcel Dekker, Inc.
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30% incidence of coagulation abnormalities in patients younger than 51 years undergoing vascular reconstruction. The abnormal clotting factors noted consisted of protein S deficiency, protein C deficiency, presence of lupuslike anticoagulants, and plasminogen deficiency. The incidence of arterial graft thrombosis in this group of patients was 20% at 30 days, which is markedly higher than one would expect from this type of vascular reconstruction.
Clinical Presentation With experience, one develops a sense for which reconstructions are likely to succeed and has some idea of the types of problems that may occur. Likewise, one develops a feel for the typical presentations of atherosclerotic occlusive disease. When unusual or unexplained thrombosis is identified—for example, a thrombosed suprarenal aorta, upper extremity thrombosis, or total fibial artery occlusion in a patient who is neither diabetic nor has any evidence of any atherosclerotic occlusive disease elsewhere—the surgeon should look for hypercoagulable disorders as a possible cause. Unusual radiographic findings, particularly occlusions in young patients or in one extremity when the other extremity has no evidence of any disease, should trigger an investigation into the coagulation system. The role of screening vascular surgery patients for hypercoagulable states is difficult to assess. Donaldson et al.[3] found, overall, that 9.5% of patients scheduled for a variety of vascular surgery procedures had test results indicating potential hypercoagulability. The three most common entities these patients demonstrated were heparininduced platelet aggregation, lupus anticoagulants, and protein C deficiency. The incidence of infrainguinal graft occlusion within 30 days was 27% among patients who were in the hypercoagulable group compared with 1.6% in patients who were not in this group. At present, we do not screen routinely for the wide variety of coagulation disorders. We depend on the history and clinical evaluation to identify patients who may be hypercoagulable. This is probably the more cost-effective and efficient approach. The greatest difficulty for the vascular surgeon is dealing with unexplained thrombosis intraoperatively. Often such an emergency occurs during late evening or nighttime hours, when support from the coagulation laboratory is not available. The first step—if, indeed, heparin has been given—is to see if there is any clotting in the operative field, which would indicate an antithrombin III deficiency, since antithrombin III is essential for heparin’s anticoagulant effect. The anesthesiologist should then test the heparin effect, by either determining the partial thromboplastin time (PTT) or doing one of the other tests that measure heparin anticoagulation. The next step is to obtain a platelet count. If it is higher than 100,000 and the PTT is not prolonged, the problem is presumed to lie with the antithrombin system. The patient is then given two units of fresh frozen plasma and two units more every 12 hours for 5 days. The antithrombin III deficiency is then confirmed, usually the next day, on blood drawn prior to the administration of any fresh frozen plasma. Patients with antithrombin III deficiency are maintained on long-term warfarin therapy. If the platelet count is less than
100,000, we presume the patient has developed heparininduced platelet aggregation. Certainly the patient’s history should be examined carefully so as to try to document the administration of heparin at some time in the past. We then start dextran intravenously with a 50-mL bolus and continue at 25 mL/h. The heparin is reversed with protamine, and the platelet aggregation abnormality is confirmed in the morning. Warfarin treatment is continued for 3 weeks to 6 months. If the platelet count is greater than 100,000 and the activated clotting time (ACT) is prolonged, we presume that the patient has some other form of hypercoagulability, such as a fibrinolytic abnormality or a problem with protein C, protein S, or lupus-type anticoagulants. In these patients, we institute continuous heparin therapy both intraoperatively and postoperatively and administer two units of fresh frozen plasma. Fresh frozen plasma is shotgun therapy for a wide variety of coagulation abnormalities. In the operating room, prior to the institution of any therapy, blood should be drawn for coagulation tests. (Many of these tests are quite involved, such as plasminogen electrophoresis, protein C, protein S, and determinations of lupus anticogulants, sometimes taking from days to a week at some centers. However, if the blood is properly handled, spun down, and frozen, the tests can be done routinely.) Our policy is to repeat, in 5 days, all tests that are abnormal. One of the problems in diagnosing coagulation abnormalities is that in the process of clotting, clotting factors can be consumed and abnormalities may be the result of clotting and not the cause of it. All factors that remain abnormal in the 5- to 7-day period are retested at 1 month. Patients who then have persistently abnormal values are labeled as truly hypercoagulable. McDaniel et al.[4] have noted the change in coagulation factors with operation. They noted that antithrombin III levels fell on the third postoperative day and returned to normal after 1 week. Antithrombin III declined from a mean preoperative level of 110% to 71% on the third postoperative day. This value had returned to normal by postop day 7, when it reached 95%. All this demonstrates the dynamic aspect of the clotting system and points out the danger of attaching significance to one isolated laboratory finding. Most patients who sustain complications due to hypercoagulable states are placed on warfarin in the perioperative and postoperative period. In patients with heparin-induced platelet aggregation, this can usually be stopped in 3 months: however, we have recommended prolonged administration in patients with protein C and S deficiencies, antithrombin III deficiency, and plasminogen abnormalities because of the risk of recurrent thrombosis.
ANTITHROMBIN DEFICIENCY Antithrombin III is an alpha globulin manufactured in the liver and by vascular endothelium, with a molecular weight of approximately 60,000 and a half-life of 2.8 days.[5] It is a serine proteinase inhibitor that binds in equimolar ratios to several enzymes participating in the intrinsic pathway of blood coagulation, including thrombin and factors Xa, Ixa, and XIa.[5] Heparin significantly accelerates the rate at which antithrombin III neutralizes these enzymes, thus limiting
Chapter 16.
sequential clotting reactions and preventing fibrin formation. In 1965, Egeberg[6] described a family with an inborn defect of antithrombin III, and subsequent work has demonstrated the genetic transmission of this disease.[7 – 10] The frequency of this defect is approximately 1 in 2000 to 1 in 5000 in the general population.[11,12] There are probably at least two types of antithrombin III deficiency. In the classic form, both the level of antithrombin III (as determined by measuring its protein concentration) and its activity level are reduced in the patient’s plasma.[13] However, there are other patients in whom the concentration of antithrombin III is normal or even slightly elevated as measured by protein level, but the biologic function as measured by activity tests is abnormal.[14] This suggests that these patients are manufacturing a defective antithrombin molecule. Acquired antithrombin III deficiency can occur in severe liver disease, nephrotic syndrome, hypoalbuminemia, malnutrition, and disseminated intravascular coagulation; it can also sometimes occur in patients taking birth control pills. Antithrombin III deficiency may be an indicator of significant protein catabolism. Flinn et al.[15] noted low antithrombin III activity in 16% of patients undergoing vascular surgery. There was low serum albumin (less than 3.0 mg/dL) in 48% of these patients, which was associated with an increased incidence of early graft failure.
Clinical Presentation Although antithrombin III deficiency is inherited, it is rare for episodes of thrombosis to be clinically manifest before the second decade of life. Despite continuously depressed levels of antithrombin III in these patients, thrombotic episodes are often related to predisposing factors such as operations, childbirth, and infection; they rarely occur spontaneously. This deficiency can cause venous thrombosis with resulting pulmonary embolism, dialysis fistula failure, arterial graft occlusion, and spontaneous arterial occlusion. In our initial report, we identified 7 patients with antithrombin deficiencies as a cause of thrombosis.[16] These included patients with spontaneous arterial occlusion in both the upper and lower extremities as well as patients whose vascular reconstructions became occluded in the perioperative period. One unusual patient presented with ischemia of one arm and both legs secondary to extensive thromboses of the brachial artery and its branches in one arm and the femoral, popliteal, and tibial systems of both legs. Extensive angiography of the entire aorta and cardiac evaluation failed to reveal a proximal origin of embolic material. What distinguishes these patients from those with thrombotic occlusive disease secondary to atherosclerosis is the unique history, distribution of occluded vessels, unusual angiographic findings, and absence of any proximal source of embolic material. Often clot formation in the operative field—despite heparin sodium administration— is the first clue that the patient may have an antithrombin deficiency. The presence of multiple thrombi on operative angiograms is suggestive of a clotting abnormality.
Diagnosis Results of routine coagulation tests are normal in patients with antithrombin III deficiency. Generally, reductions in
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antithrombin are measured by both immunologic assays (tests that measure the total amount of the protein) and functional procedures (tests that measure the activity of the antithrombin III molecules). Initially, patients with repeated episodes of venous thrombosis were identified because their levels of antithrombin III were reduced to 50– 60% of normal. Subsequent work identified patients with arterial thrombosis secondary to low antithrombin III levels. Lynch et al.[17] demonstrated a correlation between low preoperative plasma functional antithrombin III levels and the occurrence of thrombotic complications following cardiac and vascular surgery. Thrombotic complications included arterial thrombosis, graft thrombosis, deep venous thrombosis, cerebral vascular thrombosis, spinal infarction, and embolic cortical blindness. A decrease in antithrombin III levels is the mechanism of the increased thrombotic tendency of patients on oral contraceptives. Sagar et al.[18] demonstrated that antithrombin III activity was significantly lower in patients taking oral contraceptives than in control patients. During surgery, the antithrombin III activity fell in both the contraceptive and the control groups, but the decline was greater in patients on oral contraceptives. The only patients who developed deep venous thrombosis postoperatively as determined by the I125 fibrinogen test were those on oral contraceptives. Of the 31 patients on oral contraceptives, 5 had an antithrombin III activity below 50%, and of these, 3 developed deep venous thrombosis. More recent work has demonstrated that the administration of heparin tends to lower the antithrombin level. Conrad et al.[19] demonstrated that it is the presence of heparin and not the rate of administration which is the determinant of the decrease in antithrombin III. They noted that both subcutaneous and intravenous heparin cause antithrombin III levels to drop by the same amount. Since heparin is dependent on antithrombin for its antithrombotic action, the antithrombin-lowering affect of heparin in patients with an already low antithrombin concentration probably indicates that patients are at risk of thrombosis for two reasons. First, heparin is relatively ineffective in patients with low levels of antithrombin III. Second, because heparin binds with antithrombin III, the already low level is decreased even further, possibly to dangerous levels. This is the theoretic basis of the paradoxical thrombotic episodes occasionally seen after heparin is stopped. Since heparin administration has decreased the level of antithrombin III, sometimes to significantly dangerous levels, cessation of heparin is followed by a period of hypercoagulability because the patient’s lower antithrombin III level is not counteracted by the heparin. This is why warfarin administration should be overlapped with heparin cessation when thrombotic problems are being treated. Patients with a congenital antithrombin III deficiency should be on chronic long-term warfarin therapy because of the risk of recurrent thrombotic episodes. In addition to its anticoagulant effect, warfarin increases the level of antithrombin III by an as yet undetermined mechanism. More recently, purified antithrombin III had been obtained by recombinant techniques; in the future, this advance will change the treatment of antithrombin III deficiency. Antithrombin III concentrate factor is now available as factor-specific replacement.[20]
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DEFECTS IN THE FIBRINOLYTIC SYSTEM The fibrinolytic system has become better understood in recent years and has been found to be the source of coagulation abnormalities. The components of the fibrinolytic system include plasminogen; plasminogen activators, including tissue plasminogen activator (TPA) and urokinase; inhibitors directed against plasminogen activators; plasmin inhibitors, the most important of which is alpha II antiplasmin; and cellular plasmin inhibitors, which have been identified in platelets and endothelial cells.[21,22] The degradation of fibrin is normally carried out by the proteolytic enzyme plasmin, which is formed from the proenzyme plasminogen by the action of plasminogen activators such as TPA or urokinase. The process is regulated at many different levels, resulting in localized plasmin formation at the fibrin surface. TPA is the most important activator and is produced and released from vascular endothelium.[23] Plasminogen is a normal plasma protein consisting of a single polypeptide chain with a molecular weight of 90,000 – 94,000.[24] Thin-layer gel electrofocusing, coupled with immunofixation, can demonstrate up to 10 different forms of plasminogen, with each variant having a glutamic acid as its terminal amino acid. Plasminogen is converted to plasmin by activators, many of which are released from endothelial cells. Plasmin is a serine protease and is an important member of the fibrinolytic systems that acts by cleaving fibrinogen and fibrin. The biosynthesis of plasminogen and fibrinolytic inhibitors is probably under genetic control. In 1978, Aoki et al.[25] reported a patient with recurrent thrombosis who had a hereditary molecular defect of plasminogen. This was followed by reports by Kazama et al.[26] in 1981 and Soria et al.[27] in 1983. These authors demonstrated that the abnormal plasminogen did not have the functional ability of normal plasminogen, resulting in a discrepancy between the biologic activity and the amount of plasminogen detected in the serum by radioimmunoassay. These patients had normal concentrations of plasminogen antigen, with approximately half of the activity of normal plasminogen. Using electrofocusing techniques coupled with immunofixation and zymograms, they were able to identify 10 additional bands, each of which was located on the basic side in close proximity to the corresponding normal band. Determination of amino acid sequence has demonstrated defects in the arginine 516 valine bond and the substitution of alanine 600 by threonine.[28] The major function of the fibrinolytic system in vivo is the limitation of fibrin deposition. A reduction of fibrinolytic activity may provoke a thrombotic tendency by allowing the growth and development of thrombi after the initiating thrombotic event. Most patients with abnormal plasminogen are characterized by a normal antigen concentration and by decreased functional activity. Liu et al.[29] reported a plasminogen which was characterized by both low functional activity and low antigen; they called it plasminogen San Antonio. Congenital plasminogen deficiency is now divided into two groups. In Type I plasminogen deficiency the
immunoreactive plasminogen is reduced in parallel with its functional activity. In Type II plasminogen deficiency the immunoreactive plasminogen is normal and the functional activity is reduced.[30] Type I represents a problem of plasminogen production, and Type II indicates the manufacture of a defective molecule. In a study of patients with unusual and unexplained thrombosis who had an abnormal plasminogen band detected on immunoelectrophoresis, we noted that only 1 of our initial 8 patients demonstrated a decreased functional level of plasminogen as compared with antigenic levels.[31] We felt that this might be related to the assay of functional activity used in the study, or it might represent a different form of abnormality than reported in the literature. One of our patients had a low functional plasminogen level at the time of thrombotic activity, but when he was studied 4 months after the institution of warfarin therapy, an increase in the level of functional plasminogen to 70% of normal was found. One year later, he had normal plasminogen activity. The patient continued to show an abnormal band of plasminogen in the electrophoretic pattern, demonstrating persistence of an abnormal plasminogen molecule in the plasma. This patient has had two episodes of pulmonary emboli. Ikemoto et al.[32] reported that the genetic characteristics of this disorder follow an autosomal codominant inheritance pattern with the alleles completely expressed. The results of the study of two families in our series are in agreement with this. The clinical history of recurrent phlebitis in one of our patients and his sister supports the genetic aspect of this disease. The immunoelectrophoresis technique used in our study is quicker, simpler, and less costly than isoelectric focusing, and it is more applicable to screening large groups of patients. The significance of the abnormal plasminogen is uncertain. It is present in 10% of the normal population, and its presence does not ensure that a patient is going to have thrombotic complications. More likely, this abnormal plasminogen results in the relative defect of the fibrinolytic system, which places the patient at increased risk should he or she be in a thrombosis-prone situation. Our data suggest, however, that once a thrombotic episode occurs, it is likely to recur, emphasizing the need to identify and treat these patients with long-term warfarin therapy.
Clinical Presentation We have noted that thrombosis occurs on both the arterial and the venous sides of the circulation in patients with abnormal plasminogen. In our initial report of 8 patients, the age of onset of the first thrombotic episode ranged from 21 to 57 years. Of these 8 patients, 3 had venous thrombosis, 2 had spontaneous arterial thrombosis, 2 had occlusion of an arterial reconstruction in the early postoperative period, and 1 had separate episodes of both arterial and venous occlusion. Thrombosis involving the venous systems occurred in 4 patients: 2 had complete obstruction of the iliofemoral venons segment and inferior vena cava, 1 had primarily popliteal vein thrombosis, and the remaining patient had axillary and subclavian vein thrombosis. In 2 of these patients, concomitant pulmonary emboli occurred—in one case after
Chapter 16.
an interval of 4 months. Arterial thrombosis occurred in 5 patients: 2 patients presented with spontaneous thrombosis of the iliofemoral segment. Following thrombectomy with Fogarty catheters, there was no evidence of inflow obstruction, and a complete evaluation for the proximal source of the emboli was negative. Postoperative occlusions of arterial reconstructions occurred in 2 patients. Of the 6 patients who had recurrent episodes of thrombosis, 2 had three recurrences and 4 had two recurrences. The interval between thrombotic episodes ranged from 4 to 36 months. Significantly, 5 of the patients who had recurrent thrombosis were treated with warfarin following the first episode. Recurrent episodes of thrombosis occurred 2 weeks to several months following cessation of warfarin therapy, and recurrent thrombosis did not develop in any patient while on anticoagulation therapy. We subsequently identified 4 patients with an abnormal plasminogen, as detected by an abnormal arc on immunoelectrophoresis, who developed severe thrombosis in the upper extremities.[33] The lack of atherosclerosis in the upper extremities as well as the absence in these patients of any proximal embolic source further demonstrates the sometimes catastrophic consequences that can occur in patients with abnormal plasminogen. In the more than 35 patients that we have diagnosed over the last 7 years, we have seen only 1 patient develop recurrent thrombosis while on warfarin therapy.
Methods of Testing A complete coagulation profile on each patient should be performed, including tests of platelet aggregation, prothrombin time, partial thromboplastin time, fibrinogen level, and platelet count. Functional assays of (1) antithrombin III and plasminogen alpha II antiplasmin, (2) antigenic activities of antithrombin III, plasminogen, and alpha I antitrypsin, and (3) alpha II macroglobulins should be obtained. With immunoelectrophoresis, the abnormal plasminogen present as a abnormal band that is separate on the electrophoretic pattern located nearer the anode and distinct from the normal band. We have also seen a patient with a plasminogen that was separate from the main band but not confined to a distinct band. Indeed, this may represent still another species. Work by several investigators is ongoing to further characterize the molecular defect in these abnormal plasminogens and to assess the functional impairment. This requires rather sophisticated techniques to determine amino acid sequencing and to test the functional ability of the various components of the plasminogen molecule.
TPA AND ANTI-TPA With the discovery of the ability to measure tissue plasminogen activator (TPA), investigators have found that the levels of TPA can vary and may be related to the occurrence of thrombotic disease.[34] Also, the presence of an anti-TPA, which counteracts the effects of TPA, has been discovered.[35,36] Several studies have identified patients who are thrombosis-prone because of increased levels of anti-
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TPA.[34 – 37] Both the mechanisms and the effect of alterations of these mechanisms are poorly understood at the present time. Wiman[37] first developed the test to measure TPA. In a study of patients with deep venous thrombosis, he noted that 40% of his patients had a reduced fibrinolytic potential, which was found to be due to a reduced capacity to release TPA, to an increased plasma level of an anti-TPA, or to a combination of these.[34] He also noted a significant correlation between the plasma anti-TPA and serum triglycerides among patients with myocardial infarction below the age of 45. Obviously these are preliminary data, but they emphasize the need for ongoing investigation to more precisely determine the role of the fibrinolytic system in the pathogenesis of thrombotic disorders.
PROTEIN C Protein C is a vitamin K– dependent proenzyme which is involved in the control of clotting and fibrinolysis. Protein C itself is activated by thrombin, but slowly. This activation is increased up to 20,000-fold when thrombin forms a complex with an endothelial cell membrane called thrombomodulin. Activated protein C, when combined with phospholipids, calcium, and protein S, inactivates the cofactors of the two rate-limiting steps of coagulation, factors Vx and VIIIa.[38 – 40] Protein S is likewise a vitamin K–dependent factor. It acts as a cofactor for the anticoagulant activity of activated protein C by promoting its binding to lipid and platelet surfaces and thus localizing protein C activity.[41,42] Protein C, in conjunction with protein S, also acts as a profibrinolytic agent by increasing plasmin activity through the inactivation of the major inhibitor of TPA.[38,39] Heterozygous protein C deficiency is inherited in an autosomal dominant fashion. In hereditary protein C deficiency, the homozygous state is associated with a very high risk of thrombosis.[43,44] It usually presents as massive venous thrombosis in the neonatal period, which is often fatal. The survival of affected infants in utero may reflect the protection afforded by maternal transfer of protein C or reduced synthesis of other procoagulants by the fetal liver, thus compensating for the deficiency of protein C. In the heterozygous form, a protein C level of 50% is sufficient to predispose individuals to venous thrombosis.[44] The occurrence of thrombophlebitis in patients who are heterozygous for this deficiency is uncertain. Some kindreds have been identified in whom there is a very high incidence of venous thrombosis (up to 80%) by the age of 40, and there are others in whom the occurrence of thrombosis is sporadic.[45,46] Acquired protein C deficiency can be observed in the acute phase of thrombosis, in patients with disseminated intravascular coagulation, in patients with liver disease, and in postoperative patients. Protein C deficiency generally manifests with venous thrombosis. This can be in the form of lower extremity venous thrombosis, often accompanied by pulmonary embolism, or it may present as mesenteric venous thrombosis. We recently reported 5 patients with protein C deficiency. Of these, 4 had deep venous thrombosis of the lower extremity as their initial thrombotic event and 1 had mesenteric venous thrombosis
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with small bowel necrosis.[47] Our patients’ age range was 28–41 years. Two patients had recurrent lower extremity thrombosis, which was bilateral in one. One patient had only one clinical episode of deep venous thrombosis but developed venous stasis ulceration, suggesting multiple episodes of subclinical phlebitis. One patient had a pulmonary embolus. Green et al.[48] evaluated 8 consecutive patients with splanchnic venous thrombosis and demonstrated decreases in the levels of antithrombin III and protein C in all. They were unable to document whether the low levels of protein C and anithrombin III were a result or cause of the thrombosis. Of these 8 patients, 2 had an antecedent history of venous thrombotic problems, and 6 of them, on being evaluated after a period of 1–6 months, were found to have a persistently low level of protein C, which would certainly suggest a congenital etiology. The only case of peripheral arterial thrombosis secondary to protein C deficiency was reported by Coller et al.[49] That patient developed arterial occlusions of both the superficial femoral artery and radial and ulnar arteries. Nelson et al.[50] reported a patient who had two episodes of branch retinal arteriolar occlusion secondary to protein C deficiency. There reports indicate that protein C can cause arterial thrombosis, although it is unusual.
Methods of Testing Standard testing includes a radiolabeled Laurell electroimmunoassay to determine human protein C antigen in plasma samples. Activity levels of 70–130% are considered to be normal. In our patients with venous thrombosis, the level of protein C ranged from 34 to 61%. As with the evaluation of all patients with unusual or unexplained thrombosis, there should be simultaneous measurement of antithrombin III and protein S and routine coagulation studies. We evaluated the family of our patient with mesenteric venous occlusion for protein C deficiency, and the results were compatible with an autosomal dominant type of transmission. There have not, however, been any reports of thrombotic episodes among other family members with low protein C levels. Since not all family members with low protein C develop thrombosis, asymptomatic patients with low levels of protein C should be followed closely and not prophylactically anticoagulated. However, they should be prophylactically anticoagulated preoperatively if major surgery or prolonged immobilization is required. In those who develop thrombotic events, the onset is typically between 15 and 30 years of age. This delay in onset of the first thrombotic episode is not well understood. The fact that protein C rarely causes arterial thrombosis, as contrasted with our experiences with either abnormal plasminogen or antithrombin III abnormalities, is not well understood. It may be that protein C deficiency requires slower-moving blood and increased endothelial surface area, as found in the venous system. However, when protein C deficiency is homozygous, thrombosis is widespread, resulting in death in infancy unless it is treated. Because of the risk of recurrent thrombotic events with the possible sequelae of pulmonary emboli and venous stasis disease, long-term therapy with warfarin is recommended. No loading dose should be administered, as this could precipitate warfarin-associated skin necrosis.[41,42] This can occur 2–5
days following the onset of warfarin therapy and presents as an erythematous patch on the skin that rapidly progresses to a hemorrhagic area, which can become gangrenous. There is a predilection for involvement of the breasts, abdomen, buttocks, and thighs. The proposed mechanism is one of a transient hypercoagulable state, which is created by bolus loading doses of warfarin given to initiate anticoagulation. Because of warfarin’s short half-life, protein C levels fall faster than factor X and prothrombin levels; thus the inhibitory effect of protein C on the coagulation cascade is further diminished. If these levels fall to a critical degree, the procoagulant effects of the coagulation cascade proceed unabated and thrombosis ensues. Warfarin 5.0 mg by mouth once a day should be started to gradually attain a prothrombin time (PT) of 1.5 –2.0 times control. Heparin and warfarin therapy should overlap by 4 – 5 days.
PROTEIN S DEFICIENCY Protein S is also a vitamin K–dependent protein; it functions as a cofactor of anticoagulant activity of activated protein C. The liver is the major source of synthesis, although more recently the endothelial cells and megakaryocytes were identified as other sites of synthesis. Protein S functions by expediting the binding of activated protein C to lipid and platelet surfaces. To date, only heterozygous patients with protein S have been reported.[44] Symptomatic patients often have protein S levels 50% of normal, and, as in protein C deficiency, protein S likewise causes primarily venous thrombosis.[51 – 53] It has been estimated by some to be the cause of approximately 10% of spontaneous venous thrombosis. Coller et al.[49] also reported the only known case of a protein S –deficient patient who had arterial occlusive problems. As with patients with protein C problems, the clotting abnormalities tend to be recurrent; therefore it is essential that these patients remain on long-term warfarin therapy. Clark et al.[54] emphasized the importance of measuring both free protein S as well as the total, which is composed of both the free and bound factors. His patient with mesenteric venous thrombosis had a normal total protein S but a markedly decreased level of the free compound. The association of deficiencies in protein C and its cofactor protein S with hypercoagulable states has only recently been appreciated. Data now suggest that the incidence of protein C and protein S deficiencies is greater than that of either antithrombin III or plasminogen abnormalities. In a recent report evaluating 139 individuals who had at least one major venous thrombotic event, 7% were deficient in protein C, 5% were deficient in protein S, only 2% were deficient in plasminogen, and only 3% were deficient an antithrombin III[39] A majority (79%), however, had no coagulopathy detectable with current testing methods.
HEPARIN-INDUCED THROMBOSIS Paradoxical thrombotic complications of heparin sodium therapy are an uncommon but potentially limb-threatening
Chapter 16.
and occasionally fatal complication of heparin anticoagulant therapy. Several investigators[55 – 59] have identified a chemically induced, immune thrombocytopenia as the cause of the intravascular thrombosis initiated by heparin. When this complication occurs, it usually appears after 4 – 10 days of continued exposure to the drug. The implicated immune factor has been identified as an IgG antibody, which produces agglutination of normal platelets when heparin is added and is seen with both porcine gut as well as beef lung heparin. The thrombi of patients with heparin-induced thrombosis have an unusual grayish-white appearance, in distinction to the red color of most thrombi. The white color is secondary to fibrin platelet aggregates, which can be clearly identified on electron microscopy. Recent studies have demonstrated that heparin-induced thrombosis can be caused by IgA antibodies or antibodies directed against platelet Factor 4 –related chemokines.[60] Rhodes et al.[61] demonstrated an IgG-heparin –dependent antibody in the serum of several of their patients by means of the complement lysis inhibitions test. They also demonstrated a residual heparin platelet aggregating effect 12 days to 2 months after the patients’ recovery from the initial exposure to heparin. In these patients, a 24-hour infusion of heparin caused a mean reduction of platelet count of 197,000/mm3. Since heparin preparations are not pure substances, it is also possible that a high molecular weight contaminant not eliminated by the extraction procedure could be the cause of the antiplatelet effect.
Clinical Presentation We have seen heparin-induced intravascular thrombosis following a wide variety of indications for heparin administration, including thrombophlebitis with and without pulmonary embolus, perioperative heparin prophylaxis in patients prone to develop thrombophlebitis, cardiac surgery, and vascular reconstruction. Platelet aggregation induced by heparin can result from both porcine gut as well as bovine lung heparin. Heparin-induced intravascular thrombosis can affect either arterial or venous circulation. Both subcutaneous and intravenous heparin administration can produce this phenomenon.[62] Even heparin-coated catheters can cause heparin-induced thrombocytopenia. Laster and Silver[63] reported 10 patients who had heparin-coated pulmonary artery catheters inserted and developed heparin-induced thrombocytopenia, which persisted despite discontinuation of all other sources of heparin. Although all of their patients had also received intravenous heparin, it is theoretically possible that the heparin-bonded catheters alone caused the abnormal platelet aggregation. This same group has demonstrated that heparin-induced platelet aggregation can occur in neonates and is a common cause of aortic thrombosis in neonatal intensive care units.[64] Heparin-induced thrombosis can also be caused by low molecular weight heparin and other highsulfated polysaccharides, although the incidence is lower than with unfractionated heparin.[60] The clinical features of this syndrome are often dramatic. Heparin-induced platelet aggregation should be considered in any patient who develops thrombotic complications while receiving heparin therapy. This is especially important in
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patients with arterial occlusions who do not have any other evidence of atherosclerotic vascular disease. At operation, the finding of a white clot at thrombectomy should alert the surgeon to the possibility of a heparin-induced thrombosis. In contrast to several reports in the literature, increased heparin sensitivity rather than increased heparin resistance was seen in several of our patients.[62] We are uncertain as to the cause of this, but presently believe that it is unrelated to the heparininduced aggregative immune globulin.
Diagnosis The definitive diagnosis of heparin-induced intravascular thrombosis is obtained by performing platelet aggregation tests. We have noted two patterns of response. The more common is for the patient’s platelet-poor plasma to aggregate donor platelets upon the addition of heparin, indicating the presence of a relatively nonspecific platelet aggregating factor in the patient’s plasma. The less common pattern, as seen in one of our patients, is for the patient’s plasma to be active only against the patient’s platelets and to have no effect on donor platelets. A 14C-serotonin is also available. Antigen assays have been developed which should be used when functional tests are negative but there is a high clinical suspicion of heparin-induced thrombosis.[60] Other clotting factors are usually normal. The fibrinogen is normal, fibrin split products can be mildly elevated but not in the range seen with intravascular coagulation, and the prothrombin time is normal or slightly prolonged. All patients have a marked reduction in platelet count of less than 100,000/mm3 or a 50% decrease from admission level. In our series, the platelet count averaged 37,500 with a range of 6000–73,000. Patients with arterial thromboses often present with unique angiographic findings. These lesions consist of broad-based, isolated, lobulated excrescences that produce a variable amount of narrowing of the arterial lumen. Usually these signs appear abruptly, along with prominent luminal contour deformities in arterial segments that are otherwise normal. This distribution of disease is unusual and distinct from that commonly seen with atherosclerosis. These changes occur in both the suprarenal and the infrarenal portions of the abdominal aorta and represent adherent mural thrombi composed of aggregates of platelets and fibrin incorporating varying amounts of leukocytes and erythrocytes. Also, platelet aggregating tests should be performed on any patient in whom recurrent pulmonary embolism has developed in the course of adequate heparin therapy.
Treatment When heparin-induced thrombocytopenia is diagnosed, the heparin treatment should be reversed immediately with protamine, and dextran 40 should be administered for its antiaggregating and rheologic effects. We also begin warfarin therapy and continue it for several months. In patients with arterial occlusive manifestations of heparin-induced thrombosis, we recommend long-term warfarin therapy because of the possibility of coexisting latent venous occlusive disease. The response of the platelet count to discontinuation of heparin therapy is usually prompt, often rising to level of
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500,000–600,000/mm3 within several days. In our experience, the use of dextran 40 has facilitated the rebound in the platelet count, most likely because of its antiaggregating effect on the platelets.[65] Coagulation tests distinguish heparin-induced platelet aggregation from other clotting disorders. The fibrinogen level and prothrombin time are usually normal. The levels of fibrin split products and prothrombin time are normal or slightly elevated. The sole patient in our series with a noticeably elevated level of fibrin split products was the initial patient, in whom the diagnosis was not made antemortem. The heparin therapy was not stopped, and prior to her death, caused by an intracerebral hemorrhage, she had massive venous thrombosis involving both upper and lower extremities that resulted in the elevated level of fibrin split products. Early identification of the complication is necessary to minimize the catastrophic complications of major limb amputation and death. This experience suggests that it is imperative that all patients who are receiving heparin therapy have serial platelet counts done from the fourth day onward. It is our policy to perform platelet counts every other day, starting on the fourth day of heparin therapy. If a thrombocytopenia develops, platelet aggregation studies should be performed immediately. With early recognition, the mortality and morbidity of this syndrome can be minimized. Morbidity rates reported in the literature vary from 22 to 61% and mortality rates from 12 to 33%.[66,67]
Strategies for the Management of Patients with Heparin-Induced Platelet Aggregation Patients who require reexposure to heparin for other vascular or cardiac procedures require special management. Patients who develop heparin-induced platelet aggregation usually have their aggregation tests revert to normal within a 6-week to 3-month period. It is preferable to delay the vascular or cardiac procedure until these tests revert to normal. We test the patient at 6 weeks and then every 2 weeks to determine when the platelet-aggregation tests are negative. When they are negative, the patient is brought into the hospital. Cardiac catheterization or angiography is done as required without the use of heparin flush solutions. This is extremely important, since even small amounts of heparin in the flush solutions can stimulate the development of the heparin-induced antiplatelet antibodies. The patient then has the vascular or cardiac procedure done with the usual administration of heparin. At the conclusion of the procedure, all heparin is reversed with protamine and care is taken during the postoperative period to ensure that the patient does not receive heparin inadvertently, through the flushing central venous catheters or arterial lines. By using this procedure, we have not had any difficulty with reexposure to heparin. However, for those patients who require an additional vascular or cardiac procedure and cannot wait until the heparin-induced platelet aggregation tests are negative, a different strategy is necessary. When patients require procedures that can be done without the use of heparin, such as resection of abdominal aortic aneurysms, heparin is not used. However, when a complex lower extremity revascularization or cardiopulmonary bypass is required, some sort of
anticoagulation is necessary. There are basically two approaches to this. The approach favored by Silver and his group[68] consists of giving the patients aspirin and dipyridamole (Persantine) and using heparin for the operative procedure, as is customary. In addition to the aspirin and dipyridamole, we prefer also to use low molecular weight dextran, which, in addition to its rheologic properties, coats the platelets and interferes with platelet adhesion. In some patients, however, as noted by Kappa and his group,[69] the administration of aspirin had no effect on the tests of heparininduced platelet aggregation. Makhoul et al.[70] noted that aspirin abolished the aggregation in 9 of 16 patients with heparin-induced platelet aggregation and only decreased the aggregation in the remaining 7, suggesting that aspirin is not able to reverse the abnormal aggregation in all patients. Because of these reports, our procedure is to place patients who require reexposure to heparin on aspirin and dipyridamole for several days prior to the operative procedure.[1] On the day of operation, the platelet aggregation tests are performed with the addition of heparin. If the addition of heparin causes abnormal platelet aggregation, we use Iloprost to prevent heparininduced platelet aggregation during the procedure. The use of Iloprost can be complicated, particularly since it is a very potent vasodilator, and it must often be accompanied by rather large doses of alpha-adrenergic agents to support the blood pressure. Danaparoid sodium, a mixture of anticoagulant glycosaminoglycans (predominantly low-sulfated heparin sulfate and dermatan sulfate), can be used. There is an approximately 10% cross-reactivity with heparin. Prior to use, in vitro testing must be done to assure that danaparoid will aggregate a patient’s platelets.[60] Newer agents such as recombinant hirudin can be used. The advantage of hirudin is the lack of cross-reactivity with heparin-induced thrombosis antibodies. Sobel et al.[71] reported an alternate technique of placing patients on coumadin anticoagulation combined with dextran as a means of preventing intraoperative thrombosis during reconstruction. This is a reasonable alternative for peripheral vascular reconstruction but is not possible for cardiopulmonary bypass. In the future, different substances may be available to allow for adequate anticoagulation. Makhoul et al.[70] noted that, in vitro, heparinoids did not cause platelet aggregation in blood from patients with heparin-induced platelet aggregation. These new anticoagulant agents are being developed in Europe and, one hopes, may become available in this country. Cole et al.[72] have reported the use of ancrod, which is made from the venom of the Malaysian pit viper, as an anticoagulant in patients who have heparin-induced platelet aggregation. Ancrod acts enzymatically on the fibrinogen molecule to form a product that cannot be clotted by physiologic thrombin. At the present time this medication is in the investigational phase, and, like heparinoids, it may become commercially available fairly soon.
LUPUS ANTICOAGULANT Lupus anticoagulants are IgG or IgM antibodies which are directed against phospholipids that participate in coagulation disorders; they are found in 16 – 33% of the
Chapter 16.
patients who have lupus erythematosus. However, they are also found in a variety of other disorders as well as in normal individuals.[73 – 75] These antibodies belong to a family of antiphospholipid autibodies which were initially detected by their effect in vitro on the prolongation of plasma coagulation times. Most commonly, there is a prolongation of activated partial thromboplastin time; in some patients there is also a prolongation of prothrombin time. There have been only rare reports of bleeding tendencies related to the demonstration of a lupus anticoagulant; however, in the last decade there have been increasing reports of abnormal thrombosis in both the arterial and venous systems, spontaneous abortion secondary to placental thrombosis, cerebrovascular accidents, and thrombocytopenia. Lupus anticoagulants also cause falsepositive tests for syphilis. On occasion, lupus anticoagulant can occur after administration of phenothiazines, procainamide, and penicillin, following viral infections in children, and in patients with acquired immunodeficiency syndrome suffering from Pneumocystis carinii pneumonia.
Clinical Syndrome Recurrent thromboses have been reported in about one third of patients with lupus anticoagulant.[76] These consist of both venous thromboses, most commonly involving the lower extremities, and they are the most common manifestation. Patients may develop evidence of pulmonary hypertension due to recurrent pulmonary emboli or intrapulmonary thrombosis. Repeated strokes have been reported in 15 – 55% of these patients. Obstetric complications have been reported in 25–35% of women with lupus anticoagulant; they consist of spontaneous abortions, intrauterine growth retardation, and fetal death, all occurring in the second and third trimesters.[73 – 75] Ahn et al.,[77] in a study of patients undergoing surgery who had a lupus anticoagulant, noted that 9 of 18 vascular procedures were complicated by thrombosis. Seven of these patients suffered multiple postoperative thrombotic complications, resulting in amputations in three. The mechanism of action of lupus anticoagulants is not known. Several theories have been suggested, including an inhibitory activity on prostacyclin (PGI2), which is a potent in vivo inhibitor of platelet aggregation. IgG fractions with lupus anticoagulant activity have been shown experimentally to block the production of PGI2 in rat aortic endothelial cells.[78] Other investigators suggest that the lupus anticoagulant inhibits protein C activation, which is important in preventing thrombosis. Tsakiris et al.[79] feel that the inhibition of the catalytic activity of thrombomodulin might be explained by the direct attachment of lupus anticoagulant to thrombomodulin or to adjacent phospholipids of the cell membrane, preventing thrombin and/or protein C from binding to thrombomodulin.
Diagnosis Often the only indication that a patient has lupus anticoagulant is an abnormally prolonged activated partial thromboplastin time. On occasion, patients can also have a prolonged prothrombin time. An abnormal rabbit brain
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neutralization procedure and an enzyme-linked immunosorbent assay for the presence of anticardiolipin antibodies can more precisely identify the lupus anticoagulant.[77]
Treatment Because the precise mechanism whereby lupus anticoagulant causes intravascular thrombosis is not known, treatment has varied and has included antiplatelet medication with aspirin and dipyridamole, anticoagulation with warfarin and heparin, and the administration of steroids. The reason for the antiplatelet medication is that some authors feel that the lupus anticoagulant causes a decrease in the availability of arachidonic acid, which is necessary for the synthesis of prostacyclin inhibitor and platelet aggregation in vessel walls. In obstetric patients, it has been reported that steroids and aspirin are effective in preventing spontaneous abortion. Prednisone has been shown to suppress the production and/or activity of lupus anticoagulant as measured by lessened prolongation of the activated partial thromboplastin time. Until more information is available, we prefer to have patients on antiplatelet medications prior to procedures, using both aspirin and presantine. We use dextran routinely in all vascular reconstructions and have the patients on perioperative heparin. Postoperatively, the heparin is replaced by warfarin.
ACTIVATED PROTEIN C RESISTANCE The thrombomodulin/protein C anticoagulant pathway is an essential anticoagulant system. As thrombin is generated at sites of vascular injury, it activates and aggregates platelets and clots fibrinogen. It also binds to the endothelial membrane protein thrombomodulin. Upon binding to thrombomodulin, thrombin takes on anticoagulant properties by activating protein C. The activated protein C (APC) cleaves and inactivates factors Va and VIIIa in the presence of protein S. This endothelial base anticoagulant system allows blood to clot while maintaining intravascular fluidity. Defects in this anticoagulant pathway can provoke thrombosis, and indeed protein C and protein S deficiencies, discussed previously, are associated with an increased risk of thrombosis. To date, prothrombotic mutations have not been found in thrombomodulin or thrombin. A family history of thrombotic events is frequently obtained in young adults with venous thrombosis, but the inherited deficiencies in the anticoagulant protein such as protein C and protein S are found in only a small proportion of patients, approximately 5%.[80] This suggests the presence of another genetic defect that predisposes these patients to thrombosis. Work done by Svensson and Dahlba¨ck revealed a high prevalence of activated protein C resistance among young persons with a history of venous thrombosis.[80] Dahlba¨ck originally postulated that a defect in the protein C pathway interferes with the anticoagulant action of APC. He devised an assay to test this possibility in which the clotting time of blood measures the presence and absence of exogenous APC. In the normal response the clotting time is prolonged in the presence of APC because of the inactivation
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of factors Va and VIIIa. A defect is detected as a failure of prolongation of the clotting time resulting from resistance to added APC. Dahlba¨ck showed that this test detects an autosomal dominant trait associated with thrombosis. Further work done by Bertina and his group have demonstrated that the phenotype of APC resistance is associated with a heterozygosis of homozygous single-point mutation in the factor V gene, which predicts the synthesis of a factor V molecule that is not properly inactivated by APC (factor V Leiden).[81] Other data confirming these results were published by Zoller et al., who studied 50 Swedish families with inherited APC resistance.[82] They found that the specific point mutation in the factor V gene was present in 47 of 50 families. In their study, by age 33 years, 20% of the heterozygous and 40% of the homozygous patients had manifestations of venous thrombosis. The laboratory diagnosis is made by measuring the responsiveness of plasma to APC as the ratio of two activated
partial thromboplastin times: one in the presence of APC and one in its absence. The APC sensitivity ratio is normalized to the ratio obtained with a reference plasma. Resistance to APC is defined by an APC sensitivity ratio of ,0.84. A more recent way of identifying this factor V resistance to activated protein C is by direct assay for the factor V molecule, which is resistant to inactivation by APC (factor V Leiden). The question arises as to what can be done about these point mutations, which cause factor V to be resistant to activated protein C. It is clear that this is a major risk factor for thromboembolic disease, but the majority of patients with these mutant proteins will not suffer thrombosis. The risks of lifelong anticoagulation therapy in an asymptomatic patient must be weighed against the benefit of preventing infrequent yet devastating thrombotic attacks. At this point it would be a logical course of action to treat those patients who have already suffered thrombotic attacks with long-term warfarin therapy.
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Salem, H.H.; Mitchell, C.H.; Firkin, G.B. Current Views on the Pathophysiology and Investigations of Thrombotic Disorders. Am. J. Hematol. 1987, 25, 463. Broekmans, A.W.; Veltkamp, J.J.; Bertina, R.M. Congenital Protein C Deficiency and Venous Thromboembolism: A Study of Three Dutch Families. N. Engl. J. Med. 1983, 390, 340. Griffen, J.G.; Evatt, B.; Zimmerman, T.S. et al. Deficiency of Protein C in Congenital Thrombotic Disease. J. Clin. Investig. 1981, 68, 1370. Tollefson, D.F.J.; Friedman, K.D.; Marlar, R.A. et al. Protein C Deficiency: A Cause of Unusual or Unexplained Thrombosis. Arch. Surg. 1988, 123, 881. Green, D.; Ganger, D.R.; Blei, A.T. Protein C Deficiency in Splanchnic Venous Thrombosis. Am. J. Med. 1987, 82, 1171. Coller, B.S.; Owen, J.; Jesty, J. et al. Deficiency of Plasma Protein S, Protein C, or Antithrombin III and Arterial Thrombosis. Atherosclerosis 1987, 7, 456. Nelson, M.E.; Talbot, J.F.; Preston, F.E. Recurrent Multiple-Branch Retinal Arteriolar Occlusions in a Patient with Protein C Deficiency. Graefe’s Arch. Ophthalmol. 1989, 227, 443. Comp, P.C.; Esmon, C.T. Recurrent Venous Thromboembolism in Patients with a Partial Deficiency of Protein S. N. Engl. J. Med. 1984, 311, 1526. Schwarz, H.P.; Fischer, M.; Hopmeier, P. et al. Plasma Protein S Deficiency in Familial Thrombotic Disease. Blood 1984, 64, 1297. Rodgers, G.M.; Shuman, M.A. Congenital Thrombotic Disorders. Am. J. Hematol. 1986, 21, 419. Clark, D.A.; Williams, W.L.; Marlar, R.A. Mesenteric Vein Thrombosis Associated with a Familial Deficiency of Free Protein S. Arch. Pathol. Lab. Med. 1991, 115, 617. Babcock, R.B.; Dumper, C.W.; Scharfman, W.B. HeparinInduced Immune Thrombocytopenia. N. Engl. J. Med. 1976, 295, 237. Baird, R.A.; Convery, R.F. Arterial Thromboembolism in Patients Receiving Systemic Heparin Therapy. J. Bone Joint Surg. 1977, 59, 1061. Belt, W.R.; Romasulo, P.A.; Alving, B.M. et al. Thrombocytopenia Occurring During the Administration of Heparin. Ann. Intern. Med. 1976, 87, 155. Fratantomi, J.C.; Pollet, R.; Gralnick, H.R. HeparinInduced Thrombocytopenia: Confirmation of Diagnosis with In Vitro Methods. Blood 1975, 45, 395. Nelson, J.C.; Lemer, R.G.; Goldstein, R. et al. HeparinInduced Thrombocytopenia. Arch. Intern. Med. 1978, 138, 548. Warkentin, T.E.; Chang, B.H.; Greinacher, A. Heparin Induced Thrombocytopenia: Towards Consensus. Thromb. Haemostasis 1998, 79, 1. Rhodes, G.R.; Dixon, R.H.; Silver, D. Heparin-Induced Thrombocytopenia. Ann. Surg. 1977, 186, 752. Kapsch, D.N.; Adelstein, E.H.; Rhodes, G.R. et al. HeparinInduced Thrombocytopenia, Thrombosis, and Hemorrhage. Surgery 1979, 86, 148. Laster, J.; Silver, D. Heparin Coated Catheters and Heparin-Induced Thrombocytopenia. J. Vasc. Surg. 1988, 7, 667.
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64. Spadeon, D.; Clark, F.; James, E.; Laster, J.; Silver, D. Heparin-Induced Thrombocytopenia in the Newborn. J. Vasc. Surg. 1992, 15, 306. 65. Towne, J.B.; Bernhard, V.M.; Hussey, C. et al. White Clot Syndrome. Arch. Surg. 1979, 114, 372. 66. Silver, D.; Kapsch, D.N.; Tsoi, E.K.M. Heparin-Induced Thrombocytopenia, Thrombosis, and Hemorrhage. Ann. Surg. 1983, 198, 301. 67. Laster, J.; Cikrit, D.; Walker, N. et al. The Heparin-Induced Thrombocytopenia Syndrome: An Update. Surgery 1987, 102, 763. 68. Laster, J.; Elfrink, R.; Silver, D. Re-exposure to Heparin of Patients with Heparin-Associated Antibodies. J. Vasc. Surg. 1989, 9, 677. 69. Kappa, J.R.; Fisher, C.A.; Berkowitz, H.D. et al. Heparin-Induced Platelet Activation in Sixteen Surgical Patients: Diagnosis and Management. J. Vasc. Surg. 1987, 5, 101. 70. Makhoul, R.G.; Greenberg, C.S.; McCann, R.L. HeparinAssociated Thrombocytopenia and Thrombosis: A Serious Clinical Problem and Potential Solution. J. Vasc. Surg. 1986, 4, 522. 71. Sobel, M.; Adelman, B.; Szaboles, S. et al. Surgical Management of Heparin-Associated Thrombocytopenia. J. Vasc. Surg. 1988, 8, 395. 72. Cole, C.W.; Fournier, L.M.; Bormanis, J. HeparinAssociated Thrombocytopenia and Thrombosis: Optimal Therapy with Anerod. Can. J. Surg. 1990, 33, 207. 73. Espinoza, L.R.; Hartman, R.C. Significance of the Lupus Anticoagulant. Am. J. Hematol. 1986, 22, 331.
74. Tabechnik-Schor, N.F.; Lipton, S.A. Association of Lupuslike Anticoagulant and Nonvasculitic Cerebral Infarction. Arch. Neurol. 1986, 43, 851. 75. Shi, W.; Krills, S.A.; Chong, B.H. et al. Prevalence of Lupus Anticoagulant and Anticardiolipin Antibodies in a Healthy Population. Aust. NZ J. Med. 1990, 20, 231. 76. Du¨hrsen, U.; Brittinger, G. Lupus Anticoagulant Associated Syndrome in Benign and Malignant Systemic Disease. Klin. Wochenschr. 1987, 65, 818. 77. Ahn, S.S.; Kalunian, K.; Rosove, M.; Moore, W.S. Postoperative Thrombotic Complications in Patients with the Lupus Anticoagulant: Increased Risk After Vascular Procedure. J. Vasc. Surg. 1988, 7, 749. 78. Greenfield, L.J. Lupus-like Anticoagulants and Thrombosis. J. Vasc. Surg. 1988, 7, 818. 79. Tsakiris, D.A.; Settas, L.; Makris, P.E.; Marbet, G.A. Lupus Anticoagulant – Antiphospholipid Antibodies and Thrombophilia: Relation to Protein C – Protein S– Thrombomodulin. J. Rheumatol. 1990, 17, 785. 80. Svensson, P.J.; Dahlba¨ck, B. Resistance to Activated Protein C as a Basis for Venous Thrombosis. N. Engl. J. Med. 1994, 330 (8), 517. 81. Bertina, R.M.; Koeleman, B.P.; Kosta et al. Mutation in Blood Coagulation Factor V Associated with Resistance to Activated Protein C. Nature 1994, 369, 64. 82. Zoller, B.; Svensson, P.J.; Xuhaua, H.; Dahlba¨ck, B. Identification of the Same Factor V Gene Mutation in 47 Out of 50 Thrombosis-Prone Families with Inherited Resistance to Activated Protein C. J. Clin. Investig. 1994, 94, 2521.
CHAPTER 17
Anticoagulants Timothy K. Liem Donald Silver
4 are cofactors responsible for the regulation of the reactions catalyzed by the enzymatic factors, and one factor, fibrinogen, is converted to the fibrin monomer. The soluble fibrin monomer undergoes spontaneous polymerization and becomes cross-linked and stabilized by factor XIIIa. All clotting factors with the exception of factor VIII are produced by the liver. Factors II, VII, IX, and X and proteins C and S require the presence of vitamin K for their synthesis. The plasma half-lives of the coagulation factors vary from 5 to 6 hours for factor VII to 120 hours for factor XIII. All coagulation factors are found in fresh-frozen plasma. The labile factors, V and VIII, are rapidly depleted in stored plasma. Activation of the coagulation cascade may occur via the intrinsic and/or extrinsic pathway(s). Both pathways produce activated factor X and share a terminal pathway for the conversion of fibrinogen to fibrin (Fig. 17-1). Once thought to act independently, the extrinsic and intrinsic pathways are now known to have complex interactions. The integrity of the extrinsic and intrinsic pathways may be assayed by the measurement of the prothrombin time (PT) and activation partial thromboplastin time (aPTT), respectively. Excessive or continued activation of the coagulation mechanism is normally prevented by three mechanisms: blood flow reduces the local accumulation of activated clotting factors; the reticuloendothelial cells rapidly remove activated clotting factors; and natural anticoagulants [including antithrombin III (AT III), tissue factor pathway inhibitor (TFPI), protein C, and heparin cofactor II] block the action of activated coagulation factors. Antithrombin III inactivates thrombin (factor IIa), factor Xa, and the other serine proteases of the coagulation cascade. Tissue factor pathway inhibitor blocks the activity of factor VIIa, inhibiting the further activation of factor X to Xa. Protein C, a vitamin K – dependent proenzyme activated by thrombin, cleaves activated factors V and VIII and potentiates fibrinolytic activity by decreasing the activity of plasminogen activator inhibitor (PAI). Heparin cofactor II binds to and inhibits thrombin.
INTRODUCTION Antithrombotic agents are among the most frequently prescribed medications, with over a trillion units of heparin and 974 million milligrams of sodium warfarin (Coumadinw) utilized annually in the United States.[1] These agents enable vascular surgeons to alter the coagulation mechanism according to the needs of their patients. The vitamin K antagonists, unfractionated heparins (UH), and low molecular weight heparins (LMWH) are the mainstays of deep venous thrombosis (DVT) prophylaxis and have reduced the incidence of DVT and pulmonary embolism in postoperative and other at-risk patients. Intravenous or subcutaneous heparin followed by warfarin remains the primary therapy for venous thromboembolism. However, the low molecular weight heparins have been found to be as effective as UH. Heparinoids and recombinant hirudin (r-hirudin) recently have been approved for use by the U.S. Food and Drug Administration. These agents are gaining increased acceptance for patients who are otherwise unable to tolerate UH or LMWH. Various platelet function inhibitors including aspirin, ticlopidine, clopidogrel, and glycoprotein IIb/IIIa inhibitors also are being utilized with increased frequency. To optimize the benefits of anticoagulant therapy, the clinician must have a thorough knowledge of the pharmacology of each agent, the indications for their usage, and the potential complications associated with each agent.
COAGULATION MECHANISM The coagulation mechanism is composed of a series of interrelated enzymatic reactions, with feedback amplification, that result in the production of the stable hemostatic clot. Of the 12 clotting factors, 7 are proteolytic enzymes,
Hobson/Wilson/Veith: Vascular Surgery: Principles and Practice, Third Edition, Revised and Expanded DOI: 10.1081/0819-9-120024900 Copyright q 2004 by Marcel Dekker, Inc.
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Figure 17-1. The intrinsic and extrinsic pathways of coagulation. HMWK, high molecular weight kallikrein; PL, phospholipid from activated platelets or endothelial membranes. [From Hoch, J.R.; Silver, D.: Hemostasis and Thrombosis. In Moore, W.S. (Ed): Vascular Surgery: A Comprehensive Review, 3rd Ed. Philadelphia, Pennsylvania, Saunders, 1990. Reproduced by permission.]
HEPARIN AND HEPARIN-LIKE AGENTS Physical Properties and Mode of Action Unfractionated Heparins and Low Molecular Weight Heparins Heparin molecules are a heterogeneous mixture of straight-chain glycosaminoglycuronan sulfate esters. The molecular weights range from 4000 to 40,000 for UH, and 3000 to 15,000 for the LMWH preparations. The glycosaminoglycuronan chains are composed of alternating uronic acids and glycosamines with a high degree of sulfation. The sulfation imparts a negative charge to the mucopolysaccharide and is in part responsible for its anticoagulant activity when compared with other glycosaminoglycuronans. The primary commercial sources for UH are bovine lung and porcine intestinal mucosa. Most LMWH preparations are derived from the chemical depolymerization and fractionation of porcine intestinal heparin. Heparin exerts its anticoagulant effect through an interaction with the naturally circulating anticoagulants AT
III and TFPI. Heparin combines with AT III in a 1:1 stoichiometric ratio. It induces a conformational change in AT III, which makes its active centers more available for binding to thrombin and the other serine proteases of the coagulation cascade. It does not alter the ratio of binding of AT III to thrombin; however, it does increase the rate at which the complex is formed. After the AT III has neutralized the activated factor, heparin may dissociate from the complex and catalyze other AT III –protease interactions.[1,2] The ability of heparin and LMWH to bind to AT III is determined by the presence of a specific pentasaccharide unit, present in only 30% of standard UH and LMWH molecules. Thrombin (factor IIa) inactivation requires the formation of a ternary complex in which thrombin and AT III bind simultaneously to heparin molecules with at least 18 –20 saccharide units. Only 25 –50% of the heparin molecules in the various LMWH preparations contain this critical length. Thus, UH in the presence of AT III can inactivate both factors Xa and IIa (Xa:IIa ratio approximately 1:1). LMWH preparations have reduced anti-IIa activity while maintaining anti-Xa activity (Xa:IIa ratio of 3 – 5:1), (Table 17-1). The sensitivity of factor Xa to inhibition by the heparin –AT III complex is in part responsible for the effectiveness of the lowdose UH and LMWH regimens in the prophylaxis of DVT.
Chapter 17. Table 17-1. Comparison of Number of Heparin Saccharide Moieties and Specific Anticoagulant Activity Anticoagulant activity Heparin oligosaccharide 08 12 16 18 20
Molecular weight
Anti-Xa
Anti-Ha
2,400 3,600 4,800 5,400 7,200
1.30 1.58 1.60 0.95 1.30
nil nil nil 0.51 1.21
Source: Pharmacol. Rev. 1994, 46, 89–109.
The inhibition of one unit of factor Xa prevents the generation of more than 50 units of thrombin. Another important antithrombotic mechanism is the heparin-induced mobilization of TFPI into the circulation. Tissue factor pathway inhibitor is a serine protease inhibitor produced by endothelial cells and hepatocytes. Although TFPI is present in minute amounts during baseline conditions, UH and LMWH cause a two- to sixfold increase in TFPI via release from the endothelial surface. Tissue factor pathway inhibitor forms a complex with factor Xa, factor VIIa, and tissue thromboplastin and prevents the conversion of factor X to Xa. The anticoagulant effect of UH varies from subject to subject and may be a function of circulating AT III concentrations and antiheparin agents such as platelet factor 4 (PF4). Unfractionated heparin has limited anticoagulant activity in patients with congenital or acquired AT III deficiencies. Circulating AT III concentrations may fall up to 12% within 4 hours of the initiation of heparin therapy and may be decreased by as much as 33% with continued therapy. Patients with preexisting AT III deficiencies may experience an even greater decrease in circulating AT III concentrations with prolonged heparin therapy.[2] Recent studies demonstrate that LMWH administration causes less of a decrease in circulating AT III.
Low Molecular Weight Heparinoids Heparinoids are low molecular weight heparin-like glycosaminoglycuronans (molecular weight , 5000 –6000) and are derived from porcine intestinal mucosa. Numerous heparinoid agents have been developed (e.g., synthetic pentasaccharide sequences, aprosulate, pentosyn polysulfate). Danaparoid is the most widely available heparinoid, with active components including heparan sulfate (, 84%), dermatan sulfate (, 12%), and chondroitin sulfate (,4%).[3] The mechanism of action is similar to that of LMWH; danaparoid increases the activity of antithrombin III, accelerating the inactivation of factor IIa. The anti-Xa:anti-IIa ratio of danaparoid (, 22:1) is even greater than that of most LMWHs. Heparinoid administration may cause minor derangements in PT, aPTT, fibrinolysis, bleeding time, and platelet aggregation.
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Pharmacokinetics Unfractionated and Low Molecular Weight Heparins Unfractionated heparin binds rapidly to plasma proteins, and its early distribution approximates that of plasma. The half-life of circulating UH is dose-dependent, ranging from approximately 45 to 90 minutes. The most likely mechanism for its clearance is the binding of heparin by the reticuloendothelial system, where it may be concentrated up to 7500 times its concentration in plasma.[2,4] The plasma clearance of UH is reduced with increasing doses. When the amount administered exceeds the endothelial binding capacity, heparin is excreted by the kidneys in a nonsaturable fashion. The pharmacokinetic properties of the various LMWH preparations are significantly different from that of UH. Low molecular weight heparins exhibit less binding to plasma proteins (histidine-rich glycoprotein, PF4, vitronectin, fibronectin, von Willebrand factor), resulting in an increased bioavailability and predictibility of response.[5] Unlike UH, LMWH/AT-III complex inactivates free factor Xa and factor Xa bound within the prothrombinase complex. The maximum anti-Xa activity is attained 3 –5 hours after subcutaneous LMWH administration. The half-life of LMWH is approximately two- to fourfold longer than that of UH, and the elimination approximates that of first-order kinetics.[6] The half-life varies depending upon the preparation, dosage, and route of administration (2 – 3 hours after intravenous administration; 3–5 hours if given subcutaneously).
Low Molecular Weight Heparinoids Treatment with danaparoid cannot be monitored with the thrombin time or the aPTT. The maximum anti-Xa activity achieved after subcutaneous or intravenous administration of danaparoid occurs in 2–5 hours. The half-life of danaparoid is approximately 24 hours. Elimination is primarily via the kidneys; thus dosage adjustment is recommended in patients with renal impairment or failure.
THE VITAMIN K ANTAGONISTS Physical Properties The vitamin K antagonists fall into two groups: the substituted 4-hydroxycoumarins, of which sodium warfarin is the most commonly used member, and the indanediones. The indanediones are rarely used in clinical practice today because of their frequent association with toxic cutaneous and hepatic side effects. The 4-hydroxycoumarins are minimally soluble in plasma at pH 7.4; this necessitates protein binding, principally to albumin, of the drugs following absorption and intravenous administration. The metabolites of the 4hydroxycoumarins have better solubilities in plasma and less binding to albumin. The high degree of protein binding of sodium warfarin is responsible for its long half-life, volume of distribution, and mode of metabolism and elimination.
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Mode of Action Vitamin K is a coenzyme for the g-carboxylation of the 10 – 13 glutamine (glu) residues on coagulation factors II, VII, IX, and X and on proteins C and S. The liver processes vitamin K according to the cycle shown in Fig. 17-2. Vitamin K is first reduced to its hydroquinone form (KH2) via an NAD(P)Hdependent reaction. The KH2 is oxidized during gcarboxylation and must be regenerated via a dithioldependent reaction. Each molecule of vitamin K is recycled several hundred to several thousand times before it is degraded into inactive metabolites.[7] Coumarin derivatives block the regeneration of KH2, resulting in the production of vitamin K–dependent proteins with a decreased number of gcarboxyglutamate (gla) residues. These altered coagulation factors have a decreased affinity for calcium (an obligatory cofactor) and significantly decreased biologic activity (less than 5%). The activity of coumarin derivatives depends upon the natural degradation of functional coagulation factors present in the circulation and their replacement by the inactive form. The half-lives of the affected clotting factors range from 6 hours for factor VII to 72 hours for prothrombin; therefore, a therapeutic reduction of the concentrations of all the affected factors (II, VII, IX, X) may take 3 –4 days. The vitamin K antagonists also decrease the concentrations of protein C and its cofactor protein S. Because of a short half-life of 4–6 hours, levels of protein C are reduced quickly with the initiation of warfarin therapy. This creates a potential hypercoagulable state until levels of the vitamin K – dependent coagulation factors are also reduced. Consequently, anticoagulation with UH or LMWH is begun prior to the administration of warfarin and continued for the first 3 days of warfarin therapy. During long-term anticoagulant therapy, factor X activity is usually depressed to the greatest degree and factor IX activity the least. Factor X deficiency is the most common cause of bleeding due to an overdosage of the vitamin K antagonists.[8] When the maintenance dose of warfarin is changed, a new steady-state concentration of each affected factor is achieved. The time required to achieve 90% of the total change is 20 hours for factor VII, 65 hours for factor IX, 130 hours for factor X, and 8 days for factor II. The rate of recovery to normal factor concentrations after the discontinuation of anticoagulant therapy follows a similar time course.[8] The turnover of the clotting factors may be
increased in hypermetabolic states such as hyperthyroidism, sepsis, or fever and reduced in hypometabolic states such as hypothyroidism.
Pharmacokinetics of Warfarin Orally ingested warfarin is rapidly absorbed and reaches a maximum plasma concentration within 2 –12 hours. There is considerable variation in the plasma half-life of warfarin, but in most patients it averages 36 –40 hours. At therapeutic plasma levels, at least 97% of warfarin is bound to albumin. The metabolism of vitamin K antagonists occurs primarily in the microsomal fraction of the hepatocytes, although soluble enzymes in the hepatic and renal cytosol also contribute. The coumarin metabolites are water-soluble and are primarily excreted in the urine. The unchanged parent drugs are not water-soluble and are therefore not significantly excreted by the kidney. There is some evidence for an enterohepatic circulation of coumarin metabolites, but this appears to be of minimal clinical significance.[8] A few patients have a genetically determined resistance to the coumarin anticoagulants. One autosomal dominant trait produces an abnormal vitamin K sensitivity, and another leads to an enhanced metabolism of the drug. Some patients may be overly responsive to the coumarin anticoagulants during the first few days following an acute thromboembolic episode and subsequently develop a relative resistance to the anticoagulant effect. For this reason, dosage adjustment is frequently necessary to avoid too much or too little anticoagulation in the early stages of therapy.[8] The anticoagulant effect of warfarin does not correlate with free drug concentrations or plasma albumin levels. Prolongation of the PT depends on the amount of dietary vitamin K, the age of the patient, and comorbid conditions. Foods high in vitamin K derivatives (spinach, broccoli, cabbage, cow’s milk, yogurt, etc.) may make patients more resistant to the action of warfarin. Certain diseases or deficiency states (hepatic insufficiency, obstructive jaundice, starvation, long-term parenteral nutrition without vitamin K supplementation) depress the synthesis of vitamin K – dependent and non – vitamin K – dependent coagulation factors, resulting in a marked potentiation of warfarininduced anticoagulation. Uremia does not significantly affect the response to oral anticoagulant.
Drug Interactions
Figure 17-2. Warfarin and other coumarin derivatives block the dithiol-dependent reactions decreasing the amount of KH2 available for the carboxylation of glutamine (glu) to gcarboxyglutamate (gla). K, vitamin K; KH2, hydroquinone form of vitamin K; KO, vitamin K epoxide.
Several common therapeutic agents (aspirin, phenobarbital, various antibiotics) alter the response of the coagulation system to regularly administered doses of coumarin derivatives. This alteration may occur through a decreased absorption from the gastrointestinal tract, a displacement of the drug from its binding site on albumin, an increase in the rate at which it is metabolized by the hepatic microsomes, a decrease in vitamin K availability, or an increase or decrease in the plasma half-life of the affected clotting factors. Table 17-2 lists some known drug interactions with coumarin derivatives. In addition, drugs that affect platelet function, such as aspirin and indomethacin, may increase the risk of hemorrhage by impairing platelet function. Patients
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Table 17-2. Mechanisms of Drug Interactions with Oral Anticoagulants (Partial List) Drugs Agonists Chloramphenicol Ethanol Diazoxide Ethacrynic acid Indomethacin Mefenamic acid Nalidixic acid Oxyphenbutazone Phenylbutazone Sulfonamides Tolbutamides Clofibrate D -Thyroxines Oral antibioticsa Anabolic steroids Quinidine Salicylates Antagonists Barbiturates Meprobamate Griseofulvin Cholestyramine Oral contraceptives Vitamin K Pregnancy a
Mechanisms Enzyme inhibition Displacement of bound oral anticoagulant from protein
Reduced availability of vitamin K
Reduced synthesis of clotting factors
Enzyme induction
Reduced absorption Increased synthesis of clotting factors
Especially moxalactam and other second- and third-generation cephalosporines.
who receive additional medications while taking warfarin should have more frequent laboratory testing to ensure that the anticoagulant effect is maintained.
Monitoring Warfarin Therapy Prothrombin time is most commonly used to monitor warfarin therapy. This test is sensitive to changes in activity of factors II, VII, IX, and X. PT is determined by adding thromboplastin (tissue factor and phospholipid derivative from lung, heart, or brain tissue) and calcium to citrated plasma. Thromboplastins vary according to their ability to activate the external coagulation cascade and are graded by the International Sensitivity Index (ISI). The International Normalized Ratio (INR) attempts to standardize PT assays that use different thromboplastins according to the following equation: INR ¼ ½patient PT ðsÞ=laboratory PT ðsÞISI The PT should be monitored on a daily basis for the first 4– 5 days of warfarin therapy. The INR usually achieves the desired range during this period. A longer period of daily monitoring will be required in patients resistant to warfarin. Once the therapeutic range is attained, the PT can be monitored two to three times per week and, when stable, every 4–6 weeks.
Many patients are receiving heparin when warfarin therapy is initiated. Concomitant administration of heparin may prolong PT because of the increased inactivation of factors IIa, IXa, and Xa by AT III. It should be expected that PT will decrease when heparin treatment is discontinued. The effect of heparin on PT can be reduced by removing heparin from the test plasma or by stopping the heparin infusion 6 or more hours before obtaining blood for the PT.
DIRECT THROMBIN INHIBITORS Physical Properties Direct thrombin inhibitors inactivate factor IIa via mechanisms that do not involve antithrombin III. These agents include hirudin, hirugen, hirulog, hirunorms, PPACK (D-PhePro-ArgCH2Cl), argatroban, and inogatran. Hirudin and its recombinant form (r-hirudin) are 65amino-acid polypeptides which bind to the catalytic site and exosite (an additional substrate-binding site) of thrombin, preventing the further conversion of fibrinogen to fibrin. The native form is derived from the salivary gland of the medicinal leech (Hirudo medicinalis ). r-Hirudin is derived from yeast cells and varies by a single amino acid substitution at its N-terminus (leucine for isoleucine) and lacks a sulfate group on tyr-63. This alteration results in a significantly
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decreased affinity for thrombin when compared with the native form. PPACK, argatroban, and inogatran block the catalytic site of thrombin either reversibly or irreversibly. Hirugen is an 11-amino-acid fragment derived from the C-terminus region of hirudin. It blocks the substrate recognition site of thrombin, preventing the binding to fibrinogen and to the thrombin receptor on the platelet surface. Hirulog was created by combining hirugen (specific for the substrate recognition site) with a PPACK derivative [D-Phe-Pro-Arg-Pro-(Gly)4] (specific for the active site).
Pharmacokinetics of Hirudin Hirudin may be administered via an intravenous or subcutaneous route. After an initial distribution phase, hirudin follows first-order elimination kinetics. It is excreted via glomerular filtration in its active form. The renal clearances of hirudin and r-hirudin in female and elderly patients are decreased when compared with young males. The elimination T1/2 is approximately 1.3 hours in healthy subjects, but increases significantly in patients with renal insufficiency or renal failure (elimination T1/2 up to 2 days). The aPTT, PT, and thrombin time (TT) are prolonged by the administration of hirudin or r-hirudin. However, the PT and aPTT dose-response curves obtained are either not sensitive enough (PT) or too sensitive (TT) for clinical use. Hirudininduced prolongation of the aPTT is fairly linear, thus allowing this test to be used for anticoagulation monitoring.
than 80% after oral administration, and 98% is bound to plasma proteins (albumin and lipoproteins). Maximum inhibition of ADP-dependent platelet aggregation is achieved after 8–11 days. Clopidogrel is readily absorbed and is metabolized in the liver to a carboxylic acid derivative; both are highly bound to plasma proteins (.90%). Neither the clopidogrel parent compound nor its primary derivative has platelet inhibitory effects. Most likely, the active platelet inhibitory compound is a metabolite of the carboxylic acid derivative. Clopidogrel induces a dose-dependent inhibition of platelet aggregation, which is more rapid (within 2 hours after oral ingestion) than that of ticlopidine. Approximately 50% of clopidogrel is excreted in the urine, and another 46% via the fecal route.
Glycoprotein IIb/IIIa Inhibitors Fibrinogen, fibrin, von Willebrand factor, and fibronectin have recognition specificity for the platelet glycoprotein IIb/IIIa (GP IIb/IIIa) receptor via the amino acid sequence Arg-Gly-Asp (RGD). Glycoprotein IIb/IIIa inhibitors block the binding of fibrinogen to the platelet membrane, the final common pathway for platelet aggregation regardless of the agonist. The first inhibitor to be developed was c7E3, the Fab fragment of a monoclonal anti-GP IIb/IIIa antibody. Subsequently, naturally occurring proteins (trigramin) containing the RGD sequence have been isolated from the venom of several species of vipers. Synthetic RGD-containing proteins and the more potent KGD analogs recently have been manufactured and have undergone clinical trials.[10]
PLATELET FUNCTION INHIBITORS Aspirin Aspirin is the most widely used platelet function inhibitor. It acetylates platelet cyclooxygenase (prostaglandin H synthase), inhibiting the conversion of platelet and endothelial arachidonic acid to thromboxane A2 and prostacyclin, respectively. This effect lasts for the life of the platelet, whereas the endothelium may generate new cyclooxygenase. Noncoated aspirin is rapidly disintegrated and absorbed in the stomach, whereas, enteric-coated aspirin dissolves in the more neutral to alkaline pH within the duodenum. Enteric coating does not significantly delay the bioavailability when compared to noncoated aspirin.
Ticlopidine and Clopidogrel Ticlopidine and clopidogrel are thienopyridine derivatives that irreversibly inhibit ADP-mediated platelet activation and the binding of fibrinogen to the platelet membrane. These agents also may have a vasomodulatory effect on serotonin-, endothelin-, and arachidonic acid –induced vascular smooth muscle contraction.[9] Intact ticlopidine has no effect on platelets in vitro; in addition, the in vivo platelet inhibitory effects are not observed for 24 –48 hours after administration, suggesting that a ticlopidine metabolite may be a more potent platelet function inhibitor. Ticlopidine absorption is greater
THERAPY FOR VENOUS THROMBOEMBOLISM The purpose of anticoagulant therapy in deep venous thrombosis (DVT) is to halt propagation of thrombus and to decrease the risk of pulmonary embolism. Untreated isolated calf vein thrombosis propagates into proximal veins in approximately 20% of patients.[11,12] Additionally, 50% of patients with untreated proximal (popliteal and/or femoral) venous thrombosis will develop pulmonary embolism.[11,13] All patients with DVT are treated with heparin and warfarin antithrombotic therapy, unless contraindicated. Urokinase or tissue plasminogen activator are used selectively, and the criteria for their use will not be discussed in this chapter. Patients with proximal DVT are given an intravenous bolus of unfractionated heparin (100 –200 USP units/kg of heparin). This is followed by a heparin infusion, usually beginning at 1000 USP units per hour (or 15 units/kg/h). Unfractionated heparin concentrations in the range of 0.2–0.4 U/mL (measured via protamine titration) have been shown to inhibit propagation of venous thrombi.[14,15] In most laboratories, this heparin concentration correlates with an aPTT in the range of 1.5–2.5 times the normal reference range. The aPTT is monitored every 6 hours for the first 24 hours; the frequency of testing is decreased once the aPTT is
Chapter 17.
stable. Most patients who are treated with warfarin will require approximately 3 – 4 days of overlap anticoagulation with heparin to ensure that the functional vitamin K – dependent coagulation factors with longer half-lives have become depleted. In addition, daily platelet counts are performed to allow early detection of heparin-induced thrombocytopenia (HIT). Most patients who develop HIT will demonstrate a decrease in the platelet count after the fourth or fifth day of heparin therapy. If the patient has been previously exposed to heparin, the thrombocytopenia may begin within hours of the administration of heparin. Some patients will test positive for the presence of heparin-associated antibodies and develop recurrent thromboses without developing thrombocytopenia or a decrease in the platelet count.[16] Subcutaneous LMWH has been used successfully as initial therapy for patients with proximal (popliteal and/or femoral) DVT. Several large studies have demonstrated that the efficacy and safety of selected LMWH regimens are equal or superior to intravenous unfractionated heparin. Patients treated with weight-adjusted or fixed-dose LMWH (subcutaneously) followed by warfarin appear to have a similar incidence of symptomatic recurrent thromboembolism (2.8 –7.1%) when compared to patients treated with intravenous unfractionated heparin, followed by oral warfarin therapy (7.0 –12.9%).[17,18] Subsequent studies also have demonstrated the efficacy of outpatient initial therapy with LMWH when compared with inpatient intravenous standard heparin.[19,20] The rate of recurrent thromboembolism in patients treated with primarily outpatient LMWH and warfarin (5.3 –6.9%) was not significantly different than in patients treated with unfractionated heparin and warfarin in an inpatient setting (6.7–8.6%). A pooled analysis of several studies indicates that the incidence of major bleeding complications was decreased with LMWH therapy when compared to UH (3.2% versus 0.9%).[21] However, several large prospective trials have not found any significant decrease in major bleeding complications.[17,22 – 24] Regardless of the route and type of heparin administered, warfarin administration is begun simultaneously. Five to 7.5 mg of warfarin is given every evening, and the dosage is adjusted to achieve a therapeutic prothrombin time (PT), with the INR ranging from 2 to 3. Some patients may develop a prolongation of the INR within 1 –2 days, due to the rapid depletion of factor VII (half-life of approximately 6 hours). However, a truly antithrombotic state is not achieved until factors II and X are functionally depleted (approximately 3 – 4 days). Patients with iliac, femoral, and/or popliteal DVT are treated with warfarin for approximately 6 months. Warfarin is continued indefinitely if risk factors for DVT continue to be present (congenital thrombophilic disorders, patient immobility, malignancy, etc.). Some testing for thrombophilic conditions can be performed after the acute thromboembolic event has subsided and while the patient is receiving warfarin (e.g., assays for Leiden factor, homocystinemia, antithrombin III deficiency, prothrombin 20210 mutation, antiphospholipid antibodies, and dysfibrinogenemias). Other tests should be performed when there is no active DVT and after the warfarin has been discontinued for at least 3 –4 weeks. These include tests for
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protein C, protein S, and other vitamin K – dependent coagulation factors. Patients who have a history of recurrent thromboembolic events may be at risk for the development of additional thromboses during this “unprotected” time. We treat these patients with outpatient subcutaneous unfractionated or low molecular weight heparin until the testing for thrombophilic conditions has been completed. The heparin is discontinued at least 6, preferably 24, hours before the testing is done. Those patients with a congenital hypercoagulable condition and a proven thrombotic event are placed on long-term or, preferably, life-long warfarin. Patients with antiphospholipid antibodies should receive warfarin until the antibodies are no longer detectable.[25]
THERAPY FOR ARTERIAL THROMBOEMBOLISM Intravenous heparin is an important therapeutic adjunct for patients with arterial thromboembolism. Patients with acute ischemia syndromes (limb and visceral ischemia, unstable angina, anterior Q-wave myocardial infarction, transient ischemic attack, acute ischemic stroke, etc.) are commonly treated with heparin. However, convincing evidence supporting the use of heparin therapy is lacking except in patients with unstable angina and anterior Q-wave infarction.[26] In patients with native arterial thrombosis or embolic occlusion, heparin probably decreases the propagation of thrombus, thereby preserving the existing collateral arterial beds. Once blood flow is restored, anticoagulation (using heparin with or without warfarin) may also decrease the rate of recurrent embolism. Evidence for the use of anticoagulants in acute limb ischemia is conflicting (and is based on retrospective and nonrandomized studies).[27] However, most authors continue to recommend heparin and/or warfarin anticoagulation prior to and after revascularization procedures.[28 – 30]
PROPHYLAXIS AGAINST ARTERIAL THROMBOEMBOLISM Aspirin and other platelet function inhibitors decrease the risk of myocardial infarction, stroke, and vascular death in patients who develop complications related to atherosclerosis. The Antiplatelet Trialists’ Collaboration reviewed 145 randomized trials involving approximately 70,000 “highrisk” patients and 28,000 “low-risk” patients (Antiplatelet 1). Subsequent vascular events were significantly reduced in patients with (1) acute myocardial infarction, (2) a past history of myocardial infarction, (3) a past history of stroke or transient ischemic attack, and (4) a history of other vascular events including unstable angina, stable angina, vascular surgery, angioplasty, atrial fibrillation, valvular disease, and peripheral vascular disease. Taken together, those high-risk patients who were treated with antiplatelet therapy had a onethird reduction in the rate of nonfatal myocardial infarction, a one-third reduction in nonfatal strokes, and a one-sixth
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reduction in vascular death. The most widely tested antiplatelet agent was aspirin (75 –325 mg/day). The Antiplatelet Trialists’ Collaboration and other studies demonstrated that lower dosages of aspirin (75 mg/day) are also effective in reducing the risks of myocardial infarction and stroke in high-risk patients.[31 – 34] Alternative antiplatelet regimens, including aspirin plus dipyridamole, sulfinpyrazone alone, and ticlopidine alone, were also found to provide similar protection against vascular events. Among patients at low risk (no prior history of a vascular event), antiplatelet therapy decreased the rate of nonfatal myocardial infarction by approximately one third.[31] Obviously, the number of infarctions prevented in the low-risk patients (5 per 1000 subjects) were less than in the high-risk group (13.3 per 1000 subjects). Taken together, the rate of vascular events (including nonfatal myocardial infarction, nonfatal stroke, and vascular death) in low-risk patients was not significantly altered by long-term antiplatelet therapy. Ticlopidine and clopidogrel have been compared directly with aspirin in a few randomized trials involving high-risk patients.[35,36] In patients with a prior history of stroke, long-term ticlopidine therapy was associated with a significant reduction in the rate of subsequent strokes when compared with aspirin (10% versus 13%).[35] Clopidogrel, recently approved by the Food and Drug Administration for clinical use, has been advocated as an antiplatelet agent with an efficacy superior to aspirin. However, the CAPRIE (Clopidogrel versus Aspirin in Patients at Risk of Ischaemic Events) study demonstrated that the advantages of clopidogrel are marginal at best. More than 19,000 patients with a history of (1) recent ischemic stroke, (2) recent myocardial infarction, or (3) symptomatic atherosclerotic peripheral vascular disease were treated with either clopidogrel or aspirin. The risks of subsequent ischemic stroke, myocardial infarction, or vascular death were 5.32% in the clopidogrel group and 5.83% in the aspirin group. Although there was a
statistically significant relative risk reduction of 8.7% ð p ¼ 0:04Þ; the absolute reduction in the number of vascular events was quite small. Clopidogrel may be more beneficial as a combination therapy agent since aspirin and clopidogrel inhibit platelet function via different signal transduction pathways (thromboxane A2 and ADP inhibition). Long-term warfarin administration is recommended for the prevention of systemic thromboembolism in patients with tissue heart valves, mechanical heart valves, valvular heart disease, in selected patients with atrial fibrillation (AF), and in selected patients with acute myocardial infarction.[37] Patients older than 65 years with AF and younger patients with AF and additional risk factors (prior transient ischemic attack or stroke, hypertension, heart failure, diabetes, coronary artery disease, mitral stenosis, prosthetic heart valve, thyrotoxicosis) are candidates for long-term warfarin prophylaxis.[38] Patients with anterior Q-wave myocardial infarction, severe LV dysfunction, and echocardiographic evidence for mural thrombus also should be considered for warfarin anticoagulation. Recommended INR ranges from the American College of Chest Physicians (ACCP) Fourth Consensus Conference on Antithrombotic Therapy are included in Table 17-3.
PROPHYLAXIS AGAINST VENOUS THROMBOEMBOLISM The incidence of perioperative DVT depends on the number of risk factors (e:g:; . 40 years, obesity, malignancy, immobility, prior venous thromboembolism, varicose veins, low cardiac output, major trauma, oral contraceptive use) and the type of surgical procedure performed. The incidence ranges from 25 to 33% in patients undergoing general surgical procedures and 45 to 70% in patients having total hip replacement.[39] Fixed low-dose UH prophylaxis (5000 units SC every 8–12 hours) reduces the incidence of DVT in
Table 17-3. ACCP Consensus Conference on Antithrombotic Therapy Recommended INR Range for Various Indications Indication DVTa prophylaxis (high risk) Treatment of venous thrombosis Treatment of pulmonary embolism Bioprosthetic heart valve Mechanical heart valves (high risk) Myocardial infarctionb Valvular heart disease Atrial fibrillation a
INR 2.0 –3.0 3.0 –3.0 3.0 –3.0 2.0 – 3.0 (for the first 3 months) 2.5 –3.5 2.0 –3.0 2.0 –3.0 2.0 –3.0
Deep vein thrombosis. For the prevention of systemic embolism. If warfarin is being used to decrease the risk of recurrent myocardial infarction, an INR of 2.5–3.5 is recommended. Source: Modified and Reprinted with Permission (Hirsh, J.; Dalen, J.E.; Deykin, D.; Poller, L.; Bussey, H. Oral Anticoagulants: Mechanisms of Action, Clinical Effectiveness, and Optimal Therapeutic Range. Chest 1995, 108 (Suppl. 4), 231S–246S). b
Chapter 17.
moderate- and high-risk general surgery patients from approximately 25% to 8%.[40] The incidence of pulmonary embolism is reduced as well. However, fixed low-dose UH prophylaxis is not as effective in patients with hip fractures or in patients undergoing total hip or knee replacement. Orthopedic and very high-risk general surgical patients should receive more effective DVT prophylaxis (oral anticoagulants, adjusted-dose UH, LMWH, or combination prophylaxis with intermittent pneumatic compression). When using an adjusted-dose UH regimen, the aPTT should be monitored 2–6 hours after heparin administration, with a target range of 2–212 times the control. Adding pneumatic compression to fixed-dosage UH prophylaxis further decreases the incidence of perioperative DVT. The prophylactic effect of vitamin K antagonists in DVT was first demonstrated by Sevitt and Gallagher in 300 patients with hip fractures.[41] The treated group, which received phenindione, had a 3% incidence of clinically diagnosed venous thromboembolism, while the control group had a 29% incidence of venous thromboembolism. At autopsy, venous thrombosis was found in 83% of the control patients, with 10% having pulmonary emboli. Only 14% of the treated patients who died had evidence of DVT; no patient died from pulmonary embolism while receiving phenindione.[41] More recent studies have confirmed that warfarin (INR 2.0–3.0) is effective prophylaxis against DVT in patients undergoing orthopedic surgical procedures.[42,43] The administration and monitoring of warfarin prophylaxis in the perioperative period are more cumbersome than with other regimens (LMWH), limiting its widespread use.
COMPLICATIONS OF ANTICOAGULATION Heparin Heparin-induced thrombocytopenia from the development of heparin-associated antibodies is the most common nonhemorrhagic complication of heparin therapy. Depending on the type of heparin used, the definition of thrombocytopenia, and the tests used to detect the presence of HAAb, the incidence of HIT varies from 2.4 to 9.6%.[44] Heparinassociated antibody formation may occur in up to 21% of vascular surgery patients who are subjected to repeated exposures with heparin.[16] Low molecular weight heparin preparations also cause HAAb.[45] Patients who are HAAbpositive from prior exposures to UH have a variable rate of cross-reactivity (19.6– 60.8%) with various LMW heparin and heparinoid preparations.[46] The first step in the treatment of patients with suspected HAAb/HIT is the prompt discontinuation of heparin administration. The presence of HAAb may be confirmed with two-point platelet aggregation assays, 14C-serotonin release assays, and newly developed enzyme-linked immunosorbent assays (ELISA). Most patients can expect a gradual return to normal platelet counts within 4 –5 days after all forms of heparin have been discontinued. If patients require continued anticoagulation, several options arc available. Low molecular weight heparinoids
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(e.g., danaparoid) may be used only if cross-reactivity tests are negative. The low rate of cross-reactivity (10 –19.6%) indicates that most, but not all, HAAb-positive patients may safely receive LMW heparinoids.[46,47] The dosage and route of danaparoid administration depend on the indications for use. As prophylaxis against thromboembolism, danaparoid is administered at 750 –1250 units twice a day, subcutaneously. For rapid anticoagulation, it is administered as an IV bolus 2500 – 3750 units with subsequent continuous infusion. If cross-reactivity testing is not available, patients should be treated with recombinant hirudin. Rapid anticoagulation may be achieved with an IV bolus (0.4 mg/kg body weight, 44 mg maximum) followed by a continuous infusion (0.15 mg/kg body weight/h, 16.5 mg/h maximum). The aPTT should be monitored frequently, with a therapeutic range of 1.5–2.5 times control.
Warfarin The primary complication of warfarin therapy is hemorrhage. The true incidence of bleeding is probably more accurately reflected in observational and population-based studies (2.7 – 12% per year) than in well-monitored clinical trials.[48 – 51] The usual sites of major hemorrhage include the gastrointestinal tract, retroperitoneum, extremities, pelvic organ, and central nervous system. The risk factors for bleeding complications associated with oral anticoagulation include the intensity of warfarin therapy, the age of the patient, the presence of malignancy or peptic ulcer disease, and the type of coumarin derivative used.[48,49] More intense anticoagulation (INR . 3.0) is associated with a greater incidence of bleeding than less intense warfarin therapy (INR 2.0–3.0). Minor hemorrhagic events are not reliable indicators that major bleeding is likely to occur.[49] The greatest likelihood of bleeding occurs during the first months of therapy.[49,50] Increased bleeding events may occur when warfarin dosages are adjusted (e.g., in the perioperative period) or when vitamin K intake changes significantly (dietary modifications, critical illness). Bleeding, which occurs in the presence of an INR of 5.0 or less, may have other associated causes (e.g., peptic ulcer disease, malignancy). Other less common complications of warfarin include alopecia, urticaria, dermatitis, fever, nausea, diarrhea, abdominal cramping, and hypersensitivity reactions. Warfarin-induced skin necrosis is a rare complication occurring in 0.01– 0.1% of patients receiving warfarin;[52] individuals with protein C deficiency may be more susceptible.[53] The mechanism of warfarin-induced skin necrosis may involve the depletion of protein C prior to reductions of the other vitamin K– dependent proteins. This causes a temporary thrombophilic state, which may lead to dermal venous thrombosis. The most likely sites of dermal venous thrombosis are the breast, thigh, or buttocks, although other areas with increased subcutaneous fat also may be involved. This complication may occur more often with larger loading doses of warfarin, although this is not clearly established. In patients who do not require rapid anticoagulation, we recommend that subcutaneous UH or LMWH be administered concurrent with the
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first 3–5 days of warfarin to decrease the likelihood of skin necrosis.
Reversal of Warfarin Anticoagulation Patients may require reversal of anticoagulation due to an excessive warfarin effect. Another common indication for anticoagulation reversal is the need for diagnostic, surgical, or dental procedures. The method by which warfarin anticoagulation is reversed depends on the amount of INR prolongation and whether or not the patient is bleeding. Hirsh and Levine[6] have formulated recommendations as follows: if the INR is less than 6.0 and the patient is not bleeding, omit the next few doses and restart warfarin at a lower dose. If the INR is between 6.0 and 10.0 and the patient is not bleeding, vitamin K (1 –2 mg, subcutaneous injection) can be administered. If the INR is greater than 10.0 and the patient is not bleeding, higher doses of vitamin K (3–10 mg, subcutaneous injection) can be given. Additional doses of vitamin K are indicated if the INR is still significantly prolonged in 6–12 hours. If the INR is greater than 20.0 or if the patient has significant bleeding, vitamin K (10 mg subcutaneously or IV) should be administered in combination with fresh frozen plasma or prothrombin complex concentrate. Elective surgery and invasive diagnostic procedures in patients receiving warfarin should be delayed, if possible,
until the oral anticoagulation can be discontinued safely. If the patient is on lifelong warfarin therapy or if the surgical/diagnostic procedure cannot be delayed, the options for the management of these patients are as follows. The first choice is to discontinue warfarin 4 –5 days prior to surgery. Therapeutic LMWH (enoxaparin 1 mg/kg, subcutaneously twice a day) is administered during this time, discontinued 6–12 hours prior to surgery, and reinstituted several hours after surgery. Alternatively, the warfarin dosage is reduced to allow the INR to reach low therapeutic or subtherapeutic levels. The choice depends upon the original indication for anticoagulation and the type of surgical procedure being performed. Patients receiving warfarin who require emergent surgery can have the anticoagulation reversed with vitamin K (10 mg IV) and/or fresh frozen plasma (if fluid volume is not a problem). Patients with mitral or combined mechanical valve replacements have a significant incidence of perioperative thromboembolic complications that warfarin is discontinued in the perioperative period.[54] A protocol that replaces warfarin with UH or LMWH may be most appropriate in these patients.[55] Discontinuation of warfarin 3–5 days prior to noncardiac surgery (without heparin replacement) in patients with aortic valve prostheses appears to be associated with a low incidence of thromboembolism.[54,55] Patients who are to undergo relatively minor procedures, where mechanical hemostasis can be achieved without difficulty, probably do not need full reversal of warfarin anticoagulation.
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45. Warkentin, T.E.; Levine, M.N.; Hirsh, J.; Horsewood, P.; Roberts, R.S.; Kelton, J.G. Heparin-Induced Thrombocytopenia in Patients Treated with Low-Molecular-Weight Heparin or Unfractionated Heparin. [See Comments]. N. Engl. J. Med. 1995, 332 (20), 1330– 1335. 46. Kikta, M.J.; Keller, M.P.; Humphrey, P.W.; Silver, D. Can Low Molecular Weight Heparins and Heparinoids Be Safely Given to Patients with Heparin-Induced Thrombocytopenia Syndrome? Surgery 1993, 114 (4), 705– 710. 47. Greinacher, A.; Admiral, J.; Dummel, V.; Vissac, A.; Kiefel, V.; Mueller-Eckhardt, C. Laboratory Diagnosis of Heparin-Associated Thrombocytopenia and Comparison of Platelet Aggregation Test, Heparin-Induced Platelet Activation Test, and Platelet Factor 4/Heparin Enzyme-Linked Immunosorbent Assay. Transfusion 1994, 34 (5), 381– 385. 48. van der Meer, F.J.; Rosendaal, F.R.; Vandenbroucke, J.P.; Briet, E. Bleeding Complications in Oral Anticoagulation Therapy. An Analysis of Risk Factors. Arch. Intern. Med. 1993, 153 (13), 1557– 1562. 49. Gitter, M.J.; Jaeger, T.M.; Petterson, T.M.; Gersh, B.J.; Silverstein, M.D. Bleeding and Thromboembolism During Anticoagulant Therapy: A Population-Based Study in Rochester, Minnesota. [See Comments]. Mayo Clin. Proc. 1995, 70 (8), 725– 733.
50. Landefeld, C.S.; Goldman, L. Major Bleeding in Outpatients Treated with Warfarin: Incidence and Prediction by Factors Known at the Start of Outpatient Therapy. Am. J. Med. 1989, 87 (2), 144– 152. 51. Gurwitz, J.H.; Goldberg, R.J.; Holden, A.; Knapic, N.; Ansell, J. Age-Related Risks of Long-Term Oral Anticoagulant Therapy. Arch. Intern. Med. 1988, 148 (8), 1733– 1736. 52. Cole, M.S.; Minifee, P.K.; Wolma, F.J. Coumarin Necrosis—A Review of the Literature. Surgery 1988, 103 (3), 271– 277. 53. Pescatore, P.; Horellou, H.M.; Conard, J.; Piffoux, M.; Van Dreden, P.; Ruskone-Fourmestraux, A.; Samama, M. Problems of Oral Anticoagulation in an Adult with Homozygous Protein C Deficiency and Late Onset of Thrombosis. [See Comments]. Thromb. Haemostasis 1993, 69 (4), 311– 315. 54. Katholi, R.E.; Nolan, S.P.; McGuire, L.B. Living with Prosthetic Heart Valves: Subsequent Noncardiac Operations and the Risk of Thromboembolism or Hemorrhage. Am. Heart J. 1976, 92 (2), 162–167. 55. Katholi, R.E.; Nolan, S.P.; McGuire, L.B. The Management of Anticoagulation During Noncardiac Operations in Patients with Prosthetic Heart Valves. A Prospective Study. Am. Heart J. 1978, 96 (2), 163–165.
CHAPTER 18
Thrombolytic Therapy Sunita Srivastava Kenneth Ouriel
disulfide-linked heavy and light chains. The light chain of plasmin is capable of proteolytic activity and enables it to degrade active plasma proteins such as coagulation factors, complement, glucagon, ACTH growth hormone, fibrin, and fibrinogen.[5] Fibrin-bound plasminogen is more susceptible to activation than free plasma plasminogen. The fibrinolytic system in humans can be activated by two mechanisms. The first is the extrinsic pathway where plasmin activation is mediated by the presence of plasminogen activators released from endothelial cells. The physiologic plasminogen activators include direct agents such as urokinase plasminogen activator (u-PA) and tissue plasminogen activator (t-PA), while streptokinase and acetylated plasma streptokinase activator complex (APSAC) bind to plasminogen in equimolar complexes that subsequently become activators. The second mechanism of activation occurs when factor XIIa converts prekallikrein to kallikrein, a plasminogen activator. The process of fibrinolysis is self-perpetuating through a plasmin-mediated positive feedback loop. Plasmin is also capable of accelerating further plasmin formation by cleaving an activation peptide on plasminogen. This peptide converts Glu-plasminogen into a smaller Lys plasminogen, which has an increased fibrin affinity and activity.[6] Plasmin is rapidly inactivated in the free circulation by antiplasmin but is protected from it within the thrombus, where concentration of antiplasmin is low. The primary inhibitor is a2-antiplasmin, which is present in both plasma and platelets.[7] Its ability to rapidly complex with plasmin results in the very short half-life of circulating plasmin. Plasmin bound to fibrin is resistant to antiplasmin inhibition. The lysine binding sites on plasmin are bound to fibrin within a clot and therefore protect it from inactivation by antiplasmin, which also requires free lysine sites for attachment and subsequent inhibition. This allows fibrin degradation to occur with minimal systemic effects. Alpha macroglobulin may also act as a plasmin inhibitor when excess plasmin is present. Plasminogen inactivator inhibitor I, a glycoprotein present in endothelial cells, plasma, and platelets, is the primary
Thrombolytic agents are a group of proteins that dissolve intravascular thrombi. The discovery and use of these agents have transformed therapeutic options offered to patients with arterial and venous occlusions. Limb salvage, decreased morbidity and mortality, alleviation of postthrombotic symptoms, and the requirement for less invasive procedures are the potential benefits of therapy. The purpose of this chapter is to review the mechanisms of fibrinolysis and examine the various thrombolytic agents and their applications.
FIBRINOLYSIS Fibrinolysis refers to the dissolution of the fibrin network that forms the framework and supporting structure of thrombus. The process of fibrinolysis consists of a complex interaction of enzymes, which culminates in the breakdown of fibrin. Plasminogen is an inactive proteolytic enzyme and a precursor to plasmin. It is synthesized in the liver and is a constituent of plasma, although it is present in extracellular fluid as well.[1,2] Infancy, cirrhosis, and disseminated intravascular coagulation are associated with low levels of plasminogen, while conditions resulting in an increase in acute phase reactants such as trauma, surgery, and infectious processes are associated with an increase in circulating plasminogen.[3] All presently available fibrinolytic agents act indirectly through plasminogen. Human plasminogen is a single-chain glycoprotein with a five triple loop—three disulfide bridge regions of sequence homology called kringles, which function as independent domains. They are located on the heavy chain or NH2 terminal and exhibit homology with domains in lipoprotein a, tissue plasminogen activator and prothrombin.[4] The kringles have lysine-binding sites that bind to fibrin, plasminogen activators, and plasminogen inhibitors such as a2-plasmin inhibitor. The catalytic site is located at the COOH terminus and contains the amino acid triad of His 603, Asp 646, and Ser 740. Plasminogen is converted into plasmin, an active serine protease, by the cleavage of the Arg 560–Val 561 bond. This action converts the plasminogen into
Hobson/Wilson/Veith: Vascular Surgery: Principles and Practice, Third Edition, Revised and Expanded DOI: 10.1081/0819-9-120024901 Copyright q 2004 by Marcel Dekker, Inc.
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inhibitor of plasminogen activators. It inhibits single- and double-chain t-PA and double-chain u-PA. It binds to fibrin and inhibits plasminogen activation. Plasminogen inactivator inhibitor II is found during the third trimester of pregnancy, and its role in fibrinolysis is uncertain. Fibrinolysis has several mediators, including fibrin itself. Fibrin formation is a stimulus for activation of the fibrinolytic cascade. The binding of plasminogen to fibrin at the kringle sites incorporates plasminogen molecules into clot formation and allows for its availability for activation by various agents. Degradation of fibrin creates additional lysine sites for plasminogen binding and activation. Non-cross-linked fibrin and fibrinogen are degraded by plasmin in the same manner and result in the same degradation products. These include fragments A, B, D, and E. Degradation of cross-linked fibrin is slower because of increased enzymatic resistance secondary to the presence of the cross-links. This results in several noncovalently bond fragments, including DD/E (ddimer),[8] which when present, are markers of true fibrin degradation.
THROMBOLYTIC AGENTS Thrombolytic agents can be classified by mechanism of action, mode of production, and fibrin specificity. Pharmacologic actions include agents that directly convert plasminogen to plasmin versus agents that are inactive zymogens and require change to an active form before they can cleave plasminogen. In addition, agents can be classified by mode of production—either bacterial or recombinant techniques. These agents can also be divided into fibrin specific (bind to fibrin but not fibrinogen) and nonspecific, as well as their ability to bind avidly to fibrin (fibrin affinity). Discussion of the agents is most efficient based on the origin of the parent compound. These four groups include streptokinase, urokinase, tissue plasminogen activators, and a miscellaneous group of novel agents.
Streptokinase Streptokinase (SK) is isolated from b-hemolytic streptococci and is a single-chain molecule weighing 48 kDa. Streptokinase has no enzymatic activity by itself but forms an equimolar complex with plasminogen. In this state it can function as a plasminogen activator and serine protease. The complex then converts plasminogen to plasmin and also gradually transforms into the streptokinase –plasmin complex, which also activates plasminogen. Streptokinase is antigenic and antibodies to streptococci are present in individuals with previous exposure. It forms a complex with these preformed antibodies, and its activity is neutralized. The half-life of streptokinase is reduced to 18 minutes from its biologic half-life of 90 minutes with the presence of antibodies. Drug dosage must be adjusted to neutralize circulating antibodies and establish therapeutic lysis. The neutralizing antibodies inactivate exogenously administered streptokinase and thus require a large initial bolus as a loading dose. This finding has led some investigators to recommend measurement of antibody titers before initiation of streptokinase therapy.[9]
Complications of streptokinase therapy have been reported, including pyrexia and allergic reactions. The allergic reactions range from cases of skin rashes (6 –9% reported)[1,2] to anaphylaxis and angioedema (incidence of 0.9–2%).[2,9] Antihistamines, antipyretics and steroids have been used to treat adverse reactions during drug administration. The major untoward effect associated with streptokinase therapy is systemic bleeding. Streptokinase has several mechanisms of promoting systemic lysis. It causes the proteolytic depletion of coagulation factors such as fibrinogen, factor V, and factor VIII. In vitro clotting parameters such as the prothrombin time (PT), partial thromboplastin time (PTT), and thrombin time (TT) are prolonged. The streptokinase-induced hyperplasminemia results in digestion of fibrin thrombi nonspecifically. The release of fibrin(ogen)degradation products that are also potent anticoagulants worsens the coagulopathy. The streptokinase derivative APSAC was developed as the limitations of SK became apparent. APSAC is an equimolar complex of streptokinase and human Lys-plasminogen that has been acylated at its catalytic serine site, rendering the complex inactive. In plasma and in fibrin, deacylation occurs by hydrolysis, resulting in free and active agent. The greater fibrinolytic potential of APSAC is a result of its longer halflife, enhanced affinity of the Lys-plasminogen for fibrin, and protection from plasma inhibitors due to the acylated site. The agent can be given as a single bolus with a half-life of 90–105 min and therapeutic effect up to 6 h. Therapy can be associated with adverse reactions similar to streptokinase. The longer half-life of APSAC (due to its acylation) was thought at first to offer a reduced risk of rethrombosis. The agent was studied in the setting of coronary occlusion and did not offer any clinical benefit over SK or rt-PA. It is currently not employed in the setting of peripheral thrombolytic therapy.
Urokinase Urokinase (UK), originally isolated from human urine by MacFarlane and Pilling in 1946,[10] is a serine protease composed of two polypeptide chains. It exists in two forms, which have similar activity. The first is a high molecular weight entity (54 kDa), and the second is a degradation product of the former called low molecular weight (32 kDa), urokinase. The high molecular weight form predominates in UK isolated form urine, while the low molecular weight form is found in UK of kidney cell culture origin. Unlike SK, urokinase activates plasminogen directly without forming an activator complex, is nonantigenic, and exposure resulting in preformed antibodies has not been observed. Urokinase is degraded by the liver and has a half-life of approximately 15 min, which allows for rapid reversal after discontinuation of the agent. The most commonly used form of UK is of tissue culture origin and manufactured from human neonatal kidney cells (Abbokinase, Abbott Laboratories, North Chicago, IL). In addition, a recombinant form, r-UK, has been developed from a murine hybridoma cell line. r-UK is a fully glycosylated agent, has a higher molecular weight than Abbokinase and a shorter half-life. The clinical effects of the two agents are similar.
Chapter 18.
A UK precursor was characterized and manufactured by recombinant technology using Escherichia coli (nonglycosylated) or mammalian cells (fully glycoslyated). Prourokinase is an inert zymogen that becomes activated in the presence of fibrin clot and activates plasminogen. The single-chain ProUk is also activated by plasmin or kallikrein to the two-chain form of urokinase, and this results in an increase in plasminogenactivating capacity. This property results in an amplification of the fibrinolytic process so that as plasmin is generated, more prourokinase is converted to active urokinase. Prourokinase is not affected by inhibitors circulating in plasma and is therefore able to reach the clot intact, unlike urokinase. It also preferentially activates fibrin-bound plasminogen found in thrombus over free plasminogen and is thus fibrin specific. Nonselective activators such as SK and UK activate both free and bound plasminogen equally, resulting in a systemic plasminemia, fibrinogenolysis, and degradation of factors V and VII. A recombinant form of prourokinase (r-ProUK) called Prolyse (Abbott Laboratories) was produced from a murine hybridoma cell line and has been studied in multiple clinical settings including acute myocardial infarction, stroke, and peripheral arterial occlusion.
Tissue Plasminogen Activator Tissue plasminogen activator is a naturally occurring fibrinolytic agent synthesized by endothelial cells. The agent is a serine protease composed of a single polypeptide chain (527 amino acids) with a molecular weight of 65 kDa and is converted into a two-chain molecule by plasmin. While the single chain form has greater intrinsic plasminolytic activity than the double chain form, activity of both forms is enhanced by the presence of fibrin and in this setting have no appreciable difference in activity. Unlike other agents, t-PA is both fibrin specific and has high fibrin affinity. The binding of t-PA and plasminogen complex to the fibrin surface causes a change in both molecules and enhances the conversion of plasminogen to plasmin and clot dissolution. t-PA has a plasma half-life of about 4 min and is degraded by the liver. Plasminogen activator inhibitor I rapidly complexes with t-PA in plasma. Other inhibitors of less importance include a2-antiplasmin and a2-macroglobulin. t-PA has been isolated from cadaver perfusate, uterine tissue, and human melanoma cells[15] but is currently used as a recombinant preparation (rt-PA). Activase (Genetech), a single-chain form of rt-PA, was approved for use in the clinical setting of acute myocardial infarction and pulmonary embolism. The agent has been extensively studied in the setting of coronary occlusion. The GUSTO-I study of 41,000 patients with acute myocardial infarction demonstrated better vascular patency with rt-PA compared to SK.[16] Overall mortality was reduced with rt-PA despite a slightly greater risk of intracranial hemorrhage.[17] Efforts to increase the bioavailabilty of t-PA have resulted in a newer agent, TNK-tPA, with greater half-life and fibrin specificity. As a result of this improved bioavailability, the drug can be administered as a single bolus as opposed to infusion. Its greater fibrin specificity than rt-PA also renders it less likely to cause fibrinogen depletion. In acute coronary
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occlusion studies, TNK-tPA demonstrated equal efficacy and greater ease of administration than rt-PA.[18,19] As in the case of TNK-tPA, the goal of reducing therapy duration and continuous infusion led to the development of reteplase. This novel recombinant plasminogen activator comprises the kringle 2 and protease domains of t-PA and is produced in Escherichia coli cells. Reteplase (Centocor Malvern, PA) is a nonglycosylated agent that demonstrates a lower fibrin-binding activity and diminished affinity to hepatocytes, which accounts for a longer half-life than rt-PA. Like TNK-tPA, it can be administered in bolus injection. The fibrin affinity of reteplase is only 30% of that seen with tPA and thus reduces the incidence of distant bleeding complications. The agent has been studied in the coronary setting and has shown some benefit over rt-PA in the RAPID 1 and RAPID 2 studies as well as in GUSTO III.[20,21]
Miscellaneous Agents A number of novel agents have been studied but not fully evaluated in patients. Fibrolase is a metalloproteinase derived from the venom of the Southern copperhead snake. It is a direct fibrinolytic agent that does not require plasminogen or any other blood component for activation. Staphylokinase, a byproduct of the Staphylococcus aureus bacterium, has been developed in recombinant form and studied in myocardial infarction,[22] peripheral arterial occlusion,[23] and deep venous thrombosis. Like SK, it is antigenic and requires plasminogen binding for activation. Despite this similarity to SK, it is also fibrin specific and thus spares circulating fibrinogen and plasminogen. Vampire bat plasminogen activator has been cloned and derived from the saliva of the vampire bat Desmodus rotundus (DSPA a-1).[24,25] It is extremely fibrin specific and has a plasminogenolytic activity 100,000 times greater in the presence of fibrin.[26 – 28] DSPA has a longer half-life than rtPA and thus offers greater ease of administration. So far, phase 1 studies have been performed in healthy volunteers.[29]
CLINICAL APPLICATION OF THROMBOLYTIC AGENTS Arterial Thrombolysis Although thrombolytic agents have been experimentally used since the 1950s, intervention for ischemic limbs consisted primarily of amputation, surgical revascularization, or balloon catheter embolectomy.[30] Surgical intervention in acute ischemia, however, has been identified associated with a high rate of amputation and patient demise. This was first examined by Blaisdell et al.[31] and later confirmed by Jivegard et al.[32] and Yeager et al.[33] The development of thrombolytic techniques provides the potential to restore arterial patency and limb viability with less invasive procedures and resultant lower morbidity. Thrombolytic dissolution of thrombus provides several potential advantages over standard surgical measures. First, the obstructing thrombus can be ameliorated using less invasive techniques. The patency of the native artery or
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interposed graft can be restored and thus obviate the need for harvesting of alternative conduit. A primary aim of thrombolytic therapy is to identify the anatomic lesion responsible for the occlusive event. Subsequent operative intervention or an endovascular procedure can then be employed to directly address the causative lesion. Studies examining outcomes and effectiveness of thrombolytic therapy should not be based on avoidance of surgical intervention. The goal of arterial thrombolysis is the discovery and definition of the etiologic mechanism of the occlusive event, limiting the magnitude and morbidity of the subsequent intervention. Regardless of the agent, peripheral arterial thrombolysis is most effective by a catheter-directed approach, resulting in the delivery of the agent directly into the thrombus. Charles Dotter popularized the use of catheter-directed streptokinase therapy and reported success rates greater than those achieved with systemic therapy.[34] Catheters can be inserted in both an antegrade (ipsilateral) and contralateral approach fashion. The antegrade approach can be hampered by an inability to pass the catheter through the occluded graft or thrombus due to the proximity of the occlusion to the site of vascular access. This proximity also increases the risk of bleeding from the site of catheter insertion. For these reasons, an antegrade approach is only appropriate when the level of occlusion occurs distally—e.g., at the distal superficial femoral artery or popliteal level. A contralateral approach may be the safest and allow access to the occlusion. Multiple sticks can cause bleeding during thrombolytic therapy and are best avoided if possible. Small-bore catheters (5 French) and low-dose heparin therapy are employed to prevent pericatheter thrombus with possible embolization during prolonged therapy. The method of thrombolytic administration is based on the experience of the clinical team and specific patient situation. Complications are associated with duration of infusion of thrombolytic agent, and therefore the recommended duration of drug administration is limited to 48 h. In addition, it is unlikely that successful lysis will be accomplished after 48 h if it has not already been achieved. Continuous infusions are started after a bolus dose and tapered as necessary. Techniques such as “lacing,” or bolusing, entail the infusion along the length of the thrombus to achieve even and complete distribution of high concentrations of agent. Pulse spray techniques involve the administration of multiple small boluses, forced under pressure through a multisided holed catheter to increase rate of dissolution, and are also used. Despite theoretical advantages, studies examining continuous versus periodic spray infusions have not shown statistically significant difference in treatment times.[35,36] The progression of thrombolysis is followed by serial arteriograms and catheter manipulation as necessary to reposition the infusion holes within the substance of the thrombus. Distal embolization is a recognized complication of therapy, and treatment with continued infusion of lytic agent is usually successful. Distal embolization occurs as a thrombus is lysed and macroscopic particles of clot travel distally at the time arterial flow are reestablished. Bolus and lacing techniques may increase the risk of distal embolization. Coagulation parameters (e.g., fibrinogen level) can be monitored, but their use remains controversial, as such measures do not necessarily predict the risk of distant bleeding
complications.[37] The STILE trial (discussed below), however, documented an association between the fibrinogen concentration and partial thromboplastin time and the incidence of hemorrhagic complications with thrombolytic procedure.[38]
Results of Thrombolysis in Acute Peripheral Arterial Occlusion Early studies of patients treated with thrombolytic therapy were retrospective and did not examine limb salvage or morbidity.[39 – 41] Investigators such as McNamara and Graor[40,41] reported successful experiences with thrombolytic therapy in large numbers of patients. Other reports[42,43] found disfavor with thrombolytic therapy because it did not eliminate the need for surgical intervention and documented poor patency with the sole use of thrombolytic agents as definitive therapy (i.e., without adjuvant surgery to correct causative lesions). Prior to the 1990s there existed no randomized comparison of thrombolysis with standard surgical intervention. A randomized trial appeared in the European literature comparing rt-PA versus surgical thrombectomy, but it was limited by its small size of 20 patients.[44] The first randomized trial in the United States comparing intraarterial urokinase versus surgical intervention was reported in 1994 by the Rochester group.[45] They studied 114 patients with acute (less than 7 days duration with a mean of approximately 1 day) and severe limb-threatening ischemia (mean ankle brachial index of , 0.04). The urokinase group demonstrated decreased cardiopulmonary complications and improvement in patient survival. These results were achieved with a limb salvage rate identical to that observed in the operative group. The Surgery or Thrombolysis for Ischemia of the Lower Extremity (STILE) trial was published shortly after the Rochester report.[46] It was a multicenter randomized comparison of rt-PA, urokinase, and surgical intervention in patients with ischemia of less than 6 months’ duration and thus included both chronic and acute ischemia subgroups. No differences in mortality or amputation rate were noted. The endpoint of the study was not limb salvage or survival but, rather, a composite endpoint that contained subjective outcomes including renal failure, wound complications, and “ongoing ischemia.” The trial was prematurely terminated because of a higher rate of ongoing ischemia in the thrombolysis group, 54%, versus 26% in the surgical group. A post hoc analysis of STILE demonstrated that patients with symptoms of less than 2 weeks’ duration appeared to do better with thrombolysis while those with more chronic occlusions benefited more from surgery than thrombolysis, with respect to the rate of amputation. A multicenter trial evaluating thrombolytic agents, the Thrombolysis or Peripheral Arterial Surgery (TOPAS) study,[47] was a two-part study designed to compare recombinant urokinase with operative intervention in the treatment of peripheral arterial occlusions # 14 days in duration. Part I was a dose-ranging study designed to evaluate the safety and efficacy of 2000, 4000, or 6000 IU/min r-UK administration with approximately 50 patients in each group. The different initial doses were followed by 2000 IU/min for up to 48 hours of total therapy. Although 50 patients were included in a surgical group, it was not adequately empowered to critically
Chapter 18.
evaluate r-UK versus surgery. This was the goal of the Part II study, which randomized 544 patients to r-UK or surgery. Part I identified 4000 IU/min dose as the safest and most effective dose. The data from Part II demonstrated that the efficacy of r-UK was the same as surgery with respect as amputation and
Table 1.
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survival.[48] Patients were followed for one year following therapy, and the rate and magnitude of subsequent interventions were monitored. The thrombolysis group was noted to have a lower rate of invasive interventions (operative or endovascular) than the surgical group (Table 1).
Contraindications to Thrombolytic Therapy
Absolute 1. Active internal bleeding 2. Recent cerebrovascular accident, trauma, or intracranial pathology ,12 months Relative Major 1. Recent surgery or trauma ,10 days 2. Gastrointestinal or genitourinary bleeding 3. Uncontrolled hypertension (.200 systolic or . 110 diastolic) Minor 4. 5. 6. 7. 8. 9.
Pregnancy Diabetic retinopathy with hemorrhage Bleeding disorders Left-sided cardiac thrombus Bacterial endocarditis Minor trauma or surgery
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32. Jivegard, L.; Holm, H.; Schersten, T. Acute Limb Ischemia Due to Arterial Embolism or Thrombosis: Influence of Limb Ischemia Versus Pre-Existing Cardiac Disease on Post Operative Mortality Rate. J. Cardiovasc. Surg. 1988, 29, 32– 36. 33. Yeager, R.A. Basic Data Related to Cardiac Testing and Cardiac Risk Associated with Vascular Surgery. Ann. Vasc. Surg. 1990, 4, 193. 34. Dotter, C.T.; Rosch, J.; Seaman, A.J. Selective Clot Lysis with Low Dose Streptokinase. Radiology 1974, 111, 31– 37. 35. Kandarpa, K.; Chopra, P.S.; Aruny, J.E.; et al. Prospective, Randomized Comparison of Forced Periodic Infusion and Conventional Slow Continuous Infusion. Radiology 1993, 188, 1 – 7. 36. Kandarpa, K. Technical Determinants of Success in Catheter Directed Thrombolysis for Peripheral Arterial Occlusions. J. Vasc. Interventional Radiol. 1995, 6, 55– 61. 37. Marder, V.J. The Use of Thrombolytic Agents: Choice of Patient, Drug Administration and Laboratory Monitoring. Ann. Intern. Med. 1979, 90, 802– 808. 38. Graor, R.A.; Risius, B.; Young, J.R. Low Dose Streptokinase for Selective Thrombolysis: Sytemic Effects and Complications. Radiology 1984, 152, 35– 39. 39. Krings, W.; Roth, F.J.; Cappius, G. Catheter Lysis: Indications and Primary Results. Int. Angiol. 1985, 4, 117–123. 40. Graor, R.A.; Risius, B.; Lucas, F.V. Thrombolysis with Recombinant Human Tissue Type Plasminogen Activator in Patients with Peripheral Artery and Bypass Occlusions. Circulation 1986, 74, 15– 20. 41. McNamara, T.O.; Fischer, J.R. Thrombolysis of Peripheral Arterial and Graft Occlusions: Improved Results Using High Dose Urokinase. Am. J. Roentgenol. 1985, 144, 769– 775. 42. Sicard, G.A.; Schier, J.J.; Totty, W.G. Thrombolytic Therapy for Acute Arterial Occlusion. J. Vasc. Surg. 1985, 2, 65– 78. 43. Ricotta, J. Intraarterial Thrombolysis: A Surgical View. Circulation 1991, 83, 120– 121. 44. Nilsson, L.; Albrechtsson, U.; Jonung, T. Surgical Treatment Versus Thrombolysis in Acute Arterial Occlusion: A Randomised Controlled Study. Eur. J. Vasc. Surg. 1992, 6, 189–193. 45. Ouriel, K.; Shortell, C.K.; DeWeese, J.A. A Comparison of Thrombolytic Therapy with Operative Revascularization in the Treatment of Acute Peripheral Arterial Ischemia. J. Vasc. Surg. 1994, 19, 1021– 1030. 46. Weaver, F.; Comerota, A.; Youngblood, M.; Foehlich, J.; et al. Surgical Revascularization Versus Thrombolysis for Nonembolic Lower Extremity Native Artery Occlusions: Results of a Prospective Randomized Trial. J. Vasc. Surg. 1996, 24, 513– 521. 47. TOPAS Investigators; Ouriel, K.; Veith, F.; Sasahara, A. Thrombolysis or Peripheral Arterial Surgery: Phase I Results. J. Vasc. Surg. 1996, 23, 64– 75. 48. Ouriel, K.; Veith, F.; Sasahara, A. A Comparison of Recombinant Urokinase with Vascular Surgery as Initial Treatment for Acute Arterial Occlusion of the Legs. N. Engl. J. Med. 1998, 338, 1105– 1111.
CHAPTER 19
Antiplatelet Agents Richard M. Green James A. DeWeese Platelets and antiplatelet agents play an increasing role in the clinical practice and research efforts of vascular surgeons. The role of antiplatelet agents has been investigated in arterial thrombosis and embolism, occlusive and hemorrhagic strokes, angina and myocardial infarctions, venous thromboprophylaxis and pulmonary embolism, and recurrent stenoses in endarterectomized arteries and in arterial graft occlusions. Antiplatelet agents have been studied in the laboratory as a deterrent to thrombus formation, atherosclerotic plaque formation, and development of anastomotic hyperplasia in vascular grafts. It is now clear that the platelet plays a pivotal role in all of the above named processes. Our understanding of platelet function and ways to alter its activity therefore become important concerns for the vascular surgeon.
Platelet aggregation can occur via three different pathways. The first occurs after vascular injury and is due to extrinsic activators such as thrombin and collagen. This results in the release of adenosine diphosphate (ADP) and serotonin (5-HT) and the synthesis of thromboxane A2 (TXA2). Thrombin and collagen are strong platelet agonists that do not require TXA2 to produce aggregation and are therefore effective even in the presence of aspirin. The second method of aggregation is mediated by ADP and 5-HT, which are released from the dense granules of the platelet. These substances are weak agonists and cause aggregation only in the presence of TXA2. The third pathway is mediated through arachidonic acid released from the platelet membrane and then converted to prostaglandins A2 and G2.[6] The final common pathway by which all platelet agonists ultimately effect platelet aggregation is the transformation of the GPIIb/IIIa receptor on the platelet membrane to its active (high-affinity) state. This glycoprotein receptor has been the subject of much investigation, including efforts to develop potent antiplatelet agents through inhibition of the receptor.
PLATELET FUNCTION Platelets are derived from the bone marrow megakaryocytes and have a life span of approximately 10 days.[1] The intact endothelium is nonreactive to platelets. Interruption of a blood vessel or intravascular stimuli such as endotoxins or immune complexes activate the platelet.[2] The activated platelet undergoes a morphological change from a disk to a spiny sphere, and the surface membrane develops the capacity to catalyze interactions between activated coagulation proteins, resulting in thrombin formation and fibrinogen polymerization. The exposure of specific surface receptors which bind fibrinogen is inhibited when platelet (cyclic adenosine monophosphate) cAMP levels are elevated by agents such as prostacyclin (PGI2).[3] The activated platelet adheres to exposed subendothelial collagen. The most avid bond forms to the fibrillar collagen within ruptured atherosclerotic plaques or within the arterial media rather than to fibrils immediately beneath the endothelium.[4] Shear forces affect the mechanism of platelet adherence. At low shear rates, platelet adherence to collagen occurs via glycoprotein la. At high shear rates, glycoprotein 1b binds to the damaged artery via von Willebrand factor.[5] Adhesion is accompanied by the recruitment of additional platelets (aggregation) and the formation of a hemostatic plug.
Interaction with Coagulation Cascade In the early stages of thrombus formation, platelets interact with the cascade of coagulation proteins to form thrombin, which generates the fibrin necessary to stabilize the hemostatic plug. The activated platelet provides membrane receptors for formation of coagulation complexes. Factor V, released from platelets, is essential for the formation of the prothrombinase complex to act on prothrombin. This accelerates the generation of thrombin by a factor of 278,000 compared with factor Xa alone.[7] The prothrombinase complex on the surface of the platelets provides resistance to heparin via three mechanisms. First, heparin, acting on antithrombin III, is unable to inhibit factor Xa when it is bound to platelets. Second, the large amounts of thrombin generated by this complex activate more platelets, which secrete platelet factor 4; this, in turn, blocks the action of heparin. Third, thrombin generates fibrin II monomer, which also inhibits the action of heparin.[8] Components of coagulation are constantly delivered to the enlarging thrombus, where they are concentrated. Systemic
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coagulation is avoided and the response is localized, partly because of the concentration of coagulation proteins on the activated platelet membrane and partly because of endogenous inhibitors of thrombosis such as antithrombin III, proteins C and S, elevated cAMP (via prostacyclin), and the fibrinolytic system. The role of the platelet in fibrinolysis is becoming more evident. Resting platelets have a high concentration of plasminogen membrane receptors. Activated platelets secrete plasminogen activator inhibitor I. High concentrations of this at the site of thrombosis may inhibit fibrinolysis and promote clot stability. The result of this is a thrombus resistant to thrombolytic agents.[9]
Interaction with the Arterial Wall To understand the interaction of the platelet and the vessel wall, some knowledge of the field of prostaglandins is needed. These compounds interact to regulate platelet aggregability in physiological and pathological conditions. Thromboxane A2 and prostacyclin represent opposite ends of the homeostatic regulation of platelet aggregability, since TXA2 is a potent vasoconstrictor and prostacyclin induces vasodilation and is an extremely potent inhibitor of platelet aggregation. Endothelial cells are the most active producers of prostacyclin, which works by stimulating adenylate cyclase, leading to an increase in cyclic AMP levels in the platelets. Prostacyclin generation may be responsible for some of the thromboresistant properties of vascular endothelium. Prostacyclin I2 can inhibit platelet aggregation (platelet-platelet interaction) at lower concentrations than those needed to inhibit adhesion (platelet-collagen interaction), which means that platelets can stick to vascular tissue and interact with it without necessarily initiating thrombus production.[10] In humans, there is no difference between prostacyclin production in arteries and veins.[11] If antiplatelet agents have a role to play in the prevention of atherosclerosis (as opposed to the prevention of thromboembolic disease associated with existing atherosclerosis), it will probably be in the modification of the prostaglandin system and modulation of cell proliferation. Platelets from patients with arterial thrombosis and deep venous thrombosis produce more TXA2 than normal and have a shortened survival time.[12] Prostacyclin generation from atherosclerotic arterial tissue has been shown to be significantly lower than from normal arterial tissue.[13] Furthermore, the accumulation of cholesterol esters in areas of damage has been related to a decrease in prostacyclin synthesis. Prostacyclin enhances the activity of cholesterol ester hydrolase, suggesting a positive feedback between the prostacyclin system and lipid accumulation in the vessel wall.[14] Low-density lipoprotein (LDL) has been shown to reduce the release of a prostacyclin-like substance from human endothelial cells, and high-density lipoprotein (HDL) stimulates prostacyclin production.[15] Prostacyclin also plays a role in modulating cell proliferation. Smooth muscle proliferation in atherosclerotic plaques may be a consequence of inhibition of prostacyclin generation by lipid peroxidases. High concentrations of these peroxidases have been demonstrated in advanced atherosclerotic lesions.[16] Cell proliferation in vitro is inhibited by
substances such as PGI2 which stimulated cyclic AMP formation.[17,18]
ANTIPLATELET DRUGS Aspirin Mechanism of Action Aspirin exerts its antiplatelet effect through the cyclooxygenase system, by irreversibly acetylating cyclooxygenase. This prevents the first step of prostaglandin synthesis, the conversion of arachadonic acid to prostaglandin H2. The subsequent steps of conversion of prostaglandin H2 (to thromboxane A2 by platelets and to prostacyclin by endothelial cells) are thus also inhibited.[19 – 21] In theory, therefore, aspirin has prothrombotic effects via the inhibition of both prostacyclin and thromboxane A2, respectively. In reality, however, the antiplatelet effects predominate to a very high degree.
Dosage, Administration, and Efficacy The usual method of administration of aspirin is by mouth. Regular aspirin is rapidly absorbed in the stomach, with peak plasma levels occurring in 30 minutes, and inhibition of platelet function occurring in approximately one hour. Enteric coated aspirin is absorbed more slowly,[22] and shows evidence of platelet inhibition in 3 –4 hours, therefore enteric coated aspirin should not be used in situations where a rapid effect is desired, such as postoperatively. Because aspirin irreversibly inhibits cyclooxygenase, the antiplatelet effect of both regular and enteric coated aspirin persists for the life of the platelet (7 –10 days). The optimal dosage of aspirin remains somewhat uncertain. Efforts to utilize the lowest effective dose of aspirin are centered on two issues: first, the higher the dose of aspirin, the greater the chance of gastric side effects, and second, aspirin is known to inhibit platelet function at a lower dose than that at which it inhibits endothelial cell function.[23] The relative effects of different doses of aspirin on thromboxane and prostacyclin metabolism have been studied. Aspirin at all doses suppressed collagen-induced platelet aggregation by at least 80%, while suppression of prostacyclin secretion was seen only at the higher dose (324 mg).[24] The clinical implications of this finding are less clear, however. A comparison of outcome in three studies of patients treated with different doses of aspirin (75 mg/d, 325 mg/d, 1300 mg/d) shows similar results at all doses with regard to myocardial infarction and vascular death.[25 – 27] The effect on stroke reduction appears to be similar between different doses of aspirin, as well. In two separate studies, different doses of aspirin (30 mg vs. 300 mg, and 300 mg vs. 1300 mg) were compared and found to have the same efficacy in preventing stroke in patients with transient ischemic attacks.[28,29] While there is no good evidence that aspirin at higher doses is clinically superior to low-dose aspirin, based on the same studies, there is also a lack of convincing
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evidence that there is a detrimental effect of administering aspirin at doses which inhibit prostacyclin.[25 – 29]
Treatment and Prevention of Thromboembolic Complications of Atherosclerotic Cardiovascular Disease The efficacy of aspirin in the prevention of thromboembolic complications in patients with cardiovascular disease has been extensively examined in a large number of individual trials. Aspirin has been shown to be effective in reducing the incidence of myocardial infarction in males 50– 65 years of age;[30] in the treatment of acute myocardial infarction;[31,32] in the treatment of patients with unstable angina and non–Q-wave myocardial infarction;[25] in the treatment of stable angina; [33] and in patients with cerebrovascular disease.[29,31,34] In addition to information available from individual randomized studies, the Antiplatelet Trialists’ Collaboration provides an analysis and compilation of the results of 145 trials of antiplatelet agents in the treatment of thromboembolic disease. In most cases, the agent used was aspirin. The meta-analysis of 145 trials included 70,000 high-risk and 30,000 low-risk patients. Aspirin was found to reduce the risk of vascular complications as follows: from 14% to 10% in patients with acute myocardial infarction at one month, from 17% to 13% in patients with a history of myocardial infarction after 2 years, from 22% to 18% in patients with a history of stroke or transient ischemic attack after 3 years, and from 14% to 9% in patients with unstable angina after 6 months. With regard to all high-risk patients, there was a 30% reduction in the incidence of nonfatal myocardial infarction and stroke, and a 17% reduction in the incidence of vascular death.[23,34]
Use with Oral Anticoagulants The use of aspirin with oral anticoagulation (warfarin therapy) is warranted under certain circumstances. The primary indications for this combination of therapy are arterial embolization from prosthetic heart valves despite adequate anticoagulation with warfarin, and arterial embolization in patients with atrial fibrillation who have been adequately anticoagulated with warfarin.[23] Other potential indications include the prevention of thromboembolic complications in men at very high risk of cardiovascular death, and selected vascular patients who experience recurrent episodes of neointimal hyperplasia and/or graft occlusion. When aspirin and warfarin are administered together, the risk of major and minor bleeding is significantly higher than that associated with warfarin alone if both highdose aspirin (500 –1000 mg/d) and high-dose warfarin (INR 3.0–4.5) are used.[35] The use of low-dose aspirin (75 mg/d) and high-dose warfarin is associated with an increase in minor bleeding but only a trend toward a higher incidence of major bleeding when compared with warfarin alone.[36] The incidence of major bleeding is not increased, however, when low-dose aspirin and low-dose warfarin (INR 1.5 –2.0) are used.[37 – 40] In many circumstances, however, such as in patients with prosthetic heart valves, it is not feasible to reduce the dose of warfarin to this degree.
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Use in Venous Disease Aspirin has not been shown to be as effective as heparin in the prevention or treatment of acute deep venous thrombosis, although it probably has some benefit over no treatment at all.[23,41] Aspirin has been used successfully in the treatment of calf vein thrombosis in low-risk patients.
Complications and Side Effects By far the most common side effects of aspirin therapy are gastrointestinal. Aspirin-related complications range from mild erosions to frank ulceration, gastritis, and massive hemorrhage. Statistically, gastric complications are less severe with low-dose (325 mg/d or less) aspirin and shortterm use of aspirin. The proposed mechanism by which gastric injury occurs is by inhibition of prostaglandin production by gastric mucosa.[23] Two studies in which aspirin was used in the primary prevention of stroke and myocardial infarction (i.e., low-risk patients) have demonstrated a small but definite increase in the risk of intracranial hemorrhage in healthy men treated with aspirin as compared with no aspirin.[42,43] Studies in which aspirin was used in the secondary prevention of these events (i.e., higher-risk patients) failed to demonstrate this increased risk, probably because of the relatively greater benefit in reducing adverse events resulting from complications of atherosclerosis.[25,44] These findings raise the issue, therefore, as to whether or not aspirin should be used prophylactically in low-risk patients.[23]
Other Agents While aspirin remains the most widely used and most extensively studied antiplatelet agent, there are a number of alternative antiplatelet agents currently under investigation for the treatment of cardiac disease, stroke, and peripheral vascular disease. In most instances, the mechanism of action of these agents differs substantially from that of aspirin. Specifically, alternatives to the standard agents aspirin and heparin have been developed because platelet activation and thrombosis occurs at the site of exposed endothelium (i.e., ruptured atherosclerotic plaque) by mechanisms that are in large part resistant to these agents. For instance, platelet activation in this setting is mediated primarily via thrombin rather than thromboxane A2. Similarly, the heparin – antithrombin III complex is inactive against bound thrombin, thus rendering heparin ineffective in preventing thrombosis and platelet activation at the site of injured endothelium, although it is effective in preventing clot propagation.[45 – 48]
Glycoprotein IIb/IIIa Inhibitors The final common pathway for all mechanisms of platelet aggregation is glycoprotein IIb/IIIa (GPIIb/IIIa), the fibrinogen receptor on the platelet membrane. Several agents have been developed that inhibit this receptor, and they are extremely potent antiplatelet agents, generally associated with relatively more frequent and severe bleeding complications than other antiplatelet agents. Glycoprotein IIb/IIIa inhibitors have been investigated primarily for their efficacy
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in treating coronary thrombosis. They include monoclonal antibodies against the receptor and other agents such as RGDcontaining isolates from snake venom or synthetic compounds of similar structure. All of these agents act by competing with fibrinogen for occupation of the GPIIb/IIIa site.[49] The most intensely studied of the GPIIb/IIIa antagonists is the monoclonal antibody c7E3. It has been shown to improve early patency following tPA coronary thrombolysis,[50] to improve the results of coronary angioplasty (EPIC trial),[51] and to be effective in the treatment of unstable angina.[52] Similar results have been reported for Integrelin, another of the GPIIb/IIIa antagonists.[53,54]
Thienopyridines This class of antiplatelet drugs includes the oral agents ticlopidine and clopidogrel. Both agents prevent binding of ADP to the platelet receptor, thus inhibiting ADP-mediated platelet aggregation.[55] In the Canadian American Ticlopidine Study, ticlopidine was shown to be more effective than aspirin in the prevention of serious ischemic events (myocardial infarction, stroke, death) in patients who have experienced a prior ischemic neurologic event.[56] Similar reductions were demonstrated in the rates of ischemic stroke and death in the Ticlopidine Aspirin Stroke Study.[57] In the CAPRIE study, a comparison of clopidogrel and aspirin in the treatment of 19,000 patients at risk of ischemic stroke, there was a significant reduction (8.7%) in the combined risk of death, myocardial infarction, and ischemic stroke with clopidogrel as compared with aspirin.[58] Ticlopidine achieves 50% of maximal activity within 4 days of the initiation of therapy, and full activity within 7 days. Clopidogrel achieves initial inhibition of platelet activity within 2 hours of administration, and maximal platelet inhibition within 3 days. The incidence of significant gastrointestinal hemorrhage in the thienopyridines is comparable to that of aspirin (approximately 0.5%). The most important side effects of ticlopidine are reversible
neutropenia in 1.6% of patients and agranulocytosis in 0.8% of patients; therefore, regular monitoring for these events, which usually occur within the first 3 months of therapy, is required in patients receiving this medication. The major side effect of clopidogrel is a rash (0.3%); the incidence of neutropenia of even moderate severity is very low (0.1%).[58]
SUMMARY Platelets play an important role in both the progression of atherosclerosis and the occurrence of thrombotic complications of atherosclerosis. Antiplatelet agents, therefore, have been developed and studied with regard to treatment and prevention of these problems, and exert their effects through a variety of different mechanisms. Aspirin is the most widely used and most thoroughly investigated antiplatelet agent. It works by irreversibly inhibiting platelet cyclooxygenase. Aspirin has been shown to be effective in the prevention and treatment of coronary artery disease, stroke, peripheral vascular disease, and other related disorders. It appears to achieve a maximum effective at a relatively low dose (75 mg/d), which is also associated with the lowest level of gastrointestinal side effects. It is definitely indicated in highrisk patients, but may not be indicated in lower-risk patients because of a possible small increase in the risk of intracranial hemorrhage. Agents that inhibit the glycoprotein IIb/IIIa fibrinogen receptor are potent antiplatelet agents. They are primarily intravenous in nature, and are used in the treatment of coronary occlusion. Thienopyridines are a newer class of oral antiplatelet agents that inhibit ADP-mediated platelet aggregation. They have been approved for the prevention and treatment of myocardial infarction, stroke, and peripheral vascular disease. They appear to have comparable efficacy, but clopidogrel lacks the neutropenic complications associated with ticlopidine.
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Manson, J.E.; Stampfer, M.J.; Colditz, G.A. et al. A Prospective Study of Aspirin Use and Primary Prevention of Cardiovascular Disease in Women. J. Am. Med. Assoc. 1991, 266, 521. Antiplatelet Trialists’ Collaboration; Secondary Prevention of Vascular Disease by Prolonged Antiplatelet Treatment. Br. Med. J. 1988, 296, 320. ISIS-2 Collaborative Group; Randomised Trial of Intravenous Streptokinase, Oral Aspirin, Both or Neither Among 17,187 Cases of Suspected Acute Myocardial Infarction: ISIS-2. Lancet 1988, 2, 349. Juul-Moller, S.; Edvardsson, N.; Jahnmatz, B. et al. Double-Blind Trial of Aspirin in Primary Prevention of Myocardial Infarction in Patients with Stable Chronic Angina Pectoris. Lancet 1992, 340, 1421. Antiplatelet Trialists’ Collaboration; Collaborative Overview of Randomized Trials of Antiplatelet Therapy: I. Prevention of Death, Myocardial Infarction, and Stroke by Prolonged Antiplatelet Therapy in Various Categories of Patients. Br. Med. J. 1994, 308, 81. Cheesbro, J.H.; Fuster, V.; Elveback, L.R. et al. Trial of Combined Warfarin Plus Dipyridamole or Aspirin Therapy in Prosthetic Heart Valve Replacement: Danger of Aspirin Compared with Dipyridamole. Am. J. Cardiol. 1983, 51, 1537. Turpie, A.G.G.; Gent, G.; Laupacis, A. et al. A Comparison of Aspirin with Placebo in Patients Treated with Warfarin After Heart-Valve Replacement. N. Engl. J. Med. 1993, 329, 524. Altman, R.; Rouvier, J.; Curfinkel, E. et al. Comparison of Two Levels of Anticoagulant Therapy in Patients with Substitute Heart Valves. J. Thorac. Cardiovasc. Surg. 1991, 101, 427. Mead, T.W.; Roderick, P.J.; Brennan, P.J. et al. ExtraCranial Bleeding and Other Symptoms Due to Low Dose Aspirin and Low Intensity Oral Anticoagulation. Thromb. Haemostasis 1992, 68, 1. Cohen, M.; Adams, P.C.; Hawkins, L. et al. Usefulness of Antithrombotic Therapy in Resting Angina Pectoris or Non-Q Wave Myocardial Infarction in Preventing Death and Myocardial Infarction (a Pilot Study from the Antithrombotic Therapy in Acute Coronary Syndromes Study Group). Am. J. Cardiol. 1990, 66, 1287. Meade, T.W.; Wikes, H.C.; Stirling, Y. et al. Randomised Controlled Trial of Low Dose Warfarin in the Primary Prevention of Ischaemic Heart Disease in Men at High Risk: Design and Pilot Study. Eur. Heart. J. 1988, 9, 836. Antiplatelet Trialists’ Collaboration; Collaborative Overview of Randomised Trials of Antiplatelet Therapy: III. Reduction in Venous Thrombosis and Pulmonary Embolism by Antiplatelet Prophylaxis Among Surgical and Medical Patients. Br. Med. J. 1994, 308, 235. Steering Committee of the Physicians’ Health Study Research Group; Final Report on the Aspirin Component of the Ongoing Physician’s Health Study. N. Engl. J. Med. 1989, 321, 129. Peto, R.; Gray, R.; Collins, R. et al. Randomised Trial of Prophylactic Daily Aspirin in British Male Doctors. Br. Med. J. 1988, 296, 313.
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44. The SALT Collaborative Group; Swedish Aspirin LowDose Trial (SALT) of 75 mg Aspirin as Secondary Prophylaxis After Cerebrovascular Ischaemic Events. Lancet 1991, 338, 1345. 45. Fuster, V.; Badimon, L.; Badimon, J.J. et al. The Pathogenesis of Coronary Artery Disease and the Acute Coronary Syndromes. N. Engl. J. Med. 1992, 326, 242. 46. Hogg, P.J.; Jackson, C.M. Fibrin Monomer Protects Thrombin from Inactivation by Heparin-Antithrombin III: Implications for Heparin Efficacy. Proc. Natl Acad. Sci. USA 1989, 86, 3619. 47. Weitz, J.I.; Hudoba, M.; Massel, D. et al. Clot-Bound Thrombin Is Protected from Inhibition by HeparinAntithrombin III but Is Susceptible to Inactivation by Antithrombin III-Independent Inhibitors. J. Clin. Investig. 1990, 86, 385. 48. Bar-Shavit, R.; Benezra, M.; Eldor, A. et al. Thrombin Immobilized to Extracellular Matrix Is a Potent Mitogen for Vascular Smooth Muscle Cells: Nonenzymatic Mode of Action. Cell Regul. 1990, 1, 453. 49. Weitz, J.I.; Califf, R.M.; Ginsberg, J.S. et al. New Antithrombotics. Chest 1995, 108, 471s. 50. Kleinman, N.S.; Ohman, M.E.; Califf, R.M. et al. Profound Inhibition of Platelet Aggregation with Monoclonal Antibody 7E3 Fab Following Thrombolytic Therapy: Results of the TAMI 8 Pilot Study. J. Am. Cardiol. 1993, 22, 381.
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CHAPTER 20
Pentoxifylline, Vasodilators, and Metabolic Agents Samuel R. Money W. Charles Sternbergh III Far East have gained this drug marketing approval there.[6,7] However, these studies were small and had only short-term follow-up. Numerous large clinical studies on the efficacy of Cilostazol have been carried out in the United States.[8 – 11] Some of these studies will be reviewed in this section.
Over 5 million Americans suffer with peripheral arterial occlusive disease of the lower extremities. The prevalence of this disease increases with age, therefore as the population ages, there will be an increasing number of patients to treat. Intermittent claudication is the most common symptom. Some patients with intermittent claudication are so impaired that either surgical or endovascular intervention is warranted. However, for the vast majority of patients, intervention is not indicated as claudication is more of an annoyance than a disability. In the United States, pharmacologic therapy has been limited to only one approved agent. Presently, a second medication has received FDA approval, and more are under scrutiny. This chapter will evaluate some of the more promising and potentially available metabolic, hemorrheologic and vasodilating agents for the treatment of intermittent claudication secondary to peripheral arterial occlusive disease. Antiplatelet agents may also have salutary effects on claudication; these are discussed in Chapter 19.
Clinical Use In the first American study published, 239 patients were randomized to receive either Cilostazol (100 mg PO b.i.d.) or placebo for 16 weeks.[8] Patients underwent routine treadmill and ankle-brachial index (ABI) testing. The end points of the study were initial claudication time (distance-ICD) or absolute or maximal claudication distance (ACD) on the treadmill testing, which was performed at weeks 8, 12, and 16. The results of this study demonstrated significant increases in walking ability for both initial and absolute claudication time (distance) at all time points. In addition, the patients subjectively felt improvement in the physical function score of the short form-36 (medical outcomes) questionnaire at the completion of the study. In a separate study authored by Dawson et al., patients were treated with either Cilostazol or placebo for a total of 12 weeks.[10] In this study, the increase in initial claudication time (distance) in the group receiving Cilostazol improved by 58%, compared with an 8.9% increase in the placebo group. The absolute or maximal claudication time (distance) increased by 63% in those receiving drug versus 9.8% in the placebo group, a highly significant difference. Subjectively, the majority of patients felt that their walking performance was much better or better in the Cilostazol group, whereas the majority of patients in the placebo group felt that their symptoms were unchanged or worsening. The largest clinical study of Cilostazol randomly assigned 419 patients to either high-dose (100 mg PO b.i.d.) or lowdose (50 mg PO b.i.d.) Cilostazol or to placebo.[9] Patients underwent treadmill testing at baseline, and then at weeks 4, 8, 16, 20, and 24. At the completion of the study (week 24), pain-free walking distance (initial claudication distance and
CILOSTAZOL Mechanism Recently, Cilostazol has received FDA approval for the treatment of mild to moderate claudication secondary to peripheral vascular disease. Cilostazol is modified quinolinone, which exerts its action via type III phophodiesterase inhibition.[1,2] By blocking adenosine-3,5-cyclic phosphodiesterase, it serves to increase cAMP in the vessel walls and also in platelets. The principal mechanisms of action include vasodilitation and inhibition of platelet aggregation.[3 – 5] In addition to these, vascular smooth muscle relaxation will occur and platelet aggregation will be reduced due to increased prostagladin I2. Via the mechanisms described here, Cilostazol serves as both an antithrombotic agent and a vasodilator. Numerous animal studies using Cilostazol have confirmed both effects, which resulted in increases in muscle and dermal blood flow. Small preliminary studies done in the
Hobson/Wilson/Veith: Vascular Surgery: Principles and Practice, Third Edition, Revised and Expanded DOI: 10.1081/0819-9-120024903 Copyright q 2004 by Marcel Dekker, Inc.
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absolute claudication distance) were statistically increased in the Cilostazol groups compared to the placebo group. The high-dose Cilostazol group demonstrated an increase in initial claudication distance by 59% versus a 20% increase in the placebo group. The low-dose Cilostazol group demonstrated an increase of 48%. Both of these changes were highly significant. Significant improvements in both initial claudication distance and absolute claudication distance were demonstrated at week 4 and were maintained throughout the subsequent time points of testing. Overall, in the high-dose group the ACD increased from a mean baseline of 130 meters to 259 meters by week 24. In another study, patients were randomly assigned to receive Cilostazol 100 mg PO b.i.d., pentoxifylline 400 mg PO t.i.d., or placebo for a total of 24 weeks.[12] There were a total of 699 patients randomized. Patients were evaluated using standard treadmill testing, and subjective data were obtained using the short form-36 (SF-36) and the walking impairment questionnaire. The results of this study were quite interesting. Cilostazol demonstrated a significant improvement over both placebo and pentoxifylline. There was no significant difference between pentoxifylline and placebo ðp ¼ 0:82Þ in distance walked. The subjective evaluation by the patients showed that more patients in the Cilostazol group judged their outcome to be significantly better than patients who received either placebo or pentoxifylline. In addition to the mechanisms outlined above, this compound has been found to have a beneficial effect on lipids. Elam and others have demonstrated that Cilostazol has positive effects on triglycerides and high-density lipoprotein (HDL).[11] Following chronic administration of Cilostazol for 12 weeks, serum triglycerides dropped by a mean of 15%. HDL cholesterol was shown to increase by 10% and apoA1 demonstrated a 5.7% increase. The actual mechanism of this effect is presently unknown, but the beneficial affect on lipids is a welcome side effect. Cilostazol is strictly contraindicated in patients with advanced heart failure (N-Y HA III and IV). Phosphodiesterase inhibitors cause increased mortality in this group. While most other side effects of this medication were minor, they were fairly common.[9 – 11] The majority of side effects reported were described by the patients as mild to moderate and usually responsive to over-the-counter medication. The most common side effect of Cilostazol treatment was headache. This complication was reported in approximately one third of the patients who received test drugs. It is interesting to note that this occurred in approximately 15% of the patients who received placebo. Most of these headaches responded to acetaminophen, and very few patients were eliminated from the studies due to inability to tolerate the medication secondary to headache. Approximately 15% of the patients reported soft or bulky stools. This was also minor and did not cause patients to exit the study. However, approximately 10% of the patients reported significant diarrhea, and this did cause some patients to exit the study. The most common causes of withdrawal from studies were either dizziness or palpitations. Both of these occurred approximately 10% of the time. The chronic use of Cilostazol in four separate clinical studies performed in the United States demonstrated a superiority over placebo on symptoms of claudication.[9 – 11]
Overall, the drug was fairly well tolerated, with patients subjectively reporting improvement in physical function. In addition, Cilostazol was found to be significantly more effective than pentoxifylline in a comparative study. Cilostazol is a new and effective drug which may aid in the nonoperative treatment of patients with claudication.
PENTOXIFYLLINE Hemorrheologic agents such as pentoxifylline (Trental) are those which can produce increased tissue perfusion by means of decreasing blood viscosity. Factors influencing blood viscosity include erythrocyte flexibility, leukocyte adhesion and activation, platelet aggregation, and plasma fibrinogen levels. Patients with peripheral occlusive arterial disease (POAD) are known to have an elevation in blood viscosity, fibrinogen level, and leukocyte activation, the extent of which appears to correlate with the severity of the POAD.[13]
Mechanism The primary mechanism of action of pentoxifylline was initially thought to be from an increase in erythrocyte deformability. In studies from the mid-1970s, patients with POAD were found to have elevated blood viscosity, which was later found to be decreased with pentoxifylline.[14,15] However, subsequent studies using washed erythrocytes devoid of other plasma constituents failed to show any impairment in erythrocyte deformability in those patients with POAD.[16] Furthermore, pentoxyfylline did not increase erythrocyte deformability in vitro with washed cells.[17] However, pentoxifylline does have beneficial hemorrheologic effects on other plasma constituents, including a decreased fibrinogen level,[18] decreased leukocyte activation and adhesion,[16,19] and decreased platelet activation.[20] Pentoxifylline’s salutary effects on these plasma constituents are the most likely mechanism(s) for its hemorrheologic activity. Further corollary support for a non –erythrocyte-mediated mechanism of action is provided in experimental studies of damage to the microcirculation during septic shock and ischemia/reperfusion injury. Leukocyte activation, adhesion and plugging of capillaries during reperfusion after significant acute ischemia has been conclusively demonstrated to play a significant role in end-organ injury.[21,22] Likewise, septic shock can produce similar microvascular injury.[23] Pentoxifylline has demonstrated beneficial effects in models of both ischemia/reperfusion injury[24,25] and septic shock.[26] While certainly not conclusive, these data lend further credence to the theory that modulation of leukocyte activation and adhesion by pentoxifylline may be an important component of its salutary effects.
Clinical Use Since its approval by the U.S. Food and Drug Administration in 1984, pentoxifylline has become a widely prescribed medication for claudication. It has been examined extensively in multiple well-designed prospective randomized placebo-
Chapter 20.
controlled clinical trials and does have a beneficial effect, albeit modest, in increasing walking distance.[27,28] In a metaanalysis of trials published between 1976 and 1994, Hood et al. found patients treated with pentoxifylline had a 24.9 m increase (,20% vs. control) in pain-free walking and a 48.4 m increase in the absolute claudication distance.[29] Close scrutiny of these and other trials suggest that particular subgroups, those with moderately severe claudication, may have substantially greater benefit from the drug. AbuRahma and Woodruff found that those patients with an ABI of $ 0:5 fared better than those with an ABI , 0:5.[30] Lindgarde and coworkers found those patients who had an ABI of #0.8 and had symptoms for greater than 1 year had a 52% and 33% improvement over placebo controls in initial and absolute claudication distance, respectively.[28] Those patients with ABI . 0:8 and/or with more acute symptoms did not have as great a benefit. While not conclusive, these trials suggest that patients with moderate POAD as defined by a ABI of 0.5–0.8 may receive more benefit from the pentoxifylline than those with either mild ðABI . 0:8Þ or severe ðABI , 0:5Þ POAD. Pentoxyifylline is typically prescribed 400 mg three times daily. Side effects are chiefly gastrointestinal, including nausea and bloating, and should require discontinuation of therapy in less than 5% of cases.
CARNITINE While hemorrheologic agents appear to be beneficial due to their augmentation of microvascular perfusion, metabolic agents such as carnitine may improve claudication by enhancing ischemic muscle metabolism. Carnitine, an important cofactor for skeletal muscle metabolism, augments entry of pyruvate into the citric acid cycle, hypothetically increasing the production of adenosine triphosphate (ATP).[31] It also enhances oxidation of long-chain fatty acids and decreases lactate levels. Many, but not all, patients with PAOD have increased levels of acetylcarnitine, an intermediate of oxidative metabolism which correlates with impaired exercise performance.[32] Exogenously supplied carnitine may facilitate a more efficient degradation of this metabolic intermediate, improving ischemic muscle metabolism and thus exercise performance. Several studies have shown beneficial effects of carnitine and propionyl-L -carnitine on walking distance in patients with POAD. Preliminary results of a multicenter phase III trial involving 155 patients randomized to propionyl-L -carnitine or placebo have recently been reported.[33] After 6 months of treatment, there was a 26% increase in absolute claudication distance in the treated group over the placebo group. Functional status, using the medical outcomes form SF-36, was also improved.[33] Similar improvements in walking distance have been noted by other investigators.[34 – 36] Propionyl-L -carnitine may have a greater effect than carnitine.[37] Because carnitine and its analogs are naturally occuring substances which appear to be free of toxic effects, there is considerable interest in their use for patients with claudication. While not approved for such use by the FDA, the average dose used in these studies has been 2 g/day.
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NAFTIDROFURYL Naftidrofuryl (Praxilene) is another metabolic agent felt to enhance skeletal muscle ATP production. Unlike carnitine, its metabolic actions appear to stimulate the tricarboxylic acid cycle. As a serotonin receptor antagonist, it may also have salutary vasoactive properties.[38] In a meta-analysis of five European studies pooling 888 patients, those receiving the drug had a significant improvement in initial claudication distance when compared to controls.[39] A reduced need for subsequent lower extremity bypass procedures was also noted in the treatment group. Naftidrofuryl is not available in the United States but is widely prescribed in Europe at a dose of 600 mg/day in 2 –3 divided doses. It is well tolerated, with mild gastrointestinal effects requiring withdrawal of the drug in less than 2% of patients.
PROSTAGLANDINS Prostaglandins have significant vasodilator properties and are also potent inhibitors of platelet aggregation. While vasodilator drugs have generally proven ineffective in treatment of POAD symptoms,[40] there continues to be clinical interest in prostaglandins and its analogs. Most studies with these drugs have been in patients with limbthreatening ischemia, with mixed results.[41 – 43] However, there are an increasing number of studies using these agents for the treatment of claudication. Beraprost, an orally active PGI2 analog, has been evaluated in a phase II dose-ranging study.[44] While walking distance increased by as much as 50%, these differences were not statistically significant, perhaps because of scatter in the data and/or a type II error. Significant side effects including flushing, and headaches were seen in a large percentage of the patients. Further studies of this drug will be required. Intravenous PGE1 has also been evaluated in the treatment of claudication. In these studies, absolute walking distances have been increased by 20 –40% when compared with placebo controls.[45,46] These studies typically gave 1- to 2-hour infusions 5 days a week for the duration of the study. Practical use for such a drug requiring frequent intravenous delivery in the treatment of claudication is likely to be limited.
VERAPAMIL Verapamil is a well-known calcium channel blocker presently in clinical use due to its antihypertensive actions. It has been suggested by some authors that verapamil may have a positive effect in the treatment of intermittent claudication.[47,48] Other studies have demonstrated no significant effect of verapamil on claudication. However, in a study by Bagger et al.,[49] they demonstrated that verapamil can increase absolute walking distances significantly. Patients were not given a standardized dose of verapamil. In a pretrial pilot study, patients were treated to determine individual dose-
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response curves and then experimentally studied following a washout period. Patients demonstrated significant improvement in walking ability after 2 weeks of treatment. Verapamil was not studied solely because of its vasodilating effect, but because it reportedly raises the oxygen-extracting capacity of
the ischemic lower extremity. It is obvious that more work on the effects of verapamil are needed, and presently despite the availability of verapamil in the United States, its use in treating intermittent claudication has yet to be completely elucidated.
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Lehert, P.; Comte, S.; Gamand, S.; Brown, T.M. Naftidrofuryl in Intermittent Claudication: A Retrospective Analysis. J. Cardiovasc. Pharm. 1994, 23 (Suppl. 3), S48 –S52. Coffman, J.D. Vasodilator Drugs in Peripheral Vascular Disease. N. Engl. J. Med. 1979, 300L713. Norgren, L.; Alwmark, A.; Angqvist, K.A. et al. A Stable Prostacyclin Analog (Iloprost) in the Treatment of Ischaemic Ulcers of the Lower Limb: A ScandinavianPolish Placebo-Controlled, Randomized Multicenter Study. Eur. J. Vasc. Surg. 1990, 4, 463. Trubestein, G.; von Bary, S.; Breddin, K. et al. Intravenous Prostaglandin E1 Versus Pentoxifylline Therapy in Chronic Arterial Occlusive Disease—a Controlled Randomized Multicenter Study. Vasa 1989, 28, 44. Nizandowski, R.; Krolikowski, W.; Beilatowicz, J.; Szczeklik, A. Prostacyclin for Ischemic Ulcers in Peripheral Arterial Disease: A Random Assignment, Placebo-Controlled Study. Thromb. Res. 1985, 37, 21. Lievre, M.; Azoulay, S.; Lion, L.; Mornd, S.; Girre, J.P.; Boissel, J.P. A Dose-Effect Study of Beraprost Sodium in Intermittent Claudication. J. Cardiovasc. Pharmacol. 1996, 27, 788– 793. Belch, J.J.F.; Bell, P.R.F.; Creissen, D. et al. Randomized, Double Blind, Placebo-Controlled Study Evaluating the Efficacy and Safety of AS-013, a Prostaglandin E1 Prodrug, in Patients with Intermittent Claudication. Circulation 1997, 95, 2298– 2302. Diehm, C.; Balzer, K.; Bisler, H.; et al. Efficacy of a New Prostaglandin E1 Regimen in Outpatients with Severe Intermittent Claudication: Results of a Multicenter Placebo-Controlled Double-Blind Trial. J. Vasc. Surg. 1997, 25, 537– 544. Bagger, J.; Mathar, R.; Paulsen, P.; Gormsen, J.; Olsen, K. Verapamil Induced Increment of Oxygen Extraction in the Arteriosclerotic Limb. Cardiovasc. Res. 1985, 19, 567–569. Kimose, H.; Bagger, J.; Aagaard, M.; Paulsen, P. PlaceboControlled Double-Blind Study of the Effect of Verapamil in Intermittent Claudication. Angiology 1990, 41, 595–598. Bagger, J.; Helligsoe, P.; Randsbaek, F.; Kimose, H.; Jensen, B. Effect of Verapamil in Intermittent Claudication. Circulation 1997, 95, 411– 414.
CHAPTER 21
Perioperative Evaluation and Management of Cardiac Risk in Vascular Surgery Piotr Sobieszczyk Joshua A. Beckman Michael Belkin
revascularization versus medical therapy. Preoperative testing should therefore be undertaken only if the information obtained will change medical management or the type of planned surgery. Selection of patients for investigation and the appropriate studies to be performed requires understanding the risks of vascular surgery and the purpose of cardiac evaluation. While the most obvious goal of preoperative assessment is reduction of surgical risk, the combined morbidity of invasive cardiac investigation, coronary revascularization, and subsequent peripheral vascular surgery must be weighed against the risk of the latter procedure alone. Since the overall mortality for most elective vascular procedures remains well under 5%, preoperative testing should be performed selectively. Cardiovascular assessment may also help determine the propriety of surgery in some patients. Small aortic aneurysms, asymptomatic carotid stenosis, or calf claudication, for example, are only relative indications for operation. An evaluation of cardiac function or coronary anatomy may influence the decision to proceed with surgical versus conservative management. For example, it is unlikely that a patient with a life expectancy of less than 2 years will benefit from a carotid endarterectomy of an asymptomatic lesion. Finally, since cardiac disease is so prevalent in patients with peripheral vascular disease, a thorough cardiac evaluation may be justified in some patients simply to address the longterm consequences of their cardiac disorder, regardless of the need for reconstruction of the peripheral lesion. Evaluation by vascular surgical and medical specialists offers an opportunity for implementing a preventive therapy to halt disease progression and ensure longevity of surgical reconstruction.
INTRODUCTION The prevalence of heart disease in the general population and the increasingly aggressive surgery performed in the elderly make perioperative risk of cardiovascular complications a major concern for all surgeons. As the population ages, the prevalence of atherosclerotic risk factors increases commensurately, increasing the risk of the typical surgical patient.[1] The systemic nature of atherosclerosis imposes a particular challenge on the successful perioperative cardiac management of patients with peripheral arterial disease. Studies on the prevalence of coronary artery disease (CAD) in patients with intermittent claudications show that history, clinical examination, and electrocardiography typically indicate the presence of coronary artery disease in 40 –60% of such patients.[2 – 6] In patients requiring arterial reconstructive surgery, clinically evident cardiac dysfunction has been noted in 50% of the patients, while an additional 18% have highly significant but clinically silent coronary artery disease.[2 – 4] In a study of routine coronary angiography at the Cleveland Clinic, surgically correctable coronary disease was found in 31% of patients with aortic aneurysms, 26% of those with cerebrovascular disease, and 21% of patients with peripheral arterial ischemia.[3] Routine coronary angiography and revascularization is neither necessary nor desirable in all patients with peripheral vascular disease. There are no controlled trials comparing perioperative outcomes after noncardiac surgery for patients treated with surgical or percutaneous coronary
Hobson/Wilson/Veith: Vascular Surgery: Principles and Practice, Third Edition, Revised and Expanded DOI: 10.1081/0819-9-120024904 Copyright q 2004 by Marcel Dekker, Inc.
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PREOPERATIVE CARDIOVASCULAR ASSESSMENT Coronary Artery Disease Risk factors leading to peripheral arterial disease also cause atherosclerosis of the coronary vessels. A large fraction of patients undergoing vascular surgery will thus have CAD of varying severity. Many of these patients have major or intermediate predictors of perioperative risk (Table 21-1) but do not necessarily have clinically manifest CAD. The immediate goal of evaluation is to identify patients who are at an increased risk of perioperative complications: patients presenting with progressive symptoms of CAD and those with severe but clinically silent CAD. This small subgroup of patients may require preoperative coronary revascularization. The indications for percutaneous or surgical coronary revascularization in patients undergoing vascular surgery are the same as those for general population.[7,8] Patients with mild to moderate CAD, on the other hand, can usually safely undergo vascular surgery with optimal medical management. Currently available tools for cardiovascular risk assessment include careful history taking with attention to functional status and symptoms of ischemic heart disease, physical examination, resting ECG and, in selected patients, noninvasive evaluation of the severity of CAD. Patients presenting with new or escalating symptoms and signs of CAD warrant aggressive evaluation, including stress testing and coronary angiography. The decision to proceed with percutaneous or surgical revascularization should be based on the guidelines established for general population, taking the urgency of vascular reconstruction under consideration.[7,8] The optimal timing of elective vascular
surgery after catheter-based coronary intervention is controversial. There is ample evidence that PTCA and stenting induces systemic autoimmune and inflammatory responses,[9,10] which persist up to 3 weeks after percutaneous transluminal coronary angioplast (PTCA).[10] This prothrombotic state can increase perioperative cardiovascular complications. The majority of coronary interventions today involve implantation of coronary stents. In a small study of 40 patients, most of whom were asymptomatic or had stable CAD, Kaluza et al.[11] found that surgery (72% of patients had vascular surgery) within 14 days of coronary stenting was associated with a 17.5% rate of MI, a 20% rate of death, and a 20% rate of significant bleeding. Whenever possible, elective surgery should be postponed for 4–6 weeks after coronary stenting. Evaluation of patients with a recent coronary event (defined as more than 7 but fewer than 30 days) has evolved considerably over the last decade. An antecedent myocardial infarction (MI) is one of the most significant risk factors associated with subsequent surgical morbidity. Furthermore, the mortality from a postoperative reinfarction has been shown to be considerably higher than the mortality from an initial infarction, ranging from 50 to 83%.[12 – 16] The large series have indicated that the surgical risk was greatest immediately after the infarction, in the range of 30 –50%, then dropped exponentially over the next 6 months to a stable reinfarction rate of 5% with subsequent surgical procedures.[13,17] Subsequent studies, however, indicated that improved surgical and anesthetic techniques have reduced the risk of reinfarction to 8% within the first 3 months after MI and 3.5% in the subsequent 3 months.[18,19] These reports involved a variety of surgical procedures, which did not necessarily reflect the risk of specific vascular operations. Modern guidelines for management of acute MI[20,21] require
Table 21-1. Clinical Predictors of Increased Perioperative Cardiovascular Risk Major
Intermediate
Minor
Unstable coronary syndromes Acute or recent MI with evidence of important ischemic risk Unstable or severe angina (Canadian Class III-IV) Decompensated heart failure Significant arrhythmia High-degree AV block Symptomatic ventricular arrhythmia in the presence of underlying heart disease Supraventricular arrhythmia with uncontrollable ventricular rate Severe valvular disease Mild angina (Canadian Class I-II) Previous MI by history or pathological Q waves Compensated or prior heart failure Diabetes mellitus Renal insufficiency Advanced age Abnormal ECG Rhythm other than sinus Low functional capacity History of a cerebral vascular event Uncontrollable systemic hypertension
Source: Adapted from Ref. [22].
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evaluation and aggressive treatment of coronary pathology at the time of the acute presentation and risk stratification during recovery. Although there are no clinical trials to evaluate the optimal time interval before an elective surgery, most recent guidelines recommend waiting 4–6 weeks after MI before performing an elective surgery.[22] However, urgent revascularization, especially for limb salvage, should not be avoided solely on the basis of a recent infarction. Patients with established but stable coronary artery disease require a different approach. Those who underwent coronary artery bypass grafting (CABG) within 5 years or percutaneous revascularization within 2 years and have not experienced deterioration in functional capacity or recurrent symptoms of CAD usually do not require further preoperative testing.[22] Many patients will present with a diagnosis of CAD but no history of revascularization. Patients with noncritical CAD on invasive or noninvasive testing within 2 years are at an acceptable risk provided that they had no change in symptoms. This approach includes patients with stable angina. These patients do not require further testing. Noninvasive testing should be performed in patients with CAD who experienced a change in their functional status or whose functional status cannot be assessed due to immobility. A large proportion of patients undergoing preoperative evaluation will be asymptomatic and not carry a diagnosis of coronary artery disease but will have an increased probability of CAD by virtue of their risk factors. Many will have intermediate clinical predictors of perioperative risk (Table 21-1). In this group, the immediate aim of preoperative risk assessment should focus on determination of functional capacity and, if CAD is detected, the degree of the ischemic burden. Their management should be guided by the established guidelines irrespective of the planned surgery. Those whose functional capacity can be reliably established to be above 4 MET (Table 21-2) have a good long-term prognosis[24] and can generally undergo surgery under appropriate medical management without further testing. Sedentary patients who have a normal resting ECG and who are able to exercise should undergo exercise stress testing. The onset of myocardial ischemia response at a low workload is associated with increased risk of perioperative and longterm cardiac events[22,24] and warrants a more invasive evaluation. On the other hand, the onset of ischemic response at high exercise workloads is associated with significantly lower risk.[22] The utility of this test in vascular patients, however, is limited due to their inability to exercise. In a series of 100 patients scheduled for vascular surgery who could exercise, 70% could not reach the required heart rate or had an abnormal resting ECG.[25] Nonexercise stress testing should be used in patients unable to exercise. Two commonly used techniques rely on either increase in myocardial oxygen consumption (intravenous dobutamine) or induction of hyperemic response by pharmacological agents such as intravenous dipyridamole or adenosine. Dobutamine stress echocardiography and intravenous dipyridamole/adenosine myocardial perfusion imaging using thallium-201 or technetium-99m are commonly used today. The choice of diagnostic modality should be guided by local expertise and patient characteristics. Although adenosine-technetium imaging is most commonly used today, more data exist for the older
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Table 21-2. Average Metabolic Equivalent (METs) Levels for Common Activities Activity Getting dressed Walking indoors Walking at 2.0 mph Walking at 3.0 mph Golf (with cart) Golf (without cart) Light work around the house Calisthenics (no weights) Climbing a flight of stairs Gardening Cycling (leisurely) Cycling (moderately) Swimming (slowly) Swimming (fast) Climbing hills No load With 5 kg load Tennis (doubles) Tennis (singles) Running (10 min/mile) Running (7.5 min/mile)
METsa 1.0 1.5 2.5 3.5 2.5 4.9 3.9 4.0 4.0 4.4 4.0 5.7 4.5 7.0 6.9 7.5 6.0 7.5 10.2 13.2
a
Functional capacity can be expressed in metabolic equivalent (MET) levels; the oxygen consumption (VO2) of a 70 kg, 40-year-old man in a resting state is 3.5 mL/kg/min, or 1 MET, i.e., 3 MET represents an exercise intensity three times the metabolic rate at rest. Source: From Refs. [22,23].
dipyridamole/thallium imaging. A reversible perfusion defect has a positive predictive value for a perioperative cardiac event among vascular patients ranging from 5 to 20%. The negative predictive value is consistently high at 95 to 100%.[22] Patients with fixed perfusion defects have a higher risk of perioperative cardiac complications compared with those whose scan is normal, but this risk is significantly lower than in patients with reversible perfusion defects. A meta-analysis of dipyridamole thallium imaging for perioperative risk stratification prior to vascular surgery in 1994 patients confirmed the significant prognostic utility of this technique.[26] Overall, reversible myocardial perfusion defects predicted perioperative events, while fixed thallium defects predicted long-term cardiovascular events. In contradistinction to these retrospective studies and meta-analysis documenting the predictive value of nuclear stress imaging are prospective trials in which the studies were not predictive of perioperative cardiac risk. Mangano and associates studied a group of 60 patients who underwent blinded dipyridamole-thallium imaging proir to major vascular surgery.[27] In that study there was no association between redistribution defects and adverse cardiac events. Fifty-four percent (7 of 13) of adverse events occurred in patients without redistribution defects, while the relative risk
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for patients with redistribution defects to have an adverse event was only 1.5 ð p ¼ 0:43Þ: In another prospective blinded trial of 457 patients undergoing abdominal aortic surgery after blinded dipyridamole-thallium imaging, Baron and associates found no predictive value to the test.[28] The relative risk for adverse cardiac events was 1.1 for patients with redistribution defects and 1.5 for patients with fixed perfusion defects. Several studies have investigated the safety and accuracy of dobutamine stress echocardiography in patients undergoing vascular surgery.[22,29 – 33] The definition of positive and negative results varied among these studies. On the whole, however, these studies indicate that dobutamine stress echocardiography can be performed safely. The predictive value of a positive test for perioperative cardiac events (death or MI) ranged from 7 to 25%, while the negative predictive value ranged from 93 to 100%.[22] The presence of new wall motion abnormalities[29] and the extent of wall motion abnormality at a low level of pharmacological stress are particularly important and predict short- and long-term outcomes.[32,34] Current guidelines support the use of this technique in properly selected patients undergoing vascular surgery.[22] In patients in whom the presence of coronary artery disease has been established by noninvasive testing, management decisions should be based on their functional capacity and the severity of CAD. Coronary angiography and revascularization should not be undertaken just to “get the patient through surgery.” There have been no randomized trials examining the role of prophylactic coronary artery bypass graft surgery prior to noncardiac surgery. Preoperative coronary arteriography with prophylactic percutaneous revascularization has not been rigorously studied. Elmore et al.[35] and Huber et al.[36] have retrospectively examined small numbers of patients who underwent coronary balloon angioplasty before elective vascular surgery (median 10 and 9 days, respectively). The risk of MI was 0% and 5.6% and the risk of death was 0% and 1.9%, respectively. Both studies argued that percutaneous intervention prior to surgery is safe. A larger series, however, showed that patients who underwent percutaneous transluminal coronary angioplasty fewer than 90 days before the surgery had a twofold increase in the rate of perioperative MI compared with patients with uncorrected CAD.[37,38] Mason et al.[39] and Fleisher et al.[40] found that patients with CAD undergoing vascular surgery without coronary interventions had better outcomes than patients who were revascularized. Furthermore, as we have already suggested, the added risk of cardiac catheterization and coronary intervention or bypass surgery may negate the protection derived from future noncardiac surgery. In the absence of randomized, controlled trials comparing preoperative prophylactic revascularization versus medical therapy, coronary angiography and revascularization should be reserved for patients who would qualify for such treatment irrespective of planned surgery.[7,8] This would include patients with low ischemic threshold or evidence of multivessel disease. Medical therapy should be optimized in the remaining patients. Patients with no historical or ECG evidence of ischemic heart disease and excellent functional status determined by history do not require any further investigation. The surgical experience at our center demonstrates that a postoperative
cardiac morbidity and mortality of less than 0.5% can be achieved in this group, including patients undergoing aortic reconstruction.[41] Despite attempts to refine and improve the predictive value of the clinical scoring system, stress testing, and myocardial scintigraphy, these methods of evaluation all have their limitations. Recognition of these limitations, along with the gradual but steady decrease in cardiac morbidity and mortality after vascular surgery procedures, have led some authors to question the utility of preoperative attempts at cardiac risk evaluation. Taylor and associates reported only a 3.9% myocardial infarction rate (, 1% cardiac mortality) after 534 vascular operations with no routine cardiac evaluation other than history, physical exam, and ECG.[42] Only 5.8% of patients who were felt to have severe symptomatic coronary artery disease had further cardiac evaluation, and only 3 patients underwent prophylactic coronary bypass surgery prior to the planned vascular surgery operation. These authors argued that cardiac screening is unnecessary and cost ineffective when applied to the general vascular surgery population. While it has been clearly shown that the great majority of patients can be “gotten through” vascular surgical procedures with acceptably low morbidity and mortality, few would argue the merits of identifying the presence and significance of coronary artery disease in preoperative patients. While few patients will require coronary arteriography and even fewer any form of coronary revascularization, the recognition of coronary artery disease allows optimal short- and long-term care. Optimization of perioperative medical management, perioperative monitoring, and long-term risk factor modification are all facilitated by an accurate cardiac evaluation. A recent study by McDermott et al.[43] demonstrated the advantage of such multidisciplinary approach in management of patients with peripheral arterial disease.
Congestive Heart Failure Clinically evident heart failure at the time of operation is one of the most serious risk factors for postoperative cardiac morbidity.[44,45] Patients with a third heart sound or jugular venous distention have a 25–30% risk of postoperative pulmonary edema as well as a higher operative mortality.[44] The surgical risk is primarily dependent on the degree of decompensation at the time of operation rather than the historical severity of the heart failure. Furthermore, the presence of active heart failure should not be confused with a less worrisome finding of low ejection fraction in patients without fluid overload. The etiology of heart failure should be identified as it may have significant prognostic implications. Congestive heart failure due to ischemic heart disease implies a poorer prognosis than that due to longstanding hypertension. Satisfactory preoperative control of congestive heart failure substantially reduces the cardiac risk[16] and is mandatory in all but the most urgent circumstances. Rapid control of heart failure may be associated with some degree of hypovolemia. Preoperative management must therefore include appropriate anesthetic techniques to minimize sudden vasodilation.
Chapter 21.
Perioperative Evaluation and Management of Cardiac Risk in Vascular Surgery
Arrhythmias and Conduction Disturbances The presence of an arrhythmia or conduction system abnormality should prompt an evaluation of the underlying cardiopulmonary disease, drug toxicity, or metabolic abnormality. Symptomatic or hemodynamically significant arrhythmias should be treated. The indications for pacing or antiarrhythmic therapy should be the same as in the nonoperative setting.[46] Frequent premature ventricular contractions and asymptomatic nonsustained ventricular tachycardia have not been associated with an increased risk of nonfatal MI or cardiac death in the perioperative setting.[47,48] The presence of nonsustained ventricular tachycardia may, however, be a marker of underlying left ventricular dysfunction and carry an increased long-term risk of sudden cardiac death. An implantable cardiac defibrillator may be warranted in selected patients. Patients with complete heart block are at considerable risk for postoperative complications, not only because of the underlying myocardial disease but also due to their inability to augment cardiac output in response to stress.[49] This impairment is exacerbated by anesthetic agents, which further depress myocardial contractility or cause peripheral vasodilatation. These patients should be provided with a temporary pacemaker perioperatively. Management of patients with chronic bifascicular block is more controversial. Although 5% of such patients will develop complete heart block each year,[50] anesthesia and surgery do not usually precipitate this conversion. Patients with an associate history of syncope or those deemed at high risk of postoperative MI (which may lead to severe hemodynamic decompensation in the presence of heart block) may be considered for temporary pacing. Otherwise, management should be directed toward the underlying cardiac disease rather than the conduction defect itself.
Valvular Heart Disease Although there is a slight increase in the incidence of embolization and endocarditis, the cardiac mortality and morbidity of valvular disease are predominantly associated with the degree of underlying myocardial decompensation. Patients who are either asymptomatic or have only a mild degree of functional limitation (NYHA class II) do not appear to be at a higher risk. These patients do not require additional preoperative therapy with the exception of prophylactic antibiotics for endocarditis. Patients with critical valvular stenosis and significant physical limitations characteristic of NYHA class III or IV are clearly at higher risk for perioperative sudden death or pulmonary edema.[51,52] Every effort must be made to identify these high-risk individuals and to institute appropriate perioperative therapy. Severe and symptomatic aortic stenosis poses the greatest risk for noncardiac surgery. Patients with symptoms of angina, syncope, or congestive heart failure should be evaluated for aortic valve surgery prior to an elective noncardiac surgery. In patients who refuse or are not candidates for valve replacement, the noncardiac surgery is associated with a 10% mortality risk.[53,54] Percutaneous
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balloon aortic valvuloplasty may be considered in special situations as a short-term solution to lower operative mortality and morbidity. These patients will be very sensitive to perioperative fluid shifts and may benefit from perioperative pulmonary artery catheter monitoring. Mitral stenosis is decreasing in frequency but, when significant, carries an increased risk of perioperative congestive heart failure. Mild to moderate mitral valve stenosis mandates careful heart rate control to maintain the diastolic filling period and careful attention to volume status. Severe mitral vale stenosis may require preoperative balloon mitral valvuloplasty or surgical replacement. Regurgitant valvular lesions are easier to manage in the perioperative setting. Patients in congestive heart failure due to aortic or mitral regurgitation should be medically optimized but do not require valve surgery preoperatively. Aortic regurgitation requires careful perioperative attention to volume status and afterload. Low heart rate increases the regurgitant volume and, unless CAD is present, should be avoided. Patients with prosthetic valves are often maintained on chronic anticoagulation with sodium warfarin, depending upon the type of the valve. Chronic anticoagulation should be withheld during the perioperative period to avoid an increased incidence of hemorrhagic complications. Since most bleeding can be controlled, while the sequelae of a single thromboembolic event may well be irreversible, short-term anticoagulation should be provided during the perioperative period. Perioperative heparin therapy is particularly important for patients in whom the risk of thromboembolism without anticoagulation is high: patients with a mechanical valve in the mitral position, a Bjork-Shiley valve, recent (i.e., less than one year) thrombosis or embolus, or three or more of the following risk factors: atrial fibrillation, previous embolus at any time, hypercoagulable condition, or mechanical prosthesis and LVEF less than 30%.[55] Chronic warfarin therapy should be discontinued 2–3 days before the surgery. Low molecular weight heparin can be used to facilitate the transition from chronic coumadin therapy in the perioperative setting. Alternatively, intravenous heparin can be instituted until 4 –6 hours before the surgery and started again postoperatively until coumadin reaches therapeutic level.
Hypertension Several investigations[56 – 60] have demonstrated that stage 1 or stage 2 hypertension (systolic blood pressure , 180 mmHg and diastolic blood pressure , 110 mmHg) does not pose an increased risk for perioperative cardiac complications. On the other hand, stage 3 hypertension (systolic blood pressure $ 180 mmHg and diastolic blood pressure $ 110 mmHg) should be controlled before surgery even if it requires a brief postponement. An effective regimen can be achieved over several days to weeks of preoperative outpatient treatment. Based on the available evidence, beta-blockers,[61] ACE inhibitors,[62] and thiazides[63] are particularly attractive in this patient population. If surgery is more urgent, rapid-acting agents can be administered that allow effective control in a matter of minutes or hours.
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Hypertension is quite common, and treatment has been shown to decrease death rates from stroke and CHD in the nonsurgical setting. Unfortunately, few patients with hypertension are treated effectively or treated at all. Accordingly, the perioperative evaluation offers an opportunity to identify patients with hypertension and initiate appropriate therapy. Patients who are on antihypertensive therapy should continue their regimen during the perioperative period. Particular care should be taken to avoid withdrawal of beta-blockers and clonidine because of potential heart rate or blood pressure rebound. In patients unable to take oral medications, parenteral beta-blockers and transdermal clonidine may be used.
PERIOPERATIVE MANAGEMENT Surgical Procedure The type of operative procedure itself plays a major role in the risk of a cardiac complication. Aortic surgery is more stressful than infrainguinal arterial reconstruction. Nonetheless, the incidence of significant coronary artery disease and cardiac morbidity and mortality is generally higher after infrainguinal surgery. Emergency surgery is generally more dangerous than elective surgery for most procedures. The morbidity and mortality of emergent repair of symptomatic but unruptured aneurysms, for example, has been reported as much higher in some series than that associated with elective repair.[64,65] The overall mortality rate, 1.6% in our experience, applies equally to all intact aneurysms, symptomatic or not.[41,66,67] However, this low mortality rate has not been equaled in most other hospitals. Somewhat surprisingly, the duration of surgery has not proven to correlate with cardiac risk, at least for noncavitary operations. We believe that the increased complication rate sometimes noted for very long operations is related to the nature of the surgery rather than its duration.
Medical Management Several trials in the last decade have demonstrated the beneficial effect of perioperative administration of betablockers in reducing cardiac events. Mangano et al.[68] studied 200 patients with or at risk for CAD who were scheduled to undergo noncardiac surgery (40% of patients had vascular surgery). They were randomized to atenolol, administered immediately before surgery and for up to 7 days thereafter, or placebo. This randomized, double-blind, placebo-controlled trial did not show any effect on immediate postoperative mortality, but the 6-month mortality was significantly lower in the atenolol arm (0% vs. 8%). This benefit persisted for 2 years of follow-up. Moreover, there was a significant reduction in postoperative ischemia on continuous Holter monitoring.[69] Poldermans et al.[61] investigated the effect of bisoprolol in high-risk patients undergoing vascular surgery. In a randomized, multicenter trial, 112 patients with CAD documented by a positive dobutamine echocardiogram were randomized to bisoprolol, started an average 37 days before surgery, or placebo. After 30 days of follow-up,
bisoprolol significantly reduced the risk of myocardial infarction (0% vs. 17%) and death (3.4% vs. 17%) compared to placebo. Boersma et al.[70] subsequently reanalyzed the total cohort of 1351 consecutive patients enrolled in this randomized trial of bisoprolol and showed that the benefit of therapy extended to all subsets of patients except those with most extensive ischemia on dobutamine stress echocardiogram. These two trials have confirmed the finding of several smaller and older studies[71 – 74] and thus have firmly established the benefit of perioperative beta-blockers. We routinely use beta-blockers in patients with or at risk for CAD, preferably started in the outpatient setting, with target heart rate in the range of 50–70 beats per minute. Patients undergoing vascular surgery remain at an increased risk of future cardiovascular events. Perioperative medical and surgical attention offers a great opportunity for aggressive modification of risk factors and reduction of future morbidity and mortality. Several recent large trials have shown the efficacy of specific medical interventions in reaching these goals. The HOPE trial randomized 9297 patients with vascular disease or diabetes and one additional cardiovascular risk factor to treatment with the ACE inhibitor ramipril or placebo.[62] Ramipril significantly reduced the rate of death from cardiovascular cause (6.1% vs. 8.1%), rate of MI (9.9% vs. 12.3%), and rate of CVA (3.2% vs. 4.9%) when compared to placebo. The role of cholesterol-lowering therapy with statins in reducing future cardiovascular events has been well established. The recently completed Heart Protection Study confirmed this benefit across all strata of LDL levels.[75] In 20,536 patients with CAD, peripheral arterial disease or diabetes who were randomized to simvastatin or placebo, active arm treatment significantly lowered rates of all-cause mortality (12.9% vs. 14.7%), coronary death (18% relative reduction) and reduced by nearly 25% the event rate for first MI and CVA. Antiplatelet therapy continues to be the most cost-effective intervention in vascular patients. A recent update from the Antithrombotic Trialists’ Collaboration Group reviewed all randomized trials of antiplatelet therapy. In 135,000 patients studied, antiplatelet therapy (aspirin was studied most widely) significantly reduced the combined outcome of any serious vascular event by nearly 25%, nonfatal myocardial infarction by 33%, nonfatal stroke by 25%, and vascular mortality by one sixth.[76] Clopidogrel, a thienopyridine derivative platelet antagonist, is slightly superior to aspirin in reducing the combined risk of ischemic stroke, myocardial infarction, or vascular death in patients with atherosclerotic vascular disease.[77] It is an effective, though more costly, alternative to aspirin in this group of patients. Its use is increasing in patients with coronary artery disease and percutaneous coronary interventions.[78,79] The recently published ALLHAT trial[63] has shown that thiazide diuretics, when compared with a calcium channel blocker or ACE inhibitor, are equally effective in reducing coronary heart disease events and allcause mortality. In this trial of 33,357 patients, diuretic therapy was more effective in reducing blood pressure. In the absence of strong contraindications, all patients with established vascular disease should be on longterm antiplatelet therapy, cholesterol-lowering therapy,
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beta-blockers, and ACE inhibitors. Thiazide diuretics should be chosen for control of hypertension.
Perioperative Hemodynamic Monitoring Intraoperative and postoperative hemodynamic monitoring with the aid of a pulmonary artery (PA) catheter can provide significant information critical to the care of the cardiac patient. Its use, however, must be balanced against the cost and risk of complications from insertion and use of the catheter, as well as variable physician understanding of data provided by the PA catheter. There are relatively few controlled studies examining clinical outcomes in patients managed perioperatively with the guidance of PA catheters. Several trials in vascular surgical patients did not find any differences in cardiac morbidity.[80 – 84] Patients undergoing infrainguinal arterial reconstruction did not have any difference in cardiac morbidity whether monitored by a pulmonary artery catheter from the evening before surgery, 3 hours before surgery, or only if clinically indicated. Pulmonary artery catheter monitoring, however, led to fewer intraoperative hemodynamic disorders.[85] Polanczyk et al. conducted a prospective cohort study of 4059 patients aged 50 years or older who underwent major elective noncardiac surgery.[86]
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Perioperative pulmonary artery catheterization was associated with a threefold increase in the incidence of major postoperative cardiac events [34 (15.4%) vs. 137 (3.6%); p , 0.001]. More recently, Sandham et al.[87] investigated the use of PA catheters in high-risk patients (ASA class III-IV) undergoing high-risk surgery (55% underwent vascular surgery). This randomized, multicenter trial showed no difference in perioperative or long-term mortality between the two treatment groups. There was no difference in postoperative MI, CHF, or arrhythmia. The group with PA catheters suffered a higher incidence of pulmonary embolism. Current evidence does not support routine use of pulmonary artery catheters perioperatively. They may, however, be beneficial in specific clinical situations where the extent of intraoperative and postoperative fluid shifts must be closely monitored. Patients with severe aortic stenosis may fit in this category. The decision to use PA catheter monitoring should be individualized and based on patient disease, surgical procedure, and practice setting. Practice parameters for the intraoperative use of a pulmonary artery catheter have been established by the American Society of Anesthesiologists.[88] More recently, transesophageal echocardiography has been employed as an intraoperative adjunct for monitoring cardiac function and filling during aortic cross clamping.
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Eagle, K.A.; Guyton, R.A.; Davidoff, R.; Ewy, G.A.; Fonger, J.; Gardner, T.J.; Gott, J.P.; Herrmann, H.C.; Marlow, R.A.; Nugent, W.C.; O’Connor, G.T.; Orszulak, T.A.; Rieselbach, R.E.; Winters, W.L.; Yusuf, S. ACC/AHA Guidelines for Coronary Artery Bypass Graft Surgery: A Report of the American College of Cardiology/ American Heart Association Task Force on Practice Guidelines (Committee to Revise the 1991 Guidelines for Coronary Artery Bypass Graft Surgery). J. Am. Coll. Cardiol. 1999, 34, 1262– 1346. Serrano, C.V.; Ramires, J.A.; Venturinelli, M.; et al. Coronary Angioplasty Results in Leukocyte and Platelet Activation with Adhesion Molecule Expression: Evidence of Inflammatory Response in Coronary Angioplasty. J. Am. Coll. Cardiol. 1997, 29, 1276– 1283. Azar, R.R.; McKay, R.G.; Kirnan, F.J.; et al. Coronary Angioplasty Induces a Systemic Inflammatory Response. Am. J. Cardiol. 1997, 80, 1476– 1489. Kaluza, G.; Joseph, J.; Raizner, M. Catastrophic Outcomes of Noncardiac Surgery Soon After Coronary Stenting. J. Am. Coll. Cardiol. 2000, 35, 1288– 1294. Plumlee, J.E.; Boettner, R.B. Myocardial Infarction During and Following Anesthesia and Operation. South Med. J. 1972, 65, 886. Tarhan, S.; Moffin, E.A.; Taylor, W.F.; et al. Myocardial Infarction After General Anesthesia. J. Am. Med. Assoc. 1972, 220, 1451. Rose, S.D.; Corman, L.C.; Mason, D.T. Cardiac Risk Factors in Patients Undergoing Noncardiac Surgery. Med. Clin. N. Am. 1979, 63, 1271.
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15. Portal, R.W. Elective Surgery After Myocardial Infarction. Br. Med. J. 1982, 284, 843. 16. Goldman, L.; Caldera, D.L.; Southwick, F.S.; et al. Cardiac Risk Factors and Complications in Noncardiac Surgery. Medicine 1978, 57, 357. 17. Steen, P.A.; Tinker, J.H.; Tarhan, S. Myocardial Reinfarction After Anesthesia and Surgery. J. Am. Med. Assoc. 1978, 239, 2566. 18. Wells, P.H.; Kaplan, J.A. Optimal Management of Patients with Ischemic Heart Disease for Noncardiac Surgery by Complementary Anesthesiologist and Cariologist Interaction. Am. Heart J. 1981, 102, 1029. 19. Rao, T.L.K.; El-Etr, A.A. Myocardial Reinfarction Following Anesthesia in Patients with Recent Infarction. Anesth. Analg. 1981, 60, 271. 20. Braunwald, E.; Antman, E.M.; Beasley, J.W.; Califf, R.M.; Cheitlin, M.D.; Hochman, J.S.; Jones, R.H.; Kereiakes, D.; Kupersmith, J.; Levin, T.N.; Pepine, C.J.; Schaeffer, J.W.; Smith, E.E. III, Steward, D.E.; Theroux, P. ACC/AHA 2002 Guideline Update for the Management of Patients with Unstable Angina and Non-ST-Segment Elevation Myocardial Infarction: A Report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines (Committee on the Management of Patients With Unstable Angina). J. Am. Coll. Cardiol. 2002, 40, 1366– 1377. 21. Ryan, T.J.; Antman, E.M.; Brooks, N.H.; et al. ACC/AHA Guidelines for the Management of Patients with Acute Myocardial Infarction: 1999 Update: A Report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines (Committee on Management of Acute Myocardial Infarction). Available at http:/www.acc.org/clinical/guidelines. 22. Eagle, K.A.; Berger, P.B.; Calkins, H.; et al. ACC/AHA Guideline Update for Perioperative Cardiovascular Evaluation for Noncardiac Surgery: Executive Summary: A Report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines (Committee to Update the 1996 Guidelines on Perioperative Cardiovascular Evaluation for Noncardiac Surgery). Available at www.acc.orp/clinical/guidelines. 23. Myers, J. Exercise and Cardiovascular Health. Circulation 2003, 107 (1), e2 –e5. 24. Weiner, D.A.; Ryan, T.J.; McCabe, C.H.; et al. Prognostic Importance of a Clinical Profile and Exercise Test in Medically Treated Patients with Coronary Artery Disease. J. Am. Coll. Cardiol. 1984, 3, 772– 779. 25. McPhail, N.; Calvin, J.E.; Shariatmadar, A.; Barber, G.G.; Scobie, T.K. The Use of Preoperative Exercise Testing to Predict Cardiac Complications After Arterial Reconstruction. J. Vasc. Surg. 1988, 7, 60– 68. 26. Shaw, L.J.; Eagle, K.A.; Gersh, B.J.; Miller, D.D. MetaAnalysis of Intravenous Dipyridamole-Thallium-201 Imaging (1985 to 1994) and Dobutamine Echocardiography (1991 to 1994) for Risk Stratification Before Vascular Surgery. J. Am. Coll. Cardiol. 1996, 27, 787– 798. 27. Mangano, D.T.; London, M.J.; Tubau, J.F.; et al. Dipyridamole Thallium-201 Scintigraphy as a Preoperative Screening Test. A Reexamination of Its Predictive Potential. Circulation 1991, 84, 493– 502.
28. Baron, J.F.; Mundler, O.; Bertrand, M.; et al. Dipyridamole-Thallium Scintigraphy and Gated Radionuclide Angiography to Assess Cardiac Risk Before Abdominal Aortic Surgery. N. Engl. J. Med. 1994, 330, 663– 669. 29. Poldermans, D.; Fioretti, P.M.; Forster, T.; et al. Dobutamine Stress Echocardiography for Assessment of Perioperative Cardiac Risk in Patients Undergoing Major Vascular Surgery. Circulation 1993, 87, 1506 –1512. 30. Lane, R.T.; Sawada, S.G.; Segar, D.S.; et al. Dobutamine Stress Echocardiography for Assessment of Cardiac Risk Before Noncardiac Surgery. Am. J. Cardiol. 1991, 68, 976– 977. 31. Eichelberger, J.P.; Schwarz, K.Q.; Black, E.R.; Green, R.M.; Ouriel, K. Predictive Value of Dobutamine Echocardiography Just Before Noncardiac Vascular Surgery. Am. J. Cardiol. 1993, 72, 602– 607. 32. Da´vila-Roma´n, V.G.; Waggoner, A.D.; Sicard, G.A.; Geltman, E.M.; Schechtman, K.B.; Perez, J.E. Dobutamine Stress Echocardiography Predicts Surgical Outcome in Patients With an Aortic Aneurysm and Peripheral Vascular Disease. J. Am. Coll. Cardiol. 1993, 21, 957– 963. 33. Poldermans, D.; Arnese, M.; Fioretti, P.M.; et al. Sustained Prognostic Value of Dobutamine Stress Echocardiography for Late Cardiac Events After Major Noncardiac Vascular Surgery. Circulation 1997, 95, 53–58. 34. Poldermans, D.; Amese, M.; Fioretti, P.M.; et al. Improved Cardiac Risk Stratification in Major Vascular Surgery With Dobutamine-Atropine Stress Echocardiography. J. Am. Coll. Cardiol. 1995, 26, 648– 653. 35. Elmore, J.R.; Hallett, J.W.; Gibbons, R.; et al. Myocardial Revascularization Before Abdominal Aortic Aneurysmorrhaphy: Effect of Coronary Angioplasty. Mayo Clin. Proc. 1991, 68, 713– 715. 36. Huber, K.; Evans, M.A.; Bresnahan, J.; et al. Outcome of Noncardiac Operations in Patients with Severe Coronary Artery Disease Successfully Treated Preoperatively with Coronary Angiography. Mayo Clin. Proc. 1992, 67, 15– 21. 37. Posner, K.; van Morman, G. Adverse Cardiac Outcomes After Noncardiac Surgery in Patients with Prior Percutaneous Transluminal Coronary Angioplasty. Anesth Analog. 1999, 89, 553– 560. 38. van Norman, G.; Posner, K. Coronary Stenting or Percutaneous Transluminal Coronary Angioplasty Prior to Noncardiac Surgery Increases Adverse Perioperative Cardiac Events: The Evidence Is Mounting. J. Am. Coll. Cardiol. 2000, 36, 2351– 2352. 39. Mason, J.J.; Owens, D.K.; Harris, R.A.; et al. The Role of Coronary Angiography and Coronary Revascularization Before Noncardiac Vascular Surgery. J. Am. Med. Assoc. 1995, 273, 1919– 1925. 40. Fleisher, L.A.; Eagle, K.A.; Shaffer, T.; et al. Mortality After Major Vascular Surgery: Analysis of the Medicare Database (Abstr). Anesth Anal. 1997, 84, SC43. 41. Golden MA, Whittemore AD, Donaldson MC, Mannick JA: Selective evaluation and management of coronary artery disease in patients undergoing repair of abdominal aortic aneurysms: A 16 year experience. Ann Surg 1990, 212, 415. 42. Wolf MA, Braunwald E: General anesthesia and noncardiac surgery in patients with heart disease. In Braunwald E (ed): Heart Disease. Philadelphia, Saunders, 1980.
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72. Pasternack, P.F.; Imparato, A.M.; Baumann, F.G.; et al. The Hemodynamics of Beta-Blockade in Patients Undergoing Abdominal Aortic Aneurysm Repair. Circulation 1987, 76 (Suppl 3, Pt 2), III-1-7. 73. Yeager, R.A.; Moneta, G.L.; Edwards, J.M.; Taylor, L.M., Jr. McConnell, D.B.; Porter, J.M. Reducing Perioperative Myocardial Infarction Following Vascular Surgery: The Potential Role of Beta-Blockade. Arch. Surg. 1995, 130, 869– 872. 74. Raby, K.E.; Brull, S.J.; Timimi, F.; et al. The Effect of Heart Rate Control on Myocardial Ischemia Among HighRisk Patients After Vascular Surgery. Anesth. Analg. 1999, 88, 477–482. 75. Heart Protection Study Collaborative Group; MRC/BHF Heart Protection Study of Cholesterol Lowering in 20,536 High-Risk Patients: A Randomized, Placebo-Controlled Trial. Lancet 2002, 360 (9326), 23– 33. 76. Antithrombotic Trialists’ Collaboration. Collaborative Meta-Analysis of Randomised Trials of Antiplatelet Therapy for Prevention of Death, Myocardial Infarction, and Stroke in High Risk Patients. BMJ 2002, 321, 71– 86. 77. CAPRIE Steering Committee. A Randomized, Blinded, Trial of Clopidogrel Versus Aspirin in Patients at Risk of Ischaemic Events (CAPRIE). Lancet 1996, 348, 1329 –1339. 78. Yusuf, S.; Zhao, F.; Mehta, S.R.; Chrolavicius, S.; Tognoni, G.; Fox, K.K. The Clopidogrel in Unstable Angina to Prevent Recurrent Events Trial Investigators. Effects of Clopidogrel in Addition to Aspirin in Patients with Acute Coronary Syndromes Without ST-Segment Elevation. N. Engl. J. Med. 2001, 345 (7), 494– 502. 79. Steinhubl, S.R.; Berger, P.B.; Mann, J.T., 3rd.; Fry, E.T.; DeLago, A.; Wilmer, C.; Topo1, E.J. CREDO Investigators. Clopidogrel for the Reduction of Events During Observation. Early and Sustained Dual Oral Antiplatelet Therapy Following Percutaneous Coronary Intervention: A Randomized Controlled Trial. J. Am. Med. Assoc. 2002, 288, 2411– 2420.
80. Isaacson, I.J.; Lowdon, J.D.; Berry, A.J.; et al. The Value of Pulmonary Artery and Central Venous Monitoring in Patients Undergoing Abdominal Aortic Reconstructive Surgery: A Comparative Study of Two Selected, Randomized Groups. J. Vasc. Surg. 1990, 12, 754– 760. 81. Joyce, W.P.; Provan, J.L.; Ameli, F.M.; McEwan, M.M.; Jelenich, S.; Jones, D.P. The Role of Central Haemodynamic Monitoring in Abdominal Aortic Surgery: A Prospective Randomised Study. Eur. J. Vasc. Surg. 1990, 4, 633– 636. 82. Ziegler, D.W.; Wright, J.G.; Choban, P.S.; Flancbaum, L. A Prospective Randomized Trial of Preoperative “Optimization” of Cardiac Function in Patients Undergoing Elective Peripheral Vascular Surgery. Surgery 1997, 122, 584– 592. 83. Bender, J.S.; Smith-Meek, M.A.; Jones, C.E. Routine Pulmonary Artery Catheterization Does Not Reduce Morbidity and Mortality of Elective Vascular Surgery: Results of a Prospective, Randomized Trial. Ann. Surg. 1997, 226, 229– 236. 84. Valentine, R.J.; Duke, M.L.; Inman, M.H.; et al. Effectiveness of Pulmonary Artery Catheters in Aortic Surgery: A Randomized Trial. J. Vasc. Surg. 1998, 27, 203– 211. 85. Berlauk, J.F.; Abrams, J.H.; Gilmour, I.J.; O’Connor, S.R.; Knighton, D.R.; Cerra, F.B. Preoperative Optimization of Cardiovascular Hemodynamics Improves Outcome in Peripheral Vascular Surgery: A Prospective, Randomized Clinical Trial. Ann. Surg. 1991, 214, 289– 297. 86. Polanczyk, C.A.; Marcantonio, E.; Goldman, L.; et al. Impact of Age on Perioperative Complications and Length of Stay in Patients Undergoing Noncardiac Surgery. Ann. Intern. Med. 2001, 134, 637– 643. 87. Sandham, J.D.; Hull, R.D.; Brant, R.F.; et al. A Randomized, Controlled Trial of the Use of PulmonaryArtery Catheter in High-Risk Surgical Patients. N. Engl. J. Med. 2003, 348, 5 – 14. 88. Practice Guidelines for Pulmonary Artery Catheterization: A Report by the American Society of Anesthesiologists Task Force on Pulmonary Artery Catheterization. Anesthesiology 1993; 78, 380– 394.
CHAPTER 22
The Biology of Restenosis and Neointimal Hyperplasia Robert A. Larson Michael A. Golden disease. Balloon angioplasty is a common procedure used to treat the stenoses caused by atherosclerotic lesions in both the heart and periphery. Unfortunately, approximately 30 –60% of patients undergoing coronary angioplasty will develop restenosis due in large part to neointimal encroachment on the luminal area (Fig. 22-1).[4,5] Neointimal hyperplasia is also the leading cause of vein graft failure 3 months to 2 years after bypass surgery.[6 – 8] The failure rate for lower extremity vein grafts averages 20–30% in long-term follow-up.[9] The problem of neointimal hyperplasia is even worse with prosthetic grafts. Restenosis is also seen after surgical endarterectomy. As many as 20% of patients undergoing carotid endarterectomy will develop a hemodynamically significant neointimal lesion.[10] Fortunately, few of these become symptomatic. The impact of restenosis on society is significant in terms of the associated morbidity, mortality, and cost to the health care system. It is not surprising, therefore, that a great deal of research effort has been directed towards understanding and controlling this process.
INTRODUCTION Definition Since the first vascular anastamoses were constructed by Carrel,[1] it has been known that injured arteries respond with a pathologic healing process that can lead to luminal narrowing. The advances in vascular surgery and endovascular techniques over the past half century have greatly expanded the number of arterial lesions that can be treated. Unfortunately, the occurrence of restenosis is still one of the most important factors preventing acceptable long-term patency. The term neointima is used to describe the pathologic intima that forms in response to vessel wall injury.[2] The physiologic response to injury, which produces the neointima, is loosely called neointimal hyperplasia. This process is not a hyperplasia in the strict sense since it is comprised of varying degrees of cellular proliferation, cellular hypertrophy, and extracellular matrix deposition. Neointimal hyperplasia presumably represents an attempt to heal the injured arterial wall and is analogous to wound-healing responses in other areas of the body. Restenosis is the narrowing or occlusion of a vessel that was previously stenotic and has undergone a therapeutic procedure to open it. This term is often inappropriately used when a stenosis develops after the injury of a normal artery in an animal model. The mechanisms that control neointimal hyperplasia are redundant and involve the participation of multiple players, including numerous cell types, growth factors, and hormones. This complexity has likely contributed to the generally poor results in human clinical trials based on data derived from successful animal experiments.[3]
EMBRYOLOGY/HISTOLOGY The arterial wall is comprised of three concentric layers of cells and connective tissue (Fig. 22-2). The innermost layer is the intima, which is formed by a thin layer of endothelial cells on the basement membrane, a variable amount of subendothelial connective tissue, and the internal elastic lamina. There can be smooth muscle cells in the intima in humans and primates, but they are generally not present in rats and mice. The neointima that forms after injury is found inside the internal elastic lamina. Between the internal and external elastic laminae is the arterial media. This layer is made up of smooth-muscle cells (SMCs) and extracellular matrix made up of primarily elastin and collagen. The exact composition of the media depends on the size and location of the artery. Arterioles responsible for
Clinical Significance Atherosclerosis is the leading cause of morbidity and mortality in the western world. Consequently, a large number of procedures have been devised to treat the effects of this
Hobson/Wilson/Veith: Vascular Surgery: Principles and Practice, Third Edition, Revised and Expanded DOI: 10.1081/0819-9-120024905 Copyright q 2004 by Marcel Dekker, Inc.
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Figure 22-1. Thrombosed coronary artery with IH after PTCA. N ¼ Neointima; T ¼ Thrombus; IH ¼ Intimal Hyperplasia; PTCA ¼ Percutaneous Transluminal Coronary Angioplasty. Figure 22-2. Arterial wall histology. (From David Low, M.D.)
the control of systemic vascular resistance have relatively more SMCs than larger arteries like the aorta. The outer layer of the arterial wall is the adventitia. This layer is primarily made up of loose connective tissue, some SMCs, and fibroblasts. The adventitia is supplied with tiny blood vessels of its own, vasa vasorum, which also nourish the outer layers of the media. At birth, the intima of human arteries consists solely of endothelial cells lining the internal elastic lamina.[11] Two notable exceptions include the ductus arteriosus and the origin of the left main coronary artery, which have SMCs in the intima at this time.[12] In the first few years of life, however, SMCs begin to appear in the space between the endothelial cells and the internal elastic lamina in the aorta and other large muscular arteries. The areas of SMC accumulation are called intimal cushions; these represent areas prone to future development of atherosclerotic plaques.
INJURY RESPONSE Models In order to study the underlying mechanisms of neointimal hyperplasia, models of arterial injury have been developed in animals that allow for controlled environments and less complex injury responses. The rat has been the most widely used model of arterial injury and has provided many insights into the pathophysiology of neointimal hyperplasia. The rat carotid artery is a relatively simple artery, comprised of a single layer of endothelium lining the internal elastic lamina.[13] For experimental purposes, it has fairly easy access via the external carotid artery, and the common carotid artery is devoid of branches, limiting the origin of reendothelialization to the proximal and distal artery. The response of the rat carotid to injury has been studied closely and occurs without an inflammatory response or fibrin deposition (Fig. 22-3).[14,15] The simplicity of this model allows for a close examination of the basic mechanisms of the response to injury, but it may not be directly applicable
to the much more complex environment of an injured atherosclerotic human artery. Mouse models have been very useful in helping to determine the roles played by several mediators of the neointimal response. The use of transgenic and knockout mice has been helpful in determining the roles that specific mediators play in the injury response, including basic fibroblast growth factor (bFGF, or FGF-2)[16] and plasminogen activators.[17] It is, however, technically more challenging to use a mouse model due to the size of the arteries. Several methods, such as external electrocautery,[18] have been devised to provide an easier and more reproducible method of arterial injury. The degree to which these methods of injury model a physiologically relevant response, however, is debatable. Rabbits reliably develop hypercholesterolemia when fed a diet high in cholesterol. These animals provide a way to study the arterial response to injury in a physiologic milieu more complex than the rat and more closely approximating human disease. Pig models of balloon angioplasty are widely used to study the effects of coronary angioplasty and stenting. The pig responds to arterial injury with a thrombotic process similar to that seen in humans. They also develop arterial wall calcifications akin to those in human disease. This model is frequently used to study new endovascular techniques and devices. Primate models provide the model closest to human atherosclerosis and arterial response to injury. They have been used extensively to study the natural history of prosthetic grafts in vivo because both the size of the arteries and hemodynamic parameters are comparable to those in humans.[19] A neointimal injury response can be induced by a number of methods. The most commonly used method is the balloon catheter technique: the catheter is inserted into the artery, the balloon inflated, and the catheter withdrawn, with or without twisting. Other methods of injury include using a small guide wire to denude the artery, electrocoagulating the exterior of
Chapter 22. The Biology of Restenosis and Neointimal Hyperplasia
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Figure 22-3. Photomicrograph of rat carotid before and 2 weeks after balloon injury. M ¼ Media; A ¼ Adventitia; N ¼ Neointima; IEL ¼ Internal Elastic Lamina; EEL ¼ External Elastic Lamina.
the artery, distal ligation of the artery, placement of periadventitial bands, and local application of noxious chemicals. There are also vein graft models in mice, rats, and rabbits. Each method has strengths and weaknesses as a model of the neointimal response in humans. Each of the injury methods produces a different set of responses, including varying degrees of endothelial damage, medial damage, thrombosis, and flow modification. By carefully choosing the animal model (with specific genetic and metabolic characteristics, such as hyperlipidemia) and the method of injury, one can focus the experiment on a specific vascular wall process or a particular aspect of the injury response.
Cellular Response to Injury Endothelium The endothelium is an important regulator of many vessel activities, including vasomotor tone and thrombosis. It also plays a central role in the regulation of smooth-muscle cell function.[20] A baseline antiproliferative effect is exerted on the SMCs by secreted prostacyclin,[20] heparan sulfate,[21] and nitric oxide.[22] The endothelium is also a natural barrier to platelet adherence, thus preventing platelet activation, a process that results in the release of several growth factors important in the neointimal response. After experimental vascular injury, reendothelialization begins within 24 hours, starting from the leading edge of the denuded area and the ostea of branch arteries.[23] It has been shown that after mild injury, consisting of a gentle endothelial denudation, complete reendothelialization can occur.[24] However, after more severe injury involving disruption of the basement membrane and the deeper layers of the media, endothelial dysfunction persists even if the regrowth is complete.[24,25] After vascular injury and endothelial regrowth, vasodilators which work via an endotheliumdependent mechanism show a decreased effect, while the ability of the underlying SMCs to relax or contract is unchanged. This may be due to decreased levels of nitric oxide (NO) synthesis in the endothelial cells.[26] As mentioned above, the endothelium exerts an antiproliferative effect on the underlying SMCs. In fact, areas of injured artery that are covered by endothelial regrowth exhibit
less neointimal hyperplasia than areas that remain bare. Animal studies using vascular endothelial growth factor (VEGF) to stimulate endothelial regrowth have shown accelerated re-endothelialization and reduced neointimal thickening in injured arteries.[27,28]
Platelets Vascular injury and endothelial cell loss exposes the underlying basement membrane and arterial media. Without the inhibitory effect of the endothelium, platelets adhere to the denuded vascular wall and become activated. Stimulated platelets degranulate, releasing several factors, including platelet-derived growth factor (PDGF) and transforming growth factor-b (TGF-b),[29] as well as thromboxane A2, a potent platelet chemoattractant. As mentioned below, PDGF is an important factor in initiating migration of SMCs from the media to the intima.
Smooth-Muscle Cells The mass of a vessel wall is comprised largely of SMCs and the associated matrix. The luminal narrowing associated with neointimal hyperplasia is primarily due to the overabundance of SMCs and their secreted matrix. Consequently, a great deal of attention has been focused on the role of the SMC in the arterial response to injury. One of the key events in the development of a neointima is the activation of normally quiescent medial SMCs. The activation of medial SMCs occurs soon after injury and is mediated by hormones, growth factors, and mechanical factors (see Fig. 22-4). One of
Figure 22-4.
Mediators and sequence of SMC activation.
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the earliest indicators of SMC activation is the expression of proto-oncogenes (e.g., c-myc, c-myb, c-jun, and c-fos) which are associated with the events proceeding DNA replication. These have been detected as early as 30 minutes after injury.[30] Indeed, prevention of proto-oncogene expression using antisense oligonucleotides has reduced the neointimal response in animal models.[31] The first consequence of SMC activation is proliferation. Under normal circumstances, there is very little turnover in the SMC population, only 0.06% per day in the adult rat.[15] In response to hypertension[32] or direct injury,[15] however, there is a dramatic increase in the proliferation rate of medial SMCs. This is followed by the migration of SMCs to the intima and the deposition of extracellular matrix. Studies of the response of the rat carotid artery to balloon injury have lead to the division of the SMC response into three phases. This response is characterized by the reactions of the medial smooth-muscle cells.
Medial SMC Proliferation The first wave consists of a burst of medial smooth-muscle cell proliferation that is evident 24 hours after injury, peaks within 4 days, and subsides by 10–14 days.[15] At the peak, between 20 and 40% of the SMC population can become activated.[33] The primary mitogen during this phase is bFGF, which is released by dead and injured SMCs.[34] The loss of endothelial nitric oxide synthesis also plays a role in the initial wave of SMC proliferation. This phase is not dependent on the presence of platelets, as shown in experiments using thrombocytopenic animals.[35] Consequently, PDGF does not seem to play a major role in the initiation of proliferation after injury.
SMC Migration The second wave involves migration of the medial SMCs to the intima. This process, unlike the first phase, is strongly affected by platelets[35] and PDGF.[36,37] The SMCs can be seen on the luminal side of the internal elastic lamina by 4 days after injury.
Proliferation of SMCs in Intima The third wave consists of the continuing proliferation of the intimal smooth-muscle cells, which can persist for several weeks after injury. This continued proliferation is highest at the luminal surface of the lesion.[38] The control of this process is poorly understood, but it is important due to the intimal mass added to the lesion during this time.[13] The deposition of extracellular matrix (ECM) is also important during this phase and adds to the bulk of the neointima.
Inflammation Inflammatory cells are important contributors to the development of atherosclerotic lesions, but their function in the arterial response to injury is less clear. Leukocytes adhere to the denuded arterial wall after balloon injury. Indeed, several inflammatory cell chemoattractants are released by injured SMCs and activated platelets.
Mediators Growth Factors The importance of growth factors to the arterial response to injury cannot be understated. One of the most closely studied of these is basic fibroblast growth factor (bFGF).[34,39] This 18 kDa protein is a member of the heparin-binding growth factor family and is a potent SMC and endothelial cell mitogen. It is located within preformed granules in the quiescent medial smooth-muscle cell and does not contain a secretory domain. Its action, therefore, depends on its release from injured or dead SMCs into the extracellular matrix. At the time of SMC injury, bFGF is released and stimulates the initial phase of SMC proliferation. If antibodies to bFGF are given at the time of injury, the initial wave of SMC proliferation is reduced by 80%, but the final degree of neointimal thickening is not affected.[34] This is due in part to the ongoing production of bFGF in the activated SMCs and to the presence of other mediators that stimulate neointimal thickening. Platelet-derived growth factor is another important regulator of the arterial response to injury. It is a basic dimeric protein with a molecular weight of about 30 kDa, with the two isoforms of the monomers being PDGF-A and PDGF-B. It is present in the a-granules of platelets, primarily as PDGF-AB, and is released during degranulation. PDGF can also be expressed by several other cell types, including endothelium, SMCs,[40] and leukocytes. As mentioned before, PDGF does not significantly induce replication among medial SMCs in vivo, but is a potent factor in stimulating their migration to the intima.[36] In vitro, however, it does have some mitogenic effect. TGF-b is a potent stimulator of SMC collagen production and matrix deposition. In vitro, TGF has antiproliferative effects on SMCs that vary with the growth rate.[41] In rat carotid injury models, however, antibodies to TGF-b given at the time of injury reduce neointimal formation.[42] Nitric oxide, a molecule central to the regulation of vascular tone, is also an important regulator of medial SMC activation and neointimal formation after injury. NO has been found to be a potent inhibitor of SMC proliferation and migration.[43] In animal studies, adenoviral gene transfer of nitric oxide synthase (NOS) to injured arteries reduced the subsequent neointimal hyperplasia.[44,45]
Increased Response of SMCs to Mitogens Some investigators have proposed the addition of a fourth phase in SMC response. It has been shown that proliferating intimal SMCs in a previously injured artery have an increased responsiveness to restimulation with mitogens. Again, the mediation of this response is poorly understood.
Hormonal Factors The renin-angiotensin system, long known to be important in the pathogenesis of hypertension, has also been found to play a role in the neointimal response.[46] In the classic description of this system, the juxtaglomerular apparatus in
Chapter 22. The Biology of Restenosis and Neointimal Hyperplasia
the kidney produces renin in response to hemodynamic and electrolyte stimuli. Circulating renin then cleaves angiotensinogen (produced by the liver) to produce angiotensin I, which is physiologically inactive. Circulating angiotensin I is then cleaved to produce angiotensin II by the angiotensinconverting enzyme (ACE), which is expressed on endothelial cells throughout the body, especially in the lungs. Angiotensin II is a potent vasoconstrictor and is the mediator of the neointimal response. This classic description has been expanded by the observation that rennin[47] and angiotensinogen[48] are produced in vascular endothelial and smoothmuscle cells. Thus, with the ACE present, the complete system is contained within the vascular wall. The significance of this tissue renin-angiotensin system is still unclear. The exact mechanism underlying the effect of angiotensin II on neointimal hyperplasia is not known, but it is believed to stimulate the production of other growth factors, such as PDGF, and mitogens, including the proto-oncogenes c-fos, cjun, and c-myc. Angiotensin II has been shown to be a potent mitogen of SMCs in vitro[49] and in vivo.[46] Additionally, angiotensinogen gene expression is increased in arterial wall after injury, providing a higher concentration of substrate for local ACE.[50] ACE inhibitors such as captopril and enalapril block the conversion of angiotensin I to angiotensin II. The use of ACE inhibitors has been shown to reduce the amount of neointimal hyperplasia in a dose-dependent fashion in the rat model of arterial injury.[51] This response has also been shown in the rabbit model.[52] In addition, treatment with ACE inhibitors was shown to reduce the biosynthesis of PDGF-AB[53] and bFGF[54] in the arterial wall after injury. These results were promising and led to the study of the effects of ACE inhibitors in higher animals. Unfortunately, experiments using baboons were not able to replicate the beneficial effects seen in rodents.[55] Likewise, clinical trials in humans have failed to show any ability to prevent restenosis,[3] although medication doses for humans were less aggressive than those for the experimental animals. In addition to blocking the production of angiotensin II, investigators have studied the effects of blocking the angiotensin receptor. Angiotensin II receptors have been classified into two types, AT1 and AT2. The AT1 receptor mediates vasoconstriction and is the predominant type on SMCs. It has been shown that neointimal tissue possesses up to four times the number of AT1 receptors compared to the normal arterial wall, perhaps augmenting the responsiveness of the neointima to angiotensin II stimulation.[56] In the rat model, blockade of the AT1 receptor was shown to reduce neointima formation after balloon arterial injury. The receptor blockade was also shown to suppress several cell-proliferation proto-oncogenes, which likely contributed to the histologic effect.[57,58]
Mechanical Factors The pressure and high-flow environment of the arterial system produces stresses that the normal arterial wall must support. These forces can influence the development of a pathologic neointima after arterial injury and play an especially important role in vein and prosthetic grafts (see below).
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As discussed in detail below, subjecting a vein graft to arterial pressures results in repetitive stretch injuries that can lead to wall thickening. Also, grafts with lower blood velocities, and subsequently lower shear stress, have a more pronounced neointimal response.[59] Both endothelial cells and smooth-muscle cells have been shown to respond to changes in shear forces. Changes in the shear force can also affect an existing neointima. Experiments in baboons using PTFE grafts have shown that the thick neointima that forms in a low shear stress graft can be reduced by converting it to a high flow/shear stress fistula.[19] The loss in neointimal mass is represented by both decreased SMC and matrix content. The converse is also observed in the laboratory.
Extracellular Matrix In the injured rat artery, up to 80% of the intimal mass consists of matrix,[60] which is produced for up to 3 months after injury.[15] The matrix is a complex set of proteins secreted by activated SMCs and includes collagen type I, elastin, osteopontin, and proteoglycans.[61,62] Not only does the matrix provide a scaffold for the SMCs of the neointima, it also helps to facilitate the migration of activated SMCs by interacting with specific integrin receptors expressed by these cells.[63] In order for the medial SMCs to migrate to the neointima, they must be able to digest the surrounding matrix. Several proteases are activated by arterial injury and are important to neointimal formation. Both plasminogen activators[64] and matrix metalloproteinases (MMP)[65] have been shown to increase after injury in animal models. Both urokinase and tissue type plasminogen activators are stimulated by arterial injury and remain activated for about 2 weeks. The proteolytic enzymes MMP2 and MMP9 have been shown to be important in the SMC migration process after arterial injury.[65] In fact, the use of an MMP inhibitor prevents SMC migration.[66] It has also been shown that knockout mice deficient in the urokinase plasminogen activator (uPA) show a delayed and reduced neointimal response after arterial injury.[67] In addition to the structural importance of the matrix, it also functions as a repository for growth factors, especially bFGF. As SMCs die, they release bFGF into the surrounding matrix, where it adheres to the heparan sulfate proteoglycans.[68] As the matrix is degraded by proteases, the bound bFGF is released and can stimulate adjacent SMCs.
Thrombosis In animal models more complex than the rat, thrombosis appears to play a key role in the restenosis process. This is well established in porcine stent models.[69] Thrombin stimulates SMC proliferation in vitro,[70] and antibodies against the thrombin receptor reduce injury-induced neointimal thickening in vivo.[71]
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ATHEROSCLEROSIS AND HUMAN ANGIOPLASTY The pathophysiology of restenosis in a human atherosclerotic artery is probably more complex than the arterial response to injury in animal models, and may in fact represent a different process. Three mechanisms are known to be responsible for the failure of angioplasties in humans. First, there is elastic recoil of the artery, which occurs shortly after the procedure. Second, there is remodeling of the artery, which results in the change of the total vessel area. Third, there is intimal thickening. The relative contribution of these three processes determines the degree of restenosis that occurs.[72] Elastic recoil has been dealt with recently by the use of endovascular stents, thus leaving remodeling and neointimal hyperplasia as the main areas of interest. Human vessels can compensate for increased luminal mass by dilation and remodeling.[73] Vessels can maintain constant levels of blood flow until the lesion mass exceeds about 40% of the area encompassed by the internal elastic lamina. Indeed, in the hypercholesterolemic rabbit model it has been shown that compensatory enlargement occurs after experimental angioplasty, compensating for about 60% of the luminal area lost to neointimal hyperplasia. [74] The mechanisms underlying the remodeling process are not well understood, but possibly include responses to increased flow and wall stress resulting in altered extracellular matrix metabolism.[73] It appears that the endothelium plays a role in the remodeling process, likely regulated by the response to changes in shear stress.[75] In the absence of functional endothelium, or with dysfunctional regenerated endothelium, the compensatory enlargement is prevented. Constriction of the artery after injury also occurs and can greatly increase the restenotic process. Chronic inflammation has been found to occur in injured arteries.[76] Increased expression of TGF-b and tissue inhibitors of metalloproteinases (TIMP) may cause an increase in matrix deposition and a decrease in matrix digestion, resulting in the inability to remodel outwardly. The process of intimal thickening in human lesions differs from that in animal models. Human atherosclerotic lesions, unlike the uninjured rat carotid artery, are already populated with SMCs.[2] In addition, there is some evidence to suggest that smooth-muscle replication may not be as important a factor in human restenosis as in experimental models.[77] Since most of the experimental models use initially normal vessels, the process of stenosis that occurs after injury may be vastly different from that of an initially atherosclerotic and stenotic artery.
The development of neointimal hyperplasia in the vein graft is similar to that which develops after angioplasty; it is an injury response consisting of SMC proliferation and matrix deposition that is modulated by several growth factors. The difference, however, is that the injury response in vein grafts is initially one of healthy adaptation, which in some grafts progresses to a pathologic state (Fig. 22-5). The insertion of a vein into the high-pressure, high-flow environment of the arterial system subjects the vein to stresses to which it is not accustomed. The adaptation of a vein to the arterial system involves the thickening of its wall. This process is driven by the repetitive injury caused by the arterial pressures. Other factors also contribute to graft injury early on, including rough handling during harvest, hypotonic irrigation fluids, and overzealous distention.[78] The thickening of the vein wall serves to reduce the tangential stress applied to it by arterial pressures. According to LaPlace’s law, the tangential stress (t) in the wall of a sphere is proportional to the pressure (P) and the radius (r), and inversely proportional to the wall thickness (d): t ¼ Pr=d Thus, by increasing the wall thickness the stress in the wall is reduced. In an experimental rabbit model, reducing the stress exerted on a vein graft by placing a rigid cuff around the graft was shown to decrease the intimal thickening.[79] The shear stress (s), exerted longitudinally on the vessel wall, is a function of the blood flow (Q), vessel radius (r), and blood viscosity (h). Assuming laminar flow: s ¼ 4hQ=pr3
NEOINTIMAL HYPERPLASIA IN VEIN BYPASS GRAFTS The use of autologous vein for the bypass of arterial lesions is a staple of cardiac and peripheral vascular surgery. One of the main factors contributing to the failure of these grafts after one year is stenosis due to neointimal thickening.
Figure 22-5. anastamosis.
Angiogram of stenosis at SFA-RSVG
Chapter 22. The Biology of Restenosis and Neointimal Hyperplasia
With the high flow rate of the arterial system, the shear stress is increased in vein grafts and is important in the regulation of neointimal hyperplasia. It is well known that high flow grafts develop less intimal thickening than low-flow systems.[80] One hypothesis for this phenomenon is that in high-flow systems it is more difficult for bloodborne elements to adhere to the vessel wall. Adherent platelets and leukocytes secrete growth factors that can stimulate SMC proliferation and matrix deposition. It has also been shown that increased shear stress induces endothelial cells to produce nitric oxide,[81] a potent inhibitor of SMC proliferation. Shear stress is probably more important in the development of neointimal thickening in prosthetic grafts, as described below. The kinetics of the adaptation of a vein graft to the arterial environment has been studied in the rabbit model.[82] Early events include platelet aggregation and microthrombi at areas of endothelial denudation around the anastamoses. By two weeks, the denuded areas have been reendothelialized and the vein wall starts to thicken. For the first 4 weeks, proliferating SMCs provide the bulk of the neointima, followed by the progressive deposition of ECM. This process reaches a maximum at 12 weeks, by which time the ratio of wall thickness to vessel diameter is the same in the vein graft as in the artery. At this point, the wall tension in the vein graft is equal to that of the artery. Unlike neointimal hyperplasia that occurs after the angioplasty of an atherosclerotic lesion, the SMC proliferation that occurs in the vein graft takes place under an intact endothelium. Clearly, the normally antiproliferative influences of the endothelium seen in the arterial system are not present in the vein graft. It has been shown that vein graft endothelium produces less nitric oxide,[83] a potent SMC proliferation inhibitor. Restoration of nitric oxide to the vein graft reduces neointimal hyperplasia.[84,85] Stenoses are frequently seen at the anastamoses of vein grafts. The turbulent flow and compliance mismatch between the vein and artery produce additional stresses that cause local endothelial disruption and persistent intimal proliferation.[80,86] In fact, the geometry of the anastamosis may contribute to the development of neointimal hyperplasia. Biomechanical analyses have shown that the suture line stress generated by compliance mismatch is greater in end-to-side anastamoses compared to end-to-end.[87] It has also been shown that the shear stress at an anastamosis is dependent on the angle of the anastamosis, with larger angles producing more shear stress.[88,89]
NEOINTIMAL HYPERPLASIA IN PROSTHETIC BYPASS GRAFTS Prosthetic grafts are used frequently for the replacement of large arteries and when autogenous vein is not available for arterial reconstruction. Neointimal hyperplasia also develops in these grafts and is a significant contributor to their decreased long-term patency. In experimental animal models, porous grafts, such as ePTFE, become lined with a neointima made of smoothmuscle and endothelial cells. The cells populate the graft from
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capillary ingrowth through the 60 mm pores in the graft and from the arterial anastamoses.[90] Endothelialization is complete by 3 weeks, but the SMCs continue to proliferate and deposit matrix for several months.[91,92] The neointima in the prosthetic graft is quite active biologically and produces several growth factors that stimulate SMC proliferation,[93,94] including PDGF[95] and TGF-b.[94] As in vein grafts, the stresses induced by the arterial system play a central role in the development of prosthetic graft neointimal thickening. Unlike vein grafts, however, the prosthetic grafts are rigid and can support the tangential stress easily. The neointima responds primarily to the shear stress caused by the flowing arterial blood. This has been studied extensively in baboon models, where high-flow grafts were found to have less neointimal hyperplasia than normal-flow grafts.[96] It has also been shown that exposing a graft with a mature neointima to high-flow conditions (by creating a distal arterio-venous fistula) can cause the regression of the neointima.[19] Closure of the AV fistula results in an increase in neointimal thickness. As in vein grafts, it has been postulated that shear stress induces the production of nitric oxide, which has a static effect on SMCs. Indeed, nitric oxide synthase was shown to be induced in the neointima of highflow grafts.[19] Compliance mismatch between graft and artery is a greater concern when a stiff prosthetic graft is used. A Dacron graft in the end-to-side configuration was shown to have a 40% greater suture line strain than an autologous graft.[87] The geometry of the anastamosis also plays an important role. In the end-to-end position the Dacron graft was associated with only a 5% increase in suture line stress compared to an arterial graft.[87] The combination of decreased flow velocities (and thus shear force) and increased suture line stress of prosthetic grafts likely contributes to the poor performance of belowknee prosthetic bypass grafts compared to autologous vein grafts. A great deal of effort is being directed towards finding ways to increase the long-term patency of these grafts as more patients present for distal bypass without adequate autologous conduit.
RESTENOSIS AFTER ENDARTERECTOMY Since its introduction by Dos Santos[97] in 1947, the technique of endarterectomy has been an important part of vascular surgery. A natural cleavage plane tends to develop in the outer region of the media in older, atherosclerotic arteries. The careful dissection of this cleavage plane allows for the removal of the diseased intima and inner media. The result is a relatively clean surface comprised of SMCs and extracellular matrix. Endarterectomy has been used in almost every part of the vascular system with variable success. The limiting factor is generally restenosis due to neointimal hyperplasia. Results for long-term patency of endarterectomized arteries varies by location (see Table 22-1), with more proximal arteries having better results. The carotid artery system is a special case.
332 Table 22-1.
Part Two. Medical Treatment
Patency (%) After Endarterectomy 1 year
Aorto-lliac[138] CFA[139] SFA[140] CCAa
2 years 94
95 78
73 89– 93[141]
3 years 5 years 7 years 90 85 70
90 82 35 – 71 79[10]
CFA, common femoral artery; SFA, superficial femoral artery; CCA, common carotid artery. a For carotid artery, data represent patients with ,50% stenosis.
Recurrent restenosis to greater than 50% of luminal diameter develops in 16 –22% of patients.[10] It generally develops within the first year and becomes stable thereafter; about 10% of lesions will eventually regress.[10] These lesions are quite different from the atherosclerotic lesions seen in primary operations. The neointima is smooth, white, and rarely ulcerates. In addition, they do not frequently produce symptoms, with only 3–4% of patients suffering recurrent transient ischemic events or strokes.[10] Recurrent atherosclerotic stenosis usually takes many years to develop, making control of atherosclerosis risk factors critically important. The etiology of neointimal hyperplasia after endarterectomy is similar to that seen in other forms of arterial injury. Smooth-muscle cells become activated, proliferate, and produce extracellular matrix. The basic mechanisms have not been as clearly defined as in the angioplasty model, but strong parallels are evident. The endothelium is removed by the procedure, and the loss of the endothelial inhibition on Table 22-2.
SMCs likely contributes to the process. The endarterectomized artery is quite thrombogenic, and the exposed media provides a rich scaffold for platelet adhesion and activation. Growth factors are also important in the development of the neointima. Infusing bFGF locally to endarterectomized carotid arteries in a canine model has been shown to increase the degree of neointimal thickening by 72% and increase the SMC proliferation rate by 73%.[98] The inflammatory response likely also plays a role. Administration of an antibody to block very late antigen-4 (VLA-4), which is important to monocyte adhesion and migration, has been shown to reduce neointimal hyperplasia in a primate carotid endarterectomy model.[99] Mechanical stresses have also been implicated in the development of neointimal hyperplasia. Patients who were found to have residual flow disturbances by duplex scanning after carotid endarterectomy were found to have a 22% incidence restenosis compared to 9% in patients without residual flow defects.[100]
PREVENTIVE STRATEGIES Numerous attempts have been made to use the results of animal experiments to help reduce restenosis in humans. Unfortunately, these trials have been largely unsuccessful. Most of the studies have attempted to limit restenosis by controlling thrombosis, SMC proliferation, inflammatory reactions, and lipid regulation in the setting of Percutaneous Transluminal Coronary Angioplasty (PTCA). Table 22-2 lists the results of trials that have attempted to reduce restenosis pharmacologically. Selected examples are discussed in detail.
Prospective Agents to Inhibit the Formation of Neointimal Hyperplasia Animal models
Class Platelet inhibitors Anticoagulants
PGDF receptor antagonist Thromboxane A2 antagonist Calcium channel blocker ACE inhibitora
HMA CoA reductase inhibitor Corticosteroid
Drug Aspirin Dipyridamole LMWH Heparin Hirudin Warfarin Trapidil Vapiprost Diltiazem Nifedipine Cilazapril Enalapril Lovastatin Dexamethasone Predinisolone
Species
Artery
Injury
Result
Rat[142] Rabbit[144] Rabbit[127] Rat[33] Pig[146] Rabbit (HL)[147] Rabbit[149] Rat[151] Rat[153] Rabbit[155] Rat[157] Rat[159] Primate[55] Rabbit[52] Pig[160] Rabbit (NL)[114] Pig[161] Rabbit[163]
Carotid Ear Illiac Carotid Coronary Femoral Carotid Aorta Aorta Carotid Aorta Carotid Carotid Carotid Coronary Carotid Carotid Ear
Balloon denudation Crush Balloon angioplasty Balloon angioplasty Angioplasty/stent Balloon angioplasty Air desiccation Balloon angioplasty Balloon denudation Collar Balloon denudation Balloon denudation Endarterectomy Balloon denudation Angioplasty/stent Collar Angioplasty/stent Crush
# # # # N/E # # # # # # # N/E # # # N/E #
N/E = no effect; +/ 2 = limited effect; # = decreased restenosis; NL = normolipidemic; HL = hyperlipidemic. a Despite the efficacy of ACE inhibitors in lower animals, no effect was seen in the primate model. Source: De Meyer.[164]
Human PTCA restenosis N/E[143] N/E[145] N/E[107,109] N/E[105] +/ 2 [148] N/E[150] # [152] N/E[154] N/E[156] N/E[158] N/E[3,110]
N/E[116] N/E[162]
Chapter 22. The Biology of Restenosis and Neointimal Hyperplasia
Heparin Heparin has long been known to reduce the amount of neointimal hyperplasia in animals.[101] Thrombosis is an important event in the development of restenosis in humans and in larger animal models, but not in the rat model. Heparin is a potent anticoagulant, but its ability to reduce neointimal hyperplasia is not due entirely to its anticoagulant properties. Heparin reduces the intensity of the first phase of SMC activation, i.e., proliferation and the start of SMC migration to the intima. If heparin therapy is initiated more than 4 days after the experimental injury, there is no effect on neointimal hyperplasia. The inhibition of SMC activation is due, at least partly, to the ability of heparin to bind a range of growth factors, collectively called the heparin-binding growth factors. The most important of these growth factors is bFGF, which has already been shown to be a key regulator of early SMC activation. This ability of heparin to bind certain growth factors is not related to its antithrombotic effects. In fact, several heparin analogs have been developed which also bind growth factors avidly,[102] yet have no antithrombotic effects. These compounds have also been shown to reduce neointimal hyperplasia.[103] Heparin also has been shown to prevent SMC activation by other pathways, such as inhibition of mitogen-activated protein kinase (MAPK) activation,[104] which is important in the cell response to thrombin and angiotensin II stimulation. The usefulness of heparin in reducing restenosis in humans is unproven.[105] The anticoagulant effects of heparin limit the dosage and duration of therapy that can be used in human trials; bleeding is a significant concern. The doses of heparin and length of therapy that successfully reduce neointimal hyperplasia in animal models are generally not safe to use in humans. Low molecular weight heparin (LMWH) has also been used to try to prevent neointimal hyperplasia. Because of easier dosing and administration and a lower risk of severe bleeding complications compared to unfractionated heparin, LMWH would be a better choice in human trials. Indeed, studies have shown a reduction in neointimal hyperplasia in rabbits treated with LMWH.[106] Unfortunately, human trials have not been able to match these results, even when therapy is started before treatment and continued for several weeks afterwards.[107 – 109]
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degradation by ACE inhibitors may contribute to the effect on neointimal hyperplasia.[112] Differences between human and rodent metabolism of bradykinin may contribute to the different outcomes of ACE inhibitor treatment.
Lipid-Lowering Agents Lipids play a central role in atherogenesis and are important in the development of restenosis after angioplasty. Patients who have low high-density lipoprotein (HDL) levels have been shown to have a higher risk for restenosis.[113] Lovastatin, an HMG–CoA reductase inhibitor, has been shown to reduce neointimal hyperplasia in both normocholesterolemic[114] and hypercholesterolemic[115] rabbit arterial injury models. In humans, however, the results have been less than impressive in trials with lovastatin,[116] fluvastatin,[117] and pravastatin.[118]
Photodynamic Therapy Photodynamic therapy (PDT) has been used for many years in experimental cancer therapy. It involves the administration of a non-toxic photosensitizing dye, which is taken up preferentially by proliferating cells. The area of interest is then exposed to a specific wavelength and intensity of laser light, which causes the dye to produce highly reactive oxygen radicals. These radicals denature cellular proteins and lipids, resulting in cell death. The preferential uptake of the photosensitizers by proliferating cells spurred interest in its ability to prevent neointimal hyperplasia. It has been shown that intimal hyperplastic tissue accumulates photosensitizing dye more avidly than normal arterial tissue and retains it longer.[119] Consequently, PDT has been shown to prevent neointimal hyperplasia in rat[120] and rabbit[121] models of arterial injury. Histologically, the treated artery is found to contain an acellular media with little signs of inflammation. The endothelium was shown to regenerate by 4 weeks in the rat model, but the media remained barren.[122] The long-term implications of this phenotype are unclear. A great deal of research still needs to be done before PDT can be applied to human restenosis, but experience from clinical trials for cancer therapy and the development of endovascular lasers will encourage these efforts.
ACE Inhibitors The success of ACE inhibitors in the prevention of neointimal hyperplasia in animal models spurred the organization of several large clinical trials of human restenosis. Unfortunately, the human trials testing the effects of ACE inhibitors on post-PTCA restenosis have been disappointing.[3,110] Several explanations for the inability of ACE inhibitors to prevent restenosis have been postulated. One difference is that the doses used to treat experimental animals greatly exceed the doses used to treat hypertension in humans. In addition, several other vasoactive peptides are inactivated by the angiotensin-converting enzyme, including bradykinin and the enkephalins.[111] Bradykinin is a potent vasodilator and stimulator of constitutive NOS. The prevention of bradykinin
Radiation Radiation therapy plays a central role in oncology because of its ability to kill proliferating cells. Due to the importance of cellular proliferation in the development of neointimal hyperplasia, investigators have been studying the ability of locally delivered radiation to prevent restenosis. Several animal models have been used to study the effects of radiation on neointimal hyperplasia. In a porcine balloon injury model, the use of intravascular beta irradiation (14 – 56 Gy) was shown to inhibit neointimal thickening in a dosedependent manner.[123] Similarly, in a rat carotid injury model of intravascular 192Ir radiation, doses as low as 5 Gy were found to significantly inhibit neointimal hyperplasia.[124]
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Part Two. Medical Treatment
Due to the success in animal models, several clinical trials have been organized to see if radiation therapy can reduce neointimal hyperplasia in humans. The Scripps Coronary Radiation to Inhibit Proliferation Post Stenting (SCRIPPS)[125] trial used a gamma-emitting 192Ir ribbon compared to placebo in 55 patients undergoing angioplasty and stenting. At 6 months, the mean stenosis in the radiated group was 17% compared to 37% in controls. Additionally, only 11.5% of patients in the treated group required revascularization of the target lesion by 12 months, compared to 44.8% of patients in the control group. A 2-year follow-up of these patients showed that the reduced need for revascularization of the target lesion remained reduced in the radiated group (15.4%) compared to controls (44.8%).[126] The results of radiation therapy for prevention of restenosis are promising, but the long-term consequences of this technique are still to be determined. Arteries exposed to radiation for the treatment of cancer are found to undergo several pathologic changes, including aneurysm formation, occlusion, intimal and medial fibrosis, stenosis, occlusion of the vasa vasora, plaque formation, and periarterial fibrosis causing extrinsic arterial constriction. These changes can take many years to become clinically apparent.
Drug Delivery Methods In addition to oral and intravenous routes of administration of drugs for the prevention of neointimal hyperplasia, multiple catheter-based mechanisms have been devised to allow for the delivery of the test drug directly to the treated segment of artery. For example, the Dispatch[127] catheter has a central flow channel to keep the artery patent while specially designed drug compartments allow for passive diffusion of drugs to arterial wall. Iontophoresis, the movement of selectively charged drugs across a membrane by the application of an electric field, has also been used to deliver drugs via catheter.[128] Several methods have been developed for the long-term time-release delivery of substances to the arterial wall. Biodegradable microspheres containing the drug of interest have been injected into the arterial walls of rabbits.[129] Coated stents have also been used as a method of drug delivery.[130] Recently, bioresorbable microporous polymer stents have used to deliver adenoviral vectors to the vessel wall in rabbits.[131] The local sustained-release delivery of DNA plasmids has also been demonstrated using polymer matrices.[132] These new delivery technologies will play increasingly important roles in clinical trials of human restenosis. The
ability to achieve a high local concentration of a drug or biologic agent while limiting the systemic effects is crucial for the success of many emerging therapies, including future applications of gene therapy.
FUTURE DIRECTIONS We have learned much about the biology of the vessel wall and restenosis, but we are currently unable to reliably prevent clinical restenosis in humans. With continuing advances in molecular biology and gene therapy, however, several new tools are being applied in this endeavor. Adenoviral vectors have been used to transfer many different potentially beneficial genes to arterial walls. Many of these experiments have been successful in reducing neointimal hyperplasia in animal models. Examples include the transfer of nitric oxide synthase[44,45] and wild-type p53 gene.[133] Several new genes and delivery vectors are tested in experiments each year, but no large-scale human trials have been carried out. The use of antisense technology has also been successfully used to modulate the arterial response to injury. Although the mechanism of action of antisense oligonucleotides is not completely understood, they have been shown to inhibit the translation of targeted mRNA. Several cell cycle –related proteins have been targeted, such as c-myc,[31] as well as growth factors important in the injury response, including bFGF.[134,135] These methods have been successful in reducing neointimal hyperplasia in animal models. The transcription factor E2F plays an important role in the coordination of cell cycle activation and thus cellular proliferation. Adenovirally delivered double-stranded DNA with a high affinity for E2F has been used as a “decoy” and has successfully blocked cell cycle activation and reduced neointimal hyperplasia in rat models.[136] A similar technique, using liposomes instead of viruses to deliver the E2F decoy DNA, is currently being used to treat vein grafts in humans in an attempt to prevent stenosis and graft failure.[137] These new techniques not only provide potential treatments for neointimal hyperplasia, they also provide important insights into the genetic and molecular control of this complex pathologic process. Due to the multifaceted nature of the arterial response to injury, it is likely that successful control of neointimal hyperplasia will require a combination of several strategies, possibly with each working on a different pathway.
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stenosis After Percutaneous Transluminal Coronary Angioplasty. The EMPAR Study. Circulation 1996, 94, 1553– 1560. Karsch, K.R.; Preisack, M.B.; Baildon, R.; et al. Low Molecular Weight Heparin (Reviparin) in Percutaneous Transluminal Coronary Angioplasty. Results of a Randomized, Double-Blind, Unfractionated Heparin and Placebo-Controlled, Multicenter Trial (REDUCE Trial). Reduction of Restenosis After PTCA, Early Administration of Reviparin in a Double-Blind Unfractionated Heparin and Placebo-Controlled Evaluation. J. Am. Coll. Cardiol. 1996, 28, 1437– 1443. Faxon, D.P. Effect of High Dose Angiotensin-Converting Enzyme Inhibition on Restenosis: Final Results of the MARCATOR Study, a Multicenter, Double-Blind, Placebo-Controlled Trial of Cilazapril. The Multicenter American Research Trial With Cilazapril After Angioplasty to Prevent Transluminal Coronary Obstruction and Restenosis (MARCATOR) Study Group. J. Am. Coll. Cardiol. 1995, 25, 362– 369. Campbell, D.J. Circulating and Tissue Angiotensin Systems. J. Clin. Investig. 1987, 79, 1 – 6. Farhy, R.D.; Carretero, O.A.; Ho, K.L.; Scicli, A.G. Role of Kinins and Nitric Oxide in the Effects of Angiotensin Converting Enzyme Inhibitors on Neointima Formation. Circ. Res. 1993, 72, 1202– 1210. Shah, P.K.; Amin, J. Low High Density Lipoprotein Level Is Associated with Increased Restenosis Rate After Coronary Angioplasty. Circulation 1992, 85, 1279– 1285. Soma, M.R.; Donetti, E.; Parolini, C.; et al. HMG CoA Reductase Inhibitors. In Vivo Effects on Carotid Intimal Thickening in Normocholesterolemic Rabbits. Arterioscler. Thromb. 1993, 13, 571– 578. Gellman, J.; Ezekowitz, M.D.; Sarembock, J.J.; et al. Effect of Lovastatin on Intimal Hyperplasia After Balloon Angioplasty: A Study in Atherosclerotic Hypercholesterolemic Rabbits. J. Am. Coll. Cardiol. 1991, 17, 251– 259. Weintraub, W.S.; Bocuzzi, S.J.; Klein, J.L.; et al. Lack of Effect of Lovastatin on Restenosis After Coronary Angioplasty. N. Engl. J. Med. 1994, 331, 1331– 1337. Serruys, P.W.; Foley, D.P.; Jackson, G.; et al. A Randomized Placebo-Controlled Trial of Fluvastatin for Prevention of Restenosis After Successful Coronary Balloon Angioplasty; Final Results of the Fluvastatin Angiographic Restenosis (FLARE) Trial. Eur. Heart J. 1999, 20, 58– 69. Bertrand, M.E.; McFadden, E.P.; Fruchart, J.C.; et al. Effect of Pravastatin on Angiographic Restenosis After Coronary Balloon Angioplasty. The PREDICT Trial Investigators. Prevention of Restenosis by Elisor After Transluminal Coronary Angioplasty. J. Am. Coll. Cardiol. 1997, 30, 863– 869. LaMuraglia, G.M.; Ortu, P.; Flotte, T.J.; et al. Chloroaluminum Sulfonated Phthalocyanine Partitioning in Normal and Intimal Hyperplastic Artery in the Rat. Implications for Photodynamic Therapy. Am. J. Pathol. 1993, 142, 1898– 1905. Ortu, P.; LaMuraglia, G.M.; Roberts, W.G.; Flotte, T.J.; Hasan, T. Photodynamic Therapy of Arteries. A Novel Approach for Treatment of Experimental Intimal Hyperplasia. Circulation 1992, 85, 1189– 1196.
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Eton, D.; Colburn, M.D.; Shim, V.; et al. Inhibition of Intimal Hyperplasia by Photodynamic Therapy Using Photofrin. J. Surg. Res. 1992, 53, 558– 562. LaMuraglia, G.M.; ChandraSekar, N.R.; Flotte, T.J.; Abbott, W.M.; Michaud, N.; Hasan, T. Photodynamic Therapy Inhibition of Experimental Intimal Hyperplasia: Acute and Chronic Effects. J. Vasc. Surg. 1994, 19, 321– 329. Waksman, R.; Robinson, K.A.; Crocker, I.R.; et al. Intracoronary Low-Dose Beta-Irradiation Inhibits Neointima Formation After Coronary Artery Balloon Injury in the Swine Restenosis Model. Circulation 1995, 92, 3025– 30311. Sarac, T.P.; Riggs, P.N.; Williams, J.P.; et al. The Effects of Low-Dose Radiation on Neointimal Hyperplasia. J. Vasc. Surg. 1995, 22, 17– 24. Teirstein, P.S.; Massullo, V.; Jani, S.; et al. CatheterBased Radiotherapy to Inhibit Restenosis After Coronary Stenting. N. Engl. J. Med. 1997, 336, 1697– 1703. Teirstein, P.S.; Massullo, V.; Jani, S.; et al. Two-Year Follow-Up After Catheter-Based Radiotherapy to Inhibit Coronary Restenosis. Circulation 1999, 99, 243– 247. Baumbach, A.; Oberhoff, M.; Bohnet, A.; et al. Efficacy of Low-Molecular-Weight Heparin Delivery with the Dispatch Catheter Following Balloon Angioplasty in the Rabbit Iliac Artery. Catheter. Cardiovasc. Diagn. 1997, 41, 303– 307. Mitchel, J.F.; Azrin, M.A.; Fram, D.B.; Bow, L.M.; McKay, R.G. Localized Delivery of Heparin to Angioplasty Sites with Iontophoresis. Catheter. Cardiovasc. Diagn. 1997, 41, 315– 323. Valero, F.; Hamon, M.; Fournier, C.; et al. Intramural Injection of Biodegradable Microspheres as a Local DrugDelivery System to Inhibit Neointimal Thickening in a Rabbit Model of Balloon Angioplasty. J. Cardiovasc. Pharmacol. 1998, 31, 513– 519. Lincoff, A.M.; Furst, J.G.; Ellis, S.G.; Tuch, R.J.; Topol, E.J. Sustained Local Delivery of Dexamethasone by a Novel Intravascular Eluting Stent to Prevent Restenosis in the Porcine Coronary Injury Model. J. Am. Coll. Cardiol. 1997, 29, 808– 816. Ye, Y.W.; Landau, C.; Willard, J.E.; et al. Bioresorbable Microporous Stents Deliver Recombinant Adenovirus Gene Transfer Vectors to the Arterial Wall. Ann. Biomed. Eng. 1998, 26, 398– 408. Shea, L.D.; Smiley, E.; Bonadio, J.; Mooney, D.J. DNA Delivery from Polymer Matrices for Tissue Engineering. Nat. Biotechnol. 1999, 17, 551– 554. Yonemitsu, Y.; Kaneda, Y.; Tanaka, S.; et al. Transfer of Wild-Type p53 Gene Effectively Inhibits Vascular Smooth Muscle Cell Proliferation In Vitro and In Vivo. Circ. Res. 1998, 82, 147– 156. Hanna, A.K.; Fox, J.C.; Neschis, D.G.; Safford, S.D.; Swain, J.L.; Golden, M.A. Antisense Basic Fibroblast Growth Factor Gene Transfer Reduces Neointimal Thickening After Arterial Injury. J. Vasc. Surg. 1997, 25, 320– 325. Neschis, D.G.; Safford, S.D.; Hanna, A.K.; Fox, J.C.; Golden, M.A. Antisense Basic Fibroblast Growth Factor Gene Transfer Reduces Early Intimal Thickening in a
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Rabbit Femoral Artery Balloon Injury Model. J. Vasc. Surg. 1998, 27, 126– 134. Morishita, R.; Gibbons, G.H.; Horiuchi, M.; et al. A Gene Therapy Strategy Using a Transcription Factor Decoy of the E2F Binding Site Inhibits Smooth Muscle Proliferation In Vivo. Proc. Natl Acad. Sci. USA 1995, 92, 5855– 5859. Mann, M.J. E2F Decoy Oligonucleotide for Genetic Engineering of Vascular Bypass Grafts. Antisense Nucleic Acid Drug Dev. 1998, 8, 171– 176. Pretre, R.; Katchatourian, G.; Bednarkiewicz, M.; Faidutti, B. Aortoiliac Endarterectomy: A 9-Year Experience. Thorac. Cardiovasc. Surg. 1992, 40, 152– 154. Hoch, J.R.; Turnipseed, W.D.; Archer, C.W. Evaluation of Common Femoral Endarterectomy for the Management of Focal Atherosclerotic Disease. Vasc. Surg. 1999, 33, 461– 470. van der Heijden, F.H.; Eikelboom, B.C.; Banga, J.D.; Mali, W.P. Management of Superficial Femoral Artery Occlusive Disease. Br. J. Surg. 1993, 80, 959– 963. Moore, W.S.; Kempczinski, R.F.; Nelson, J.J.; Toole, J.F. Recurrent Carotid Stenosis: Results of the Asymptomatic Carotid Atherosclerosis Study. Stroke 1998, 29, 2018– 2025. Volker, W.; Faber, V. Aspirin Reduces the Growth of Medial and Neointimal Thickenings in Balloon-Injured Rat Carotid Arteries. Stroke 1990, 21 (Suppl V), IV4– IV-45. Thornton, M.; Gruentzig, A.R.; Hollman, J.; King, S.I.; Douglas, J.S. Coumadin and Aspirin in Prevention of Recurrence After Transluminal Coronary Angioplasty: A Randomized Study. Circulation 1984, 69, 721– 727. Ingerman-Wojenski, C.M.; Silver, M.J. Model System to Study Interaction of Platelets with Damaged Arterial Wall. II. Inhibition of Smooth Muscle Cell Proliferation by Dipyridamole and AH-P719. Exp. Mol. Pathol. 1988, 48, 116– 134. Schwartz, L.; Bourassa, M.G.; Lesperance, J.; et al. Aspirin and Dipyridamole in the Prevention of Restenosis After Percutaneous Transluminal Coronary Angioplasty. N. Engl. J. Med. 1988, 318, 1714– 1719. Kornowski, R.; Hong, M.K.; Tio, F.O.; Choi, S.K.; Bramwell, O.; Leon, M.B. A Randomized Animal Study Evaluating the Efficacies of Locally Delivered Heparin and Urokinase for Reducing In-Stent Restenosis. Coron. Artery Dis. 1997, 8, 293– 298. Sarembock, I.J.; Gertz, S.D.; Gimple, L.W.; Owen, R.M.; Powers, E.R.; Roberts, W.C. Effectiveness of Recombinant Desulphatohirudin in Reducing Restenosis After Balloon Angioplasty of Atherosclerotic Femoral Arteries in Rabbits. Circulation 1991, 84, 232 –243. Mitchell, J.R.A. Clinical Aspects of the ArachidonicThromboxane Pathway. Br. Med. Bull. 1983, 39, 289– 295. August, D.; Tilson, M.D. Modification of Myointimal Response to Arterial Injury: Effects of Aspirin and Warfarin. Surg. Forum 1980, 31, 337– 338. Urban, P.; Buller, N.; Fox, K.; Shapiro, L.; Bayliss, J.; Rickards, A. Lack of Effect of Warfarin on the Restenosis
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158. Whitworth, H.B.; Roubin, G.S.; Hollman, J.; et al. Effect of Nifedipine on Recurrent Stenosis After Percutaneous Transluminal Coronary Angioplasty. J. Am. Coll. Cardiol. 1986, 8, 1271– 1276. 159. Powell, J.S.; Clozel, J.P.; Mu¨ller, R.K.M.; et al. Inhibitors of Angiotensin-Converting Enzyme Prevent Myointimal Proliferation After Vascular Injury. Science 1989, 245, 186– 188. 160. Veinot, J.P.; Edwards, W.D.; Camrud, A.R.; Jorgenson, M.A.; Holmes, D.R., Jr.; Schwartz, R.S. The Effects of Lovastatin on Neointimal Hyperplasia Following Injury in a Porcine Coronary Artery Model. Can. J. Cardiol. 1996, 12, 65– 70. 161. Muller, D.W.; Golomb, G.; Gordon, D.; Levy, R.J. SiteSpecific Dexamethasone Delivery for the Prevention of Neointimal Thickening After Vascular Stent Implantation. Coron. Artery Dis. 1994, 5, 435– 442. 162. Stone, G.W.; Rutherford, B.D.; McConahay, D.R.; et al. A Randomized Trial of Corticosteroids for the Prevention of Restenosis in 102 Patients Undergoing Repeat Coronary Angioplasty. Catheter. Cardiovasc. Diagn. 1989, 18, 227– 231. 163. Voss, R.; Mueller, I.R.; Matthias, F.R. Effect of Monocytopenia on Trauma-Induced Atherosclerotic Lesions in the Rabbit Ear Artery. Exp. Mol. Pathol. 1988, 49, 75– 86. 164. De Meyer, G.R.; Bult, H. Mechanisms of Neointima Formation—Lessons from Experimental Models. Vasc. Med. 1997, 2, 179–189.
CHAPTER 23
Basic Nomenclature Edward B. Diethrich peripheral interventions is distinctly different, and recommendations regarding minimal requirements for credentialing in percutaneous endovascular therapy vary from organization to organization. There are currently no formal requirements for training in endovascular surgery as part of the standard one-year instruction in general vascular surgery. According to the Accreditation Council for Graduate Medical Education, “residents [should] have an acquaintance with the methods and techniques of angiography,” while guidelines for radiologists require a minimum of a year’s training and 500 cases that include arteriography, venography, angioplasty, related percutaneous vascularization procedures, and placement of stents and filters. Despite considerable interest in training for peripheral endovascular intervention in the United States and abroad, there are relatively few opportunities available. The majority of the approved vascular surgery fellowship programs in the United States provide very limited exposure to endovascular techniques and tend to emphasize the classic vascular procedures instead. Surgeons may participate in endovascular fellowships to become thoroughly proficient in endovascular surgery techniques, and intensive training is also available through clinical “hands-on” courses or through association with a professional endovascular specialist in a private or teaching hospital setting. Approximately 90% of transluminal peripheral vascular interventions are performed percutaneously, and interventionists should be familiar with a variety of access approaches. Decisions about access should be based on the patient, target lesion, and intended procedure—there is no realistic justification for inadequate percutaneous access skills. A surgical approach is an important alternative in some situations (e.g., cutdown for direct vessel needle puncture or combined endoluminal/reconstructive procedures). All interventionists should develop proficiency in wire manipulation and fluoroscopically guided intraluminal navigation. Coordination of fluoroscopic imaging and hand guidance has become an important component of endoscopic training and should provide the vascular trainee with an added advantage when performing endoluminal procedures. Prior experience with catheter techniques in an angiography suite or cath lab is very helpful for the aspiring endovascular surgeon. A competent radiological technologist who possesses adequate knowledge of the procedure maximizes the
INTRODUCTION Endovascular surgery is relatively new, but the techniques it encompasses have already made a substantial impact on the treatment of vascular disease. The profusion of new devices available for percutaneous intervention is staggering, and specialized training is a necessity for those clinicians interested in performing these procedures. Advancements in endovascular device design have yielded low-profile catheters, hydrophilic catheter coatings, and significant improvements in catheter flexibility and in balloon materials. The introduction of stents has taken percutaneous intervention to a whole new level of efficacy; these devices demonstrate an ability to restore patency and flow in occluded vessels and limit restenosis. Both the Palmaz stent (Cordis, Warren, NJ), and the Schneider Wallstent (Schneider, Minneapolis, MN) have FDA approval for the iliac arterial location. When applied in the larger-sized vessels with diameters of .6 mm, the results of stenting in these locations have been excellent.[1 – 4] Successful use of these new endovascular techniques relies on adequate imaging capability. Knowledge of sophisticated imaging techniques, such as angioscopy and intravascular ultrasound (IVUS), and experience with radiologic and monitoring equipment are extremely important in achieving optimal results during complex endovascular procedures. The future of endovascular intervention is very bright, and the introduction of new technologies, such as endoluminal grafts (ELGs), is certain to ensure additional success in endovascular intervention. In this chapter, a basic introduction to clinical training requirements, vascular access, equipment, and imaging techniques is provided. A discussion of the future of endovascular intervention is also presented.
ENDOVASCULAR SURGICAL TRAINING Adequate training in the field of endovascular intervention is vital to a successful practice, and a certain degree of technical proficiency is required to obtain hospital privileges. The training of a vascular surgeon, an interventional radiologist, and a cardiologist performing
Hobson/Wilson/Veith: Vascular Surgery: Principles and Practice, Third Edition, Revised and Expanded DOI: 10.1081/0819-9-120024906 Copyright q 2004 by Marcel Dekker, Inc.
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ACCESS There are a number of different access approaches; some techniques are used periprocedurally as well as preprocedurally (Fig. 23-1). In general, the closer the puncture site is to the area of therapy, the easier it is to maneuver and access the area of interest. The retrograde femoral approach is the most familiar to many interventionists and can be used for visualization of any portion of the arterial tree. The antegrade femoral route limits the operator to lower extremity visualization. Retrograde brachial, like the retrograde femoral, may also be used for visualization of any portion of the arterial tree. The transaortic approach is useful for contralateral techniques—especially when there is occlusive disease in the lower iliac and femoral regions (Fig. 23-2).
Anesthesia Most endovascular procedures do not require the use of a general anesthetic. At the Arizona Heart Institute and Arizona Heart Hospital, we prefer a local anesthesia with mild sedation for percutaneous retrograde femoral interventions. It is possible to use agents that allow the patient to be completely comfortable and conversant during the procedure so that immediate assessment of any neurologic change may be made.[5] This is particularly important when aortic arch and carotid lesions are being treated during the endovascular procedure. In the rare case in which a neurologic deficit arises from ischemia caused by balloon inflation, rapid deflation quickly reverses the symptoms. Balloon inflation at the carotid bifurcation more commonly yields baroreceptor stimulation, causing bradycardia. Cardiac standstill may result, and momentary sternal compression may be required. One milligram of atropine sulfate administered 60 seconds before balloon expansion usually prevents this complication but does not guarantee against it. Thus, careful attention should be paid to the EKG monitor during ballooning.
Figure 23-1. Diagram illustrating the various access sites for arterial visualization and intervention. The site selected depends on several factors, including the device the operator intends to use. (A) The retrograde brachial, (B) the retrograde femoral, and (C) the antegrade femoral are the most commonly used approaches and are sometimes used simultaneously.
endovascular surgeon’s potential for success; the importance of optimal image acquisition in endovascular procedures cannot be underestimated.
Figure 23-2. The transaortic approach is often used when there is occlusive disease in the iliac and femoral regions. When the iliac artery is occluded, this approach may be used to instill thrombolytics such as urokinase.
Chapter 23. Basic Nomenclature
In the carotid region, direct or open access techniques may be required, and the positioning of the patient and need for immobilization during the procedure may dictate a preference for general anesthesia. Short-acting, rapidly reversible drugs should be used so that the patient may be awake and extubated in the endovascular suite immediately following the procedure.[5] Although cervical block and local anesthesia have been used successfully in carotid interventions,[6,7] immobilizing the head and neck during the procedure is difficult, particularly if the patient is not intubated and the anesthesiologist must support a mask over the patient’s face. For most noncervical procedures, a local anesthesia is very effective; the exception is in cases where an entirely motionless field is essential for exact deployment of a stent or an ELG. Heavy sedation requiring respiratory assistance may be required in these settings.
EQUIPMENT The rapid advancement in angioplasty and stenting techniques has placed a demand on equipment manufacturers to supply sheaths, catheters, wires, balloons, and stents in a greater variety of dimensions and to incorporate design features that address specific pathologies.
Sheaths Sheaths come in a number of lengths and diameters with assorted sideports for infusion. The “profile” of the equipment continues to be reduced, and it is now possible to perform most standard angioplasty procedures through 6F and 7F sheaths. Some sheaths (e.g., Super Flex Introducer, Arrow International, Reading, PA) are particularly useful in obese patients and those with heavy scarring from previous interventions. For angioplasty techniques using the brachial approach (aortic arch vessel origins and aorta), a 7F sheath is generally used. Long sheaths, such as the 7.5F and 8F, 70 cm made by Daig Corporation (Minnetonka, MN) are also useful. In some situations, using a sheath to cross the lesion where a stent is to be deployed is effective in preventing any movement of the device. This is certainly more important when balloon-expandable devices such as the Palmaz stent are being used; self-expanding stents such as the Wallstent and Symphony stent (Boston Scientific/Meadox, Watertown, MA) are deployed without mounting on the sheath. When the retrograde or antegrade femoral approaches are used for the deployment of an ELG in the superficial femoral artery or the iliac vessels, we have typically used a 7–9F, 30–45 cm Cordis sheath. The radiopaque tip marker is particularly helpful in defining the tip of the catheter, which may be placed precisely at the desired location of stent or ELG deployment and then retracted. A similar technique can be employed for stent deployment in the renal artery. A Cobra (Fig. 23-3) or similar catheter can be guided across the renal lesion, the stent positioned, and the sheath withdrawn; this technique is extremely safe and may
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be an ideal method for use by the relatively inexperienced interventionist. We have found the Flexor sheath (Cook, Bloomington, IN) (Fig. 23-4) to be advantageous when it is necessary to perform a high-volume contrast injection in an over-the-wire configuration. The nonkinking sheath of this catheter has a 0.073 in. internal diameter that permits ample space for fluid injection even when a 0.035 in. wire is used. Devices like this allow efficacy and safety in complex endovascular procedures such as angioplasty and stenting of the carotid or in ELG exclusion of aneurysmal disease.
Guidewires Hydrophilic-coated guidewires (Glidewire, Boston Scientific/Meditech) (Fig. 23-5) have greatly increased the ease and safety of lesion traversal, and high-resolution fluoroscopic equipment ensures more accurate positioning of all wires. Steerable guidewires add another measure of control and cost, but in our experience, the nitinol alloy core of the Glidewire resists bending and kinking, making it functionally identical to the steerable wires in all but the most circuitous vessels. At times, the lubricity of a wire may not be as important as its relative rigidity. The Glidewire is available in an extra stiff version, but when an artery has to be “straightened out” in order to deliver a stent or an ELG, the Amplatz Superstiff wire (Cook) is probably the one most commonly used. It comes in both flexible and “J”-tip versions and offers the operator maximum leverage in working through difficult arterial lesions.
Balloons Advances in balloon technology have been considerable, and manufacturers have succeeded in lowering the profile of their products and improving performance capabilities with new materials. Indeed, a number of designs have successfully overcome the traumatic aspects of the traditional overflagged balloon design. For peripheral interventions, catheter lengths
Figure 23-3. Photograph of a Cobra angiographic catheter, which is particularly useful for renal angiograms and angioplasty with stent deployment.
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Figure 23-5. Hydrophilic-coated wires like the Glidewire (Meditech/Boston Scientific) have greatly increased the success rate of angioplasty in tortuous vessels and occlusive lesions.
Stents
Figure 23-4. (A) Photograph of the Flexor sheath (Cook), which is relatively kink resistant and constructed with a 0.073 in. internal diameter that permits high-volume injections for good opacification. The 0.073 in. size requires an internal adapter such as the Tuohy-Borst (Cook) to prevent excessive bleeding (B).
Stents represent an extremely important technological advance in endovascular surgery. The Palmaz stent and the Wallstent were the first two stents to be approved by the FDA for use in the iliac artery system. These devices were introduced to treat abnormal dilation characteristics (e.g., resistance, recoil and dilation failure, persistent filling defects, dissection, intimal flaps).[8,9] The results of stenting in the iliac region have been excellent and equally as good in the abdominal aorta.[10,11] Stenting has also been used successfully to treat lesions in the brachiocephalic arteries arising from the aortic arch.[12 – 16] Large series now document the use of stents in ostial renal artery stenosis for treatment of hypertension and preservation of renal function.[17,18] More recently, stenting technology has been applied to lesions in the extracranial carotid arteries.[19,20]
from 65 cm to 150 cm are commonly inventoried for a variety of balloon dimensions. Balloons of all diameters and shaft lengths are now being made by a number of different manufacturers. While there are some specific features noted among these products, the most important common characteristics are the lower profile shafts and better quality balloons, which help reduce both the incidence of breakage or leakage. As an example, when iliac artery stenting was initiated, the deployment of the Palmaz stent was performed through a 9F sheath long enough to cross the lesion. The technology has now advanced to the point that the same stent can be delivered and deployed in the iliac arterial system using a 6F sheath placed retrograde in the common femoral artery (Fig. 23-6). The major impact of these techniques is in reduction of access complications. The small puncture site lessens the potential for bleeding and hematoma formation and also diminishes patient discomfort.
Figure 23-6. sheaths.
Low profile systems permit stenting through 6F
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There are several models of stents now being used in the peripheral vessels from the carotids to the popliteals, and there are many more under study. All have certain advantages and varying degrees of radiopacity that make high-resolution fluoroscopy mandatory. The Palmaz balloon-expandable stent is a stainless steel tube designed with multiple rows of staggered rectangular slots that assume a diamond shape when expanded, reducing the amount of metal in contact with the luminal surface to just 10%. The Palmaz design is available in varying lengths from 10 to 39 mm with expansion ranges of 4–18 mm; newer models will permit expansion to even longer lengths (42– 78 mm) (Fig. 23-7). Despite their length, these stents are considerably more flexible than the standard Palmaz design (e.g., P308) because the components are connected with bridging members to permit some bending. This feature allows enough flexibility that the stent can be deployed in tortuous arteries but does not compromise the device’s radial strength. The Wallstent is a cylindrical device constructed by braiding multiple stainless steel monofilaments. Because of its spring-like structure, the Wallstent is flexible, compliant, and self-expanding, making it useful for delivery through curved arteries, implantation overlying the graft-artery junction in end-to-side anastomoses, and in vessels subject to flexion from adjacent joints or structures, such as in the common femoral and popliteal arteries. The Wallstent comes in a variety of lengths ranging from 50 to 150 mm and in diameters from 5 to 10 mm. Larger sizes have been approved for nonarterial applications but are available for “off-label” uses. A new generation of flexible stents has been introduced; these are very useful at sites of articulation, where flexion and extension of the artery is common. The Symphony stent (Fig. 23-8) and others like it may provide answers to the challenges faced near or across joint spaces. The Symphony stent permits transaortic deployment, a highly useful technique in settings of diffuse disease. The major disadvantage of this stent, however, is its low radiopacity.
IMAGING
Figure 23-7. Longer stents have become available for treatment of diffuse lesions. The medium-long Palmaz stent (Cordis) shown here is more flexible than the shorter versions but retains its radial strength.
Figure 23-8. New stent designs like the Symphony (Boston Scientific/Meadox) are particularly useful in situations where there is flexion and extension of the vessel. The Symphony resists deformity under these conditions.
Angiography Despite the development of many new imaging modalities to assess arterial pathologies, arteriography continues to be the gold standard. All arterial systems can be visualized using one of several access options; the choice of an access method depends on the particular location of the pathology being studied. There is a trend, however, away from the use of classic arteriography in favor of less invasive imaging techniques. Digital subtraction angiography (DSA) has become a favorite tool of radiologists and allows visualization of wide areas of the arterial tree using minimal amounts of contrast. The main problem with DSA is the appearance of artifacts, which are also present in magnetic resonance angiography (MRA) and may obscure accurate diagnosis. Choosing the appropriate contrast material, injection rate, and volume is extremely important in minimizing the risk associated with imaging. Types of contrast agents include high-osmolality ionic, low-osmolality ionic, and lowosmolality nonionic preparations. In general, the highosmolality preparations are more toxic and cause more pain during administration, but they are considerably less expensive than low-osmolality formulations. Low-osmolality ionic and nonionic preparations, such as Isovue, Omnipaque, Optiray, and Hexabrix, are associated with far fewer side effects than their high-osmolality counterparts. Injection rates and volumes should provide complete opacification of the vessel over the entire field of view and satisfactory density of the contrast/blood admixture to allow uniform opacity; the use of automated injectors should be considered. Reactions to contrast are relatively infrequent and generally occur within the first 5 minutes of administration; delayed reactions may be seen in a small number of patients. Most mild reactions may be treated by administering an antihistamine (e.g., diphenhydramine 25 –50 mg IV or IM) and reassuring the patient. When a reaction is more severe, 0.1–0.2 mL of a 1:1000 solution of epinephrine may be administered IV at 1- to 3-minute intervals until the reaction
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dissipates. Severe reactions may necessitate steroid administration or even cardiopulmonary resuscitation. Many centers have now eliminated any type of preoperative arteriographic studies for carotid artery bifurcation disease by substituting duplex scanning. The procedure of endarterectomy is carried out based on the findings of this single noninvasive study. Certainly, there is some controversy regarding this approach since both proximal arch vessel and intracranial pathology may be completely overlooked. At the opposite extreme, all protocols under study for deployment of ELGs in abdominal aortic, thoracic, and peripheral aneurysm exclusion demand high-resolution arteriography for preoperative evaluation. This has, indeed, proved to be extremely important in assessing visceral artery location, patency, and the size and condition of the iliac arteries (through which the relatively large device must pass). Computed tomography (CT) and now spiral CT are also used for preoperative evaluation of vessels in which ELGs will be used. These techniques are important in measuring the sites for ELG deployment and may help the interventionist minimize the potential for complications such as endoleaks, migration, and other procedural difficulties.
Angioscopy Complex percutaneous and open interventions often require imaging techniques that are complementary to angiography. Angioscopy provides direct visualization and is particularly useful in viewing the suture lines and lumens of grafts, evaluating hemorrhagic plaques, determining the flowinhibiting potential of flaps, assessing intimal hyperplasia in stents, and in estimating thrombosis volume and marking the progress of its removal. Angioscopic imaging is also valuable in assessing the etiology of restenosis after interventional therapy. Poststent dissection, bulging of tissue into the lumen at the stent articulation site, gaps between stents, and thrombus are easily visualized. Angioscopic data may motivate changes in therapy or guide the selection of treatment before and after stent deployment.[21 – 23] Angioscopic equipment is available from a variety of manufacturers. We use a 2.3F disposable angioscope (Baxter Healthcare Corp., Irvine, CA) connected to high-quality medical video color monitors with video recorders for hard copy documentation. Irrigating systems provide computerassisted pulsed irrigation and image storage for maximum visibility with minimal flush volume. On-demand delivery of heparinized saline under pressure at preset pulse durations via a foot pedal is extremely convenient. Both freeze-frame and real-time imaging are possible when flushing is synchronized with image capture for digitized output.
plasty (intraluminal cross sections and arterial circumferences) along with precise determination of arterial architecture and lesion pathology. In most cases, the IVUS examination following balloon dilation plays a significant role in both determining the need for stenting and in assessing adequate deployment of the devices. It is also invaluable in studying stents over the long term, allowing detection and definition of the extent of intimal hyperplasia (Fig. 23-9). IVUS has become a standard tool in the ELG program for exclusion of abdominal aortic aneurysms. Exact measurements can be acquired to facilitate selection of the proper device size, and IVUS also allows for assessment of the device after it has been deployed. Both have proven to be important uses of this imaging technique.
The Imaging “Workshop” Regardless of the multiple interventional tools and the imaging modalities available today, the end result of endovascular intervention depends heavily on the quality and flexibility of equipment in the operating suite at the time of the procedure. Unfortunately, many surgeons do not have the proper “workshop” and are forced to perform endovascular procedures using standard operating tables and mobile fluoroscopic equipment. Under some circumstances, satisfactory results can be obtained using these tools. As procedures become more complex, however, surgeons who do not have access to the most sophisticated imaging tools will be at a distinct disadvantage. Endoluminal grafting, which is proliferating at a rapid rate, is a prime example of the kind of procedure that demands advanced imaging capabilities. Over the last 25 years, clinicians at the Arizona Heart Institute have advocated the use of ceiling-mounted C-arm image intensifiers and carbon fiber operating tables that are completely free of metallic obstructions. Innovation in equipment and in suite design has been extremely important
Intravascular Ultrasound Other imaging techniques used in interventional procedures include duplex scanning and intravascular ultrasound. At the Arizona Heart Institute and Heart Hospital, we incorporate IVUS as an adjunct to angiography and angioscopy. IVUS provides baseline luminal dimensions pre- and postangio-
Figure 23-9. Intravascular ultrasound study showing intimal hyperplasia on a stent deployed 12 months earlier. This imaging modality is useful for periprocedural control images and for longterm surveillance.
Chapter 23. Basic Nomenclature
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Figure 23-10. Photograph of an ideal “workshop” that incorporates a completely sterile environment for sophisticated endovascular procedures. The new Arizona Heart Hospital has three endovascular suites like this to permit maximum efficiency and flexibility during complex procedures.
to us during the planning and construction of our new facility at the Arizona Heart Hospital. The fixed, ceiling-mounted fluoroscopy system [Institutional Surgical Systems (ISS), Phoenix, AZ] shown in Fig. 23-10 is ideal for the operating environment. Among the most important of its many advantages is that the unit allows the operator to pan a long area or distance quickly and without image distortion.
THE FUTURE OF ENDOVASCULAR TECHNOLOGY Although angioplasty has been used with some excellent results, long-term efficacy in small-diameter vessels has been elusive. Even catheter-based recanalization tools and
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endovascular stents have not provided the solutions we had hoped for in some anatomic locations. A number of investigators now believe one way to discourage cellular growth in the intima is to provide a new, artificial intraluminal surface that resists the proliferation of cells. This idea has prompted the development of ELGs and covered stents. Lining the diseased arterial wall with biomaterials that exclude contact with blood may protect the lumen from the cellular overgrowth that results in constriction and restenosis. In addition, placement of the device effectively eliminates the conventional anastomotic junction—a site of inherent flow disturbances. The incidence of graft thrombosis may also be decreased. The use of ELGs has proven valuable in the exclusion of abdominal aortic, thoracic, or peripheral aneurysms. Although the procedure was initially designed for use in patients with cardiac pathologies, pulmonary insufficiency, a hostile abdomen, or other conditions that heighten the risk of classical surgical intervention,[24] it is now used even in patients with small, asymptomatic aneurysms.[25] The beauty of the endoluminal procedure cannot be challenged; a minimal incision, limited potential for complications, short hospitalization and rapid recovery are obvious advantages. Improvements in device design and deployment techniques have brought us closer to routine success with this new procedure. Review of clinical results with the various devices indicates a reduction in endoleaks and distal embolization (the major disadvantages of the procedure) with second- and thirdgeneration devices. Still, it is clear that we have yet to achieve a perfect device, and we continue to see shifts in research efforts to clinical arenas outside the United States, where more lenient regulatory climates encourage a rapid and, perhaps, less costly development effort to bring the product to market. At present, it is impossible to draw any firm conclusions about whether or not the covered stent-graft or ELG may increase long-term patency as compared to the classic uncovered stent. However, if intimal hyperplasia on the stent
can be reduced by covering the stent on one or both sides with a fabric such as polytetrafluoroethylene,[26] some of the newer stent-grafts under development may have significant promise for increasing long-term patency. Questions remain about the potential for occlusion of collateral vessels with a covered stent and the ultimate effect on distal perfusion.
CONCLUSIONS The field of endovascular surgery is constantly changing as new techniques and devices are adopted. The introduction of stent technology has been a very important breakthrough in the treatment of coronary and peripheral lesions, and the use of modern endovascular and imaging equipment requires specialized training. Indeed, innovations in imaging techniques such as angioscopy and IVUS have helped to provide the interventionist with indispensable information about lesion morphology and appropriate stent placement. The future for surgeons to expand their roles in these new and exciting developments will depend to a great extent on whether or not they are able to establish proper “workshops” for endovascular procedures. ELG technology is proliferating at an unprecedented rate, and clinical trials are in progress at institutions throughout the world. A great deal of progress has been made in ELG design, and advancements in deployment technique have also been realized. ELG technology has already changed the indications for treatment in many centers, and we can anticipate numerous opportunities for additional investigation with this exciting treatment modality. It is certainly clear that successful endovascular procedures depend on knowing how to properly access the lesion, choosing the correct device for treatment, and using imaging and monitoring equipment to maximize device placement and ensure the patient’s well-being.
REFERENCES 1. No¨ldge, G.; Richter, G.M.; Ro¨ren, T.; et al. A Randomized Trial of Iliac Stenting Versus PTA in Iliac Artery Stenoses and Occlusions: Updated 6-Year Results. (Abstract). J. Endovasc. Surg. 1996, 3, 99– 100. 2. Murphy, K.D.; Encarnacion, C.E.; Le, V.A.; Palmaz, J.C. Iliac Artery Stent Placement with the Palmaz Stent: Follow-Up Study. J. Vasc. Intervent. Radiol. 1995, 6 (3), 321– 329. 3. Murphy, T.P.; Webb, M.S.; Lambiase, R.E.; et al. Percutaneous Revascularization of Complex Iliac Artery Stenoses and Occlusions with Use of Wallstents: ThreeYear Experience. Vasc. Intervent. Radiol. 1996, 7 (1), 21–27. 4. Vorwerk, D.; Guenther, R.W.; Schu¨rmann, K.; et al. Primary Stent Placement for Chronic Iliac Artery Occlusions: Follow-Up Results in 103 Patients. Radiology 1995, 194, 745– 749.
5. Kharrazi, M.R. Anesthesia for Carotid Stent Procedures. J. Endovasc. Surg. 1996, 3, 211– 216. 6. Bergeron, P.; Chamabran, P.; Benichou, H.; et al. Recurrent Carotid Disease: Will Stents Be an Alternative to Surgery? J. Endovasc. Surg. 1996, 3, 76–79. 7. Alessandri, C.; Bergeron, P. Local Anesthesia in Carotid Angioplasty. J. Endovasc. Surg. 1996, 3, 31– 34. 8. Palmaz, J.C.; Garcia, O.J.; Schatz, R.A.; et al. Placement of Balloon-Expandable Intraluminal Stents in Iliac Arteries: First 171 Procedures. Radiology 1990, 174, 969– 975. 9. Becker, G.J. Intravascular Stents. General Principles and Status of Lower Extremity Arterial Applications. Circulation 1991, 83 (Suppl 11), 1122– 1136. 10. Diethrich, E.B.; Santiago, O.; Heuser, R.R.; Gustafson, G. Preliminary Observations of the Use of the Palmaz Stent in the Distal Portion of the Abdominal Aorta. Am. Heart J. 1993, 125, 490– 501.
Chapter 23. Basic Nomenclature 11.
12.
13.
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15.
16.
17.
18.
Diethrich, E.B. Endovascular Treatment of Abdominal Aortic Occlusive Disease: The Impact of Stents and Intravascular Ultrasound Imaging. Eur. J. Vasc. Surg. 1993, 7, 228–236. Diethrich, E.B. Initial Experience with Stenting in the Innominate, Subclavian, and Carotid Arteries. J. Endovasc. Surg. 1995, 2, 196– 221. Diethrich, E.B.; Cozacov, J.C. Subclavian Stent Implantation to Alleviate Coronary Steal Through a Patent Internal Mammary Artery Graft. J. Endovasc. Surg. 1995, 2, 77– 80. Kumar, K.; Dorros, G.; Bates, M.; Palmer, L.; Mathiak, L.; Dufek, C.; et al. Primary Stent Deployment in Occlusive Subclavian Artery Disease. Catheter. Cardiovasc. Diagn. 1995, 34, 281– 285. Sullivan, T.M.; Bacharach, M.; Childs, M.B. PTA and Primary Stenting of the Subclavian and Innominate Arteries. (Abstract). Circulation 1995, 92, 1 – 383. Martinez, R.; Rodriguez-Lopez, J.; Torruella, L.; Ray, L.; Lopez-Galarza, L.; Diethrich, E. Stenting for Occlusion of Subclavian Arteries: Technical Aspects and Follow-Up Results. Tex. Heart Inst. J. 1997, 24, 23– 27. Dorros, G.; Jaff, M.R.; Mathiak, L.; Dorros, I.I.; Lowe, A.; Murphy, K.; He, T. Stent Revascularization for Atherosclerotic Renal Artery Stenosis. One-Year Clinical FollowUp. Tex. Heart Inst. J. 1998, 25, 40– 43. Fiala, L.A.; Jackson, M.R.; Gillespie, D.L.; O’Donnell, S.D.; Lukens, M.; Gorman, P. Primary Stenting of Atherosclerotic Renal Artery Stenosis. Ann. Vasc. Surg. 1998, 12, 128– 133.
19.
20.
21.
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24.
25.
26.
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Diethrich, E.B.; Ndiaye, M.; Reid, D.B. Stenting in the Carotid Artery: Initial Experience in 110 Patients. J. Endovasc. Surg. 1996, 3, 42– 62. Diethrich, E.B.; Rodriguez-Lopez, J.A.; Lopez-Galarza, L.A. Stents for Vascular Reconstruction in the Carotid Arteries. (Abstract). Circulation 1995, 92, 1 – 383. Tierstein, P.S.; Schatz, R.A.; Rocha-Singh, K.J. Coronary Stenting with Angioscopic Guidance. (Abstract). J. Am. Coll. Cardiol. 1992, 19, 223A. Strumpf, R.K.; Heuser, R.R.; Eagan, J.T. Angioscopy: A Valuable Tool in the Deployment and Evaluation of Intracoronary Stents. Am. Heart J. 1993, 126, 1204– 1210. Senneff, M.J.; Schatz, R.A.; Tierstein, P.S. The Clinical Utility of Angioscopy During Intracoronary Stent Implantation. J. Intervent. Cardiol. 1994, 7, 181– 186. Parodi, J.C.; Palmaz, J.C.; Barone, H.D. Transfemoral Intraluminal Graft Implantation for Abdominal Aortic Aneurysms. Ann. Vasc. Surg. 1991, 5, 491– 499. May, J.; White, G.; Yu, W.; Waugh, R.; Stephen, M.S.; Harris, J. Concurrent Comparison of Endoluminal Repair Versus No Treatment for Small Abdominal Aortic Aneurysms. Eur. J. Vasc. Endovasc. Surg. 1997, 13, 472–476. Diethrich, E.B. Polymeric Covers and Coats for Metallic Stents: Microporous PTFE and the Inhibition of Intimal Hyperplasia. J. Endovasc. Surg. 1995, 2, 266– 271.
CHAPTER 24
Peripheral Atherectomy Samuel S. Ahn Kyung M. Ro INTRODUCTION
INDICATIONS
Recent advances in endovascular technology have generated numerous alternative procedures in the treatment of peripheral arterial occlusive disease. The application of catheter-based endovascular systems has provided a less invasive method to enhance or replace standard revascularization procedures. Mechanical atherectomy, which is based on the concept of “debulking” plaque, has been developed as an alternative to conventional percutaneous balloon angioplasty due to the limitations of PTA. Unlike PTA, which is not ideally suited for use in complex lesions (i.e., heavily calcified or intimal hyperplastic lesions), diffusely diseased vessels, and eccentric stenosis, atherectomy has a wider application to lesions not amenable to percutaneous balloon angioplasty. Atherectomy has proven to have a greater immediate success rate with less intimal dissection and occlusion; however, the long-term results are less promising. Atherectomy selectively removes atheromatous materials from diseased arteries by cutting, pulverizing, or shaving it using a mechanical catheter-deliverable endarterectomy device. Atherectomy is performed either percutaneously or through a small arteriotomy located romote from the diseased site. More than a dozen atherectomy devices have been developed over the years to meet the current challenges, each offering its own unique advantages and disadvantages. Of these atherectomy devices, four have undergone critical evaluation with extensive preclinical or clinical investigation: Simpson AtheroTrak (Mallinckrodt Medical Inc., St Louis, MO), the Transluminal Extraction Catheter (TEC) (Interventional Technologies, San Diego, CA), the OmniCath (American Biomed, Inc., The Woodlands, Texas), and the Auth Rotablator (Boston Scientific Corp., Natick, MA). Atherectomy devices are either extirplative (directional atherectomy) or ablative (rotational atherectomy). Of the four catheters mentioned above, only the Rotablator is an ablative device. Extirplative catheters shave or slice the atheroma and directly remove the excised plaque from vessels with a collection chamber, while ablative catheters use a highspeed rotary device that pulverizes atheroma into microparticles small enough to be aspirated or removed through the reticuloendothelial system.
Indications for atherectomy vary with each catheter (Table 24-1). Atherectomy may be a suitable option for high-risk patients with severe disabling claudication or limb-threatening ischemia and short stenotic lesions less than 5 cm. In addition, atherectomy can be performed as an adjunct to standard revascularization in high-risk patients. In the iliac artery, atherectomy can be used as an adjunct to standard open revascularization in heavily calcified eccentric plaques; however, the use of atherectomy in the femoropoliteal artery should be determined by the type of plaque in the region as well as the length of the lesion. Lesions in the tibioperoneal artery are generally diffused, calcified and not suitable for PTA; therefore, atherectomy using the Auth Rotablator is recommended. It has been suggested that patients with failing lower extremity bypass grafts should be treated with atherectomy, rather than PTA, because graft failure is often caused by intimal hyperplastic tissue not readily amenable to balloon angioplasty. Atherectomy has been shown to be successful in the treatment of recurrent stenoses resulting from intimal hyperplasia.
TYPES OF ATHERECTOMY DEVICES Simpson AtheroTrak Device Description The Simpson AtheroTrak is the modified version of the AtheroCath. The AtheroTrak catheter is available in 7, 8, 9, 10, and 11 French sizes. The improved AtheroTrak offers both an over-the-wire and fixed wire shaft design that enhances the steering maneuverability for easier introduction into complex or simple stenotic lesions. The housing unit, which contains a cutter within a longitudinal opening on one side and a balloon attached to the other side, is located at the distal end of the catheter (Fig. 24-1). Once inflated, the balloon engages the atheroma against a 20 mm cutter window.
Hobson/Wilson/Veith: Vascular Surgery: Principles and Practice, Third Edition, Revised and Expanded DOI: 10.1081/0819-9-120024907 Copyright q 2004 by Marcel Dekker, Inc.
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352 Table 24-1.
Indications for Use by Atherectomy Device
Device Simpson AtheroCath
TEC
OmniCath
Auth Rotablator
Amenable lesions
Arterial site
Stenoses Short (,5 cm) Eccentric atheroma Intimal hyperplasia Ulcerative plaques Stenoses Short (,5 cm) Eccentric atheroma Stenoses Short (,5 cm) Eccentric atheroma Stenoses Eccentric atheroma Hard calcified plaques Recurrent vein graft stenoses
Iliac Superficial femoral Popliteal
Bulky/stiff catheter Lengthy procedure Hematoma Restenosis
Superficial femoral Popliteal
Small lumen Restenosis Reocclusion Hematoma Restenosis
The cutter then slices the plaque at 2000 rpm while simultaneously pushing the excised particles into a collection chamber. The wire tip of the catheter is protected with a tip guard containing a hemostasis valve. The proximal assembly consists of a balloon inflation port, a flush port and an adaptor spline for the drive cable connector. To lock the cutter in place before advancing it manually, a small lever is attached to the cable.
Iliac Superficial femoral Popliteal Superficial femoral Popliteal Tibial
Complications/limitations
Dissection Restenosis Reocclusion Thrombosis
Indications The AtheroTrak is ideally suited to treat short, discrete, eccentrically located atheroma. Unless occlusions can be crossed with a guidewire, they are not amenable to this device. Heavily calcified lesions, although not contraindicated, can create difficulties for the cutter. Similar to balloon angioplasty, the AtheroTrak, with its own balloon,
Figure 24-1. Simpson AtheroTrak catheter system. 1, cylindrical housing; 2, longitudinal opening; 3, cutter; 4, cutter drive cable (to motor); 5, specimen collection area; 6, balloon support mechanism; 7, fixed guidewire; 8, motor; 9, cutter advance lever; 10, balloon inflation port; 11, flush port; 12, Touhy – Borst opening for cable connector. (From Simpson J. B., Selmon M. R., Robertson G. C., et al.: Transluminal atherectomy for peripheral vascular disease. Am. J. Cardiol. 61: 96G – 101G, 1988.[5])
Chapter 24.
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can create an arterial lumen larger than the catheter used. As indicated in Table 24-1, this catheter can be used to treat ulcerative lesion, concentric stenoses and intimal hyperplasia located in the iliac, superficial femoral, and popliteal arteries. Recent studies have indicated that Simpson atherectomy provides more durable results when compared to balloon angioplasty in treating recurrent infrainguinal bypass graft stenoses.[1,2] In addition, the Simpson atherectomy has been indicated for use in the treatment of failing hemodialysis access fistulas with promising results.[3,4]
Technique The choice of catheter size should be based on the size of the adjacent normal artery; the catheter should be the same size or slightly larger. A 9 Fr catheter is most commonly used. Figure 24-2 illustrates the Simpson catheter procedure. Diluted contrast solution should be injected into the balloon port and aspirated until all air is evaporated and the balloon filled with solution. The inflation device is then attached to the balloon port and the removable collection chamber and nose cone secured by turning the proximal and distal thread joints clockwise with an Atherowrench. The motordrive can then be turned on to test the advancement and retraction capabilities of the cutter. With the cutter fully advanced, the AtheroTrak catheter is inserted through the introducer sheath and advanced past the stenotic lesion. Under fluoroscopic guidance, the cutter window is positioned against the stenotic lesion. The opposing balloon is inflated to 20–40 psi to push the window open and to press the plaque into it. The motor drive of the cutter is activated, the balloon completely deflated, and the plaque sliced off and pushed into the distal collecting chamber. To obtain full atherectomy, the collecting chamber can be rotated; multiple cuts and passes are usually required to achieve a final lumen of less than 25% residual stenosis. Before retracting the cutter, the balloon should be reinflated to 10 psi to prevent embolization; after the cutter is retracted, the balloon pressure should be increased to 20– 40 psi. The catheter must be withdrawn to remove the excised particles from the collecting chamber. Perform a completion angiogram to assess patency and to determine if residual stenosis is less than 25%. Repeat atherectomy should be performed until recanalization is complete. Throughout the procedure, contrast should be periodically injected via the sidearm of the introducer to facilitate positioning of the cutter window for subsequent passes. Before the catheter is removed, the cutter is advanced completely within the housing unit and the tip guard passed through the hemostasis valve.
Results In 1988, Simpson et al.[5] first reported their use of atherectomy for peripheral arterial occlusive disease on 130 lesions in 61 patients with a 6-month patency rate of 64%. Since then, several clinical studies using the Simpson atherectomy device to treat peripheral arterial occlusive disease have been reported, promising initial success rates ranging from 80% to 100%.[1 – 4,6 – 8] Graor and Whitlow[6] reported a less than 20% residual stenosis in 100% of lesions less than or equal to 5 cm and 93% of lesions greater than 5 cm. Other investigators, however, reported less enthusiastic
Figure 24-2. Simpson atherectomy procedure. (A) The lesion before atherectomy. (B) Atherectomy catheter in position across the lesion. (C) The balloon support is inflated. (D) The cutter is advanced. (E) The specimen is trapped in the housing. (F) The balloon is deflated and the catheter removed. (From Hinohara T., Robertson G. C., Selmon M. R., Simpson J. B.: Transluminal atherectomy. The Simpson atherectomy catheter. In Moore W. S., Ahn S. S. (eds): Endovascular Surgery. Philadelphia, WB Saunders Company, 1989, pp 310 – 322.)
intermediate patency rates at 6 –24 months (Table 24-2). Vroegindewij and colleagues[7] and Lugmayr et al.[8] reported discouraging 2-year patency rates of 35% and 42%, respectively. Adjunctive use of balloon angioplasty with atherectomy appears to provide more durable results. Kim and associates[12] used balloon angioplasty to either facilitate the passage of the atherectomy catheter or further improve the final lumen. In this study, the investigators attempted to assess the results of the Simpson device with those of balloon angioplasty. They compared lesions treated with atherectomy alone ðn ¼ 68Þ with lesions treated with both atherectomy and supplemental balloon angioplasty ðn ¼ 17Þ: Lesions treated with the Simpson device alone had patencies of 92%, 84%, and 84% at 1, 2, and 3 years, respectively, and reduced patencies of 78%, 67%, and 57% at 1, 2, and 3 years, respectively, were obtained with the combined treatment modality. In this study, however, it was difficult to delineate the respective roles of atherectomy and balloon angioplasty or to make a comparison between the groups. In another prospective randomized study conducted by Vroegindewij and colleagues,[7] 2-year cumulative patency rates of 35% ðn ¼ 38Þ in lesions treated with Simpson atherectomy alone versus 56% ðn ¼ 35Þ in patients treated with balloon angioplasty alone were found. The results of this study indicated that atherectomy with the Simpson catheter did not result in an improved clinical or hemodynamic outcome and was associated with a notably worse patency rate than balloon angioplasty for patients with lesions of 2 cm or greater. In a recent study conducted by Osborn and associates,[15] combination therapy involving Simpson atherectomy, balloon angioplasty, and video angioscopy was used to treat focal stenotic lesions ðn ¼
354 Table 24-2.
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Results Reported Using the Simpson Atherectomy Device Primary patency (%)
Authors
Patient (no.)
Lesion (no.)
Technical success (%)
6 months
12 months
24 months
Simpson et al.[5] Graor and Whitlow[6]
61 106
136 106
Vroegindewij et al.[7] Lugmayr et al.[8] Polnitz et al.[9] Hinohara et al.[10] Dorros et al.[11] Kim et al.[12] Savader et al.[13] Widenhain et al.[14]
38 94 60 100 126 77 61 75
38 132 94 195 213 85 136 84
87 100 (lesions #5 cm) 93 (lesions . 5 cm) 92 95 82 90 99 92 80 92
69 NA NA 84 NA 99 83 45 94 NA NA
NA 93 86 42 69 72 NA NA 86 76 78
NA 88 73 35 42 NA NA NA 86 58 57
NA = not available.
96Þ in the superficial femoral and popliteal arteries with greater than 80% stenoses. The investigators reported a promising 94% technical success rate and 1- and 2-year patency rates of 78% and 71%, respectively. Although longterm studies are warranted, this study combining atherectomy and balloon angioplasty may prove to be more durable than any one treatment modality alone. A number of recent studies have shown much improved mid-term and long-term results from Simpson atherectomy in the treatment of vein graft stenoses, with sustained patency rates better than that historically reported for balloon angioplasty. Dolmatch et al.[1] reported a 92% technical success rate in treating 18 lower extremity bypass grafts (11 PTFE, 7 autologous saphenous veins) with 23 areas of anastomotic stenoses. The authors reported a 92% technical success rate in 19 lower extremity bypass grafts with a mean 14-month patency of 88%. In addition, Porter et al.,[2] in an attempt to evaluate the long-term results of Simpson atherectomy, performed 52 procedures (atherectomy alone = 42, atherectomy plus PTA = 10) to treat 67 stenoses (28 anastomotic, 39 intragraft) in 44 infrainguinal grafts. The technical success rate was an impressive 96%, with a mean diameter reduction from 81% to 11% stenosis after treatment. In addition, the sustained patency rates were 83%, 80%, and 80% at 1, 2, and 3 years, respectively. These results clearly
Table 24-3.
surpass those previously reported for balloon angioplasty and rival those of standard surgical revision in the treatment of recurrent stenosis in infrainguinal bypass graft. The Simpson atherectomy device has also been indicated for use in the treatment of failing hemodialysis access fistulas. Zemel et al.[3] reported a 77% technical success rate in treating stenotic hemodialysis fistulas in 13 patients. Gray and colleagues[4] reported an 83% technical success rate and a 50% patency rate a 6 months in treating hemodialysis access with 12 intragraft stenoses. Although the data are preliminary and further clinical trials are warranted, the use of atherectomy in the treatment of recurrent stenotic hemodialysis access fistulas appears to be a safe and durable alternative.
Complications and Limitations Although there have been reported complications of hematomas caused by bleeding at the atherectomy entry site, pseudoaneurysm, and distal embolization, the Simpson atherectomy catheter is a relatively safe catheter. Table 24-3 outlines the complications associated with the Simpson device. Savader and colleagues[13] stated that Simpson atherectomy has similar patency compared with that reported for balloon angioplasty in the treatment of femoral and
Complications Associated with the Simpson Catheter
Complications
Simpson et al.[5]
Graor and Whitlow[6]
Vroegindewij et al.[7]
Polnitz et al.[9]
Hinohara et al.[10]
Kim et al.[12]
Dissection Embolization Hematoma Pseudoaneurysm Retroperitoneal bleeding Thrombosis
3/61 (5%) 1/61 (2%) — — — 1/61 (2%)
— — 7/106 (7%) 1/106 (1%) — —
2/38 (5%) — — — — 1/38 (3%)
— 1/60 (2%) 2/60 (3%) — — —
— 2/100 (2%) 1/100 (1%) — — 1/100 (1%)
— 3/77 (4%) 11/77 (14%) 3/77 (4%) 1/77 (1%) —
Chapter 24.
popliteal artery lesions but also a high complication rate of 42.8%, equally divided into major and minor complications. The major complications included 4 puncture-site hematomas, which were attributed to the use of sheaths 9 Fr or larger and subsequently required vessel repair or an extended hospital stay; 7 embolizations treated with aspiration embolectomy and/or urokinase therapy; 2 contrast-induced renal failures that required rehydration or dialysis; a pseudoaneurysm that required surgical repair; a thrombosed arterial lesion within 24 hours. All minor complications were related to puncture-site hematomas and required no additional treatment. Other complications reported by Kim et al.[12] were primarily related to the bulky sheaths, which caused 11 cases of hematomas; less prevalent complications included problems related to distal emboli and 3 cases of pseudoaneurysms that required surgical repair. One of the primary limitations of the Simpson atherectomy device for widespread use in the treatment of peripheral arterial occlusive disease is its failure to reduce restenosis. Generally, short-terms results are disappointing; at 6 months, Simpson and his colleagues[5] reported a restenosis rate of 36%; Polnitz and others[9] reported restenosis rates of 24% and 11% for concentric and eccentric lesions, respectively; and Dorros and associates[11] reported a significant 55% recurrence rate. In the treatment of recurrent infrainguinal bypass graft stenosis, Dolmatch et al.[1] reported a 26% restenosis and reocclusion rate while Porter and his colleagues[2] found a low 12% restenosis rate in treating vein graft stenosis. Another significant limitation of the Simpson atherectomy device is its inability to treat long, diffusely diseased segments and long, completely occluded lesions. The reported restenosis rates in these long lesions are higher; Polnitz et al.[9] found restenosis rates of 14% in lesions with complex occlusions 5 cm or greater as compared to 7% in simple stenosis less than 5 cm. Vroegindewij and others[7] found that their treated lesions of 2 cm or greater had notably worse patency rates (14%) at one year as compared to lesions smaller than 2 cm (50%).
Transluminal Extraction Catheter Device Description The Transluminal Extraction Catheter (TEC, Inventional Technologies, Inc., San Diego, CA) is a semi-flexible, torquecontrolled catheter with a rotating, cone-shaped cutter that is placed through an introducer sheath over a central guidewire (Fig. 24-3). The catheter itself is hollow, so that the particles resulting from atherectomy can be suctioned out of the vessel and collected in a separate collecting chamber. The coneshaped cutter itself rotates at approximately 700 rpm and leaves relatively large-sized (1 mm) particles; the cone also has openings on its distal tip. Suction is applied from the proximal port to suction the particles into a separate collecting chamber (125 mL), thereby minimizing embolic complications. Continuous heparin irrigation is required through the introducer sheath’s sidearm to maintain efficiency in the aspiration of the excised particles. The catheter is currently available in 6, 7, 8, 9, 10, 12, and 14 Fr sizes.
Figure 24-3.
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The TEC device. See text for description.
Indication The current indications for the TEC device are the same as those previously described for the Simpson AtheroTrak. The TEC device is currently recommended for short stenotic lesions with eccentrically placed atheroma. The use of this atherectomy device in treating total occlusions and long stenotic lesions has produced suboptimal results.[16,17] Adjunctive use of balloon angioplasty to facilitate the recanalization of such lesions is recommended.
Technique Atherectomy with the TEC device is usually performed percutaneously but can be done intraoperatively. Due to the limited size of the TEC catheter, standard balloon angioplasty is often required to achieve a channel that is of adequate size. Under fluoroscopic guidance, an appropriately sized introducer sheath is placed into the artery in antegrade fashion for the superficial, popliteal, and tibial arteries. A guidewire is then passed through the introducer sheath and the obstructing lesion. Once the guidewire is in place, a 4- or 5-Fr polyethylene exchange catheter is inserted. The existing guidewire is then replaced with a TEC 0.014-in. guidewire. The exchange catheter is then removed, followed by the passing of the TEC over the TEC guidewire until the catheter meets resistance at the obstructive lesion. The motor drive unit, which rotates the cutter, is turned on and the suction is applied. The rotating cutter is advanced freely but gently over the guidewire until the obstructing lesion is traversed. The shaved particles are then aspirated through the hollow catheter into the collecting bottle. Fluoroscopy is used to document the progress of the atherectomy and the final lumen. Continuous heparin irrigation is administered via the sidearm of the introducer sheath to minimize embolic complications. If there is significant residual stenosis (. 25%), adjunctive balloon angioplasty can be used to dilate the artery to its final lumen.
Results Very few results using the TEC device in the treatment of peripheral arterial occlusive disease have been reported.
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Wholey and Jarmolowski[16] reported promising initial technical success rates of 92% and an immediate clinical success rate of 90%. However, only 50 of 95 patients (53%) underwent follow-up at 6 months; furthermore, 16 had undergone repeat angiography, 4 of whom had angiographic evidence of reocclusion. Myers and associates[17] achieved a 6-month patency rate of 80% for lesions 5 cm or smaller and 64% for lesions greater than 5 cm. In addition, adjunctive balloon angioplasty was performed in 76% of patients.
Complications/Limitations Complications associated with the TEC device have not been reported in full detail. Table 24-4 outlines the complications associated with this device. Wholey and Jarmolowski[16] reported only 2 of 126 (2%) thrombotic complications, both of which were treated with urokinase infusion. Myers and associates[17] reported a 6% complication rate in treating long, complex lesions including 2 deaths, 2 catheter fractures requiring removal and replacement, 2 cases of thromboembolism, and 3 patients with puncturesite bleeding. Restenosis and reocclusion are the primary limitation of the TEC device. Of the 16 patients who underwent repeat angiography during follow-up, Wholey and Jarmolowski[16] found restenosis in 4 patients at 3-month follow-up and reocclusion in 4 whose lesions were longer than 8 cm. Myers and associates[17] found restenosis in 26 lesions (18%) and reocclusion in 51 lesions (35%) at 6 months.
OmniCath Device Description The OmniCath is a new atherectomy device currently approved by the U.S. Food and Drug Administration (FDA) for investigational use only (Fig. 24-4). It is a radiopaque, torqueable, braided catheter with a hollow cylindrical housing at the distal end. The housing unit contains the cutter within a longitudinal window on one side and a unibody tripod extendible deflector wire configuration on the opposite side, which serves as an anchoring pad. The internal beveled cutter spins at 11,000 rpm and is stabilized by an axial guide or track when making a cut. The cutter is activated by a batterypowered motor via a hollow drive shaft. An idler shaft covers a 2-cm section of the drive shaft at the distal end to minimize or eliminate the potential of tissue wrapping or binding onto
Figure 24-4. The OmniCath atherectomy device tip.
the shaft. The catheter is then advanced transluminally over a 0.014 or 0.018 in. guidewire. Once the cutter window is positioned over the stenotic lesion, the cutter is activated and passed back and forth across the lesion, shaving off thin segments of the atheroma with each pass. The atheromatous debris is then collected in the housing unit and continuously aspirated through a removable port at the proximal end of the catheter. A radiopaque gold dot just beyond the distal end of the window enhances operative visualization of the device. The atraumatic deflector wire is designed to anchor the cutter assembly securely against the obstructing lesion and allow for continuous distal perfusion during atherectomy. The anchoring system can be adjusted to regulate the depth of cut by its degree of extension; it can withhold a maximum pressure of 27 psi, which is designed to prevent injury to the vessel wall (i.e., perforation) and reduce the occurrence of acute closure and restenosis.
Indications The OmniCath is designed to treat short stenotic lesions with concentrically or eccentrically placed atheroma. From animal as well as preliminary clinical data, it can be used in the iliac, superficial femoral, and popliteal arteries. The OmniCath is currently under investigative trial for peripheral atherectomy. The OmniCath may potentially have application in the treatment of arteriovenous dialysis fistulas. Clinical trials are currently in progress as of this writing.
Techniques Complications Associated Transluminal Extraction Catheter
Table
24-4.
Complication Bleeding Catheter fracture Death Embolization Thrombosis
with
the
Wholey and Jarmolowski[16]
Myers et al.[17]
— — — — 2/126 (2%)
3/144 (2%) 2/144 (1%) 2/144 (1%) — 2/144 (1%)
Atherectomy with the OmniCath device is generally performed percutaneously. The OmniCath is prepared by flushing the injection port through the guidewire lumen with heparinized saline. All the air should be evacuated from the device. Using fluoroscopic guidance, the catheter can be introduced to the obstructive lesion by either placing the OmniCath over a 0.014 in. exchange guidewire or by placing the catheter onto the exchange guidewire and then inserting this unit into an introducer sheath. The OmniCath is then advanced slowly until the cutting window is positioned against the stenotic lesion. The radiopaque gold dot at the
Chapter 24.
distal end helps confirm the proper positioning of the cutter window, which is opened by moving the cutter actuation slide to its “advanced” or closed position. The anchoring deflector wire pad is extended by advancing the wire actuation ring to stabilize the catheter and brace the cutter window against the plaque site. Before atherectomy is initiated, the guidewire is withdrawn from the catheter tip and the aspiration tubing clamp opened to provide suction to the aspiration port. The motor drive of the cutter is then activated and the cutter advanced slowly across the obstructing lesion until it has traversed the full length of the window. Aspiration should only be done during the cutting process to limit blood loss and should be performed gently. The deflector wire pad may need to be adjusted to maintain a portion of the lesion within the window. Multiple passes across the lesion may be made with the cutter window in the same location until completion angiography confirms a residual stenosis of less than 25%. If residual stenosis persists, reposition the catheter and repeat the above cutting and removal process. If the catheter is removed before completion of the procedure, aspirate heparinized saline through the catheter lumen to remove all atheromatous debris and blood remaining within the lumen.
Results Animal data using the OmniCath device for peripheral atherectomy have been published by Mazur and coworkers.[18] Concentric and eccentric lesions were induced in the bilateral external iliac arteries of 10 miniature swine and subsequently underwent atherectomy with the OmniCath device. Five swine were sacrificed 3 days after the atherectomy procedure and the other five at 6 weeks. Histologic sections of the 6-week atherectomized lesions revealed minimal healing response. No evidence of vessel wall injury or significant neointimal proliferation at the anchoring wire deployment sites was found. Angiography revealed 20% luminal narrowing in one lesion at 6 weeks. In evaluating a prototype of the device in microswine, Sapoval and colleagues[19] determined the maneuverability to be satisfactory but its aspiration apparatus inefficient. The OmniCath device underwent several modifications before it was used in humans. In an ongoing clinical trial comparing atherectomy with the OmniCath device versus balloon angioplasty in the treatment of peripheral arterial occlusive disease, Ahn et al.[20] recently reported their preliminary results on 13 patients. They concluded that in this group of high-risk, comorbid patients, atherectomy or balloon angioplasty alone demonstrated high technical failure rates, 71% and 33% for atherectomy and balloon angioplasty, respectively. However, patients who failed their initial randomization treatment were immediately crossed over to the alternate treatment modality (i.e., atherectomy ! PTA, PTA ! atherectomy) to achieve a 100% initial technical success rate and future clinical success. The primary, primary-assisted, and secondary patency rates at a mean follow-up of 9 months using the life tables method were 57%, 91%, and 100%, respectively. These results suggested that a combined therapy of atherectomy plus balloon angioplasty will increase the immediate technical success rate and may increase the long-term patency rates with additional follow-up.
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Complications/Limitations Mazur and coworkers[18] reported spasm at the atherectomy site in most animals, and Sapoval et al.[19] reported arterial rupture in 3 out of 4 animals. In the preliminary clinical data reported by Ahn et al.,[20] there were no perioperative mortalities; however, 2 of 13 patients developed hematomas at the puncture site, one requiring surgical drainage. Long-term clinical trials are currently warranted to determine the clinical safety and efficacy of the OmniCath device in the treatment of peripheral arterial occlusive disease.
Auth Rotablator Device Description The Auth Rotablator (Biophysics International, Bellevue, WA) is a flexible, ablative catheter-deliverable atherectomy device with a variable-sized, football-shaped metal burr on the distal tip (Fig. 24-5). A 0.009 in. guidewire must first traverse the lesion before rotational atherectomy can be provided. The burr is studded with multiple diamond chips (22–45 mm in size) that function as multiple microknives. The burr is available in various sizes, ranging from 1.25 to 6.0 mm in diameter. Burrs of different sizes are used during the recanalization process until a satisfactory lumen is achieved. The metal burr is welded onto a flexible drive shaft that is encased within a protective plastic sheath to form a flexible catheter-deliverable system. A control knob on top of the plastic casing allows the operator to deliberately advance or retract the burr over the guidewire. The burr rotates at 100,000–200,000 rpm and tracks along a central guidwire. The guidewire must first traverse the lesion before rotational atherectomy can proceed. The high-speed rotation allows the diamond microchips to preferentially attack hard, calcified
Figure 24-5. The Rotablator atherectomy burr and guidewire. Burrs 1.25 and 4.5 mm in diameter, respectively, are shown. Note the diamond microchips are embedded in the distal half of the burr. Also note coaxial spring tip (top) and semirigid guidewires (bottom). (From Ahn S. S.: The Rotablator-high speed rotary atherectomy: Indications, techniques, results and complications. In Moore W. S., Ahn S. S. (eds): Endovascular Surgery. Philadelphia, WB Saunders Co, 1989, pp 327 – 335.)
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atheroma while leaving the surrounding elastic soft tissue of normal arterial wall intact. The device leaves a smooth, polished intraluminal surfaces and no intimal flaps. The pulverized particles are generally smaller than red blood cells and have been shown to pass harmlessly through the circulation in previous canine studies.[21]
Indications The Auth Rotablator is ideally suited for hard calcified lesions, especially in diabetic patients who have disabling claudication or limb-threatening ischemia. Recanalization can be achieved expeditiously in short as well as long lesions. Superficial femoral, popliteal, and tibial artery lesions can be treated. Stenotic lesions are better suited for this device because a central guidewire must first traverse the lesion. Total occlusions can be treated if the guidewire can be passed. Eccentric plaques can be treated adequately since the atherectomy device preferentially attacks hard, calcified plaque.
Technique Atherectomy with the Auth Rotablator is performed preferentially through an open arteriotomy, although the percutaneous method can be used. The open cutdown approach is generally preferred because the percutaneous technique limits the burr size to 3.0 mm and ultimately required subsequent balloon angioplasty. When performing atherectomy alone, an open arteriotomy using a larger-sized burr is preferred. A 9- or 12-Fr introducer sheath is inserted into the artery through the arteriotomy. An angioscope may be inserted to document the lesion and to help with proper placement of the guidewire. Alternatively, conventional fluoroscopy can be used and is more readily available. A small atraumatic guidewire is placed through the sheath and advanced using fluoroscopic guidance through the obstructing lesion, after which an exchange guide catheter is inserted. A 0.014 in. high-torque floppy coronary guidewire is recommended. The initial guidewire is removed and replaced with a more rigid 0.009 in. atherectomy guidewire. The exchanged guide catheter is then removed while the atherectomy guidewire is left in place. The burr is backloaded onto the atherectomy guidewire followed by the drive shaft Table 24-5.
and advanced to the site of the obstructing lesion. The burr is advanced slowly in a vibratolike to-and-fro manner over the guidewire, recanalizing the artery; residual stenosis is , 25%. Initially, the burr size is half the diameter of the native artery; the size of the burr is increased incrementally until a large enough lumen is obtained. Following this initial atherectomy, the burr is removed, leaving the guidewire in place. The burr is advanced using fluoroscopic guidance. Nitrogen pressure should be set at 40 –45 psi; this will cause the surrounding tissue to snag onto the burr, and as rotation quickens, excessive heat may be produced and quickly dissipated due to the fluid around the burr. The control knob is used to slowly and gently advance the burr back and forth. Once the burr traverses the obstructive lesion it is removed; fluoroscopy is used to confirm and maintain the guidewire’s position across the lesion. Angiography is performed through the sidearm of the introducer sheath; if residual stenosis persists, a slightly larger burr is loaded onto the guidewire and the procedure is repeated until the stenosis is less than 25%. The patient is placed on anticoagulation therapy for the first 24 hours postoperatively to prevent early thrombosis. Long-term aspirin is maintained postoperatively.
Results Clinical studies reported promising and immediate clinical success rates with the Auth Rotablator (Table 24-5). However, half of these series reported only a short followup of 6 months, and patencies obtained at time interval were suboptimal, ranging from 47 to 82%. Furthermore, patencies obtained at 1 year were worse.[23,25,27] Ahn et al.[23] performed atherectomy with the Auth Rotablator in 20 patients with claudication, ulcer or gangrene, rest pain, and asymptomatic failing graft. A total of 25 lesions were treated; 20 lesions had 50–95% stenosis, and 5 lesions were occluded. Although the initial success rate was an impressive 93%, the in-hospital success rate dropped to 72% as a result of complications that developed in 17 of 25 (68%) of the cases. The 2-year cumulative patency rate was only 12%. The Collaborative Rotablator Atherectomy Group (CRAG)[25] reported their experience with the Auth Rotablator from a multicenter trial. Technical angiographic success (,25% residual stenosis) was achieved in 70 of 79
Results Reported Using the Auth Rotablator Clinical patency (%)
Authors [22]
Dorros et al. Ahn et al.[23] White et al.[24] CRAG[25] Henry et al.[26] Myers et al.[27] a
Patency at 4 months.
Patients (no.)
Lesions (no.)
Technical success (%)
Immediate clinical success (%)
6 months
12 months
24 months
43 20 17 72 150 34
82 42 18 107 212 36
95 93 94 89 97 94
88 72 94 77 85 92
— 66 82 47 58a 68
— 47 — 31 — 61
— 12 — 19 — —
Chapter 24.
limbs (89%) and in 82 of 107 arteries (77%). In addition to the 9 technical failures, in-hospital thrombosis occurred in nine limbs, resulting in an in-hospital success rate of 77% (61 of 79 limbs). Furthermore, complications occurred in approximately half of the patients, and half of them subsequently underwent an urgent or emergent surgical procedure within 30 days. Of these patients, 6 underwent an amputation, 2 of which were associated with this device. Late failure was observed in 32 limbs within a period of 15–41 months; 4 of the 32 failures also resulted in an amputation. The cumulative patency rate at 2 years was a dismal 18.6%.
Complications/Limitations As a result of the poor intermediate and long-term results discussed above, coupled with the complications associated with this device, peripheral atherectomy with the Auth Rotablator currently has limited application. Table 24-6 outlines the complications associated with device. Ahn et al.,[23] the CRAG,[25] and Henry and associates[26] all reported significant early thrombosis; Ahn et al.[23] reported 5 in-hospital cases of thrombosis, 4 of which were related to the hypercoagulable states. The CRAG[25] reported 9 cases of early thromboses (11%), 2 of which subsequently led to amputation. Henry and colleagues[26] associated the 12 thromboses (8%) in their series with a number of factors, including dissection, elastic recoil, intimal flaps, lengthy lesion, residual stenosis, and vasospasm. In addition, arterial spasm was found in 23% of cases by Dorros et al.[22] and 11% by Henry and associates,[26] most often in small distal arteries. These spasms were largely attributed to the use of large burrs, long rotational sequences, and/or rotational speed. Gross hemoglobinuria without any clinical sequalae was found in 63% of cases by Dorros and others,[22] in 20% by Ahn et al.,[23] and in 13% by the CRAG.[25] These cases were transient and developed in lesions that required larger burrs and prolonged rotational sequences. Contrary to previously reported studies, the atherectomized particles are not always small enough to pass through the reticuloendothelial system safely.[21] Indeed, embolic complications developed in 20% of cases described by Ahn et al.,[23] 10% by the CRAG,[25] and 1% by Henry and associates.[26] Three of the 8 embolic events reported by the CRAG[25] resulted in cutaneous necrosis, and one resulted in toe amputation. Similar to the other atherectomy devices, the Auth Rotablator was also reported to cause dissections, perforations, and puncture-site hematomas.[22 – 26] Also, late restenosis and reocclusions are the significant limiting factor Table 24-6.
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of the Auth Rotablator. Although most of the residual lumens achieved were less than 20%, Ahn et al.[23] reported restenosis in 45% (9 of 20) of their patients and reocclusion (4 of 5) within 18 months. Intimal hyperplasia was believed to be the causative factor in these cases. The CRAG[25] reported late restenoses and reocclusion in 40% of their patients (32 of 79 limbs) during a long-term follow-up of 15 –41 months. Henry and associates[26] reported a 24% restenosis rate, primarily in lesions 7 cm or longer. The inability to ablate and pulverize chronic thrombus and/or rubbery plaque limits the Auth Rotablator.[28] These lesions preferentially deflect away from the rotating burr, leading to suboptimal recanalization. The need for multiple burrs and the exchange of burrs over the guidewire lengthens the procedure. Although particles are generally small, a large particle burden could create a potential problem. Thus, in dealing with long, completely occluded lesions, an atherectomy-induced large-particle burden could lead to problems that have yet to be identified or defined. The device should not be used for carotid lesions, since the microemboli could lead to focal neurological deficits and perhaps even frank global cerebral dysfunction.
COMMENTS All atherectomy devices that have undergone extensive clinical investigation have failed to improve the restenosis rate of standard balloon angioplasty in the treatment of peripheral arterial occlusive disease. Despite actual removal, debulking, and polishing of the plaque, the invariable arterial wall trauma still induces intimal hyperplasia, which subsequently results in restenosis. Initial studies of atherectomy reported promising results, but subsequent follow-up has demonstrated poor intermediate and long-term patency rates. Moreover, follow-up illustrated that the intermediate and long-term patencies were less than satisfactory when compared with standard balloon angioplasty. These results contradicted the postulate that physical removal of arterial plaque using atherectomy would lower the rate of restenoses compared to the mechanical reorganization seen in PTA. Until the problem of restenosis can be resolved, atherectomy will be limited to those instances when balloon angioplasty may be ineffective or contraindicated. Such instances might include the presence of hard, calcified lesions that are difficult to dilate, the presence of intimal flaps or dissections
Complications Associated with the Auth Rotablator
Complications Bleeding Dissection Embolization Hematoma Hemoglobinuria Thrombosis
Dorros et al.[22]
Ahn et al.[23]
White et al.[24]
CRAG study[25]
Henry et al.[26]
Myers et al.[27]
— — — 10/43 (23%) 27/43 (63%) 1/43 (2%)
— 1/20 (5%) 4/20 (20%) 1/20 (5%) 4/20 (20%) 5/20 (25%)
— — — 1/17 (6%) — 1/17 (6%)
10/79 (13%) 5/79 (6%) 8/79 (10%) 4/79 (5%) 10/79 (13%) 9/79 (11%)
— — 2/150 (1%) — — 12/150 (8%)
1/34 (3%) — — — — —
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secondary to the balloon angioplasty itself, or ulcerative lesions that have lead to thromboembolic complications. Furthermore, Porter et al.’s[2] report of their 6-year experience using directional atherectomy for vein graft stenoses is encouraging. They showed that the technique has a high technical and clinical success rate and approached patency rates seen in surgical vein patch angioplasty. Recently, atherectomy has been indicated for the treatment of failing hemodialysis fistulas; although the data are not definitive, the initial results are encouraging. Also, the
preliminary data on the combined use of atherectomy and balloon angioplasty appear promising. The results reported by Ahn et al.[20] suggest that combined therapy will increase the intermediate success rate and may increase the long-term patency rates with additional follow-up, further validating the study conducted by Osborn and associates.[15] Continued long-term follow-up and further investigation of combined therapy, as well as the use of atherectomy in the treatment of vein graft stenoses and failing hemodialysis fistulas, is clearly warranted.
REFERENCES 1. Dolmatch, B.L.; Gray, R.J.; Horton, K.M.; Rundback, J.H.; Kline, M.E. Treatment of Anastomotic Bypass Graft Stenosis with Directional Atherectomy: Short-Term and Intermediate-Term Results. J. Vasc. Intervent. Radiol. 1995, 6, 105– 113. 2. Porter, D.H.; Rosen, M.P.; Skillman, J.J.; Kent, K.C.; Kim, D. Long-Term Results with Directional Atherectomy of Vein Graft Stenoses. J. Vasc. Surg. 1996, 23, 554– 567. 3. Zemel, G.; Katzen, T.; Dake, M.D.; Benenati, J.F.; Lempert, T.E.; Moskowitz, L. Directional Atherectomy in the Treatment of Stenotic Dialysis Access Fistulas. J. Vasc. Intervent. Radiol. 1990, 1, 35– 38. 4. Gray, R.J.; Dolmatch, B.L.; Buick, M.K. Directional Atherectomy Treatment for Hemodialysis Access: Early Results. J. Vasc. Intervent. Radiol. 1992, 3, 497 –503. 5. Simpson, J.B.; Selmon, M.R.; Robertson, G.C.; et al. Transluminal Atherectomy for Occlusive Peripheral Vascular Disease. Am. J. Cardiol. 1988, 61, 96G – 101G. 6. Graor, R.A.; Whitlow, P.L. Transluminal Atherectomy for Occlusive Peripheral Vascular Disease. J. Am. Coll. Cardiol. 1990, 15, 1551– 1558. 7. Vroegindewij, D.; Tielbeek, A.V.; Buth, J.; Schol, F.P.G.; Hop, W.C.J.; Landman, G.H. Directional Atherectomy Versus Balloon Angioplasty in Segmental Femoropopliteal Artery Disease: 2-Year Follow-Up with Color Flow Duplex Scanning. J. Vasc. Surg. 1995, 21, 255– 269. 8. Lugmayr, H.; Pachinger, O.; Deutsch, M. Long-Term Results of Percutaneous Atherectomy in Peripheral Arterial Occlusive Disease. Rofo. Fortschr. Geb. Ro¨ntgenstr. Bildgeb. Verfahr. 1993, 158, 532– 535. 9. Polnitz, A.; Nerlich, A.; Berger, H.; Hofling, B. Percutaneous Peripheral Atherectomy. J. Am. Coll. Cardiol. 1990, 15, 628– 688. 10. Hinohara, T.; Selmon, M.R.; Robertson, G.C.; Braden, L.; Simpson, J.S. Directional Atherectomy: New Approach for Treatment of Obstructive Coronary and Peripheral Vascular Disease. Circulation 1990, 81 (Suppl. IV), IV79– IV-91. 11. Dorros, G.; Iyer, S.; Lewin, R.; Zaitoun, R.; Mathiak, L.; Olson, K. Angiographic Follow-Up and Clinical Outcome of 126 Patients After Percutaneous Directional Atherectomy (Simpson AtheroCath) for Occlusive Peripheral Vascular Disease. Catheter. Cardiovasc. Diagn. 1991, 22, 79–84. 12. Kim, D.; Gianturco, L.E.; Porter, D.H.; Orron, D.E.; Kuntz, R.E.; Kent, K.C.; Siegel, J.B.; Schlam, B.W.; Skillman, J.J.
13.
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20.
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23.
Peripheral Directional Atherectomy: 4-Year Experience. Radiology 1992, 183, 773– 778. Savader, S.J.; Venbrux, A.C.; Mitchell, S.E.; Trerotola, S.O.; Wang, M.C.; Sneed, T.A.; Tudder, G.B.; Rosenblatt, M.; Lund, G.B.; Osterman, F.A. Percutaneous Transluminal Atherectomy of the Superficial Femoral and Popliteal Arteries: Long-Term Results in 48 Patients. Cardiovasc. Intervent. Radiol. 1994, 17, 312– 318. Widenhain, P.M.; Wholey, M.H.; Jarmolowski, C.R.; Hill, K.L. Infrainguinal Directional Atherectomy: Long-Term Follow-Up and Comparison with Percutaneous Transluminal Angioplasty. Cardiovasc. Intervent. Radiol. 1994, 17, 305– 311. Osborn, J.J.; Pfeiffer, R.B.; String, T. Directional Atherectomy and Balloon Angioplasty for Lower Extremity Arterial Disease. Ann. Vasc. Surg. 1997, 11, 278–283. Wholey, M.H.; Jarmolowski, C.R. New Reperfusion Devices: The Kensey Catheter, the Atherolytic Reperfusion Wire Device, and the Transluminal Extraction Catheter. Radiology 1989, 172, 947– 952. Myers, K.A.; Denton, M.J.; Devine, T.J. Infrainguinal Atherectomy Using the Transluminal Endarterectomy Catheter: Patency Rates and Clinical Success for 144 Procedures. J. Endovasc. Surg. 1994, 1, 61– 70. Mazur, W.; Ali, M.N.; Rodgers, G.P.; Schulz, D.G.; French, B.A.; Raizner, A.E. Directional Atherectomy with the Omnicath: A Unique New Catheter System. Catheter. Cardiovasc. Diagn. 1994, 33, 79. Sapoval, M.R.; Gaux, J.C.; Bruneval, P.; Peronneau, P. Animal Evaluation of the Prototype OmniCath Catheter. Cardiovasc. Intervent. Radiol. 1994, 17, 226. Ahn, S.S.; Daniel, E.J.; Ro, K.M. Personal Communication. Presented at the XI Annual International Congress Endovascular Interventions, Scottsdale, Arizona, February 1998. Ahn, S.S.; Arca, M.; Brauel, G.; Marcus, D.L.; Auth, D.C.; Moore, W.S. Histological and Morphological Effects of Rotary Atherectomy on Human Cadaver Arteries. Ann. Vasc. Surg. 1990, 4, 563– 569. Dorros, G.; lyer, S.; Zaitoun, R.; Lewin, R.; Cooley, R.; Olson, K. Acute Angiographic and Clinical Outcome of High Speed Percutaneous Rotational Atherectomy (Rotablator). Catheter. Cardiovasc. Diagn. 1991, 22, 157– 166. Ahn, S.S.; Eton, D.; Yeatman, L.R.; Deutsch, L.S.; Moore, W.S. Intraoperative Peripheral Rotary Atherectomy: Early
Chapter 24. and Late Clinical Results. Ann. Vasc. Surg. 1992, 6, 272– 280. 24. White, C.J.; Ramee, S.R.; Escobar, A.; Jain, S.; Collins, T.J. High Speed Rotational Ablation (Rotablator) for Unfavorable Lesions in Peripheral Arteries. Catheter. Cardiovasc. Diagn. 1993, 30, 115– 119. 25. The Collaborative Rotablator Atherectomy Group (CRAG); Peripheral Atherectomy with the Rotablator: A Multi-Center Report. J. Vasc. Surg. 1994, 19, 509 – 515.
26.
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Henry, M.; Amor, M.; Ethevenot, G.; Henry, I.; Allaoui, M. Percutaneous Peripheral Atherectomy Using the Rotablator: A Single Experience. J. Endovasc. Surg. 1995, 2, 51– 66. 27. Myers, K.A.; Denton, M.J. Infrainguinal Atherectomy Using the Auth Rotablator: Patency Rates and Clinical Success for 36 Procedures. J. Endovasc. Surg. 1995, 2, 67– 73. 28. Ahn, S.S. Peripheral Atherectomy. Semin. Vasc. Surg. 1989, 2, 143– 154.
CHAPTER 25
Endovascular Grafts for Aneurysms, Occlusive Disease, and Vascular Injuries Takao Ohki Evan C. Lipsitz Frank J. Veith direct exposure of the diseased artery through extensive incisions and/or dissection. This chapter reviews the design and use of endovascular grafts in the treatment of various vascular pathologies including aortoiliac aneurysms, aortoiliac occlusive disease and traumatic vascular lesions. In addition, it will explore the future potential of this technology.
INTRODUCTION The past several decades have witnessed a marked improvement in the treatment results for a variety of vascular lesions. The operative mortality for elective repair of aortic aneurysms has decreased from 21% in early surgical series to less than 5% in recent studies.[1 – 5] Lower extremity occlusive disease with ischemic tissue loss which at one time mandated major amputation can now be treated by either interventional techniques, bypass surgery, or a combination of the two with favorable limb salvage rates.[6] Finally, despite advances in the delivery of emergency medical services and in critical care medicine, major arterial injury secondary to penetrating or blunt trauma has remained a challenging problem, especially when central arteries such as the aorta, the iliacs, or the subclavian arteries are involved.[7 – 9] Despite these improvements in the management of vascular lesions, significant perioperative morbidity and mortality still occur, particularly in cases associated with severe comorbid medical illness, scarring from previous operations, or multiorgan trauma.[10 – 13] Even in good-risk patients, standard vascular repairs have associated morbidity. Additionally, standard surgical treatment adversely impacts quality-of-life measures such as incisional pain and paresthesias, sexual dysfunction, and other problems. Finally, lengthy hospital stays are a major contributing factor to rising health care costs. These problems are at least in part related to the large incisions and extensive tissue dissection required for surgical access to major arterial lesions. Endovascular grafting is a blend of intravascular stent and prosthetic graft technologies, which offers an alternative to standard open treatment of vascular pathology. Endovascular grafts are inserted through remote arterial access sites to treat vascular lesions at a distance, thus eliminating the need for
HISTORY OF ENDOVASCULAR GRAFTS Attempted repair of aortic aneurysms using an intraluminal approach has a long history, which predates both early and modern open surgical techniques. In 1813 an Italian surgeon, Giovanni Monteggia, unsuccessfully attempted to “harden” the wall of an aneurysm by injecting a sclerosing agent into the lumen.[14] In 1864 Charles Moore attempted to promote thrombosis of a thoracic aneurysm by injecting 75 feet of silver wire into the sac.[15] This latter technique was expanded in 1879 by Corradi, who passed an electrical current through intraluminally placed wires to increase thrombosis.[16] Blakemore and King further refined this technique in 1938 when they described electrothermic methods for inducing thrombosis of aneurysms by heating intraluminal wires with an electric current.[17] The beginning of the modern era of endovascular grafting can be traced back to 1969, when Dotter placed plastic tubular endovascular prostheses into canine femoral and popliteal arteries.[18,19] The problem of thrombosis in these grafts was addressed by replacing them with a stainless steel wire made into a coilspring configuration. Although acceptable longterm patency was obtained, significant intimal hyperplasia
Hobson/Wilson/Veith: Vascular Surgery: Principles and Practice, Third Edition, Revised and Expanded DOI: 10.1081/0819-9-120024908 Copyright q 2004 by Marcel Dekker, Inc.
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developed within the grafts. Due to size constraints and the lack of compressibility of these devices, only small-bore grafts could be placed. The use of nitinol, a nickel –titanium alloy that possesses temperature-dependent memory, in these stents allowed for larger devices to be placed. The experimental work of Balko, Mirich, and their colleagues[20,21] with exclusion of experimental aneurysms and Lazarus’s patent for an endovascular graft appeared in the late 1980s.[22] The first endovascular graft placed in a patient was reported by Volodos et al. in 1986,[23] but this Russian report received little attention. However, the report of Parodi and his colleagues in 1991 of five cases of abdominal aortic aneurysms treated with endovascular grafts stimulated a great deal of interest in this approach.[24] These authors described a Dacron graft sutured to balloonexpandable slotted stainless steel Palmaz stent to treat a large abdominal aortic aneurysm using epidural anesthesia in a 70-year-old symptomatic patient who was felt not to be a candidate for conventional open repair. A total of five cases were reported in this preliminary series, and, although one patient required conversion to open repair after accidental stent deployment within the iliac artery, subsequent follow-up showed patent grafts without aneurysm related complications in the remaining patients. The first endovascular repair of an abdominal aortic aneurysm (AAA) in North America was performed by the Montefiore Hospital group in 1992.[25]
ENDOVASCULAR GRAFTS FOR ABDOMINAL AORTIC ANEURYSMS Almost a decade has passed since Parodi’s group first reported the use of endovascular stented grafts to treat abdominal aortic aneurysms.[24] During this early experience, we and others utilized largely physician-made devices constructed
from either Palmaz or Gianturco (self-expanding) stents.[26] Each of these physician-made devices consists of a single unit, and although there are several different configurations, the majority consist of a tubular aortoaortic or an aortouniiliac configuration. It was several years after Parodi’s report before the first industry-made stent-grafts appeared. Recently, a number of these industry-made devices have become available for clinical trials in the United States, including Vanguard (Boston Scientific Corp.), Talent (World Medical), Ancure (Guidant-EVT), AneuRx (Medtronic), Corvita (Schneider), Excluder (W.L. Gore), Zenith (Cook), and Baxter grafts (Baxter) (Fig. 25-1). These industry-made devices are mostly bifurcated grafts, the majority of which consist of two or more components (modular grafts), although they are also made in tubular versions. Endovascular graft devices can be categorized into a few distinct types based on device design and the anatomic variations of the aneurysm they can treat.
Construction and Design Self-Expanding vs. Balloon-Expandable Stents Endovascular grafts are a combination of vascular stents and prosthetic grafts where the stents serve as fixation devices and sometimes as support skeletons. Depending on the type of stent that is used, endovascular grafts can be categorized into two distinct types, self-expanding or balloon-expandable. The advantages of self-expanding devices include ease of deployment and the ability to accommodate some degree of subsequent aortic neck enlargement. All manufactured grafts except the LifePath (Baxter) employ self-expanding stents. An example of a “surgeon-made” device with a selfexpanding stent is the Chuter graft. The balloon-expandable stent that has been used for endovascular grafts has predominantly been the large Palmaz stent (P5014)(Cordis, Johnson and Johnson, Warren, NJ).
Figure 25-1. Various types of endovascular grafts used for the treatment of AAA. From left: Montefiore endovascular graft, Ancure graft, Vanguard graft, Corvita endoluminal graft, Talent graft, AneuRx graft, Excluder graft, Zenith graft.
Chapter 25.
Endovascular Grafts for Aneurysms, Occlusive Disease, and Vascular Injuries
Although this stent may be technically more demanding to deploy accurately at the desired location, it has stronger radial (hoop) strength than self-expanding stents. This may be important in preventing graft migration if one considers the high aortic flow and pressures that these endovascular grafts must withstand. The Palmaz stent has been used for many surgeon-made devices, including the Parodi graft, the Montefiore endovascular graft (Fig. 25-1), and the Leicester graft. The LifePath has a specially made, balloon-expandable stent that is called a graft attachment device (GAD).
Fully Supported vs. Partially Supported Grafts Most manufactured grafts are “fully supported” or have a stent that supports the entire length of the graft. This feature has several advantages. First, when endovascular grafts are deployed in tortuous arteries, this fully supported framework will help to prevent compression or kinking of the graft, a phenomenon that has been encountered more frequently in grafts that lack this support.[27] Second, this full support adds additional column or longitudinal strength to withstand distortion or displacement by the aortic flow. This strength is essential to keep the graft in position during deployment. In addition, this feature may help prevent distal migration of the graft even if the proximal stent lacks secure fixation.
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Examples of Individual Devices for Endovascular AAA Repair Ancure (Guidant EVT, Menlo Park, CA) Unlike other devices, the Ancure device secures the graft to the proximal and distal aneurysm necks with stents that have hooks. A balloon is used to ensure seating of the stent hooks into the aortic wall. In addition to the tubular version of this graft, second-generation models consist of bifurcated and aortouniiliac versions, which lack hooks on the distal stents. The latter version of this graft resembles that originally used by Parodi and requires the placement of a femorofemoral bypass graft and an occluder in the contralateral iliac artery. Regardless of the configuration, all Ancure grafts consist of a
Single Component vs. Multiple Component (Modular) Since the anatomy, length, and diameter of aortic and aortoiliac aneurysms vary significantly from patient to patient, it is advantageous for an endovascular graft to have a certain dimensional adaptability to accommodate this variability. Variability in length between the proximal and the distal ends or termination points can be managed by changing the amount of overlap between each of two modular components. This concept was first described by the Sydney group and was called the “trombone” graft.[28] In the bifurcated grafts the additional limb of a modular bifurcated graft as well as extenders will serve to achieve this form of lengthwise dimensional adaptability.[29] The distal landing zone of the limb can be adjusted by changing the amount of overlap between the main body and the limb. In addition, the length of the main limb can be extended distally with an extender stent-graft. All industry-made devices except for the Ancure graft utilize such a system. Another approach to achieve length adaptability is demonstrated by the Montefiore endovascular graft system (MEGS) (Fig. 25-2), and the Leicester graft.[26] These grafts have enough length so that the distal end of the graft emerges from the insertion femoral arteriotomy site, thereby allowing the surgeon to customize the length of the graft during the procedure. The distal end of the graft is cut to the appropriate length and a sutured endoluminal anastomosis is performed within the femoral artery. Endovascular grafts that lack such length versatility include the Chuter and the Ancure grafts. Precise preoperative measurement of the length of the graft is therefore crucial when using these grafts.[26]
Figure 25-2. A schematic drawing of the Montefiore endovascular graft. The bare portion of the proximal stent is placed above the renal arteries in order to maximize the fixation within the aorta. The graft covered portion of the stent marked by the radiopaque bead is placed just below the renal arteries (m). The distal end of the graft is brought out of the insertion arteriotomy site where it is cut to the appropriate length and fixed with a hand-sewn endoluminal anastomosis (e). (c: embolization coils, o: occluder device). (From Ref. [26].)
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single component. This means that the graft lacks the ability for intraoperative customization, and therefore, precise preoperative length measurement is essential when using this device. Since the size of the introducer sheath is 24 Fr in outer diameter, difficulties inserting the device through the femoral and iliac arteries as well as injuries to these vessels have been encountered. The Ancure graft is the only industrymade device that lacks a stent in the midportion of the graft. This has led to compression or kinking of the graft limb, which has resulted in graft occlusion.[27] In such cases, placement of an additional intragraft stent, either a Wallstent (Schneider, Minneapolis, MN) or a Smart stent (Johnson & Johnson, Warren, NJ), has been required.
Vanguard Endovascular Aortic Graft (Meadox, Oakland, NJ) and AneuRx Graft (Medtronic, Eden Prairie, MN) The Vanguard device employs a temperature-dependent Nitinol stent for fixation and structural support of the graft body, which is made of Dacron fibers. The stent is placed inside the graft to which it is held by sutures. This device is modular and is composed of a main graft and a separate contralateral limb component.[30] The main graft is loaded into a 20.5 Fr outer-diameter introducer sheath and delivered through a femoral arteriotomy site. The proximal stent is deployed just below the lowest renal artery. An extender graft may be added to the iliac limb of the main graft if required. Following deployment of the main graft, a contralateral limb is inserted via the contralateral femoral artery and deployed. This graft is currently undergoing Phase II FDA trials in the United States for good-risk patients. The AneuRx graft (Medtronic, Eden Prairie, MN) resembles the Vanguard graft, except for the fact that the entire supporting Nitinol stent is located outside the graft material.
Talent Endovascular Bifurcated Spring Graft (World Medical Manufacturing Corporation, Sunrise, FL) The Talent graft is similar to the Vanguard in regard to its modular configuration and its utilization of a Nitinol stent skeleton. Since the proximal stent has wide interstices, one can place the uncovered portion of the stent above and across the renal artery orifices. This feature along with the high hoop strength of the stent allows this device to treat some abdominal aortic aneurysms with a short proximal neck (# l.5 cm). In addition, this graft is supported with longitudinal Nitinol wire throughout its entire length. This gives the graft additional column strength, which prevents downward displacement of the graft by aortic flow during deployment as well as helping to prevent distal migration in cases where the proximal stent lacks secure fixation. In addition to the standard sizes, this graft can be custom-made to fit those patients that cannot be treated with standard-sized grafts. This customization includes graft diameter (up to 36 mm) as well as length and configuration.
The Zenith (Cook, Inc., Indianapolis, IN) The Zenith is a derivative of surgeon-made graft. It initially was used by Chuter et al. and subsequently by many others around the world. It is a combination of a large Gianturuco stent and Dacron fabric. The Zenith is unique in several aspects of its design. First, it has a long uncovered stent at its proximal end. This stent also has multiple long barbs that assures secure fixation of the stent into the suprarenal aortic neck. Second, although it is a modular bifurcated design, it is composed of three components: the main body and the two limbs. This allows for intraoperative customization of both length and diameter of each attachment site. Finally, it can treat aneurysms with proximal neck diameter up to 30 mm and distal neck diameter up to 22 mm, which is the widest range among all industry-made bifurcated grafts. It also can be custom-made.
The Excluder (W.L. Gore and Associates, Flagstaff, AZ) The Excluder is composed of an external Nitinol framework and an ultrathin polytetrafluoroethylene (PTFE). This is the only endovascular graft that does not utilize an outer introducer sheath as a deployment mechanism. Instead, the selfexpanding graft is encased in a thin membrane, which is connected to a strip cord. Once the graft is in place, the operator will pull the strip cord, releasing the thin membrane and thereby deploying the graft. Because of this unique deploying system that does not require a rigid sheath, the introducer system is extremely flexible. In addition, the fact that each Nitinol stent is independent and is not attached to another contributes to the flexibility of the system. The ease of use and the flexibility of the graft are the strengths of this graft.
The Montefiore Endovascular Graft System (MEGS) The MEGS device is a derivative of the original Parodi graft, which was fabricated from a Palmaz stent and a Dacron graft. [24] The current MEGS has undergone several modifications and has several improvements, which have increased its versatility and its ease of use (Fig. 25-2).[26] It utilizes a tulip-shaped PTFE graft instead of a Dacron graft. Originally, the length of the graft needed to be measured precisely preoperatively so that the distal end could be fixed in the common or the external iliac artery by a second stent. This precise measurement was difficult, and placement of the second stent added complexity to the procedure. The current MEGS endovascular graft is made long enough so that in each case, the distal end of the graft will emerge from the insertion site in the femoral artery. The graft is then cut to the appropriate length as it emerges from the artery and is sutured to the inside of the femoral artery to fashion an endoluminal anastomosis. This has enhanced the ease of the procedure by eliminating difficult preoperative length measurements and a potential endoleak site (distal attachment site leak). Another beneficial modification has been the placement of the proximal uncovered portion of the stent above the orifice of the renal arteries. This provides more secure fixation of the proximal stent even in cases with necks shorter than 1.5 cm.
Chapter 25.
Endovascular Grafts for Aneurysms, Occlusive Disease, and Vascular Injuries
Furthermore, contralateral iliac outflow obstruction during stent-graft deployment allows for more precise control and has increased the accuracy of stent placement, which is of paramount importance in cases where the proximal neck is short.[31] For the delivery system, we have been able to decrease the outer diameter of the introducer sheath from 24 Fr to 16 Fr. These modifications, along with some technical improvements such as the occasional use of a brachial wire and snare (which adds tension to the guidewire and helps to straighten tortuous iliac arteries and aneurysm necks), have facilitated device insertion. This has expanded the anatomic variations that can be treated with this type of endovascular graft. There is little question that the industry-made modular devices have made the insertion of these grafts easier and less complicated than was the case with the surgeon-made grafts. This relative ease of device delivery led many to believe that surgeon-made devices might become obsolete. However, as experience with endovascular grafting has increased, it has become apparent that the modular devices are largely applicable only in selected cases with favorable anatomy, as already discussed (Fig. 25-3). On the other hand, surgeonmade devices, especially the MEGS, have become far more versatile in their ability to treat a wide range of patients, including many who were excluded from industry-made protocols (Figs. 25-4 and 25-5). This is attributable to the versatility of the MEGS device itself and to the strong radical force generated by the Palmaz stent. At our institution, we have shown that 80% of consecutive AAA cases can be treated with an endovascular graft, while only 20% required open repair (Fig. 25-6).[32] Of the endovascular grafts used in this series, various industry-made devices accounted for approximately 50% of grafts placed while the MEGS accounted for the remaining 50%. The ability to treat such a high proportion of patients by endovascular methods depends on having access to a wide variety of grafts, each of which expands the inclusion criteria for and/or the advantages of endovascular repair.
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Basic Setup of the Operating Room The operator and first assistant usually stand on the right side of the patient and the screen of the fluoroscope is placed so that it faces the operator (Fig. 25-7). The operating table must be radiolucent and is controlled (height, oblique, and longitudinal adjustments) by the surgeon using a foot pedal. An extension table is attached to the caudal end of the operating table so that the lengthy guidewires and catheters are supported and do not become contaminated. This extension table has wheels so that it simultaneously moves with the operating table.
Basic Technical Considerations Unlike open repair, endovascular repair is performed from remote access sites. Therefore, the surgeon does not have direct control of the devices employed for repair such as
Required Equipment for Endovascular Grafting The vast majority of endovascular grafts are currently performed in an operating room using a portable C-arm digital fluoroscope with road-mapping capabilities (Philips Models BV-212, BV-312 Philips Medical systems, Bridgeport, CT; OEC Diasonics, Model 9600, OEC Medical Systems, Inc., Salt Lake City, UT). The rationale for performing procedures in an operating room environment includes: (1) the potential need for rapid conversion to an open major surgical procedure without delay when necessary; (2) an optimally sterile environment, which is mandatory since all the devices currently leave prosthetic material within the body and require surgical exposure of the femoral artery (although infection has not been a major problem, the risk of graft infection must be minimized); and (3) the ability to perform open procedures simultaneously, such as femorofemoral bypass or repair of a damaged iliac or femoral artery.
Figure 25-3. (A) Preoperative angiogram of an aneurysm suitable for industry made devices. The aneurysm is characterized by (1) long straight proximal neck, (2) good quality common iliac artery, (3) minimal tortuosity. (B) Completion angiogram. This particular case was treated using the Vanguard bifurcated graft. Complete exclusion of the aneurysm as well as preservation of renal and hypogastric arteries are demonstrated. (From Ref. [129].)
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Figure 25-4. (A) Preoperative angiogram of an aneurysm with short proximal neck and bilateral iliac artery occlusive disease. In addition there is a large left internal iliac artery aneurysm that precludes the use of current bifurcated grafts. (B) Completion angiogram following deployment of an aortounifemoral graft, femorofemoral bypass (f) and an occluder device (o). Note that the bare portion of the proximal stent (s) is placed across the renal arteries. (c: embolization coils.)
catheters, guidewires, and the graft itself. In addition, all endovascular manipulation is performed under fluoroscopic guidance, which gives the surgeon only a two-dimensional image. Moreover, the information provided by these fluoroscopic images is quite limited. Radiolucent structures including thrombus, plaque, arterial wall, radiolucent catheters, and graft material are not visualized. Therefore, throughout the procedure the operator must conceptualize all events that may be occurring, including those not revealed on fluoroscopic imaging. These events include arterial dissection, rupture, embolization, and kinking or tearing of the graft. Another limiting factor is the size of the field fluoroscopy provides compared to open repair in which the surgeon can obtain a great deal more information visually by simply adjusting his/her field of view or by tactile sensation. Therefore, when performing an endovascular repair, the operator must constantly be cognizant of those elements that are both outside the fluoroscopic field or not visualized fluoroscopically. The operative technique required for endovascular AAA repair is not simply a blend of surgical and interventional
techniques, but rather involves many techniques that are unique to this procedure. These techniques are constantly evolving and are yet to be standardized. Although the basic principles are consistent among various devices, it is likely that some new and different techniques will be required for each new device that is developed.
Techniques to Obtain Vascular Access All currently available devices require surgical exposure and an arteriotomy in the femoral artery due to the large profiles of the introducer systems. The incision is placed higher (close to the inguinal ligament) than for a standard femoropopliteal bypass, and retraction of/or partial division of the inguinal ligament may be necessary in order to dissect the external iliac artery. This technique is helpful in straightening a tortuous external iliac artery, which is not an uncommon finding in complex AAA cases. Following arterial exposure, vessel loops are placed around the artery proximal and distal to the puncture site. It is usually not
Chapter 25.
Endovascular Grafts for Aneurysms, Occlusive Disease, and Vascular Injuries
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Figure 25-5. (A) Intraoperative angiogram of a 7 cm aneurysm with (1) severely angulated proximal neck and (2) aortoiliac occlusive disease which precluded the use of industry-made endovascular grafts (EVGs). The patient had oxygen-dependent chronic obstructive pulmonary disease (COPD) and severe coronary artery disease (CAD) and was not a good candidate for open repair. (B) Endovascular repair was successfully performed under epidural anesthesia utilizing the Montefiore endovascular graft. Completion angiogram reveals complete exclusion of the aneurysm and absence of an endoleak.
necessary to dissect the origin of the deep femoral artery unless the common femoral artery is heavily calcified and unclampable. An 18-gauge, one-wall needle is used to puncture the artery, and a 0.035 inch guidewire is inserted through the needle. The needle is then removed and an introducer sheath (7–9 Fr. 10–25 cm long) is inserted over the guidewire.
Deployment Technique of a Bifurcated Modular Graft The previously placed guidewire is then exchanged for a superstiff wire to help to straighten any tortuosity in the access vessel and to improve trackability of the device. A
marker pigtail catheter is inserted in the proximal neck through a sheath inserted in the contralateral femoral artery. The ipsilateral femoral artery is clamped proximally and distally to the sheath insertion site with a hydrogrip clamp and the sheath is then removed. A vertical artcriotomy is made with a knife for the insertion of the large sheath containing the main graft. Once the introducer sheath is advanced to the proximal neck of the AAA, an angiogram is performed via the pigtail catheter to identify the location of the lowest renal artery. The position of the sheath containing the stented graft is adjusted based on this angiogram. In general, since it is possible to pull the stent graft caudally, but difficult to push it cranially, when it is partially deployed it is recommended to begin the deployment at a point higher than the desired site. After partial deployment, the stent-graft is pulled caudally to
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Figure 25-6. Breakdown of how AAAs were treated at Montefiore Medical Center during 1997 –1998. MEGS: Montefiore endovascular grafting system.
the target site and the deployment completed. Deployment is performed by maintaining the pusher rod stationary and retracting the outer sheath. Following complete deployment, a balloon is inflated within the entire length of the graft to ensure full expansion and anchoring (Fig. 25-8). The pigtail catheter that was inserted from the contralateral side is retracted into the aneurysm prior to final deployment and exchanged to a directional catheter after deployment. This is then used to cannulate the short limb of the graft (Fig. 25-8). Since the short limb orifice is located within the aneurysm, difficulties in cannulating it may be encountered. An alternative means to cannulate the short limb is to pass a guidewire either from within the contralateral (main graft) side (over the top of the bifurcation) or from the brachial artery. This wire can then be introduced down to the femoral
Figure 25-7. Basic setup of the operating room. The operator stands on the right side of the patient and the screen of the fluoroscope (S) is placed so that it faces the operator. A foot switch (F) for the fluoroscope and the table are placed in front of the operator (O). An extension table (E) is attached caudal to the operating table. The cranial end of the operating table is placed towards the caudal end of the patient and the post of the table (P) is under the patient’s lower extremity. The left arm is also prepped in case a brachial access is required. A, assistants; N, nurse; C, fluoroscope; AN, anesthesiologist; T, table for endovascular equipment. (From Ref. [130].)
Figure 25-8. Implantation sequence of a modular graft. (A) The delivery system containing the main body is advanced in to the aorta over a superstiff guidewire. (B) Deployment is performed by maintaining the pusher rod stationary and retracting the outer sheath. Following complete deployment, a balloon is inflated within the entire length of the graft to ensure full expansion and anchoring. (C) Once the short limb is cannulated with a guidewire, a sheath containing the contralateral limb is passed over the wire. (D) Retraction of the outer sheath will expose the graft and deployment will be completed. (From Ref. [131].)
Chapter 25.
Endovascular Grafts for Aneurysms, Occlusive Disease, and Vascular Injuries
artery or can be captured with a snare inserted from the ipsilateral (short limb side) femoral artery. Once the short limb is cannulated with a guidewire, an angiogram is taken through the side port of the sheath to localize the orifice of the hypogastric artery. The marker pigtail can be used to measure the distance between the short limb and the hypogastric artery. Based on this measurement, the appropriately sized contralateral limb is chosen and inserted over the wire into the short limb. At this point, the operator should focus on the distal end of the extension limb so that it does not cover the orifice of the hypogastric artery (Fig. 25-8) while assuring that there is sufficient overlap between the stent limb and the extension. Retraction of the outer sheath will expose the graft and deployment will be completed. An angioplasty balloon is used to ensure full expansion and fixation. Following a completion angiogram, all the sheaths and wires are removed and the arteriotomics arc closed. At this point, the abdomen should be palpated to confirm resolution of the pulsatility of the AAA. If an endoleak is identified on angiogram, the source should be identified and corrected. If the endoleak is due to too low a deployment of the proximal stent, a covered stent may be deployed proximal to the stent graft. For distal attachment site leaks, an extra limb may be used. Those endoleaks that originate from the junction site between the main body and the limb may be corrected by deployment of a Palmaz stent or an additional covered stent. Stenosis due to buckling, twist, or kink of the limb is more often found in grafts that lack stent support, and these stenoses are best treated with a Wallstent (Schneider). A pull through pressure gradient study is then performed, which can sometimes detect an abnormality even in those cases without angiographic findings. Although we do not routinely use intravascular ultrasound, in this circumstance it may be a very useful tool to clarify the cause of unexpected pressure gradients. In cases where the femoral artery is small or diseased, a patch closure of the arteriotomy may be performed. Before completing the procedure, pulse examination or angiography should document adequacy of the distal circulation or restoration of the preoperative status.
Patient Selection for Endovascular Graft Repair of AAA Three basic graft configurations are utilized for the endovascular repair of abdominal aortic aneurysms: aortic tube, bifurcated modular aortobiiliac, and aortouniiliac or aortounifemoral with placement of a contralateral common iliac occlusion device and femorofemoral bypass graft. Only a certain proportion of abdominal aortic aneurysms are anatomically suitable for endoluminal repair with each of these devices. It has been estimated that 4 –14% of aneurysms are suitable for aortic tube stent-grafts,[33 – 36] 30–50% for aortobiiliac stent-grafts,[30,37] and 55% for aortouniiliac stentgrafts.[38] The exact selection criteria and contraindications for these procedures have yet to be precisely defined, but are evolving rapidly. Suitability for endovascular repair varies depending on which endovascular graft system is chosen and its suitability for a given patient’s anatomy. Moreover, the selection criteria utilized for each of the endovascular grafting
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systems are completely different from those traditionally used for open repair. This section reviews the unique selection criteria for endovascular AAA repair with reference to the different endovascular grafting systems currently available.
PREOPERATIVE IMAGING The evaluation of patients for endovascular AAA repair includes a screening abdominopelvic computed tomography (CT) scan. This study should be performed with intravenous contrast on a spiral scanner using 3 –6 mm cuts. Aneurysm length, diameter, and the quality and dimensions of the proximal and distal necks are evaluated along with the characteristics and diameter of the access vessels. The presence or absence of mural thrombus at the necks, which is of paramount importance, can only be ascertained on CT scan. If it appears that the patient may be a candidate for endovascular grafting based on the CT findings, then a contrast aortogram is performed. This permits assessment of the renal, inferior mesenteric, and iliac arteries. The mesenteric circulation as a whole, lumbar arteries, and any other aberrant vessels are evaluated. Tortuosity, kinking, size (diameter), and calcification of the iliac vessels, which have implications for device insertion and deployment, are noted. The study is performed with a calibrating catheter, which contains radiopaque markers at 1 cm intervals allowing for precise measurement of the vessels by minimizing the effects of parallax and magnification. However, since preoperative arteriography has some morbidity (0.5 – 1%) and cost ($2000–$3500), a magnetic resonance angiogram (MRA) or an intraoperative angiogram at the time of endovascular graft insertion may be used in place of preoperative arteriography.[39,40]
ANATOMIC SELECTION CRITERIA Regardless of the type of endovascular graft used, there are several anatomic criteria that must be fulfilled prior to attempting endovascular repair. If these criteria are not fulfilled, the procedure is generally contraindicated. These criteria will vary somewhat depending on the graft used, the risk status of the patient, and the experience of the operator.[26,27,30,41 – 44] The basic criteria that render an AAA suitable for endovascular repair include: 1. Quality and dimensions of the proximal aortic neck. In our experience, this is the most important factor determining suitability and outcome. (a) Optimally, the proximal neck should consist of a normal caliber, cylindrical aortic segment at least 1.5–2 cm in length (Fig. 25-9A, length a) and not more than 25 –30 mm in diameter (Fig. 25-9A, diameter b), distal to the renal ostia and proximal to the aneurysm to afford adequate proximal fixation of the graft. This area should be free of thrombus and not conical or flaring in shape, i.e., no more than 3–4 mm widening from
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Figure 25-9. (A) Measurements used in determining suitability for endovascular AAA repair. Lines a, d, and f represent the lengths of the proximal neck, distal neck, and common iliac artery, respectively. Line c represents the length of aorta from the renal arteries to the bifurcation. Lines b, e, g, and h represent the diameters of the proximal neck, the distal neck, the common iliac artery, and the external iliac and/or femoral arteries, respectively. (Adapted from Ref. [132].) (B) Angles essential for determining suitability for endovascular AAA repair and device selection. The dashed lines represent the angle (1) created by the neck of the aneurysm and the aneurysm itself. The dotted lines represent an angle (2) created by tortuosity of the iliac artery. (From Ref. [133].)
the proximal to distal ends of the neck. One exception to these guidelines involves the Talent graft, which can be customized to accommodate proximal aortic neck diameters up to 40 mm. This ability clearly enables surgeons to treat a wider range of patients. However, since larger aortic necks tend to dilate more than smaller necks, the long-term durability of endovascular repair in these circumstances remains questionable.[45] In addition, larger grafts require larger sheaths making access more difficult. Certain endovascular grafts with an uncovered portion of the stent at the proximal end permit transrenal
deployment of the stent. This has allowed the treatment of some abdominal aortic aneurysms with proximal necks , 15 mm. Grafts with this property include those which utilize a large proximal Palmaz stent (including the MEGS), the Talent graft, the Zenith graft, and to some extent the Vanguard graft. The patency of the renal arteries and maintenance of renal function following such transrenal stent deployment has been documented in most cases in both animal studies and human experience, although there have been occasional problems in humans and animals.[46,47] (b) Another important factor is the angle between the proximal neck and the suprarenal aorta or the proximal neck and the aneurysm. If this angle is quite large, it may preclude endovascular repair, especially if one is using an endovascular graft with a self- expanding stent or framework (Fig. 25-9B, angle 1). The Vanguard and Talent devices, for example, require that these angles not be greater than 60 degrees, and the Corvita graft requires that it not be greater than 30 degrees. As the aorta enlarges in diameter, it often elongates. This elongation results in angulation of the proximal neck. and accordingly larger aneurysms tend to have more angulated necks. In our experience, this angulation has been a leading factor which precludes endovascular repair.[32] Parodi-type grafts and their derivatives including the MEGS and the Leicester graft are unique in that they utilize a Palmaz stent, which generates the strongest radial force.[26,47] This has enabled successful treatment of abdominal aortic aneurysms with severe proximal angulation. 2. Quality of the distal landing zone. (a) If a straight or tubular graft is to be employed, the presence of a normal distal aortic segment approximately 2 cm in length (Fig. 25-9A, length d) and not greater than 25 mm in diameter (Fig. 25-9A, diameter e) without thrombus proximal to the aortic bifurcation (distal neck) is a requirement. Since tube grafts have tended to fail at the distal attachment site, some researchers have advocated that minimal distal neck length for tube grafts should be . 25 mm.[48] We believe very few abdominal aortic aneurysms need such treatment. (b) Quality of the iliac arteries. If the site selected for distal implantation is the common or external iliac artery, its morphology must be adequate for obtaining an adequate seal with the attachment system. Patients with tortuosity of . 90 degrees at any point (Fig. 25-9B, angle 2), significant dilatation to 16–20 mm bilaterally (Fig. 25-9A, diameter g), or severe circumferential iliac artery calcification are generally poor candidates. The presence of a short (, 30 mm) common iliac (Fig. 25-9A, length f) or the use of the external iliac as the target vessel requires
Chapter 25.
Endovascular Grafts for Aneurysms, Occlusive Disease, and Vascular Injuries
embolization of the internal iliac artery, if patent, to prevent back filling of the aneurysm. Unfavorable characteristics of the iliac arteries are other reasons that preclude the use of most industry-made bifurcated grafts. In fact, it has been shown that up to 16% of patients with abdominal aortic aneurysms have at least one iliac artery aneurysm, and 12% have them bilaterally.[49] The aortounifemoral or aortouniiliac type of endovascular graft such as the MEGS device is very useful in dealing with patients with large diameter iliac arteries, (Fig. 25-5). 3. Quality of the access arteries. (a) The common iliac, external iliac, and femoral arteries must be of sufficient caliber to allow passage of the introducer sheath or must be amenable to balloon dilatation to facilitate passage (Fig. 25-9A, diameter h). The size of the access vessels determines not only whether or not the patient is a candidate for endovascular repair but also which devices may be used. The outer diameter of the delivery sheath for each device varies. The outer diameters of the introducer systems are as follows: Talent (20 – 24 Fr), Vanguard (20.5 Fr), Ancure (24 Fr), AneuRx (24 Fr), Corvita (21 Fr), Excluder (20 Fr), Zenith (20 Fr), and MEGS (18 Fr)(3 Fr is equivalent to 1 mm). Future miniaturization of delivery systems will make endovascular graft introduction easier, safer, and feasible in more patients. However, due to the large introducer sizes of currently available devices as listed above, the size and quality of the access vessels remain important factors in selecting patients for endovascular repair. (b) The femoral and iliac vessels must demonstrate limited tortuosity after arterial straightening maneuvers, e.g., use of superstiff guidewires or dissection and caudal traction on the external iliac artery, use of through-and-through (brachial-to-femoral) wire traction, are employed.
Figure 25-10.
373
Tortuosity of the access vessels is seldom a factor that precludes endovascular graft repair, since it usually responds to straightening maneuvers. However, tortuosity plus heavy calcification may prevent device passage and obviate endovascular repair. 4. Presence of indispensable branches. (a) Aberrant vessels, particularly an indispensable accessory renal artery, must not arise from the segment of aorta to be excluded from the circulation by the graft. (b) The patient cannot be dependent on the inferior mesenteric artery for perfusion of the intestine, since this artery will be excluded from the circulation. This is especially true in cases with an occluded superior mesenteric artery and/or in which an aortounifemoral system is used, since coil embolization of the ipsilateral hypogastric artery will be required. 5. The patient must be both willing and able to comply with the appropriate follow-up regimen.
Summary of Selection Criteria for Endovascular Grafts Based on Anatomical AAA Classification Abdominal aortic aneurysms have been classified into five distinct groups according to their morphology and the extent of the aneurysm (Fig. 25-10).[50] The feasibility and the selection of an appropriate endograft for the treatment of a given aneurysm may be summarized on the basis of this classification. Type I: Abdominal aortic aneurysm with sufficient proximal (. 15 mm) and distal (. 15 mm) aortic necks (tube graft). Type IIA: Proximal neck . 15 mm, absence of distal aortic involvement (bifurcated graft) Type IIB: Proximal neck . 15 mm with proximal common iliac artery involvement. (bifurcated graft)
Classification of abdominal aortic aneurysms. (From Ref. [37].)
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Part Three. Endovascular Intervention
Type IIC1: Proximal neck .15 mm with iliac artery involvement to the iliac bifurcation on one side (aortouniiliac graft with contralateral iliac occlusion, femorofemoral bypass, and coil embolization of one hypogastric artery) Type IIC2: Both iliacs involved needing sacrifice of both internal iliac arteries or replant of one internal iliac artery Type III: Proximal neck , 15 mm (requires grafts that permit suprarenal stent placement). In cases where there is no proximal neck and the aneurysm involves one of two renal arteries arising at different levels of the aorta, one option is to use a graft that covers one renal artery, but leaves the opposite one patent. This is especially true if the patient is a prohibitive risk for open repair.
PATIENT SELECTION BASED ON RISK STATUS Good-Risk Patients Some endovascular graft protocols select patients whose general health is good and who have favorable anatomy for endovascular repair. The rationale in these protocols is that if the endovascular procedure fails, the patients are likely to tolerate conversion to an open procedure. However, emergent conversions have been shown to be associated with a high morbidity and mortality.[51] Although a reduction in the already low mortality rates of standard AAA repair would be a welcome result of any new procedure, the primary goal of endovascular repair in these good-risk patients is to improve quality of life by reducing postoperative pain, sexual dysfunclion, and complications resulting from an extensive intraabdominal operation. An additional goal is to reduce costs by decreasing both the need for ICU care and the postoperative length of stay. Most of the manufactured devices, including the Ancure, Vanguard, AneuRx, Corvita, Excluder, and Talent grafts are currently being evaluated in the United States in good-risk patients.
High-Risk Patients Although the morbidity and mortality rates of standard open abdominal aortic aneurysm repair have proven to be excellent in good-risk patients, these rates increase with the presence of associated diseases. Mortality rates as high as 60% have been reported in very high-risk patients.[52] Furthermore, standard repair may be difficult or impossible in patients with severe cardiopulmonary disease or a “hostile” abdomen secondary to such factors as multiple previous abdominal operations that produce extensive scarring, hernias, or infection. Selection of these high-risk patients for endovascular repair is justified on a “compassionate need” basis.[24] The goal of the endovascular repair in this group of patients is not only to reduce costs and improve the postoperative quality of life, but also to broaden the indications for AAA repair by providing
treatment for those patients who might otherwise be deemed untreatable. The devices that are presently available in such a high-risk group are primarily “surgeon-made” devices, which include the Parodi graft, the Leicester graft, the MEGS and the Nottingham graft.[43,53,54] In the United States, the Talent and to some extent the Excluder graft also have an FDA investigational device exemption that permits some usage in high-risk cases.
PATIENT SELECTION BASED ON ANEURYSM SIZE As previously discussed, in contrast to open repair where patient selection is not strictly dependent on the anatomical characteristics of the abdominal aortic aneurysm, both the feasibility and technical success of endovascular repair depend heavily on these anatomical features. Although Armon et al. have postulated that abdominal aortic aneurysm size does not influence the feasibility of endovascular repair, it is generally believed that smaller abdominal aortic aneurysms have better quality proximal and distal landing zones and straighter access vessels compared to those of larger AAAs.[55 – 57] Therefore, endovascular repair applied to abdominal aortic aneurysms at earlier stages of growth is expected to be both more feasible and possibly safer than if applied at later stages. In this way a higher proportion of patients with abdominal aortic aneurysms could benefit from endovascular repair. Based on this notion, some authors have advocated early endovascular intervention for small abdominal aortic aneurysms.[57] Despite these recommendations, the benefit of such early intervention has yet to be proven, and several issues suggest it may be unwise. First, patients with smaller aneurysms are generally younger and healthier. Therefore the endovascular graft must be more durable than when used for sicker patients. It is also known that with current stent-graft technology, the failure rate increases with time.[48] On the other hand, the failure of an endovascular graft does not always lead to death, and more often than not an endovascular solution is possible.[58,59] However, if surgical conversion is required, it has been shown that such secondary open repairs carry a higher mortality rate than a primary operation.[51] Second is the mortality that endovascular graft repair carries. May et al.[51] performed endovascular graft repair in 43 small aneurysms with a mortality rate of 14%. This rate is clearly higher than that of untreated small abdominal aortic aneurysms. However, some recent results from prospective trials using the Ancure and AneuRx grafts had impressively low mortality rates of 1% to 2%, respectively.[60,61] The third reason for questioning the use of stented grafts in patients with small abdominal aortic aneurysms is the risk of immediate open conversion. Such conversions may result from renal artery occlusions, obstruction of flow to the lower extremities, or the presence of a proximal attachment site endoleak. Although conversion rates are declining rapidly with increasing operator expertise and technological advancements, they are still in the range of 2 –8%. Therefore, we believe that at present endovascular grafts should only be
Chapter 25.
Endovascular Grafts for Aneurysms, Occlusive Disease, and Vascular Injuries
used to treat abdominal aortic aneurysms of a size that justifies open repair. The recent U.K. randomized trial showed no benefit of open repair over ultrasound surveillance in abdominal aortic aneurysms ranging between 4 and 5.5 cm in diameter.[62] The end point was survival rate at 6 years. This study concluded that there is no justification for early surgical intervention on abdominal aortic aneurysms that are smaller than 5.5 cm. The surgical mortality rate in this study was 5.8%. However, it is noteworthy that 60% of the patients assigned to the surveillance group ultimately underwent surgery during the study period, mainly due to the enlargement of the aneurysm beyond 5.5 cm. In addition, 7% of those in the surveillance group with aneurysm size of 5–5.5 cm died from aneurysmal rupture during surveillance period. Only when endovascular graft repair demonstrates further reduction in mortality rate and conversion rate and when these grafts are proven to have long-term durability can this form of treatment be advocated for patients with smaller abdominal aortic aneurysms (, 5 cm). It is apparent that endovascular repair is far less invasive than open repair. However, it should be remembered that endovascular repair is still far more invasive and carries a higher mortality than no repair, Thus, we currently believe that the indications for endovascular repair of abdominal aortic aneurysms based on their size should be equal to those of open repair. As advocated by May et al., when further improvements in endovascular repair occur, a randomized prospective trial comparing endovascular repair and ultrasound surveillance may be warranted.[60] Isolated iliac artery aneurysms may also be amenable to endovascular graft repair depending on their anatomic characteristics. A variety of MEGS configurations has been used to treat these aneurysms (Fig. 25-11).
SUMMARY OF RESULTS OF ENDOVASCULAR GRAFT REPAIR OF ABDOMINAL AORTIC ANEURYSMS At least 10 endovascular devices have been employed clinically for the treatment of abdominal aortic aneurysms. These devices are highly variable with significant differences in configuration, attachment mechanism and graft composition. Whether any single device will prove more effective in the treatment of aneurysmal disease cannot be determined at present. The feasibility of endovascular abdominal aortic aneurysm repair has been established, and both the safety and technical success of endovascular repair have improved substantially over the past several years. These improvements are attributable to refinements in device manufacturing and operative technique as well as in patient selection. However, complications including deaths and technical difficulties specific to endovascular repair of abdominal aortic aneurysms have been encountered. Just as the deployment of these stent-grafts have their inherent techniques, a number of early and late complications inherent to the endovascular method of repair have been identified (Tables 25-1 and 25-2; Fig. 25-12). Early
375
Figure 25-11. Techniques for the endoluminal repair of aortoiliac aneurysms: (A) A localized common iliac artery aneurysm treated with stents anchoring the endovascular graft proximal and distal to the aneurysm. (B, C) If the aneurysm of the common iliac artery extends to the hypogastric vessel, either placement of occlusion coils in the internal iliac artery or deployment of an additional stent within the endovascular graft is performed to prevent retrograde flow from the hypogastric artery into the common iliac artery aneurysm. In cases in which there is no proximal neck of the iliac aneurysm (D) or in cases with common iliac artery aneurysms with aortic aneurysms (F), a large aortic stent will be placed in the distal aorta. Prior to graft insertion, an occlusion coil will be placed in the hypogastric artery or its branches. In order to perfuse the contralateral limb, a standard femorofemoral bypass will be performed. (E) If a wide mouth opening to a internal iliac artery aneurysm is present, the anterior and posterior divisions of the hypogastric artery are individually coil embolized and the endovascular graft is secured with a stent above and below the origin of the aneurysmal artery, functionally excluding it from the circulation. In any of these reconstruction techniques, the second (distal) stent which is responsible for fixing the distal portion of the graft to the arterial wall may be eliminated by extending the endovascular graft to the common femoral artery (site of device insertion) and performing an endoluminal anastomosis. (From Ref. [102].)
complications of endovascular procedures include arterial dissections and ruptures, endoleaks, renal dysfunction from contrast agents, inaccurate deployment requiring device retrieval or removal, neurologic deficits, buttock claudication, groin wound infections, and early graft thromboses. The majority of graft failures tend to occur within the first month after operation (Fig. 25-13).[63] After that time there
1996
1996
1997
Moore and Rutherford[67] Balm et al.[70]
Yusuf et al.[38]
29 (81) 19 (95) 15 (75)
36 20 20
16 (89) 20 (80)
18 25
106 (88) 106 (88) 106 (88)
17 (81)
21
54 26 41
25 (83)
24 (77)
22 (48)
43 (80)
81 (74) 81 (74)
81 (74)
18 (86) 116 (87)
Primary technical success
30
31
46
54
46 12
51
21 133
n
n.a.
n.a.
5
n.a.
15 15 15
2 1 5b
32 (89) [1]a 19 (95) 15 (75) n.a. n.a. n.a.
0
n.a.
5
1
27 (87) [3]a 25 (83)
7
32 (70) [9]a
4 4
93 (85) [2]a 93 (85) [2]a 3
4
93 (85) [2]a
n.a.
0 3
Conversion to open repair
21 (100) 128 (96) [3]a
Success after additional endoluminal procedure
n.a.
0 (0)
n.a. n.a. n.a.
6 (8) 0 (8) 0 (8)
7 (33)
3 (10)
3 (10)
7 (15)
14 (26)
16 (15) 16 (15)
16 (15)
(6) (6)
Persisting endoleak or other late failure
3 (6)
5 (5) 5 (5)
5 (5)
1 (1) 1 (1)
30-day mortality
6 (24)
8 (44)
(15) (15) (15)
(33) (33) (33)
11 (52)
2 (8)
5 (28)
6 (5) 6 (5) 6 (5)
3 (4) 3 (4) 3 (4)
1 (5)
27 complications (rate 0 (0) not stated) 34 complications in 1 (3) 23 patients 6 (20) 2 (7), 3 (10) in hospital
n.a.
8 (7) 8 (7)
8 (7)
15 (10) 15 (10)
Other postoperative complications
Values in parentheses are percentages. Primary success refers to primary technical success rate as defined in the SVS/ISCVS (Society for Vascular Surgery/International Society for Cardiovascular Surgery) reporting standards. a Totals include cases in which spontaneous thrombosis of endoleaks occurred (number is square brackets) within 6 months of surgery (primary clinical success[23]). b Includes one failed deployment treated by axillofemoral grafting. n.a., Data not available; GAD, graft attachment device. Source: Ref. [138].
Thompson et al.[68]
Marin et al.[53]
May et al.[56][60]
Aortoaortic (EVT)
Aortouniiliac Aortobiiliac (Parodi device) Aortobiiliac (Chuter-Gianturco) Aortoaortic (EVT)
Aortouniiliac (Ivancev-Malmo) 1996 Aortobiiliac (Perth device) 1997 Aortoaortic Aortouniiliac Aortobiiliac (White-Yu GAD) 1996, 1997 Aortoaortic Aortouniiliac Aortobiiliac (GAD[41] and others) 1995 All types (EVTand Parodi) 1997 Aortouniiliac (Leicester device)
1997
LawrenceBrown et al.[44] White et al.[28]
Device
Aortoaortic Aortobiiliac (Vanguard or Passager) 1995, 1997 Aortoaortic
1997
Year
Chuter et al.[64]
Parodi et al.[69][65]
Blum et al.[30]
Reference
Table 25-1. Reported Results of Endoluminal Repair of Abdominal Aortic Aneurysm
376 Part Three. Endovascular Intervention
1 10 6 — — 3 — 4 — — — — — — — — — — — —
3 2 7 — 4 1 — — 2 1 1 — — 87 2 — — — — 1
Parodi[65] ðn ¼ 109Þ
— — — —
9 — —
2 — — 1 — — — —
8 1 7 6 —
Moore[67] ðn ¼ 46Þ
1 1 2 1
5 2 2
2 6 — 1 — — — —
6 2 — 1 1
Blam[70] ðn ¼ 31Þ
1 2 — —
— — 1
1 — — — — — 1 —
— 3 — — —
Yusuf[38] ðn ¼ 30Þ
1 1 — —
— — 1
— — — — — — — —
— 4 — 1 3
Lawrence-Brown[44] ðn ¼ 21Þ
3 — — —
— 7 8
— 1 — — 1 — — —
9 3 5 6 4
May[60] ðn ¼ 121Þ
— — 1 —
— 1 —
— — 1 — — — — 1
— — — 2 1
Thompson[68] ðn ¼ 25Þ
6 (1) 4 (1) 3 (1) 2
101 (19) 12 (2) 12 (2)
9 (2) 7 (1) 5 (1) 4 (1) 2 1 1 1
27 (5) 25 (5) 25 (5) 16 (3) 13 (2)
Total ðn ¼ 537Þ
Values in parentheses are percentages. Only series in which individual complications are specified have been included. Complications are categorized according to the SVS/ISCVS (Society for Vascular Surgery/International Society for Cardiovascular Surgery) reporting standards for infrarenal aortic aneurysm repair. Source: Ref. [138].
Local vascular complications Arterial access injury requiring surgery Persisting endoleaks Late-onset endoleaks Wound or minor graft infection Thromboembolic events leading to surgery Minor embolic events Blood loss requiring . 2 units transfusion Fatal embolic events Lymph leak Hematoma requiring surgical treatment Arteriovenous fistula Colonic ischaemia Bowel perforation Remote systemic complications Pyrexia Renal failure Myocardial infarct, cardiac failure, or arrhythmia Cerebrovascular event Pneumonia Respiratory failure Hepatic or multiorgan failure
Complication
Blum[30] ðn ¼ 154Þ
Table 25-2. Complications Reported Following Endoluminal Repair of Abdominal Aortic Aneurysm Chapter 25. Endovascular Grafts for Aneurysms, Occlusive Disease, and Vascular Injuries 377
378
Part Three. Endovascular Intervention
Figure 25-12. Classification of endoleaks. Type I: endoleak occurs at the proximal and/or distal attachment zones. Type II: endoleak is caused by retrograde flow from patent lumbar or inferior mesenteric arteries. Type III: endoleak arises from a defect in the graft fabric, inadequate seal, or disconnection of modular graft components. Type IV: endoleak is due to graft fabric porosity, often resulting in a generalized mild blush of contrast within aneurysm sac. (From Ref. [134].)
is a slow, steady rate of failure. Late complications include persistent endoleaks or de novo endoleaks. Both can cause ongoing pressurization and enlargement of the aneurysm leading to potential rupture. Other late complications are graft disruption secondary to suture or graft material fatigue and late graft thrombosis. The majority (. 55%) of late failures are due to problems at the fixation sites of the endovascular graft (Table 25-3).[28,30,44,64 – 67] However, device migration, fabric and/or suture fatigue, retrograde flow into the aneurysm sac from lumbar vessels or the inferior mesenteric artery, and graft distortion leading to occlusion all contribute significantly to the late failure rate. The initial technical success rate of endoluminal repair ranges from 48 to 95%, but when additional endoluminal interventions performed at the time of graft placement are included these figures jump to 70 –100%.[28,30,44,53,54,64 – 72] The overall reported incidence of reported postoperative complications ranges from 7 to 52%, with the incidence of persistent endoleaks and other late failures being 6 –33%. Recently, a number of investigators have reported their midterm results with mixed conclusions. One favorable
Figure 25-13. Durability of endovascular grafts according to the configuration of grafts shown by Kaplan– Meier curves. The curve is adjusted for death without prior procedure failure. (From Ref. [135].)
article was published by May et al.[73] In their analysis, they showed that the long-term patient survival was better during a follow-up period up to 5 years following EVG repair than it was after open surgical repair in a control group of patients. Zarins et al. reported an encouraging rupture-free rate of 99.5% at 3 years using the AneuRx graft.[74] There have been similar encouraging reports on the outcome of the Ancure graft as well.[75,76] However, a number of others have raised concerns regarding the midterm durability of EVG repair. Zarins himself and his colleagues reported 7 unexpected AAA ruptures after EVG repair with 5 deaths.[77] Furthermore, the European collaborators reported their experience with 2464 EVGs over a 4-year period. Of these, 14 patients presented with aneurysm rupture 0–24 months following EVG repair with 9 deaths.[78] Ho¨lzenbein et al. reported that 26% of their patients needed to undergo a secondary procedure to treat EVG-related complications during a follow-up period of 18 months.[79] Others reported similar results and raised similar concerns.[78,80 – 84] We have also reported our midterm results which expand on these findings and concerns.[85] Two hundred and thirty-nine patients who were treated endovascularly were followed over a 6-year period (mean 16 months). During this period, 2 AAAs ruptured and were surgically repaired with one death. Other late complications included: type I endoleak (7), aortoduodenal fistula (2), graft thrombosis/stenosis (7), limb separation or fabric tear with a subsequent type III endoleak (1), and a persistent type II endoleak (13). Secondary intervention or surgery was required in 23 cases (10%). These included: deployment of a second EVG (4), open AAA repair (5), coil embolization (6), extraanatomic bypass (4) and stent placement (3). At 3 years, the primary clinical success, secondary clinical success, and freedom from aneurysm-related death were 86%, 92%, and 84% respectively. The increasing occurrence of late failure with time in patients whose treatment was originally successful for more than one year is alarming.[73,74,77 – 93] From our and others’ experience, it is clear that EVG repair is not as durable as open surgical repair. EVGs can fail in a greater number of ways and with greater frequency than standard AAA grafts
Chapter 25. Table 25-3.
379
Endovascular Grafts for Aneurysms, Occlusive Disease, and Vascular Injuries
Causes of Late Failure Reported Following Endoluminal Repair of Abdominal Aortic Aneurysm Endoleak
Fabric failure
Lumbar or mesenteric backbleed
Further endoluminal treatment successful
0 0 4 0
6 0 0 0
3 0 2 2
7 2 2 0
4
0
0
0
0
6
0
0
0
2
Fixation Graft Graft site Device thrombosis infection failure migration
Reference
Year
Total no. of late failures
Blum et al.[30] Parodi et al.[65] Chuter et al.[64] Moore and Rutherford[67] LawrenceBrown et al.[44] White et al.[28]
1997 1997 1997 1996
9 16 14 7
0 0 5 0
0 0 1 0
0 16 2 5
1996
7
3
0
1997
6
0
0
Endoleak refers to clinical failure of endoluminal surgery because of leaks persisting or arising de novo more than 6 months after graft implantation. Source: Ref. [138].
placed at an open operation. These modes of endovascular graft failure included occurrence of late endoleaks, graft thrombosis, aortoenteric fistula, and ultimately rupture of the aneurysm with and sometimes without a known endoleak. Such disadvantages of EVG repair must be weighed against several positive attributes. These include the low mortality rate, even in patients at high risk for open surgery, and the short length of hospital stay. Also, the fact that most late failures can be detected prior to causing a catastrophic event or death is a positive finding. This allows one to perform secondary salvage procedures in a timely fashion to prevent aneurysm rupture or limb loss. Moreover, the secondary procedures, when required, are mostly minimally invasive and the technical success rate is high. Most of the late problems that have been encountered have been treated with percutaneous procedures, and many were done transfemorally.[79,80,85,89,92,94] Therefore, late failure in itself does not necessarily produce a bad overall outcome. On the other hand, failure to detect late failure can lead to aneurysm rupture and death.[77,78] Therefore, diligent postoperative surveillance is critically important after an EVG repair.
inducing thrombosis in this circumstance may lead to a successful outcome.[80,91,94,97,98] In contrast, short endoleak channels with a wide diameter will require covering of the feeding orifice with graft material in order to obliterate pressure transmission. Thus, although the type of endoleak will influence the method of treatment, we believe that the treatment method should also be determined by the length and diameter of the endoleak channel, and we have applied this concept in the treatment of endoleaks (Fig. 25-14).[85,91] For endoleaks with short, large-diameter channels (most type I and III endoleaks), deployment of a second EVG or an extension cuff is needed as opposed to inducing thrombosis. Placement of such a second graft is often possible. However, when it is not, surgical conversion should be performed if the patient was deemed an acceptable risk. For those patients with long, narrow endoleak channels (most type II endoleaks and some type I), inducing thrombosis can be performed by either temporarily terminating chronic anticoagulation therapy or by percutaneous coil embolization or injection of a biological glue. For methods of access, we have utilized both trans-
TREATMENT OF VARIOUS TYPES OF ENDOLEAKS Various methods of endoleak treatment have been attempted and reported. Options for treating endoleaks include coil embolization by transarterial or translumbar access routes, addition of stent-graft cuffs and extensions, endoscopic ligation of inferior mesenteric and lumbar arteries, redo endovascular stent-graft repair, and open surgical repair.[79,80,84,89,91 – 95] The method of treatment for a given endoleak is the subject of considerable controversy and debate. Based on the findings of various experimental models, we believe that when an endoleak has a long and narrow channel, pressure transmission across thrombus induced in this channel may be significantly reduced.[91,96] Thus,
Figure 25-14. Treatment strategy for various types of endoleaks. (From Ref. [85].)
380
Part Three. Endovascular Intervention
arterial and translumbar approaches.[80] Since most type II endoleaks have more than one inflow and/or outflow, it may be difficult to coil embolize all the endoleak channels via a transarterial approach. Thus, we currently recommend the translumbar approach for all type II endoleaks.[80,85,91]
ENDOVASCULAR GRAFT REPAIR OF AORTOILIAC OCCLUSIVE DISEASE Endovascular Grafts For aortoiliac occlusive disease we have used exclusively a modification of the Montefiore endovascular graft system. For this indication the graft is composed of a Palmaz balloonexpandable stent (P-294, Cordis, Johnson & Johnson Interventional Systems, Warren, NJ) and a 5 or 6 mm thinwalled (PTFE) graft (W.L. Gore and Associates, Flagstaff, AZ; or IMPRA, Inc., Tempe, AZ) (Fig. 25-15). The stent is attached to the proximal end of the PTFE graft by four interrupted CV-6 PTFE sutures (W.L. Gore and Associates) such that one-half of the stent protrudes beyond the end of the graft. After suturing the graft to the stent, the stent-graft complex is mounted onto an angioplasty balloon by manually crimping the stent over the 6–8 mm £ 4 cm angioplasty balloon (OPTA, Cordis, Johnson & Johnson Interventional Systems, Warren, NJ). The entire stent-graft and balloon complex is then inserted into a delivery sheath. A smooth transition zone at the end of the sheath is created by using a
6 mm £ 4 cm tip balloon. The tip balloon is adjusted so that one-half of the tapered portion of the balloon protrudes from the distal portion of the delivery sheath. A modified form of this delivery system consists of a dual balloon catheter (tip balloon and stent-deploying balloon) on a single shaft (Fig. 25-15). In both delivery system configurations, the tip balloon functions to create a smooth transition zone at the distal end of the delivery sheath as well as to occlude the sheath, which permits pressurization of the sheath with saline is injection from the flush port. This pressurization provides variable pushability and flexibility of the sheath, depending on the amount of pressure applied. This feature facilitates the insertion of the delivery sheath through diseased and tortuous iliac arteries. More recently, a single balloon system with a tapered introducer tip has been used. This modification permits the sheath size of the entire system be 16 French outer diameter.
Endovascular Graft Insertion and Location of Stent Deployment in Bilateral Iliac Disease In cases in which both iliac arteries are occluded or diffusely stenotic, a bilateral stent-graft aortobifemoral repair can be performed (Fig. 25-16A). We performed this procedure early in our experience. However, since bilateral reconstructions were technically more difficult and resulted in some suboptimal outcomes, we now prefer to perform a unilateral repair followed by a femorofemoral bypass (Figs. 25-16B and
Figure 25-15. Schematic drawings of an endovascular graft and the delivery systems for occlusive disease. (A) An endovascular thinwalled PTFE graft. A Palmaz balloon expandable stent (S) is sutured to the graft using four diametrically opposed “U” sutures (two on each side), which permit one-half of the stent to protrude from the graft. (B) Double balloon catheter introducer/delivery system used for the delivery and deployment of endovascular stented grafts. In this system the introducer catheter is equipped with two separate balloon catheters. Balloon “A” functions as a mechanism to form a tapered tip to the catheter system and also allows pressurization of the flexible sheath (C) after saline is injected from port D. The second balloon (B) functions to deploy the overlying Palmaz stent (S). With expansion of balloon B, the endovascular graft (G) becomes firmly fixed to the underlying arterial wall. (V = hemostatic valve.) (C) An alternative delivery system consisting of a single balloon catheter which has two balloons on a single shaft. The first balloon serves as a tip balloon (A), while the stent graft complex is mounted onto the independent deploying balloon (B). (V = hemostatic valve.) (From Ref. [99].)
Chapter 25.
Endovascular Grafts for Aneurysms, Occlusive Disease, and Vascular Injuries
381
Figure 25-16. (A) Drawing of bilateral endovascular aortofemoral graft insertion. Two stents are squeezed into a small, diseased distal aorta. (From Ref. [90].) (B) Drawing depicting the completion of an endovascular aortoiliac bypass and a standard femorofemoral bypass. (From Ref. [99].)
25-17A and B).[100] The iliac artery in which the endovascular graft is to be deployed and the positioning of the proximal stent are determined by preoperative angiographic findings. Deployment of the endovascular graft across the origin of the common iliac artery will certainly result in occlusion of the internal iliac artery and all the small branches along the vessel that are covered by the graft. The presence of a patent internal iliac artery(ies) will therefore influence the side of endovascular graft access and deployment. Every effort should be made to preserve a patent internal iliac artery in cases of occlusive disease. In addition, the length and degree of disease within the common or external iliac artery will often determine the technical difficulty associated with vessel recanalization. Generally, it is easier and safer to recanalize through a stenotic rather than an occluded lesion. Shorter lesions are also easier to recanalize. The classification of disease patterns, the choice of side for endovascular graft insertion, and the location of the proximal stent can be determined using the algorithm outlined in Fig. 25-18.
Operative Technique Following sheath placement in the femoral artery, either a Benson wire (Cook, Inc., Bloomington, IN) or a Glidewire
(Terumo, Tokyo, Japan) is used to recanalize the occluded iliac artery. Under fluoroscopic control, a directional catheter is used to direct and control the guidewire through the occluded or stenosed iliac artery (Fig. 25-19).[91] It is of paramount importance to return to the true lumen at the proximal end of the occluded segment, since the guidewire has a tendency to traverse the dissection plane (between the adventitia and the media) through the occluded segment. In cases where the contralateral iliac artery is patent, recanalization of the occluded iliac artery may be performed in a prograde fashion with a catheter placed through a percutaneous puncture of the contralateral femoral artery (Fig. 25-19). This technique has the advantage of assuring that the recanalized lumen will always join the true lumen at the proximal end of the occlusion. After successful wire passage, a 6 – 8 mm diameter angioplasty balloon is passed over the wire and the iliac artery is fully dilated along its entire length. The previously prepared endovascular graft device is then inserted into the newly created tract within the arterial wall over the same guidewire. Once the fixation stent is fluoroscopically located at the appropriate predetermined site, the sheath is partially retracted while holding the balloon catheter in place. If a tip balloon is used, it is deflated before sheath retraction. The exposed proximal stent can now be deployed The introducer
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Figure 25-17. (A) Preoperative arteriogram of patient with critical bilateral aortoiliac occlusive disease. This patient had received axillobifemoral bypass twice, both of which had failed. Angiogram demonstrates diffusely stenosed right iliac artery system and total occlusion of the left side. Since the right internal iliac artery is negligible, the right side was chosen for recanalization and graft insertion. The pelvic circulation is maintained by the inferior mesenteric artery (open arrow). (B) Completion arteriogram. By placing the stent (S) above the lesion (within the distal aorta), a good angiographic result was obtained. (C) Arch arteriogram of same patient reveals a 90% stenosis at the origin of the innominate artery and occluded left common carotid and subclavian arteries. Unrecognized inflow disease may have contributed to the failure of the two previous axillofemoral bypasses. (From Ref. [99].)
Figure 25-18. Algorithm and classification of endovascular grafting for bilateral aortoiliac occlusive disease. The classification of the distribution of disease, the determination of the appropriate side for graft insertion, and the identification of the location for proximal stent deployment may be approached using this algorithmic outline. (From Ref. [99].)
Chapter 25.
Endovascular Grafts for Aneurysms, Occlusive Disease, and Vascular Injuries
383
Figure 25-19. (A) Intraoperative angiogram of an iliac artery with occlusive disease demonstrating complete occlusion of the left external iliac artery. The left internal iliac artery is patent. (B) The “up and over” technique for recanalization. Recanalization is performed from the contralateral side in order to assure that the recanalized tract joins the true lumen at the proximal end of the occlusion. (C) Endoluminal anastomosis. Following proximal stent deployment, the distal end of the endovascular graft emerges from the arteriotomy site at which point it is cut to an appropriate length. An endoluminal anastomosis (EA) is then carried out. (D) Completion angiogram. The external iliac artery is recanalized with the endovascular graft. The proximal stent is placed at the orifice of the internal iliac artery, thus preserving this artery. (C reprinted from Ref. [130].)
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Part Three. Endovascular Intervention
sheath is then completely withdrawn, permitting the redundant portion of the distal end of the endovascular graft to emerge from the arteriotomy in the access vessel. The distal, redundant portion of the graft is then cut to an appropriate length and endoluminally hand-sewn into a patent, distal runoff vessel (Fig. 25-19). For bilateral occlusions, a 6 mm, externally supported, thin-walled PTFE graft is used to create a femorofemoral bypass. The arteriotomy site used for insertion of the endovascular graft serves as the proximal anastomotic site of the femorofemoral bypass (Fig. 25-20). The graft is then subcutaneously tunneled to the contralateral side and the recipient anastomosis is performed in a standard fashion to the patent distal runoff vessel.
Results of Endovascular Grafting for Aortoiliac Occlusive Disease We have performed endovascular graft repair for aortoiliac disease in 55 patients over a 5-year period. The vast majority of these patients had major contraindications to standard treatment (Fig. 25-17). The mean age of the patients was 67, and there were 28 males and 27 females. Forty-six percent of the patients had diabetes, 81% had coronary artery disease, and 19% had COPD. Of note is
Figure 25-20. The distal end of the endovascular graft is endoluminally hand-anastomosed in a customized fashion to the patent runoff vessel. The proximal anastomosis of a femorofemoral bypass is then performed over the arteriotomy site.
that 60% of the patients had a history of myocardial infarction. Technical success was achieved in 94% of the patients. Cases that failed were due to inability to recanalize the occluded segment. The mean graft length was 23 cm, and a simultaneous infrainguinal bypass was performed in 47% of the cases. The complication rate was 10%, and 30-day mortality was 4%. Using life table analysis employing the intention-to-treat principle, primary (78 ^ 7%) and secondary (86 ^ 6%) rates were achieved at 3 years. Graft failures were attributed to the endograft in 2 patients (4%), progression of inflow or outflow disease in 2 patients (4%) and 6 patients (12%), or an undefined cause in 1 patient (2%), respectively. Limb salvage and patient survival rates at 3 years were 93 ^ 4% and 71 ^ 7%, respectively.
Endovascular Grafts for the Treatment of Vascular Trauma Following the first report of endovascular grafting for the treatment of abdominal aortic aneurysms by Parodi in 1991,[24] the indications for endovascular grafting have expanded to include arterial occlusive disease,[99,100] occluded grafts,[101] peripheral aneurysms,[102,103] and traumatic arterial lesions (pseudoaneurysms, arteriovenous fistula, etc.). Although the treatment of abdominal aortic aneurysms with endovascular grafts seems to hold the major interest for both physicians and manufacturers, the longterm effectiveness of this treatment for this indication remains to be proven. This is due to a continuing significant rate of complications including “endoleaks,” some of which occur long after the graft is placed, as well as to the availability of standard aneurysm repair, which has been proven to be both safe and durable. On the other hand, based on reported results from our group and others,[104 – 118] the use of endovascular grafts already seems to be justified for the treatment of some traumatic arterial injuries, especially those involving large central vessels. This is particularly true in patients who are critically ill from other injuries or medical comorbidities. The surgical repair of vascular injuries may be complicated by the inaccessibility of the vascular lesion when trauma occurs to a vessel within the thorax or abdomen, by distorted anatomy due to a large hematoma or a false aneurysm, and by venous hypertension when an arteriovenous fistula is present. These conditions make the use of endovascular techniques appealing, since repair can be performed from a remote access site obviating the need for direct surgical exposure of the injury site, thus reducing the morbidity and mortality rates of the repair. Endovascular techniques for the treatment of vascular trauma includes the use of coil embolization, intravascular stents, and more recently the use of stented grafts or covered stents. Furthermore, when endovascular grafts are used for traumatic lesions, there are usually normal, healthy proximal and distal arterial segments available for use as graft fixation zones, which is not always the case with aortic aneurysms. This contributes to the high technical success rate and a low rate of endovascular graft migration or leakage in this setting.
Chapter 25.
Endovascular Grafts for Aneurysms, Occlusive Disease, and Vascular Injuries
Review of Endovascular Stented Grafts for Arterial Trauma Endovascular grafts have significantly extended the potential of endovascular therapy for vascular trauma. These grafts have been used to treat almost every kind of injury at various locations in the body, as well as in circumstances in which coil embolization or stent placement was deemed inappropriate.[104 – 118] In some instances, endovascular grafts have been used to treat life-threatening acute hemorrhage.[118] The types of devices that have been reported are predominantly a combination of Palmaz stents and expanded polytetrafluoroethylene (ePTFE) grafts. Since the traumatized field is often contaminated, the use of a vein graft in combination with a Palmaz stent has also been reported.[105,110] The different types of stented grafts that have been reported are shown in Fig. 25-21.
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Characteristics of the lesions, site of arterial access, technical success rate, and outcome of endovascular graft treatment of vascular trauma are summarized in Table 25-4. The results reported included a high technical success rate (94– 100%) and a complication rate of 0 –7%. These results are encouraging, especially when one considers the difficulties that could be encountered in treating these lesions by a direct surgical repair. In addition, the minimal access required and the potential for cost-effectiveness of these endovascular techniques is apparent from the short length of stay (3.3 –5.3 days) in patients so treated. Since these endovascular grafts are inserted into nonatherosclerotic central vessels of a large caliber, it is not surprising that they have proven to be more durable than grafts used to treat other arterial lesions. With a mean follow-up of 16 months, excellent midterm patency rates ranging from 85 to 100% have been
Figure 25-21. Endovascular stented grafts. (A) Palmaz stent covered with PTFE. (B) Autologous vein can be used to cover the stents. creating biological stented grafts. The collapsed stent-graft assumes a small profile, which effectively covers the struts of the stent following deployment (inset). (C) Dacron graft material may be used to cover the balloon-expandable stents. (D) Corvita endovascular graft used for arterial trauma. This polycarbonate clastima covered stent structurally resembles the Wallstent. Corvita graft is manually crimped into a 9 or 10 Fr delivery sheath.
386 Table 25-4.
Part Three. Endovascular Intervention
Endovascular Grafts for Arterial Trauma: Lesion Characteristics and Outcome by Arterial Site
Location of trauma Number of cases Cause of injury
Axillary-subclavian artery 15 Bullet: 57% Catheterization: 29% Others: 14%
Presence of pseudoaneurysm Presence of AV fistula Arterial access
60% 47% Brachial arteriotomy: 27% Brachial percutaneous: 47% Femoral percutaneous: 27% 100%
Technical success rate Complication: Minor Major Mean length of stay Mean follow-up Primary patency
0% 7%a 3.6 days 18 months 81%c
Aortoiliac artery 15 Surgical: 36% Catheterization: 18% Bullet: 9% Others: 36% 67% 73% Femoral arteriotomy: 64% Femoral percutaneous: 36%
Superficial femoral artery 5 Bullet: 60% Catheterization: 40%
80% 40% Femoral arteriotomy: 80% Femoral percutaneous: 20%
100%
100%
7% 7%b 4 days 10.5 months 100%
0% 0% 5.3 days 17.4 months 100%
a
Brachial artery injury during device insertion. Distal embolization requiring thrombectomy. c Two failures due to stent deformity. Source: Ref. [116]. b
achieved, depending on the location in which they were inserted.
graft in position while the outer sheath is retracted allowing the covered graft to expand and be deployed.
MONTEFIORE EXPERIENCE WITH ENDOVASCULAR GRAFTS FOR ARTERIAL TRAUMA
Results
Technique and Devices We have predominantly used the Palmaz stent (Cordis, Johnson and Johnson Company, Warren, NJ) in combination with a thin-walled ePTFE graft (W.L. Gore and Associates, Flagstaff, AZ; or IMPRA, Inc., Tempe, AZ) covering to perform arterial repairs of pseudoaneurysms and arteriovenous fistulas. Depending on the length of the lesion, either a singly stented or a doubly stented device was used. The stents varied between 2 and 3 cm in length (Palmaz P-204, 294, 308) and were fixed inside 6 mm ePTFE (W.L. Gore and Associates, Flagstaff, AZ) by two “U” stitches (Fig. 25-21A). The stented graft was then mounted on a balloon angioplasty catheter which had a tapered dilator tip firmly attached to its end. The entire device was placed within a 12 Fr delivery system for over-the-wire insertion either percutaneously or through an open arteriotomy. Another device used by our group was the Corvita stentgraft (Corvita Corporation, Miami, FL), which is fabricated from a self-expanding stent of braided wire. The stent is covered with polycarbonate –urethane elastomer fibers (Fig. 25-21D). This stent-graft may be cut to the desired length in the operating room using a wire-cutting scissors and then loaded into a specially designed delivery sheath. This sheath has a central “pusher” catheter, which is used for maintaining the
All procedures but one were performed in the operating room under fluoroscopic and intravascular ultrasonographic control (Hewlett-Packard Company, Paramus, NJ). A total of 17 stented grafts or covered stents have been used to treat 17 patients with traumatic arterial lesions. Seven injuries resulted from gunshot wounds, one from a knife wound, four from iatrogenic catheterization injuries, two from iatrogenic arterial trauma (gynecological surgery or lumbar disk surgery) (Fig. 25-22), and three from arterial graft disruptions possibly associated with infection. All injuries except one were associated with an adjacent pseudoaneurysm. In 5 instances the arterial injury formed a fistula to an injured adjacent vein. Associated injuries were present in 8 patients with arterial trauma. The majority of the cases were performed under local or epidural anesthesia. One patient who had an axillary pseudoaneurysm repaired with a stented graft required a vein patch to close the insertion site in a small brachial artery. Procedural complications were limited to one distal embolus treated with suction embolectomy and one wound hematoma, which resolved without further intervention. Graft patency was 100%, and there were no early or late graft occlusions with a mean follow-up of 30 months (range 6 – 46 months). One patient with a left axillary-subclavian stentgraft developed compression of the stent after 12 months, which was treated with balloon angioplasty. The problem recurred 3 months later, but no intervention was required. This device remains patent with normal circulation to the extremity now with an additional 312 years of follow-up.
Chapter 25.
Endovascular Grafts for Aneurysms, Occlusive Disease, and Vascular Injuries
387
Figure 25-22. (A) Preinterventional angiogram of an iatrogenic arteriovenous fistula (F) involving the right common iliac artery due to lumbar disc surgery. The left common iliac vein and the inferior vena cava (V) is visualized by the contrast flowing through the fistula. (B) Intravascular ultrasound (IVUS) image taken at the time of angiography. The amount of substance loss and the location (by identifying the location of the probe (P) of the IVUS under fluoroscopy) are well demonstrated (arrows denote the extent of the fistula). (C) Coil embolization of the right internal iliac artery. Since the location of the fistula was close to the origin of the internal iliac artery, the internal iliac artery was embolized with multiple coils (C) at the time of angiogram. (D) Completion angiogram. A Corvita graft (10 mm £ 6 cm) was used to repair the arteriovenous fistula. Note the preservation of iliac flow and the obliteration of the arteriovenous fistula. (From Ref. [136].)
CONCLUSIONS Endovascular grafts have greatly extended the potential of endovascular therapy for vascular trauma. These grafts have been used to treat almost every kind of injury at various locations in the body. Intravascular ultrasound as an adjunct can provide certain details that are otherwise difficult to obtain, including the exact location and size of the injury or fistula. These details are especially important when a coexisting arteriovenous fistula makes the angiographic interpretation difficult and may be essential when performing an endovascular repair. Regardless of the type of the device used, stented grafts appear to be associated with a low morbidity rate, high success rate, a less invasive surgical procedure, reduced requirements for anesthesia, and a limited need for extensive dissection in the traumatized field. These advantages are especially important in patients with central arteriovenous fistulas or false aneurysms, particularly those who are critically
ill from other coexisting injuries or medical comorbidities. In such instances, the use of endovascular grafts may already be justified. Endovascular grafts are important tools for the treatment of vascular trauma and should be included in the armamentarium of the vascular surgeon.
FUTURE DIRECTIONS There has been tremendous growth in the endovascular treatment of vascular lesions as evidenced by the increasing number of procedures performed throughout the world and the variety of commercial grafts becoming available. This increased graft availability has expanded the potential indications for endovascular repair in a number of patients while simplifying the approach. With further improvements in the materials and designs of these grafts, more complex
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Part Three. Endovascular Intervention
Figure 25-23. CT scan images of a ruptured AAA treated endovasacularly. This 71-year-old man was admitted to another hospital for medical treatment of his pneumonia secondary to chemotherapy for leukemia. Other comorbid disease includes severe COPD requiring home oxygen and congestive heart failure with ejection fraction of 25%. The patient experienced sudden onset of severe abdominal pain, which was confirmed by CT scan to be ruptured AAA. Due to his coexisting disease, standard repair was deemed prohibited and was transferred to our institution. On arrival, his systolic blood pressure was 75 mmHg and hematocrit was 18%. (A) Preoperative CT scan reveals possible rupture site (arrow) in the AAA. (B) Preoperative CT scan showing more distal portion of the AAA. The AAA measures 7.5 cm. In addition, a large hematoma (H) can be seen in the right retroperitoneal space, which is displacing the duodenum (D). (C) Postoperative enhanced CT scan. Contrast is confined within the EVG (E) with evidence of complete aneurysmal exclusion. The ureter, which is displaced by the large hematoma, is visualized. Despite his comorbid condition, he was extubated 6 hours following the procedure and was on diet on the second postoperative day. (C reprinted from Ref. [137].)
lesions may be amenable to endovascular repair. Despite this progress, the long-term durability of these grafts, for both aneurysmal and occlusive disease, has yet to proven. One emerging area of great promise is the endovascular graft treatment of ruptured aortoiliac aneurysms (Fig. 25-23). There are some significant theoretical advantages to this
approach, especially in patients who have undergone previous abdominal surgery. Over a 7-year period we have treated 20 patients with ruptured aortoiliac aneurysms.[119] All patients were felt to be a prohibitive surgical risk. The MEGS system was used in most cases. Both of these systems allow for intraoperative length customization of the graft. Stent-graft deployment was successful in all cases, with a perioperative mortality of 10%. Among the potential advantages of this approach are the following. First, endovascular grafts can be inserted and deployed through a remote access site, thereby obviating the need for laparotomy and, more importantly, eliminating the technical difficulties that one encounters when performing a standard repair in this setting. The anatomy of the retroperitoneal structures are often distorted and obscured because of the large hematoma. This may lead not only to technical difficulties but also to inadvertent injury of the inferior vena cava, the left renal vein, or genital branches. The iliac veins, inferior mesenteric vein, ureters, or the duodenum can also be injured. These iatrogenic injuries are the cause of significant operative mortality and morbidity following standard surgery for ruptured aneurysms.[120 – 125] In contrast, endovascular repair is performed from within the arterial tree, and as such is unaffected by the extravasated blood or by scarring from previous operations. In fact, from a technical standpoint the endovascular treatment of a ruptured aneurysm does not differ significantly from that performed electively. These advantages are magnified in patients with a “hostile” abdomen. Indeed, in such cases we believe that proximal arterial control may be obtained not only more safely but also more rapidly than in a standard repair. Second, the blood loss associated with endovascular graft repair may be reduced compared to standard repair. We found that the average blood loss was much less (mean 715 mL) than that reported in the literature for standard repair (range 2600– 8000 mL).[125 – 128] This reduction in blood loss is largely due to the fact that the tamponade effect within the retroperitoneum and surrounding structures is not released during endovascular repair. Coagulopathy and poor organ perfusion, which generally follow a large blood loss, are major problems associated with standard repair. Additional blood loss associated with free bleeding as the retroperitoneum is opened and decompressed can lead to complete cardiovascular collapse. This may be exacerbated by hypothermia, which is promoted by having an open abdomen. The endovascular approach greatly reduces this problem. Other major sources of blood loss during standard repair include backbleeding from the iliac and lumbar arteries, bleeding from the anastomotic suture lines, and iatrogenic venous injuries. Each of these can be largely eliminated by endovascular repair and offer a major advantage over standard repair. There are, however, some inherent limitations to the endovascular graft repair of ruptured aneurysms. These include the lack of preoperative aneurysmal and arterial length and diameter measurements, the time required to fabricate the graft, and the time needed to accurately deploy the graft. However, these problems may not be insurmountable. Having a stock of appropriately sized grafts or one or two sizes of graft that will fit most patients (as with the MEGS devices) should overcome measurement and fabrication problems. Obtaining proximal control with a balloon catheter
Chapter 25.
Endovascular Grafts for Aneurysms, Occlusive Disease, and Vascular Injuries
introduced through the brachial artery and guided fluoroscopically into the para-renal aorta should prevent exsanguination and allow adequate time for graft deployment. Even without the latter maneuvers we have found that many patients with ruptured aneurysms, if allowed to remain hypotensive, will remain stable with intact organ function long enough for the endograft to be deployed. In light of the results presented in this chapter, and the fact that endovascular grafting is still a young field with
389
technological improvements occurring at a rapid rate, we believe that endovascular graft treatment of patients with aneurysms and occlusive and traumatic arterial lesions will have improved success rates in the future. As long-term durability of these endovascular grafts are proven and they become applicable to a larger proportion of patients with vascular lesions, we believe their role will increase and they will become a major tool that will become integrated into vascular surgical practice.
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Adjunctive Endovascular Procedures: Techniques to Facilitate Operative Vascular Surgery Reese A. Wain Frank J. Veith necessary to begin the imaging process. After the radiation passes through the patient, it is collected by an image intensifier which forms an optical representation of the relevant anatomy. Next, a video system turns the optical representation into an electronic image consisting of shades of black and white. Finally, a computer converts the video image into a digital image by assigning numeric values to the shades of black and white. The entire process occurs in real time, and the resulting image can be viewed on a video display monitor or sent to a storage disk or printer.
INTRODUCTION Endovascular procedures require an imaging modality that provides real-time image acquisition. Although some investigators have reported success using intravascular or conventional ultrasound to guide endovascular procedures, the vast majority of these procedures are performed using digital fluoroscopy. In the past, digital fluoroscopes were only available in the radiology department. However, digital imaging equipment is becoming increasingly available to vascular surgeons in the operating room. Armed with a portable digital fluoroscope or a specially constructed interventional suite, vascular surgeons can use digital imaging and endovascular techniques as adjuncts to standard vascular procedures. This chapter will describe digital imaging and show how this modality can be used in conjunction with endovascular procedures to improve and simplify conventional vascular operations.
Subtraction Current digital imaging systems can process an image to enhance its quality or to add subtraction, roadmapping, and magnification effects. Subtraction is a process whereby radiopaque structures are electronically removed from an image so that contrast within the vasculature can be viewed in an unobstructed fashion. To accomplish this, the computer stores a noncontrast view of an imaged structure in its memory. A second contrast-enhanced image of the vasculature is then obtained. Finally, the computer “subtracts” the digitized information in the first image from that in the second image. The resulting “subtracted” image therefore contains only the contrast-filled vasculature and not over- or underlying radiodense structures. In theory, by removing the effect of soft tissue and bone, the quality of the resulting image can be better than that produced by conventional unsubtracted techniques. In addition, smaller amounts of contrast are usually required for a satisfactory subtracted arteriogram when compared to that required for a standard arteriogram. Therefore, patients with crural and pedal disease, especially in the presence of proximal lesions, may be better imaged using this technique. Also, patients with renal
DIGITAL FLUOROSCOPY Basic Principles Conventional film-based arteriography uses x-rays to precipitate silver crystals on a photographic plate. A picture of the imaged vasculature is produced when shades of black and white appear on the developed film according to the density of x-rays passing through the radiated object. Rather than relying on a chemical reaction to produce an image of the relevant anatomy, digital arteriography relies on a computer to assess the density of x-rays traversing the patient.[1,2] First, conventional x-ray tubes and generators produce the radiation
Hobson/Wilson/Veith: Vascular Surgery: Principles and Practice, Third Edition, Revised and Expanded DOI: 10.1081/0819-9-120024909 Copyright q 2004 by Marcel Dekker, Inc.
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insufficiency or an allergy to contrast dye may benefit from a digital arteriogram obtained with less of a contrast load than would have otherwise been possible[3 – 8] (Fig. 26-1).
Roadmapping Roadmapping is another feature of digital fluoroscopes that can facilitate endovascular procedures. This feature causes a contrast-enhanced “map” of the vasculature to remain on the video screen to guide real-time interventions such as selective arterial cannulations. As an example of this technique, a contrast-enhanced image of the common femoral artery bifurcation can remain on the monitor while a guidewire and catheter are selectively positioned within the superficial femoral artery. Without roadmapping, it might be difficult to ascertain whether the guidewire and catheter have been correctly positioned without repeating a contrast study.[9]
Magnification Digitized images can be magnified to aid in their interpretation. Magnification can be performed by focusing the x-ray beam over a smaller area or by “zooming” in on a section of a previously stored image using computer software. Both types of magnification result in a smaller field of view, but the former approach produces an image with greater resolution while the latter sacrifices resolution to increase image size. The degree of magnification that can be obtained by focusing the x-ray beam is hardware limited, while the degree to which the image can be magnified by the computer is not.
images can also be viewed individually in sequence. Visualization of the cine loop of stored images at regular speed allows the interpreter to assess flow-dependent events while the playback of individual images is ideal for diagnosing native vessel or bypass graft lesions.
TECHNIQUES TO FACILATE STANDARD VASCULAR OPERATIONS The remainder of this chapter will describe how we use digital fluoroscopy-based techniques to enhance standard vascular procedures such as intraoperative preprocedure and completion arteriograms, thromboembolectomies, and the repair of traumatic arterial lesions. In addition, we will explain how this modality can be used in conjunction with other endovascular techniques to precisely localize hemodynamically significant, angiographically occult arterial lesions, facilitate balloon angioplasty and stent insertion, perform thrombolysis, and obtain proximal arterial control using a balloon catheter. All of our vascular operating rooms contain radiolucent tables as well as portable digital C-arm fluoroscopes with subtraction, magnification, and roadmapping features. (Figs. 26-2 and 26-3) The equipment is arranged so that all table movements and the most frequently used fluoroscopic settings can be controlled by the operating surgeon. Therefore, additional assistance from radiology technicians or other support personnel is not required.
Completion Arteriography Cine Loop Playback Another attraction of current digital fluoroscopes is cine loop playback. This feature enables a continuous sequence of stored fluoroscopic images to be played back and viewed at the same rate at which they were acquired. Alternatively, the
Figure 26-1. Example of the effect of subtraction on an intraoperative arteriogram of the pedal vasculature. (left) Photograph of an unsubtracted arteriogram. (right) The same vasculature imaged using a subtraction technique.
It is our practice to obtain completion angiograms in the majority of patients undergoing lower extremity reconstructions to discover native arterial or bypass graft lesions which could result in early procedural failure.[10,11] Therefore, all peripheral interventions are performed on fluoroscopy tables. After a reconstructive procedure has been completed, we insert a 21 gauge angiocatheter or butterfly needle into an exposed proximal vessel. If this vessel is circumferentially calcified or otherwise unsuitable, the catheter is introduced into the proximal hood of a prosthetic graft or a side branch of a vein graft. Next, the fluoroscope is brought into the operative field and appropriately positioned. Five to 10 cc of iodinated contrast is required to obtain one subtracted image. By moving the fluoroscope or changing the position of the table, both anastomoses, the entire bypass graft, and outflow vessels can all be imaged. In this fashion, potential problems such as technically imperfect anastomoses, tunnel defects, or distal emboli can be discovered. This examination can be performed within 5 minutes—less time than it used to take to develop a single arteriographic film which visualized only a small part of the relevant vasculature (Fig. 26-4). Arteriograms obtained with the digital fluoroscope can be considerably better than those obtained using conventional imaging techniques. In the past, errors due to incorrect timing of the contrast injection or improper positioning of the film cassette often resulted in a suboptimal image that had to be repeated. With digital fluoroscopy, the contrast bolus can be
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Figure 26-2.
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An adjustable fluoroscopic table, which is used to perform all of our endovascular procedures.
visualized in real time as it travels through the vessels and timing errors do not occur. For similar reasons, over- and underfilling of the vasculature with contrast also do not occur. Finally, a portable fluoroscope and a movable table help assure that the extremity being imaged is not subjected to excessive manipulation as occurs when photographic plates are used. Therefore, the potential to inadvertently displace an arterial cannula can be decreased. Once images of the desired vasculature have been obtained, suspicious lesions can be magnified to better evaluate their significance. Alternatively, the angiogram can be repeated after repositioning the fluoroscope at an
Figure 26-3.
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alternative oblique angle. Magnification cannot be performed using standard arteriographic techniques, and obtaining multiple oblique views with conventional equipment is time consuming and labor intensive. A real-time assessment of a fluoroscopic run can provide additional information that is unavailable on a single shot arteriogram. Namely, the time required for the contrast to travel the length of a bypass graft and reach the distal anastomosis may reflect resistance within the outflow vasculature. In our experience, longer transit times occur in patients with disadvantaged outflow. In addition, collateral vessels adjacent to the course of the bypass graft may opacify
Typical setup of a C-arm digital fluoroscope for an endovascular procedure in the operating room.
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the cine loop of the contrast run. After the fistula is repaired a repeat study can be performed to confirm the success of the procedure (Fig. 26-5). In our experience this technique has been most useful when fistulae originate from the deep femoral artery or one of its branches.
Catheter Pressure Localization of Arterial Stenoses
Figure 26-4. Completion arteriogram following a popliteal to anterior tibial artery bypass with a reversed greater saphenous vein. Using a subtraction technique the proximal anastomosis (left), the entire length of the vein graft (middle) and the distal anastomosis (right) can all be satisfactorily imaged.
before the graft itself in these patients. Conversely, bypass grafts with good outflow evidence faster contrast flow rates and a lag in collateral visualization. Intraoperative digital fluoroscopy can also be used to locate patent vein branches following in situ bypasses. After both anastomoses have been completed, contrast is injected and the site of the arterialized branches can be marked on the skin relative to radiopaque landmarks such as metallic staples. Next, the branches can be individually ligated through small precisely placed incisions. This technique is especially useful following procedures in which the vein has not been exposed throughout its entire length.
Most vascular surgeons obtain preoperative arteriograms to document the pattern of disease and to help plan an appropriate bypass. In the majority of cases, these studies will provide the requisite information. However, the hemodynamic significance of lesions in the inflow vasculature may be underestimated if these vessels are diffusely diseased or have serial stenoses. In addition, borderline lesions which may not cause pressure gradients on preoperative imaging studies could become flow limiting following insertion of a bypass graft. Digital fluoroscopy and endovascular techniques are ideally suited to discover and treat these lesions in the intraoperative setting. If the pulse in a bypass graft is weak or there is a significant pressure gradient within the graft, we perform catheter-based pullback pressure measurements to localize the offending lesion. To accomplish this, a hemostatic sheath is first inserted over a guidewire into the relevant inflow vessel. Under fluoroscopic guidance, the guidewire is advanced atraumatically into the abdominal aorta using a guiding catheter when necessary. Next, an endhole catheter is inserted and attached to a calibrated pressure transducer. As the catheter is pulled back its position is followed fluoroscopically. If the pressure at the leading edge of the catheter is noted to decrease acutely relative to systemic pressure, the site of the lesion has been identified. Further arteriographic studies may then be required to decide
Preprocedure Arteriography Intraoperative preprocedure digital fluoroscopy can result in the discovery of suitable outflow vessels in patients not felt to be bypass candidates based on preoperative imaging studies. When preoperative contrast studies are suboptimal, we frequently directly infuse contrast into a crural or pedal vessel to assess its patency. This approach can save patients an attempt at a bypass that is doomed to fail or discover that a bypass is a feasible option whereas an amputation would otherwise have been indicated.[12 – 15] For the reasons discussed above, digital imaging is better suited in this role than conventional techniques. Intraoperative preprocedure digital imaging can also be used to precisely localize hard-to-find arteriovenous fistulae. When the origin of a fistula is readily apparent, intraoperative imaging is usually unnecessary. However, if the fistula involves a small arterial branch, radiographic localization may be preferable to an extensive and potentially dangerous dissection. To localize such fistulae, we first dissect the anterior surface of a proximal uninvolved vessel and perform a contrast examination through a small angiocatheter. The origin of the fistula can usually be identified after reviewing
Figure 26-5. Intraoperative arteriogram used to identify a traumatic arteriovenous fistula. (left) Contrast injected through a catheter in the common femoral artery reveals early filling of the femoral vein (arrow). On cine loop playback, the fistula is noted to arise from the superficial femoral artery. (right) After the fistula has been ligated, a completion arteriogram confirms its disappearance.
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whether the lesion should be treated by balloon angioplasty or whether a direct operative approach is preferable. If the source of the pressure gradient cannot be localized to the inflow vasculature, then the tunnel or the bypass graft itself is further scrutinized.[16]
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and requires setting up, exposing and developing multiple photographic plates. Perhaps even more importantly, if residual clot remains despite multiple passages of a balloon
Proximal Arterial Control Using a Balloon Catheter Obtaining proximal aortic control with a vascular clamp in the setting of acute traumatic hemorrhage or a ruptured aneurysm may be problematic. It may also be difficult to achieve conventional control of a vessel when it lies within an infected or scarred field, is circumferentially calcified, or harbors an intravascular stent or graft. In these situations, we have found it useful to obtain proximal arterial control in an endovascular fashion using an occlusion balloon technique. This technique requires open or percutaneous exposure of an access vessel proximal or distal to the artery requiring control. Under fluoroscopic guidance a guidewire is advanced through an 18 gauge needle previously placed within the access vessel. After the needle has been retrieved, a hemostatic sheath is situated within the vessel and a guiding catheter is used to direct the wire to the site requiring occlusion. Finally, an angioplasty balloon of the appropriate size is brought to this site and inflated enough to occlude prograde arterial flow. When the reconstruction is finished, the balloon is deflated and flow is restored. When control immediately proximal to the arterial site is needed, a simple balloon catheter can be inserted under direct vision and guidewires and fluoroscopic control are not necessary[17] (Fig. 26-6).
Fluoroscopically Assisted Thromboembolectomy In the past, most patients with acute embolic disease did not have underlying atherosclerotic disease and the success of an embolectomy could be assured by retrieving an embolic “bullet” and visualizing backbleeding. However, now that patients with embolic disease also tend to have underlying arterial lesions, these findings are no longer the sine quo non of success. Instead, we believe that arteriographic confirmation of restored luminal patency should accompany all but the most straightforward thromboembolectomies. Prior to surgery, we routinely obtain preoperative imaging studies to ascertain the patient’s pattern of disease and the extent of the thromboembolic process. In addition, we perform routine intraoperative completion studies to confirm the success of our thromboembolectomies. These studies not only confirm that the clot burden has been removed and that straight-line flow has been restored but may diagnose hemodynamically significant lesions which could compromise an otherwise successful procedure.[18 – 22] Digital fluoroscopy has distinct advantages over conventional arteriography in these cases. First, it is easy to obtain images following retrieval of the balloon catheter using the digital fluoroscope so that the need for further intervention can be assessed. Contrarily, the same approach using conventional techniques is cumbersome, time consuming,
Figure 26-6. A patient underwent three failed peripheral bypasses, all of which originated from the right common femoral artery. Ultimately, an external iliac to anterior tibial artery bypass was successful in restoring distal perfusion. However, the patient experienced massive hemorrhage from the hood of a prosthetic graft that had been incompletely excised during a debridement of the right groin. Emergency local control of the bleeding site by conventional measures was deemed impossible, and proximal control of the common femoral artery was achieved with a balloon catheter. (A) Access to the relevant vasculature was achieved percutaneously through the left femoral artery. (left) A preprocedure arteriogram demonstrating (a) the external iliac artery, (b) the bypass graft to the anterior tibial artery, (c) the common femoral artery and (arrow) the location of the bleeding hood of the prosthetic graft. (right) A guiding catheter has been used to advance a wire over the aortic bifurcation and into the right external iliac artery. Note the presence of a previously placed stent (arrow) within the proximal external iliac artery. (B) (left) An angioplasty balloon was advanced into the right common femoral artery and inflated to occlude prograde flow. (right) A repeat arteriogram demonstrates flow in the bypass graft (arrow) and the lack of flow in the common, superficial, and deep femoral arteries. Following successful balloon occlusion, the disrupted prosthetic graft was removed and the femoral artery was repaired in a conventional fashion.
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catheter or if additional lesions are unmasked, digital fluoroscopy can guide intraoperative balloon angioplasty or the infusion of thrombolytic agents. In our practice, patients with emboli at or below the level of the knee were formerly subjected to a medial belowknee incision after which each of the three crural arteries was individually mobilized and thrombectomized.[23] We currently perform fluoroscopically assisted thromboembolectomies to avoid the lengthy and potentially difficult dissection needed to expose and control the origin of each crural vessel. To carry out this procedure, we dissect and mobilize only the proximal below-knee popliteal artery. After confirming that the patient is fully anticoagulated, proximal and distal arterial control are achieved and a small longitudinal arteriotomy is made. Next, a local thrombectomy is performed to facilitate insertion of a hemostatic sheath within the distal popliteal artery. A contrast injection is performed through the sheath and the status of the distal vasculature is assessed. If any of the crural or pedal vessels harbor thrombus, roadmapping techniques are used to selectively catheterize the involved vessels(s) with a guidewire. Finally, an over-the-wire embolectomy catheter is used to clear the vasculature. A similar technique can also be used to treat thromboemboli within bypass grafts or the aortoiliac vessels.[24] Conventional equipment may be used to perform thromboembolectomies if dual lumen embolectomy catheters and fluoroscopes with roadmapping capabilities are not available. In these circumstances, standard embolectomy catheters can be guided into one crural or pedal vessel at a time using a conventional fluoroscope. To accomplish this, a small amount of dilute contrast can be injected into the balloon catheter to confirm its position fluoroscopically relative to the known course of a vessel- or bone-based landmark. Blind balloon insertion is still avoided and the potential for intimal injury or perforation is therefore minimized (Figs. 26-7 and 26-8). Vascular injury secondary to balloon overinflation can also be limited when thromboembolectomies are performed under fluoroscopic control. If a balloon containing contrast is noted to inflate in an asymmetric fashion or if a significant deformity in its shape is noted, the balloon can be partially deflated and the procedure resumed. Using this technique, intimal injury leading to an exuberant hyperplastic response and diffuse arterial narrowing can be avoided.[25 – 30] In addition, significant balloon deformation might highlight the site of a stenotic lesion which could be treated by intraoperative balloon angioplasty. Finally, fluoroscopic guidance during balloon inflation can help prevent balloon underdistention, inadequate balloon-arterial wall apposition, and an imperfect procedure.
Intraoperative Thrombolysis Following a thrombectomy of the distal vasculature, it is not uncommon for clot to remain within a diseased crural of pedal vessel. In these cases, multiple attempts to remove the clot with a balloon catheter may not only prove ineffective but may cause the vessel to become occluded. One option for eliminating the thrombus is to infuse thrombolytic agents
Figure 26-7. Fluoroscopically assisted thrombectomy of a femoropopliteal bypass graft. An attempt at thrombolysis of a recently occluded femoropopliteal bypass graft resulted in restoration of flow through the graft however, residual thrombus within the graft and distal anastomosis could not be lysed. (A) (left) Filling defects within the graft (arrows) on a pre-procedure intraoperative contrast study represent residual thrombus. (right) A balloon catheter has been advanced and inflated (arrow) in the native popliteal artery under fluoroscopic guidance prior to thromboembolectomy. (B) (left) A filling defect noted in the balloon (arrow) during its retrieval indicates the location of adherent thrombus. (right) Completion arteriogram demonstrating complete removal of all residual thrombus and a widely patent distal anastomosis (arrow).
through an infusion catheter placed proximal to or within the affected artery. A pulse-spray technique is used to inject 50,000 IU of urokinase over a 10-minute interval. If the clot has not entirely lysed, the catheter can be repositioned if necessary and additional urokinase can be infused up to doses of 250,000 IU or more. After successful lysis, unsuspected lesions which are amenable to balloon angioplasty may be revealed. Despite partial or unsuccessful clot lysis, thrombolytic therapy may make the residual clot more susceptible to balloon thromboembolectomy. In addition, the lytic treatment may open important collaterals which might otherwise have remained occluded.[31 – 34]
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Intraoperative Balloon Angioplasty and Stenting Digital fluoroscopy has also made it feasible to perform balloon angioplasty and stent insertions during standard vascular procedures. [35 – 38] We have employed these techniques intraoperatively when hemodynamically significant lesions are found during native arterial of bypass graft thromboembolectomies. In addition, balloon angioplasty and stenting have a well-documented role in treating inflow lesions during infrainguinal bypass procedures. The ability to perform these techniques intraoperatively can save the patient from an extended unanticipated operation or an
Figure 26-8. Fluoroscopically assisted thrombectomy of an occluded prosthetic bypass graft. (A) (left) After thrombectomy of the body of a prosthetic femoral – distal bypass graft an arteriogram demonstrates residual flow limiting thrombus within the proximal anastomosis (arrow). Conventional embolectomy catheters could not be advanced through the anastomosis so an endovascular approach was undertaken. (right) Under fluoroscopic control, a guidewire (arrow) was advanced atraumatically through the anastomotic site. (B) (left) An over-the-wire embolectomy catheter (arrow) was then inserted and the thromboembolectomy was performed. (right) In addition, thrombectomy of the outflow vasculature was performed under fluoroscopic guidance to avoid balloon overinflation (arrow). (C) Completion arteriograms demonstrating a thrombus free proximal anastomosis (left) and patent runoff vasculature (right).
Figure 26-9. (A) (left) A patient with toe gangrene underwent a preoperative angiogram demonstrating a high grade, focal, right common iliac artery stenosis and a long segment superficial femoral artery occlusion (not shown). The patient was brought to the operating room for simultaneous femoropopliteal bypass grafting and balloon angioplasty and stenting of his iliac lesion. (right) An intraoperative pre-procedure arteriogram obtained through the right femoral artery demonstrates minimal reflux of contrast into the aorta confirming the pre-occlusive nature of the iliac lesion (arrow). (B) (left) After pre-dilating the stenotic segment, an appropriately sized balloon inflatable stent was deployed. (right) A completion arteriogram demonstrates that the iliac lesion has been adequately treated. The patient then underwent an uneventful femoropopliteal bypass.
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additional interventional procedure in the pre- or postoperative period. When a hemodynamically significant lesion is discovered, a guidewire is advanced through an introducer sheath and across the stenotic lesion. An appropriately sized angioplasty balloon is used to perform the dilatation, and the results can be readily visualized with a repeat angiogram. In the presence of a residual stenosis, repeated attempts at balloon dilatation can be performed or a stent can be inserted (Fig. 26-9).
CONCLUSIONS Digital fluoroscopy and endovascular skills must be considered indispensable tools for surgeons performing vascular procedures. In addition to improving and simplifying standard vascular operations, they allow surgeons to undertake a host of therapeutic interventions previously impossible to perform in the operating room.
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15. Patel, K.R.; Semel, L.; Clauss, R.H. Extended Reconstruction Rate for Limb Salvage with Intraoperative Prereconstruction Angiography. J. Vasc. Surg. 1988, 7, 531– 537. 16. Kinney, T.B.; Rose, S.C. Intraarterial Pressure Measurements During Angiographic Evaluation of Peripheral Vascular Disease: Techniques, Interpretation, Applications and Limitations. Am. J. Roentgenol. 1996, 166, 277– 284. 17. Veith, F.J.; Sanchez, L.J.; Ohki, T. Technique for Obtaining Proximal Intraluminal Control When Arteries Are Inaccessible or Unclampable Because of Disease or Calcification. J. Vasc. Surg. 1998, 27, 582– 586. 18. Bosma, H.W.; Jorning, P.J.G. Intra-Operative Arteriography in Arterial Embolectomy. Eur. J. Vasc. Surg. 1990, 4, 469– 472. 19. Crolla, R.; van de Pavoordt, E.; Moll, F.L. Intraoperative Digital Subtraction Angiography After Thromboembolectomy: Preliminary Experience. J. Endovasc. Surg. 1995, 2, 168– 171. 20. Giordano, J.M.; Trout, H. The Use of Fluoroscopy with the C-Arm for Femoral Arterial Embolectomy and Cannulation of the Popliteal Trifurcation Vessels. Surg. Gynecol. Obstet. 1984, 158, 503– 505. 21. Hill, S.L.; Donato, A.T. The Simple Fogarty Embolectomy: An Operation of the Past. Am. Surg. 1994, 60, 907– 911. 22. Robicsek, F. Dye-Enhanced Fluoroscopy-Directed Catheter Embolectomy. Surgery 1984, 95 (5), 622– 624. 23. Gupta, S.K.; Samson, R.H.; Veith, F.J. Embolectomy of the Distal Part of the Popliteal Artery. Surg. Gynecol. Obstet. 1981, 153, 255– 256. 24. Parsons, R.E.; Marin, M.L.; Veith, F.J.; et al. Fluoroscopically Assisted Thromboembolectomy: An Improved Method for Treating Acute Arterial Occlusions. Ann. Vasc. Surg. 1996, 10 (3), 201– 210. 25. Bowles, C.R.; Olcott, C.; Pakter, R.; et al. Diffuse Arterial Narrowing as a Result of Intimal Proliferation: A Delayed Complication of Embolectomy with the Fogarty Balloon Catheter. J. Vasc. Surg. 1988, 7, 487– 494. 26. Cronenwett, J.L.; Walsh, D.B.; Garrett, H.E. Tibial Artery Pseudoaneurysms: Delayed Complication of Balloon Catheter Embolectomy. J. Vasc. Surg. 1988, 8, 483– 488. 27. Dobrin, P.B. Mechanisms and Prevention of Arterial Injuries Caused by Balloon Embolectomy. Surgery 1989, 106 (3), 457– 466. 28. Dobrin, P.B.; Jorgensen, R.A. Balloon Embolectomy Catheters in Small Arteries: A Technique to Prevent Excessive Shear Forces. J. Vasc. Surg. 1985, 2, 692– 696.
Chapter 26. 29.
Masuoka, S.; Shimomura, T.; Ando, T.; et al. Complications Associated with the Use of the Fogarty Balloon Catheter. Cardiovasc. Surg. 1980, 21, 67– 74. 30. Schwarcz, T.H.; Dobrin, P.B.; Mrkvicka, R.; Skowron, L.; Cole, M.B. Early Myointimal Hyperplasia After Balloon Catheter Embolectomy: Effect of Shear Forces and Multiple Withdrawals. J. Vasc. Surg. 1988, 7, 495– 499. 31. Beard, J.D.; Nyamekye, I.; Earnshaw, J.J.; et al. Intraoperative Streptokinase: A Useful Adjunct to BalloonCatheter Embolectomy. Br. J. Surg. 1993, 80, 21– 24. 32. Knaus, J.; Ris, D.; Stirnemann, D. Intraoperative Catheter Thrombolysis as an Adjunct to Surgical Revascularization for Infrainguinal Limb-Threatening Ischaemia. Eur. J. Vasc. Surg. 1993, 7, 507– 512. 33. Quinones-Baldrich, W.; Baker, J.D.; Busuttil, R.W.; et al. Intraoperative Infusion of Lytic Drugs for Thrombotic
34. 35. 36.
37.
38.
Adjunctive Endovascular Procedures
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Complications of Revascularization. J. Vasc. Surg. 1989, 10, 408– 417. Wasselle, J.; Bandyk, D.F. Intraoperative Thrombolysis in Peripheral Arterial Occlusion. JCC 1993, 36 (4), 354– 335. Al-Salman, M.M. Intraoperative Balloon Angioplasty: A Useful Adjunct. Int. Surg. 1998, 83, 79– 83. Ammar, A.D.; Hutchinson, S.A. Management of Acute Infrainguinal Arterial Thrombosis: Combined Intraoperative Balloon Thrombectomy with Balloon Angioplasty: A Preliminary Report. Surgery 1987, 101 (2), 176–180. Demasi, R.J.; Snyder, S.O.; Wheeler, J.R.; et al. Intraoperative Iliac Artery Stents: Combination with Infrainguinal Revascularization Procedures. Am. Surg. 1994, 60, 854– 859. Pfeiffer, R.B.; String, S.T. Adjunctive Use of the Balloon Dilatation Catheter During Vascular Reconstructive Procedures. J. Vasc. Surg. 1986, 3, 841– 845.
CHAPTER 27
Acute Arterial Insufficiency F. William Blaisdell James W. Holcroft now is more commonly caused by coronary artery disease. A less common cardiac source of emboli is a left ventricle that is damaged by myocardial infarction; ventricular aneurysms can harbor a mural thrombus, and an infarcted endocardium can predispose to clot formation. The most common extracardiac sources of arterial emboli include ulcerating atheromatous lesions in the abdominal aorta and common iliac arteries. The lesions may be associated with aneurysmal disease of these vessels as well as more distal vessels. Other sources or causes of emboli are listed in Table 27-1 and include atrial myxoma, endocarditis, prosthetic heart valves, complications of arterial catheterization, and paradoxical embolization. In approximately 25% of cases of acute ischemia caused by embolism, no source for the embolus can be identified. These cases may be due to small ulcerative lesions not demonstrated angiographically or may be caused by paradoxical emboli in which a septal defect cannot be demonstrated. Thrombus is the second major cause of acute arterial ischemia, and in one recent review it accounts for 50% of all acute ischemic episodes reported.[5] Thrombosis usually occurs at a point of narrowing in an atherosclerotic vessel, particularly in association with a flow-related disorder such as congestive heart failure, shock, dehydration, or polycythemia. Additionally, hemorrhage within an atherosclerotic plaque can result in sudden occlusion.[6] Traumatically induced ischemia is covered in Chaps. 74 through 77.
Whenever the motion of the blood in the arteries is impeded, by compression, by infarction, or by interception, there is less pulsation distally, since the beat of the arteries is nothing else than the impulse of blood in these vessels. William Harvey The concept of occlusion or “interception” of arterial flow was introduced by William Harvey[1] in 1628. John Hunter[2] has been credited with proposing embolectomy in 1768 as a procedure for restoring flow. One hundred and forty years later, Labey[3] performed the first successful embolectomy. The twentieth century has witnessed rapid progress in salvaging limbs that are threatened by acute arterial ischemia, primarily because of two developments. First, heparin anticoagulation has made it possible to limit the propagation of clot distal to the point of occlusion and to reduce the incidence of recurrent embolus and thrombosis. Second, the Fogarty balloon catheter, introduced in 1963, has made it possible to extract emboli and thrombi from arteries, the Fogarty catheter being far better suited for this purpose than the devices used in the past such as corkscrew wires or suction catheters.[4] This chapter describes current procedures for dealing with acute arterial insufficiency. The chapter describes the etiology, pathophysiology, diagnosis, and treatment of acute arterial insufficiency.
ETIOLOGY
PATHOPHYSIOLOGY
Acute arterial ischemia is caused by emboli or by acute thrombosis superimposed on a chronic underlying partial obstruction (Table 27-1). Emboli can be of cardiac or noncardiac origin. In the past, 80% of all emboli originated from the heart, the majority of these being of left atrial origin in patients with rheumatic heart disease and atrial fibrillation. With the recent decreased incidence of rheumatic heart disease, other embolic sources of acute arterial ischemia are becoming more prevalent. The most common cardiac source of an embolus remains a fibrillating atrium, but the fibrillation
Emboli of cardiac origin tend to obstruct at bifurcations of large arteries where the luminal diameter suddenly decreases. These arteries are usually more than 5 mm in diameter. Atheroemboli, consisting of debris from atheromatous lesions of the proximal arterial system, are smaller and occlude vessels less than 5 mm in diameter. The size of the obstructed vessel then can help in differentiating between emboli that originate from the heart and emboli that originate from the aorta or common iliac arteries. For example, an embolus that lodges in the common femoral artery is usually of cardiac
Hobson/Wilson/Veith: Vascular Surgery: Principles and Practice, Third Edition, Revised and Expanded DOI: 10.1081/0819-9-120024910 Copyright q 2004 by Marcel Dekker, Inc.
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406 Table 27-1.
Part Four. Peripheral Occlusive Disease
Etiology of Acute Arterial Occlusion
Embolic Cardiac Atrial fibrillation Valvular heart disease (rheumatic heart endocarditis) Myocardial infarction (with or without aneurysm) Prosthetic heart valves Left atrial myxoma Paradoxical embolus Congestive cardiomyopathy Hypertrophic cardiomyopathy Mitral annulus calcification Mitral valve prolapse Peripheral Ulcerating atherosclerotic lesions Aneurysms (aortic, iliac, femoral, popliteal, axillary) Arterial catheterization complications Thrombotic Narrowed atherosclerotic segment (with or flow-related disorder) Intraplaque hemorrhage Drugs of abuse
disease or ventricular
subclavian,
without a
origin; an embolus that leads to infarction of an isolated toe usually arises from the distal aorta or common iliac arteries. Once an embolus lodges in an artery, or once a thrombus occludes a previously diseased artery, the vasculature distal to the obstruction goes into spasm. Clot then forms proximal to the site of the obstruction, back to the point of adequate collateralization. The distal spasm lasts for approximately 8 hours and then subsides. At this point clot forms in the arterial system distal to the site of obstruction and propagates downward, obstructing any residual collateral flow, resulting in worsening of the ischemia. As a result the skin usually becomes patchy, blue, and mottled. Skeletal muscle and peripheral nerves withstand acute ischemia for some 8 hours without permanent damage; skin can withstand severe ischemia for as long as 24 hours. The extent of the ischemic necrosis depends on the adequacy of collateral circulation, the patient’s underlying cardiovascular function, viscosity of the blood, oxygen-carrying capacity of the blood, propagation of clot into the microvasculature, and effectiveness and promptness of treatment. If muscle ischemia progresses to necrosis, the muscle becomes paralyzed and acquires a firm, spastic consistency. When peripheral nerves become ischemic, they cease to function, and the affected parts become anesthetic. As the skin undergoes profound ischemia, maximum oxygen extraction results in a cyanotic, blotchy appearance. When these blotchy, cyanotic areas no longer blanch with pressure, the skin is gangrenous and the ischemia is no longer reversible.[7] The reperfusion of an ischemic extremity poses a threat to the rest of the body.[8,9] Anaerobic metabolism produces
unbuffered acid, dead cells release potassium and myoglobin, microthrombi form in the areas of stasis and acidosis, and procoagulants and inflammatory products accumulate. With reperfusion, oxygen radicals, leukotrienes, and many other inflammatory mediators are generated, and all of these products are released into the systemic circulation. Here they produce systemic vascular permeability, extravasation of plasma into the interstitium, and damage to remote organs. The lungs receive the first onslaught, but damage to the heart and kidneys also occurs.[10] We have documented a mortality rate of 85% when a limb with advanced ischemia is revascularized. The degree of insult to the body as a whole depends upon the mass of ischemic tissue, the duration of the ischemia, and the underlying condition of the remote organs.
DIAGNOSIS In most cases a history and physical examination allow identification of the level of obstruction, the probable cause, and the degree of ischemia (Tables 27-2 and 27-3). This information is usually all that is needed to direct the therapy. The history should review the duration and progression of the symptoms and should document prior cardiac or vascular disease that might complicate the treatment. A history of claudication indicates prior atherosclerotic occlusive disease. In a nonsmoker, aortoiliac occlusive disease is unlikely. A history of heart disease, particularly one associated with arrhythmias, makes the possibility of embolization from the heart likely. The physical examination gives information about the heart and the likelihood that the heart is the source of an embolus. Signs of chronic ischemia in the lower extremities—
Table 27-2. Signs of Ischemia Acute ischemia Pale extremity at resting position Temperature change, with sharp line of demarcation Pain and paresthesias Decreased sensation Mottled cyanotic color that blanches with pressure Mottled cyanotic color that does not blanch Paresis progressing to paralysis Firm, spastic musculature Chronic ischemia Atrophic musculature Decreased hair Hypertrophic nails Pulse deficits Temperature Venous troughinga Slow capillary refill Prolonged pallor with elevation Dependent rubor a
Collapse of the superficial veins of the foot.
Chapter 27. Table 27-3.
Patient Evaluation
Cardiac evaluation
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Table 27-4. Laboratory Assessment Vascular evaluation
History Myocardial infarction Transient ischemic attack Arrhythmias—syncope Amaurosis fugax Angina Claudication Palpitations Impotence Medications Intestinal angina Congestive heart failure Prior surgery Physical examination Rate and rhythm Absent pulses Murmurs and gallops Aneurysmal vessels Blood pressure Bruits Cardiomegaly Acute ischemia Peripheral edema Chronic ischemia Jugular venous distension Dehydration
hypertrophic nails, atrophic skin, and hair loss on the feet— indicate previously existing obstructive disease. The presence of an acute arterial insufficiency is usually manifest by an abrupt temperature change in an extremity distal to the level of the obstruction (Fig. 27-1). The ability to dorsiflex and plantarflex the toes indicates the viability of the musculature in the calves; the inability to move the toes indicates impending necrosis of at least some of those muscles. Development of firm, spastic musculature, especially if the contralateral side is normal, indicates extensive necrosis or impending necrosis of the musculature. Paresthesias and anesthesia indicate the status of the nerves in the ischemic extremity. Waxy, white skin is characteristic of active spasm and indicates that there are viable arterioles supplying blood to the skin; blotchy cyanosis that does not blanch with pressure indicates thrombosed capillaries in the subcuticular areas and skin necrosis.
Hematocrit, PT/PTT, platelets Electrolytes, BUN, creatinine, glucose Urinalysis—test for myoglobinuria CPK with isoenzymes Chest radiograph Electrocardiogram Two-dimensional echocardiogram Arteriogram
Laboratory tests are aimed at evaluating hydration, oxygen-carrying capacity of the blood, renal function, cardiac function, and muscular damage (Table 27-4). A chest x-ray shows the size of the heart and may identify thoracic aortic disease. A hematocrit can make a diagnosis of polycythemia. A urinalysis that shows protein and pigment suggests the presence of myoglobin in the urine. The determination of creatinine phosphokinase with isoenzymes can give information about muscle necrosis. An electrocardiogram defines arrhythmias and gives information about the status of the heart. Two-dimensional echocardiography identifies the cardiac chamber size, estimates the ejection fraction, studies the valvular pathology, evaluates the wall motion, and sometimes identifies intracardiac thrombus or tumor.[11,12] Echocardiography may also detect a potentially patent atrial septal defect. Echocardiography is not helpful acutely in deciding whether to operate, anticoagulate, or amputate.[13] It is of value in discovering underlying cardiac disease that requires attention after successful management of the acute ischemic event. An ultrasound examination of the abdomen may reveal an abdominal aortic aneurysm. Ultrasonography of the popliteal fossa may demonstrate a nonpalpable thrombosed popliteal aneurysm. Unless a therapeutic decision hangs in the balance, we do not obtain arteriograms initially. When an arteriogram is
Figure 27-1. Level of temperature and color change with occlusion of different arteries.
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obtained later, however, it can give useful information. An arteriogram sometimes shows a sharp cutoff of a proximally normal artery, indicating an embolus. It may also show preexisting underlying atherosclerotic occlusive disease. Abdominal aortic aneurysms or atheromatous disease involving the distal aorta and common iliac arteries may be demonstrated.
TREATMENT All patients with limb-threatening acute arterial insufficiency should be anticoagulated with heparin to prevent distal clot propagation. Heparin is the drug of choice because it is fastacting, rapidly metabolized, and reversible by protamine sulfate. Many surgeons use conventional dosages of heparin (100–200 USP units/kg by bolus, followed by 15 –30 USP units/kg/h by constant infusion). We strongly advise higher dosages and prefer a bolus of 300 USP units/kg, followed by 60–70 USP units/kg/h.[14] An activated clotting time, partial thromboplastin time, or Lee-White clotting time should be obtained to ascertain that the patient is responding to the anticoagulants, preferably maximizing at our upper limit of laboratory assessment ðPTT . 15000 Þ: We do not use these tests, however, to gauge the adequacy of our heparin dose. The degree of anticoagulation distal to an obstruction is not the same as the anticoagulation of blood taken from an antecubital vein. We use the higher doses of heparin because we want the anticoagulation to be adequate in the ischemic areas; we judge the amount of anticoagulation by the patient’s clinical response rather than by a laboratory test.[15] Regardless of the dosage, if the limb fails to improve following anticoagulation, the dosage is not adequate. Active clotting results in the downstream release of inflammatory factors that produce vascular “spasm.” This results in narrowed vessels and is protective in that it tends to prevent propagating clot from filling the vascular lumen. However, this spasm interferes with collateral flow. When full anticoagulation is obtained in the ischemic limb, spasm reverses and collateral flow improves. This is followed by a decrease in pain and a drop in the level of ischemic demarcation. Inevitably the viability of the limb will improve. If the limb is viable at initiation of anticoagulation, viability will improve with adequate anticoagulation, and revascularization, if necessary, can be carried out electively. If the patient is seen within 4 –6 hours of onset of ischemia and viability of the limb is in question—as manifest by pain, paralysis, or paresthesia—immediate operative intervention is indicated. Meticulous surgical technique is necessary to ensure wound hemostasis so that the patient can remain fully anticoagulated postoperatively. In the patient with probable thrombosis superimposed on preexisting vascular disease who has an ischemic but viable limb, revascularization is delayed until anticoagulation has resulted in improved collateralization and stabilization of the level of ischemia. An extensive early reconstructive procedure compromises the ability to administer full heparin therapy postoperatively because of a prohibitively high rate of hemorrhage.
We do not operate as an emergency on patients who present with ischemia of longer than 8 hours duration. If the ischemic insult is severe enough to result in muscle necrosis, the necrosis will already be established within 8 hours. Revascularization after this period of time salvages no more muscle beyond that salvaged by anticoagulation, a treatment associated with a lower mortality. We do not attempt immediate revascularization in patients with serious underlying medical problems. Revascularization of ischemic tissue washes products of ischemia into the central circulation, where those products damage the lungs, heart, kidneys, liver, and perhaps other organs. The patient’s medical condition should be considered with respect to the amount of ischemic tissue that would be revascularized. Only a fairly strong patient can tolerate revascularization of an extremely ischemic entire lower extremity, whereas a patient with a modest degree of cardiopulmonary disease will tolerate the establishment of flow into a moderately ischemic foot. No arteriogram is obtained initially because arterial punctures are likely to bleed with full anticoagulation. The heparin anticoagulation is given to achieve clinical improvement. The improvement can be gauged by the patient’s symptoms, by progression of the line of temperature demarcation distally along the leg, by recovery of sensation in the extremity, by maintenance or recovery of skeletal muscle function in the extremity, and by the appearance of the skin. As long as the skin blanches with pressure, it is potentially salvageable; when the skin develops blotchy, cyanotic areas that do not blanch with pressure, the tissue involved is beyond salvage. Hemorrhage is the major complication of anticoagulation with heparin.[16] Patients without surgical wounds and without underlying bleeding dyscrasias seldom bleed on heparin, even high-dose heparin, for the first several days of therapy. Bleeding becomes more common on about the fifth day, when heparin-induced thrombocytopenia can contribute to the anticoagulant effect of the heparin itself. Fortunately, most patients receive most of the benefit form heparin anticoagulation within the first few days of treatment. This permits a gradual reduction of heparin dosage, over the next 3–4 days, to more conventional levels. Failure to maintain therapeutic benefit on these lower doses, however, requires raising the level of anticoagulation. If bleeding should develop on the fifth day or later, the heparin can usually be stopped at that time, and in most instances therapeutic benefit will be maintained. The heparin should be given for 48 –72 hours at the high recommended doses. It should then be decreased and the patient’s clinical condition assessed. If the patient’s status remains unchanged with lower doses of heparin, the heparin can be decreased approximately 1000 USP units/h every 24 hours until the heparin is stopped about 7 days after the initiation of therapy or the patient is transferred to oral anticoagulation or low-dose subcutaneous heparin. At that time the extremity will be viable or partially necrotic. Amputation, revascularization, or chronic anticoagulation are treatment options in this situation. Revascularization is performed 7 days or more after the acute ischemic insult to maximize the chance of healing of an amputation or to alleviate residual ischemic symptoms.
Chapter 27.
We have found that this treatment, a plan that emphasizes the importance of anticoagulation, results in low mortality and salvages extremities as well as those treatment regimens that emphasize immediate revascularization in all patients, both low risk and high risk.[14] We do advocate thromboembolectomy in patients who are seen shortly after the onset of symptoms. In the remaining patients who present with ischemic but viable limbs, revascularization can be performed at a time of election if anticoagulation is given in adequate dosages to prevent thrombus propagation. In these patients with ischemic skin necrosis or dead muscle, initial anticoagulation followed later by amputation is the treatment of choice. Patients presenting with a viable extremity more than 48 hours after the onset of symptoms can be managed like patients with chronic severe obstructive disease. High-dose heparin therapy is of limited value, as these extremities have already survived the initial ischemic insult by developing collateral flow. An angiogram to evaluate the vasculature should be obtained. Many of these patients will require revascularization. Some have benefited from embolectomy as a form of revascularization up to 7 weeks after the onset of symptoms.[17] Chronic anticoagulant therapy with warfarin (Coumadin) or subcutaneous heparin is subsequently indicated in many of these patients.
Embolectomy Technique Low-risk patients who present with ischemia of less than 8hour duration should have an embolectomy performed if it is likely that the acute ischemia is caused by an embolus. With the patient under local or regional anesthesia, thrombus or embolus can frequently be easily removed via a peripheral incision.[18] A Fogarty balloon catheter is passed through the clot or embolus, the balloon inflated gently, and the catheter withdrawn. There are several important aspects to the application of this technique. Proximal and distal control of the vessel should be ensured before arteriotomy. The common femoral, popliteal, and brachial arteries allow access to most vessels with extractable material. Catheter-related complications can be kept to a minimum by continually modifying the amount of fluid in the balloon while the catheter is being withdrawn to prevent overinflation at plaque sites and consequent vessel damage. Backbleeding as well as distal pulsation do not guarantee adequate clot extraction. Therefore, an angiogram should be obtained after the removal of the embolus to confirm an adequate clot extraction. The nature of the operation is subsequently dictated by the arteriographic and operative findings. Most acute thromboemboli can be removed completely through the groin. However, if the occlusion is atherosclerotic or is distal to the distal superficial femoral artery, clearing the occlusion may be difficult or impossible. In such cases the arteriotomy is better performed in the distal popliteal artery or in the tibioperoneal trunk opposite the origin of the anterior tibial artery. Balloon catheter embolectomy of the tibial arteries can then be performed gently and accurately. In some cases, with arteriosclerotic or aneurysmal changes, a bypass operation must be performed with or without extraction of the proximal thrombus or embolus.
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There are four primary complications associated with the use of the balloon catheter: rupture, perforation, intimal injury, and fragmentation of clot resulting in inadequate removal and distal embolization. These complications serve to emphasize another reason for obtaining an angiogram after an embolus extraction. If the angiogram demonstrates an intimal injury compromising circulation, repair is necessary. If there is extravasation of contrast material but good distal perfusion without signs of ongoing hemorrhage, repair may or may not be necessary. These patients can often be followed clinically and studied later with arteriograms to confirm the resolution of the problem. For at least 24 hours after surgery, the patient should be placed in an intensive care unit so that the distal circulation can be monitored. If evidence of rethrombosis or recurrent embolus is identified, the patient should be returned to the operating room immediately. Pulmonary, cardiac, and renal complications should be treated in standard fashion as they present. Common complications of revascularization are noted in Table 27-5.
Postoperative Anticoagulation All patients should be maintained on heparin anticoagulation postoperatively for at least 72 hours, and warfarin (Coumadin) should be started in those patients presumed to have had embolic occlusions. Hemorrhage is a frequent postoperative complication in patients receiving heparin. Postoperative bleeding can be minor, as indicated by melena, hematuria, ecchymosis, or small wound hematomas, in which case the heparin therapy can be continued with monitoring of the hematocrit, platelet count, and partial thromboplastin time. The conversion to oral anticoagulation therapy should be accomplished as soon as possible. If the bleeding is major, the heparin effect should be reversed with protamine. Major bleeding can be defined as that requiring transfusion for stabilization, cerebrovascular accidents, pulmonary infarction, and large wound hematomas. Further anticoagulation therapy should then await the stabilization of the patient and reevaluation. Acutely, heparin is used in the postoperative period to prevent recurrent embolus or thrombosis. In our experience and that of others, mortality is decreased with postoperative anticoagulation.[19] The trade-off is a 20% incidence of wound complications, including an 8% incidence of hematomas requiring drainage.[20] Table 27-5. Complications of Revascularization Hemorrhage Thrombosis Recurrent emboli Pulmonary embolus Microembolic acute respiratory distress syndrome Extremity edema Acute renal failure Cardiac dysfunction—myocardial infarction, arrhythmias Mesenteric infarction
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Fasciotomy Following revascularization of an ischemic limb, some degree of muscle edema is the rule. The amount of edema parallels the severity and duration of the ischemia. When the subfascial compartments become tense, and in particular when compartment pressures exceed 40 mmHg, many surgeons feel that four-compartment fasciotomy is indicated to preserve circulation and enhance muscle viability.[21] When the increased compartment pressure is due to direct tissue injury, hemorrhage, or venous obstruction, fasciotomy is noncontroversial. However, when increased compartment pressure is due to swelling of ischemic muscle, fasciotomy that exposes this muscle will not necessarily reverse the damage, which is often irreversible necrosis. Exposed ischemic or dead muscle is vulnerable to infection, and when infection occurs above knee, amputation is usually the result. Limbs are lost only when the covering (skin) is lost. Necrotic muscle, protected from infection, atrophies and resorbs. Lower leg muscles, which are the ones most commonly involved, affect ankle function, but a partially paralyzed limb is still functional. Moreover, a below-knee amputation, should this be required, is associated with much less disability than is amputation above the knee. Finally, the decision for or against fasciotomy is a judgment decision in which the risk/benefit ratio must be weighed. Fasciotomy is rarely necessary when the ischemic limb is revascularized within the period of muscle tolerance (6–8 hours of profound ischemia) or when the muscle is still functional.[21]
be caused by the antigen–antibody interaction of streptokinase with preformed streptococcal antibodies. Urokinase is harvested from human renal cells in tissue culture and is not antigenic. It is a trypsinlike protease that directly converts plasminogen to plasmin. Low-dose urokinase at 20,000 IU/h, selectively infused, has been effective in restoring vessel patency. Its primary disadvantage is that it is six times more expensive than streptokinase. Ideally, fibrinolytic therapy would be most useful for fresh thrombosis prior to clot organization, propagation, or vessel wall damage. In contrast to heparin, the streptokinase actively lyses clot and therefore might accelerate the return of circulation to normal. Heparin prevents the formation of new clot, allowing fibrinolysis to predominate over clotting. Heparin can be given systemically and, by preventing clot formation, allows collateral circulation to develop while the patient’s fibrinolytic system slowly lyses clot. Lytic therapy has been combined with percutaneous transluminal angioplasty. It has also been successful in restoring patency in vessels occluded for several weeks. The appropriateness of chronic anticoagulation in both of these groups of patients should be determined on an individual basis. Even with low-dose selective treatment, systemic fibrinolysis can be documented, and complications have been identified. Thrombin time, fibrinogen levels, prothrombin times, partial thromboplastin time, platelet counts, hematocrit, and fibrin split products should be monitored to prevent complications associated with fibrinolytic therapy (Table 27-6). Posttreatment anticoagulation should be monitored because patients have an increased susceptibility to bleeding complications.
Fibrinolytic Therapy We do not use fibrinolytic therapy as primary treatment in limbs with advanced ischemia because therapy requires 12 – 24 hours to become effective and permanent muscle death follows 6–8 hours of ischemia. For limbs with subacute ischemia, which often is associated with thrombotic rather than embolic occlusion, lytic therapy will often unmask the underlying lesion and permit many conservative and operative alternatives. Initially, systemic thrombolytic agents, administered intravenously, were evaluated in acute arterial ischemia, and they effectively restored patency in occluded vessels at the expense of hemorrhagic complications. More recently, lowdose plasminogen activators have been selectively infused through a percutaneous arterial catheter placed in the occluding thrombus.[22 – 24] In theory, the hemorrhagic complications of systemic fibrinolytic therapy are avoided by low-dose local infusion; however, the dosages currently advocated for local therapy are similar to those recommended for systemic treatment. Streptokinase is a nonenzymatic protein product of group C b-hemolytic streptococci that combines with plasminogen to form an active enzymatic complex capable of converting plasminogen to plasmin. The low-dose intraarterial regimen provides for 5000–10,000 IU/h to be selectively infused for 12–48 hours with the therapeutic effect monitored by physical examination or by serial arteriography. The lowgrade fever at times accompanying the treatment is thought to
EVOLUTION OF ISCHEMIC MANIFESTATIONS The nature of ischemic manifestations has slowly changed such that the incidence of embolic occlusion has dropped dramatically in recent decades in favor of thrombotic occlusion. Although thrombotic occlusion may produce severe ischemia, more often the lesion responsible for the occlusion has, through gradual build-up, stimulated collateral development. Under these circumstances limb ischemia is less severe and more therapeutic options are available. If limb sensation and muscle function are present, initiation of anticoagulation may be deferred in favor of
Table 27-6.
Complications of Fibrinolytic Therapy
Intracranial hemorrhage Arterial site hematomas Distal embolization Extravasation of blood through graft interstices—lysis of pseudointima of Dacron prosthesis Retroperitoneal hemorrhage Mild allergic reaction
Chapter 27.
urgent arteriographic evaluation. Arteriography offers many potential advantages, including detection of other unsuspected emboli and atypical localization of thromboembolic occlusions—a very common condition in the elderly atherosclerotic patients that currently comprise the bulk of those presenting with acute limb ischemia. Moreover, arteriography defines the patency and degree of atherosclerotic involvement of the inflow and outflow arteries available for a bypass procedure. Such a bypass is often required for the definitive treatment of acute ischemia, whether it be due to thrombosis or embolism. In this group of patients, the arteriogram may also reveal an unexpected popliteal or aortic aneurysm, or, in the occasional patient, nonocclusive unilateral ischemia due to a low flow state. Immediate arteriography followed by lytic therapy to unmask the lesion responsible for the ischemia is a popular option. Once uncovered, the lesion may lend itself to stenting or bypass depending on its location and extent. In summary, there are multiple options for treatment of the acutely ischemic limb. The limb that has been cold, paralyzed, and insensate for more than 8 hours is best treated with high-dose anticoagulation initially since revascularization attempts will be associated with high morbidity and mortality. If sensation and motor function in the foot are abnormal and the limb can be revascularized within 8 hours, attempt to restore blood flow to the limb is appropriate. In the viable but ischemic limb, emergent arteriography may be optimal. Armed with the findings obtained by performing urgent or emergency arteriography in the marginally viable limb, aggressive management is possible. Options include lytic therapy, stenting of stenotic lesions, or surgical bypass. The decision as to when and when not to attempt revascularization is often difficult and must be based on a surgeon’s experience and ongoing evaluation of results in order to optimize the chances for saving a given patient’s life and limb in this high-risk setting. Many variables influence the choice of treatment for acute ischemia of the lower extremity. The severity of the ischemia, the condition of the patient, and—to some extent—the surgeon’s preference and experience will determine whether treatment with surgery, heparin, or lytic agents should be the preferred therapeutic option. Finally, it should be recognized that revascularization for arterial ischemia carries with it considerable risk. The current mortality for restoration of flow to severely ischemic extremities remains anywhere from 8 to 50%, depending upon the location of the arterial lesion and the duration of the ischemia. Mortality rates were reported as follows: 8%,[25] 22%,[26] 50%,[27] 12%,[28] 17.8%,[29] 19%,[30] and 9.7%.[31]
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UPPER EXTREMITY ISCHEMIA In contrast to lower extremity ischemia, cardiac embolization accounts for the vast majority of cases of upper extremity ischemia.[32] Thoracic outlet obstructions at the third portion of the subclavian artery can result in intimal damage, aneurysmal or poststenotic dilation, and subsequent atheroemboli or thrombosis[33] (see Chap. 62). The principles of management of upper extremity ischemia are similar to those of lower extremity ischemia. Because collateral flow to the upper extremity is extensive, conservative treatment with high-dose heparin is often effective. Embolectomy is more dangerous in the upper extremity because of the smaller size of the vessels and because of the danger of dislodging thrombus into the carotid or vertebral arteries. The mortality is lower and the limb salvage rate is higher for upper extremity ischemia compared with lower extremity ischemia, presumably because the amount of tissue necrosis is less and collateral circulation is better.
CEREBRAL ISCHEMIA Embolism has been estimated to cause 20 –30% of all cerebral infarctions, and the incidence of stroke is five times greater in patients with atrial fibrillation than in the general population.[34] Because the risk of recurrent stroke in these patients is approximately 20% per year, the treatment is directed at controlling cardiac arrhythmias and at preventing further cerebral infarctions with oral anticoagulants.[35]
VISCERAL ISCHEMIA Most visceral ischemia of sudden onset occurs when the superior mesenteric artery is occluded acutely by an embolus or by thrombosis (see Chap. 59). Abdominal catastrophe associated with cardiac disease is the classic setting. Traditionally, mortality has been 80% and treatment has focused on resection of necrotic bowel rather than revascularization. However, revascularization by aortomesenteric bypass, transaortic endarterectomy, or embolectomy may rarely be successful in the acute case. More recently a combination of revascularization followed by resection of necrotic bowel has been advocated to improve mortality.[36] A second-look procedure is always indicated and is of particular value when marginal bowel has been left behind at the initial operation.
REFERENCES 1.
Harvey, W. Exercitatio Anatomica de Motu Cordis et Sanguinis in Anjmalibus; English Translation by Leake, C.D. Charles C Thomas: Springfield, IL, 1931; 37. 2. Shor, P.M.; Fogarty, T.J. Acute Arterial Insufficiency. In Diagnosis and Management of Peripheral Vascular
Disease; Miller, D.C., Avon, A.J., Eds.; Addison-Wesley: Menlo Park, CA, 1982. 3. Mosney, M.; Dumont, N.J. Embolie Fe´morale Aucours d’un Re´tre´cissement Mitral pur. Arte´riotomie. Guerison Bull. Acad. Med. 1911, 66, 358.
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4. Abbott, W.M.; Maloney, R.D.; McCabe, C.C.; et al. Arterial Embolism: A 44 Year Perspective. Am. J. Surg. 1982, 143, 460. 5. Dale, W.A. Differential Management of Acute Peripheral Arterial Ischemia. J. Vasc. Surg. 1984, 1, 269. 6. Lusby, R.J.; Wylie, E.J. Acute Lower Limb Ischemia: Pathogenesis and Management. World J. Surg. 1983, 7, 340. 7. Jivegard, L.; Holm, J.; Schersten, T. Acute Limb Ischemia Due to Arterial Embolism or Thrombosis: Influence of Limb Ischemia Versus Pre-existing Cardiac Disease on Postoperative Mortality Rate. J. Cardiovasc. Surg. 1988, 29, 32. 8. Blaisdell, F.W.; Lim, R.G.; Amberg, J.R.; et al. Pulmonary Microembolism: A Cause of Morbidity and Death After Vascular Surgery. Arch. Surg. 1966, 93, 776. 9. Stallone, R.J.; Blaisdell, F.W.; Cafferata, H.T.; Levin, S.M. Analysis of Morbidity and Mortality from Arterial Embolectomy. Surgery 1969, 65, 207. 10. Haimovici, H. Metabolic Complications of Acute Arterial Occlusions. J. Cardiovasc. Surg. 1979, 20, 349. 11. Nishide, M.; Irino, T.; Gotoh, M.; et al. Cardiac Abnormalities in Ischemic Cerebrovascular Disease Studied by Two-Dimensional Echocardiography. Stroke 1983, 14, 541. 12. Caplan, L.R.; Hier, D.B.; D’Cruz, I. Cerebral Embolism in the Michael Reese Stroke Registry. Stroke 1983, 14, 530. 13. Robbins, J.A.; Sagar, K.B.; French, M.; Smith, P.J. Influence of Echocardiography on Management of Patients with Systemic Emboli. Stroke 1983, 14, 546. 14. Blaisdell, F.W.; Steele, M.; Allen, R.E. Management of Acute Lower Extremity Arterial Ischemia Due to Embolism and Thrombosis. Surgery 1978, 84, 822. 15. Blaisdell, F.W. Use of Anticoagulants in the Ischemic Lower Extremity. In Management of Lower Extremity Ischemia; Kempczinski, R.F., Ed.; Year Book: Chicago, 1989. 16. Walker, A.M.; Jick, H. Predictors of Bleeding During Heparin Therapy. J. Am. Med. Assoc. 1980, 244, 1209. 17. Jarrett, F.; Dacumos, G.C.; Crummy, A.B.; et al. Late Appearance of Arterial Emboli: Diagnosis and Management. Surgery 1979, 86, 898. 18. Fogarty, T.J.; Cranley, J.J.; Krause, R.J.; et al. A Method for Extraction of Arterial Emboli and Thrombi. Surg. Gynecol. Obstet. 1963, 116, 241. 19. Holm, J.; Schersten, T. Anticoagulant Treatment During and After Embolectomy. Acta Chir. Scand. 1972, 138, 683.
20. Tawes, R.L.; Beare, J.P.; Scribner, R.G.; et al. Value of Postoperative Heparin Therapy in Peripheral Arterial Thromboembolism. Am. J. Surg. 1983, 146, 213. 21. Patman, R.D.; Thompson, J.E. Fasciotomy in Peripheral Vascular Surgery. Arch. Surg. 1970, 101, 663. 22. Hallett, J.W.; Yrizarry, J.M.; Greenwood, L.H. Regional Low Dosage Thrombolytic Therapy for Peripheral Arterial Occlusions. Surg. Gynecol. Obstet. 1983, 156, 148. 23. Hargrove, W.C.; Barker, C.F.; Berkowitz, H.D.; et al. Treatment of Acute Peripheral Arterial and Graft Thrombosis with Low-Dose Streptokinase. Surgery 1982, 92, 981. 24. Marder, V.J.; Sherry, S. Thrombolytic Therapy: Current Status. N. Engl. J. Med. 1988, 318, 1585. 25. Cambria, R.P.; Abbott, W.M. Acute Arterial Thrombosis of the Lower Extremity: Its Natural History Contrasted with Arterial Embolism. Arch. Surg. 1984, 119, 784. 26. Balas, P.; Bonatsos, G.; Xeromeritis, N. Early Surgical Results on Acute Arterial Occlusion of the Extremities. J. Cardiovasc. Surg. 1985, 26, 262. 27. Litooy, F.; Baker, W.H. Acute Aortic Occlusion: A Multifaceted Catastrophe. J. Vasc. Surg. 1986, 4, 211. 28. Tawes, R.L., Jr.; Harris, E.J.; Brown, W.H. Acute Limb Ischemia: Thromboembolism. J. Vasc. Surg. 1987, 5, 901. 29. Stryga, O.; Myracha, P.; Zmijewski, M. Acute Limb Ischemia After Arterial Surgery. Wiad. Lek. 1993, 46, 420. 30. Harward, T.R.; Ingegno, M.D.; Carlton, L.; Flynn, T.C.; Seeger, J.M. Limb-Threatening Ischemia Due to Multilevel Arterial Occlusive Disease. Ann. Surg. 1995, 221, 498. 31. Neuzil, D.F.; Edwards, W.H., Jr.; Mulherin, J.L. Limb Ischemia: Surgical Therapy in Acute Arterial Occlusion. Am. Surg. 1997, 270, 63. 32. Haimovici, H. Cardiogenic Embolism of the Upper Extremity. J. Cardiovasc. Surg. 1982, 23, 209. 33. Haimovici, H. Arterial Thromboembolism of the Upper Extremity Associated with the Thoracic Outlet Syndrome. J. Cardiovasc. Surg. 1982, 23, 214. 34. Sage, J.I.; Van Uitert, R.L. Risk of Recurrent Stroke in Patients with Atrial Fibrillation and Non-Valvular Heart Disease. Stroke 1983, 14, 537. 35. Easton, J.D.; Sherman, D.G. Management of Cerebral Embolism of Cardiac Origin. Stroke 1980, 11, 433. 36. Bergan, J.J.; Dean, R.H.; Conn, J.; Yao, J.S.T. Revascularization in Treatment of Mesenteric Infarction. Ann. Surg. 1975, 182, 430.
CHAPTER 28
Microcirculatory Dysfunction in the Pathophysiology of Skeletal Muscle Ischemia Walter N. Dura´n Mauricio P. Boric´ Peter J. Pappas Robert W. Hobson II
molecular oxygen occurs after ischemia has depleted or reduced cellular energy stores. Under these conditions it appears that cellular oxygen sensors adjust themselves to an apparently lower pO2, so that reintroduction of normoxic blood constitutes a hyperoxic and toxic insult to the ischemic tissues. The microcirculation represents the first barrier in ischemia-reperfusion injury in all tissues, and thus may serve as a useful target for therapeutic interventions. Increased permeability to macromolecules, stimulated adhesion and emigration of leukocytes, and the no-reflow phenomenon are characteristic responses of ischemic microvessels. However, the relationship between microvascular dysfunction and tissue damage in the ischemiareperfusion (I/R) injury has not been fully investigated, even though they are intimately related. Increased microvascular permeability to macromolecules is one of the earliest signs of microvascular dysfunction in skeletal muscle. It is difficult to assess to what extent ischemia and reperfusion contribute differentially to microvascular dysfunction. Changes in permeability occur during ischemia and a large increase in macromolecular transport can be measured immediately upon reperfusion.[10,11] Application of clearance and intravital microscopy techniques indicate that a significant increase in macromolecular transport is observed in the reperfusion phase (Fig. 28-1).[12] Some studies have examined the reperfusion period exclusively due to methodological reasons.[13,14] It is important to evaluate carefully the limitations imposed by the experimental design in the assessment of the differential contributions of ischemia and of reperfusion to microvascular dysfunction. It is safe to state that, inasmuch as functional hyperemia does not cause
INTRODUCTION The basis for tissue injury during ischemia depends on depletion of tissue oxygen and energy substrates with predominance of anaerobic metabolism. Decreasing cellular energy stores and accumulation of toxic metabolic byproducts[1,2] alter cellular membrane integrity leading to fluid and electrolyte movement, release of intracellular components, cell injury, and ultimately cell death.[3] Cell injury appears to begin after only 30 minutes of ischemia, as is evidenced by progressive cellular edema[4] and lysosomal degranulation.[5] Irreversible changes in skeletal muscle occur after 4 – 6 hours of warm ischemia.[4] The injury associated with acute arterial occlusion is not limited to the period of ischemia alone. Revascularization and restoration of blood flow initiates a series of complex events that lead to the reperfusion syndrome. Light microscopic studies have documented that cell injury following an ischemic period occurs after blood flow has been reestablished.[4] This injury also has been found to be maximal in areas with the greatest degree of blood flow during reperfusion.[5] The reintroduction of molecular oxygen appears to be an important and critical event in the genesis of reperfusion injury in postischemic muscle. Damage occurs in part as the result of the formation of oxygen-derived free radicals leading to lipid peroxidation.[6,7] Reperfusion with hypoxic blood decreases the incidence of injury while reperfusion with normoxic blood leads to postischemic damage.[8] Similar results are obtained by limiting the rate of blood flow during the first hour of reperfusion.[9] The reintroduction of
Hobson/Wilson/Veith: Vascular Surgery: Principles and Practice, Third Edition, Revised and Expanded DOI: 10.1081/0819-9-120024911 Copyright q 2004 by Marcel Dekker, Inc.
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MICROVASCULAR PERMEABILITY Structural and Biochemical Bases for Microvascular Permeability
Figure 28-1. Microvascular permeability alterations in ischemia-reperfusion injury in striated muscle. The rat cremaster muscle was prepared for intravital microscopy as described in Ref. [10]. The animal received FITC-dextran-150, a fluorescent macromolecular tracer. (A) The control observation. Note that the fluorescent macromolecule is confined to the vascular compartment. (B) Observations made within 10 minutes after onset of reperfusion. Note that the fluorescent macromolecular tracer has extravasated into the interstitial space, and there are a few microvessels showing signs of the no-reperfusion phenomenon (dark vessels on right-hand side).
either microvascular or tissue damage, reperfusion exaggerates cellular alterations produced by ischemia and, in addition, causes new injury due to complex interactions between newly reintroduced molecular oxygen and the cellular metabolic state set up by ischemia. Regardless of whether it is an ischemic- or a reperfusiondriven event, the reproducibility of alterations in microvascular permeability in I/R injury has led to its wide utilization as an index for microvascular dysfunction[13 – 16] and as an endpoint to test the mechanisms of damage and to assess the efficacy of potential therapies. In this chapter, which builds on the previous edition, we will review the fundamental basis of the regulation of microvascular permeability by biochemical signaling as well as its impact on ischemia-reperfusion injury.
An early and productive interpretation of the morphological basis of increased microvascular permeability is the concept that endothelial cell contraction widens the intercellular gap and allows passage of macromolecules.[11] Electron and fluorescence microscopy identified postcapillary venules as the morphologic main site of action of modulation of permeability by inflammatory mediators.[17 – 19] These microvessels are also responsible for the permeability alterations in I/R injury (Fig. 28-1). Several observations have led to the consideration of an alternative hypothesis of the structural and biochemical basis of microvascular permeability. Experiments in single microvessels demonstrated that transport of protein remains elevated even though the intercellular gap has returned to normal dimensions.[20] Increased transport of macromolecules also occurs in I/R injury despite the normal appearance of microvascular ultrastructure in striated muscle.[10,11] Based on the properties and biochemical structure of the glycocalyx, the alternative hypothesis proposes that the endothelial cell regulates the composition of its glycocalyx in response to environmental physical and chemical stimuli. This capacity of the endothelium has been demonstrated both in tissue culture[21] and in vivo.[22] Changes in the order or structure of the molecules that make up the glycocalyx can determine the rate of transport of solutes from blood to tissue. This latter concept, based broadly on the physicochemical behavior of chromatographic columns, is termed the fiber matrix theory of capillary transport.[23] If indeed changes in the order of fiber matrix glycoproteins are responsible for the observed increased permeability, then it is plausible that therapies based on the administration of macromolecules may work by sealing the larger gap interstices developed by I/R[24 – 26] or by interacting with endothelial integrins and adhesion molecules.
Mechanisms of Signal Transduction in Hyperpermeability Biochemical signaling determines the action of vasomediators in the control of microvascular permeability and flow. Signaling interactions between vascular wall and blood cells provide a unique way of communicating, coordinating, and integrating an appropriate physiologic response to the changing tissue environment in vivo. This brief review of cell signaling in the microcirculation focuses preferentially on in vivo studies of increased permeability (hyperpermeability) in health and in inflammatory microvascular permeability dysfunction. Intravital microscopy has been applied to study microvascular permeability in health and disease using physiologic and pharmacologic approaches to gain insights into regulatory mechanisms. The intravital microscopy approach is greatly enhanced by the utilization of computerassisted digital image analysis (Fig. 28-2).[27 – 29] An example of the application of intravital microscopy is the in vivo investigation of the biochemical signaling pathways in our
Chapter 28.
Figure 28-2. Diagram of video-microscopy computer-assisted image analysis. The fluorescent intensity of a macromolecular tracer is measured at a window adjacent to a postcapillary venule. The measuring window is usually 100 £ 120 pixels (a TV image has 512 £ 512 pixels). The fluorescent intensity is measured according to a computer grayscale (0 – 255) in which 0 = black and 255 = white. The integrated optical intensity of the fluorescent tracer reflects its permeation through the microvascular wall.
laboratory. The basic working scheme, derived from the in vitro literature and our own experimental results, is shown on Fig. 28-3. The signaling pathways for inflammatory agents that cause hyperpermeability [e.g., platelet-activating factor (PAF), bradykinin (BK), histamine, leukotriene C4 (LTC4), and vascular endothelial growth factor (VEGF)] involve the activation of protein kinase C (PKC), activation of nitric oxide synthase (NOS), and synthesis of nitric oxide (NO).[30 – 41] Because of the short duration of the stimulus and the brief delay between stimulus and permeability response (seconds to minutes), endothelial constitutive nitric oxide synthase (eNOS) is the most likely candidate for the generation of NO under these experimental conditions. These reactions are followed by the synthesis of cyclic guanylate monophosphate (cGMP)[42] and are independent of changes in calcium influx.[43] In isolated coronary venules, blood flow modulates permeability also via a mechanism mediated by the synthesis of NO.[44] Flow may possibly induce NO production in endothelial cells due to changes in shear stress.[45] Our own work and the reports of others are consistent with the hypothesis that eNOS activity and release of NO serve to increase microvascular permeability. The issue of whether NO is a universal signaling mechanism remains, however, unresolved. There is persuasive evidence that endogenous NO serves to maintain a tight microvascular barrier. This view is supported by studies showing that inhibition of NOS with L -arginine analogs increases extravasation of macromolecules in the intestine.[46] The action of the NOS inhibitor could be reversed by administration of an NO donor. In the mesentery, the maintenance of a tight microvascular barrier characteristic is thought to involve the participation of cGMP.[47] In either view, the compelling evidence for endogenous NO involvement as a modulator of permeability is based mainly on either the specificity of L -arginine analogs to block NOS or the ability of NO donors to mimic NO actions. The studies cited have not measured NO production under the experimental conditions. In order to fill this gap in
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Figure 28-3. Biochemical signaling pathways in the control of microvascular permeability. The diagram indicates possible molecular interactions leading to hyperpermeability. Because eNOS plays a pivotal role in signal transduction, several upstream pathways converge on eNOS. Among the upstream elements, PKB is being recognized as an important regulator that may directly phosphorylate eNOS and increase NO production (see Refs. [63] and [64]). Nitric oxide stimulates soluble guanylate cyclase to produce cGMP, which in turn activates PKG and leads to the activation of MAP kinases. It is plausible that MAP kinases lead to conformational changes of skeletal and junctional proteins to achieve an increase in microvascular permeability. Abbreviations: PLD, PLC, PLA2 = phospholipases; PKB, PKC, PKG = protein kinases B, C, and G, respectively; PA = phosphatidic acid; DG = diacyl glycerol; Ca2+-CAM = calcium-calmodulin; IP3 = inositol triphosphate; eNOS = endothelial constitutive nitric oxide synthase; cGMP = cyclic guanylate monophosphate; MAP kinase = mitogen-activated protein kinases.
knowledge, we have measured NO in preliminary experiments—using a chemiluminescence method recently validated for its application in the hamster cheek pouch[48]—and determined that PAF increases NO synthesis, causes vasoconstriction, and increases macromolecular transport.
Regulation of Nitric Oxide Synthase by Phosphorylation The genes encoding for human and bovine endothelium eNOS have been characterized and their cDNA have been cloned.[49 – 55] It is important to recognize that while the gene sequence is highly conserved among species, the regulatory modalities may vary in different species.[56] The possibility of eNOS regulation by phosphorylation is supported by its deduced amino acid sequence, which contains phosphorylation sites (largely serine/threonine phosphorylation consensus, even though tyrosine phosphorylation consensus sites also have been identified). However, whether phosphorylation leads to activation or inactivation of eNOS and/or nNOs activity is controversial. PKC and calmodulin kinase II have been reported to phosphorylate
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nNOS by one group,[57] while another group failed to induce phosphorylation of nNOS through these kinases.[58] Activation of PKC (30 minutes exposure to tetradecanoyl phorbol acetate, TPA) leads to nNOS phosphorylation.[57,59] Bradykinin leads to phosphorylation of eNOS and to an increase in the activity of eNOS[60] in bovine aortic endothelial cells (BAEC). However, and in contrast to nNOS, pharmacologic inhibition of PKC as well as PKC depletion by prolonged exposure to TPA elevates the production of NO-related nitrites in BAEC.[61] Tyrosine phosphorylation may play a role in the regulation of eNOS, particularly in its interactions with cavcolin-l.[62] Two recent reports have established that protein kinase B (PKB; a serine/threonine kinase) phosphorylates eNOS directly and leads to an increase in NO production.[63,64] It is tempting to postulate that this direct phosphorylation of eNOS by PKB plays a role in the regulation of microvascular permeability. Dr. Haruo Aramoto, in our laboratory, has shown that wortmannin (a blocker of phosphatidylinositol-3kinase and, thus, an indirect inhibitor of PKB) inhibits in vivo the elevation in microvascular transport of macromolecules caused by VEGF. In reference to the pathway depicted in Fig. 28-3, it is plausible that PAF and other agonists stimulate PKB in its modulation of microvascular permeability. In fact, a recent study suggests that VEGF-induced hyperpermeability is mediated in vivo by PAF.[65] The full functional significance of PKB-induced phosphorylation and its enhanced NO production remains to be elucidated. The impact of the available data on eNOS phosphorylation on our knowledge of microvascular transport is difficult to evaluate. It is important to recognize that the main focus of the molecular biology studies of eNOS has been the role of NO in control of blood flow and blood pressure.[45,66,67] These studies have been conducted in endothelial cells (EC) derived from large vessels. Because of an interest in long-term regulation, these studies have also exposed endothelial cells to agonists for several hours.[61] Under these experimental conditions, in addition to the uncertainty of translating in vitro to in vivo experiments, investigators of the microcirculation are forced to extrapolate data from large vessel endothelium, not normally involved in blood-tissue transport processes, to postcapillary venular endothelium, where the majority of the transport of macromolecules occurs. Moreover, the uncertainty of the extrapolation may be compounded by the possible phenotypical changes undergone by EC grown in specifically designed and controlled culture media. The tissue culture situation is, by necessity, at variance with the dynamic environment of EC in the microcirculation. These considerations underscore the importance and the need to investigate the influence of eNOS phosphorylation on the regulation of permeability under conditions that closely resemble its microvascular environment.
Molecular Movement of eNOS Changes in eNOS activity may be associated with its translocation from the membrane to the cytosolic compartment.[60] However, the location of eNOS to the Golgi complex seems to enhance the efficiency of NO synthesis.[56] Both membrane-bound and cytosolic eNOS are able to release
NO, but the relative importance of each pool for basal or stimulated release of NO has not been fully determined.[68] It has been suggested, however, that “biologically active eNOS resides in different subcellular compartments and that each pool can be differentially regulated and responsive to different forms of stimulation.”[68] Translocation of eNOS to the nuclear environment has been reported under hormonal stimulation.[69,70] In preliminary experiments conducted by Dr. Koichi Yoshimura in our laboratory, we find evidence for eNOS movement from membrane to cytosol after prolonged ischemia. Thus, it is plausible that the cellular location of eNOS may represent a mechanism that determines the rate of NO production under different experimental (physiologic or pathophysiologic) conditions.
Microvascular Permeability, eNOS, and Junctional Proteins The cellular events that are necessary to account for the translation of agonist stimulation to the final microvascular permeability response are the subject of active investigation. The final step in the sequence of molecular modifications appears to involve proteins located at the cell junctionalcytoskeletal complex. Studies performed mainly in tissue culture have identified VE-cadherin and b-catenins as possibly key molecules. VE-cadherin is unique in that it is distributed specifically in the vascular endothelial intercellular junction (zonula adherens), as opposed to other cadherins that are present nonspecifically along the cell membrane in most cell types.[71 – 75] As a transmembrane glycoprotein. VE-cadherin forms a complex with b-catenins. The presence and distribution of VE-cadherin at junctions is modulated by Ca2+.[71] However, it is not known whether eNOS activity influences this apparently key permeabilityrelated protein. Evidence for the role of VE-cadherins in permeability has been obtained in HUVEC and in mesenteric venules. In both tissues, the organization of VE-cadherins is altered at the endothelial cell junction by agents that cause hyperpermeability.[76,77]
Nitric Oxide Synthase and Permeability Changes in Ischemia-Reperfusion The role of eNOS in I/R injury is still unresolved. There is compelling evidence that inhibition of eNOS ameliorates the impact of I/R on hyperpermeability, and also compelling evidence that inhibition of eNOS leads to enhanced leukocyte adhesion and exaggerated macromolecular leakage. We have demonstrated that the increased permeability associated with I/R injury is, at least partially, mediated by PAF and NOS.[78,79] Importantly, inhibition of PAF with a specific receptor antagonist or inhibition of NOS with L-NMMA are efficacious when applied either before the onset of ischemia or at the time of reperfusion.[78,79] Evidence obtained by other investigators indicates that inhibition of NOS leads to an indirect increase in permeability due to enhanced leukocyte adhesion.[80] The difference in results may be due in part to
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the specific model of ischemia applied to the tissue under examination. We have investigated models of global ischemia in the hamster cheek pouch[79,81] and in rat striated muscle,[10,11,78,82] while other investigators have studied partial ischemia in the rat and cat mesentery.[80,83] The differences in degree of ischemia and oxygen availability may lead to variations in the biochemical and physiologic mechanisms of the signaling sequence that stimulates NOS under specific experimental conditions.
FACTORS AND MECHANISMS OF MICROVASCULAR DYSFUNCTION Endothelial and Vascular Wall Cells The pathophysiology of ischemia-reperfusion injury involves a sequence of events that lead to inadequate oxygen delivery, reduction in cellular energy stores, accumulation of noxious metabolites, and reperfusion injury mediated by oxygenderived free radicals.[13] The formation of reactive oxygen metabolites is pivotal to the biochemical basis of injury. There are many potential biologic sources of oxygen free radicals. The microvascular endothelial cell containing xanthine oxidase and the neutrophil with its membranebound NADPH oxidase have been subject to the closest scrutiny. Ischemia activates a calcium-dependent protease that catalyzes the conversion of xanthine dehydrogenase to its oxidase form (Fig. 28-4). As ischemia continues, ATP is degraded to hypoxanthine which is then converted to uric acid by xanthine oxidase with the production of superoxide anion. Superoxide dismutase converts superoxide anion to hydrogen peroxide, which in the presence of ferric ion, produces the hydroxyl radical. The hydroxyl radical is capable of reacting with proteins, lipids and nucleic acids making it a highly toxic oxidant.[84] The ability of the hydroxyl anion to promote lipid peroxidation of cell membranes may be a major contributor to the mechanisms by which microvascular permeability is increased following reperfusion of ischemic tissues. Oxygen-derived free radicals play an important role in the genesis of reperfusion damage.[85] The formation of oxygenderived free radicals depends on the generation of O2 2 through endothelium– and leukocyte-stimulated biochemical reactions. A major contribution comes from the conversion of xanthine dehydrogenase (XDH) to xanthine oxidase (XO). Endothelial cells have been identified as a major site of localization of xanthine oxidase,[86] while parenchymal cells appear to have a low concentration of XDH.[87] However, based on measurements of XDH activity in isolated endothelial cells, it is estimated that skeletal muscle cells contain a significant amount of XDH.[6] Xanthine oxidase activity increase in postischemic skeletal muscle from a baseline of 3:6 ^ 0:3 to 5:2 ^ 0:4 mU=g wet tissue;[88] a measurement that includes both endothelial and muscle XDH. In favor of the importance of the role of endothelial cells and of microvascular dysfunction in skeletal muscle I/R injury is the report that the conversion of XDH to XO proceeds at a slow rate in skeletal myocytes.[89] Support for the role of oxygen-derived free radicals in the microvascular dysfunction associated with I/R comes from
Figure 28-4. Interactions between endothelium and leukocytes in ischemia-reperfusion injury. During ischemia parenchymal cell energy is depleted. Macrophages may influence the process by production and release of cytokines (e.g., interleukin-1, or IL-1). The endothelium appears to be the site capable of significantly converting xanthine dehydrogenase (XDH) to xanthine oxidase (XO) during ischemia and responsible for the formation of oxygen-derived free radicals (superoxide anion ¼ O2 2 ; OH = hydroxyl radical). The endothelium also releases PAF. The adherent leukocyte also forms oxygen-derived free radicals and through its myeloperoxidase (MPO) generates hypochlorous acid (HClO). Weak adhesion (rolling) is the result of interactions between P-selectin (P-Sel; endothelium) and L-selectin (L-sel; leukocyte). Upon stimulation by PAF, the CD11/CD18 adhesion complex interacts with the endothelial ICAM-1, leading to firm adhesion.
experiments using free radical scavengers. Compounds such as superoxide dismutase (SOD), catalase, mannitol, allopurinol, deferoxamine, and apotransferrin have proven to be efficacious in reducing changes in capillary solvent drag reflection coefficient[13] and in salvaging skeletal muscle.[15] The efficacy of SOD, catalase, and mannitol is predicated on the basis of their ability to scavenge either superoxide anions or hydroxyl radicals. Conversely, the efficacy of deferoxamine and apotransferrin, two chemically different ironbinding compounds, indicates an important role for iron in the genesis of postischemic damage, particularly as a catalyst for the Haber-Weiss reaction between superoxide and hydrogen peroxide. Free radical scavengers, as a group, are able to reduce the indices of I/R-induced microvascular dysfunction to about half of their unopposed values (Fig. 28-4). Nitric oxide has been implicated among the substances produced by vascular and perivascular cells that may play a role in I/R-induced microvascular dysfunction. Nitric oxide is a product of the metabolism of L -arginine and can be produced by most cells. In the case of I/R injury the more
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likely vascular and perivascular sources of NO include endothelial cells, mast cells, resident macrophages and leukocytes. Under normal conditions, NO is a strong vasodilator,[90 – 93] it may enhance the transport of macromolecules across postcapillary venules,[37,38] and it may serve as an antiadhesive substance to protect the endothelium against leukocyte adherence.[94] With the onset of ischemia, the levels of NO seem to decrease. It is possible that the reduced levels of NO result in enhanced leukocyte adhesion and increased microvascular permeability.[6,94] In addition, NO reacts with superoxide to form peroxynitrite, a powerful reactive oxygen metabolite, and leads also to further formation of hydroxyl radicals.[95] Experimental evidence for the involvement of the L -arginine –nitric oxide pathway in myocardial reoxygenation injury has been reported in the piglet heart in which NO synthase inhibitors afford adequate protection during cardiopulmonary bypass reoxygenation.[96] In this framework, the L -arginine –NO pathway represents an alternative or additional mechanism to produce hydroxyl radical. It must be kept in mind that peroxynitrite (ONOO2), the reaction product of superoxide and NO, is potentially more harmful and more toxic than either superoxide or hydroxyl radical due to its longer half-life.
leukopenia that reaches a nadir in 3 days. Leukopenia decreases the impact of I/R on changes in microvascular permeability and solvent drag reflection coefficient.[100,102] The impact of leukocytes is exemplified by the observation that leukopenia reduces the increase in transport of macromolecules to a 2-fold increase, down from a 7-fold increase obtained in the untreated ischemic muscle.[100] The extent of skeletal muscle I/R injury, as measured by the infarct size demarcated by triphenyl-tetrazolium chloride reduction, is significantly decreased by leukopenia.[99] Circulating leukocytes do not appear to become activated by traversing the circulation of postischemic muscle.[103] Leukocyte adhesion to microvascular endothelium and emigration to tissue are fundamental required steps for PMN-associated damage in I/R.[104]
Leukocytes Leukocytes, and in particular polymorphonuclear leukocytes (PMNs), have been the subject of much investigation recently in regard to their contributions to injury in ischemiareperfusion (Figs. 28-4, 28-5). Leukocytes produce superoxide anion by the activity of their membrane-bound NADPH oxidase, which converts cytoplasmic NADPH to NADP+. The Haber-Weiss (Fenton) reaction then proceeds to form superoxide anion and hydrogen peroxide, with subsequent release of hydroxyl radicals. Leukocytes possess myeloperoxidase, an enzyme that further catalyzes a reaction between hydrogen peroxide and chloride to form hypochlorous acid, a powerful oxidant agent. In addition, activated PMNs release elastase, collagenase, and cathepsin G, substances that are able to degrade microvascular basement membrane and lead to increases in permeability and cellular dysfunction. Much attention has been directed at understanding the mechanisms that activate leukocytes and contribute to their adherence to and emigration across microvascular endothelium. The levels of myeloperoxidase (MPO, an index of PMN) have been found to remain constant during ischemia and to increase at 15 minutes and 1 hour of reperfusion.[97] These data are interpreted as an indication of influx of leukocytes into the tissue upon reperfusion. Other investigators have failed to find significant increases in MPO in postischemic canine gracilis muscle until 24 hours of reperfusion.[98] Further support for the involvement of leukocytes in I/R comes from experiments in which either the animal or the experimental muscle have been rendered leukopenic by radiation or chemical or physical means. Chemotherapeutic agents such as hydroxyurea, nitrogen mustard,[99] and vinblastine[100] may be administered prior to the onset of ischemia to render the animal leukopenic. Similarly, animals may be subjected to whole-body irradiation,[101] resulting in
Figure 28-5. Illustration of leukocyte adhesion to postcapillary venular endothelium in the rat cremaster muscle. (A) Adhering and rolling leukocytes can be visualized by brightfield transillumination. The leukocytes can be identified as the cells palisading along the venular wall near the vessel bifurcation. (B) The animal was injected with acridine orange, a fluorescent dye, prior to the microscopic observation. Leukocytes are the first cells to take up the dye. The leukocytes are the bright white dots decorating the faintly stained postcapillary venular wall.
Chapter 28.
Endothelium-Leukocyte Interactions The actions of the endothelial cell (EC) and the PMNs are not independent of one another (Figs. 28-4, 28-5). Xanthine oxidase –derived free radicals may influence the interaction between the leukocyte and the endothelial cell. These reactive oxygen metabolites may attract PMNs to the site of injury or they may initiate the release of other chemoattractants [platelet-activating factor, (PAF); leukotriene B4, (LTB4)]. The oxidants produced may serve to alter the adhesion properties of the EC surface by allowing the expression of intercellular adhesion molecules (ICAM-1, ICAM-2). These molecules are inducible proteins on the EC surface which modulate neutrophil adhesiveness in areas of inflammation. The PMN also has a membrane glycoprotein, designated CD11/CD18 complex—a b2-integrin, which is involved in regulating PMN-EC adhesion. The mechanisms that link xanthine oxidase –mediated oxygen free radical production to reperfusion-induced leukocyte activation, adhesion, and extravasation form the foundation for all the events that are described as ischemia-reperfusion (I/R) injury. Adhesion molecules, such as b2-integrins and L-selectin, are constitutively expressed on the PMN surface. The stimuli produced by I/R are able to induce upregulation of the number and/or functional state of these proadhesive molecules. Monoclonal antibodies (MAbs) directed against these molecules specifically and efficaciously block the adhesion of PMNs to EC. The endothelium also expresses adhesion molecules. Normally, ICAM-1 is weakly expressed, while P-selectin is stored presumably in Weibel-Palade bodies. Appropriate stimuli cause upregulation of ICAM-1 and translocation of Pselectin to the membrane. Conversely, E-selectin is induced very effectively by activation with interleukin 1 (IL-1). As with leukocyte adhesion molecules, the development of specific monoclonal antibodies has become a most useful tool in demonstrating the critical role of EC adhesion molecules in I/R injury. Firm adhesion of leukocytes to endothelium is preceded by a weak adhesion, also termed “rolling” by intravital microscopists. This weak adhesion occurs under rheological conditions of relatively high shear rate. Nonetheless, leukocytes roll along venular walls at rates about 100-fold slower than the rate of local flow.[105] The use of MAbs to Lselectin has demonstrated the importance of L-selectin for leukocyte rolling[105] and by inference for the initiation of the PMN-EC adhesion process. Evidence obtained in vitro in laminar flow chambers under conditions mimicking venular shear rates shows that endothelial P-selectin modulates leukocyte rolling.[106] Strong PMN-EC adhesion requires the involvement of integrins and ICAM-1 and possibly Eselectin. Much knowledge has been derived in vivo from the administration of MAbs prior to the induction of the ischemia-reperfusion protocol in animal models. Under baseline conditions only a few leukocytes adhere to venular endothelium (2 – 4 leukocytes per 100 mm vessel length).[81,104,107] Upon reperfusion of postischemic tissue the number of adherent leukocytes increases severalfold.[81,104,107] The monoclonal antibody 60.3, which is directed against the beta chain of the CD18 complex, inhibits
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neutrophil adherence and attenuates extravasation of plasma proteins in the intestinal mucosa.[108] Similarly, MAb IB4, also directed against the CD11/CD18 glycoprotein adhesive complex, successfully inhibits the adhesion of leukocytes to venular endothelium induced by PAF in the intestine.[109] In canine gracilis muscle, MAb IB4 administered prior to ischemia has the ability to diminish the I/R-induced increase in microvascular solvent drag reflection coefficient.[110] Similarly, using MAbs against CD11b/CD18 and against ICAM-1 in the rat cremaster muscle, we demonstrated that inhibiting leukocyte adhesion caused a reduction of the impact of I/R on microvascular transport and decreased infarct size[104] (Fig. 28-6). Taken together, these in vivo data demonstrate that EC-PMN adhesion and PMN emigration are a cause of I/R-induced microvascular dysfunction. The preceding observations suggest that xanthine oxidase– derived free radicals may be among the primary mediators of I/R injury and PMN infiltration and that subsequent release of other mediators may occur as a secondary event. Conversely, reactive oxygen metabolites produced by xanthine oxidase may act primarily to stimulate PMN infiltration and activation, and thus the leukocyte would be ultimately responsible for tissue damage. In addition, if the PMN represents the prime effector of cell injury, by what mechanisms does it actually perform this role? There is in vitro evidence that activated neutrophils cause endothelial
Figure 28-6. Evaluation of tissue damage in rat cremaster muscle by computer-assisted digital image analysis. Muscles were stained with nitroblue tetrazolium (NBT). Dye uptake is related to muscle viability: the greater the uptake, the more viable the muscle is and the darker the muscle becomes. The darker the muscle, the lower its optical density is, i.e., the lower values of optical density show greater viability, while the higher optical density values demonstrate greater muscle damage. Labels are: No Rx = group subjected to I/R without therapeutic treatment; IgG = group subjected to I/R and received IgG; 1B6 = group subjected to I/R and treated with monoclonal antibody 1B6 (directed against the CD11ba-subunit of the leukocyte’s CD11/CD18 adhesion glycoprotein); 1A29 = group subjected to I/R and treated with monoclonal antibody 1A29 (directed against the endothelial ICAM-1 adhesion molecule). Note that sham-operated muscle group shows the least tissue damage, while the No Rx muscle group displays the greater tissue damage. The monoclonal antibodies IB6 and 1A29, administered at the time of reperfusion, decreased leukocyte adhesion to endothelium and effectively reduced tissue damage. (From Ferrante et al. J. Vasc. Surg. 24: 187 – 193, 1996. Reprinted with permission.[104])
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cell detachment that is inhibited by neutral protease inhibitors, but not by catalase or superoxide dismutase.[111] These observations suggest that the I/R injury to the microvasculature and tissue is multifactorial and can be explained by the release of neutrophil-derived proteases as well as by leukocyte-endothelium– produced oxygen free radicals.
Other Chemical Mediators and Signaling Molecules Eicosanoids have been thought of as important chemical mediators in I/R injury for a long time. However, no clear picture is currently available regarding the involvement or importance of these arachidonic acid derivatives in either the genesis or the consequences of I/R. Thromboxane A2 (TXA2) has been implicated in causing microvascular alterations in the lung following reperfusion of ischemic canine hindleg.[99,112] Most of the evidence for this interpretation comes from transient elevations in TXA2 associated with a transient, self-resolved increase in lung water. These events are prevented by the use of TXA2 inhibitors prior to the onset of ischemia. In the specific instance of changes in microvascular permeability, no clear correlation appears to exist between eicosanoid levels and transport of macromolecules in postischemic striated muscle.[113] Prostaglandins have physiologic and pharmacologic properties that may be useful in attempts to ameliorate the consequences of I/R. In particular, prostacyclin is a vasodilator, but it also prevents platelet aggregation and may inhibit leukocyte adhesion to endothelium. Stable analogs of prostacyclin, such as Iloprost, have also shown some degree of protection against microvascular alterations in postischemic muscle[114] and adequate protection against platelet sequestration and infarct size.[115] Similar protection against I/R damage has been afforded by Iloprost in the myocardium.[116] Calcium, a universal signaling molecule, plays an important role in the pathophysiology of skeletal muscle I/R injury and associated microvascular injury. Both calcium entry and calcium mobilization are involved. In regard to muscle damage, muscle function is impaired in part due to a slower calcium uptake by the sarcoplasmic reticulum, which is partially prevented by pretreatment with scavengers of oxygen-derived free radicals.[117] In regard to microvascular dysfunction, calcium ions modulate the activity of leukocytes as well as the contractile properties of endothelial cells. The impact of calcium entry on microvascular dysfunction is supported by the prevention of changes in microvascular permeability to macromolecules afforded by verapamil, a calcium entry blocker.[113] One attractive putative mediator of ischemia-reperfusion is PAF. Even though not constitutively present in ECs, PAF can be quickly synthesized upon stimulation with thrombin, histamine, and other agonists, including PAF itself. This short-lived phospholipid (1-O-alky1-2-acetyl-sn-3-phosphocholine) is a vasoconstrictor,[118] a strong promoter of microvascular permeability,[119,120] and a powerful chemoattractant for PMNs at concentrations of l0211 M and 10 29 M.[120,121] It is worth noting that subthreshold
concentrations of PAF prime the microcirculation for strong responses to subthreshold doses of histamine, another important proinflammatory agent of potential importance in I/R.[122] Recent evidence, based on the use of chemically different inhibitors of PAF receptors, indicates that some of these microvascular functions of PAF are mediated by different receptors in the pre- and postcapillary segments.[123] Pharmacologic advances based on this finding may permit to differentially block the activity of PAF to prevent or counteract the damage of I/R. In vitro studies provide strong support for a role for PAF in ischemia-reperfusion. It is possible that the production of H2O2 serves as the stimulus for the synthesis of PAF. Primary cultures of bovine pulmonary artery endothelium and human umbilical vein endothelium synthesize PAF when stimulated with H2O2.[124] This PAF synthesis is associated with an increase in intracellular Ca2+, suggesting that a transmembrane Ca2+ flux may serve as a signal to initiate PAF production. Furthermore, H2O2 also induces endothelial cell – dependent adhesion of neutrophils to human umbilical vein endothelial cell monolayers. Current theories indicate that PAF synthesized by activated ECs is expressed on the cell surface and binds to a receptor on the PMNs.[125,126] This interaction causes upregulation of CD11a/CD18 and CD11b/CD18 leading to firm adhesion of PMNs to ECs. The role of PAF in mediating endothelial cell –leukocyte interaction in vivo has been studied in inflamed and in reperfused tissues. Exogenously administered PAF, an agonist for PAF synthesis by microvascular ECs, increases leukocyte adherence at concentrations of 1029 M[120] and enhances permeability at 1027 M[119] in the hamster cheek pouch. The possibility that H2O2 may be the stimulus for PAF synthesis in I/R is indirectly supported by experiments in which human recombinant superoxide dismutase, administered intravenously, caused a 30% decrease in PMN adherence.[107] In isolated autoperfused segments of feline intestine, reperfusion after 1 hour of ischemia increased the adhesion and extravasation of leukocytes, and pretreatment with intravenous doses of the PAF-receptor antagonists BN 52021 and WEB 2086 reduced the rates of leukocyte adhesion and extravasation during reperfusion.[127] These results suggest that PAF plays a role in mediating the adhesive interaction between the leukocyte and the endothelial cell during I/R and promotes extravasation. It is worth noting that administration of WEB 2086 (a PAF-receptor antagonist) just prior to reperfusion successfully protects against increased leukocyte adherence.[128] In addition to strengthening the viewpoint of PAF’s role in I/Rinduced leukocyte adhesion, this finding may provide a valuable basis for development of therapeutic approaches applicable to acutely ischemic patients at the critical step of starting reperfusion. PAF may also play a paracrine role in I/R-induced increased leukocyte adhesion. In models of focal I/R in which other areas of the tissue remain perfused at normal flowrates, the number of adherent leukocytes tends to increase in the nonischemic, normally perfused areas.[81,128] These observations have been tentatively interpreted to indicate the release of a soluble chemical mediator by the ischemic area, which in turn diffuses into the normal microcirculation and stimulates the increment in leukocyte adhesion. The
Chapter 28.
possibility that PAF is the paracrine chemical mediator derives (a) from in vitro data in which the supernatant of hypoxic-reoxygenated endothelial cells increased leukocyte adhesion in normoxic endothelial cells[129] and (b) from the in vivo demonstrated characteristic of soluble PAF of being a powerful chemoattractant for leukocytes.[120,121] Cytokines are also potentially important in the sequel of I/R, particularly when the ischemic period is prolonged enough to allow for protein synthesis. Among cytokines, tumor necrosis factor alpha (TNF-a) has been the subject of investigation because it may upregulate adhesion molecules in both leukocytes and endothelium. The leukocyteendothelium interactions initiated by TNF-a can serve as a positive feedback and lead to a cascade of stronger reactions. We tested the hypothesis that synthesis of TNF occurs during ischemia and is related to the observed microvascular hyperpermeability. We reasoned that inhibitors of protein synthesis (actinomycin D, an antibiotic that blocks transcription) would prevent synthesis of TNF-a and attenuate the increase in permeability to macromolecules. Our initial results showed that striated muscle I/R causes a significant and long-sustained elevation in plasma TNF-a.[82] Topical administration of actinomycin D, during ischemia and reperfusion, reduced synthesis of TNF-a and decreased the hyperpermeability response to I/R[82] (Fig. 28-7). Our results, in agreement with those of other investigators,[130 – 132] support an association between protein synthesis, TNF-a levels, and transport of macromolecules in postischemic muscle.
Figure 28-7. Statistical analysis of impact of inhibition of protein synthesis on microvascular transport in the rat cremaster muscle. Actinomycin D (AMD) did not change baseline microvascular transport (Control + AMD). Integrated optical intensity (IOI, an index of microvascular transport) values for control groups represent the final 120 minutes of a 6-h sham experimental preparation. The influence of ischemia-reperfusion (I/R) on transport of macromolecules is demonstrated by the I/R group. Topical superfusion with 1026 M AMD attenuated significantly the increase in postischemic microvascular transport (I/R + AMD). *p , 0:05, ***p , 0:001 compared with control group. ###p , 0:001 compared with I/R + AMD Group. +++ p , 0:001 compared with control + AMD group. (From Takenaka et al. Am J Physiol 274: H1914-H1919, 1998. Reprinted with permission.[82])
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Clinical Considerations Current management of acute limb ischemia is based on the restoration of blood flow to the ischemic extremity as rapidly as possible in order to reduce the degree of ischemic injury. However, reperfusion occurs in the setting of cellular damage secondary to ischemia, creating new significant injury. As discussed, interactions between endothelial cells and leukocytes with associated PMN activation and infiltration are largely responsible for microvascular dysfunction and also play a significant role in the onset and final outcome of parenchymal injury. The arsenal of pharmacological agents available to the vascular surgeon is limited. Administration of antioxidants directed against the hydroxyl radical (mannitol) or agents acting at various times along the path of hydroxyl radical formation (superoxide dismutase, or polyethyleneSOD) may have modest success when applied at the time of reperfusion. Heparin may also have a role, not only as an anticoagulant but possibly related to its nonanticoagulant properties. Heparinization is a preventive part of current clinical protocols, and its use may preserve skeletal muscle viability,[133,134] in addition to reducing intravascular propagation of thrombus. In addition, lytic therapy[135] may be useful to distal vasculatures and facilitate tissue salvage. However, there is a need to develop a variety of modern pharmacologic approaches to diminish the impact of ischemia-reperfusion on parenchymal structure, biochemistry, and function. Modulation and control of leukocyte –endothelial cell interaction may contribute to afford greater protection against the damage caused by I/R. The administration of PAFreceptor inhibitors at reperfusion offers promise in animal models.[128] Similarly, inhibition of leukotriene B2—another potent chemoattractant—may be useful in decreasing firm adhesion of leukocytes. The use of MAbs to block adhesion molecules also shows promise of contributing to ameliorate I/R injury.[104] Potential problems in their clinical application include half-life (if too long they may mimic the condition of leukocyte adhesion deficiency and render the patient susceptible to infectious diseases) and the possibility of further interactions with the patient’s immune system. On the other hand, investigators have suggested that molecules derived from the known structures of the selectin carbohydrate ligands may offer the greatest potential to inhibit leukocyte-endothelium adhesion.[136] This possibility is supported in part by the observation that dextrans attenuate leukocyte rolling and adhesion.[137] Gene therapy promises an attractive future to vascular surgeons as a possible treatment for I/R. Local administration of vascular endothelial growth factor (VEGF, also termed vascular permeability factor, VPF) appears to improve perfusion in ischemic limbs.[138 – 141] The mechanisms of action of VEGF, a powerful angiogenic and permeability factor, are not completely elucidated yet, but they involve the specific VEGF-R2 receptors (also known as flk-1/KDR) and stimulation of PKB, NOS, and MAP kinases.[142 – 144] The double jeopardy facing the vascular surgeon is that unattended ischemia leads to necrosis, making prompt restoration of blood flow a must; however, reperfusion compounds the problem, and its consequences may interfere
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significantly with survival of the organ and/or patient. Furthermore, any therapy to be instituted must be delivered effectively and quickly to the injured site. The best way to deliver substances to parenchymal cells is the microcirculatory system of convection and exchange vessels. When no reflow is present, the ability to deliver therapeutic agents via the bloodstream is greatly impaired. Therefore, in addition to developing more refined chemical therapeutic agents, it is important to develop ways of bypassing the obliterated vessels to access the compromised microcircula-
tion and contribute to salvaging viable tissue. Significant steps in this direction are being taken in the methodologies associated with intramuscular administration of VEGF. Advances in molecular biology, gene therapy, and catheterbased procedures have opened new horizons for comprehensive treatment of ischemia-reperfusion damage. These advances demonstrate how skilled vascular surgeons and physiologists are meeting the formidable task and exciting challenge of solving the intrinsic dilemma of ischemiareperfusion injury.
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CHAPTER 29
Arterioarterial Atherothrombotic Microemboli of the Lower Limb Dhiraj M. Shah R. Clement Darling III Benjamin B. Chang Philip S. K. Paty Paul B. Kreienberg Sean P. Roddy Robert P. Leather microemboli were dislodged from atheromatous aortoiliac lesions and were observed in the digital arteries of the toes. Although this possibility has also been mentioned by other authors,[2,5,7,8] little attention has, in general, been paid to its ultimate pathological implications. Moreover, the natural history of this syndrome was not clearly defined by these observers. The threatened survival of a single toe is not in itself of great clinical consequence, but continuing experience with this pathological entity indicates that when untreated, these episodes are such omens of disaster for the leg that subsequent diagnostic and therapeutic measures should promptly be concentrated on the location and eradication of the source of microemboli.
Although attention has recently been paid to atherothrombotic microembolism from atheromatous plaques or from adherent thrombotic material, such pathological occurrences were first mentioned in the German literature over a century ago.[1] However, within the last several decades, the pathological implications of this specific entity have come to our attention, showing it to be a mechanism of serious pathology of the brain, viscera, and both upper and lower limbs. The lodgment of atherothrombotic microemboli (defined as particles 1 mm in size or smaller) into end arteries has now been documented in virtually every part of the human body. The production of stroke or cerebral insufficiency by this mechanism is discussed in Chap. 48, but atherothrombotic emboli are also known to cause renal cortical ischemia,[2,3] left colonic gangrene,[4] and ischemia of the fingers (Chap. 63). This chapter deals specifically with such embolization in the lower limbs. The sudden appearance of a painful, discolored toe may be very baffling when the rest of the foot appears to be well perfused, particularly when the pedal pulses can be readily felt by digital examination. The confusion has been deepened by the application of a variety of misleading labels to this condition, including vasospasm, cold injury, localized Raynaud’s phenomenon, polymyositis, and idiopathic digital artery thrombosis.[5] However, in most of these patients the ischemia is due to microembolization to the digital arteries. Crane[6] reported on this entity in 3 patients in whom distal
INCIDENCE OF THIS CONDITION From the literature, it has been difficult to gain any idea of the incidence of this problem. However, examination of our own data tends to offer some perspective. In the 7-year period from 1978 to 1985, 4820 vascular consultations were held on the Vascular Service of Albany Medical Center; of these, 120 (2.5%) were for suspected microembolism to the lower limbs. Of this entire group, 4043 vascular reconstructions were carried out, and of these, 93 (2.3%) were done specifically for eradication of emboligenic sources of microemboli to the
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Incidence of Microembolic Sources
Number of vascular consultations Number of consultations for atherothrombotic microemboli Number of vascular procedures Number of reconstructions for microembolizations
4820 120 (2.5%) 4043 93 (2.3%)
lower limb. In general, therefore, these data suggest that perhaps 1 in 50 of all vascular reconstructions will be carried out for these purposes in a general vascular service (Table 29-1).
SOURCES AND NATURE OF MICROEMBOLI A variety of lesions will act as sources of microemboli, and these range in location from the infrarenal aorta to the termination of the popliteal artery. Aneurysms of the popliteal artery have long been recognized for this predisposition and are discussed in Chap. 45. Iliac and common femoral aneurysms rarely produce distal embolization and are more prone to acute thrombotic occlusion. In marked contrast, however, atherosclerotic lesions of the iliac, common, and superficial femoral arteries are important sources of microemboli. While it may be instinctively surmised that pathological degeneration of the larger arteries would be the predominant origin of such arterioarterial emboli, Table 29-2 indicates the somewhat surprising finding that the femoral arteries are the most common emboligenic sources. Apart from popliteal aneurysms, which occupy a special category (as previously mentioned), stenotic, irregular, and ulcerated lesions of the iliac and femoropopliteal arteries are frequently microembolic sources, as shown by their relative incidence. However, when there is widespread atheromatous degeneration of the infradiaphragmatic arteries, it can be difficult to identify precisely the specific area that has been responsible for the clinically apparent downstream release of microemboli.[9]
Many authors have expressed the view that these microemboli result solely from fragmentation of atheromatous plaques and subsequent dislodgment of the debris.[2,3,5,8,10 – 12] Indeed, atheromatous plaques are known to undergo ulceration and fragmentation, and atheromatous or cholesterol-containing material has been identified in digital vessels and in the smaller arteries of the calf muscles.[10] However, many of the microemboli of the lower limb have been identified as being made up of fibrinoplatelet or thrombotic material. The microemboli released from aneurysmal sources (popliteal, aortic, etc.) are part of the flocculent laminated thrombus that lines the arterial flow path. A common surgical finding is that atheromatous plaques are very friable, but the shaggy, frondlike clumps of fibrinoplatelet debris which are invariably present on these lesions are not only impressive but also appear more likely to be dislodged. It has also been confirmed[4,6,7,13] that in addition to cholesterol fragments, fibrinoplatelet aggregates are loosely attached to ulcerated or stenotic atheromatous plaque and are easily swept off. Schechter[14] has recovered a shred of atheromatous plaque (gravel) from a tibial artery and has postulated that after these particles impact, surrounding fibrinoplatelet aggregates and propagated thrombus increase the degree of obstruction. Branowitz and Edwards[7] concluded that the clinical and pathological processes involve either distal embolization of atheromatous debris or fibrinoplatelet or thrombotic material. Kempezinski[13] has further clarified this by showing that cholesterol emboli tend to originate in the infrarenal aorta, to be diffuse, and to lodge in arteries 100 –200 mm in size (e.g., muscular arteries). By contrast, microemboli formed from hemocellular elements tend to be larger and occlude vessels up to 1 mm in size. Digital arteries are customarily involved, but emboli have been recovered that were large enough to occlude the tibial, popliteal, and superficial femoral arteries (Fig. 29-1).[3,7,15,16] Larger emboli of this type usually arise within the infrarenal aorta in an area of severe atheromatous degeneration, which has larger, loosely attached fibrinoplatelet clumps.[17] These larger emboli form far less often than do the microemboli. This clinical entity has been described in various ways in the literature. It has been called the blue-toe syndrome,[18] atheromatous embolization,[12,14] acute focal ischemia,[19] and peripheral atheroembolism.[16] From the
Table 29-2. Location of Embolic Sources Embolic sources Author Karmody et al.[4] Kwaan and Connolly[15] Schechter[14] Crane[6] Carvajal et al.[2] Branowitz and Edwards[7] Kempezinski[13] Mehigan and Stoney[19] Keen et al.[23]
No. of cases
AAA
Aortoiliac
Femoropopliteal
93 15 17 3 4 4 10 12 87
12
18 15 9 3
63
3
2
4 2 20
4 8 5 47
7 20
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in which there was repeated microembolization, and the report of Mehigan and Stoney[19] mentions 4 patients who also experienced this problem, each with threatened tissue loss. This tendency has also been confirmed by Branowitz and Edwards (Table 29-2).[7] Early diagnosis and treatment are, therefore, necessary if recurrence is to be prevented, and it is this aspect of microembolization that enhances its clinical importance and makes recognition and treatment mandatory. The natural history of atherothrombotic microembolization of the lower limb consists, therefore, of a repetition of embolic episodes. Each successive event causes progressive
Figure 29-1. Good example of emboligenic lesion in midsuperficial femoral from which a distal embolus has occluded the popliteal artery.
foregoing pathological description, the term arterioarterial atherothrombotic microembolism, although cumbersome, is preferred, since it most accurately describes all of the pathological events.[17]
NATURAL HISTORY OF ATHEROTHROMBOTIC MICROEMBOLIZATION Gore and Collins[20] have shown by autopsy examination that atherothrombotic microembolization is a more frequent clinical problem than has been generally recognized. This has been confirmed by Maurizi et al.,[11] who conclude that the microemboli usually lodge in the lower limbs and that recurrent microembolization, which finally leads to extensive tissue loss, is common (Fig. 29-2). In 12 of our patients, repeated microemboli to the foot were clinically recognized, and loss of one or more toes occurred in 5 of these patients. In another patient, the second embolic shower resulted in ischemic death of the forefoot. Schechter[14] reported 11 cases
Figure 29-2. Natural history of arterial microemboli. The great toe, which was ischemic from the first microembolus, has been hastily amputated, and the wound is healing poorly. In addition, another microembolus has lodged (arrow ) at the side of the foot. This process will continue until the emboligenic source is corrected.
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Figure 29-4. Most common appearance of microembolic disease, consisting of a deep-blue painful area of the great toe.
Figure 29-3. Occlusion of anterior tibial artery (arrow ) by microembolus, jeopardizing entire foot.
loss of collateral arteries until tissue necrosis finally occurs. Larger emboli, of course, are likely to occlude the popliteal or tibial arteries and cause acute, profound ischemia of the foot (Fig. 29-3). It has been well documented[7,11,13,14,18] that initially both the patient and the physician are frequently lulled into a false sense of security, since in most instances the signs are evanescent and recovery is prompt. Further embolization may occur in a few hours or even after many weeks, but the repetitive tendency remains pronounced in any event. Although this pattern of events is well recognized in the cerebral circulation, the probable reason that more emphasis has been placed on the carotid lesion relates to the relative ease of identifying serious pathological effects of cerebral microemboli (i.e., stroke potential, as compared to less clinical concern about small emboli to the digits or feet).
Figure 29-5. More diffuse involvement of the foot, with uniform discoloration and mottling resulting from embolization of the plantar arch.
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noticeable disability, but, more commonly, the initial insult will provide symptoms and signs for a few days, although gangrenous changes will rarely occur at this time (Fig. 29-6). The eventual outcome is obviously determined by the available collateral pathways, which are themselves determined both by the site of embolic impaction and the effects of previous or unrecognized embolic episodes. Even if the first or subsequent episodes are short-lived and cause little clinical difficulty, it should be recognized that further emboli are not only probable but also tend to “stream” to the identical area, thus increasing the risk of tissue loss because of progressive reduction of collateral capacity. In
Figure 29-6. Nonhealing wound caused by injudicious amputation of great toe without correction of proximal stenotic lesion (cf. Fig. 29-2).
Early and complete eradication of the embolic source has been well established as the definitive treatment in the cerebral arterial system, and these same principles also apply to the peripheral limb arteries, because microemboli cause comparable transient ischemic attacks of the foot and also carry a serious threat of tissue loss, which deserves attention similar to that of loss of brain tissue.
CLINICAL DIAGNOSIS The typical picture of patients suffering from this condition includes the sudden appearance of a painful digit or small area on the foot (Fig. 29-4), which is generally bluish in color (hence the name blue-toe syndrome ), has a sluggish capillary return, and is quite tender to the touch. The discoloration may be either uniform or mottled in character (Fig. 29-5). These symptoms may last only a few minutes and cause little
Figure 29-7. Typical popliteal aneurysm filled with large quantities of mural thrombus.
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DIAGNOSTIC INVESTIGATIONS When the emboligenic arterial lesion is also hemodynamically significant, the systolic pressures in the pedal arteries with the patient at rest may show such a small gradient that they may not be discernible on digital palpation of pulses. Repeated examination after exercise in most instances will produce a bruit with diminution of the ankle pulses and a measurable decrease in the arterial systolic pressure. Segmental plethysmographic tracings (waveforms) should be obtained at the thigh, calf, ankle, transmetatarsal, and digital levels. As mentioned above, although these may be normal at rest, exercise of the affected limb will commonly
Figure 29-8. Well-marked aortic stenosis, which was responsible for bilateral microemboli. Treated by endarterectomy.
many patients, a detailed history will reveal that sudden attacks of pain in the muscles of the lower limbs, particularly in the gastroenemius muscle complex, have been caused by unrecognized microembolization that preceded the most clinically obvious episodes of digital ischemia.[2,10] Physical examination should include the pulses from the aorta to the foot. As noted previously, the presence of palpable pedal pulses is the rule rather than the exception in these patients, but manual examination of the abdominal aorta and femoral and popliteal arteries may reveal clinically significant aneurysmal enlargement (Fig. 29-7). A bruit is frequently present over the affected artery, particularly in the common and superficial femoral vessels. The Doppler ultrasound signal over the distal arteries is usually normally pulsatile, as are the arterial plethysmographic tracings at rest. In many instances in which the toes are affected, ultrasound mapping of the course of the digital arteries with a 10 MHz Doppler probe will demonstrate abrupt occlusion of the digital arteries. This may be hard to accomplish in the smaller toes; for practical purposes, it is useful only in the transmetatarsal arteries and the great toe.
Figure 29-9. The other end of the scale (i.e., lesion in distal popliteal). These two figures (Figs. 29-8 and 29-9) stress the need for complete angiography.
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Figure 29-10. Lateral view of proximal popliteal showing emboligenic lesion, which was poorly identified in the anteroposterior projection.
Figure 29-11. Anteroposterior arteriogram of the pedal arch, in which the arrows demonstrate well-defined sites of microembolic impaction.
produce changes in the waveforms, which are clearly diagnostic of a hemodynamic lesion. The use of B-mode duplex ultrasound scanning in the investigation of abdominal aortic aneurysms, particularly in obese patients, and in the common femoral to distal popliteal arteries is especially useful. Computerized tomography body scan may also be helpful, particularly in the abdominal region. With continued development of these techniques and an increasing ability to obtain more accurate soft-tissue evaluation by newer methods (e.g., nuclear magnetic resonance), it is sometimes possible at present to actually demonstrate intraluminal debris in both the aorta and arteries of the limb. Muscle biopsies have been used[2,10] as a diagnostic tool in the evaluation of patients with microemboli. The biopsies were taken either surgically or by needle from the gastrocnemius muscles, and a high correlation with the clinical symptomatology has been reported. We have not found this diagnostic method to be very useful, although it may have a place in evaluating patients with atherosclerosis who have obscure symptoms of the calf and foot. Although, in the modern context, angiography should not be considered a diagnostic tool but rather a preoperative
Figure 29-12. Lateral view of foot is more easily obtained, and obstruction of the dorsalis pedis (arrow ) is easily seen.
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Figure 29-13. (A ) Typical emboligenic lesion in the superficial femoral artery. The stenosis is easily recognized, but immediately distal to it is the characteristic foamy appearance of fibrinoplatelet debris, which forms the basis of the emboli. (B ) Surgical exposure of this lesion. The arrow points to the dark gray fibrinoplatelet mass.
measure, biplane angiography in this particular context is the most accurate of all diagnostic methods. Ideally, this examination should define the arteries from the infrarenal aorta (Figs. 29-8 and 29-9) to the toes. Arterial irregularities may be present in many areas, and a complete angiographic examination is necessary if correct clinical decisions are to be made about the most probable source of emboli. The use of high-quality biplane angiograms obtained with a single arterial injection and radiological magnification has greatly improved these studies (Fig. 29-10). Although it is generally quite difficult to obtain anteroposterior angiograms of the pedal arches, these can be quite informative (Fig. 29-11). However, routine and satisfactory lateral views of the foot can readily be made, and when the obstructions occur within the plantar arch or dorsalis pedis artery, they are easily identified (Fig. 29-12). It should be stressed that one of the prerequisites for the diagnosis of microembolization is the identification of a
continuous anatomic arterial channel between the site of the emboligenic source and the point at which the embolic impaction has occurred. While it is also possible that extensive collaterals around an obstructive lesion may be large enough to carry emboli distally, such occurrences are rare in our experience. The ischemia of the toe or foot that has resulted from microembolic problems should, therefore, be clearly differentiated from the more common form of ischemia, which has been caused by extensive proximal obliterative arterial disease.
SURGICAL MANAGEMENT The foremost principle of treatment of this condition is the removal of the source of emboli. In addition, since many of these emboligenic lesions also cause acute hemodynamic flow
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not only tedious but is also less durable; the standard bypass procedure with distal interruption of the native artery is the preferable method of treatment.[21] When these lesions are identified angiographically, the physician should be alerted to the possibility of microembolic dislodgment, particularly following intraluminal catheter passage during subsequent attempts at intraluminal balloon dilation. In some instances, the exact identification of the emboligenic area can be quite difficult. Flynn et al.[22] have shown that intrainguinal bypasses can be threatened by dislodgment of sizable emboli from the infrarenal aorta and iliac arteries. We have seen this on two occasions, and its onset can be both frustrating and puzzling. Such experiences have led to the suggestion that a total arterial reconstruction may be needed to remove or bypass all the lesions from the infrarenal to the popliteal arterial system. However, this extensive surgical approach is generally not warranted in the management of most of these cases, because it is usually not difficult to identify precisely the responsible lesion and treat it by a relatively local procedure.
MEDICAL MANAGEMENT
Figure 29-14. Treatment of the lesion in Fig. 29-13A by thrombointimectomy and vein patch graft.
reduction, their repair also brings about reversal or improvement of ischemic changes in the foot. The operative procedures for the various aneurysms that are the source of emboli are described in Chapters 43 –47, and the principles of endarterectomy and/or bypass of arterial lesions are also well known. In highly localized stenotic lesions (1 –2 cm) of the femoral and popliteal arteries, operative removal of the fibrinoplatelet clumps together with adherent intima (thrombointimectomy) (Fig. 29-13) followed by vein patch angioplasty has produced very satisfactory long-term results (Fig. 29-14), although all of these arteries inevitably display various degrees of atheromatous degeneration both proximally and distally to their actual stenotic lesion. The great majority of patients treated by this method have maintained patency of these arteries up to 5 years (Figs. 29-15 and 29-16).[9] In patients with longer segments of significant atherosclerotic changes (. 5 cm), vein-patch angioplasty is
In the carotid distribution, nonsurgical therapy for what are undoubtedly atheroembolic events has become popular in some medical circles. The efficacy of such treatment remains controversial. In the case of peripheral atheroembolism, no controlled clinical trial to date has demonstrated any efficacy for nonsurgical therapy in the long-term treatment of these events. Nevertheless, there is some rationale for the use of antiplatelet medications to prevent mural thrombus formation in the case of a single atheroembolic event from a patent yet diseased artery. Typically, a combination of aspirin and dipyridamole is given in these instances, but other nonsteroidal anti-inflammatory agents may be used. It is unclear whether some of the perceived therapeutic benefit of these drugs is in their anti-inflammatory effect rather than in the prevention of further episodes. The use of full anticoagulation with warfarin has been reported in some cases to lead to paradoxical increases in the severity of embolic events (“purple-toe syndrome”), probably due to the increased severity of plaque hemorrhage associated with degenerating plaques. If nonsurgical treatment is to be selected for clinical phenomena typical of atheroembolism, angiographic confirmation of the arterial pathology should be entertained before initiation of therapy. This is particularly important in order to avoid missing an easily treatable preocclusive lesion.
SPECIAL NEW OR IATROGENIC MICROEMBOLIC CIRCUMSTANCES DURING FIBRINOLYTIC THERAPY Fibrinolytic enzymes (e.g., streptokinase, urokinase) are now in reasonably widespread use for the dissolution of thrombi that occur either in native arteries or in grafts. These enzymes
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Figure 29-15. (A ) Similar lesion to Fig. 29-13A treated in the same fashion. (B ) Five-year follow-up showing durability of reconstruction.
are used both as a primary means of treatment of acute occlusion and in an attempt to determine the nature of the precipitating pathological lesion by angiography after thrombolysis. It is now well documented that in some instances, after the majority of thrombus in the conduit has been dissolved, the final residual fragments of thrombus are now exposed to full arterial pressure and may suddenly be dislodged and swept into the distal arterial tree. There appears to be no way of preventing this event, which in some instances may prove to be a fatal blow to the foot.
Performance of Catheter Angiograms Through Diseased Arteries The passage of angiographic catheters, particularly of larger size (6 French or greater), and their subsequent manipulation
for selective catheterization may in fact cause the dislodgement of fibrinoplatelet clumps or the fragmentation of atheromatous plaques, which may embolize distally. This is not a common event but should be recognized by the angiographers and clinicians concerned.
Balloon Angioplasty Balloon widening of stenotic areas in arteries is also widely carried out, but in lesions that appear to be stenotic, as mentioned previously, fibrinoplatelet clumps may exist as part of the pathology of the lesion; when compressed or manipulated by the balloon, these may, in fact, be suddenly dislodged. Such lesions should be noted on the previous arteriograms wherever possible, since they contraindicate intraluminal instrumentation.
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Thrombotic Occlusion of Synthetic Grafts We have observed that one of the terminal events following sudden thrombotic occlusion of certain synthetic grafts may, in fact, be a dislodgment of small thrombi as microemboli distally, thus compromising the collateral circulation and the survival of the foot in addition to the jeopardy already caused by the occlusion of the graft. This unwelcome event usually necessitates even more difficult and more distal arterial reconstructions to provide limb salvage.
Suprarenal Atherosclerosis as a Source of Blue-Toe Syndrome Atherosclerotic disease from the suprarenal aorta such as arch and descending thoracic aortic and shaggy aorta syndrome may be the source of this syndrome in a certain number of cases. Actual incidence is unknown, but in larger series it may account for 2 – 13% of patients.[23 – 26] Diagnosis and treatment of this condition is somewhat challenging. There is no accurate diagnostic tool that offers uniform delineation of lesions of all segments of the suprarenal aorta. Transesophageal echo, magnetic resonance angiogram, enhanced computed-tomography angiogram, and aortogram all offer about equal specificity and sensitivity for making the diagnosis, depending on the location of the disease.[23] Still, contrast angiogram probably is the “gold standard.”[23,24] Ultrasonogram in the thoracic aorta was not found to be that accurate. Once diagnosis is made, the treatment options are very few. Direct repair by surgical treatment is most durable and effective,[26] but thoracotomy and replacement of the arch vessels have high complications, mortality, and morbidity.[23,25] Any medical treatment besides aspirin is not effective; anticoagulation has occasionally been used with conflicting results. Most mortality and morbidity from this disease are caused by embolization to the brain, visceral artery, or renal artery and not necessarily from the consequences of blue-toe syndrome. Thus, when the source of blue-toe syndrome is not found in conventional locations, one should keep in mind and explore the possibility of arterial atheroemboli arising from the suprarenal, supraceliac, and thoracic aorta.
Figure 29-16. An example of a longer patch that has lasted for over 7 years.
REFERENCES Paunam, P.L. Experimentalle Beitra¨ge zur Lehre von deren Embolie. Arch. Pathol. Anat. 1962, 25, 308. 2. Carvajal, J.A.; Anderson, W.R.; Weiss, L.; et al. Atheroembolisms: An Etiological Factor in Renal Insufficiency, Gastrointestinal Hemorrhages and Peripheral Vascular Disease. Arch. Intern. Med. 1977, 119, 593. 3. Kaplan, K.; Millar, I.D.; Canilla, P.A. “Spontaneous” Atheroembolic Renal Failure. Arch. Intern. Med. 1962, 110, 218. 4. Karmody, A.M.; Jordan, R.F.; Zaman, S.M. Left Colon Gangrene After Acute Interior Mesenteric Artery Occlusion. Arch. Surg. 1976, 111, 972.
1.
5.
Haygood, T.A.; Fessel, W.J.; Strange, D.A. Atheromatous Microembolism Simulating Polymyositis. J. Am. Med. Assoc. 1968, 203, 135. 6. Crane, C. Atherothrombotic Embolism to Lower Extremities in Arteriosclerosis. Arch. Surg. 1967, 94, 96. 7. Branowitz, J.B.; Edwards, W.S. The Management of Atheromatous Emboli to the Lower Extremities. Surg. Gynecol. Obstet. 1976, 143, 941. 8. Kazmie, F.J.; Sheps, S.G.; Bernatz, P.E.; Sayre, G.P. Livedo Reticularis and Digital Infarctions: A Syndrome Due to Cholesterol Emboli Arising from Atheromatous Abdominal Aortic Aneurysms. Vasc. Dis. 1966, 3, 12.
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9. Karmody, A.M.; Leather, R.P. Atherothrombotic Microemboli of the Lower Limb. In Vascular Surgery; Rutherford, R.B., Ed.; Saunders: Philadelphia, 1984;. 10. Anderson, W.R.; Richards, A.M. Evaluation of Lower Extremity Muscular Biopsies in the Diagnosis of Atheroembolism. Arch. Pathol. 1968, 86, 528. 11. Maurizi, C.P.; Barker, A.E.; Trueheart, R.E. Atheromatous Emboli: A Post-Mortem Study with Special Reference to the Lower Extremities. Arch. Pathol. 1968, 86, 528. 12. Wagner, R.B.; Martin, A.S. Peripheral Atheroembolism: Confirmation of a Clinical Concept with a Case Report and Review of the Literature. Surgery 1973, 73, 353. 13. Kempezinski, R.F. Lower Extremity Arterial Emboli from Ulcerating Atherosclerotic Plaques. J. Am. Med. Assoc. 1979, 214, 807. 14. Schechter, D.C. Atheromatous Embolization to Lower Limbs. N. Y. State J. Med. 1979, 79, 1180. 15. Kwaan, H.J.; Connolly, J.E. Peripheral Atheroembolism. Arch. Surg. 1977, 112, 987. 16. Williams, G.M.; Ricotta, J.J.; Zimmer, M. The Extended Retroperitoneal Approach for Treatment of Extensive Atherosclerosis in the Aorta and Renal Vessels. Surgery 1980, 88, 846. 17. Williams, G.M.; Harrington, D.; Burdick, J.; White, R.I. Mural Thrombosis of the Aorta: An Important, Frequently Neglected Cause of Large Peripheral Emboli. Ann. Surg. 1981, 194, 737.
18. Karmody, A.M.; Powers, S.R.; Monaco, V.J.; Leather, R.P. “Blue Toe Syndrome”: An Indication for Limb Salvage Surgery. Arch. Surg. 1976, 111, 1263. 19. Mehigan, J.T.; Stoney, R.J. Lower Extremity Atheromatous Emboli. Am. J. Surg. 1976, 132, 163. 20. Gore, I.; Collins, D.P. Spontaneous Atheromatous Embolization: Review of the Literature and a Report of 16 Additional Cases. Am. J. Clin. Pathol. 1960, 33, 416. 21. Corson, J.D.; Karmody, A.M.; Shah, D.M.; et al. In Situ Vein Bypasses to Distal Tibial and Limited Out-Flow Tracts for Limb Salvage. Surgery 1984, 96, 756. 22. Flynn, W.R.; Harris, J.P.; Rudo, M.D. Atheroembolism as a Cause of Graft Failure in Femoro-Distal Reconstruction. Surgery 1981, 90, 698. 23. Keen, R.R.; McCarthy, W.J.; Shireman, P.K.; Feinglass, J.; Pearce, W.H.; Durham, J.R.; Yao, J.S. Surgical Management of Atheroembolization. J. Vasc. Surg. 1995, 21 (5), 773. 24. Baumann, D.S.; McGraw, D.; Rubin, B.G.; Allen, B.T.; Anderson, C.B.; Sicard, G.A. An Institutional Experience with Arterial Atheroembolism. Ann. Vasc. Surg. 1994, 8 (3), 258. 25. Kvilekval, K.H.; Yunis, J.P.; Mason, R.A.; Giron, F. After the Blue Toe: Prognosis of Noncardiac Arterial Embolization in the Lower Extremities. J. Vasc. Surg. 1993, 17 (2), 328. 26. Bujar, R.M.; Payne, D.D.; Murphy, R.E.; Schwartz, S.L.; Belden, J.R.; Caplan, L.R.; Rastegar, H. Surgical Treatment of Systemic Atheroembolism from the Thoracic Aorta. Ann. Thorac. Surg. 1996, 61 (5), 1389.
CHAPTER 30
Aortoiliofemoral Occlusive Disease K. Wayne Johnston Peter G. Kalman Atherosclerotic occlusive disease commonly occurs in the aortoiliac segment. Two-thirds of these patients are male, and the vast majority have a history of prolonged cigarette smoking. Most often, they present in their mid-fifties 25–10 years earlier than patients with more distal occlusive disease.[1] The purpose of this chapter is to review the surgical therapy for aortoiliac occlusive disease, with attention to the historical aspects, pathology, diagnostic methods, conservative and operative management, and complications.
In the past decade, the most common operation for correction of aortoiliac occlusive disease, an aortobifemoral bypass, has been performed less commonly because of the impact of percutaneous transluminal balloon angioplasty and stenting, the increasing tendency to extra-anatomical bypass, and the recognition that claudication is generally a benign disease.[14]
PATHOPHYSIOLOGY HISTORICAL ASPECTS
Chronic Atherosclerosis
The possibility for surgical correction of aortoiliac obstruction was suggested by Leriche[2] in 1940, when he described the syndrome of bilateral claudication, sexual impotence, and absent common femoral pulses. Thromboendarterectomy was introduced by Dos Santos[3] in 1947 and first described for the aortoiliac segment by Wylie[4] in 1952 and later by Barker and Carmon[5] in 1953. Resection of the obstructed segment and replacement with an arterial allograft was described by Oudot[6] in 1951, Julian et al.[7] in 1952, and DeBakey et al.[8] in 1954. The allografts were cumbersome to obtain and were complicated by the development of late aneurysms. Following the description by Voorhees et al.[9] of a fabric arterial prosthesis in 1952, durable grafts made of Teflon or Dacron were introduced by Edwards[10] and DeBakey and Crawford[11] in 1957. Throughout the 1960s, bypass grafting from the aorta to the external iliac arteries increased in popularity. Moore et al.[12] in 1968 and Perdue et al.[13] in 1970 suggested that superior long-term results followed anastomoses to the common femoral rather than the external iliac level, and this was confirmed by Baird et al.[1] in 1977. At present, operations are selected that correct the entire aortobifemoral occlusive segment as well as the frequently associated disease involving the profunda femoris. The current focus is on the durability of the procedure and the prevention of complications.
Atherosclerosis may produce partial or complete occlusion of the distal aorta and one or both common iliac arteries, and it frequently extends into the proximal portion of the external and/or internal iliac arteries. Usually the plaque is more extensive on the posterior wall; thus the distal lumbar and median sacral arteries are occluded at an early stage. Immediately distal to the renal arteries, the aorta is usually free of disease or minimally involved, and the periarterial surgical planes are well preserved. These features are exploited in the surgical repair: the upper clamp is placed immediately below the renal arteries and the upper anastomosis is performed about 2 cm distally. In some cases, the disease process extends proximally and involves the orifices of the renal arteries. In these cases, clamps must be placed at a higher level and care taken to ensure that the arterial supply to the kidneys is not compromised by embolization of atherosclerotic debris or inadequate removal of the obstructive material. The origin of the inferior mesenteric artery may be occluded, and the status of this vessel influences the design of the operation. With chronic aortoiliac occlusive disease, collateral vessels enlarge and compensate to some degree. The potential for collateral flow is higher with aortoiliac than with femoral, popliteal, or tibial artery obstruction. Important collateral pathways include internal mammary to inferior epigastric; superior mesenteric to inferior mesenteric and internal iliac;
Hobson/Wilson/Veith: Vascular Surgery: Principles and Practice, Third Edition, Revised and Expanded DOI: 10.1081/0819-9-120024913 Copyright q 2004 by Marcel Dekker, Inc.
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intercostals and lumbars to circumflex iliac and internal iliac; inferior mesenteric to internal iliac; and internal iliac to profunda femoris. Patients with isolated aortoiliac disease generally present with complaints of intermittent claudication and/or sexual impotence. By the time symptoms are noted, half the patients also have occlusive disease in the femoral popliteal and/or tibial arteries. By comparison to the patients with only aortoiliac involvement, those with multilevel disease present at an earlier age, and the viability of the leg may be threatened.[1,15,16]
Occlusive Mid-Aneurysmal Disease Although patients with abdominal aortic aneurysms rarely have claudication, symptoms from occlusive disease may be associated with aortoiliac aneurysms if there is significant coexisting atherosclerotic occlusive disease, embolic occlusion from the mural thrombus, or kinking of the arteries.
Hypoplastic Aorta The hypoplastic aortoiliac syndrome almost always occurs in women with a history of significant, long-standing cigarette smoking. Characteristic features include a high aortic bifurcation, acute angle of the aortic bifurcation, straight iliac arteries without the normal lateral bowing, an aortic diameter less than 14 mm (or less than one-quarter of the diameter of the lumbar vertebrae), and a common iliac diameter less than 7 mm.[17] Collaterals are poorly developed and the femoral and distal vessels are also small. Symptoms of claudication are more severe than expected from the angiographic pattern.[18] Recognition of this syndrome is important because the operative procedures are technically difficult and the longterm results of bypass surgery are often poor.[17,19] If conservative treatment fails, aortoiliac endarterectomy with patch grafting or percutaneous transluminal angioplasty is recommended for those with localized disease. For patients with extensive occlusive disease, an aortofemoral bypass graft is indicated, using a small prosthesis (12 £ 6 mm in diameter) with a proximal end-to-side anastomosis to minimize the size discrepancy.[17] Burke et al.[20] noted improved results with a PTFE prosthesis, although this has not been our experience. In a group of 24 women less than 50 years of age with aortoiliac occlusive disease, Gagne et al. found a high incidence of coagulation abnormalities, particularly antiphospholipid antibody, and encouraged further investigation and aggressive anticoagulant management of this group.[21]
Acute Obstruction Acute aortoiliac occlusion may result from an embolus originating in the heart or from an aortic aneurysm. Other causes include an aortic dissection, blunt or penetrating trauma, or iatrogenic injury (e.g., diagnostic catheters, intraaortic balloons, or percutaneous transluminal dilatation).
Since collateral channels are poorly developed in these cases, severe ischemia and the risk of tissue loss is usual.
CLINICAL DIAGNOSIS Typically, patients with isolated aortoiliac disease are male cigarette smokers who present with buttock, thigh, and calf claudication and often have some degree of sexual impotence. Complaints of rest pain or ischemic night pain are usually absent unless multilevel disease is present or the occlusion extends up to the renal arteries, thereby interfering with collateral pathways. On physical examination, one or both femoral pulses are reduced and iliac or femoral bruits are audible. The feet usually appear warm and well perfused, without nutritional changes. An accurate clinical diagnosis of aortoiliac occlusive disease is usually straightforward; however, one-quarter of the patients with isolated aortoiliac disease complain only of calf claudication rather than thigh or buttock pain. Conversely, one-quarter of the patients with normal aortoiliac segments and isolated femoral popliteal disease have low thigh as well as calf claudication.[22] Femoral bruits are present in only two-thirds of the patients with symptomatic isolated aortoiliac obstruction. The differential diagnosis must identify patients complaining of buttock and thigh pain of neurogenic or musculogenic origin. The symptoms from spinal stenosis may be difficult to distinguish; however, these patients usually complain of leg pain or “weakness” on standing or on walking very short or variable distances, and relief is achieved only by sitting or lying down for prolonged periods or after adequate analgesics. Numbness and tingling are common and are usually localized in the distribution of one or more nerve roots. An uncommon clinical presentation of aortoiliac disease is the blue-toe syndrome.[23] These patients present with an ischemic blue and tender toe and peripheral pulses are palpable. Arteriography may demonstrate an ulcerating plaque, but occasionally a high-resolution computed tomography (CT) scan is necessary to demonstrate the ulcerating atherosclerotic lesion.
OBJECTIVE DIAGNOSIS Noninvasive Assessment Noninvasive tests augment clinical and arteriographic assessment and in general have a role in determining the severity of arterial occlusive disease, localizing the site of involvement, and clarifying the differential diagnosis. The ankle-brachial systolic blood pressure ratio objectively determines the severity of the vascular insufficiency but can be artifactually high if the tibial arteries are calcified, e.g., in diabetics. Through the use of treadmill exercise testing, the physician can assess the extent of the patient’s disability and distinguish the symptoms of claudication from pain secondary to musculoskeletal or neurologic disease.
Chapter 30.
Several noninvasive methods are potentially useful for assessing the severity of aortoiliac disease.[22] Although the thigh systolic blood pressure can be measured, it is not sufficiently accurate for assessing the aortoiliac segment, particularly in patients with combined aortoiliac and femoral popliteal disease. It is not possible to place the pressure cuff high enough on the thigh to measure a pressure equivalent to that in the common femoral artery and thus accurately assess the severity of the iliac disease. Hemodynamically significant aortoiliac disease can be detected through analysis of Doppler recordings of bloodflow velocity from the common femoral artery using duplex Doppler equipment.[24] The Doppler waveform is normally triphasic, with a large initial forward component followed by a reverse and then a second smaller forward flow component. If the waveform is dampened (i.e., monophasic or a reverse flow lost), significant iliac disease is likely to be present. The waveforms are usually analyzed by subjective evaluation or quantified by the calculation of pulsatility index[25] or other measurements. Alternatively, peak velocity measurements can be made along the length of the aortoiliac segment. A stenosis .50% is diagnosed if the peak velocity is at least two times greater than the velocity in an adjacent normal arterial segment, the waveform becomes monophasic, and spectral broadening is present.[26]
Arteriography An arteriogram is obtained only when the history indicates that the symptoms are sufficiently disabling to warrant a consideration of percutaneous transluminal angioplasty or surgery. Although arteriography remains the most important method for evaluating the severity of aortoiliac disease, standard anterior –posterior views may underestimate the severity of the occlusive disease[27] in which case biplane views will be necessary. Even with digital subtraction techniques, the diagnostic accuracy of arteriography is better with the retrograde femoral than the translumbar approach, since it is easier to obtain biplane views and to achieve a more rapid injection of a larger bolus of dye. In most patients, it is optimum to obtain biplane aortoiliac views unless a severe lesion is demonstrated on the anterior –posterior arteriogram. The aortogram should be of sufficient quality to allow the surgeon to see adequate details from the renal arteries to at least the midcalf. Although magnetic resonance angiography (MRA) is a noninvasive and cost-effective method for imaging providing angiograms without the use of iodinated contrast agents, the visualization of the proximal aortoiliac segment is often not ideal in the authors’ experience, However, in a small series, Carpenter et al. have demonstrated that it provides adequate information to plan aortobifemoral bypasses, and that the results are comparable to those expected with standard arteriography.[28]
Direct Pressure Measurements When the severity of aortoiliac occlusive disease is difficult to determine from the arteriogram, the best method for assessing the hemodynamic significance of an aortoiliac lesion is to
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directly measure the aortofemoral pressure gradient at rest or after reactive hyperemia has been induced. The aortofemoral pressure difference is measured from pressure recordings which are made as the angiographic catheter is withdrawn from the aorta to the level of the external iliac or common femoral artery. A systolic pressure gradient of more than 10 mmHg at rest is considered to be hemodynamically significant. Alternatively, the difference between the femoral systolic pressure at rest and after intra-arterial injection of 30 mg of papaverine is obtained. Normally, the femoral artery systolic pressure does not fall significantly, but a fall of more than 15% is indicative of significant iliac disease.[24,29]
CONSERVATIVE TREATMENT Mild intermittent claudication from aortoiliac disease causes minimal disability and its natural history is usually favorable.[30] Although significant symptomatic improvement is unlikely, the symptoms usually remain stable for many years. Consequently, investigation and treatment of patients with claudication is indicated only for significant disability – that is, when their employment and enjoyment of life are threatened. After the discovery of significant atherosclerosis, steps should be taken to identify and control risk factors such as smoking, hypertension, hyperlipidemia, and diabetes. If the patient is obese, weight reduction will reduce the work load associated with walking and improve the claudication distance. The patient often believes that walking to the point of claudication is harmful to the leg. The patient should be informed, however, that exercise therapy is of proven value and frequently improves the claudication distance.[31,32] Vasodilators, megavitamins, and most pharmacologic products are unproved or of little benefit. Although studies have suggested that pentoxifylline (Trental) is useful in the treatment of claudication,[33,34] we have not found this drug to be particularly effective.
SUMMARY ALGORITHM FOR INTERVENTION For patients with significant vascular symptoms secondary to localized aortoilaic occlusive disease, the recommended approach is percutaneous transluminal angioplasty (PTA) if feasible. There is little evidence to support routine primary stenting after successful aortoiliac PTA other than for a few specific indications: recoil, eccentric lesion, and dissection after PTA. In general, the results with PTA are less satisfactory than surgical reconstruction, but considering the low morbidity and the option for the procedure, PTA is justified for localized aortic or iliac stenoses or short occlusions. The only lesions not amenable to PTA are the less common focal aortic or iliac “coral-reef” plaques that are best managed with endarterectomy. For diffuse aortioiliac occlusive disease, surgical revascularization can be achieved by anatomic or extraanatomic bypass. Aortobifemoral (ABF) bypass is the
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standard operation for treating good-risk patients with aortic and bilateral iliac disease. Although popular in the 1960s, the role of aortoiliac endarterectomy has decreased considerably. The long-term results of localized endarterectomy are excellent; however, the results for extensive endarterectomy are poor. Many patients with localized disease who were previosly treated by endarterectomy are now treated by PTA. Endarterectomy is tedious and time consuming and is associated with a greater blood loss than bypass grafting and a higher incidence of sexual dysfunction in males. In certain circumstances, ileofemoral, axillofemoral, and femorofemoral bypasses are acceptable alternatives to ABF. A unilateral ileofemoral bypass is preferred over femorofemoral bypass provided that the aorta and ipsilateral common iliac artery are normal or only minimally diseased. Ileofemoral has a small patency advantage compared to femorofemoral but the main advantage is avoidance of a second groin incision with the potential for lymphatic complications and infection. Axillofemoral bypass is indicated in patients with a high anesthetic risk or when a transabdominal approach is contraindicated (e.g., sepsis, dense adhesions, prior irradiation, malignancy). Femorofemoral bypass is indicated with extensive unilateral iliac disease in the presence of a normal donor iliac artery. A more durable long-term alternative to axillofemoral bypass is desirable for low-risk patients in whom a transabdominal approach is considered hazardous. In these cases, inflow from a more proximal aortic source such as the ascending or descending thoracic or supraceliac aorta is available. Both the ascending and descending thoracofemoral bypass provide excellent inflow and have comparable patency, and the choice depends upon individual preference. With the exception of concomitant aortocoronary surgery, most surgeons prefer the descending thoracic to femoral bypass.
PERCUTANEOUS TRANSLUMINAL ANGIOPLASTY In our experience with 667 iliac balloon angioplasties, the average success rates were 75 ^ 2% (mean ^ 1 standard error) at 1 year, 60 ^ 2% at 3 years, and 53 ^ 3% at 5 years. The results were better if the common iliac artery was dilated versus the external iliac artery, the indication for the procedure was claudication versus salvage, a stenosed versus an occluded artery was dilated, and the runoff was good versus poor.[35] Aortic angioplasty was carried out in 17 patients, 16 of whom were women. The success rates were 80 ^ 10%, 80 ^ 10%, and 70 ^ 10% at 1, 3, and 5 years, respectively. Although these results are less satisfactory than surgical repair, the low morbidity of the procedure when performed by an experienced radiologist justifies its use in treating localized iliac stenoses or occlusions. Thrombolytic therapy can be used to open chronically occluded aortoiliac segments and the underlying occlusive disease treated by percutaneous transluminal angioplasty. Although one series reported that lysis allowed subsequent
angioplasty in approximately 50% of cases, long-term results with this approach are not available.[36]
SURGICAL TREATMENT The surgical repair of atherosclerotic aortoiliac occlusive disease is achieved by aortoiliac endarterectomy, an anatomic bypass graft, or an extra-anatomical bypass graft.
Aortoiliac Endarterectomy Endarterectomy still has a role in the management of aortoiliac disease, but its place has diminished greatly since the 1960s. The procedure usually involves an open endarterectomy of the distal aorta and either an open or semiclosed endarterectomy of one or both common iliac segments down to the level of the external iliac arteries. Extensive aortoiliac femoral endarterectomy has been abandoned. Closed endarterectomy using the LeVeen “plaque cracker” was popularized in Europe and permits extensive retroperitoneal endarterectomy of the aorta, iliac, and femoral segments.[37,38] In general, the long-term results of endarterectomy for localized disease are excellent and are comparable to those of bypass grafting; however, the results of extensive endarterectomy are poor.[15] By comparison to bypass grafting, endarterectomy is more tedious, time-consuming, and technically demanding and is associated with a greater blood loss. The procedure should be considered in young patients with localized aortoiliac occlusive disease that does not involve the external iliac artery, since involvement of this site is often associated with recurrence of symptoms necessitating reoperation.[39] Many patients with this distribution of localized disease can now be treated quite satisfactorily by percutaneous transluminal angioplasty. If the risk of infection is high, endarterectomy is preferable to prosthetic bypass grafting. In selected cases, aortoiliac endarterectomy is useful as a salvage procedure for the treatment of an infected aortofemoral bypass graft. After removal of the infected prosthesis, the arterial channel to the leg can be reconstituted by endarterectomy of the native vessels and patching with autogenous material.[40] In spite of its limited application at the present time, every vascular surgeon should be aware of and competent in the techniques of aortoiliac endarterectomy.
Anatomical Bypass Grafts Over the past three decades, bypass grafting has become the standard method for aortoiliac repair. An iliofemoral bypass graft is a durable procedure for managing external iliac occlusive disease that is not amenable to percutaneous transluminal angioplasty, especially when it extends down to the level of the common femoral artery or is the result of iatrogenic occlusion following arterial catheterization.[41] A unilateral aortofemoral bypass graft is rarely indicated. The standard operation for aortoiliac disease is an aortobifemoral bypass and is discussed in detail in the following sections. This operation is indicated for good-risk
Chapter 30.
patients with bilateral aortoiliac occlusive disease. Although we advocate a unilateral reconstruction of iliac occlusive disease if feasible, others prefer an aortobifemoral bypass for the management of unilateral disease, especially if the superficial femoral artery is also occluded.[42]
General Principles of Aortobifemoral Bypass The aortic anastomosis can be made either end-to-side or end-to-end. End-to-side anastomosis is indicated in the following circumstances: if a large aberrant renal artery that supplies a significant amount of renal parenchyma is present; if a large inferior mesenteric artery is present, especially if pelvic flow is reduced because of associated severe iliac disease; if the patient is a male who is concerned about his sexual potency and there is a significant occlusive disease involving both external iliac arteries, therefore compromising retrograde flow to the internals after aortobifemoral bypass; or if the aorta is hypoplastic. End-to-end anastomosis is indicated in patients with coexisting aortic aneurysmal disease or a complete aortic occlusion extending up to the renal arteries. We prefer the end-to-end technique and argue that the long-term hemodynamic results may be better than with end-to-side. Furthermore, the incidence of intraoperative atheromatous embolization and the risk of subsequent aortoenteric fistulas may be lower.[43 – 49] Despite the fact that this preference has been supported by others,[14,35 – 40,49] the evidence does not strongly support either technique. Melliere et al.[50] could not find any difference between the results of end-to-end and end-to-side anastomoses and suggested choosing the simplest procedure that maintains adequate pelvic and colonic flow according to the angiographic findings. The distal anastomosis is usually made to the common femoral artery. If the distal anastomosis is made to the external iliac artery, there is an increased chance that a subsequent downstream repair will be required unless the external iliac artery is completely free of disease. lf the superficial femoral artery is occluded or severely stenosed and any narrowing of the profunda femoris artery is present, the toe of the graft should be extended onto the profunda as far as necessary beyond palpable disease.
The Technique of Aortobifemoral Bypass Preoperatively, bowel preparation is achieved by a fluid diet for 24 hours and administering enemas until clear the evening prior to surgery. Prophylactic antibiotics, usually a cephalosporin, are administered preoperatively and continued for 48 h. Important aspects of preoperative preparation and intraoperative management are described below, under “Myocardial Infarction.” The electrocardiogram (ECG), arterial blood pressure, and central venous pressures are monitored routinely, and a Swan –Ganz catheter is used in only selected cases. Routine use of a Swan– Ganz catheter does not reduce perioperative mortality.[51] The patient is positioned in the supine position and draped so that the groins and legs are exposed and the feet are visible in transparent plastic “bowel” bags.[1] Longitudinal groin incisions are made to expose the common femoral artery from the inguinal ligament to the bifurcation. If the superficial
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femoral artery is occluded, the first 1–2 cm of the profunda femoris artery is also exposed and is carefully palpated to confirm the absence of disease at its origin. The anterior 3 – 4 mm of the inguinal ligament is cut and the incision carried posteriorly to divide the posterior layer as well. Gentle blunt dissection is used to create a tunnel into the retroperitoneal space anterior to the iliac artery and the lateral circumflex iliac vein. The groin wounds are loosely packed with a moist sponge and the self-retaining retractors removed. The abdomen is opened through a midline incision from the xiphoid to midway between the umbilicus and pubis, using a blended cautery to reduce blood loss. Laparotomy is performed and a large fixed abdominal retractor is positioned. The transverse colon is elevated, and the small bowel is gathered to the right (either inside or outside the abdomen depending on body habitus) and protected by moist towels. A retroperitoneal incision to expose the aorta may be a good alternative to the standard transperitoneal incision.[52] It can be carried out without endotracheal intubation and general anesthetic and may be of advantage in high-risk patients. The surgeon identifies the duodenum on the right and the inferior mesenteric vein on the left and dissects between them directly down to the anterior wall of the aorta. The origin of the inferior mesenteric artery is noted but is not dissected. The anterior and lateral walls of the aorta are exposed up to the level of the renal vein. No attempt is made to divide lumbar arteries or to encircle the aorta. In the male, postoperative sexual dysfunction can be minimized by preserving the preaortic autonomic nerves and dissecting the preaortic tissue longitudinally and toward the right side and by not dividing the tissue in the region of the inferior mesenteric artery or near the aortic bifurcation.[53,54] Heparin (75–100 units per kilogram, usually approximately 5000 units) is administered by the anesthetist. Before the aorta is crossclamped, the anesthetist is given appropriate warning so that pharmacologic intervention is possible as required to reduce the cardiac afterload if necessary. We prefer knitted Dacron rather than woven because of its greater ease of handling, improved healing properties, and ease of appropriate fashioning for distal anastomoses without fraying of edges. However, the type of Dacron prosthesis implanted does not appear to be of great importance for outcome. There is no significant difference in early or late thrombogenicity between knitted and woven Dacron prostheses as assessed by 111In-labeled platelet deposition studies,[55] nor is there a difference in the early or late patency rotes.[56] Collagen- or gelatin-coated grafts are commonly used because they eliminate the necessity for preclotting and reduce blood loss. Since current Dacron grafts usually exhibit an initial dilatation upon exposure to arterial blood pressure and 10–25% diameter dilatation over the first year,[57] we prefer a 14 £ 7 mm graft rather than a larger prosthesis. When the graft was selected to match the size of the native arteries, there was no difference in long-term patency between small (12 or 14 mm) and large (16 or 18 mm) grafts.[58] For an end-to-end anastomosis, the proximal clamp is placed just below the renal arteries and the distal clamp approximately 3 cm distally. The clamps are placed from an anterior position and no attempt is made to dissect behind the aorta. The aorta is divided 1 cm, proximal the distal clamp,
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with great care being taken to avoid entering posterior lumbar veins. Removal of a small wedge of the anterior wall of the distal aorta often allows the surgeon to visualize the posterior aortic wall more clearly prior to dividing it. The distal stump of aorta is oversewn with a 2 –0 or 3–0 monofilament polypropylene suture, starting at the posterior wall and coming anteriorly with both needles in two layers so that only one knot is required. The lower clamp is removed as this suture is pulled tight and tied, so that the aortic tissue comes together snugly. Debris in the proximal aortic trunk is carefully removed. The graft is cut so that the aortic trunk is about 3 –3.5 cm long. It is sewn to the end of aorta with a double-ended 2 –0 or 3–0 monofilament polypropylene suture which is started on the left lateral wall and continued across the back wall to the right lateral wall with a “parachute” technique in which the end of the prosthesis is held about 4 –5 cm from the aorta. All tissue bites are taken in a forehand manner and great care is taken not to exert caudad traction on the aortic stump. The suture is moistened with saline, pulled down into place, and tightened. A nerve hook is used to tighten any loose strands and the final traction is exerted in the plane parallel to the posterior wall of the aorta. The left limb of the suture is then fixed in a taut position and held in place by a rubber-shod clamp. The right side is continued to the midline of the graft, where it is then held tautly while the left suture is continued to meet it. The clamp is temporarily released and hemostasis is confirmed by inspecting the circumference of the anastomosis. Any leaks are repaired with interrupted sutures. A long curved clamp is then passed from each groin to grasp the limbs of the prosthesis and draw them into the femoral incisions. Care is taken to make each tunnel behind the ureter if possible and, on the left, behind the sigmoid arterial and venous branches. In performing an end-to-side anastomosis, the proximal aorta is clamped just distal to the renal arteries and this distal clamp is positioned just above or below the inferior mesenteric artery and clamped in an oblique direction so that patent lumbar arteries are occluded. An arteriotomy 3.5 – 5 cm, in length is made. Atheromatous debris is removed, the arteriotomy is flushed with saline, and the clamps are released temporarily to expel loose debris. The graft is suitably beveled and anastomosed using a single running monofilament suture starting at the base. The design of each lower anastomosis is determined by the severity of disease in the infrainguinal arteries. If the superficial and profunda femoris arteries are normal, the anastomosis is made to the common femoral artery. Narrowing at the origin of the superficial or profunda femoris arteries is corrected by appropriate arterioplasties. Good-quality preoperative angiograms with oblique views are helpful in detecting stenosis at the origin of the profunda femoris artery, but the final decision about a stenosis involving this artery is made in the operating room. If there is any doubt, the common femoral arteriotomy is continued into the profunda. The profunda femoris artery is often quite fragile and thin-walled; great care is taken to avoid injury to it or its branches, and extensive endarterectomies are avoided.[59 – 66] The groin anastomoses can be performed simultaneously if two experienced surgeons are available. The anastomoses are made with 5 –0 or 6–0 monofilament
polypropylene sutures, starting and finishing on one side of the heel and using a one-knot technique. Before the anastomoses are completed, adequate flushing of all the vessels is necessary, including the native superficial femoral, profunda femoris, and common femoral arteries as well as the graft. The anesthetist is given 5–10 minutes warning before the graft is opened. The surgeon controls the flow through the new conduit until the blood pressure has stabilized. The heparin is then reversed with protamine. Hemostasis is checked, the color of the sigmoid colon is noted, and the retroperitoneal space is closed. All blood is removed from the abdomen, a careful sponge and instrument count is completed, and the abdominal incision is closed with a single-layer continuous 1 –0 monofilament polypropylene suture. Before the groin incisions are closed, the femoral pulses are checked and the feet inspected to ensure that the peripheral flow is adequate. If there is any concern, intraoperative angiograms should be obtained or the anastomoses reopened and a Fogarty catheter passed. Groin closure is important and should be done in two to three layers to minimize dead space and avoid a lymphatic leak. Skin closure is with metallic skin clips. Postoperatively, the patient is monitored for hemodynamic stability, respiratory function, renal function, and the status of the circulation to both legs. In most cases the patient can be extubated in the operating room or shortly after surgery. If the patient is hemodynamically stable, observation in a stepdown unit, rather than an intensive care unit, is adequate. Ambulation begins on the first or second day and most patients are ready for discharge between the fifth and seventh postoperative days. Before discharge, they are evaluated in the noninvasive vascular laboratory to provide an objective baseline for follow-up studies.
Multilevel Occlusive Disease The optimum management of patients with multilevel occlusive disease (i.e., combined aortoiliac and femoral popliteal disease) remains controversial. Our current practice is to perform the proximal reconstruction with a profundaplasty if necessary and to delay femoropopliteal bypass grafting until the results of the initial procedure are assessed. Even in patients with extensive profunda disease requiring an extended profundaplasty, the results are good. This approach provides adequate outflow to maintain graft limb patency, good distal perfusion with adequate relief of symptoms even if the popliteal artery is occluded, and durability.[67,68] Local wound complications and lymphoceles are frequent with extended profundaplasties.[48] However, with this approach, some patient will have persistent significant claudication and require a subsequent distal procedure; in others, a limb of the aortobifemoral bypass will thrombose as a result of poor outflow.[69 – 71] In our experience, it is uncommon to require distal reconstruction at the same time as a proximal repair; however, there are some situations in which synchronous aortobifemoral and femoropopliteal grafting should be considered.[64] If the iliac disease and profunda disease are not severe by comparison to the femoropopliteal disease as assessed by clinical evaluation, noninvasive vascular
Chapter 30.
laboratory studies, biplane angiography, and intraoperative findings, proximal repair alone will not produce a good hemodynamic result. In this case, PTA of the iliac arteries is attempted if feasible. If the profunda is extensively diseased and has a poor collateral supply to the distal vascular bed, many surgeons prefer to perform a distal reconstruction rather than an extended profundaplasty of a small artery. Patients with severe distal ischemia and ulceration or gangrene may have poor collateralization from the profunda bed to the distal circulation, and concomitant distal reconstruction should be considered.[1,62] Although some surgeons argue that synchronous procedures can be carried out without an increase in morbidity or mortality, yield better long-term patency rates, and eliminate the need for subsequent distal reconstruction,[65,66] this approach cannot be recommended as routine for the average vascular surgeon.
Juxtarenal Occlusion If the thrombotic material extends up to the level of the renal arteries, the proximal clamp should be placed on the suprarenal aorta. Exposure of this area is improved if the left renal vein is retracted by vessel loops. The aortic clamp is placed in the anterior posterior direction, and the aorta is divided about 2 –3 cm below the renal arteries. When thrombotic material in this area is removed, it is essential that the surgeon clearly see each renal artery orifice and be assured that they are absolutely clear of loose debris. If necessary, the aortotomy can be extended up the anterior wall of the aorta so that this inspection can be made carefully. The trunk of the graft is cut appropriately and sutured as described above. Alternatively, the anterior aortic incision can be closed and the clamp repositioned distal to the renal arteries, thus reestablishing the renal perfusion. With an ischemic time of less than 30 minutes, postoperative renal dysfunction is rarely a problem.
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Extra-Anatomical Bypass Grafts When indicated, femorofemoral and axillobifemoral bypasses are good alternatives to aortoiliac revascularization. Femorofemoral graft is the procedure of choice if a normal donor artery is available to bypass extensive unilateral iliac disease.[77,78] Axillobifemoral bypass is justified in high-risk patients, especially those in whom a transabdominal approach is contraindicated.[79] There are certain low-risk patients in whom a transabdominal approach is contraindicated but who should be considered for a more durable procedure than axillobifemoral bypass. Baird et al.[80] described the technique of using the ascending aorta as an inflow source for revascularization to the level of the femoral arteries and have reported excellent, durable results. Alternatively, the descending thoracic aorta can be used as the inflow site.[81 – 86] The choice between these two procedures is largely dependent on personal preference. The advantage of using the descending aorta is that it is a shorter bypass, is less susceptible to kinking, and does not interfere with future abdominal or coronary surgery. However, a lateral thoracotomy is more painful than a sternotomy.
Endovascular Bypass In patients with major comorbid conditions, an endovascular procedure may be possible. A unilateral endovascular aortofemoral bypass procedure is performed using a prosthesis which is held in place at the proximal end by a Palmaz stent and is sewn into the ipsilateral outflow vessel. The procedure is completed with a standard femorofemoral reconstruction.[87] The role of this approach remains to be established when long-term results are available.
RESULTS Transfusion Transfusion can usually be avoided by careful attention to hemostasis or if a significant blood loss is anticipated by using a cell saver or encouraging the patients to donate their own blood prior to the aortic procedure.[72] Although the hemoglobin on discharge may be low, there are usually no untoward consequences. In a study comparing the postoperative hemoglobin measurements, complications, and length of stay, Kelley-Patteson et al.[73] concluded that routine use of autotransfusion was not necessary when performing an aortobifemoral bypass but that it should be used selectively.
Laparoscopic Aortobifemoral Bypass Recent experimental and human studies have demonstrated the feasibility of performing an aortobifemoral bypass using laparoscopic methods.[74 – 76] With the further development of new instruments, the technique will be able to be applied in humans with good results; however, the advantage of a laparoscopic approach over an open technique will have to be demonstrated in a carefully controlled comparative study.
In a recent meta-analysis of 23 studies, de Vries and Hunink reported a mortality rate of 3.3% for studies that started after 1975.[88] In the hands of very experienced surgeons, the perioperative mortality for aortobifemoral reconstruction is now between 2 and 3%.[1,43,44] Perioperative myocardial infarction accounts for half the deaths, and stroke, respiratory failure, or renal failure for the remainder.[44] Five years postoperatively, 25% will be dead, and 10 years postoperatively, 50%.[44,89] There is general agreement that the expected long-term patency rates of aortofemoral bypasses are excellent. From their meta-analysis, de Vries and Hunink reported that limbbased patency rates for patients with claudication were 91.0% and 86.8% at 5 and 10 years, respectively, as compared with 87.5% and 81.8% for patients with severe ischemia.[88,90 – 95] Thus, patency rates are lower if the indication for the operation is ischemic rest pain or ulceration but also the results are less satisfactory if coexisting femoropopliteal occlusive disease is present.[41] Gender does not appear to play a major factor in determining the selection of the type of aortoiliac procedure or the results of intervention. Schneider reviewed his own
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experience and the reports by other investigators and concluded that gender did not have an effect on the indications for aortoiliac surgery as assessed by clinical and hemodynamic measures of severity or on the results of reconstruction. He concluded that concerns that results of aortoiliac reconstruction would be inferior in women due to small arteries or other differences appear unfounded.[58]
COMPLICATIONS AND THEIR PREVENTION Complications of vascular surgery can be classified as systemic, local vascular, local nonvascular, or remote. The most significant complications associated with an aortobifemoral bypass are discussed below.
Systemic Complications Myocardial Infarction Patients with significant coronary artery disease can frequently be identified prior to surgery, and cardiac complications can be avoided by careful preoperative preparation, the selection of appropriate operative procedures, and careful intraoperative monitoring and postoperative care. Patients without a history of coronary artery disease and with a normal ECG have a low risk of fatal myocardial infarction and can undergo surgery without further cardiac investigation.[96] On the other hand, for patients with symptomatic coronary disease, screening by radionuclide ventriculography, dipyridamole thallium scanning, or exercise stress testing may be necessary to identify those high-risk patients who will benefit from coronary revascularization. Dipyridamole thallium imaging is very specific[97] and is our preference. Unless an exercise ECG shows evidence of severe ischemia (i.e., ST segment depression greater than 2 mm), it is a poor screening test because of its low sensitivity.[97] Furthermore, it is rarely feasible in this group of patients with disabling claudication. In spite of previous reports[98,99] angiography is not likely to prove cost-effective for screening but is indicated if the noninvasive tests are strongly positive or severe crescendo angina is present and the patient is a potential candidate for coronary repair. Patients who are suitable for coronary revascularization should have balloon angioplasty or coronary surgery performed before their elective aortofemoral bypass. The protective effect of this approach has been demonstrated.[98 – 100] Selected patients with unstable coronary artery disease and severe peripheral arterial insufficiency can undergo simultaneous coronary artery bypass grafting and peripheral arterial bypass grafting with a low mortality.[100,101] Patients who are not candidates for myocardial revascularization represent the greatest risk. Although some will tolerate aortic surgery if extensive monitoring is used to minimize the cardiac stress, in general an extra-anatomic reconstruction is preferable.
The use of a Swan-Ganz catheter aids in optimal fluid management in the perioperative period; however, the measurements may be misleading in some patients with coronary disease.[102] Preoperatively, by fluid loading and assessment of myocardial performance, the optimum preload can be determined.[103]
Stroke Patients with symptomatic internal carotid artery stenosis should have carotid artery repair before their aortoiliac surgery. However, those with an asymptomatic lesion should receive their aortoiliac repair, and carotid repair is usually delayed until symptoms occur.[104]
Pulmonary Problems Poor pulmonary function is not a contraindication to abdominal aortic surgery; however, patients with significant pulmonary disease require specific management. Careful preoperative preparation includes abstinence from smoking, chest physiotherapy, a trial of bronchodilators, and antibiotics if there is evidence of pulmonary infection. In order to reduce the incidence of pulmonary damage caused by microaggregates in stored blood, it is ideal to minimize blood administration, use blood filters, and consider an autotransfusion device. lf postoperative mechanical ventilation is necessary, the patient should be extubated early. It is important to minimize narcotic administrations, and epidural morphine may be of benefit.
Renal Problems Renal failure is rare following an aortobifemoral bypass.[105] It is likely that the same three factors that predict the risk of renal damage associated with abdominal aortic aneurysm surgery are relevant to aortobifemoral bypass.[96] Deterioration of renal function is more likely if the preoperative serum creatinine is elevated, the aorta is clamped above the renal arteries, and/or the renal vein is ligated. Since these three factors are additive, it is important to consider the risk of renal damage due to their combined effects in planning the operative procedure. Additional disposing factors include toxicity from angiographic dye, reduced intravascular volume, and atheromatous embolization.
Coagulation Complications The most common coagulopathy is dilutional after multiple transfusions when appropriate blood components are not replaced by administering fresh frozen plasma and platelets. A preexisting familial or acquired coagulopathy can be diagnosed preoperatively by routine screening with a platelet count, prothrombin time, activated partial thromboplastin time, and bleeding time. In rare patients, heparinassociated antiplatelet antibodies are produced on exposure to heparin; on reexposure to the drug during angiography or vascular surgery, bleeding may occur due to thrombocytopenia or thrombosis secondary to platelet activation.[106] In patients with heparin-associated antibodies, thromboembolic complications can be prevented by the administration of
Chapter 30.
aspirin 325 mg bid and dipyridamole 75 mg tid.[107] In our experience, Malayan pit viper venom (Arvin) has been used successfully as an alternative to heparin for cardiopulmonary bypass and vascular reconstructive surgery.[108]
Local Vascular Complications Graft Infection Infection of a prosthetic aortofemoral bypass is a very serious complication. Since the most likely cause is graft contamination at the time of the original operation, prevention is directed toward the perioperative period. Prophylactic antibiotic coverage preoperatively, intraoperatively, and for 48 h postoperatively has reduced the incidence to about 1%.[24,27,35,36,43,44,63,89] Generally, a cephalosporin is prescribed, but if an open wound is present in the extremity, specific antibiotic coverage is indicated based on the results of appropriate cultures. Retrograde femoral angiography may be associated with an increased incidence of positive cultures from the ipsilateral groin puncture, but there is no apparent increased incidence of graft infection.[109] In the operating room, one study showed that contamination of the prosthesis can be reduced if the surgeon changes gloves prior to the preclotting process.[110] The management of an infected graft usually involves the administration of systemic antibiotics, removal of all infected prosthetic material, and arterial reconstruction if indicated. If the infection is limited to the graft in the area of the groin and there is no bleeding, a trial of nonoperative treatment is justified, especially if the organism is of low virulence.[111 – 113] If this approach is not successful, a retroperitoneal approach through clean tissue, division of the prosthetic limb near its origin, and extraction of the distal portion via the groin is required. The native groin arteries are closed with a monofilament suture or an autogenous patch, if necessary, and the wound is allowed to granulate. If the viability of the limb is threatened, an extra-anatomic bypass through clean tissue is indicated— from the axillary artery, the contralateral femoral artery, or the ipsilateral or contralateral limb of the bifurcation graft via the obturator foramen. When an infection involves the body of the graft and both limbs, complete removal of the prosthesis is necessary. Although aortoiliac endarterectomy and patch grafts may be possible, usually an axillary graft must be taken to the distal profunda, superficial femoral, or popliteal artery.[32,40] In situ replacement with autogenous superficial femoral veins is an important current approach for patients with extensive aortic prosthetic infection.[114] Isolated case reports suggest that cryopreserved arterial homografts constitute a good alternative to prosthetic grafts for in situ reconstruction.[115] Groin wound debridement and coverage with a muscle flap has produced clinical salvage in selected cases, but the role of this technique in long-term salvage remains to be established.
False Aneurysm Formation Van den Akker et al.[116] report that the chance of a patient developing a false aneurysm in late follow-up after an aortoiliac or aortobifemoral bypass graft is quite high. At
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15 years, the cumulative chance of a false aneurysm is 7.7% at an aortic anastomosis. 15.5% at an iliac anastomosis, and 23.8% at a femoral anastomosis. It is likely that the current incidence is lower as the result of improved techniques, grafts, and sutures. Since most false aneurysms were asymptomatic and detected by clinical examination, ultrasound, or angiography, lifelong follow-up of patients having aortobifemoral bypass grafts is recommended. Etiologic factors include excessive graft tension, graft dilatation or degeneration, suture disruption, degeneration of the host arterial wall or primary aneurysm formation, poor suture technique with inadequate bites, or infection. Host artery degeneration appears to be the most common cause,[117,118] but graft dilatation and secondary arterial dilatation was a major cause in the series reported by Carson et al.[88,118] The etiologic importance of a low-grade infection due to organisms such as Staphylococcus epidermidis remains to be defined; however, by disrupting the graft surface biofilm using ultrasound oscillation, Kaebnick et al.[119] demonstrated a very high incidence of growth of these bacteria on prostheses removed because of a false aneurysm. Based on this evidence, it is important to culture all explanted prostheses using a technique that increases the recovery of microorganisms and to consider long-term suppressive antibiotics. Clinical factors associated with an increased incidence of false aneurysms include hypertension and multilevel progressive atherosclerotic disease.[87,117] Carson et al.[118] reported that recurrent false aneurysms are most likely due to graft dilatation with secondary arterial degeneration of the host artery, but infection due to a lowvirulence organism may be important. The importance of this latter factor is supported by Ernst et al.,[120] who noted that recurrent false aneurysms were more common in patients with previous wound complications. Since false aneurysms slowly enlarge, may rupture, and may be associated with thrombosis or distal embolization, elective surgery is indicated. In repairing a false aneurysm of the femoral anastomosis, once the inflow limb of the prosthesis is clamped, control of the groin arteries is best accomplished by intraluminal occlusion with balloon catheters. The anastomosis is revised by extension or replacement of the distal portion of the graft. False aneurysms of an aortic anastomosis are rare, irrespective of whether the anastomosis is end-to-side or end-to-end. They are usually asymptomatic and are found during investigation of a concurrent groin aneurysm. Repair is by resuture or by the replacement of at least the upper end of the graft.
Hemorrhage Hemorrhage is a complication in 1 –2%[30] and may be due to a coagulopathy or venous or arterial bleeding. A preexisting coagulopathy is detected by preoperative screening. A dilutional coagulopathy due to the administration of a large volume of stored blood is prevented by the concomitant administration of appropriate blood components. Venous injuries are avoided by employing the technique of minimal dissection. Arterial bleeding from the proximal anastomosis
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requires the placement of additional sutures, often with a felt pledget.
Deterioration of the Prosthesis Sporadic cases of generalized dilatation of the prosthesis, elongation, kinking, or localized aneurysm formation have been reported. With current prostheses, these risks are rare. However, irrespective of the type of Dacron prosthesis employed, late graft degeneration and aneurysm formation can occur because of imperfections in the Dacron- or graftmanufacturing process or damage or fracture of the fibers by improper handling by the surgeon.[121,122]
Unilateral Limb Occlusion Diagnosis of graft limb occlusion in the immediate postoperative period can be difficult in a patient with multilevel occlusive disease, since peripheral perfusion may not begin to increase for 4– 6 h and consequently the limbs remain cool and pulses are poor.[123] Graft occlusion may result from inadequate inflow, kinking or twisting of the graft, a technical error in making the distal anastomosis, or inadequate outflow. Although early thrombosis is most often due to a technical defect at the distal anastomosis and can usually be corrected by thrombectomy with Fogarty catheters and appropriate refashioning of the distal anastomosis, it is often prudent to expose the entire aortobifemoral bypass and explore it for defects. The causes of late graft occlusions are anastomotic abnormalities in about 80% (i.e., neointimal hyperplasia, false aneurysm, progressive atherosclerosis), graft infection, reduced inflow, or hypercoagulability.[124] If the occlusion is recent, the inflow can usually be reestablished through the use of Fogarty catheters.[125] An endarterectomy curette or Fogarty thrombectomy catheter is useful in removing fibrocollagenous plugs at the prosthetic bifurcation.[126] In our view, fibrinolysis has little advantage over surgical treatment since invariably it demonstrates a distal anastomotic lesion which requires repair.[124] However, others have found that the underlying cause may be amenable to endovascular treatment in a significant number of cases.[127] lf prograde flow cannot be obtained, a cross-femoral bypass is employed or the limb of the prosthesis is replaced. Outflow stenosis can usually be corrected by graft extension onto the deep femoral artery. A femoropopliteal bypass graft is indicated if the profunda is small or extensively diseased. In our experience, a distal bypass is rarely necessary, but Brewster et al.[93,125] used this approach in 32% of their reoperative cases. Although the reoperative procedures are generally difficult, the results are usually good.[63,66,89,92]
Aortoenteric Fistula A communication between a portion of the gastrointestinal tract and the aortic prosthesis or periprosthetic space is a tragic complication of intra-abdominal vascular surgery. It is more common after emergency aneurysm repair than after bypass grafting for occlusive disease.[37,38,45,46] Of such communications, 75% communicate with the duodenum, 20% to the remaining small bowel or the colon, and 5% to the
stomach or a combination of sites.[37,45] Aortoenteric fistulas result from a sterile or infected perigraft collection that drains into adjacent bowel, erosion of the mobile viscera by the fixed and pulsatile prosthetic graft, or erosion by the suture. The diagnosis must be suspected whenever an episode of GI hemorrhage or septicemia occurs in a patient with an intra-abdominal prosthetic graft. An upper GI series may show distortion of the terminal portion of the duodenum. Endoscopy may visualize the prosthesis or the site of the hemorrhage. A computed tomography (CT) scan that demonstrates air or fluid collection around the prosthesis is considered positive. White blood cell –labeled nuclear scans may localize an area of infection. An aortogram may demonstrate a false aneurysm but will only rarely show dye passing into bowel; nonetheless, it is essential for planning vascular reconstruction. Sequential cultures along the graft may reveal one consistently positive site. The standard method of treatment is removal of all the prosthetic material, closure of the hole in the bowel, and an extra-anatomic reconstruction. The overall mortality is 50– 70%,[45] therefore, attention to prevention is important. We believe that our technique of using an end-to-end anastomosis with a short stump and a high bifurcation keeps the graft in the plane of the aorta and minimizes contact with the bowel.[1,43,48] To reattach the terminal portion of the duodenum to the right of the prosthesis and thus avoid contact is rational but risks causing bowel obstruction. Graft coverage with interposition of free or attached omentum between the duodenum and the graft may minimize the complication.
Local Nonvascular Complications Lymphatic Fistula or Lymphocele The division of lymphatics during femoral arterial exposure may result in a lymphatic fistula or a lymphocele. This complication is avoided by using an incision directly over the common femoral artery or somewhat laterally, cauterizing any divided lymph nodes or lymphatics, and carefully and completely closing the groin wound in layers. The management of this problem may be conservative or operative; both approaches are aimed at stopping the leak of lymphatic fluid and preventing graft contamination. With conservative treatment, the patient is confined to bed to reduce the lymphatic flow from the leg, appropriate antibiotics are given, and a pressure dressing is applied. Most fistulas close within 2–3 weeks; however, a more aggressive surgical approach may shorten the hospital stay and reduce the chances of a wound or graft infection.[128] At reoperation, the feeding lymphatic is sutured or cauterized if it can be identified, the cavity is obliterated, and the wound is drained with suction. Operative identification of the offending lymphatic may be facilitated by preoperative intradermal injection of Evans blue dye. In our series, delayed graft infection and false aneurysm were rare following both conservative and surgical treatment.[129] It is not proven if early surgical exploration leads to more prompt healing.[130]
Chapter 30.
Sexual Dysfunction Erection involves the complex interaction of vascular, neurologic, hormonal, and psychologic mechanisms. Aortobifemoral bypass grafting may affect male sexual function by dividing the preaortic fibers of the autonomic nervous system or by reducing pelvic blood flow. The preaortic sympathetic fibers control the closure of the bladder neck during ejaculation; if they are damaged, retrograde ejaculation may result. The surgical techniques described above minimize aortic dissection and reduce the risk of injuring these nerves. Specifically, the aorta is controlled just distal to the renal arteries, and the preaortic tissue is divided longitudinally more toward the right side and is reflected toward the left, particularly in the region of the inferior mesenteric artery.[53] In the presence of severe external iliac artery occlusive disease, an end-to-end aortic anastomosis will reduce the flow to the internal iliac arteries. In this situation, an end-to-side anastomosis is preferred. By following these principles of nerve sparing and preserving pelvic blood flow, Flanigan et al.[54] demonstrated that it was possible to maintain sexual function in most patients and sometimes to improve it. In selected cases, it is possible to improve the pelvic blood flow by an internal iliac endarterectomy or an appropriate bypass graft, although there is some risk of autonomic nerve damage during the dissection.[131]
Ureteric Obstruction Ureteric obstruction and hydronephrosis and consequent urinary sepsis and renal failure may follow an aortobifemoral bypass. Obstruction may be caused by direct operative trauma to the ureter, ischemic damage, inadvertently grasping the periureteric tissue during tunneling and kinking the ureter, or the dense fibrotic reaction surrounding the prosthesis which invades the muscular wall of the ureter.[132 – 134] Care in tunneling may reduce the risk of ureteric damage. Although the ureter may be trapped by a graft placed anterior to it, this mechanism does not appear to be a major factor. Ureteric abnormalities consist of three clinical types. Early transient hydronephrosis occurs in 10 –15% of aortic cases due to edema from the dissection and is of no clinical significance, since it usually resolves.[135] Early persistent hydronephrosis is uncommon, occurring in approximately 1–2% of aortic cases.[135] Operation is necessary only for those patients who develop further complications. Wright et al.[136] clarified the pathology associated with delayedonset hydronephrosis, which occurred in 1.2%. In half the cases, delayed ureteric obstruction was due to a dense local fibrotic reaction, the etiology of which is unknown. To detect this complication during late follow-up, patients should be studied by ultrasound, CT scan, or intravenous pyelogram (IVP). The other half of the cases were associated with graft complications including thrombosis, false aneurysm, graftenteric fistula, and infection.[136,137] Thus, patients who present with ureteric complications should be investigated for associated graft complications, and, conversely, patients who present with aortic graft complications should have a full urological workup, since 5% will have an abnormality. Ureteric obstruction is treated in conjunction with a urologist and involves renal decompression, lysis of
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periureteric fibrosis, and ureteric reimplantation or repositioning of the arterial graft.
Remote Ischemic Vascular Complications Sigmoid Colon Ischemia Clinically significant ischemic colitis is observed in 1 –2% of cases but is detected by colonoscopy in 6 –7%.[138] The sigmoid colon is perfused by the inferior mesenteric artery and collateral branches from the internal iliac and the superior mesenteric arteries. Measurements by Iliopoulos et al.[139] suggest that the branches of the superior mesenteric artery provide the major collateral pathways to the inferior mesenteric artery bed. Sigmoid ischemia may result if prograde flow through a large inferior mesenteric artery is diminished by the reconstructive procedure, collateral flow is poor because of superior mesenteric artery occlusive disease, or perfusion is reduced by inadvertent dissection in the sigmoid mesocolon, operative trauma to important collateral pathways, or atheromatous emboli. If a large inferior mesenteric artery is present and will not be perfused by retrograde flow up the native circulation from the femoral level, the surgeon should consider an end-to-side aortic anastomosis with preservation of the inferior mesenteric artery or reimplantation of the vessel. However, based on clinical observations, routine reimplantation is not justified. Further, in a study of a small group of patients, pH in the sigmoid mucosa was not improved in patients who underwent inferior mesenteric artery reimplantation in comparison to those who had ligation of the artery.[140] The sigmoid colon should always be inspected before the abdomen is closed. If it appears ischemic, the origin of a patent inferior mesenteric artery can be anastomosed to the prosthesis, a direct pass to an internal artery constructed,[138] or Fogarty catheters used to ensure that there is no thrombus in the iliac arteries. If a superior mesenteric artery stenosis is present, revascularization may improve collateral flow to the colon. In the early postoperative period, left lower quadrant abdominal pain, tenderness, or bloody diarrhea require prompt diagnosis by sigmoidoscopy and early decompression or sigmoid resection is indicated, since transmural infarction is associated with a 60% mortality rate.[138] Based on data from the Swedish Vascular Registry, the authors concluded that systemic hypotension, surgical skill and decision making (namely, operating time, cross-clamp time, ligation of one or both internal iliac arteries) and patient-related factors (namely, renal disease, age) were important predictors of intestinal ischemia.[141] The complications of chronic sigmoid ischemia include fibrosis or stenosis; they may appear months to years later and require resection.
Trash Foot Atheromatous debris or loose intraluminal debris or clot formed in areas of stasis may be washed downstream during the operation. The material may shower in such a way that distal gangrene may occur even with good ankle pulses. Prevention is important and is achieved by gentle
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manipulation of the aorta prior to cross clamping and adequate flushing of the graft via open arteriotomies.
Spinal Cord and Cauda Equina Ischemia Following an aortobifemoral bypass, spinal cord or more likely cauda equina or lumbosacral plexus injury is very rare.[142 – 146] Severe hypotension, reduction of pelvic flow by interruption of internal iliac flow, or atheromatous emboli are the major etiological factors.[147] Since the cauda equina begins at the level of the LI-L2 vertebrae, injury may involve spinal roots rather than the cord, thereby producing incomplete paralysis in the distribution of peripheral nerve roots with asymmetric reduction in tendon reflexes and flexor plantar responses as well as patchy sensory loss. Lumbosacral plexus damage may produce similar but unilateral clinical findings. Usually the level of injury can be distinguished on purely clinical grounds, but in difficult cases, spinal cord
lesions may be differentiated from those of the cauda equina or lumbosacral plexus by electrophysiologic evaluation. Treatment is supportive. Although spinal cord injury is usually permanent, some patients continued to show neurologic and functional improvement for years following their injury, particularly those with incomplete deficits. If the site of damage is the cauda equina or lumbosacral plexus, the prognosis for recovery is better since the lesion involves lower motor neurons with capacity for regeneration.
CONCLUSION With proper patient selection and operative technique, gratifying long-term results are achieved by the surgical repair of aortoiliac occlusive disease.
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Ehrenfeld, W.K.; Wieber, B.C.; Olcott, C.N.; Stoney, R.J. Autogenous Tissue Reconstruction in the Management of Infected Prosthetic Grafts. Surgery 1979, 85, 82. Kalman, P.G.; Hosang, M.; Johnston, K.W.; Walker, P.M. Unilateral Iliac Disease: The Role of Iliofemoral Bypass. J. Vasc. Surg. 1987, 6, 139. Piotrowski, J.J.; Pearce, W.H.; Jones, D.N. et al. Aortobifemoral Bypass: The Operation of Choice for Unilateral Iliac Occlusion? J. Vasc. Surg. 1988, 8, 211. Baird, R.J. Techniques and Results of Arterial Prosthetic Bypass for Aortoiliac Occlusive Disease. Can. J. Surg. 1982, 25, 476. Crawford, E.S.; Bomberger, R.A.; Glaeser, D.H. et al. Aortoiliac Occlusive Disease: Factors Influencing Survival and Function Following Reconstructive Operation Over a 25 Year Period. Surgery 1981, 90, 1055. Perdue, G.D., Jr.; Smith, R.B., III.; Ansky, J.D.; Costantino, M.J. Impending Aortoenteric Hemorrhage: The Effect of Early Recognition on Improved Outcome. Surgery 1980, 192, 237. Baird, R.J.; Garry, J.F.; Kellam, J.F.; Wilson, D.R. Abdominal Aortic Aneurysms: Recent Experience with 210 Patients. Can. Med. Assoc. J. 1978, 118, 1229. Pierce, G.E.; Turrentine, M.; Stringfield, S. et al. Evaluation of End-to-Side v End-to-End Proximal Anastomosis in Aortobifemoral Bypass. Arch. Surg. 1982, 117, 1580. Dunn, D.A.; Downs, A.R.; Lye, C. Aortoiliac Reconstruction for Occlusive Disease: Comparison of End-to-End and End-to-Side Proximal Anastomoses. Can. J. Surg. 1982, 25, 382. Madiba, T.E.; Mars, M.; Robbs, J.V. Choosing the Proximal Anastomosis in Aortobifemoral Bypass. Br. J. Surg. 1997, 84, 1416– 1418. Melliere, D.; Labastie, J.; Becquemin, J.P. et al. Proximal Anastomosis in Aortobifemoral Bypass: End-to-End or End-to-Side? J. Cardiovasc. Surg. 1990, 31, 77. Valentine, R.J.; Duke, M.L.; Inman, M.H.; Grayburn, P.A.; Hagino, R.T.; Kakish, H.B.; Clagett, G.P. Effectiveness of Pulmonary Artery Catheters in Aortic Surgery: A Randomized Trial, 1998. Rosenbaum, G.J.; Arroyo, P.J.; Sivina, M. Retroperitoneal Approach Used Exclusively with Epidural Anesthesia for Infrarenal Aortic Disease. Am. J. Surg. 1994, 168, 136– 139. DePalma, R.G.; Levine, S.B.; Feldman, S. Preservation of Erectile Function After Aortoiliac Reconstruction. Arch. Surg. 1978, 113, 958. Flanigan, D.P.; Schuler, J.J.; Keifer, T. et al. Elimination of Iatrogenic Impotence and Improvement of Sexual Junction After Aortoiliac Revascularization. Arch. Surg. 1982, 117, 544. Robicsek, F.; Duncan, G.D.; Anderson, C.E. et al. Indium III-Labeled Platelet Deposition in Woven and Knitted Dacron Bifurcated Aortic Grafts with the Same Patient as a Clinical Model. J. Vasc. Surg. 1987, 5, 833. Robicsek, F.; Daughtery, H.K.; Cook, J.C. et al. Patency Rate of Bifurcated Aortic Grafts: Comparative Analysis of Woven Versus 69, Knitted Prostheses in the Same Patient. Ann. Thorac. Surg. 1985, 40, 172.
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Part Four. Peripheral Occlusive Disease Blumenberg, R.M.; Gelfand, M.L.; Barton, E.A.; Bowers, C.A.; Gittleman, D.A. Clinical Significance of Aortic Graft Dilation. J. Vasc. Surg. 1991, 14, 175– 180. Schneider, J.R.; Zwolak, R.M.; Walsh, D.B.; McDaniel, M.D.; Cronenwett, J.L. Lack of Diameter Effect on ShortTerm Patency of Size-Matched Dacron Aortobifemoral Grafts. J. Vasc. Surg. 1991, 13, 785– 790, Discussion 7901. Sterpetti, A.V.; Feldhaus, R.J.; Schultz, R.D. Combined Aortofemoral and Extended Deep Femoral Artery Reconstruction: Functional Results and Predictors of Need for Distal Bypass. Arch. Surg. 1988, 123, 1269. Pearce, W.H.; Kempczinski, R.F. Extended Autogenous Profundaplasty and Aortofemoral Grafting: An Alternative to Synchronous Distal Bypass. J. Vasc. Surg. 1984, 1, 455. Nevelsteen, A.; Beyens, G.; Smet, G.; Suy, R. Aortofemoral Reconstruction for Multilevel Disease: A Prospective Hemodynamic Study. Acta Chir. Belg. 1989, 89, 179. Sladen, J.G.; Gerein, A.N.; Maxwell, T.M.; Wong, R. Reoperation Within 2 Years of Aortofemoral Bypass. Can. J. Surg. 1988, 31, 224. Brewster, D.C.; Perler, B.A.; Robison, J.G.; Darling, R.C. Aortofemoral Graft for Multilevel Occlusive Disease: Predictors of Success and Need for Distal Bypass. Arch. Surg. 1982, 117, 1593. Kalman, P.G.; Johnston, K.W.; Walker, P.M. Is Aortoprofunda Bypass a Successful Operation for Multilevel Occlusive Disease? Vasc. Surg. 1989, 23, 265. Harris, P.L.; Bigley, D.J.; McSweeney, L. Aortofemoral Bypass and the Role of the Concomitant Femorodistal Reconstruction. Br. J. Surg. 1985, 72, 317. Eidt, J.; Charlesworth, D. Combined Aortobifemoral and Femoropopliteal Bypass in the Management of Patients with Extensive Atherosclerosis. Ann. Vasc. Surg. 1987, 1, 453. Sterpetti, A.V.; Feldhaus, R.J.; Schultz, R.D. Combined Aortofemoral and Extended Deep Femoral Artery Reconstruction: Functional Results and Predictors of Need for Distal Bypass. Arch. Surg. 1988, 123, 1269. Pearce, W.H.; Kempezinski, R.F. Extended Autogenous Profundaplasty and Aortofemoral Grafting: An Alternative to Synchronous Distal Bypass. J. Vasc. Surg. 1984, 1, 455. Nevelsteen, A.; Beyens, G.; Smet, G.; Suy, R. Aortofemoral Reconstruction for Multilevel Disease: A Prospective Hemodynamic Study. Acta Chir. Belg. 1989, 89, 179. Sladen, J.G.; Gerein, A.N.; Maxwell, T.M.; Wong, R. Reoperation Within 2 Years of Aortofemoral Bypass. Can. J. Surg. 1988, 31, 224. Brewster, D.C.; Perler, B.A.; Robison, J.G.; Darling, R.C. Aortofemoral Graft for Multilevel Occlusive Disease: Predictors of Success and Need for Distal Bypass. Arch. Surg. 1982, 117, 1593. Glazier, D.B.; Ciocca, R.G.; Gosin, J.S.; Murphy, D.P.; Graham, A.M. Elective Aortic Surgery with Minimal Banked Blood. Am. Surg. 1998, 64, 171– 174. Kelley-Patteson, C.; Ammar, A.D.; Kelley, H. Should the Cell Saver Autotransfusion Device Be Used Routinely in
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Induced Thrombocytopenia and Thrombosis. Ann. Thorac. Surg. 1989, 48, 712. Ameli, F.M.; Knackstedt, J.; Provan, J.L.; St. Louis, E.L. The Effect of Femoral Arteriography on the Incidence of Groin Contamination and Postoperative Infections. Ann. Vasc. Surg. 1990, 4, 328. Wooster, D.L.; Louch, R.E.; Krajden, S. Intraoperative Bacterial Contamination of Vascular Grafts: A Prospective Study. Can. J. Surg. 1985, 28, 407. Hannon, R.J.; Wolfe, J.H.; Mansfield, A.O. Aortic Prosthetic Infection: 50 Patients Treated by Radical or Local Surgery. Br. J. Surg. 1996, 83, 654– 658. Towne, J.B.; Seabrook, G.R.; Bandyk, D.; Freischlag, J.A.; Edmiston, C.E. In Situ Replacement of Arterial Prosthesis Infected by Bacterial Biofilms: Long-Term Follow-Up. J. Vasc. Surg. 1994, 19, 226– 233. Evans, G.R.; Francel, T.J.; Manson, P.N. Vascular Prosthetic Complications: Success of Salvage with Muscle-Flap Reconstruction [see comments]. Plast. Reconstr. Surg. 1993, 91, 1294– 1302. Clagett, G.P.; Bowers, B.L.; Lopez-Viego, M.A.; Rossi, M.B.; Valentine, R.J.; Myers, S.I.; Chervu, A. Creation of a Neo-Aortoiliac System from Lower Extremity Deep and Superficial Veins. Ann. Surg. 1993, 218, 239 – 248. Alonso, M.; Caeiro, S.; Cachaldora, J.; Segura, R. Infected Abdominal Aortic Aneurysm: In Situ Replacement with Cryopreserved Arterial Homograft. J. Cardiovasc. Surg. (Torino.) 1997, 38, 371– 375. Van den Akker, P.J.; Brand, R.; van Schilfgaarde, R. et al. False Aneurysms After Prosthetic Reconstructions for Aortoiliac Obstructive Disease. Ann. Surg. 1989, 210, 658. Schellack, J.; Salarn, A.; Abouzeid, M.A. et al. Femoral Anastomotic Aneurysms: A Continuing Challenge. J. Vasc. Surg. 1987, 6, 308. Carson, S.N.; Hunter, G.C.; Palmaz, J.; Guernsey, J.M. Recurrence of Femoral Anastomotic Aneurysms. Am. J. Surg. 1983, 146, 774. Kaebnick, H.W.; Bandyk, D.F.; Bergamini, T.W.; Towne, J.B. The Microbiology of Explanted Prostheses. Surgery 1987, 102, 756. Ernst, C.B.; Elliott, J.P., Jr.; Ryan, C.J. et al. Recurrent Femoral Anastomotic Aneurysms: A 30-Year Experience. Ann. Surg. 1988, 208, 401. Wilson, S.E.; Krug, R.; Mueller, G.; Wilson, L. Late Disruption of Dacron Aortic Grafts. Ann. Vasc. Surg. 1997, 11, 383– 386. Han, I.; Shigematsu, H.; Nunokawa, M.; Matsuzaki, H.; lwata, K.; Nakamura, S.; Ishimaru, M.; Sugiura, A.; Kobayashi, Y.; Morioka, Y. Nonanastomotic Aneurysm Formation in a Dacron Arterial Graft: Report of a Case. Surg. Today 1994, 24, 1007– 1010. Walker, P.M.; Johnston, K.W. When Does Limb Blood Flow Increase After Aortoiliac Bypass Grafting? Arch. Surg. 1980, 115, 912. Erdoes, L.S.; Bernhard, V.M.; Berman, S.S. Aortofemoral Graft Occlusion: Strategy and Timing of Reoperation. Cardiovasc. Surg. 1995, 3, 277– 283. Brewster, D.C.; Meier, G.H., III.; Darling, R.C. et al. Reoperation for Aortofemoral Graft Limb Occlusion:
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Part Four. Peripheral Occlusive Disease Optimal Methods and Long-Term Results. J. Vasc. Surg. 1987, 5, 363. Ernst, C.B.; Daughterly, M.E. Removal of a Thrombotic Plug from an Occluded Limb of an Aortofemoral Graft. Arch. Surg. 1978, 113, 301. Enon, B.; Reigner, B.; Lescalie, F.; Hoste, P.; Peret, M.; Chevalier, J.M. In Situ Thrombolysis for Late Occlusion of Suprafemoral Prosthetic Grafts. Ann. Vasc. Surg. 1993, 7, 270–274. Kwann, I.; Bernstein, J.; Connolly, J. Management of Lymph Fistula in the Groin After Arterial Reconstruction. Arch. Surg. 1979, 114, 1416. Kalman, P.G.; Walker, P.M.; Johnston, K.W. Consequences of Groin Lymphatic Fistulae After Vascular Reconstruction. Vasc. Surg. 1991, 25, 210. Tyndall, S.H.; Shepard, A.D.; Wilczewski, J.M.; Reddy, D.J.; Elliott, J.P.J.; Ernst, C.B. Groin Lymphatic Complications After Arterial Reconstruction. J. Vasc. Surg. 1994, 19, 858– 863. Flanigan, D.P.; Sobinsky, K.R.; Schuler, J.J. et al. Internal Iliac Artery Revascularization in the Treatment of Vasculogenic Impotence. Arch. Surg. 1985, 120, 271. Frusha, I.D.; Porter, J.A.; Batson, R.C. Hydronephrosis Following Aorto-Femoral Bypass Grafts. J. Cardiovasc. Surg. 1982, 23, 371. Barber, N.J.; Emberton, M.; Das, G.; Derodra, J. Symptomatic Unilateral Hydronephrosis: A Late Complication of Aortobifemoral Bypass Graft Surgery. Eur. J. Vasc. Endovasc. Surg. 1997, 13, 419– 420. Bastounis, E.; Papastamatiou, M.; Picoulis, E.; Balas, P. Obstructive Uropathy, Following Redo Aortobifemoral Bypass Surgery. Int. Angiol. 1994, 13, 343– 346. Goldenberg, S.L.; Gordon, P.B.; Cooperberg, P.L.; McLouglin, M.G. Early Hydronephrosis Following Aortic Bifurcation Graft Surgery: A Prospective Study. J. Urol. 1988, 140, 1367. Wright, D.J.; Ernst, C.B.; Evans, J.R. et al. Ureteral Complications and Aortoiliac Reconstruction. J. Vasc. Surg. 1990, 11, 29.
137. Schubart, P.; Fortner, G.; Cummings, D. et al. The Significance of Hydronephrosis After Aortofemoral Reconstruction. Arch. Surg. 1985, 120, 377. 138. Zelenock, G.B.; Strodel, W.E.; Knot, J.A. et al. A Prospective Study of Clinically and Endoscopically Documented Colonic Ischemia in 100 Patients Undergoing Aortic Reconstructive Surgery with Aggressive Colonic and Direct Pelvic Revascularization, Compared with Historic Controls. Surgery 1989, 106, 771. 139. Iliopoulos, J.I.; Pierce, G.E.; Hennreck, A.S. et al. Hemodynamics of the Inferior Mesenteric Arterial Circulation. J. Vasc. Surg. 1990, 11, 120. 140. Kuttila, K.; Perttila, J.; Vanttinen, E.; Niinikoski, J. Tonometric Assessment of Sigmoid Perfusion During Aortobifemoral Reconstruction for Arteriosclerosis. Eur. J. Surg. 1994, 160, 491– 495. 141. Bjorck, M.; Troeng, T.; Bergqvist, D. Risk Factors for Intestinal Ischaemia After Aortoiliac Surgery: A Combined Cohort and Case-Control Study of 2824 Operations. Eur. J. Vasc. Endovasc. Surg. 1997, 13, 531– 539. 142. Dunki, J.P.B.; Dicke, H.W. Ischemic Damage to the Spinal Cord Following Surgery of the Abdominal Aorta. Neth. J. Surg. 1984, 36, 1. 143. Paaschburg, N.B. Ischemic Injury to the Spinal Cord as a Complication to Abdominal Aortic Surgery. Acta Chir. Scand. 1985, 151, 433. 144. Friedman, S.G.; Moccio, C.G. Spinal Cord Ischemia Following Elective Aortoiliac Reconstruction. Ann. Vasc. Surg. 1988, 2, 295. 145. Sutton, J.; Nesbit, R.R., Jr. Spinal Cord Ischemia Following Surgery for Aortoiliac Occlusive Disease. J. Vasc. Surg. 1984, 1, 697. 146. Plecha, E.J.; Seabrook, G.R.; Freischlag, J.A.; Towne, J.B. Neurologic Complications of Reoperative and Emergent Abdominal Aortic Reconstruction. Ann. Vasc. Surg. 1995, 9, 95– 101. 147. Picone, A.L.; Green, R.M.; Ricotta, J.R. et al. Spinal Cord Ischemia Following Operations on the Abdominal Aorta. J. Vasc. Surg. 1986, 3, 94.
CHAPTER 31
Femoral-Popliteal-Tibial Occlusive Disease Frank J. Veith Evan C. Lipsitz or occlusion occurs in one or more of the arteries below the inguinal ligament. As the average age of our population increases, the number of individuals with this hemodynamically significant infrainguinal arteriosclerosis also increases. This chapter deals with the present status of treatment for arteriosclerotic occlusive disease of the femoral, popliteal, and tibial arterial systems. Obviously, this disease is associated in varying degrees with arteriosclerotic involvement elsewhere in the body, and this fact must constantly be considered when one is making therapeutic decisions in afflicted patients. Frequently, it is this consideration that guides those caring for the patient to correctly seek palliation rather than cure and to attempt a lesser intervention or operation that maintains function rather than one that will restore a normal circulation. The generalized and slowly progressive nature of the disease process and the imperfect results of all interventional treatments should also deter any who might be unwisely tempted to treat asymptomatic or minimally disabling arteriosclerotic occlusive lesions. In the management of the increasingly common entity of infrainguinal arteriosclerosis, diagnostic and therapeutic restraint and the desire to minimize risks and avoid doing harm must be paramount considerations if the disease is not producing major functional impairment or tissue necrosis. On the other hand, despite the advanced age and poor general condition of many afflicted patients, aggressive intervention for both diagnosis and treatment is justified if limb loss is truly threatened by the disease process.
The last three decades have witnessed enormous advances in the treatment of lower-limb ischemia from infrainguinal arteriosclerosis. In the late 1960s most patients with a threatened ischemic limb were subjected to a major amputation because they had infrainguinal arterial occlusive disease, which was deemed too difficult or risky to treat. This was particularly true of diabetic patients, who were often regarded as having such advanced distal or smallartery occlusive disease that they were categorically inoperable. Although some patients were undergoing successful aortofemoral or femoropopliteal bypasses for segmental occlusive disease of the iliac or superficial femoral arteries, many of them had only intermittent claudication. Most patients with rest pain or necrosis had complex, multilevel occlusive disease in patterns that were deemed unfavorable to treat surgically, and these patients were often subjected to primary amputation. This situation has changed dramatically in the last 20 –25 years as interventional management strategies have been developed to treat virtually all patterns of arteriosclerotic disease underlying severe limb ischemia.[1] Moreover, the resulting aggressive therapeutic approach to threatening ischemia of the lower limb has proven to be effective and worthwhile.[1,2] This form of treatment has gained increasing acceptance throughout the world, even though some still question its value and cost-effectiveness.[3] Despite this residual skepticism, most vascular surgeons, most physicians, and virtually all patients acknowledge the value of the aggressive surgical and radiological approach to patients with limb-threatening ischemia. Indeed, almost all these individuals regard the advances in this field, which will be summarized in this chapter, as one of the most important positive developments that has occurred in vascular surgery in the last quarter century. Arteriosclerosis may involve the common femoral artery and its branches; the above-knee and below-knee popliteal artery; any of the infrapopliteal arteries, including their terminal branches; or any combination of these arteries. This involvement generally begins early in adult life and progresses slowly to the point where a flow-reducing stenosis
CLINICAL PRESENTATION The reserve of the human arterial system is enormous. Hemodynamically significant stenoses or major artery occlusions can exist in the infrainguinal arterial tree in patients with minimal or no symptoms. This is particularly true if collateral pathways are normal or the patient’s activity level is limited by coronary anteriosclerosis or other disease processes. Accordingly, the most common manifestation of a
Hobson/Wilson/Veith: Vascular Surgery: Principles and Practice, Third Edition, Revised and Expanded DOI: 10.1081/0819-9-120024914 Copyright q 2004 by Marcel Dekker, Inc.
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short segmental occlusion of the superficial femoral artery— the most common site of major arteriosclerotic involvement below the inguinal ligament—will be mild intermittent claudication. Similarly, this lesion will often be totally asymptomatic, and this is usually the case if only one or two tibial arteries are occluded without other significant lesions. Thus the usual patient who presents with severe disabling intermittent claudication or tissue necrosis has multiple sequential occlusions or so-called combined segment disease. Hemodynamically significant lesions at the aortoilic level and the femoral/popliteal level can occur in any combination with severe infrapopliteal disease as well.[1]
Staging Patients with hemodynamically significant infrainguinal arteriosclerosis may be classified into one of five stages, depending on their presentation, as indicated in Table 31-1. Patients in stages III and IV are those whose limbs may be considered imminently threatened, although some patients with mild ischemic rest pain may remain stable for many years and an occasional patient with a small patch of gangrene or an ischemic ulcer will heal a lesion with conservative inhospital treatment.[4] With the exception of these few patients, invasive diagnostic procedures such as angiography are easily justified for those with stages III and IV disease, which is usually associated with disease at several levels. Rest pain as an isolated symptom in patients with infrainguinal arteriosclerosis can be difficult to evaluate unless it is accompanied by other findings. Many patients with significant arterial lesions have pain at rest from causes other than their arteriosclerosis, such as arthritis or neuritis. Such pain will not be relieved even by a successful revascularization. Significant ischemic rest pain is almost always associated not only with decreased pulses but also with other objective manifestations of ischemia, such as atrophy, decreased skin temperature when compared to the other extremity, and marked rubor and
relief of pain with dependency. In some patients whose rest pain has a complex etiology, it may be necessary to perform a noninvasive laboratory and angiographic evaluation before the predominant cause can be determined and appropriate treatment instituted. Every patient with pain at rest and decreased pulses is not a candidate for angiography and an interventional arterial procedure. Some of these patients will be relieved by appropriate treatment for gout or osteoarthritis. Others can be well managed with simple analgesics and reassurance that their limb is not in jeopardy. Such reassurance generally suffices for patients with stage I disease and those with stage II disease who are elderly (over age 80) or at high risk because of intercurrent disease or atherosclerotic involvement of other organs such as the heart, kidneys, or brain. This conservative approach to patients with stage I involvement from infrainguinal arteriosclerosis is becoming increasingly widespread, albeit not universally so.[5] Conservatism appears to be clearly justified by the numerous reports of the benignity and slow progression of stage I disease to more advanced stages.[6 – 8] Only 1% of claudicators per year will develop a threatened limb. Moreover, without treatment, 10–15% of patients in stage I will improve over 5 years, and 60–70% will not progress over the same period. The 10–15% who do worsen are, in our opinion, best treated with a primary operation or other therapeutic intervention after their disease progresses. We further believe that this conservative approach to stage I disease is justified by the greater surgical difficulty encountered when a procedure for claudication fails in the early or remote postoperative period and the patient then has a threatened limb, a situation that we have been presented with all too frequently. The fact that some patients in stage II and a few in stage III or IV may remain stable and easy to manage without operation for protracted periods of 1 or more years justifies a cautiously conservative nonoperative approach to selected patients in these stages.[4] This often requires a careful evaluation and frequent visits to the physician so that the patient and the progression of ischemia can be assessed.
Staging of Infrainguinal Arteriosclerosis with Hemodynamically Significant Stenosis or Occlusions
Table 31-1.
Stage 0 I
II
III
IV
Presentation No signs or symptoms Intermittent claudication (. 1 block) No physical changes Severe claudication (, 1/2 block) Dependent rubor Decreased temperature Rest pain Atrophy, cyanosis Dependent rubor Nonhealing ischemic ulcer or gangrene
Invasive diagnostic and therapeutic intervention Never justified Sometimes justified Not always necessary May be stable or improve Often justified Not always necessary May remain stable Usually indicated but may do well for long periods without revascularization Usually indicated
Chapter 31.
Moreover, this conservative nonoperative approach is particularly indicated if the patient is elderly and a poor surgical risk from a systemic or anatomical point of view. An example of this would be an octogenarian with intractable congestive heart failure in whom a difficult distal small-vessel bypass would be required to alleviate stage III signs and symptoms. Close observation can and often should be the preferred management for such a patient for several months or even years; however, we would not hesitate to revascularize such a patient when his rest pain became intolerable or he developed a small patch of gangrene.[1,2]
Impact of Newer Interventional Treatments on Threshold for Therapy The relative simplicity of percutaneous balloon angioplasty alone or in combination with other new endovascular treatments (atherectomy devices, stents, or endovascular grafts) to recanalize arteries with arteriosclerotic plaque has prompted some physicians to recommend lowering the therapeutic thresholds for treatment of infrainguinal arteriosclerosis. Some surgeons, radiologists, and particularly cardiologists new to the peripheral vascular field, armed with these new techniques and devices, have used them routinely to treat stage I and even stage 0 disease detected incidentally during physical examination or arteriography. This practice is to be condemned at this time for many reasons.[9] Most importantly, except for simple balloon angioplasty, the mid- and long-term results of these newer treatments remain largely unknown. Even if they are successful immediately, they can initiate a healing process in the artery that causes late failure or, worse, an acceleration of the occlusive process and ultimately net harm to the patient. Therefore, they subject patients to risks they may not fully appreciate. Although these newer high-tech treatments are exciting and interesting to patients and doctors alike and although they may prove to be safe and effective, this has not yet been shown. Accordingly, although balloon angioplasty may be used when an operation would not, there is otherwise little justification as yet to lower the threshold for intervening in patients with infrainguinal arteriosclerosis. This fact should be communicated freely to patients to offset the unjustified marketing efforts of uninformed practitioners.
Differential Diagnosis Intermittent claudication, or pain brought on by exertion and relieved by rest, is a fairly distinct symptom and usually a manifestation of arteriosclerotic occlusive disease, although mild calf claudication can be produced by a significant stenotic lesion in the iliac, superficial femoral, or popliteal artery. An occasional patient will describe claudication as a sense of heaviness, weakness, or fatigue in the limb without pain, and such patients may be mistakenly diagnosed as having neuromuscular disorders. Sometimes claudication-like symptoms can be produced by lesions compressing the lower spinal cord or cauda equina.[10,11] Such pseudoclaudication is most often produced by spinal stenosis and can easily be suspected when peripheral pulses are normal. Occasionally,
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neurologic problems will coexist with arterial occlusive disease, making an exact determination of the cause of the patient’s symptoms a difficult challenge for the neurologist and the vascular surgeon. In such circumstances, angiography, computed tomography (CT), or magnetic resonance imaging (MRI) of the lumbar spine may be necessary. Some of the difficulties that can be encountered in differentiating pain at rest from true ischemic rest pain have already been discussed. Again, these difficulties are greatest when arterial occlusive disease coexists with other pathology. Similar difficulties can be encountered in determining the primary cause of ulcerating lesions in the ankle region and on the foot. The typical venous ulcer is easy to recognize. It occurs in a setting of chronic venous disease, is associated with stasis changes and normal arterial pulses, is usually relatively painless, and heals with leg elevation and compressive measures. The typical arterial or ischemic ulcer is far more painful and is often associated with other manifestations of ischemia. It usually has a more necrotic base and is located at an area of chronic pressure or trauma, such as over the mallcoli or the bunion area. It can also occur between the toes. Both conditions may be improved by hospitalization, bed rest, and local care. Ulcer differentiation is usually only difficult when chronic venous and arterial disease coexist. Noninvasive arterial and venous evaluation with duplex scanning and even arteriography may be required. In some patients the primary cause of the ulcer can only be determined when arterial reconstruction produces healing after a period of intense conservative management has failed to do so. When a patient presents with a gangrenous (black) or pregangrenous (blue) toe, several etiologies other than progression of chronic arteriosclerotic occlusive disease must be considered. Local infection can be the sole or a contributing cause of the toe lesion. This is particularly common in diabetics. If foot pulses or noninvasive tests of arterial perfusion are normal, the gangrenous condition can be presumed to result from local thrombosis secondary to infection. Radical local excision and drainage of all involved tissue will usually result in a healed foot. Diagnosis is more difficult when infection coexists with arterial occlusive disease. Noninvasive studies and arteriography are usually required before it can be determined whether treatment should consist of excision and drainage alone or combined with an arterial reconstruction. The decisions to be made under these conditions can be very difficult. Black or blue toes may also develop as the result of embolic phenomenon. Such emboli may originate from the heart, a proximal aneurysm, or any proximal atherosclerotic lesion. In the latter circumstance, small cholesterol, platelet, or fibrin emboli may lodge in interosseous or digital arteries. Peripheral pedal pulses may be normal, and spontaneous improvement of the resulting blue toe often occurs. This sequence of events has been termed the “blue toe syndrome,” and its pathogenesis is thought to be analogous to that of transient ischemic attacks from atherosclerotic disease at the carotid bifurcation.[12] If a single dominant large-artery lesion can be identified by angiography, it should be treated by endarterectomy or more commonly by an appropriate bypass. However, in our experience it has been difficult to identify a single lesion in the arterial tree of many of these patients, and
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we have usually operated on them only after they have had several embolic episodes. In any patient whose ischemia developed suddenly, the possibility of a major embolus from the heart or from a proximal aneurysm must be considered. In such circumstances, angiography is indicated even if limb viability is not in question, since major emboli should be removed or lysed as soon as they are identified. In the last several decades, with improvements in cardiac surgery for rheumatic heart disease, major arterial emboli and acute arterial occlusions in almost all such patients that we have seen have been superimposed on extensive arteriosclerosis. Even with arteriography, which we employ routinely in such cases, the diagnosis and treatment of embolic disease is difficult and the results are imperfect.[13] The only certain diagnostic feature of an embolus is multiplicity. Furthermore, the location of the embolus may be atypical, and the vascular surgeon treating a presumed embolus in the presence of extensive arteriosclerosis must be prepared to perform an extensive arterial reconstruction or bypass even if the operation is undertaken soon after the acute event.[13] Because of these facts and because acute thrombosis sometimes cannot be differentiated in any way from an embolus, complete preoperative arteriography should be mandatory in any suspected embolic occlusion of the lower extremity in a patient who could have arteriosclerosis. Exploration of the distal popliteal artery is usually the best surgical approach in patients with severe ischemia due to an acute occlusion of the popliteal or distal superficial femoral arteries.[14] The use of intraarterially administered lytic agents, particularly urokinase, may have significant therapeutic advantages in the management of acute thromboembolic occlusions of lower-extremity arteries, especially those with some underlying atherosclerosis.[15] Moreover, the care and surgical treatment of such cases should be undertaken only by an experienced vascular surgeon. A more complete discussion of the management of acute thromboembolic arterial occlusions appears in Chaps. 27 and 28.
PATIENT EVALUATION Local Factors and Physical Examination of the Extremity As already indicated, the findings on physical examination of the involved extremity contribute to the staging of the atherosclerotic process and provide a rough guide to whether or not diagnostic or therapeutic intervention is justified. Physical examination, by revealing discoloration and swelling, should also provide evidence of the presence and extent of infection in the involved foot. As a general rule, the extent of infection and necrosis deep to the skin is greater than one might expect from an examination of the skin. Reexamination after a short period of soaking to soften the epidermis and dried exudate may also be helpful in revealing purulent collections and subcutaneous necrosis. Exploration of suspicious areas can sometimes be carried out without anesthesia if the patient has diminished sensation from diabetic neuropathy. If not, such exploration and necessary
debridement should be performed in the operating room under anesthesia. In the initial examination of a patient with suspected infrainguinal arterial disease, careful inspection for previous operative scars is essential, since patients may be unaware of a prior sympathectomy or the nature and extent of previous arterial surgery. The site of scars can provide clues as to whether the arteries below the knee were used, whether the ipsilateral saphenous vein was utilized, and, if so, how much is left. Physical examination can also provide evidence of associated chronic disease. In evaluating an ischemic limb, particular attention must be given to careful inspection of the heel and the area between the toes, where unsuspected ischemic ulcers or infection may be present. A flashlight is extremely helpful in this regard. The uninvolved extremity must also be examined carefully. Because of the symmetry of atherosclerosis, the opposite extremity may harbor unsuspected ischemic lesions. Moreover, such findings as coolness and bluish discoloration are far more meaningful if they are asymmetrical, since cool or dusky extremities may sometimes be present without major arterial disease.
Pulse Examination Pulse examination in the lower extremities of a patient with suspected ischemia is extremely important. It requires considerable experience and must be performed with proper technique and care.[16] The strength of a pulse as assessed by an experienced examiner is a valuable semiquantitative assessment of the arterial circulation at that level. Pulses are graded from 0 to 4+, and a pulse should not be described as “plus or minus” or “questionable.” The latter indicates an incomplete exam. A 0 pulse cannot be felt. A 1+ pulse is definitely present but diminished. Both 2+ and 3+ are normal intensities, and 4+ is an abnormally strong pulse, as with an aneurysm or aortic insufficiency. If a pulse is 2+ on one side and 3+ on the opposite side, the 2+ is a decreased pulse, and arterial pressure at that site is probably decreased (unless the 3+ pulse is due to an aneurysm). In examining a patient with diminished pulses, it is extremely helpful to count the peripheral pulse with an assistant who is palpating the patient’s radial pulse. This will ensure that the examiner is not feeling his or her own pulse or spurious muscular activity. Before one describes a pulse as being absent, considerable time and effort must be expended, and ectopic localization of pulses, such as the lateral tarsal artery pulse, must be attempted. In this era of too frequently performed noninvasive arterial tests, the value of a carefully performed and recorded pulse examination cannot be overemphasized. It provides a basis for comparison if subsequent disease progression occurs, and it is a simple way of accurately assessing the arterial circulation in the lower extremities at a given point in time. It also provides an indicator of what type of approach will be required to save a threatened foot. Many examples of this value can be cited. If a patient with a gangrenous toe lesion has a pedal pulse, local treatment without reconstructive arterial surgery will almost always be the correct approach to achieve a healed foot, although there are rare exceptions.[17] If a patient with an ischemic foot lesion has a normal popliteal pulse but no pedal pulses, some
Chapter 31.
form of infapopliteal or small-vessel bypass will almost always be the correct approach to obtain a healed foot. If a patient with an ischemic foot lesion has a normal ipsilateral femoral pulse without distal pulses, some form of infrainguinal arterial reconstruction—a femoropopliteal bypass, it is hoped — will be the correct approach to achieve a healed foot. If such a patient has a diminished femoral pulse, often with an associated bruit, some form of proximal arterial reconstruction or angioplasty above the inguinal ligament will almost certainly be required, with or without a concomitant infrainguinal reconstruction.
Systemic Factors Systemic factors that are important in the patient who is a candidate for interventional treatment for infrainguinal arteriosclerosis include all those in the history, physical examination, and routine laboratory tests that might indicate major organ failure. Most important are evidence of heart disease, diabetes, kidney disease, hypertension, chronic pulmonary disease, and atherosclerotic involvement of arteries to the brain. All these intercurrent diseases, if present, require appropriate medical management before, during, and after diagnostic and therapeutic interventions, so that risks will be minimized. A detailed discussion of this management is beyond the scope of this chapter. However, since all patients with infrainguinal arteriosclerosis also have some degree of coronary involvement and since myocardial infarction is the principal cause of operative as well as late mortality in this group of patients, some details of cardiac evaluation and management should be mentioned. Evidence of myocardial ischemia and congestive heart failure should be sought. If severe angina pectoris is present, some patients should be subjected to coronary arteriography, coronary angioplasty, and even aortocoronary bypass, if indicated, prior to treating their limb ischemia. Patients with recent myocardial infarctions and those in congestive heart failure should have a Swan-Ganz catheter inserted and have their fluid and volume replacement optimized before, during, and after operation on the basis of appropriate cardiac output and pressure measurements.[18,19] It is also especially important to monitor renal function repetitively after any angiographic procedure, since transient renal failure is common. If detected and appropriately treated, this is almost always reversible and rarely a serious problem.
Noninvasive Vascular Laboratory Tests Although the nature and value of these tests are the subject of Chap. 7, several relevant points should be made regarding their role in patients with infrainguinal arteriosclerosis. In the early stages, in which interventional measures are not required, segmental arterial pressures and pulse volume recordings provide an objective and semiquantitative assessment of the circulation and help to confirm the diagnosis made by the history and physical examination, including a careful pulse exam. These tests provide a baseline against which future changes can be measured; they also provide a rough index of the localization of occlusive lesions and the degree of ischemia in the foot. However, the correlation is not absolute,
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and flat ankle and forefoot wave tracings with ankle pressures less than 35 mmHg can be unassociated with foot lesions or serious symptomatology. In addition, decreased thigh waveforms and pressures may be associated entirely with disease below the inguinal ligament as well as with aortoiliac disease. The differentiation between these two levels of disease can only be made by femoral pulse examination and direct pressure measurements. The exact localization and definition of these lesions can be made using duplex scanning, but arteriography, sometimes in two phases, is necessary before planned endovascular or open surgical treatment. Noninvasive testing can be extremely helpful in predicting when a toe amputation or local procedure on the foot has virtually no chance of healing. A flat-line forefoot tracing with an ankle pressure below 50 mmHg indicates that a toe amputation or other foot operation for an ischemic lesion will not heal without prior revascularization. But these tests do not evaluate the severity or extent of infection; therefore, favorable readings do not necessarily point to a successful outcome. Good forefoot pulse waves and ankle pressures do not guarantee healing, although they suggest that it will occur if infection can be eliminated. Furthermore, there is a gray zone of intermediate values in which the noninvasive tests are of little value and a therapeutic trial of a local foot procedure is justified and appropriate.
Angiographic Evaluation As in other areas of vascular surgery, proper high-quality arteriography is essential to make the most accurate diagnosis of infrainguinal arteriosclerosis, to determine whether a therapeutic intervention is possible and justified by its risks, and to permit the surgeon to plan the optimal form that this intervention should take.[1,2] Adequate arteriography also defines the localization and extent of arteriosclerotic involvement in the infrarenal aorta and iliac arteries, although, for optimal accuracy, it may have to be supplemented by direct pressure measurements taken at the time of arteriography or operation. To provide adequate information, the arterial tree from the groin to the forefoot should be well visualized in continuity, preferably by the transfemoral route. This is generally possible only if a long film changer, multiple exposures, large boluses of contrast, and other technical modifications described elsewhere[20] are employed. Oblique views may be required to visualize completely the origin and proximal portion of the deep femoral artery. Good preoperative visualization of the distal arteries is, in our opinion, the key to performing optimal bypass surgery to arteries in the foot and lower leg. Reactive hyperemia, digitally augmented views, and delayed films may be necessary to achieve the needed visualization, although in our recent experience these measures were rarely required. Although others have advocated intraoperative arteriography to achieve this end,[21] we have found it less effective and very rarely necessary. Recently MRI of flowing blood (MR angiography) has provided preoperative evaluation of patient distal leg and foot arteries without the need for dye injection.[22,23] These techniques are not yet widely available but continue to rapidly improve due to technical advances with MR angiography. It
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will likely provide in the future excellent visualization of the whole arterial tree and may replace diagnostic arteriography. Saphenous venography and, more recently, duplex ultrasonography have also been helpful in planning long bypasses.[24,25] They can reveal vein defects preoperatively and thereby spare both patient and surgeon the needless effort of harvesting a saphenous vein that cannot be used. These techniques are particularly indicated in patients who have undergone prior coronary lower extremity bypasses, since many of these patients have had their veins used or inadvertently injured at their first operation. However, surgical exploration is the only way to assess vein quality with complete certainty in questionable situations.
TREATMENT: PRINCIPLES, PROCEDURES, AND JUDGMENTAL ISSUES In general, our approach, which is outlined below, represents the most aggressive effort to salvage limbs that are threatened because of infrainguinal arteriosclerosis. Patients who have ischemic foot lesions or pain but who can be treated successfully with aortofemoral, femorofemoral, or axillofemoral bypasses alone should be so treated. These patients are excluded from the following discussion, even though many of them have infrainguinal arteriosclerosis in addition to their more proximal disease.[1]
General Considerations According to our aggressive approach to patients whose limbs are threatened because of infrainguinal arteriosclerosis, limb salvage should be considered and attempted if feasible unless gangrene extends into the deeper tissues of the tarsal region of the foot or unless the patient has a severe organic mental syndrome with inability to ambulate, communicate, or provide self-care.[1,2] Patients in the latter categories should undergo primary below- or above-knee amputation. Primary above-knee amputation should also be employed if a patient with foot gangrene is unable to stand or walk because of longstanding severe flexion contractures.
Medical Considerations As expected, there is in these patients a high incidence of other arteriosclerotic manifestations, and more than 60% have diabetes mellitus.[2] The mean age is over 70, and many patients are in their eighties. Many have suffered prior myocardial infarctions (some within 3 months of presentation), some are in uncompensated congestive heart failure, have renal failure, or have chronic obstructive pulmonary disease, and a few have concurrent malignancies.[2,26] The general plan of medical management is to achieve maximal improvement of cardiac, renal, pulmonary, and diabetic status before proceeding with arteriographic examination and operation. In some instances, the urgency of the ischemic situation, coupled with progressive infection
in the foot, make it necessary to perform angiographic examination and operation before ideal medical control can be achieved. In these patients, decisions to proceed are made jointly by the surgeon and internists. Almost without exception, age, medical status, incurable malignancy, and/or a contralateral amputation are not absolute contraindications for arterial reconstruction.[1,2]
Surgical Considerations and Criteria for Reconstructibility Femoropopliteal Bypass Patients whose limbs are clearly threatened and who have undergone arteriographic examination should undergo femoropopliteal bypass when the superficial femoral or popliteal artery is occluded and the patent segment of the popliteal artery distal to the occlusion has luminal continuity, on arteriographic examination, with any of its three terminal branches. This is true even if one or more of these branches ends in an occlusion anywhere in the leg. Even if the segment of the popliteal artery into which the graft is to be inserted is occluded distally, femoropopliteal bypass to this isolated segment may be the procedure of choice.[27 – 29] If the isolated popliteal segment is less than 7 cm in length or there is extensive gangrene or infection in the foot, a femoral-topopliteal-to-distal artery bypass or sequential bypass is sometimes performed in one or two stages.[28,30] All femoropopliteal bypasses can be classified on the basis of their relationship to the knee joint and runoff from the popliteal artery, as determined radiographically by previously described criteria.[28,31] However, it should be noted that all angiographic evaluations of popliteal runoff are imperfect and correlate in only a limited way with outflow resistance and bypass patency.[32]
Infrapopliteal Bypass Bypasses to arteries beyond the popliteal (small-vessel bypasses) are performed only when a femoropopliteal bypass is not deemed possible according to the foregoing criteria. These small-vessel bypasses are performed to the posterior tibial, the anterior tibial, or the peroneal arteries. A tibial artery is generally used only if its lumen runs without obstruction into the foot, although vein bypasses to isolated segments of tibial arteries and other disadvantaged outflow tracts have been performed and remained patent over 4 years.[33,34] A peroneal artery is usually used only if it is continuous with one or two of its terminal branches, which communicate with foot arteries. Absence of a plantar arch and vascular calcification are not contraindications to a reconstruction.[2,32] Some patients require a bypass to an artery or arterial branch in the foot.[1,2,33,34] Very few patients fail to have in their leg or foot an artery that meets these requirements, so that less than 1% of our patients are now considered unreconstructible on the basis of angiographic findings alone.[1] With both femoropopliteal and small-vessel bypasses, stenosis of less than 50% of the diameter of the vessel is acceptable at or distal to the site chosen for the distal
Chapter 31.
anastomosis. Although an effort is made to find the most disease-free segment of artery to use for the distal anastomosis, this consideration may be tempered by the advisability of using the most proximal patent segment possible so as to shorten the length of the bypass. For example, we believe that a mildly diseased proximal popliteal artery should be used for a distal anastomosis in preference to a nondiseased distal popliteal artery. The common femoral artery has been generally used as the site of origin for all bypasses to the popliteal and more distal arteries. However, over the last 20 years we have also used as inflow sites the superficial femoral, popliteal, or tibial arteries when these vessels were relatively undiseased or vein length was limited.[33,35] The superficial femoral and popliteal arteries are now used preferentially if possible—that is, if there is no proximal lumenal stenosis in excess of 40% of the cross-sectional diameter.[36]
Axillopopliteal Bypass This operation is employed only when amputation is imminent and a more standard arterial reconstruction is not feasible because of groin infection, previous operative scarring, or extensive bilateral arteriosclerotic involvement of the iliac and femoral artery systems.[37,38]
Profundaplasty Endarterectomy or patching of the origin and proximal portion of the deep femoral artery is chiefly of value in salvaging threatened limbs when it is combined with some form of inflow operation, such as an aortofemoral or axillofemoral bypass.[39] As an isolated procedure in patients whose limbs are threatened because of infrainguinal arteriosclerosis, we have found profundaplasty to be of little value. Perhaps it is occasionally justified as the sole procedure if the patient has rest pain without necrosis and a tight stenosis or occlusion of the deep femoral artery with a demonstrable pressure gradient across the lesion at operation. In practice we have employed a short vein bypass to the distal deep femoral artery more frequently than an isolated profundaplasty.
Graft Material Until 1976, reversed autologous saphenous vein (ASV) graft was clearly the graft material of choice, with a variety of polyester grafts serving as the alternate material if the vein was unavailable. Tubular expanded polytetrafluoroethylene (PTFE) grafts became available in 1976 and were first used only when ipsilateral saphenous vein was unavailable or unusable. Promising early and intermediate results with this material in femoropopliteal bypasses[40 – 42] prompted liberalization of the indications for its use in this operation to include patients whose life expectancy was less than 3 years, and that remains our current philosophy based on more recent data.[43] However, some surgeons, after adequately analyzing their results, still advocate the preferential use of PTFE grafts for femoropopliteal bypass.[44] In 1986 we completed, with Dr. Bergan, Dr. Bernhard, Dr. Yao, Dr. Flinn, Dr. Towne, and others, a cooperative,
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randomized, prospective study comparing ASV to PTFE grafts in all infrainguinal bypass operations.[43,45] ASV and PTFE grafts were compared in 845 infrainguinal bypass operations: 485 to the popliteal artery and 360 to infrapopliteal arteries. Life-table primary patency rates for randomized PTFE grafts to the popliteal artery paralleled those for randomized ASV grafts to the same level for 2 years and then became significantly different [4-year patency of 68 ^ 8% (^ S.E.) for ASV versus 47 ^ 9% for PTFE, p , 0.025]. Four-year patency differences for randomized above-knee grafts were not statistically significant (61 ^ 12% for ASV versus 38 ^ 13% for PTFE, p . 0.25), but they were significant for randomized below-knee grafts (76 ^ 9% for ASV versus 45 ^ 11% for PTFE, p , 0.05). Four-year limb salvage rates after bypasses to the popliteal artery for critical ischemia did not differ for the two types of randomized grafts (75 ^ 10% for ASV versus 70 ^ 10% for PTFE, p . 0.25). Although primary patency rates for randomized PTFE grafts and obligatory PTFE grafts to the popliteal artery were significantly different ( p , 0.025), 4-year limb salvage rates were not (70 ^ 10% versus 68 ^ 20%, p . 0.25). Primary patency rates at 4 years for infrapopliteal bypasses with randomized ASV were significantly better than those with randomized PTFE (49 ^ 10% versus 12 ^ 7%, p , 0.001. At 312 years, limb salvage rates for infrapopliteal bypasses with both randomized grafts (57 ^ 10% for ASV and 61 ^ 10% for PTFE) were better than those for obligatory infrapopliteal PTFE grafts (38 ^ 11%, p , 0.01). These results fail to support the routine preferential use of PTFE grafts for either femoropopliteal or more distal bypasses. However, this graft may be used preferentially in selected poor-risk patients for femoropopliteal bypasses, particularly those that do not cross the knee. Although every effort should be made to use autologous vein for infrapopliteal bypasses, the PTFE distal bypass is a better option than a primary major amputation. Recent reports have shown improved results for femoropopliteal bypasses using PTFE grafts with or without anastomotic vein patches or cuffs. The last reported primary patency rates of these grafts at 5 years with a distal anastomotic vein patch are 54 ^ 10%.[46] A recent report of distal PTFE grafts without a distal vein patch reported 5-year secondary patency rates of 43 ^ 10% and limb salvage rates of 66 ^ 8%.[47] Although we believe that PTFE grafts are the best currently available alternative arterial prosthetic if the ipsilateral ASV is not available for femoropopliteal bypass or if no vein is available for infrapopliteal bypass, other grafts have also been used with some success. The tanned umbilical vein graft has received the greatest attention, and patency rates similar to those of PTFE grafts have been reported in both the fermoropopliteal and infrapopliteal positions.[48] A number of randomized comparisons of the two grafts have been completed, but results are mixed, and those studies that demonstrate higher patency with umbilical vein grafts have unusually poor patency rates for their PTFE grafts. In addition, reports of a high incidence of aneurysmal degeneration occurring in umbilical vein grafts after even a few years are worrisome and suggest that this graft be employed with caution, even though the manufacturers have recently strengthened the external polyester mesh.[49,50]
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Another alternative prosthetic that may have some usefulness in infrainguinal bypasses is the polyester fabric graft with or without external support.[51 – 53] It is thought that the external ring support provides kink resistance as the graft is flexed at joints such as the knee. Polyester and PTFE grafts have been compared in a randomized, prospective fashion as conduits for femoropopliteal bypasses to the above-knee segment At 2 years there is no difference in primary or secondary patency rates between the grafts.[54] At present and until appropriate randomized prospective studies comparing the prosthetic to vein have been completed, it is clearly wrong to use any new prosthetic grafts in preference to ipsilateral ASV. Many surgeons are too easily tempted to find a rationale for the preferential use of a prosthetic graft. We believe that this temptation must be resisted, and we encourage randomized study of all promising new prosthetics before they are used preferentially. Sixty to 80% of patients will have a usable vein if a real effort is made to find it.[25,55] On the other hand, many patients do not have an adequate autologous vein. In such cases, use of a prosthetic graft is far better than an unwise attempt to use a small (less than 3 mm in distended diameter), fibrotic, or otherwise inadequate autologous vein.[55 – 57] These considerations should be kept in mind when one is evaluating the “all-autologous policy” espoused by some capable vascular surgeons.[58] As more and more secondary operations become necessary to save limbs, the proportion of patients who do not have an adequate autologous vein conduit will increase. In such patients a prosthetic (PTFE) graft will yield better results than ill-advised use of a poor or intrinsically diseased vein.[57,59]
In Situ Versus Reversed Saphenous Vein Grafts The in situ saphenous vein graft was described as an infrainguinal arterial conduit by Hall[60] in 1962. Leather and Karmody[61,62] devised new methods for rendering the venous valves incompetent, and the Albany group and Gruss[63] of West Germany have popularized the use of in situ vein grafts for infrainguinal arterial reconstructions. A number of claims have been made regarding the superiority of in situ vein grafts to reversed vein grafts, particularly for tibial and peroneal bypasses. While better endothelial preservation may be possible with in situ veins and they may offer advantages when long bypasses with small veins are required, superior patency rates in comparable situations have never been proven. Comparisons using historical controls are not valid. In a multicenter prospective randomized comparison of in situ and reversed vein grafts that we carried out with Gregor Shanik of Dublin and Peter Harris of Liverpool, no significant patency differences emerged[64] with follow-up of meaningful numbers of cases for more than 212 years. Moreover, we have shown that many of the striking results that can be accomplished with in situ vein grafts can also be successfully accomplished with reversed vein grafts[33] including the use of small-caliber veins to disadvantaged outflow tracts (Figs. 31-1 through 31-6). In addition, many patients who have autologous vein suitable for an ectopic reversed vein graft do not have a vein suitable for an in situ graft. Patients without any remaining major superficial vein in the ipsilateral lower extremity but with a good vein in the opposite leg or an arm are one example. Thus, until the superiority of in situ grafts is
clearly documented by adequately controlled studies, we will adhere to the belief that the technical perfection of the operation and the commitment of the surgeon and his or her colleagues to the goal of limb salvage are far more important in achieving good results than whether the vein graft is of the reversed or in situ type. Taylor and colleagues[46] published their results with infrainguinal reversed vein bypasses and claim that reversed vein grafts are better than in situ grafts. However, more than 20% of the patients whom these authors include in their studies were operated on for indications other than limb salvage. Thus their claims of superiority for reversed vein grafts are based on data without comparable concurrent controls, the same defect that they noted in the reports of others who claimed that the in situ technique gave superior results. Thus, the question of which type of vein graft is best remains an unanswered one that will require further study. However, we have noted extremely poor late patency rates for long reversed vein grafts less than 3.5 mm in diameter and short vein grafts less than 3.0 mm in diameter.[65] Since similar poor patency has not been reported in small-diameter in situ grafts,[66] the in situ technique may be superior in patients whose vein is less than 3.0 mm in distended diameter, but this has not yet been conclusively proven.[63,64]
Upper Extremity Veins The cephalic and basilic veins have been advocated for use as a graft when lower extremity autologous vein is unavailable. Although the work of Schulman and Badley[67] and many others suggests that arm veins are inferior to the saphenous vein in infrainguinal bypasses, other observations indicate that the cephalic vein can be used with good success in lower extremity arterial reconstructions.[68] However, arm veins are more thin walled and more difficult to work with than the saphenous vein. Moreover, in our experience arm veins can have frequent fibrotic, recanalized segments from previous trauma and venipunctures. When several healthy segments are joined to form a composite graft, poorer patency results. On this basis and because of the high degree of symmetry in infrainguinal arteriosclerosis, we believe it is presently justified to use a prosthetic graft in the femoropopliteal position if the ipsilateral saphenous vein is unsuitable or unavailable. However, for infrapopliteal bypasses, every effort should be made to find usable autogenous vein. In this regard, lesser saphenous veins, accessory saphenous veins, and veins from the opposite thigh and upper extremities may be useful, and we use them in that order of preference.
Operative Technique All operations are performed with the patient under light general, epidural, or spinal anesthesia.[69] Care is taken to protect the opposite heel by placing a small pillow under the Achilles tendon. The arterial blood pressure is monitored by a radial artery catheter. Surgical techniques, detailed elsewhere,[70] are illustrated in Figs. 31-7, 31-8, and 31-9. Vessels are occluded with a minimum of force and distortion. We have found tourniquet occlusion, as recommended by
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Figure 31-1. (A) and (B) Arteriogram 3 years after a bypass from the posterior tibial artery in the midleg to a heavily calcified posterior tibial artery distal to the ankle joint. The plantar arch is incomplete, and this patient had only this short segment of saphenous vein available. This graft remains patent after 8 years. (From Veith et al.[33] Reproduced by permission.)
Bernhard and Towne, to be extremely useful during the distal anastomosis.[71] Anastomoses are meticulously constructed with continuous 6-0 polypropylene sutures, with particular care to take small, evenly spaced bites of all layers of the vessel wall and to exclude all adventitia from the anastomotic lumen (Fig. 31-7I). Intraoperative angiographic examination is performed after almost all small-vessel bypasses, but after a femoropopliteal bypass only if special problems are encountered. Although many vascular surgeons think of completion angiography as a panacea, it is not. Defects can be overlooked or not visualized because the proximal portion of the reconstruction is not included on the film. Moreover, “pseudodefects” or artifacts may be visualized and may prompt time-consuming, needless, and harmful further manipulation.[72] Intraoperative fluoroscopy is a very useful
adjunct to infrainguinal bypasses. The surgeon can evaluate in detail the vascular conduit, both anastomoses, and the runoff vessels in multiple planes enhancing the accuracy of the study.[73] Intraoperative duplex can also be helpful to evaluate the graft hemodynamics at the completion of the bypass.[74] Both techniques allow prompt diagnosis and correction of any technical problems.
Bypasses to Ankle or Foot Arteries For many years, our group has advocated the effectiveness of performing bypasses to arteries near the ankle or in the foot (Fig. 31-10) in patients who have no usable patent artery for distal bypass insertion at a more proximal level.[2,33] With
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Figure 31-2. Intraoperative arteriogram after bypass from tibioperoneal trunk to posterior tibial artery at its bifurcation in the foot. Note small size of vein graft and intact plantar arch. (From Veith et al.[33] Reproduced by permission.)
adequate preoperative arteriography, these very distal arteries can usually be visualized if they are patent. Indeed, visualization of the dorsalis pedis and posterior tibial arteries and their branches (Fig. 31-10) and our use of them for bypass insertion have been major factors in reducing the proportion of patients whose arterial disease was so distal that they were “unsuitable for an attempt at limb salvage” or inoperable.[33,34] Although our advocacy of these very distal perimalleolar and inframalleolar bypasses was at first greeted with skepticism, these procedures are now being performed and advocated more widely, and the effectiveness of bypasses to pedal arteries and their main branches has been well documented (Figs. 31-1 through 31-5).[1,2,33,34]
Perioperative and Postoperative Drug Treatment All patients receive prophylactic antibiotic treatment with 1 g of cefazolin 12 hours preoperatively, during operation, and 12 and 24 hours after operation. All receive heparin, 100 – 150 units/kg, during periods of vascular occlusion. Based on the experimental observations of Oblath et al.[75] and a number of clinical studies, all patients are given 325 mg of aspirin once daily beginning 48 hours before operation and continued throughout the period of hospitalization and after discharge.
Management of Foot Lesions Approximately 75% of our patients have gangrenous or necrotic foot or toe lesions.[1,2] Small (2 cm2), uninfected gangrenous lesions on the toe or foot are treated locally.
Larger gangrenous lesions and any areas of infection associated with necrosis are usually extensively debrided at the end of any arterial reconstruction. These debridements often require excision of one or more toes and frequently consist of a partial transmetatarsal amputation. An attempt is made to excise enough bone so there is overhanging skin and soft tissue. These wounds are usually left open, and drying of the soft tissues is prevented by placing a normal saline wet dressing on the wound initially. This is changed as needed to an algenate for fluid absorption or a hydrogel to maintain the moist environment. Subsequent debridement of foot lesions is often required on the ward or in the operating room. This is performed to remove all infected or necrotic tissue and exposed cartilage without regard for anatomic landmarks. It is sometimes necessary, particularly in diabetics, to perform multiple secondary operative procedures to achieve a healed foot. Skin grafts are used to cover large cutaneous defects but are placed only when the wound is rendered entirely clean and granulating by debridement and frequent dressing changes. In some patients, particularly those with extensive foot gangrene or infection and a femoropopliteal bypass that is inserted into an isolated popliteal artery segment, it is impossible to achieve healing at the metatarsal or even tarsal level, and below-knee amputation is required even though the bypass is patent.[76] In some similar instances, it has been possible to obtain foot healing by performing a secondary bypass to an artery distal to the popliteal segment.[28,29,76] However, in the occasional patient with extensive infection and necrosis, a healed foot cannot be obtained even with straight-line arterial flow into pedal arteries.[26] This is most common in patients with end-stage renal disease and diabetes.[76,77]
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Figure 31-3. Postoperative arteriogram after bypass to the lateral tarsal artery, which appears to end in a total occlusion. There is also no patent plantar arch. (From Veith et al.[33] Reproduced by permission.)
Reoperation Most patients whose bypasses thrombose in the first month after operation undergo reoperation.[1,2] The techniques employed have been described elsewhere.[77,78] Intraoperative fluoroscopy is a very useful adjunct to graft thrombectomy and for complete evaluation of the arterial tree. It significantly improves the intraoperative evaluation and the surgical endovascular manipulations that may be needed to correct all hemodynamically significant lesions.[73] Vein grafts that failed immediately after operation usually require interposition of a segment of PTFE[79] or total replacement with this material, although in our experience an occasional thrombectomized vein graft will remain patent if no underlying lesion is present. Patients whose bypasses thrombose after the first postoperative month are considered for an intervention, and femoral angiography is usually performed; however, the patients are subjected to an intervention only if the bypass
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Figure 31-4. Arteriogram obtained 6 months after a bypass to an anterior tibial artery segment that is totally obstructed proximally and distally. A large collateral branch supplied the foot. This bypass has remained patent over 3 years. (From Veith et al.[33] Reproduced by permission.)
failure is associated with a renewed threat to limb viability. The options include thrombolysis of the graft or reoperation. The value and limitations of lytic agents are discussed in detail in Chap. 16. If the patient has originally undergone an operation elsewhere and details of the first operation are not known or the distal anastomosis is at or below the knee joint, a totally new bypass is performed. This is best accomplished using a variety of unusual approaches that permit access to infrainguinal arteries via unscarred, uninfected tissue planes.[79,80] These unusual approaches include a direct approach to the distal two zones of the deep femoral artery (Figs. 31-11 to 31-13),[81] lateral approaches to the popliteal artery above and below the knee,[82] and medial or lateral
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Figure 31-5.
Arteriogram 212 years after a short vein bypass to the lateral plantar branch of the posterior tibial artery.
approaches to all three of the infrapopliteal arteries.[83] In addition to permitting dissection in virginal tissue planes, these access routes facilitate use of shorter grafts, which enable the surgeon to use the patient’s remaining segments of good vein when the ipsilateral greater saphenous vein has been used or inadvertently injured by the primary operation.[79] If the surgeon elects to salvage an old PTFE graft, which may be appropriate if the original distal anastomosis was above the knee and the patient’s veins are poor—as determined by venography or duplex ultrasonography— appropriate surgical techniques are critical to obtaining a favorable outcome.[78,79,84] The prior distal incision is opened and the distal end of the graft, the distal anastomosis, and the proximal and distal artery are dissected free. The graft is opened with a longitudinal incision to within a few millimeters of its distal tip (Fig. 31-14). The graft is then thrombectomized by passage of balloon catheters, best performed under fluoroscopic control.[73] Thrombus is gently removed from the distal anastomosis under direct vision, and balloon catheters are passed proximally and distally in the artery, using extreme gentleness and care. If no disease or defect is seen within the anastomotic lumen, the opening in the graft is closed and an arteriogram is obtained to evaluate the inflow vessel, anastomotic sites, graft, and distal runoff. If no lesion is found, the operation is terminated. If intimal hyperplasia or other disease is noted at or just distal to the anastomosis, the opening in the graft is extended across its toe and down the artery to a point beyond the disease (Fig. 31-15).[78,84] A patch graft is placed to close this opening, and an intraoperative arteriogram is performed. If graft thrombosis has resulted from progression of arteriosclerosis proximal or distal to an anastomosis, an appropriate graft extension is constructed after removing all thrombis (Fig. 31-16). Failed below-knee PTFE femoropopliteal and small-vessel bypasses can be similarly managed but are probably best treated by performance of an entirely new
bypass, preferably with vein and using previously undissected arteries, if possible.[79,84]
Concept of the Failing Graft Intimal hyperplasia, progression of proximal or distal disease, or lesions within the graft itself can produce signs and symptoms of hemodynamic deterioration in patients with a prior arterial reconstruction without producing concomitant thrombosis of the bypass graft.[85 – 90] We have referred to this condition as a “failing graft” because if the lesion is not corrected, graft thrombosis will almost certainly occur.[86] The importance of this failing-graft concept lies in the fact that many difficult lower extremity revascularizations can be salvaged for protracted periods by relatively simple interventions if the lesion responsible for the circulatory deterioration and diminished graft blood flow can be detected before graft thrombosis occurs. In our experience, most failing grafts are vein grafts, but over one third are prosthetic grafts.[86,89] Invariably the corrective procedure is simpler than the secondary operation that would be required if the bypass went on to thrombose. Some lesions responsible for the failing state could be remedied by percutaneous transluminal angioplasty (PTA), although many required a vein patch angioplasty, a short bypass of a graft lesion, or a proximal or distal graft extension. Some of the transluminal angioplasties of these lesions have failed and required a second reintervention; others have remained effective in correcting the responsible lesions, as documented by arteriography more than 2 – 5 years later. If the failing graft is a vein bypass, detection of the failing state permits accurate localization and definition of the responsible lesion by arteriography and salvage of any undiseased vein. In contrast, if the graft is permitted to thrombose, the responsible lesion may be difficult to identify; the vein may be difficult or impossible to lyse or
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performing infrainguinal bypass operations follow their patients closely in the postoperative period and indefinitely thereafter. Ideally, noninvasive laboratory tests, including duplex studies, should be performed with similar frequency.[89,91,92] If the patient has any recurrence of symptoms or the surgeon detects any change in peripheral pulse examination or other manifestations of ischemia, the circulatory deterioration must be confirmed by noninvasive tests and urgent arteriography. If a lesion is detected as a cause of the failing state, it is corrected urgently by PTA or operation. Surgical correction is the treatment of choice for most lesions leading to failing grafts, but simple nonrecurrent vein graft lesions , 1.5 cm in length within grafts more than 3.0 mm in diameter have yielded reasonable long-term results after successful PTA.[93] The role of stents and atherectomy devices for these lesions is still under evaluation.
Role of Angioplasty
Figure 31-6. Arteriogram performed 712 years after a belowknee popliteal-to-posterior tibial bypass. The outflow tract was limited and disadvantaged at operation and has remained so. (From Veith et al.[1] Reproduced by permission.)
thrombectomize; and the patient’s best graft, the ipsilateral greater saphenous vein, may have to be sacrificed, rendering the secondary operation more difficult and more likely to fail, with associated limb loss. Most importantly, the results of reinterventions for failing grafts, in terms of both continued cumulative patency and limb salvage rates, have been far superior to the results of reinterventions for grafts that have thrombosed and failed.[86 – 92] This difference in results—together with the ease of reintervention for failing grafts—mandates that surgeons
Opinions regarding the usefulness of this modality vary considerably, and its exact role in the treatment of infrainguinal arterioscelerosis is still somewhat controversial. Our own[1,2,94] and others’ experience[95,96] suggests that with appropriate patient selection and in skilled hands, this procedure has a low complication rate. Moreover, when complications or failure of PTA do occur, they can generally be well treated by relatively simple surgical procedures with little if any increased patient morbidity or mortality.[94] On this basis we presently will attempt a PTA on any patient with sufficiently severe disease and ischemia (usually stage III or IV) to warrant intervention and in whom the procedure is deemed suitable.[1,2] Patients with stage III or IV ischemia who have a hemodynamically significant segmental iliac stenosis and infrainguinal arteriosclerosis generally have a PTA (without or with a stent) of the iliac lesion as their first therapeutic intervention. If the PTA is unsuccessful, a bypass to the femoral level is performed. If the PTA is successful, further arterial intervention, usually some form of infrainguinal bypass, is performed only if the ischemia is unrelieved and a healed foot cannot be obtained. We do not hesitate to perform a bypass distal to an iliac artery treated by PTA, or a stent, and subsequent experience has borne out the effectiveness of this approach.[1,2,9,97 – 99] PTA is also used as the primary therapeutic intervention in patients without hemodynamically significant iliac artery disease who have a short (# 5 cm) segmental stenosis of the superficial femoral or popliteal artery if this lesion is judged hemodynamically significant on the basis of pulse examination or noninvasive testing. In slightly less than half of our cases treated by angioplasty, some form of direct arterial surgery has also been required, usually for bypass of a second lesion distal to the one successfully treated by angioplasty.[1,2] PTA has also been effective in the treatment of stenotic lesions in tibial arteries and stenoses developing in or proximal or distal to a still-functioning vein or PTFE graft.[58,87,96,100]
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Figure 31-7. Small-vessel bypass in the upper and middle third of the leg. This may be performed to the tibioperoneal trunk, the posterior tibial artery, or the peroneal artery using a medial approach below the knee joint to gain access to these vessels. The anterior tibial artery requires an additional anterior incision (shown in Fig. 31-5). (A) In heavy lines, the position of the incisions required to perform bypasses from the femoral artery to the tibioperoneal trunk or the peroneal or posterior tibial arteries in the upper third of the leg. The upper incision provides access to the common or superficial femoral artery. The above-knee incision allows tunneling under the sartorius muscle and along the course of the popliteal vessels behind the knee. The dashed extension to the lower incision provides access to the posterior tibial and peroneal arteries in the middle third of the leg. If the saphenous vein is to be used, all incisions should be placed over the vein as shown by the double line and access to deeper structures obtained when needed by raising thick flaps. (B) The below-knee incision opened through the skin, subcutaneous fat, and deep fascia of the popliteal space. The gastrocnemius muscle is retracted posteriorly. The more superficial popliteal vein is encircled with a Silastic loop to facilitate dissection of the underlying popliteal artery (arrow), which can be seen disappearing deep to the fibers of the soleus muscle. (C) A finger or right-angle clamp being placed deep to the soleus muscle prior to cutting it at its origin from the fibrous band that attaches to the back of the tibia. This exposes the origin of the anterior tibial artery and its accompanying vein or veins. (D) Division of these veins allows further retraction of overlying veins and exposure of the tibioperoneal trunk and its terminal branches. (E) Tunnels are fashioned by finger dissection. (F) Details of vein preparation using a long (6-in.) cannula to permit the vein to be distended in segments so that leaks can be controlled and recanalized segments detected. (G) Elevation of the arteries by Silastic vessel loops and the beginning of the scalpel incision in the artery. In this view, except for the posterior tibial artery, which also has a microvascular clip applied to it, only the taut Silastic loops are required to control bleeding. (H) Placement of a mosquito clamp to facilitate extension of the initial opening in the artery (1). Alternatively, a microvascular scissors may be used to extend the arteriotomy if the vessel is thin-walled and normal (2). (I) Details of the anastomosis suturing, which is begun at the distal end and continued to the midportion of each side of the anastomotic of the artery and the saphenous vein graft. Equal bites of all layers of each vessel are included in each stitch, which is always placed under direct vision. (J) Completed graft in place. If more distal exposure of the posterior tibial or peroneal arteries is required, further separation of the soleus muscle from the posterior surface of the tibia and its overlying muscles provides access to the neurovascular bundles. Careful dissection of the veins with ligation of crossing branches provides access to the more deeply placed arteries. These can be dissected free, taking great care to preserve all branches, so that an appropriate segment of artery can be elevated and controlled to perform the distal anastomosis. (From Veith and Gupta. [70] Reproduced by permission.)
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Figure 31-8. Bypass of the anterior tibial artery in the upper and middle thirds of the leg. (A) This requires an anterolateral incision in the leg midway between the tibia and fibula over the appropriate segment of patent artery. Additional small medial incisions are also required for tunneling. (B) The anterior incision in carried through the deep fascia, and the fibers of the anterior tibial muscle and the long extensors of the toes are separated to reveal the neurovascular bundle. Mobilization of accompanying veins with division of branches allows visualization of the anterior tibial artery, which can then be carefully mobilized. (C) After the artery is freed, it is elevated and retracted along with the accompanying veins by Silastic loops. This permits further posterior dissection, which allows the interosseous membrane to be visualized and incised in a cruciate fashion. (D) Careful blunt finger dissection from this anterior approach and from the popliteal fossa via the medial incision facilitates creation of a tunnel without injuring the numerous veins in the area. Alternatively, the tunnel for the bypass may be placed lateral to the knee in a subcutaneous plane. (E) By elevating the anterior tibial artery, a meticulous distal anastomosis can be constructed, as already described. (F) The resulting graft in place. The anterior tibial artery can also be approached by a lateral incision with fibulectomy, but we believe this approach to be bloodier and more time-consuming than the one we have described. (From Veith and Gupta.[70] Reproduced by permission.)
RESULTS OF TREATMENT Arteriosclerotic involvement is generally less, both in regard to extent and multiplicity of lesions, in patients with intermittent claudication than in those whose limb is
threatened. It is therefore not surprising that the short- and long-term patency results of infrainguinal arterial bypasses performed for intermittent claudication are generally better than those of procedures done for limb salvage, and this difference has been documented by virtually every author who evaluated results on the basis of operative indi-
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Figure 31-9. Bypasses to the distal third of the leg and the foot. Bypasses to the anterior tibial, posterior tibial, or peroneal arteries in the distal leg can be performed by techniques similar to those already described, with the exception of certain features illustrated here. (A) The distal posterior tibial artery can be approached by an incision along the posterior edge of the tibia. By deepening this incision along the tibialis posterior muscle and the posterior surface of the tibia, the distal peroneal artery can also be located and isolated just medial to the medial edge of the fibula. By dividing restraining fascia and fibers of the flexor hallucis longus muscle, it is possible to free this artery and elevate it into the wound so that a careful anastomosis can be constructed. However, in its distal third and particularly in patients with a stout calf and ankle, this vessel is approached by a lateral incision with excision of the fibula (B). (C) This is accomplished by freeing a long segment of fibula from its muscle attachments using a combination of blunt and sharp dissection. Particular care should be taken in the dissection along the medial edge of the bone, since the peroneal vessels are just deep to this edge and are easily injured by instruments. Once a finger has been passed around the fibula, this free edge of bone can be further developed by pushing a right-angled clamp forcefully inferiorly and superiorly. A right-angled retractor can then be passed behind the bone and a hole drilled in it. Then the fibula can be divided easily and cleanly with a rib shears. The peroneal artery can then be dissected free from surrounding veins so that it can be used for construction of a distal anastomosis. Gentle blunt finger dissection is required to develop a tunnel from this lateral wound to the lower popliteal fossa. Great care is taken to avoid injury to the numerous veins in the area. From there, the tunneling to the femoral artery wound is performed in the previously described fashion. Because it is the least accessible of the three leg arteries and normally has the poorest connections with the arteries of the foot, we recommend use of the peroneal artery as a distal implantation site only when the anterior and posterior tibial arteries are not suitable for use. (D) The tunnel from the popliteal fossa to the distal posterior tibial artery is made just deep to the deep fascia. This is best accomplished with a long, gently curved clamp. The distal anterior tibial artery is approached by an anterior incision midway between the tibia and fibula (B). For bypass to this vessel, a tunnel is made from the distal popliteal fossa, deep to the deep fascia, to a point 5 – 7 cm above the medial malleolus (D). From this point, the tunnel is made subcutaneously in a gentle curve across the tibia and adjacent tendons to reach the anterior tibial wound. The underlying tendons are those of the anterior tibial muscle and the long extensors of the toes. The tunnels are marked with umbilical tapes for subsequent identification. (E) After completion of the distal anastomosis and drawing the graft through these tunnels, any tendons that distort or compress the graft in its course around the tibia are divided. This is usually required in low anterior tibial bypasses. (F,G) When no more proximal procedure is possible, bypasses to the ankle region or foot can be used to salvage limbs. The dorsalis pedis artery can easily be approached via an incision on the dorsum of the foot. We place this incision laterally, curve it, and raise a flap so that the incision will not be directly over the anastomosis. If this artery must be approached at the ankle, it is necessary to divide the extensor retinaculum. Otherwise the operation is performed as already described for distal anterior tibial bypasses. The posterior tibial artery can be approached down to a point several centimeters below the medial malleolus. (From Veith and Gupta.[70] Reproduced by permission.)
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Figure 31-10. Diagram of named arteries in the ankle region and foot. Any of the main arteries or their branches, if patent, may be approached surgically and used as the distal outflow for a limb salvage bypass. (From Ascer et al.[34] Reproduced by permission.)
Figure 31-11. Portions or zones of the deep femoral artery. The distal two zones may be approached directly without exposing the common femoral artery or the proximal zone if either is involved with scarring or infection. (From Nunez et al.[81] Reproduced by permission.)
cations.[55,101] Since we believe that femoropopliteal bypass should rarely be performed for intermittent claudication and that other infrainguinal bypasses should never be performed for this indication alone, we will restrict our discussion of results to operations performed because of severe ischemic rest pain, a nonhealing ulcer, or
gangrene. However, it is true that many vascular surgeons still believe that femoropopliteal bypasses for truly disabling claudication are justified by their good results and low risk rate. We do not disagree with this opinion, provided that the patient is informed of the risks of intervention.[5]
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Figure 31-12. Incisions and anatomy for direct approaches to the distal two thirds of the deep femoral artery. (From Nunez et al.[81] Reproduced by permission.)
Results of infrainguinal bypasses clearly vary with the training, technical skill, and commitment of the surgeon. These operations are demanding and should be performed only be surgeons doing them regularly and, more importantly,
Figure 31-13. Cross-sectional anatomy for direct approaches to the distal two thirds of the deep femoral artery. (From Nunez et al.[81] Reproduced by permission.)
by surgeons with the skill and commitment to reoperate successfully should a bypass fail in the early or late postoperative period. In deciding whether these operations and an aggressive approach to limb salvage are in fact
Figure 31-14. Technique for a reoperation in which graft salvage will be attempted. Control of the artery proximal and distal to the anastomosis must be obtained. The opening in the graft is placed so that the interior of the anastomosis can be visualized. (From Veith et al.[79] Reproduced by permission.)
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Figure 31-15. Stenosis just distal to an anastomosis can be caused by intimal hyperplasia or an unrecognized artherosclerotic lesion. This can be corrected by extending the graft incision across its apex and down the recipient artery until the lumen is no longer narrowed. A vein or PTFE patch is then inserted across the stenosis to widen the lumen. (From Ascer et al.[84] Reproduced by permission.)
justified in a given setting, every vascular surgeon should continually examine his or her own results to see if they are good enough to justify continued application of these sometimes difficult operations in these often brittle patients.
Operative Mortality The 30-day mortality for all patients undergoing infrainguinal arterial reconstructions for threatened limbs ranges from 2 to
Figure 31-16. permission.)
6%.[1,2,102] Operative mortality is slightly greater for infrapopliteal than for femoropopliteal bypasses, probably because the former operations are required in patients with more advanced generalized as well as lower extremity disease. The principal cause of death from these operations is myocardial infarction. These low operative mortalities contrast with the high latedeath rates reflected in Fig. 31-17, which shows that only 48% of all patients having arterial reconstructions were alive 5
If disease is detected in the outflow tract, a graft extension is performed. (From Ascer et al.[84] Reproduced by
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years later. Almost all later deaths were unrelated to the original operation, most being due to intercurrent arteriosclerotic events, chiefly myocardial infarction. These findings again reflect the advanced stage of generalized arteriosclerosis present in these patients.
Limb Salvage When the aggressive approach already outlined for the management of patients whose limbs are threatened by infrainguinal arteriosclerosis was used and only those patients who had organic mental syndrome and extensive local gangrene were excluded, 96% of patients underwent arteriographic examination. [2] Ninety-four percent of patients who underwent arteriography were suitable candidates for some form of arterial revascularization procedure. With recent technical advances, less than 1% of patients undergoing arteriography do not have some patent distal artery suitable for use in an attempt at revascularization, and most of these are patients who have had previous failed operations.[1]
Figure 31-17. Cumulative life-table patient survival rates after 318 femoropopliteal (Fem. pop.), 204 small-vessel (infrapopliteal), and 29 axillopopliteal (Ax. pop.) bypasses. Fifty-two percent of all patients undergoing all reconstructive arterial operations for limbthreatening infrainguinal arterioselerosis were dead within 5 years. (From Veith et al.[2] Reproduced by permission.)
Immediate Limb Salvage Defined as relief of ischemia and healing of ischemic lesions for 1 month after the first revascularization procedure, immediate limb salvage was achieved in 86% of patients in whom revascularization was possible.[2] This immediate limb salvage rate was calculated by subtracting from the number of patients who could undergo revascularization procedures those patients who died or whose arterial reconstructive operation and/or angioplasty failed irretrievably within 1 month of the primary procedure as well as those patients who required major amputations despite a successful revascularization procedure. Multiple (4– 7) local operations and 2–4 months of hospitalization were required to achieve foot healing in 7% of our patients. Heel and forefoot gangrene did not preclude ultimate limb salvage, although they could, if extensive, contribute to the need for prolonged periods of hospitalization. Even when the initial procedure attempting to achieve limb salvage failed immediately, the involved extremity could often be saved by promptly performing some secondary procedure.[1,2,87,92,103] This was particularly common if a PTA was technically unsuccessful or failed to improve the arterial supply to the foot.[1,2]
original operation and the limb remained intact when the bypass thrombosed; moreover, in many instances when the limb was rethreatened, bypass patency could be restored by appropriate reoperation. This was particularly common if the original procedure had been a femoropoliteal bypass.[29,78] On the other hand, limb salvage rates could be rendered lower than bypass patency rates if a major amputation was required despite a patent arterial reconstruction,[76] which is most common in patients with endstage renal disease.[77]
Late Limb Salvage The cumulative limb salvage rates for all patients having arterial reconstructive operations are shown in Fig. 31-18. Sixty-six percent of the patients who survived 5 years after a reconstructive arterial operation below the inguinal ligament for limb salvage had an intact limb up to that time. The limb salvage rates were better after femoropopliteal bypass than after a small-vessel bypass or an axillopopliteal bypass ( p , 0.25) (Fig. 31-19). Even though all operations were performed because the limb was threatened, limb salvage rates (Fig. 31-19) could not be equated with bypass patency rates (Fig. 31-20). In some patients, gangrene and infection had been healed by the
Figure 31-18. Cumulative life-table limb salvage rates of all patients undergoing reconstructive arterial operations for limbthreatening infrainguinal arteriosclerosis. The number with each point indicates the number of cases observed with intact limbs for that length of time. (From Veith et al.[2] Reproduced by permission.)
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Figure 31-19. Cumulative life-table limb salvage rates of 318 femoropopliteal (Fem. pop.), 204 small-vessel, and 29 axillopopliteal (Ax. pop.) bypasses performed for limb-threatening infrainguinal arteriosclerosis. The number with each point indicates the number of cases observed with intact limbs for that length of time. (From Veith et al.[2] Reproduced by permission.)
Figure 31-20. Cumulative life-table patency rates of 318 femoropopliteal (Fem. pop.). 204 small-vessel, and 29 axillopopliteal (Ax. pop.) bypasses performed for limb-threatening infrainguinal arteriosclerosis. The number with each point indicates the number of cases observed to be patent for that length of time. (From Veith et al.[2] Reproduced by permission.)
Patency of Arterial Reconstructive Operations
intermittent claudication. Thus, while some improvement in results may be real, much of it is due to patient selection and differences in the methods of reporting or analyzing results.
Older cumulative life-table patency rates for all reconstructive arterial operations are shown in Fig. 31-20. More recent patency rates have improved somewhat and continue to be significantly better for femoropopliteal bypasses than for small-vessel or axillopopliteal bypasses ( p , 0.01). Our small-vessel bypass patency rate was not affected by age, sex, hypertensive or diabetic status, or previous ipsilateral bypass. In contrast to reports from other groups, an incomplete plantar arch, a heavily calcified bypass insertion site, an unusable saphenous vein, and a very low ankle pressure did not preclude long-term success, although these factors were associated with a somewhat higher early failure rate.[1,2]
Recent Results Several reports have documented better late limb salvage and bypass patency results than those presented. While some of these apparently improved results may reflect more refined surgical and management techniques, these more optimistic reports have generally included only patients operated on by a particular surgical technique, such as reversed vein bypass or in situ vein bypass. Since these techniques, although ideal, are not applicable to all patients with a threatened lower extremity, it is probable that the older statistics presented above are still representative of the overall results achievable in an entire group of patients undergoing lower limb arterial reconstruction to save an extremity. Moreover, some articles with favorable late bypass patency results are actually reporting secondary patency figures that are achievable with a more aggressive policy of detecting and reintervening on failing or failed bypasses, and some reports include results on substantial numbers of patients undergoing operation for
Durability of Angioplasty Eleven percent of our iliac angioplasties and 8% of our femoropopliteal angioplasties were initially unsuccessful. If one considers the durability of those angioplasties that were initially successful, cumulative life-table patency at 4 years was 78% for the iliac angioplasties and 50% for the femoropopliteal angioplasties. The use of stents has further improved the results of secondary angioplasties of the iliac arteries, but their role for infrainguinal lesions is still unproven. In addition, the role of new endovascular grafts for the treatment of infrainguinal occlusive disease is still unclear. Femoropopliteal angioplasties are reserved for short stenotic lesions, while surgical techniques are used for more extensive lesions and angioplasty failures (see Chap. 26). Appropriate surgery when an angioplasty fails and a limb is rethreatened results in protracted limb salvage in more than 70% of cases.[1,2,94] Generally, the operative procedure required was the same one that would have been performed had the angioplasty not been selected as the initial interventional treatment.[94] These facts—coupled with our angioplasty mortality of less than 1% in this elderly, sick group of patients—indicate that the risk of angioplasty failure is not excessive. We therefore continue to regard PTA, when performed by a committed radiology-surgery team, as an important part of an aggressive approach to salvaging limbs.[1,9] However, 81% of patients with threatened limbs will require operative treatment at some point in their course; only 19% can be treated by PTA alone.[1]
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Reoperations Our policy of performing a graft thrombectomy on all thrombosed small-vessel and axillopopliteal bypasses if and when the thrombosis is associated with a threat to the limb has not resulted in any operative deaths but has generally been unrewarding. The majority of such reoperated grafts rethrombosed within a few days, weeks, or months. In occasional instances, comprising approximately 10% of such reoperated cases, patency was restored and persisted more than 3 years.[78,79] Thus, our present policy for the treatment of failed smallvessel bypasses if the limb is rethreatened is to use lytic agents in appropriate cases or perform an entirely new bypass to another unoperated segment of an infrapopliteal artery. Our results with such secondary small-vessel bypasses have not differed greatly from those of primary procedures, although others have not had a similar experience.[79,84] The results of aggressive reoperation for failed vein and nonvein femoropopliteal bypasses have been surprisingly good.[1,2,79,83,87,103 – 105] This is true whether the bypasses fail early—within the first month—or after the first month. In one early series of our patients, 39 femoropopliteal bypasses failed more than 1 month after operation and were considered for aggressive reoperation. A conservative approach to a failed bypass that did not place the limb in jeopardy was justified by the continued viability for 2 –72 months of all eight limbs in this category. Reoperation was performed in the remaining 31 patients with threatened limbs. In 28 patients, bypass patency was reestablished for at least 2 months. In 20 patients, graft patency persisted until death or the last followup obtained. The range of patency after reoperation in this group of 20 patients was 2–48 months, with a mean of over 17 months, although 7 patients required a secondary reoperation to maintain bypass patency and limb viability. Sixteen grafts remained open more than 1 year after reoperation. Only 8 of the 39 patients in whom late graft occlusion occurred ultimately required a major amputation, and in all but 2 instances this could be successfully performed below the knee. One of the 31 patients died within 1 month of the reoperation. The sustained effectiveness of appropriate reoperations when limb salvage femoropopliteal bypasses fail in the early or late postoperative period is illustrated by Fig. 31-21, which shows that reoperation increased overall patency rates by 15% at 5 years. When the same calculations were applied to 440 patients with longer periods of follow-up, the difference between primary and secondary patency rates at 5 years fell to 8%. Limb salvage rates were, of course, similarly increased by effective reoperations. The efficacy of such reoperations in maintaining durable patency is further shown by the cumulative life-table 6-year patency rate of 56% for 44 of our femoropopliteal bypasses requiring reoperation for thrombosis. Limb salvage rates were even higher. Similar patency rates and limb salvage rates have also been achieved by Whittemore and his colleagues,[87] who employed reoperations in the management of a group of patients with failed vein femoropopliteal bypass and threatened limbs. Both we and Whittemore’s group as well as many other groups have found that detection of failing reconstructions before graft thrombosis has occurred permits simpler corrective
Figure 31-21. Cumulative life-table patency rates of 318 femoropopliteal bypasses performed for limb salvage. The upper curve was calculated without regard to whether or not a reoperation was required to maintain patency. The lower curve was calculated on the basis of time to first bypass occlusion even if reoperation restored patency. The number with each point indicates the number of cases observed to be patent for that length of time. (From Veith et al.[2] Reproduced by permission.)
measures to be used and results in much better long-term graft patency and limb salvage.[84 – 90,92] Although Craver and his colleagues[106] showed many years ago that reoperation for early postoperative thrombosis of femoropopliteal vein grafts was associated with poor longterm patency rates, we have found this not to be the case with PTFE bypasses above the knee.[84] In addition, Whittemore and his associates[87] have reported similar protracted successes after reoperation for failure of saphenous vein femoropopliteal grafts. Appropriate use of intraoperative angiography and other technical details of these reoperations are important in achieving the reported good results. Surgical clot removal from thrombosed PTFE grafts sometimes allows these conduits to be used effectively for protracted periods if all other lesions encroaching substantially on the lumen are corrected or bypassed.[79,84] This is only occasionally true with vein grafts if the clot is removed within a day or two of its occurrence.
Lytic Agents Although we believe that a totally new bypass is the best treatment for a thrombosed graft that is associated with limb-threatening ischemia, a number of recent reports have advocated the use of intraarterially administered lytic agents to restore patency to thrombosed infrainguinal grafts. These agents, especially urokinase, are useful in treating some failed grafts. In addition, in most cases they permit detection of the cause of failure. PTA or surgical graft revision is then almost always required to correct the lesion causing thrombosis. Late results with these lysed grafts have been mixed, although better methods to use these lytic agents are constantly being developed. More-
Chapter 31.
over, these agents have real value in the treatment of patients with native artery occlusions, such as those occurring with a popliteal aneurysm. The use and value of lytic agents is discussed in more detail in Chap. 16.
Arteriographic Outflow Characteristics and Patency of the Popliteal Artery With significant numbers of patients now followed for 5 years or more, patency rates of femoropopliteal bypasses inserted into popliteal artery segments isolated were not significantly different from those of bypasses inserted into popliteal arteries that appeared to be continuous with one or more of their main terminal branches. These results support the use of femoropopliteal bypass to isolated segments of popliteal artery as an option for limb salvage.[28,29,107] This appears to be true even when the absence of a usable saphenous vein makes it necessary to use a PTFE graft.[28,29] A major disadvantage of such use of isolated popliteal segments is the high incidence of continued threat to the limb despite a patent bypass. This is particularly common if there is extensive gangrene or infection in the foot.[28,29,76] In such circumstances, a femoral-topopliteal-to-small vessel bypass or sequential bypass is indicated, and it is best to perform the distalmost portion of this complex bypass with autologous vein if it is available in any of the patient’s extremities.[28 – 30,108,109]
Relationship of Position of Anastomosis to Patency In our hands, femoropopliteal bypass patency was not significantly influenced solely by the position of the distal anastomosis relative to the knee joint. This was true with both PTFE and vein grafts. Other patient-related factors are probably more important in determining patency than is the location of the popliteal anastomosis. These factors are not controlled in any study comparing above-knee and belowknee results, thereby rendering the comparisons meaningless in terms of selecting the best level of popliteal artery to use if it is patent above and below the knee in a given patient.
Amputation Level When major amputation was required after a revascularization procedure had been performed, every effort was made to perform it at the below-knee level. In one of our series, this was possible in all 18 patients who required amputation despite a patent bypass, in 90% of patients who required a major amputation when a femoropopliteal bypass occluded, in 69% of patients who required a major amputation after a failed small-vessel bypass, and in 30% of major amputations required after thrombosis of an axillopopliteal bypass. [2] The operative mortality rate for these secondary amputations was 4%.
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ANALYSIS OF COST-BENEFIT RATIO OF AGGRESSIVE EFFORTS AT LIMB SALVAGE Our results indicate that more than 98% of patients whose limbs are threatened because of infrainguinal arteriosclerosis have a distribution of occlusive and stenotic arterial lesions that is suitable for reconstructive arterial surgery, which can relieve the ischemia at least partially and salvage the limb. The results also show that it is possible to obtain immediate limb salvage in more than 85% of the patients in whom revascularization is possible, with an operative mortality rate of less than 4% and a low morbidity rate despite the existence in many patients of local and systemic factors that might, in the past, have precluded attempts at revascularization and limb salvage. These factors include advanced age, recent congestive heart failure or myocardial infarction, concurrent malignancy, extensive forefoot or heel gangrene, a contralateral amputation, an isolated popliteal artery segment, absence of a usable saphenous vein, and the presence of a popliteal pulse with three-vessel infrapopliteal occlusive disease extending to the ankle region. Diabetes does not negatively prejudice the chances of limb salvage, although it may be associated with more extensive necrosis or infection in the foot. On the other hand, end-stage renal failure is associated with a higher early and late mortality, a higher morbidity, and a higher incidence of limb loss with a patent graft.[77] Limb salvage efforts are still worthwhile in this difficult group of patients. The fact that limbs can now be saved in all these circumstances is of interest. Alone, it does not mean that all these limb salvage attempts, which may require multiple operations and prolonged periods of hospitalization to obtain a healed foot, are justified in this group of patients, whose life expectancy is known to be poor. Is the cost-benefit ratio such that attempts at limbs salvage are worthwhile in these patients? This is a difficult question to answer with certainly since, in part, the answer depends on one’s philosophy and perspective and on subjective factors such as quality of life and the ability to live and function independently. However, certain objective parameters are relevant. Among these are the durability of limb salvage in surviving patients and the longevity of the patients. Figure 31-17 is an index of patient longevity. Figure 31-18 is a measure of the durability of limb salvage in surviving patients. Of the 48% of patients who survived 5 years after operation, two thirds retained their limb at least that long. It is also relevant to know that of every 100 patients who underwent operation in one series of our patients, 68 lived at least 1 year after operation with an intact limb, and 54 lived at least 2 years with a viable, usable extremity.[2] Moreover, of the 52% of patients who died within 5 years, 88% (81–95%) retained the salvaged limb until they died (Fig. 31-22). Both we and almost all of our patients believe that these benefits outweigh the risks and costs of an aggressive attempt at limb salvage, even if this attempt entails a lengthy period of hospitalization with several operative procedures to achieve a healed foot. Similar conclusions have been reached by Reichle and Tyson,[102]
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Figure 31-22. Percentage of all patients who underwent limb salvage attempts and who died in the various intervals after operation. The cross-hatched areas indicate the portion of these patients who died without losing their previously threatened limb. (From Veith et al.[2] Reproduced by permission.)
Maini and Mannick,[110] Perdue et al.,[111] Bartlett et al.,[103] and Auer et al.[112] in their analyses of patients with limbthreatening ischemia. A case can also be made for performing a primary belowknee amputation in some or all of these patients, and relatively rapid rehabilitation may be achieved with such a procedure.[113,114] However, our experience has shown that older, poor-risk patients do not ambulate easily or quickly with a below-knee prosthesis. Such patients may never walk, and, if they do, they may require 2 or 3 months of institutional training to learn. For some patients, limb salvage offers the only opportunity to care for themselves, maintain their independence, and avoid permanent admission to an institution. Furthermore, in many patients the opposite limb soon becomes threatened because of the symmetry of the disease process, and salvage of at least one limb is critical for the patient to maintain independence. Finally, the point has been made that unsuccessful attempts at limb salvage result in a high incidence of loss of the knee.[55,113,115] Our data fail to confirm this except after failed axillopopliteal bypass, a procedure performed in patients with the most advanced disease. Thus, we believe that unless the patient has severe organic mental syndrome or gangrene and infection proximal to the midfoot, limb salvage should be attempted if suitable vessels for revascularization are present.
Recent Evaluations of Aggressive Approaches to Limb Salvage Two decades ago, most patients with limb-threatening ischemia were treated by a primary major amputation above or below the knee. With the introduction and widespread use of better arteriography and the interventional and operative techniques already outlined, efforts to save more and more threatened lower limbs have become increasingly common around the world. Although the aggressive approach to saving
limbs threatened because of ischemia seemed to be worthwhile, an analysis of a single decade’s experience from the state of Maryland cast doubt on the value of balloon angioplasty and bypass techniques as methods for preventing major amputations.[3] This article reportedly showed that amputation rates in Maryland remained stable while usage of angioplasty and reconstructive arterial surgery increased markedly over the period of the study. The value of the procedures and their cost-effectiveness were questioned. Unfortunately, these conclusions were based on flawed analyses of flawed data. For example, transmetatarsal amputations, a most successful component of many limb salvage efforts, were considered major amputations in this study. Moreover, many of the reported angioplasties and bypasses in the study were performed for claudication and not for limb salvage. Amputation was obviously not an appropriate index of success in these cases. And finally, this study did not consider the possibility that, as the population aged and became more infirm, amputation rates would have increased without the benefits of the increasing numbers of angioplasties and bypasses performed. Further conclusive evidence that interventional techniques are effective in preventing amputation was reported in an analysis of major amputation rates from our own institution over a 16-year period.[1] In this study of all patients with limbs threatened because of arteriosclerotic ischemia, primary amputation rates fell from 41 to 7% over the 16 years (Fig. 3123). This was an index of increasing operability as our ability to perform bypasses to ever more distal and disadvantaged outflow tracts increased. Fewer than 1% of patients were inoperable because of the pattern of their arterial disease. Over the same period, secondary amputations were also decreasing (Fig. 31-23), so that we were not, by our aggressive use of bypass operations, merely converting primary amputations to secondary procedures. Most importantly, total major amputation rates fell from 49 to 14%, showing conclusively that our limb salvage efforts were effective in preventing amputations—usually until the patient died from a cause other than the threatened limb or the procedure employed to save it (Figs. 31-22 and 31-23).[1,2]
Economic Impact of Limb Salvage The dollar cost of an aggressive approach to salvage limbs is high, with a mean expense of $19,000 for femoropopliteal bypasses and $29,000 for small-vessel bypasses. These figures include all physician, hospital, and rehabilitation costs, including those of reoperations. On the other hand, the mean total cost of below-knee amputation, which in 26% of our patients resulted in failed rehabilitation with a need for chronic institutional care or professional assistance at home, was $27,000. Thus, limb salvage surgery is expensive, but no more so than the less attractive alternative of amputation.[116,117]
NEW DEVELOPMENTS Clearly all the principles and practices outlined thus far describe our attitudes toward the treatment of a complex
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Figure 31-23. Amputation rates in all patients with threatened limbs. Primary amputations were those at the above-knee or below-knee levels without previous vascular interventions. Secondary amputations were major amputations performed any time after an arterial intervention. Total amputations were all major amputations. (From Veith et al.[1] Reproduced by permission.)
disease process. As we have tried to point out, many of these attitudes are controversial. More importantly, they are all in a state of constant evolution. As more data and newer methodology become available, our attitudes and those of others interested in the problems of femoral-popliteal-tibial arteriosclerosis should and will change. In this section we will describe briefly some of the new developments that are most likely to lead to further therapeutic improvements.
Improvements in Diagnostic Techniques Noninvasive arterial evaluations including duplex scanning[118] and magnetic resonance angiography (MRA)[22,23] are rapidly improving and may become the initial diagnostic modality for patients with aortoiliac and infrainguinal aneurysmal and occlusive disease, but further refinements need to occur before these techniques completely replace diagnostic arteriography. Intravascular ultrasound (IVUS) is another diagnostic modality being developed to better assess the extent of arterial disease and to evaluate immediate results after endovascular interventions.[119,120]
Improvements in Endovascular Devices Angioplasty has been successfully used for the treatment of stenotic iliac lesions, and the results have improved further with use of intravascular stents.[121] The role of infrainguinal angioplasty has been limited, and to date the use of stents has not significantly improved results. However, stents are being used for selected lesions in the femoral and popliteal arterial segments. Atherectomy has been successfully used in the coronary circulation, but the results for infrainguinal disease to date have been very poor.[122,123] A further development is the use of endovascular grafts. These have been successfully used for the treatment of a variety of arterial lesions with early and midterm success.[124] The role of these envolving technologies for the treatment of infrainguinal disease is still unclear.
New Developments in Tibial and Pedal Bypasses Over the last 12 years, because of some of the promising results already discussed, we have been evaluating other procedures to simplify or extend the limits of operability for limb salvage. Tibiotibial bypasses are an extension of our concept of using more distal arteries as bypass origins than were previously thought optimal.[32,33] All these distal origin procedures allow shorter segments of saphenous vein to be used, shorten operative time, and avoid dissection in obese or infected groins, and they may have superior patency. We have now performed more than 200 distal vein bypasses to the lower third of the leg or foot using the infrapopliteal (tibial arteries) as inflow sites, and many of these grafts remained patent more than 4 years. Small-vessel bypasses to blind tibial artery segments have also been performed in some patients facing imminent amputation. These operations have been done in patients in whom no other procedures were possible because of the arterial anatomy or local infection in the foot. Several of these bypasses have remained patent over 2 years, and many otherwise unsalvageable limbs have been saved.[33] Use of heavily calcified tibial arteries for distal bypass insertion sites has been possible with a variety of techniques that include intraluminal occlusion and sometimes even gentle crushing of the involved artery to permit incision and suture placement. Acceptable early and midterm patency rates resulted.[36] Small-vessel bypasses to plantar and tarsal arterial branches can be achieved successfully in patients with patent pedal arches with acceptable long-term patency and excellent limb salvage results.[33]
Minimally Invasive Adjunctive Techniques for Lower Extremity Vein Bypasses Less invasive techniques are being developed for the performance of in situ and reversed saphenous vein bypasses.
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The use of long flexible valvulotomes, angioscopic visualization,[125] coil occlusion techniques for side branches,[126] and subcutaneous vein dissection and harvesting[127] may allow the performance of these lower extremity bypasses through minimal incisions, allowing diminished pain, fewer local wound complications, and decreased hospital stays for some patients.
Intraoperative Adjunctive Techniques and Procedures The intraoperative use of fluoroscopy has added a new dimension to the options of the vascular surgeon. Diagnostic
arteriography can be performed before and after a bypass procedure. Graft and arterial thrombectomies can be performed using catheter-guidewire techniques to improve success and safety.[73] The greater saphenous vein can be evaluated for in situ bypasses. Proximal and distal arterial lesions can be treated using balloon angioplasty[127] with or without the addition of intravascular stents. Finally, it allows the performance of complex procedures, like endovascular grafting, that require the combined use of interventional and standard surgical techniques.[124] In addition, angioscopy, duplex scanning, and intravascular ultrasound are being increasingly used to improve the results of intraoperative procedures.
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Mannick, J.A.; Jackson, B.T.; Coffman, J.D.:. Success of Bypass Vein Grafts in Patients with Isolated Popliteal Artery Segments. Surgery 1967, 61, 17. Veith, F.J.; Gupta, S.K.; Daly, V. Femoropopliteal Bypass to the Isolated Popliteal Segment: Is Polytetrafluoroethylene Graft Acceptable? Surgery 1981, 89, 296. Kram, H.B.; Gupta, S.K.; Veith, F.J.; et al. Late Results of 217 Femoropopliteal Bypasses to Isolated Popliteal Segments. J. Vasc. Surg. 1991, 14, 386. Flinn, W.R.; Flanigan, D.P.; Verta, M.J.; et al. Sequential Femoral-Tibial Bypass for Severe Limb Ischemia. Surgery 1980, 88, 357. Rutherford, R.B.; Flanigan, D.P.; Gupta, S.K.; et al. Suggested Standards for Reports Dealing with Lower Extremity Ischemia. J. Vasc. Surg. 1986, 4, 90. Ascer, E.; Veith, F.J.; Morin, I.; et al. Components of Outflow Resistance and Their Correlation with Graft Patency in Lower Extremity Arterial Reconstructions. J. Vasc. Surg. 1984, 1, 817. Veith, F.J.; Ascer, E.; Gupta, S.K.; et al. Tibiotibial Vein Bypass Grafts: A New Operation for Limb Salvage. J. Vasc. Surg. 1985, 2, 552. Ascer, E.; Veith, F.J.; Gupta, S.K. Bypasses to Plantar Arteries and Other Libial Branches: An Extended Approach to Limb Salvage. J. Vasc. Surg. 1988, 8, 434. Veith, F.J.; Gupta, S.K.; Samson, R.H.; et al. Superficial Femoral and Popliteal Arteries as Inflow Site for Distal Bypasses. Surgery 1981, 90, 980. Wengerter, K.R.; Yang, P.M.; Veith, F.J.; et al. A TwelveYear Experience with the Popliteal-to-Distal Artery Bypass: The Significance and Management of Proximal Disease. J. Vasc. Surg. 1992, 15, 143. Veith, F.J.; Moss, C.M.; Daly, V.; et al. New Approaches in Limb Salvage by Extended Extraanatomic Bypasses and Prosthetic Reconstructions to Foot Arteries. Surgery 1978, 84, 764. Ascer, E.; Veith, F.J.; Gupta, S.K. Axillopopliteal Bypass Grafting: Indications, Late Results, and Determinants of Long-Term Patency. J. Vasc. Surg. 1989, 10, 285. Towne, J.B.; Bernhard, V.M.; Rollins, D.L.; Baum, P.L. Profundaplasty in Perspective: Limitations in the LongTerm Management of Limb Ischemia. Surgery 1981, 90, 1037. Campbell, C.D.; Brook, D.H.; Webster, M.W.; et al. Expanded Microporous Polytetrafluoroethylene as a Vascular Substitute: A Two-Year Follow-Up. Surgery 1979, 85, 177. Veith, F.J.; Moss, C.M.; Fell, S.C.; et al. Comparison of Expanded Polytetrafluoroethylene and Autologous Saphenous Vein Grafts in High Risk Arterial Reconstructions for Limb Salvage. Surg. Gynecol. Obstet. 1978, 147, 749. Gupta, S.K.; Veith, F.J. Three Year Experience with Expanded Polytetrafluoroethylene Arterial Grafts for Limb Salvage. Am. J. Surg. 1980, 140, 214. Veith, F.J.; Gupta, S.K.; Ascer, E.; et al. Six Year Prospective Multicenter Randomized Comparison of Autologous Saphenous Vein and Expanded Polytetrafluoroethylene Grafts in Infrainguinal Arterial Reconstructions. J. Vasc. Surg. 1986, 3, 104. Quinones-Baldrich, W.J.; Busuttil, R.W.; Baker, J.D.; et al. Is the Preferential Use of Polytetrafluoroethylene Grafts
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77. Sanchez, L.A.; Goldsmith, J.G.; Rivers, S.P.; et al. Limb Salvage Surgery in End Stage Renal Disease: Is It Worthwhile? J. Cardiovasc. Surg. 1992, 33, 344. 78. Veith, F.J.; Gupta, S.K.; Daly, V. Management of Early and Late Thrombosis of Expanded Polytetrafluoroethylene (PTFE) Femoropopliteal Bypass Grafts: Favorable Prognosis with Appropriate Reoperation. Surgery 1980, 87, 581. 79. Veith, F.J.; Gupta, S.K.; Ascer, E.; et al. Improved Strategies for Secondary Operations on Infrainguinal Arteries. Ann. Vasc. Surg. 1990, 4, 85. 80. Veith, F.J.; Ascer, E.; Nunez, A.; et al. Unusual Approaches to Infrainguinal Arteries. J. Cardiovasc. Surg. 1987, 28, 58. 81. Nunez, A.; Veith, F.J.; Collier, P.; et al. Direct Approach to the Distal Portions of the Deep Femoral Artery for Limb Salvage Bypasses. J. Vasc. Surg. 1988, 8, 576. 82. Veith, F.J.; Ascer, E.; Gupta, S.K.; Wengerter, K.R. Lateral Approach to the Popliteal Artery. J. Vasc. Surg. 1987, 6, 119. 83. Dardik, H.; Dardik, I.; Veith, F.J. Exposure of the TibialPeroneal Arteries by a Single Lateral Approach. Surgery 1974, 75, 372. 84. Ascer, E.; Collier, P.; Gupta, S.K.; Veith, F.J. Reoperation for PTFE Bypass Failure: The Importance of Distal Outflow Site and Operative Technique in Determining Outcome. J. Vasc. Surg. 1987, 5, 298. 85. O’Mara, C.S.; Flinn, W.R; Johnson, N.D Recognition and Surgical Management of Patent but Hemodynamically Failed Arterial Grafts. Ann. Surg. 1981, 193, 467. 86. Veith, F.J.; Weiser, R.K.; Gupta, S.K.; et al. Diagnosis and Management of Failing Lower Extremity Arterial Reconstructions. J. Cardiovasc. Surg. 1984, 25, 381. 87. Whittemore, A.D.; Clowes, A.W.; Couch, N.P.; Mannick, J.A. Secondary Femoropopliteal Reconstruction. Ann. Surg. 1981, 193, 35. 88. Berkowitz, H.D.; Hobbs, C.L.; Roberts, B.; et al. Value of Routine Vascular Laboratory Studies to Identify Vein Graft Stenosis. Surgery 1981, 90, 971. 89. Sanchez, L.; Gupta, S.K.; Veith, F.J.; et al. A Ten-Year Experience with One Hundred Fifty Failing or Theatened Vein and Polytetrafluoroethylene Arterial Bypass Grafts. J. Vasc. Surg. 1991, 14, 729. 90. Smith, C.R.; Green, R.M.; DeWeese, J.A. Pseudoocclusion of Femoropopliteal Bypass Grafts. Circulation 1983, 68 (Suppl. II), 88. 91. Bandyk, D.F.; Cata, R.F.; Towne, J.B. A Low Flow Velocity Predicts Failure of Femoropopliteal and Femorotibial Bypass Grafts. Surgery 1985, 98, 799. 92. Bandyk, D.F.; Bergamini, T.M.; Towne, J.B.; et al. Durability of Vein Graft Revision: The Outcome of Secondary Procedures. J. Vasc. Surg. 1991, 13, 200. 93. Sanchez, L.A.; Suggs, W.D.; Marin, M.L.; et al. Is Percutaneous Balloon Angioplasty Appropriate in the Treatment of Graft and Anastomotic Lesions Responsible for Failing Vein Bypasses? Am. J. Surg. 1994, 168, 97. 94. Samson, R.H.; Sprayregen, S.; Veith, F.J.; et al. Management of Angioplasty Complication, Unsuccessful Procedures and Early and Late Failures. Ann. Surg. 1984, 199, 234.
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CHAPTER 32
In Situ Saphenous Vein Arterial Bypass Robert P. Leather Dhiraj M. Shah R. Clement Darling III Benjamin B. Chang Philip S. K. Paty Paul B. Kreienberg procedure was practical only because most of the operations were carried out to the above-knee popliteal artery with veins of large size. By 1973, Hall[8] had developed an instrument for serial transluminal retrograde valve disruption, as had Cartier[9] and Samuels.[10] Valve excision has now been largely abandoned, as has the method of prograde blind blunt valve fracture.[11] However, a continuing experience with retrograde valve disruption using the instruments of Hall and Cartier has accumulated in Europe.[12 – 14] These instruments appear to have two serious disadvantages. The first is that blunt avulsion of the valve leaflets may cause serious damage to the adjacent vein wall. The second is that both instruments must be introduced and withdrawn through the distal divided end of the vein, which invariably has the smallest diameter and is most prone to spasm. Both factors thus combine to produce the greatest potential for the most devastating injury to the vein wall, i.e., circumference endothelial avulsion. These limitations preclude the successful use of these instruments in veins less than 4 mm in diameter. Valve incision achieves the goal of an efficient and minimally traumatic method of producing valvular incompetence by division of valve leaflets in their major axes while they are in the functionally closed position.
INTRODUCTION The removal of a venous conduit from its bed subjects it to the cumulative injurious effects of surgical manipulation, transmural warm ischemia, contact with nonhemic solutions, and hydrostatic dilatation.[1] With the rapid increase in aortocoronary and infrainguinal vein grafting as the stimulus for the evaluation of these injuries,[2,3] it has now been shown that there is widespread destruction of the endothelium with alterations in normal prostacylin and thromboxane production, thus producing a relatively thrombogenic surface. Furthermore, the rate of degeneration in such veins appears to be inversely related to the subsequent rate of flow.[4] All these factors may contribute to the initial failure rate of these bypass conduits, particularly when the outflow tracts are limited.[5] Although the most recent methods of preparing excised vein grafts have been directed toward the prevention of these injuries,[6] none is perfect. At present we believe that the closest approximation to an ideal conduit (i.e., one with normal, viable, physiologically functioning endothelium and a natural taper) is a vein that has been retained in situ and is minimally damaged during its preparation for bypass.
HISTORY OF IN SITU VEIN BYPASS TECHNIQUES
PREOPERATIVE SAPHENOUS VEIN ANATOMY
In 1962, Hall[7] published a preliminary report of successful in situ vein bypasses done by the method of valve excision through transverse venotomies. This necessarily tedious
An invaluable aid to all saphenous vein operations and in situ techniques in particular has been the preoperative definition
Hobson/Wilson/Veith: Vascular Surgery: Principles and Practice, Third Edition, Revised and Expanded DOI: 10.1081/0819-9-120024915 Copyright q 2004 by Marcel Dekker, Inc.
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of the anatomy of the greater saphenous vein, previously by phlebography and, at present, by duplex Doppler ultrasound.[15 – 17] With the patient standing, the position of the saphenous vein should also be marked before operation by inducing a pressure wave distally. This is done by tapping or brushing the distended vein and detecting its propagation digitally or by Doppler ultrasound methods. Surface duplex mapping of the saphenous vein has been found to be an effective and noninvasive method of determining the venous anatomy provided that the procedure is performed by an experienced technician. This method provides a detailed three-dimensional map of the course of the saphenous vein, which may be traced onto the overlying skin. This map aids in the placement of skin incisions and the location of venous access points for instrumentation (Fig. 32-1). During the past 15 years, we have utilized B-mode imaging to preoperatively assess and map the greater saphenous vein in more than 10,000 limbs.[18,19] With the patient’s limb in a dependent position, the greater saphenous vein is marked on the overlying skin for its entire course from the saphenofemoral junction to the level of the medial malleolus. All branches, especially deep perforators, are noted. The internal diameter of the vein is measured at both the upper and lower thigh and calf. Diameter measurements are also made of any double systems to determine which is dominant. Valves are easily detected, but their positions are not marked unless they are stenotic or abnormal. If there is a
complex system or B-mode imaging is felt to be otherwise inadequate or in question, the patients then undergo phlebography. However, our results demonstrate that in over 90% of patients B-mode imaging is the optimal technique of venous assessment. In the patients in whom complex systems are encountered, phlebography may be utilized since it provides additional information for accurate planning of the procedure. In spite of these considerations, many surgeons remain resistant to these preoperative assessments, preferring to determine anatomic variations at operation. However, such attempts to define anatomic variations surgically may be frustrating and ineffective and may result in inappropriate excessive dissection, increasing the potential for significant spasm, postoperative wound complications, and other forms of injury to the vein that can lead to failure and abandonment of the procedure.
SURGICAL TECHNIQUE After sterile preparation and draping of the entire extremity, warm (378C) papaverine solution 1 mg/mL N.S. is injected percutaneously into the subcutaneous tissue adjacent to the saphenous vein along its course below the knee. The proximal saphenous vein, which lies immediately deep to the superficial fascia, is then exposed, and additional papaverine
Figure 32-1. Duplex “vein map” illustrating a double saphenous system. It is important to remember that the diameter measured by duplex is an internal dimension (ID) under relatively low venous pressure, whereas surgeons are accustomed to gauging its attributes as a conduit in terms of outside (external) diameter (OD) when under arterial pressure.
Chapter 32.
solution is infiltrated into the surrounding tissue to minimize spasm. Although the common femoral artery has been considered the proper site for proximal anastomosis of all distal bypasses, there is evidence that use of the superficial femoral artery in the limb-salvage patient population is equally satisfactory. Furthermore, technical circumstances such as a previous surgical scar or exposure of the common femoral artery or its involvement with circumferential calcification may make either the deep femoral (profunda femoris) or the superficial femoral artery a better alternative inflow source.[20,21] Offsetting its less accessible anatomic location, the deep femoral artery is usually less invested with thick, calcified plaque than either the common or superficial femoral artery and, therefore, frequently provides the most satisfactory site for proximal anastomosis. It is best approached from the medial aspect (with the surgeon on the opposite side of the table) by incision of the subcutaneous tissue immediately lateral to the saphenous vein and down to the underlying investing myofascia (Fig. 32-2). Dissection laterally in this fusion plane to the superficial femoral artery is bloodless. The fascia is incised over the superficial femoral artery, and, if it is occluded, a segment of 3–5 cm can be excised, thus facilitating exposure of the deep femoral artery. If patent, a plane is developed between the femoral vein and the superficial femoral artery. The lateral circumflex femoral vein is divided, exposing the proximal deep femoral artery which lies immediately deep to it (Fig. 32-3). Having determined the most satisfactory site of proximal anastomosis, the length of the proximal saphenous vein required to reach it is apparent. If the common femoral artery is to be used as the inflow source, a complete dissection of the saphenous bulb and secure ligation of its branches is performed. If additional length is required to facilitate anastomosis to the common femoral artery, a portion of the anterior aspect of the common femoral vein is removed in continuity with the saphenous bulb. The valve leaflets at the saphenofemoral junction are excised, removing only the transparent portion, leaving the usually prominent insertion ridge intact. The second valve invariably present 3–5 cm distal to this can be incised easily with a retrograde valvulotome through a side branch distal to the valve before the vein is divided or alternatively cut either with scissors or an antegrade valvulotome through the open end of the vein, as is the valve immediately distal to the medial accessory branch. These valves are identified by gently distending the vein through its open end with dextran or heparinized blood and are cut with scissors with the thumb and index finger around the shank of the scissors while the valve is held in the functionally closed position by fluid trapped between the open end of the saphenous vein and the valve (Fig. 32-4). The plane of closure of the valve cusps is invariably parallel to the skin. This dictates the orientation of all instruments with relation to the valve cusps. If a valve cutter cannot be used, the location of the next valve site is determined by advancing a No. 6 F catheter, with the infusion solution running through it under 200 mmHg pressure, until it impacts in the valve sinus. This valve location is marked on the adjacent skin before the proximal anastomosis is carried out.
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Figure 32-2. Proximal and distal incisions will be used for the in situ bypass. The proximal incision (inset) will start approximately at the level of the femoral-artery bifurcation and will continue directly over the medial course of the great saphenous vein. The distal incision will be made later in the operation. (Illustration by William, B.; Westwood, M.S., AMI, copyright 1993.)
If the valve cutter is to be used, a 3- to 5-cm-long incision is made 5 mm posterior to the marked position of the main saphenous vein below the knee, identifying a branch previously localized by Duplex scan or venogram, and using it to gain access to the lumen of the saphenous vein. A No. 3 Fogarty catheter is introduced into the saphenous vein through this side branch and passed proximally, with the leg straightened, to exit through the open end of the vein. The catheter is then divided at an acute angle at the 20 or 30 cm mark, whichever is closest to the open end of the vein. The valve cutter (2 or 3 mm) is screwed onto the catheter and a 6 F or 8 F infusion catheter is then secured to the cutter with a loop of fine suture (Fig. 32-3). The leading cylinder of the valve cutter is drawn back into the open proximal end of the saphenous vein, partially obstructing venous flow while permitting visualization of the cutting blade and minimal resistance to torque. This allows precise orientation of the cutting edges at 90 degrees to
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Figure 32-3. A 3- to 5-cm segment of the deep femoral artery has been mobilized, and a vessel loop is used to estimate the length of vein necessary for the proximal anastomosis. A portion of the great saphenous vein 2 cm longer than the 5- to 7-cm length required for anastomosis will be dissected free, clipped, and divided at the saphenofemoral junction. (Illustration by William, B.; Westwood, M.S., AMI, copyright 1993.)
Figure 32-4. Valve incision scissors are inserted into the great saphenous vein, and the nearer valve leaflets are incised perpendicular to their plane of closure. The valves along the remaining bypass segment of the vein will be divided with the valve cutter or the retrograde valvulotome. (Illustration by William, B.; Westwood, M.S., AMI, copyright 1993.)
the plane of closure of the valves, that is, to the plane of the overlying skin surface (Fig. 32-5). The catheter-cutter assembly is then drawn slowly distally while the dextran solution or blood is introduced through the catheter at 200 – 300 mmHg pressure, sealing leakage from the end of the vein
by a 1 mm Silastic (polymeric silicone) “vessel loop” secured by a small hemostat near its end (Fig. 32-4). This pressurized fluid column in the proximal vein snaps each successive valve into the closed position so that the cusps can be efficiently engaged by the blades of the cutter. A slight but definite
Chapter 32.
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489
Figure 32-5. The leading cylinder of the cutter has been drawn partway into the vein to limit blood loss, and a No. 6 or 8 infusion catheter is attached with a suture loop to the opposite end. (Illustration by William, B.; Westwood, M.S., AMI, copyright 1993.)
resistance is felt as the cutter encounters each valve and cuts the leaflets. Greater resistance than this should be managed by axially rotating the cutter 45 degrees and making another attempt at advancement. If this does not produce the desired result, the cutter should be withdrawn, dismounted, and the area of impaction exposed directly by a longitudinal incision. The cutter is advanced through a safe distance, predetermined by duplex scanning or venogram generally to the knee-joint level, and is then withdrawn again to the femoral exposure. Here the cutter is dismounted and the catheter removed from the saphenous vein. Proximal anastomosis of the saphenous vein to the selected inflow artery is performed using a “no-touch” technique (Fig. 32-5) and the palpable pulsatile impulse thus provided makes the location of the next competent valve readily apparent (Fig. 32-6). The remaining valves are incised by a retrograde valvulotome introduced through a side branch or the distal end of the vein. Prior to the use of this instrument any narrowing due to spasm should be dilated with controlled pressure of 200 mmHg. In passing the valvulotome intraluminally to and from a valve site, it is important that any pressure on the vein wall resulting from its curving path be exerted on the shaft of the instrument rather than the projecting blade tip. This lessens the likelihood of the blade becoming lodged in the side branch and lacerating the vein wall when being withdrawn. This instrument is so designed that it engages a leaflet, centers itself, and cuts the leaflet in its longitudinal axis. It is then readvanced, carefully rotated through 180 degrees, and withdrawn, thus engaging the remaining leaflet (Fig. 32-7). However, before the cutting force is applied to the tip of the valvulotome, it should be maneuvered toward the center of the vein lumen by finger depression of the vein itself, allowing division of the remaining leaflet without the risk of entering a side branch, which is invariably present on the posterior wall close to every valve sinus. Unobstructed pulsatile arterial flow is thus brought down to the desired level adjacent to the proposed distal
anastomosis. Before transection and mobilization of the distal vein, exposure of the anticipated outflow anastomotic site is carried out. This sequence is desirable not only to minimize the warm ischemia time of the endothelium, but also to assess the appropriate length required, always allowing an additional 1–2 cm so that the manipulated (and thus traumatized) terminal segment can be excised and discarded. After completion of the distal anastomosis, adequate flow in the bypass as well as the outflow vessel is confirmed with a quantitative appraisal made by the use of the sterile Doppler ultrasonic probe. A completion angiogram is then performed with radiopaque reference markers (19-gauge needles in their plastic containers attached to the skin by sterile adhesive strips, a radiologic strip marker, or skin clips) to correlate roentgenographic position of any residual A-V fistulas with the surface anatomy.
TECHNICAL REQUIREMENTS OF IN SITU BYPASS Efficient atraumatic functional destruction of the valves which obstruct arterial flow is both the most important and most difficult technical maneuver associated with the procedure. The vein may have a number of valves, ranging from 3 to 13, although the usual number for a proximal tibial bypass is between 5 and 7. Valve incision is an efficient technique for rendering the valves incompetent, and the instruments described have increased the ease and speed with which the operation can now be performed.[22] Careful follow-up has shown that the incised valve is neither a source of microemboli nor a frequent site of later pathologic degeneration. To better understand the problems encountered with valve incision, it is important to have a clear concept of venous valve function. The normal closing mechanism in a symmetrical venous valve is initiated by tension along
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Figure 32-6. (A) The vein is partially divided with a no. 11 scapel. A “handle” is retained to allow traction on the vein. (B) Proximal anastomosis of the bypass vein to the deep femoral artery is carried out by the “open parachute” technique, which allows for accurate and atraumatic placement of each individual suture in the heel portion of the anastomosis. A single, double-needle suture of 7-0 prolene is used. (C) After placement of as many sutures as the length of suture material allows, the vein is drawn down to the artery. The “handle” will be excised. (D) Arterialization of the saphenous vein is completed by continuing the medial suture line clockwise around the end of the arteriotomy to meet the lateral suture line at the midpoint of the arteriotomy. (Illustration by William, B.; Westwood, M.S., AMI, copyright 1993.)
Chapter 32.
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491
steady, undiminished pulsatile flow, it is unlikely that such a lesion is present proximally.
VENOUS SPASM
Figure 32-7. Before any intraluminal instrumentation is carried out, the mobilized segment of vein is dilated with a dextran solution at a controlled pressure of 200 mmHg. (A) A retrograde valvulotome is introduced through the distal end of the vein, and as it is withdrawn, it cuts one valve leaflet. (B) It is readvanced, rotated 180 degrees, and again withdrawn, cutting the second leaflet. (Illustration by William, B.; Westwood, M.S., AMI, copyright 1993.)
the leading edge of the valve leaflet caused by expansion of the valve sinus as intraluminal pressures are raised. This brings the edge of the leaflet toward the center of the lumen, where flow forces it into a closed, competent position. In any segment of vein where a valve is mechanically opened from below by passage of any instrument (e.g., a valvulotome or catheter) in the proximal direction, the potential exists for a valve leaflet to be pushed against the wall and to remain temporarily against it in an open position. This is most likely to occur in asymmetrical valves. In such valves, the normal closing mechanism may not be operative so that the valve may remain open for an indefinite period. The subsequent closure of the artificially opened valve leaflet, either spontaneous or induced by manipulation (for example, palpation of the pulse in this segment) results in the partial or even complete obstruction of arterial flow. Therefore, before the distal anastomosis is performed, deliberate attempts should be made to precipitate closure of any incompletely lysed valves by the following maneuver. With the distal vein open and free flow observed, or high flow via a fistula distally, a sponge is rolled along the in situ conduit from top to bottom. When the valve cutter is used, the most frequent location of a missed valve is in the segment immediately distal to the point of the lowest cutter travel, at the level of exposure of the vein. This segment should be checked routinely with the valvulotome because, in the absence of flow, an undiminished pulse can be transmitted through an intact valve held in a static column of blood. The simple expedient of assessing flow from the distal divided end of the saphenous vein before construction of the distal anastomosis is very reliable in detecting any proximal hemodynamically significant obstructive lesions. If there is
Spasm of the saphenous vein is a well-known phenomenon. In excised veins, hydraulic dilatation provides a permanent solution, but the in situ vein retains its neuromuscular activity and thus its propensity for spasm. At present, there is no means of determining which patient or vein will exhibit this behavior. All veins are prone to spasm to some degree, but in general this is more prevalent and difficult to manage in smaller veins (i.e., below 3 mm). It is better to prevent venous spasm by minimizing surgical handling and using topical antispasmodic drugs (e.g., papaverine) and controlled intraluminal pressure than to correct it after it occurs.[23] Apart from its deleterious effect on endothelium and blood flow, spasm also makes intraluminal instrumentation dangerous because it increases endothelial abrasion.
ARTERIOVENOUS FISTULAS Most branches of the saphenous vein drain superficial subcutaneous tissues, and their orifices are generally guarded by a competent valve, thus preventing flow away from the arterialized saphenous vein. Only valveless branches immediately become arteriovenous fistulas. However, these branches are usually small and generally undergo spontaneous thrombosis postoperatively. This event is signaled by the development of a superficial phlebitis, the extent of which is determined by the size of this iatrogenic A-V fistula. Although occasionally a large area of induration results, it is sterile and self-limiting, and it usually resolves within a few days. Even if such superficial veins remain patent, the loss of distal arterial flow is generally small and does not threaten the continued patency of a bypass. As a rule, only branches with sufficient flow to visualize the deep venous system with radiopaque dye on the completion angiogram need be ligated. The effects of A-V fistulas on in situ saphenous vein bypass hemodynamics and patency has been of great concern to some, even to the point of regarding these as a frequent cause of in situ bypass occlusion. For more than 10 years, following the observation that most of the residual subcutaneous iatrogenic A-V fistulas undergo spontaneous thrombosis, it has been our practice to ligate only fistulas that conduct enough dye on completion angiography to visualize the deep venous system. We have studied more than 600 such bypasses longitudinally using duplex ultrasonic scanning to assess overall hemodynamic function. The results indicate a steady reduction in fistula flow with time, with no overall effect on distal perfusion (Fig. 32-1). There is a small group of patients in whom high fistula flow is poorly tolerated, usually those with limited flow due to proximal stenosis or a small vein (less than 3-mm OD). However, in most (other) patients, the flow capacity of the in situ conduit far exceeds the volume demanded by a fistula and provides adequate, undiminished distal perfusion.
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The allegation that fistulas are a potential cause of occlusive bypass failure is not supported by our experience. The probable cause of failure in this setting is endothelial injury in the distal vein, the portion of the in situ conduit proximal to the fistula remaining patent because of flow down through the fistula. Therefore, we regard fistulas as, at most, an annoyance to the patient and the surgeon, but not as a potential cause of thrombosis of the bypass.
RESULTS Among 4344 distal arterial reconstructions for limb salvage, 2613 were performed in situ in toto. In addition 136 were completed with short segment of harvested vein (partial in situ bypass). In 965 limbs the vein had been harvested or previously used. In 311 limbs the vein was spared for later use. Life-table analysis of secondary patency of bypasses for limb salvage to the popliteal level (up to the date of this writing) is shown in Table 32-1 and to the infrapopliteal level in Table 32-2. Early detection of stenoses and correction of defects with in situ conduits before occlusion occurs is now achieved by a comprehensive surveillance program. Our patients are seen and examined every 3–4 months up to the second year, and every 6 months thereafter. Each examination includes pulse volume recordings and segmental pressures and audible Doppler assessment along the course of the bypass. Direct visualization of the conduit and estimates of volume flow by duplex ultrasonic scanning, both at rest and after reactive hyperemia induced by 3 minutes of tourniquet occlusion, have recently been used and evaluated. Among 2613 in situ conduits constructed, 133 stenotic lesions developed in 109 patients. More than 62% of these were discovered within the first 12 months (82/133). Forty occurred in the distal mobilized segment, 52 were present in the proximal mobilized segment, and 41 in the midportion of the bypass conduit—an even distribution. Stenotic lesions tended to occur with increased frequency in smaller veins [52 (7%) occurring in 769 veins of 3.0 mm or less as compared Table 32-1.
Secondary Patency Popliteal In Situ Bypasses
for Salvage Interval
At risk
Occlusions
Int patency
Cum patency
0 –1 2 –12 13– 24 25– 36 37– 48 49– 60 61– 72 73– 84 85– 86 97– 108 109– 120 121– 132
728 611 371 280 193 150 116 90 76 61 46 28
32 24 13 3 9 1 5 1 0 4 0 1
0.953 0.952 0.961 0.987 0.949 0.993 0.953 0.988 1.000 0.928 1.000 0.960
0.953 0.908 0.872 0.861 0.817 0.811 0.773 0.763 0.763 0.708 0.708 0.680
Table 32-2. Secondary Patency Infrapopliteal In Situ Bypasses for Salvage Interval
At risk
Occlusions
Int patency
Cum patency
0 –1 2 –12 13–24 25–36 37–48 49–60 61–72 73–84 85–96 97–108 109– 120 121– 132
1885 1549 881 579 401 285 212 153 110 85 64 40
71 73 26 19 12 5 3 6 4 0 5 1
0.959 0.942 0.965 0.962 0.966 0.980 0.984 0.955 0.960 1.000 0.908 0.971
0.959 0.904 0.872 0.839 0.810 0.794 0.781 0.746 0.716 0.716 0.650 0.632
with 79 (4%) in 1795 veins of 3.5 mm or larger]. All of these stenoses were treated operatively, and all but 4 remained patent beyond 30 days. In addition there were 121 residual AV fistulas that required ligation under local anesthesia 3 days to 128 months after the initial procedure (5%). Finally, there were 103 occlusions within 30 days (immediate patency rate 96%) and 99 deaths within the same period (operative mortality 3.8%).
PERSPECTIVE Initially, the results of our prospective randomized study indicated the superiority of in situ vein bypass over reversed vein grafts.[23] With recent reports of improved patency rates using reversed vein grafts,[24] the question has again been raised as to whether the in situ vein bypass is superior to the reversed vein bypass at all levels. However, 75% of bypasses in this reported series were short bypasses. Other recent prospective randomized[25 – 27] and nonrandomized[28] comparison studies did not demonstrate any difference in performance between in situ and reversed vein bypasses. These studies were done using techniques that may render venous injuries, mostly for popliteal bypasses, and had patency rates much lower that those reported in recent major series of in situ bypasses.[29 – 31] These instruments (e.g., Hall, Cartier, LeMaitre, Bush) all use a cylindrical disruptor/cutter introduced retrogradely. Injury to the endothelial monolayer is produced by the passage of these instruments along the wall of the distal, smaller end of the saphenous vein. Thus, results with these instruments are satisfactory only in a high-flow situation (i.e., femoropopliteal) with larger ($4 OD) veins. When applied to smaller veins going to more distal tibial or pedal arteries, the importance of this degree of endothelial injury increases. In distal bypasses, with their inherently lower flow volumes and velocities, these instruments exhibit a high 30-day failure rate (, 20%).[32] Currently, a multicenter prospective randomized study[33] reports no difference in overall patency rates for long tibial bypasses between in situ and reversed vein bypasses. This study has a small number of
Chapter 32.
cases for each center and patency rates are also low. In addition, 15% of veins were deemed inadequate suggesting selection bias to larger veins. In spite of these shortcomings, this study shows that in situ bypasses are superior to reversed vein bypasses for small (, 4.0 mm OD) veins, although this difference is not yet statistically significant.[33] Indirect evidence of in situ bypass superiority is its patency which is insensitive to length, whereas it is generally accepted that harvested vein bypass patency is clearly inversely proportioned to length (shorter is better). Our technical methodology for performing the in situ bypass has been developed with the primary goal of universal application. An in situ bypass can be performed by this technique in virtually all cases, regardless of the vagaries of venous anatomy, while minimizing the extent of exposure of the vein necessary for consistently safe and atraumatic valve incision. The high incidence of venous anomalies (up to 30% of double systems) and smaller veins distally (greater than 50%, , 3.5-mm OD) makes the use of a cylindrical transluminal retrograde valve disruptor such as the Hall, Cartier, or LeMaitre strippers hazardous. To date, the in situ vein arterial bypass seems to be
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the best conduit for long bypasses to distal arteries particularly with small diameter veins. Use of an angioscope in performing in situ bypass has its enthusiasts and is industry driven.[34,35] This new technology demands accommodation and training with a new instrumentation that requires not only a large initial investment ($60,000 to $75,000), but an ongoing disposable/replacement expense (, $1,000/case). Although application of this approach produces comparable results, our experience with the method, which evolved in Albany and is essentially unchanged in over a decade, is that it is simpler, safe, and reliable with all anatomic venous variations. Clearly, problems with rendering the valves fully incompetent while at the same time not injuring the wall of the vein or its endothelium have discouraged some from using in situ techniques. So also have difficulties in locating and controlling arteriovenous fistulas. Nevertheless, we believe that the potential benefits of in situ vein bypasses outweigh the disadvantages of having to master critical new operative techniques to overcome the difficulties associated with their use.
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20. Darling, R.C., III.; Shah, D.M.; Chang, B.B.; Lloyd, W.E.; Leather, R.P. Can the Profunda Femoris Artery Reliably Be Used as an Inflow Source for Infrainguinal Reconstructions? Long Term Results in 563 Patients. J. Vasc. Surg. 1994, 20, 889– 895. 21. Veith, F.J.; Gupta, S.K.; Samson, R.H.; et al. Superficial Femoral and Popliteal Artery as Inflow Sites for Distal Bypass. Surgery 1981, 90, 980. 22. Leather, R.P.; Shah, D.M.; Corson, J.D.; Karmody, A.M. Instrumental Evolution of the Valve Incision Method of In Situ Saphenous Vein Bypass. J. Vasc. Surg. 1984, 1, 113. 23. Buchbinder, D.; Singh, J.K.; Karmody, A.M.; et al. Comparison of Patency Rate and Structural Changes of the In Situ and Reversed Vein Arterial Bypass. J. Surg. Res. 1981, 30, 213. 24. Taylor, L.M.; Edwards, J.M.; Phinney, E.S.; Porter, J.M. Reversed Vein Bypass to Infrapopliteal Arteries: Modern Results Are Superior to or Equivalent to In Situ Bypass for Patency and for Vein Utilization. Ann. Surg. 1987, 205, 90. 25. Harris, P.L.; How, T.V.; Jones, D.R. Prospectively Randomized Clinical Trial to Compare In Situ and Reversed Saphenous Vein Grafts for Femoropopliteal Bypass. Br. J. Surg. 1987, 74, 252. 26. Watelet, J.; Cheysson, E.; Poels, D.; et al. In Situ Versus Reversed Saphenous Vein for Femoropopliteal Bypass: A Prospective Randomized Study of 100 Cases. Ann. Vasc. Surg. 1986, 1, 441. 27. Moody, A.P.; Edwards, P.R.; Harris, P.L. In Situ Versus Reversed Femoropopliteal Vein Grafts: Long Term Follow Up of a Prospective, Randomized Trial. Br. J. Surg. 1992, 79, 750–752.
28. Veterans Administration Cooperative Study Group 141; Comparative Evaluation of Prosthetic, Reversed, and In Situ Vein Bypass Grafts in Distal Popliteal and TibialPeroneal Revascularization. Arch. Surg. 1988, 123, 434. 29. Fogel, M.A.; Whittemore, A.D.; Couch, N.P.; Mannick, J.A. A Comparison of In Situ and Reversed Saphenous Vein Grafts for Infra-Inguinal Reconstruction. J. Vasc. Surg. 1987, 4, 46. 30. Bandyk, D.F.; Kaebnick, H.W.; Steward, G.W.; Towne, J.B. Durability of the In Situ Saphenous Vein Arterial Bypass: A Comparison of Primary and Secondary Patency. J. Vasc. Surg. 1987, 5, 256. 31. Shah, D.M.; Darling, R.C., III.; Chang, B.B.; Fitzgerald, K.M.; Paty, P.S.K.; Leather, R.P. Long Term Results of In Situ Saphenous Vein Bypass: Analysis of 2058 Cases. Ann. Surg. 1995, 222, 438– 448. 32. Harris, P.L.; Veith, F.J.; Shanik, G.D.; Nott, D.; Wengerter, K.R.; Moore, D.J. Prospective Randomized Comparison of In Situ and Reversed Infrapopliteal Vein Grafts. Br. J. Surg. 1993, 80, 173– 176. 33. Wengerter, K.R.; Veith, F.J.; Gupta, S.K.; et al. Prospective Randomized Multicentered Comparison of In Situ and Reversed Vein Infrapopliteal Bypass. J. Vasc. Surg. 1991, 12, 189. 34. Mehigan, J.T. Angioscopic Control of In Situ Bypass: Technical Consideration. In Seminars in Vascular Surgery; Rutherford, R.E., Ed.; W.B. Saunders: Philadelphia, 1993; 176– 179. 35. Rosenthal, D.; Piano, G. Endovascular Technique in In Situ Vein Graft. In Progress in Vascular Surgery; Yao, J.S.T., Pearce, W.H., Eds.; Appleton and Lange: Stamford, CT 1997; 271– 276.
CHAPTER 33
Combined Aortoiliac and Femoropopliteal Occlusive Disease David C. Brewster Frank J. Veith aortoiliac segment requires careful assessment to determine appropriate forms of therapeutic intervention. Pertinent to the second basic question is the observation of many studies that even successful proximal revascularization done for hemodynamically important inflow disease may fail to improve distal circulation sufficiently in patients with MLD to attain adequate relief of their ischemic symptoms. In addition, while good long-term patency of proximal procedures is well established, it is important to emphasize that graft patency does not necessarily equate with results assessed in terms of functional outcome in patients with MLD. Prior reports of patients with MLD treated in conventional fashion by an initial inflow procedure have indicated that approximately one quarter to one third of patients may have an unsatisfactory clinical result from proximal revascularization alone,[6 – 21] and that clinically important persistent ischemia due to uncorrected distal disease will require subsequent distal arterial reconstruction in 10 –25% of patients.[6,8,13,14,21 – 25] Data from our own review[6] of clinical outcome following aortofemoral grafting in patients with MLD is representative (Table 33-1). Although 74% of patients were deemed improved, 26% were judged to have an unsatisfactory outcome of proximal operation alone. Of the 74% of patients categorized as improved, only 24% had total relief of ischemic symptoms and 50% were still restricted by varying degrees of claudication. When analyzed according to indications for surgical intervention, 82% of claudicators were improved, but only 35% were totally cured. For limb-salvage patients, 67% were improved, but almost all noted residual claudication. Distal bypass was subsequently required in 17% of patients overall, 10% of the claudicators, and 29% of those patients who had limb-threatening problems preoperatively. If results are assessed strictly by hemodynamic measures rather than clinical outcome, the figures may be even more discouraging.[18 – 20] In addition to the sometimes disappointing results of inflow revascularization alone, there is also often concern that
Although arteriosclerotic occlusive disease is usually segmental in nature and therefore generally amenable to corrective treatment, it is well recognized that obliterative disease is usually a generalized process, which often involves multiple segments of the arterial tree.[1,2] In the lower extremities, combined involvement of both the aortoiliac and femoropopliteal systems is a commonly encountered manifestation of such characteristic diffuse distribution of the disease process. The combination of occlusive lesions involving both inflow and outflow vessels of the lower extremity is commonly referred to as multilevel disease (MLD). Other frequently employed terms to designate involvement both above and below the inguinal ligament are combined segment disease, multisegment disease, or tandem disease. Appropriate treatment decisions regarding MLD are of extreme importance in the proper management of patients with lower extremity ischemic symptoms. In each individual patient, two basic and closely related questions must be answered: Is inflow disease present and clinically significant, and if so, will inflow revascularization alone suffice in providing adequate relief of ischemic symptoms? In regard to the first question, it is well established that failure to first correct hemodynamically significant inflow disease will adversely effect both immediate and late results of infrainguinal arterial revascularization procedures.[3 – 5] Recognition of this has led to the appropriate axiom of vascular reconstructive surgery that proximal disease must be corrected first in patients with MLD. Conversely, it is clear that an inflow procedure done for clinically insignificant aortoiliac disease will fail to provide clinical benefit and subjects the patient to needless risks, discomfort, inconvenience, and expense. Hence, in all patients with lower extremity ischemic symptoms, the
Supported in part by the Gordon P. Lovell Fund for Vascular Research and Education.
Hobson/Wilson/Veith: Vascular Surgery: Principles and Practice, Third Edition, Revised and Expanded DOI: 10.1081/0819-9-120024916 Copyright q 2004 by Marcel Dekker, Inc.
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Table 33-1.
Clinical Outcome of Proximal Aortic
Reconstruction Postop symptom status
Percent of patients
Good result Total relief Improved Unsatisfactory result Unimproved Worse
74 24 50 26 18 8
Source: From Brewster et al.[6] Reproduced by permission.
untreated distal disease may result in a higher failure rate of the proximal procedure or lead to progression of distal ischemic symptoms, which might ultimately preclude successful limb salvage if a “wait-and-see” approach is adopted. This has led some surgeons to favor more frequent concomitant correction of both inflow and outflow disease by simultaneous, two-level revascularization, despite the previously held perceptions that such synchronous procedures carried excessive morbidity and mortality risk and generally lower long-term patency. Such dilemmas highlight the important and often controversial nature of the proper management of patients with MLD. Decisions regarding the relative importance of disease at each level and the best means of treating such disease are frequently difficult and tax even the most experienced surgeon’s judgment. This chapter will review the clinical characteristics of MLD, the various diagnostic approaches available to evaluate and assess the problem, and therapeutic options and strategies for specific clinical circumstances.
diabetes, hypertension, or associated atherosclerotic disease of coronary, cerebral, and/or visceral arteries.[12,21,26,27,31] These increased risk factors not unexpectedly lead to a significant decrease in life expectancy of 10 or more years in patients with diffuse multisegment disease, whereas life expectancy may be near normal in patients with localized aortoiliac disease.[33] Because of involvement of both inflow and outflow segments, patients with MLD have more hemodynamic compromise and correspondingly typically present with more advanced ischemic symptoms.[8,9,19,20,26,27] For example, Harris et al.[25] noted that patients with MLD were three times more likely to have rest pain or gangrene than were patients with aortoiliac disease and a patent femoropopliteal segment. Therefore, the goal of intervention is more often limb salvage rather than simply relief of caludication. In addition, the prognosis for disease progression appears to be different. Those patients with localized aortoiliac disease have a reduced propensity to develop progressive distal occlusive disease.[29,34] Mozersky and colleagues[18] documented a 14% incidence of disease progression in patients with isolated aortoiliac disease, in contrast to a 38% frequency in patients with multisegment involvement. These investigators concluded that there was an apparent biologic difference between patients with solitary aortoiliac disease and those with more diffuse lesions. From the above data, it is apparent that the frequent occurrence of MLD, usually in higher-risk patients with limbthreatening indications for revascularization, requires careful evaluation and thoughtful management if a beneficial outcome is to be achieved.
METHODS OF EVALUATION INCIDENCE AND PATIENT CHARACTERISTICS The exact incidence of combined aortoiliac and femoropopliteal disease is unknown. However, in most series of patients with symptoms severe enough to warrant angiographic assessment in consideration of surgical reconstruction or other forms of interventional therapy, it is the most common pattern of disease. MLD affects 66% of patients requiring aortoiliac surgery in our experience[6,26,27] and is reported in 50% or more of patients in other major series of aortoiliofemoral revascularization. [7 – 9,11 – 14,21,23,28 – 30] While it is likely that more frequent localized aortoiliac disease exists earlier in the disease process, such patients often have relatively mild symptomatology and frequently do not undergo arteriographic investigation.[31] Associated distal disease is most commonly in the form of superficial femoral artery (SFA) stenosis or occlusion, but atherosclerotic involvement of infrainguinal vessels may include lesions in the deep (profunda) femoral artery in up to 15% of patients or involve the popliteal or infrageniculate crural vessels.[2,7,32] In contrast to patients with more limited aortoiliac disease, patients with combined segment disease are typically older, more predominantly male (6:1 ratio or greater), and much more likely to have associated comorbid conditions such as
It is clear that assessment of the contribution of each segmental level of disease to the patient’s overall clinical status is of paramount importance in the management of patients with MLD. As previously stated, preoperative evaluation must be directed at the acquisition of sufficient information to determine if inflow disease exists and if its correction will be enough.
Inflow Assessment Evaluation of the aortoiliac segment by traditional methods is acknowledged often to be difficult. While a careful history and physical examination remain important, several shortcomings in MLD patients are apparent. Even experienced examiners often differ on the grading of femoral pulse palpation. Several studies have shown that 15 –30% of femoral pulses classified as diminished by palpation are associated with normal femoral artery pressures (FAP) at rest as determined by direct needle-puncture measurements, while a similar percentage with pressure-proven inflow disease were judged to have “normal” femoral pulses.[35 – 37] The presence of obesity, groin scarring, femoral artery calcification, and variations in body habitus may lead to misinterpretation of inflow disease by femoral pulse examination alone.[35,38]
Chapter 33.
Combined Aortoiliac and Femoropopliteal Occlusive Disease
Likewise, a femoral bruit may be heard in up to 14% of patients with hemodynamically normal inflow segments and may be absent in as many as 42% of patients with documented aortoiliac disease.[37] Similar difficulties exist in attempting to judge the presence of possible inflow disease by the patient’s history—as, for example, the level of claudication. While patients with isolated aortoiliac disease will often complain of proximal claudication in the thigh, hip, or buttock areas, 25 – 50% of patients with MLD will complain only of calf claudication, so that the absence of proximal muscle-group symptoms is not a reliable indicator of normal inflow.[35,37] While arteriography remains a cornerstone of patient evaluation, it is well understood that functional assessment and physiologic conclusions made from the anatomic information provided by angiography are frequently incorrect, especially when only a single plane study is obtained.[7,11,14,16,39] In addition, angiographic interpretation is subject to wide interobserver variability.[40] While lateral and/or oblique projections may improve the accuracy of arteriographic assessment, there is often a discrepancy between conclusions based upon the morphological information and actual hemodynamic significance as determined by FAP measurements. We have noted such disagreement in about 25% of patients, particularly when aortoiliac disease is only “moderately” severe by arteriographic interpretation.[35] It seems apparent that more accurate methods of hemodynamic evaluation of possible inflow disease are necessary in some patients to supplement information provided by history, physical examination, and standard arteriographic imaging. A voluminous literature has developed on the topic of noninvasive vascular laboratory methods of assessing aortoiliac disease (see also Chap. 7). Standard segmental Doppler pressures and pulse volume recordings (PVR) are quite useful in evaluating the overall severity of occlusive disease but are often relatively inaccurate in anatomic localization of disease and in defining the hemodynamic importance of disease at each level in patients with MLD.[41 – 43] The major problem with using thigh pressure (TP) values to detect inflow disease in MLD patients is that the coexistent SFA disease usually reduces TP values unless it is situated low in the distal vessel. Although the use of two narrow cuffs for determining high and low TP may improve accuracy,[44,45] most investigators conclude that thigh pressures or indices are too variable in MLD patients to be a reliable method of assessing inflow status.[46 – 48] Similarly, some idea about the presence of combined disease may be obtained by noting the ankle pressure recovery time after exercise,[49] but this method is rather cumbersome and relatively imprecise. Analysis of the femoral Doppler waveform has also been proposed to assess the aortoiliac segment. In its simplest form, if the waveform is triphasic and well defined, the proximal vessels will most likely not contain a hemodynamically significant lesion.[50] However, this method has many inherent errors and potential artifacts. Accordingly, the more accurate method of real-time frequency analysis has been suggested. Angle-independent techniques are used because velocities cannot be calculated without knowledge of the angle of incidence of the Doppler beam with the arterial wall. Spectral broadening and pulsatility index can be examined for evidence of proximal stenosis.[51 – 56] Although
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such methods may be accurate in identifying relatively isolated aortoiliac disease, most authorities acknowledge that they have significant limitations in the accurate assessment of inflow disease in MLD, as they are affected by distal as well as proximal disease.[57 – 60] Recently, other more complex modifications for Doppler waveform analysis have been devised,[61 – 63] but their accuracy and value in combined segment disease remain uncertain. Because of the well-recognized difficulties in determining the hemodynamic significance of lesions in the aortoiliac segment with indirect noninvasive tests, direct methods of diagnostic evaluation of aortoiliac occlusive disease have been increasingly advocated. Duplex ultrasound, which provides both anatomic and physiologic information, is being used by some laboratories more frequently in current practice.[64 – 66] Duplex ultrasound evaluation of the aorta and iliac arteries has been shown to have a sensitivity of approximately 80 – 90% when compared to arteriography.[64,66] In addition, stenoses can almost always be correctly distinguished from occlusions, thus helping to identify patients more likely to be treatable by transluminal balloon angioplasty.[5,66] However, comparison to actual intraarterial pressure measurements has not been done, and a threshold criterion in local increase of peak systolic velocity for hemodynamically significant iliac disease has not been conclusively established. Such examinations are time consuming, require the patient to have fasted for 12 hours, and require a high degree of technical expertise. Some arterial segments may not be visualized even by skilled technologists, thereby limiting accuracy of the method, which requires examination of the entire length of the aortoiliac segment. Further experience and technical improvements may make duplex scanning a more important tool in the future. At present, there is general agreement that the most accurate hemodynamic assessment of suspected aortoiliac disease is by direct measurement of intraarterial FAP.[35,39,47,68] Resting pressure values alone may be insufficient, as it is well established that the percent stenosis at which a lesion becomes hemodynamically significant can vary depending upon pressure, flow rate, length, and distal resistance factors.[69] Therefore, flow augmentation by pharmacologic vasodilatation or inducement of reactive hyperemia by cuff occlusion is required. A difference between resting systemic (distal aortic or brachial) and femoral artery systolic pressures of . 5 mmHg or a decrease in peak systolic FAP of . 15% with flow augmentation (Fig. 33-1) signifies hemodynamically significant inflow disease. The accuracy of such studies in identifying clinically important inflow disease has been amply validated in terms of correlation with outcome following a proximal revascularization procedure.[6,35,67,68] In an earlier study, we found that good improvement of ischemic symptoms was obtained with an inflow procedure in 96% of patients with a positive FAP test result, despite the presence of uncorrected distal disease in a high percentage of patients. If proximal procedures were done despite a negative FAP study, only 43% of patients improved and 57% required subsequent distal bypass for adequate relief of ischemic symptoms.[35] Our subsequent study in MLD patients, all with total SFA occlusions, confirmed its utility in predicting benefit from inflow operation. Of patients with a positive FAP study, 91% were
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Figure 33-1. Femoral artery pressure (FAP) measurement (compares peak systolic pressure in distal aorta and common femoral artery at rest and after reactive hyperemia). A pressure fall is noted on the left tracing (arrowhead ) as the diagnostic arteriography catheter is pulled down from the distal aorta to the femoral artery puncture site. Any gradient on the contralateral side, both at rest and with flow augmentation, can be determined by needle puncture of the femoral artery and comparison of brachial pressure and FAP. (From Brewster, in Rutherford.[85] Reproduced by permission.)
judged improved, in contrast to only 40% with negative FAP results.[6] Flanigan et al.[67] reported a 98% accuracy in assessment of the aortoiliac segment, as compared with 80% accuracy with arteriography. In a related study by this group, long-term results of infrainguinal bypasses done below stenotic but hemodynamically normal aortoiliac vessels were not related to the amount of angiographically demonstrated inflow disease. Hence, selection of patients for infrainguinal bypass on the basis of FAP testing, irrespective of angiographic findings in the aortoiliac segment, can eliminate unnecessary inflow procedures without a detrimental effect on long-term patency.[70]
Will Proximal Revascularization Be Enough? Even if hemodynamically significant proximal disease is corrected, the crucial dilemma in many patients with MLD often remains whether sufficient improvement in distal perfusion will be obtained. Despite better inflow, the hemodynamic impairment attributable to uncorrected infrainguinal disease may be more important in a particular patient. In other words, the segment with the greatest resistance may not have been corrected.[71] In addition, some authors feel that late patency of inflow procedures is adversely affected by the presence of uncorrected distal disease. While most surgeons agree that uncorrected profunda disease is an extremely important factor,[7,26] some feel that SFA occlusion alone may compromise late patency of aortoiliofemoral or extraanatomic inflow grafts.[20,25,72 – 74]
Numerous studies have examined various clinical, angiographic, and hemodynamic features that might assist the clinician in predicting outcome of initial proximal revascularization in the patient with MLD.[6,10,15 – 17,20,22,75 – 84] Space constraints do not allow detailed review of all proposed methods, but it is the current consensus that, despite intensive interest in and study of this topic, no single reliable predictor of the subsequent need for distal revascularization is currently available. Nonetheless, several parameters do exist that, when carefully considered together, may be of considerable help in this difficult decision. The most important of these are listed in Table 33-2. In considering such factors, the surgeon must evaluate the severity of inflow disease, assess the adequacy of infrainguinal collateral circulation to compensate for distal disease, and finally consider the clinical problem for which revascularization is undertaken. In our study correlating potentially predictive variables with clinical outcome, a series of 181 consecutive patients with MLD who underwent aortofemoral grafting was examined.[6] All had a total SFA occlusion in the most symptomatic limb. Correction of any stenosis of profunda origin was accomplished by means of patch angioplasty utilizing the beveled tip of the graft limb, as previously described.[26,27] Limb-threatening ischemic symptoms were present in 52% of patients. Operative mortality was 2.2%, all in patients in the limb salvage category. As previously noted, 26% of patients were ultimately determined to have an unsatisfactory clinical result and 17% eventually underwent distal arterial reconstruction at varying time intervals. Our analysis suggested that the most helpful predictors of a
Chapter 33.
Combined Aortoiliac and Femoropopliteal Occlusive Disease
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Key Variables in Prediction of Result of Inflow Revascularization in MLD
Table 33-2.
Clinical Factors Strength of femoral pulse Type of ischemic symptoms Extent of gangrene or infection Angiographic Factors Severity of inflow disease Status of profunda Patency of popliteal and runoff vessels Hemodynamic Factors Femoral artery pressure (FAP) gradient Infrainguinal pressure gradient (DP, IRR) Predicted increase in postoperative ABI Intraoperative hemodynamic assessment (PVR, ABI)
successful result are findings that firmly establish the presence of severe, hemodynamically important, proximal disease. This is indicated by the findings of an absent or unequivocally diminished femoral pulse and totally occluded or obviously severely stenotic inflow vessels on arteriography. The true hemodynamic importance of inflow disease is best determined, if any doubt exists, by the use of FAP studies. Data from our experience and that of others indicates that a positive FAP result (i.e., a large gradient between the aorta and the femoral artery) is associated with a favorable response to inflow operation alone in over 90% of patients.[6,35,47,67,68] It is well recognized that the functional severity of distal disease is largely dependent upon the adequacy of collateral circulation around an occlusive lesion in the femoropopliteal segment (Fig. 33-2). The importance of the profunda femoris artery and profunda-popliteal collateral networks in providing compensatory blood flow has been stressed by many authors.[7,26,71,86 – 91] In addition, an adequate popliteal and tibioperoneal runoff tract must exist to accept such collateral flow and ensure adequate distal perfusion.[76,83,84,92,93] While good-quality arteriography can identify disease in the profunda, popliteal, and tibial vessels, the functional capacity of profunda and geniculate collateral systems is difficult to assess angiographically and best evaluated by noninvasive hemodynamic modalities.[71] Exactly what vascular laboratory methods are best in this regard, and particularly their utility in predicting outcome following inflow revascularization, remains the most controversial aspect of this subject. Our data and those of others suggest that thigh pressure index (TPI), as originally proposed by Bone and coworkers,[16] fails to be predictive. Both the profunda-popliteal collateral index (PPCI) suggested by Boren and colleagues[76] and differences in thigh and ankle PVR amplitudes (FPV), as devised by O’Donnell et al.,[15] approached but did not achieve statistical significance in our study.[6] Differences in the technique of noninvasive thigh pressure measurement may account for some of these discrepancies. We did find, however, that comparison of preoperative thigh (single cuff) and ankle pressure was useful (Fig. 33-3). A gradient (DP ) of # 30 mmHg was associated with a good result in 87% of cases. Conversion to an index (AP/BP) increased predictive ability slightly. Such an “index
Figure 33-2. Profunda-popliteal network, the major source of collateral blood supply to the lower limb around an SFA occlusion.
of runoff resistance” (IRR), as originally proposed by Sumner and Strandness,[10] was correlated with satisfactory relief of ischemic symptoms in 89% of patients when using a cutoff point of IRR # 0:2: Both of these hemodynamic parameters logically indicate well-developed profunda-popliteal collaterals and satisfactory runoff down the limb. Although such measurements may seem to be theoretically sound, not all authors have found them to be reliable predictors.[10,15,84] Several investigators have suggested that the actual predicted postoperative ankle pressure expected after inflow revascularization may be estimated with reasonable accuracy if preoperative FAP is known.[80 – 83] According to this theory, the percent increase in FAP will be approximately the same as the percent increase anticipated in postoperative ankle pressure (AP). This can be expressed as follows: Expected AP ¼ initial AP £
systemic pressure FAP
Thus, if the systemic (aortic or brachial) pressure is 160 mmHg, FAP 80 mmHg, and preoperative AP 30 mmHg, successful correction of inflow disease would double initial
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Figure 33-3. The adequacy of distal compensatory collateral blood flow is best assessed by noninvasive vascular laboratory methods. In our experience, DP and IRR (see text) are useful.
FAP and would be expected to produce a similar increase in AP, predicting a rise to 60 mmHg. Several reports have documented good accuracy in prediction of postoperative AP by this method, using actual invasively determined FAP values.[80,81] Moneta and coworkers[82] and Dalman and associates[83] also feel that accurate prediction of the extent of improvement of postoperative distal perfusion is possible and feel that this can be accomplished by using pressure information derived from high-thigh cuffs rather than direct FAP measurements. Rutherford et al.,[20] however, did not find noninvasive data obtained with a single wide thigh cuff or two narrow cuffs to provide reliable prediction.[20] Because of acknowledged limitations of thigh pressure measurements in MLD, even with a high-thigh cuff, we believe actual FAP must be known to enable reasonably accurate prediction of postoperative AP. This may be known preoperatively or simply determined in the operating room after femoral artery exposure. Even if the postoperative increase in perfusion pressure can be predicted, the actual need for two-level reconstruction cannot always be determined with absolute precision in every patient due to the imperfect correlation between distal pressure and symptom relief.[94] Dalman et al.[83] have suggested that patients with claudication require a postoperative ankle-brachial index (ABI) of .0.75 for symptom relief. Those with rest pain and/or minor ischemic lesions (, 5 cm2) or limited gangrene confined to distal toes are thought to need an ABI of . 0.55, while patients with extensive pedal gangrene or infection required a postoperative ABI of . 0.80. While such guidelines are generally helpful, all would agree they are not infallible. Intraoperative hemodynamic measurements obtained immediately after proximal revascularization have obvious appeal in the determination of the necessity to add a concomitant distal reconstruction. Garrett et al.[17] originally proposed that an immediate increase in ABI of . 0.1
would be an accurate predictor of benefit from inflow operation alone, and Sumner and Strandness[10] observed uniform improvement in such patients. Similarly, our data revealed that an immediate increase in the amplitude of calf or ankle PVR tracings after aortofemoral grafting in MLD patients was correlated with a good result in 97% of cases.[6] While both methods do appear helpful if positive, unfortunately neither has good specificity, as a negative initial result does not reliably predict failure and a definite need for distal grafting. In our study, 48% of patients with an unimproved intraoperative distal PVR tracing were still judged improved subsequently, while Garrett noted that 54% of those limbs with either no rise or an actual fall in immediate ABI still had symptomatic improvement. Such results no doubt reflect the well-known observation that distal perfusion through collateral channels may increase only gradually as these vessels dilate gradually in response to increased inflow. Maximal increase in ABI may not occur for several days or even longer in MLD patients.[10,22,49,79,95,96] Intraoperative variation in peripheral resistance, systemic hypothermia, possible hypovolemia, and reduced cardiac output may all limit immediate increase in distal flow and pressure. A final key variable in considering whether inflow operation alone will be sufficient is the clinical indication for revascularization. While a successful inflow procedure that corrects hemodynamically significant inflow disease will almost always suffice to relieve ischemic rest pain or heal minor foot lesions, the presence of more extensive necrosis, particularly when associated with infection or the likely need for subsequent local amputation to salvage the foot, will frequently require more substantial improvement in distal perfusion. Consequently, we and many others believe synchronous correction of both inflow and outflow segments must be considered more strongly in such circumstances.
Chapter 33.
Combined Aortoiliac and Femoropopliteal Occlusive Disease
COMBINED INFLOW AND OUTFLOW PROCEDURES If the surgeon could reliably identify patients who will not attain sufficient clinical improvement from initial inflow revascularization, it would appear sensible and appropriate, in many patients, to proceed immediately with simultaneous distal reconstruction. This would perhaps enhance the chances of limb salvage, spare the patient the inconvenience and risk of another vascular operation, and enable the surgeon to avoid the sometimes difficult task of a later groin redissection. An important but seldom analyzed consideration is how much symptom improvement is acceptable to the patient. As previously described, although most claudicators are improved by correction of significant inflow disease, only 25– 35% are totally relieved of exercise-limiting symptoms.[6,8,9,19] Similarly, even though rest pain is alleviated, will the patient be disappointed to be left with significant claudication symptoms, as is commonly the case? While proximal operation will “improve” the condition, how much symptom improvement is enough for the patient to consider the procedure truly successful? One must recognize that total correction of disease in many vascular patients is not feasible or appropriate, but if more total revascularization is possible and generally successful in contemporary practice, should it be more widely applied? In the early era of arterial reconstructive surgery, total correction of both levels of disease was often employed, frequently utilizing all prosthetic reconstructions. However, it became apparent that morbidity and mortality were frequently increased and long-term function, particularly of the femoropopliteal grafts, was relatively poor.[97] In addition, it was observed that many patients did satisfactorily as long as profunda revascularization was maintained.[86] Such experience, as well as the perception that identification of patients who would not improve was rarely possible and that, if necessary, distal grafts could be performed later with good results, led to the accepted tenet of initial management of MLD patients by proximal segment revascularization alone.[10,93] Even recently reported experience has emphasized the potential increase in morbidity and mortality of combined revascularization procedures and suggested the advisability of staging the two operations, especially when a complex distal reconstruction will likely be necessary.[98] Nonetheless, some groups have advocated more frequent simultaneous operation for disease above and below the inguinal ligament in selected patients.[25,78,83,99 – 101] These reports document that more complete revascularization and correspondingly improved functional results, without significant increased morbidity, can be achieved. The recent series of Dalman and colleagues[83] is particularly noteworthy in this regard. Using a two-team approach, the Portland group reported results in 62 patients undergoing simultaneous repair for MLD. Operative mortality was 1.8%; the mortality rate, perioperative morbidity, and operative time were not significantly different from those of a concurrent group who had isolated inflow procedures. Life-table primary patency for inflow procedures was 92.6 and 94.9% for outflow procedures at 2 and 4 years, while cumulative limb salvage was 90.9% at
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4 years follow-up. All patients with claudication were totally relieved of their symptoms. Therefore, it appears appropriate to consider combined procedures in a greater percentage of patients, given such current improved results. Such a trend is reflected in our own experience at the Massachusetts General Hospital and Montefiore Medical Center, with synchronous operations now performed in 10– 15% of MLD patients as opposed to only 4% in our 1982 report.[6] While careful clinical judgment is required in each individual patient, simultaneous operation should be seriously considered if a combination of several criteria are evident. These are listed below and illustrated schematically in Fig. 33-4: 1.
2. 3.
4. 5.
Only modest inflow disease (mildly reduced femoral pulse, moderate iliac disease on arteriogram, minimal FAP gradient) Small, diffusely diseased profunda femoris, not correctable with origin profundaplasty (Fig. 33-5) Hemodynamically severe infrainguinal disease (DP $ 30 mmHg; IRR $ 0:2; low predicted postop ABI) Poor outflow tract (occluded popliteal, diseased tibial runoff on arteriogram) Severe ischemic necrosis or infection in foot
TREATMENT OPTIONS Selection of the best methods of revascularization for patients with multilevel disease is based upon the same indications and principles pertinent to patients with more isolated aortoiliac or femoropopliteal disease. In each patient, the surgeon must devise a treatment strategy from a variety of approaches and methods. Decisions are based primarily upon the general condition of the patient, the extent and location of disease, and the experience and training of the surgeon. In MLD, the foremost principle is that identification of significant inflow disease requires initial correction first, by whatever means is best for the individual patient under consideration. If, however, hemodynamically significant inflow disease is not detected—as, for example, when FAP measurements do not demonstrate a pressure gradient—the surgeon may appropriately elect to proceed with distal reconstruction alone despite the presence of proximal atheromatous changes.[70] Later progression of inflow disease is a concern, but much progression has been documented to be significant or to cause late failure of distal bypass grafts in only about 10% of patients.[102,103] On rare occasions, substantial inflow pressure gradients have been noted immediately after distal arterial reconstructive procedures despite negative preoperative FAP studies.[104] We speculate that the failure of the papaverine test to detect important inflow disease in these patients may have been due to extremely limited common femoral artery outflow. With increased flow achieved by distal grafts, a functionally important inflow pressure gradient may be generated. In this setting, concern about early failure of distal grafts may require proceeding immediately with some form of an inflow
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Figure 33-4. Schematic representation of factors favorable and unfavorable to satisfactory relief of ischemic symptoms with inflow revascularization alone in patients with multilevel disease.
procedure or iliac percutaneous transluminal angioplasty (PTA); the surgeon and the patient should be prepared for those possibilities.[104] Correction of proximal disease is unquestionably best accomplished in the good-risk patient by aortobifemoral bypass grafting (see Chap. 32). It is clearly the most effective and durable method available, and most reports indicate that excellent long-term patency can be expected even in the presence of SFA occlusion.[8,9,26,105] Although distal anastomosis of the aortic graft to the external iliac artery may be feasible in some cases, for patients with MLD it is almost always advisable to extend the graft to the femoral level. For patients with such diffuse disease, this obviates the chances of progressive disease in the external iliac or common femoral arteries distally and, most importantly, affords the surgeon the best opportunity to ensure unimpeded inflow into the profunda femoris system.[7,22,26] The crucial importance of profunda revascularization in MLD patients is well established. It is imperative to assess the profunda by preoperative arteriography and at the time of surgery by inspection, palpation, and gentle calibration with vascular probes. In our experience, a satisfactory proximal profunda should accept at least a 4-mm probe.[6,26,27,85] Correction of any proximal profunda disease by profundaplasty, using the tip of the inflow graft (Fig. 33-6) or more formal endarterectomy with or without patching, is a key factor in the long-term success of such procedures.[26,85] Although Berguer et al.[106] have suggested that the presence
of an SFA occlusion in itself causes even a normal profunda orifice to represent a functional stenosis, most evidence suggests that “routine” profundaplasty, even in patients without demonstrable profunda disease, does not improve the hemodynamic result or late patency of aortofemoral grafts for MLD.[20] On the other hand, correction of significant deep femoral orificial disease in conjunction with an inflow procedure should further enhance distal blood flow and would be an important factor favoring proximal operation alone in a patient with MLD. Isolated profundaplasty alone has little to no role in the management of patients with MLD. Addition of lumbar sympathectomy (see Chap. 39) has not been shown to increase patency or limb salvage rates or to decrease the need for distal grafts following aortoiliac reconstruction.[107,108] However, available evidence does suggest that decreased vasomotor tone does increase flow to the limb and that reduction in pedal vascular resistance may be helpful to the patient with MLD.[107,109] While some investigators[110,111] suggest that most or all of the improved distal blood flow represents arteriovenous shunting and not increased capillary circulation, Moore and Hall[112] have documented increased skin nutritional flow by xenon-133 washout studies. Thus, there may be support for use of adjunctive lumbar sympathectomy with aortic surgery for patients with MLD who have early manifestations of pedal ischemia, such as minor skin necrosis or limited digital ischemic lesions.[107,113] Indeed, we continue to utilize limited sympathectomy L2-3 in conjunction with direct aortic
Chapter 33.
Combined Aortoiliac and Femoropopliteal Occlusive Disease
Figure 33-5. Intraoperative arteriogram after aortofemoral graft insertion, demonstrating diffusely diseased nonreconstructible profunda femoris artery. A distal femoropopliteal bypass graft was performed simultaneously.
operation in many such patients, particularly when it has been decided to limit operation to an initial inflow reconstruction alone. This is usually easily and quickly accomplished, but its benefit remains unproven. Certainly lumbar sympathectomy has no place as a primary form of treatment in MLD. Although localized disease of the aortoiliac segment can be successfully treated by aortoiliac endarterectomy, the diffuse disease present in many MLD patients would often require carrying the procedure into the external iliac vessels and beyond. Such extended endarterectomies are more difficult and have inferior long-term results compared to aortofemoral grafts and hence are rarely utilized in current practice.[26,31] Occasionally, more limited and localized iliac disease may be managed by endarterectomy.[114] However, in the current era many of these sorts of lesions are likely to be treated by transluminal balloon angioplasty (PTA) with or without stents. Because patients with MLD are older and generally have substantially increased comorbid risk factors, extraanatomic
503
grafts may be an important consideration for some of them. Although long-term function of axillofemoral grafts is inferior to direct methods of aortoiliac reconstruction, such a compromise may be the best choice for truly high-risk patients or those with “hostile” conditions that require avoidance of a direct approach to the aorta.[115] O’Donnell et al.[78] noted that axillofemoral grafts achieved inferior hemodynamic and functional results as compared to aortofemoral bypass in combined segment disease, even with attempts to classify patients with equivalent amounts of distal disease. Although some groups[116] found no difference in patency of axillofemoral grafts whether the SFA was open or not, Rutherford and coworkers and other authors have stressed the adverse impact of SFA occlusion on long-term patency of extraanatomic grafts.[74,115,117] These observations suggest that one should more seriously consider adding a distal bypass to improve outflow if an axillofemoral graft is chosen to correct inflow disease in a patient with MLD, especially if a unilateral procedure is done.[78] The concept of enhancing long-term function by increasing flow through the long subcutaneous axillofemoral graft is no doubt similar to the explanation given for the better late results when crossover grafts are added to create axillobifemoral grafts as opposed to axillounifemoral bypasses.[74,115,117,118] The striking improvement in the late patency of axillofemoral grafts performed with externally supported polytetrafluoroethylene (PTFE) reported recently by Passman et al.[119] suggests that such grafts should be performed with such a prosthesis, although this point has not been proven conclusively. For high risk patients with MLD who have largely unilateral ischemic symptoms, it may be appropriate to limit revascularization procedures to the one symptomatic side.[120,121] Such a strategy often enables the surgeon to focus attention on the major problem at hand, perhaps utilize procedures acknowledged to have less physiologic impact, and more easily combine proximal and distal revascularization procedures. All these considerations have obvious appeal in the typical older, high-risk patient with MLD, who often has advanced ischemia which may require multilevel reconstruction to optimize the chance of limb salvage. Retroperitoneal bypass or iliac artery endarterectomy may be employed and is readily combined with simultaneous ipsilateral distal bypass.[120 – 123] Similarly, iliofemoral bypass grafts can be done via a limited extraperitoneal approach with low morbidity and mortality in patients with relatively limited unilateral iliac disease; they can also be conveniently done with synchronous profundaplasty or an outflow procedure.[124 – 129] The utility and good long-term results of femorofemoral grafts are obviously well established in the management of unilateral iliac disease, as long as no hemodynamically significant lesions exist in the donor iliac system.[115,128,129] Again, because of the adverse effect of infrainguinal disease on the long-term patency and functional results of these grafts, profundaplasty must be done when indicated or the addition of a distal bypass in the recipient limb seriously considered.[129,130] In some MLD patients who have extensive disease and are poor risks for more conventional procedures, unusual approaches may occasionally be necessary. Although unilateral aortofemoral grafts are rarely indicated in
504
Part Four. Peripheral Occlusive Disease
Figure 33-6. Correction of profunda origin disease with the beveled tip of the inflow graft. (A and B ) The common femoral arteriotomy is extended into the proximal profunda, beyond orificial stenosis. Endarterectomy per se may or may not be required. (C ) Patch closure with the hood of the graft tip, begun on common femoral artery. (D ) Three to five interrupted sutures placed at the tip of the anastomosis and not tied until all are inserted facilitates accurate placement and avoidance of any stricturing of this critical outflow point. (From Brewster, in Rutherford.[85] Reproduced by permission.)
general,[26,85,131 – 133] it may be appropriate to originate unilateral inflow grafts from the lower aorta, usually via a retroperitoneal approach, in some of these patients if the entire iliac system is heavily diseased and the aorta will allow end-to-side proximal anastomosis, particularly if concomitant ipsilateral distal grafting is felt necessary.[100,125] In other high-risk patients with extensive uncorrectable common and deep femoral artery disease or heavily scarred groins, direct axillopopliteal, crossover axillopopliteal, crossover femoropopliteal, or iliopopliteal grafts have been used with acceptable results in these difficult situations.[130,134 – 136]
Combined Endovascular and Surgical Revascularization A final strategy occasionally very useful in some patients with multilevel disease is to treat the inflow lesion by an endoluminal method and then proceed with distal surgical reconstruction.[137 – 141] For patients with relatively localized iliac disease, iliac PTA (see Chaps. 24 and 28) is now well established as an effective treatment mode.[142 – 145] Based upon such accumulating long-term experience, a combination of iliac PTA and distal surgery has obvious appeal in MLD patients. This approach allows correction of hemodynamically limiting inflow disease, which, although limited in extent, would normally require initial surgical repair (Fig. 33-7). With adequate inflow reestablished by a
minimally invasive procedure, the surgeon can then focus attention on correction of distal disease by conventional surgical methods. Distal reconstruction is required in the great majority of such MLD patients with relatively limited iliac disease, as the infrainguinal segment constitutes the principal hemodynamic obstacle in most. However, surgeons have often been reluctant to perform distal procedures based upon inflow achieved by PTA alone, fearing a higher late failure rate of distal grafts and a generally poor result. Several recent reports, however, have documented the longterm durability of such a combined approach in properly selected patients.[146,147] In our study of 79 combined PTA and distal surgical procedures done over a 12-year period,[146] relief of inflow pressure gradients by PTA allowed 55 ipsilateral femoropopliteal or tibial grafts to be carried out, while 18 femorofemoral grafts were performed for correction of more advanced contralateral iliac disease (Fig. 33-8). Six patients had isolated ipsilateral profundaplasties after iliac PTA. Our preference is often to perform PTA as a separate procedure one or more days before proceeding with distal operation.[146,148] This allows PTA to be done under optimal conditions in the angiography suite and, more importantly, allows identification of complications of PTA or inadequate hemodynamic results which are known to occur in approximately 10–15% of patients undergoing iliac PTA.[12,144] Other groups, however, have recommended intraoperative PTA via the surgically exposed femoral artery and then to proceed immediately with distal surgery.[139,140,149,150]
Chapter 33.
Combined Aortoiliac and Femoropopliteal Occlusive Disease
505
Figure 33-7. Arteriogram of patient with ischemic foot ulcer and MLD. (A ) Iliac stenosis (arrow ), with 40 mmHg pressure gradient at rest, treated by PTA, allowing femoropopliteal bypass to be performed for (B ) superficial femoral artery occlusion. Note diffusely diseased profunda femoris artery. (From Brewster, in Veith.[148] Reproduced by permission.)
In our series, mean follow-up was 43 months. By lifetable analysis, the 5-year primary patency of distal surgical procedures was 76%, and a secondary patency of 88% at 5 years was achieved by various means of reintervention. Recurrent stenosis of the dilated iliac lesion or new areas of
Figure 33-8. Artist’s depiction of types of distal surgical procedures performed after correction of limited iliac artery inflow disease by PTA. (From Brewster et al.[146] Reproduced by permission.)
progressive iliac disease in nondilated iliac artery segments was felt responsible for the failure of distal procedures in only 5% of patients. There was no perioperative mortality, and major complications of PTA occurred in only 6% of patients. Most of these complications could be successfully corrected at the time of the distal surgical procedure without alteration of the original planned operation. Most importantly, combined PTA and distal surgery achieved excellent symptom relief and outcome results. Mean pretreatment ABI of 0:31 ^ 0:14 increased to 0:80 ^ 0:16 following subsequent distal operation. If these results are compared to our prior experience in MLD patients with aortofemoral grafts alone,[6] the improved outcome is evident. As shown in Table 33-3, with PTA/distal surgery, 90% of patients had improvement in their clinical symptom grade by at least one category, as compared with 74% treated by inflow operation alone; 71% in the combined treatment group were totally relieved of claudication versus 35% in the aortofemoral graft group. Although limb salvage was good in both groups, 29% of patients with initial proximal operation alone required later distal grafts to achieve this. There were no deaths in the PTA/distal surgery group, as contrasted with a 2.2% incidence of perioperative death in patients having aortofemoral grafts. Thus, in carefully selected patients, this approach is
506 Table 33-3.
Part Four. Peripheral Occlusive Disease
Results of Aortofemoral Grafts and Combined Iliac PTA/Distal Surgery in MLD
Adequate clinical symptom improvement Total relief of claudication Limb salvage Operative mortality
Inflow surgery alone, %
Combined PTA/distal surgery, %
74 35 85 (29% required later distal grafts) 2.2
90 71 90 0
Source: From Brewster et al.[6,146] Reproduced by permission.
effective and durable, safely reducing the extent of surgical intervention required while increasing the comprehensiveness of revascularization. While less published experience with distal balloon angioplasty as an adjunct to inflow operations is available, this may have obvious application to some patients with MLD as well. One may consider balloon catheter dilatation of localized areas of stenosis in more distal and difficult-toaccess portions of the deep femoral artery, or for appropriate lesions in the femoropopliteal segment, in order to improve runoff and maximize clinical results. Careful judgment is required, however, as well as experience and familiarity with the principles and technique of transluminal angioplasty. Adequate fluoroscopic equipment and dilatation over a guidewire remain important prerequisites for safe intraoperative balloon dilatation.
Endovascular Grafts While iliac PTA may be effectively combined with distal surgical procedures to treat patients with MLD and fairly focal inflow disease, patients with more extensive and diffuse iliac occlusive disease remain a problem, particularly when they are at high risk for standard inflow operations. Marin, Veith, and coworkers have shown in a small series of patients that transluminally placed stent grafts are technically feasible and may be combined with conventional infrainguinal arterial reconstructions to manage patients with MLD who are otherwise difficult to treat due to multiple previous reconstructions or severe comorbid medical illness.[141] This approach has great promise for the future.
SUMMARY Multilevel involvement is a common problem in patients with lower extremity occlusive disease. As the majority of such patients have advanced ischemic symptoms and are often higher-risk operative candidates, careful evaluation and planning are necessary for good results. The segmental contribution of each level of disease to the patient’s overall symptomatology must be assessed as well as possible by available clinical, angiographic, and hemodynamic methods. If significant inflow disease is present, it must be corrected first by whatever means is best for that particular patient. While the majority of MLD patients will improve with a successful inflow procedure, up to one-third of patients may have an unsatisfactory clinical result. Although no single reliable predictor is available, thoughtful consideration of several key factors can often identify those most likely to require a subsequent distal graft because of insufficient relief of ischemia with proximal revascularization alone. In such patients, current evidence suggests that simultaneous inflow and outflow operation may be best. In carefully selected patients with multisegmental disease, a combination of iliac PTA and distal surgical reconstruction is particularly advantageous. With current advances and improvements of endoluminal therapies, a growing role is anticipated for combined use of such methods to correct inflow lesions while infrainguinal disease is managed by conventional open surgical procedures. Such strategies are particularly helpful for high-risk, elderly patients with MLD, in whom necessary multisegment revascularizaton would otherwise carry high morbidity and mortality risk. Careful clinical judgment and proper patient selection for such combined therapies remains of paramount importance.
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O’Donnell, T.F., Jr.; McBride, K.A.; Callow, A.D.; et al. Management of Combined Segment Disease. Am. J. Surg. 1981, 141, 452. Kozloff, L.; Collins, G.J.; Rich, N.M.; et al. Fallibility of Postoperative Doppler Ankle Pressures in Determining the Adequacy of Proximal Arterial Revascularization. Am. J. Surg. 1980, 139, 326. Williams, L.R.; Flanigan, D.P.; Schuler, J.J.; et al. Prediction of Improvement in Ankle Blood Pressure Following Arterial Bypass. J. Surg. Res. 1984, 37, 175. Faris, I.; Tonnesen, K.H.; Agerskov, K.; et al. Femoral Artery Pressure Measurements to Predict the Outcome of Arterial Surgery in Patients with Multilevel Disease. Surgery 1982, 92, 10. Moneta, G.L.; Yeager, R.A.; Taylor, L.M., Jr.; Porter, J.M. Hemodynamic Assessment of Combined Aortoiliac/Femoropopliteal Occlusive Disease and Selection of Single or Multilevel Revascularization. Semin. Vasc. Surg. 1994, 7, 3. Dalman, R.L.; Taylor, L.M., Jr.; Moneta, G.L.; et al. Simultaneous Operative Repair of Multilevel Lower Extremity Occlusive Disease. J. Vasc. Surg. 1991, 13, 211. Sterpetti, A.V.; Feldhaus, R.J.; Schultz, R.D. Combined Aortofemoral and Extended Deep Femoral Artery Reconstruction: Functional Results and Predictors of Need for Distal Bypass. Arch. Surg. 1988, 123, 1269. Brewster, D.C. Direct Reconstruction for Aortoiliac Occlusive Disease. In Vascular Surgery, 4th Ed.; Rutherford, R.B., Ed.; W. B. Saunders Company: Philadelphia, 1995; 492 –521. Morris, G.C., Jr.; Edwards, W.; Cooley, D.A.; et al. Surgical Importance of the Profunda Femoris Artery: Analysis of 102 Cases with Combined Aortoiliac and Femoropopliteal Occlusive Disease Treated by Revascularization of Deep Femoral Artery. Arch. Surg. 1961, 82, 32. Bernhard, V.M.; Ray, L.I.; Militello, J.P. The Role of Angioplasty of the Profunda Femoris Artery in Revascularization of the Ischemic Limb. Surg. Gynecol. Obstet. 1976, 142, 840. Martin, P.; Frawley, J.E.; Barabas, A.P.; Rosengarten, D.S. On the Surgery of Atherosclerosis of the Profunda Femoris Artery. Surgery 1972, 71, 182. Heyden, B.; Vollmar, J.; Voss, E.U. Principles of Operation for Combined Aortoiliac and Femoropopliteal Occlusive Lesions. Surg. Gynecol. Obstet. 1980, 151, 519. Edwards, W.H.; Jenkins, J.M.; Muherin, J.L., Jr.; et al. Extended Profundaplasty to Minimize Pelvic and Distal Tissue Loss. Ann. Surg. 1990, 211, 694. Ouriel, K.; DeWeese, J.A.; Ricotta, J.J.; Green, R.M. Revascularization of the Distal Profunda Femoris Artery in the Reconstructive Treatment of Aortoiliac Disease. J. Vasc. Surg. 1987, 6, 217. Bernhard, V.M. Limits of Profunda-Femoris Revascularization. In Critical Problems in Vascular Surgery; Veith, F.J., Ed.; East Norwalk, Connecticut: Appleton-CenturyCrofts, 1982; 251 – 262. Collins, G.J., Jr.; Rich, N.M.; Andersen, C.A.; McDonald, P.T. Staged Aortofemoropopliteal Revascularization. Arch. Surg. 1978, 113, 149.
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Conduct for Iliofemoral Occlusive Disease?: An Analysis of 514 Aortoiliac Reconstructions. J. Vasc. Surg. 1993, 17, 15. Dick, L.S.; Brief, D.K.; Alpert, J.; et al. A Twelve-Year Experience with Femorofemoral Crossover Grafts. Arch. Surg. 1980, 115, 1359. Kalman, P.G.; Hosang, M.; Johnston, K.W.; Walker, P.M. The Current Role for Femorofemoral Bypass. J. Vasc. Surg. 1987, 6, 71. Ellenby, M.I.; Sawchuk, A.P.; Schwarcz, T.H.; et al. A Nine-Year Experience with Crossover Femoro-FemoroPopliteal Sequential Bypass. Am. J. Surg. 1991, 161, 672. Levinson, S.A.; Levinson, H.J.; Halloran, L.G.; et al. Limited Indications for Unilateral Aortofemoral or Iliofemoral Vascular Grafts. Arch. Surg. 1973, 107, 791. Crawford, E.S.; Manning, L.G.; Kelly, T.F. “Redo” Surgery After Operations for Aneurysm and Occlusion of the Abdominal Aorta. Surgery 1977, 81, 41. Piotrowski, J.J.; Pearce, W.H.; Jones, D.N.; et al. Aortobifemoral by Pass: The Operation of Choice for Unilateral Iliac Occlusion? J. Vasc. Surg. 1988, 8, 211. Veith, F.J.; Moss, C.M.; Daly, V.; et al. New Approaches to Limb Salvage by Extended Extra-Anatomic Bypasses and Prosthetic Reconstruction to Foot Arteries. Surgery 1978, 84, 764. Ascer, E.; Veith, F.J.; Gupta, S. Axillopopliteal Bypass Grafting: Indications, Late Results, and Determinants of Long-Term Patency. J. Vasc. Surg. 1989, 10, 285. Kwaan, J.H.M.; Connolly, J.E. Extended AxillopoplitealAxillotibial Bypass: Valuable Adjunct to Limb Revascularization. Arch. Surg. 1983, 118, 25. Veith, F.J.; Gupta, S.K.; Samson, R.H.; et al. Progress in Limb Salvage by Reconstructive Arterial Surgery Combined with New or Improved Adjunctive Procedures. Ann. Surg. 1981, 194, 386. Roberts, B.; Gertner, M.H.; Ring, E.J. Balloon-Catheter Dilation as an Adjunct to Arterial Surgery. Arch. Surg. 1981, 116, 809. Corey, C.J.; Bush, H.L.; Widrich, W.C.; Nabseth, D.C. Combined Operative Angiodilation and Arterial Reconstruction for Limb Salvage. Arch. Surg. 1983, 118, 1289. Pfeiffer, R.B.; String, S.T. Adjunctive Use of the Balloon Dilatation Catheter During Vascular Reconstructive Procedures. J. Vasc. Surg. 1986, 3, 841. Marin, M.L.; Veith, F.J.; Sanchez, L.A.; Cynamon, J.; Suggs, W.D.; Schwartz, M.L.; Parsons, R.E.; Baka, C.W.; Lyon, R.T. Endovascular Aortoiliac Grafts Combination with Standard Infrainguinal Arterial Bypass in the Management of Limb-Threatening Ischemia: Preliminary Report. J. Vasc. Surg. 1995, 22, 316. Johnston, K.W.; Rae, M.; Hogg-Johnston, S.A.; et al. Five-Year Results of a Prospective Study of Percutaneous Transluminal Angioplasty. Ann. Surg. 1987, 206, 403. Johnston, K.W. Iliac Arteries: Reanalysis of Results of Balloon Angioplasty. Radiology 1993, 186, 207. Wilson, S.E.; Wolf, G.L.; Cross, A.P. Percutaneous Transluminal Angioplasty Versus Operation for Peripheral Arteriosclerosis: Report of a Prospective Randomized Trial in a Selected Group of Patients. J. Vasc. Surg. 1989, 9, 1. Bosch, J.L.; Hunink, M.G. Meta-Analysis of the Results of Percutaneous Transluminal Angioplasty and Stent Place-
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ment for Aortoiliac Occlusive Disease. Radiology 1997, 204, 87. 146. Brewster, D.C.; Cambria, R.P.; Darling, R.C.; et al. LongTerm Results of Combined Iliac Balloon Angioplasty and Distal Surgical Revascularization. Ann. Surg. 1989, 210, 324. 147. Peterkin, G.A.; Belkin, M.; Cantelmo, N.L.; et al. Combined Transluminal Angioplasty and Infrainguinal Reconstruction in Multilevel Atherosclerotic Disease. Am. J. Surg. 1990, 160, 277. 148. Brewster, D.C. Durability and Late Results of Combined Iliac Angioplasty and Infrainguinal Bypass. In Current
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Critical Problems in Vascular Surgery; Veith, F.J., Ed.; Quality Medical Publishing: St. Louis, MO, 1991; Vol. 3, 290– 299. 149. Lau, H.; Cheng, S.W.K. Intraoperative Endovascular Angioplasty and Stenting of Iliac Artery: An Adjunct to Femoro-popliteal Bypass. J. Am. Coll. Surg. 1998, 186, 408. 150. Schneider, P.A.; Abcarian, P.W.; Ogawa, D.Y.; Leduc, J.R.; Wright, P.W. Should Balloon Angioplasty and Stents Have Any Role in Operative Intervention for Lower Extremity Ischemia? Ann. Vasc. Surg. 1997, 11, 574.
CHAPTER 34
Adventitial Cystic Disease and Entrapment Syndromes Involving the Popliteal Artery Norman M. Rich George J. Collins, Jr. Jerry R. Youkey James M. Salander Hugh J. Donohue Bruce M. Elliott
The popliteal artery in disease and injury remains an enigma and an interesting challenge in both diagnosis and therapy. It is well documented that despite attempted repair of arteries and associated venous injury when indicated, trauma to the popliteal artery continues to be associated with a relatively high amputation rate when compared to other major extremity arterial injuries in most civilian and military experiences.[1,2] During the past 20 years, two unusual popliteal arterial lesions have been identified. Initial case reports of adventitial cystic disease of the popliteal artery[3 – 74] and of popliteal artery entrapment syndrome [75 – 114] have been supplemented with extensive reviews of both entities.[115 – 123] Although intermittent claudication is usually associated with arteriosclerotic occlusive disease involving lower extremity arteries in elderly males with a long history of smoking, this symptom also occurs in men in their middle forties with adventitial cystic disease of the popliteal artery and in relatively young athletic men with popliteal artery entrapment syndrome. Noninvasive laboratory tests have proliferated during the past 25 years and an extensive literature has evolved. Specifically pertinent to this review is a 1969 contribution by Yao and associates, who described measurements of ankle systolic pressure in arterial disease affecting the lower extremities.[124] In 1972, Barnes and Strandness[125] outlined physiologic observations regarding specific isolated popliteal arterial occlusions. Darling and colleagues[85] at Massachusetts General Hospital and McDonald and coworkers[126] at
Walter Reed Army Medical Center attempted to correlate noninvasive test results with the angiographic diagnosis of popliteal artery entrapment. This chapter will review the history and current status of adventitial cystic disease and entrapment syndrome of the popliteal artery. The increasing interest in these two unusual lesions has led to an improved ability to diagnose them. The therapeutic implications of this increased identification of these two lesions will be emphasized.
ADVENTITIAL CYSTIC DISEASE OF THE POPLITEAL ARTERY History Ejrup and Hiertonn[23] in 1954 in Stockholm, Sweden, first described adventitial cystic disease of the popliteal artery. In the year preceding their report, Hiertonn, while operating on a patient’s popliteal artery, had made a transverse incision in the middle of a thickened area of the popliteal artery and found a mass filled with gelatinous material. He regarded this finding tentatively as mucoid degeneration in the media of the popliteal artery. The involved segment of popliteal artery was resected and replaced with a segment of autogenous greater saphenous vein. Hiertonn, with coauthors Lindberg and Rob,[33] produced a subsequent publication, which described
Hobson/Wilson/Veith: Vascular Surgery: Principles and Practice, Third Edition, Revised and Expanded DOI: 10.1081/0819-9-120024917 Copyright q 2004 by Marcel Dekker, Inc.
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cystic degeneration of the popliteal artery. They reviewed four known cases encountered up to 1957. A number of valuable descriptive terms were applied to the lesion including “clear, jelly-like material similar in appearance to that seen in a ganglion,” “the specimen looked like a sausage and was 7 cm in length,” and “the lumen was compressed by an intramural cyst containing jelly under high tension.” Hiertonn and his coauthors made reference to a report by Atkins and Key,[5] stating their belief that in 1947 these researchers were the first to report on adventitial cystic degeneration of an artery when they described this lesion in the external iliac artery. While the majority of adventitial cystic lesions have been identified in the popliteal artery, other publications have described a similar pathology in a variety of arteries. These include the iliac arteries,[127,128] the femoral artery,[128] and the radial artery.[129] The general subject of cystic adventitial degeneration of blood vessels has also been reviewed.[130,132] An important diagnostic sign was described in 1961 by Ishikawa, Mishima, and Kobayshi[36] when they noted in their report of cystic arterial disease of the popliteal artery that normal distal pulsations were obliterated by complete flexion of their patient’s affected knee. These authors noted that the pulses returned to normal immediately after the knee resumed a straight position. They found that this sign was present only in patients whose cystic disease produced a stenosis without total occlusion of the popliteal artery. A year earlier, Jaquet and Meyer-Burgdorff[37] had noted that the cystic lesion might present as a localized stenosis, which allowed distal arterial flow through the lesion only at the peak of systolic pressure. In 1963 Eastcott[20] suggested that an arterial murmur over the popliteal fossa was an important sign in establishing the proper diagnosis of adventitial cystic degeneration of the poplitial artery in a young athletic nonsmoker who developed intermittent claudication. In their report of a cyst of the popliteal artery in 1967, Taylor and colleagues[70] documented that “the sudden onset of symptoms in our case may have been due to the floor of the superficial cyst giving way, resulting in the extrusion of the contents into the dissection plane of the vessel, so forming an internal projection which constricted the lumen.” These authors believe that the cysts were similar to ganglia, which are degenerative cysts containing collagenous material and which may result from previous trauma. Despite the increasing recognition of adventitial cystic disease of the popliteal artery during the past 20 years, the true cause remains unknown. The lesion has been treated successfully both by evacuation or aspiration of the cyst when there is associated patency of the popliteal artery and by arterial reconstruction when the popliteal artery is occluded.
Incidence and Demographics The increasing recognition of popliteal artery adventitial cystic disease stimulated Flanigan and associates[118] to establish a registry for this lesion at Northwestern University and to correspond with authors who had documented previous cases all over the world.[118] In 1979 they were able to report a review of the history and findings in 115 cases. Their reference is a classic review of this entity. Approximately
50% of their cases came from continental Europe; an additional 12 cases were diagnosed in Scandinavia and 14 in Great Britain. North America and Australia each had identified 13 cases. Cystic adventitial disease of the popliteal artery is found more frequently in men than in women. The report from Northwestern University in 1984 by Bergan and colleagues[116] emphasized that the usual patient is a man who is a high-performance athlete or a heavy manual laborer. Although the lesion can occur between 11 and 70 years of age with a mean age of 42 years, it usually presents in patients in their twenties or thirties.[116,118]
Etiology and Pathogenesis The exact cause of cystic degeneration of the adventitia in the popliteal artery remains uncertain. Repetitive trauma is one of three possible causes. However, the lesion’s occurrence in childhood makes it unlikely that trauma is the sole cause. A second possible etiology suggests that the lesion is part of a generalized body disorder of connective tissue. However, the process has never occurred bilaterally, and generalized connective tissue disorders have not appeared in patients who have been followed after identification of popliteral artery adventitial cystic disease. The third and most likely possibility is that developmental inclusion of mucin-secreting cells within the adventitia of the artery could allow a cyst to develop within its adventitia. Several investigators believe that the lesion’s pathogenesis is similar to that of the simple ganglion. They have suggested that there can be a developmental mechanism for inclusion of the cells in the arterial wall. There are numerous references that compare ganglia to adventitial cystic disease, with representative reports by Clark, [133] McEvedy,[134] and Parkes.[135] Recently, there have been suggestions that an enlargement of the knee joint capsular synovial cyst could develop along a geniculate artery to involve the adventitia of the popliteal artery or that synovial cysts can be sequestered into the arterial wall during development. This could explain why the cysts can be either entirely adventitial or involve other layers of the artery wall and why not all cysts can be enucleated.
Pathophysiology Although there is wide variation, the suddent onset of ischemic symptoms in the leg in men in their third decade of life can be associated with cystic adventitial disease of the popliteal artery. The rapid change in the size of the cyst, which has been developing over a long period of time, causes these sudden symptoms. Some degree of stenosis may be associated with the cyst for a long period of time with preservation of luminal patency in the popliteal artery until the intracystic pressure exceeds that of the artery, causing occlusion with or without thrombosis and the resultant sudden onset of associated symptoms. Intermittent claudication without severe ischemia is a common finding because collateral circulation develops. The nature of the content of the cyst has been the subject of numerous studies. Endo and colleagues[24] isolated and identified proteohyaluronic acid in the cyst, and they believe
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that this represents cystic mucoid degeneration. Leaf[41] performed amino acid analysis of the protein present in adventitial cystic disease of the popliteal artery and showed similarities between ganglia and adventitial cysts by both chemical and histologic analyses. Both lesions involve mucoproteins and mucopolysaccharides.
Clinical Presentation Typically, a patient in his twenties, thirties, or forties presents with the sudden onset of intermittent claudication that is quite limiting. Both the pedal and popliteal pulses may be present if there is only a stenosis of the popliteal artery associated with the cyst. Depending on the degree of stenosis, there may be an associated bruit audible over the popliteal fossa. Palpable distal pulses may disappear during acute flexion of the knee. In other patients, both pedal and popliteal pulses may be absent, indicating arterial occlusion, which is less frequent than stenosis. After the initial sudden onset of cramping pain in the calf, the patient may experience some relief followed by typical intermittent claudication as good collateral circulation develops. This results from the gradual stenosis of the popliteal artery prior to the rapid enlargement of the cyst, which produces either a more significant stenosis or occlusion. Occasionally, ischemic neuropathy may be present.
Laboratory Evaluation Although physical examination as alluded to above is the essential first step of evaluation, the noninvasive blood flow laboratory can be employed to corroborate the initial physical findings by both pressure measurements and waveform analysis.[116,124 – 126] This evaluation can be performed in a manner similar to that for conventional arteriosclerotic occlusive disease. Comparison with the opposite nonaffected lower extremity will be impressive. In contrast to the normal segmental limb pressures, the affected limb below the cystic lesion will show a decrease in segmental limb pressures. Also, in contrast to the normal pulse waveforms in the unaffected limb, the affected limb will show a flattening of the pulse wave below the cystic lesion. Because of the excellent collateral circulation that usually develops in young men, total absence of pulse waves over the distal tibial arteries is rare. Angiography, as emphasized by Sutton in 1962,[136] is important. This will outline normal arteries except in the location of the lesion. Frequently, a smooth wall stenosis will be identified, usually at the midportion of the popliteal artery extending from 1 to 8 cm in length. There may be a curvilinear defect, which has been described as a “scimitar sign” (Fig. 34-1), caused by the displacing the contrast column within the arterial lumen. With expansion of the cyst to encircle the arterial lumen, a concentric smooth taper of this lesion has been described as resulting in an “hourglass” appearance. It is important to have both lateral and anteroposterior angiographic views to ensure that the lesion is not missed. In contrast to typical angiographic findings with popliteal artery entrapment, there will be no medial deviation of the popliteal artery with the cystic lesion. The angiographic
Figure 34-1. This angiogram of the popliteal artery reveals smooth tapering above and below the popliteal artery cyst that created severe stenosis of the popliteal artery. The “scimitar sign” is diagnostic for adventitial cystic disease of the popliteal artery. (From McAllister HA: Armed Forces Institute of Pathology, Washington, D.C. Reproduced by permission.)
findings combined with the clinical evaluation of the patient should allow certain diagnosis of the lesion and differentiate it from arteriosclerotic occlusive disease. There may, on occasion, be some confusion with popliteal artery entrapment if total occlusion of the middle portion of the popliteal artery has occurred. Thus, there might be a localized complete occlusion of the midpopliteal artery, with the remainder of the lower extremity arterial anatomy having a normal appearance and with excellent collateral circulation around the limited occlusion. The total occlusion may have a “beaklike” appearance of the proximal contrast column.[116]
Treatment Treatment of adventitial cystic disease of the popliteal artery can be conservative. Adequate experience has documented that aspiration of the cyst can be successful in eradicating the cyst and resultant arterial stenosis or occlusion in some patients. Bergan and colleagues[116] have emphasized that previous difficulties with aspiration can be avoided by the use of ultrasound needle localization. Because the cystic content
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is quite viscous and gelatinous, aspiration must be done with a relatively large-bore needle. However, aspiration can be the treatment of choice if the cyst is diagnosed before the development of total occlusion of the artery.[116] Surgical intervention can also provide effective treatment. Surgical procedures have been divided into nonresectional techniques and resectional techniques. Nonresectional techniques are employed mainly when occlusion of the popliteal artery has not occurred. Evacuation of the cyst or enucleation is the most frequent nonresectional form of therapy (Table 34-1). The popliteal artery can be approached through either a posterior S-shaped incision or a medial incision; however, the posterior approach provides the best exposure of the affected vessel. The normal popliteal artery above and below the lesion can be easily mobilized. The popliteal artery involved by the cystic lesion will be enlarged and sausage-shaped. There may be adhesions binding the cystic adventitial structure to the adjacent vein or to the posterior aspect of the joint capsule. Although the cyst is usually unilocular, there may be multilocular cysts with septa present (Fig. 34-2). An incision into the cyst and evacuation of its contents usually restores arterial patency. The fluid extruding through the incision is usually crystal clear. However, the fluid may be light yellow or even currant jelly in color if there has been recent or old hemorrhage into the cyst. While evacuation or enucleation of the cyst is preferred if occlusion of the popliteal artery and resultant intimal damage have not occurred, resection and arterial reconstruction may be required if total occlusion of the artery has occurred, with or without thrombosis. Resection and replacement of the involved arterial segment with an autogenous greater saphenous vein graft is the operation of choice for this latter stage of the disease process. Result of such treatment should be excellent. Recurrent stenosis and/or occlusion of the popliteal artery secondary to cystic adventitial lesions have been treated successfully by needle aspiration, recovering varying amounts of gelatinous material. Many advocate simple evacuation of the cyst by aspiration even for recurrent lesions because of the relatively high degree of success. If this is not
Table 34-1.
successful, a direct surgical approach may be required with evacuation of the cyst or with replacement or bypass of the involved segment of the popliteal artery with an autogenous saphenous vein graft.
POPLITEAL VASCULAR ENTRAPMENT SYNDROMES Although the usual emphasis in these syndromes is related to entrapment of the popliteal artery, the popliteal vein can also be involved with the artery, or, rarely, the popliteal vein can be entrapped alone.
History Although there has been considerable interest in and recognition of this anomaly in the past 25 years, it was first described in 1879 by a medical student in Edinburgh, Scotland. T. P. Anderson Stuart[112] was dissecting the amputated leg of a 64-year-old man, and he described the anatomic abnormality associated with the abnormal course of the popliteal artery (Fig. 34-3). The following quotation documents Stuart’s observations: In May of last year, I was requested by Professor Spence to make for him a preparation of the popliteal space of limb of a man aged 64, who had had to submit to amputation on account of gangrene of the foot, resulting from a very large popliteal aneurysm. As the dissection proceeded a most striking abnormality in the course of the artery came to light, and so far as I have been able to ascertain, it is now put on record for the first time. The popliteal artery, after passing through the opening in the adductor magnus, instead of, as it usually does, coursing downwards and outwards towards the middle of the popliteal space, so as to lie between the two heads of the gastrocnemius muscle, passes almost vertically downwards internally to the inner head of the gastrocnemius. It reaches the bottom
Surgical Treatment of Adventitial Cystic Disease of the Popliteal Artery Nonresectional treatment (56 patients)
Number Failures Initial success
Evacuation
Evacuation with vein patch
Evacuation with synthetic patch
Aspiration
Total procedures
41 4/41 90%
9 2/9 78%
4 1/4 75%
2 0/2 100%
56 7/56 89%
Homograft 2 0/2 100%
Total procedures 42 3/42 93%
Resectional treatment (42 patients)
Number Failures Initial success
Vein graft 30 2/30 93%
Source: Modified from Flanigan et al.[118]
Synthetic graft 7 1/7 86%
End-end anastomosis 3 0/3 100%
Chapter 34. Adventitial Cystic Disease and Entrapment Syndromes Involving the Popliteal Artery
517
Figure 34-2. The gross specimen of the adventitial cyst of the popliteal artery outlined angiographically in Fig. 34-1 is demonstrated. Note the sausage like lesion from the external view (A ) and the longitudinal transected view which shows the multilocular cystic structure filled with gelatinous material (B ). These are classic findings of advential cystic disease of an artery. (From McAllister HA: Armed Forces Institute of Pathology. Washington, D.C. Reproduced by permission.)
of the space by turning around the inner border of that head, and then passes downwards and outwards beneath it—between it and the lower end of the shaft of the femur. The inner head of the gastrocnemius arises much higher up than usual, namely, from the inner division of the linea aspera about an inch and a half above the condyle, thus leaving a considerable space between it and the condyle, over which space the artery passes. The other structures are normal. The preparation is now in the possession of Mr. Spence. In 1959 Hamming[98] at Leyden University in the Netherlands reported a similar anomaly in a 12-year-old boy. However, nearly 80 years had passed since the original observation by Stuart. Hamming gave credit to the initial report by Stuart and acknowledged that Chambardel-Dubreuil in 1925 in France had described a case in which the popliteal artery was separated from the popliteal vein by an accessory slip of gastrocnemius muscle. Hamming’s case report is a classic reference because it represents the first successful clinical treatment of complications associated with popliteal arterial entrapment. In 1962 Servello[111] at the University of Padua, Italy, described a similar patient, a 28-year-old farmer who complained of intermittent claudication. Servello had the benefit of reviewing Hamming’s article, and he based his diagnosis on this report. In addition, Servello’s patient had a small aneurysm of the popliteal artery distal to the entrapped segment in a fashion similar to Stuart’s original description in 1879. In the Scandinavian literature, Hall[96] in 1961 described the anomalous insertion of the medial head of the gastrocnemius muscle with circulatory complications in one
of his patients. In 1964 Hall[97] followed his initial report with an additional report of what he called intravascular gastrocnemius insertion. In 1964 Carter and Eban[83] described a case of a bilateral developmental anomaly of the popliteal arteries and the gastrocnemius muscles. In these early reports, most of the patients were young athletic men. The term popliteal artery entrapment syndrome was first used by Love and Whelan[106] in reporting two cases in 1965 from Walter Reed General Hospital. Stimulated by this report, Rich and Hughes [109] added an additional case and documented for the first time that the popliteal vein, as well as the popliteal artery, could be involved in a variety of anomalies that frequently include abnormal lateral attachment of the medial head of the gastrocnemius muscle. Connell[137] in 1978 first noted that isolated entrapment of the popliteal vein could be one of these anatomic variants.
Classification and Etiology There are a variety of congenital anatomic variants associated with entrapment of both the popliteal artery and/or the popliteal vein (Fig. 34-4). Classification of the anomalies remains confusing; however, this is of little consequence to surgical treatment. An initial attempt at classification was made in 1970 by Insua and associates.[103] This was modified subsequently by Delaney and Gonzalez.[86] Ferrero and his colleagues[120] extended this classification to a total of 10 lesions. In 1979, using the Walter Reed Army Medical Center experiences, Rich and coworkers[122] identified five major classifications, which are outlined graphically in Fig. 34-4.
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Figure 34-3. (A ), (B ), and (C ) represent an artist’s interpretation of the written description by T. P. Anderson Stuart in 1879 from the first published observation of a congenital anomaly associated with the resultant abnormal course of the popliteal artery: (B ) entrapment; (C ) usual course. (With appreciation to the artist, Gary G. Wind, M.D.)
In addition, Evans and Bernhard[89] described an unusual variant of vascular entrapment in a patient following injury to the lower extremity. These authors could not identify a congenital anomaly or compressive band in their patient, who presented with external compression of both the popliteal artery and the popliteal vein. The authors concluded that popliteal vascular entrapment could be caused by massive edema of the heads of the normal gastrocnemius muscle following trauma. Baker and Stoney[78] reported another form of acquired popliteal artery entrapment where the popliteal artery entrapment was associated with arterial bypass surgery. An interesting question that cannot be answered is the relationship between popliteal artery aneurysms identified in mid- or later life and popliteal vascular entrapment. This relationship will be difficult to clarify, since bypass of the aneurysm is now the preferred treatment, and when this is performed via medial incisions the identification of entrapment is usually not possible. It is also unclear how often muscle abnormalities are present but fail to produce significant signs or symptoms. Gibson and coworkers[138] found three unsuspected cases of popliteal vascular entrapment in 86 cadavers in whom the popliteal artery was dissected.
Prevalence and Incidence There has been international interest in popliteal vascular entrapment syndromes. Although the true incidence of these lesions cannot be established, they are being identified and documented with increasing frequency. Cases have been reported from countries around the world.[80,93,94,102,121] This is emphasized by two recent reviews in the surgical literature that provide extensive data regarding this worldwide experience.
Pathophysiology The variety of anatomic variants already emphasized can be associated with entrapment of either or both the popliteal artery and the popliteal vein with a variety of effects on normal lower extremity physiology. External compression can vary from minimal in the asymptomatic patient to marked compression that causes a significant stenosis of the popliteal artery or vein. This external compression can advance to total occlusion of the popliteal vessels. This can occur either temporarily with varying positions of the patient’s leg and
Chapter 34. Adventitial Cystic Disease and Entrapment Syndromes Involving the Popliteal Artery
519
Figure 34-4. These drawings outline the normal course of the neurovascular bundle in the popliteal fossa from the posterior approach and show four generally accepted types of anomalies involving entrapment of the popliteal artery. All are usually associated with an abnormal configuration of the medial head of the gastrocnemius muscle. This classification, however, does not satisfy all anatomic variants. Empirically, type IV was expanded to include a branch of the tibial nerve as a structure compressing the popliteal artery, and type V was added to emphasize that the popliteal vein can be entrapped with the artery in all four types. (From Rich et al.[122] Reproduced by permission.)
foot or permanently with intraluminal thrombosis. The arterial pathology associated with external compression of the popliteal artery can range from poststenotic dilatation to the presence of a true aneurysm (Fig. 34-5). The potential for embolization of thrombus from the aneurysm to the distal arterial runoff represents an additional threat to the patient’s extremity distal to the lesion. Figure 34-6 provides angiographic demonstration of thrombosis of the popliteal artery at the site of entrapment. Midpopliteal arterial occlusion is a classic finding of popliteal artery entrapment with thrombosis. Development of extensive collateral arterial circulation can occur, and the patient may be only mildly symptomatic. Figure 34-7 demonstrates aneurysmal changes that might also develop in the entrapped popliteal vein. Thrombosis of the entrapped vein with resultant venous hypertension and/or chronic venous stasis with associated complications can develop. An important question remains related to the segment of popliteal artery immediately distal to the area of entrapment. Even after release of the entrapment, will the recurrent trauma from the external compression cause intimate damage and subsequent thrombosis? Certainly the potential exists; however, no study has clarified this relationship. Similarly,
it is unclear after release of the entrapment whether or not the segment of popliteal artery distal to the entrapment— minimally dilated or not—will progress to a true aneurysm and how long this process will take. Only long-term follow-up of surgically treated cases in which the compression is released and the artery is not replaced will help answer these important questions. There are so few cases of documented entrapment of the popliteal vein that answers to similar questions related to the popliteal vein will probably go unanswered for a long time.
Clinical Evaluation Diagnosis of popliteal vascular entrapment should be considered and is made most frequently in young, active, athletic men who develop intermittent calf claudication with exercise. Despite the male dominance, an increasing number of similar lesions are being recognized in young athletic women, with the diagnosis of these lesions being made in long-distance runners in an increasing number of cases. With more young men and women jogging and running, it is anticipated that there will be an increasing
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Angiographic demonstrations identified classic findings of medial deviations of the popliteal artery as illustrated in Fig. 34-6. However, this classic finding may or may not be present. There may also be a midpopliteal artery segmental occlusion, as illustrated in Fig. 34-6. The angiographic identification of an isolated occlusion of the middle third of the popliteal artery alone should lead one to suspect popliteal arterial entrapment. Although similar occlusions can be associated with adventitial cystic degeneration of the poplitcal artery, proximal tapering of the popliteal artery will probably exist with the latter. Phlebograms can also be utilized to outline and identify similar entrapment of the popliteal vein, as demonstrated by Connell.[137]
Treatment
Figure 34-5. Longitudinal incision through an aneurysm of the popliteal artery associated with an entrapment syndrome. Laminated clot is present within the lumen. (From Rich et al.[122] Reproduced by permission.)
number of cases identified and reported. In addition, an increasing number of middle-aged patients are being diagnosed as having popliteal vascular entrapment. In the older population, particularly those who present with a diagnosis of a popliteal artery aneurysm, entrapment of the popliteal artery might also be considered in the differential diagnosis. Although popliteal vascular entrapment was believed initially to be predominantly a unilateral lesion, its bilaterality is being recognized with increasing frequency. The syndrome may be present bilaterally in 30–40% of patients with the anomaly.
Even when these anatomic variants are identified in asymptomatic patients, it is now believed that operative intervention should be undertaken to help protect against the later development of complications of the popliteal vascular entrapment. If the vascular involvement extends to thrombosis and/or aneurysm formation, the operative management becomes more difficult and complicated. Operative treatment by release of the entrapping anomalous head of the gastrocnemius muscle, anomalous bands, or associated structures has become widely accepted in both symptomatic and asymptomatic patients. Although the medial approach to the popliteal artery can be utilized, exact identification of the pathology may not be obvious via medial incisions. We therefore favor a posterior S-shaped incision and have used this approach bilaterally at the same operation in three patients. The Sshaped posterior incision provides adequate exoposure for the management of all associated complications such as popliteal artery aneurysm and thrombosis of the midpopliteal artery. The S-shaped incision also provides excellent exposure to identify the variety of anatomic anomaly that is associated with the popliteal vascular entrapment. On the other hand, some surgeons believe that the exact identification of pathology is unimportant and that the midpopliteal artery thrombosis or aneurysm can be adequately managed through the medial approach. Autogenous greater saphenous vein may also be easier to harvest by this approach.
Diagnosis
Results
The history of intermittent claudication in a young patient during strenuous exercise should raise the suspicion of a tentative diagnosis of popliteal vascular entrapment. Such patients might also have adventitial cystic disease of the popliteal artery. As already emphasized, extensive efforts have been made to establish the diagnosis of popliteal vascular entrapment by noninvasive techniques in the vascular laboratory. Results have been accurate in some patients and misleading in others. Table 34-2 illustrates the evaluation of a group of patients at Walter Reed Army Medical Center.[126]
Table 34-3 outlines the most recent Walter Reed Army Medical Center experience. Transection of the anomalous gastrocnemius muscle, accessory slips, fibrous bands, etc. was utilized successfully in the majority of cases. Either autogenous saphenous vein patch grafts or autogenous greater saphenous vein bypass grafts were used successfully to manage the associated complications of thrombosis and aneurysm. Successful results should be achieved on the management of the majority of patients with popliteal vascular entrapment whether the entrapment involves the popliteal artery and/or popliteal vein.
Chapter 34. Adventitial Cystic Disease and Entrapment Syndromes Involving the Popliteal Artery
521
Figure 34-6. (A ) Anteroposterior and (B ) lateral angiographic views demonstrate medial deviation of the popliteal artery and thrombosis of the midpopliteal artery with development of extensive collateral circulation in a young male that heralded the clinical probability of popliteal vascular entrapment syndrome. (From Rich et al.[122] Reproduced by permission.)
Figure 34-7. The drawing shows entrapment with formation of aneurysms in both the popliteal artery and the popliteal vein caused by an accessory slip of the gastrocnemius muscle (left ). Arterial reconstruction by autogenous greater saphenous vein bypass with ligation of the popliteal arterial aneurysm was performed successfully (right ). The accessory slip of muscle was incised near its insertion to release the entrapment of both the artery and vein. (From Rich and Hughes.[109] Reproduced by permission.)
26
21
27 25
23
38
31
32
30
2
3
4 5
6
7
8
9
10
1.2
1.3
1.5
1.1
1.1
1.3 1.1
1.3
0.7
0.8
Rest
1.5
1.3
1.7
1.2
1.2
1.3 1.2
1.3
0.5
0.4
3 min
1.4
1.1
1.3
1.1
1.1
1.4 —
1.2
—
—
10 min
1.2
1.1
1.5
1.1
1.3
1.4 1.2
1.2
1.1
1.4
Rest
1.4
1.2
1.5
1.3
1.3
1.4 1.3
1.2
1.4
1.3
3 min
1.4
1.3
1.2
1.1
1.1
1.4 —
0.6
—
—
10 min
Left leg
Completed test complaining of L foot fatigure None Stopped at 3 min due to bilateral leg exhaustion Minor nonspecific complaints Minor nonspecific complaints Minor nonspecific complaints Minor nonspecific complaints Minor nonspecific complaints
Stopped 1 min 45 s due to R foot, calf pain Stopped 2 min 45 s due to R foot, calf pain
Symptoms
Not done
Not done
Not done
Not done
Not done
R occluded 4-cm segment, medial deviation: L normal R occluded 3-cm segment; medial deviation: L medial deviation, stenosis with maneuver (Figs. 34-2, 34-6, 34-7) R normal: L occlusion with maneuver (Fig. 34-3) R normal: L normal R normal: L normal
Popliteal arterial angiographic findings
Note: The 3-min treadmill exercise was performed at 3 mi/h at a 0 grade. The 10-min treadmill exercise was performed at 4.2 mi/h at a 10 grade. L = left; R = right. Source: Modified from McDonald et al.[126]
49
Age, yr
1
Case no.
Right leg
Ankle-brachial pressure index with treadmill exercise testing
Table 34-2. Patient Evaluation: Representative Findings in Male Soldiers with Leg Symptoms of Possible Arterial Insufficiency
Normal
Normal
Normal
Normal
Idiopathic leg cramps Primary neuromuscular disease Normal
R normal: L entrapment
R entrapment: L entrapment
R entrapment
Final diagnosis
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Chapter 34. Adventitial Cystic Disease and Entrapment Syndromes Involving the Popliteal Artery Table 34-3.
523
Popliteal Vascular Entrapment Treated at Walter Reed Army Medical Center from September 1966 to April 1979
Patient/year
Age, yr/sex
Side
1/1966 1967 2/1967 3/1968 4/1970 3/1974 5/1974 1974 6/1977 7/1978 8/1978 1978 9/1979 1979
50/M 50/M 57/M 23/M 22/M 29/M 59/M 59/M 21/M 49/M 26/M 26/M 35/M 35/M
L R L L L R R L L R R L R L
Lesion type 1 1–3 4 2 4 1 1 3a 3 1 1 4 4
Popliteal artery Aneurysm Aneurysm Aneurysm Normal Thrombosis Normal Normal Normal Normal Thrombosis Thrombosis Normal Normal Normal
Operation
Result
SVG SVG SVG + SVPG-TEA + + + + SVG SVPG-TEA + + +
Excellent Excellent Excellent Excellent Excellent Excellent Excellent Excellent Excellent Excellent Excellent Excellent Good Good
Note: SVG = autogenous saphenous vein bypass graft; + = transection of abnormal gastrocnemius muscle, accessory muscle, fibrous bands, and so forth; SVPG-TEA = autogenous saphenous vein patch graft and thromboendarterectomy. a Although similar to type 3, popliteal vein was also entrapped. Source: Modified from Rich et al.[122]
Prognosis Long-term follow-up of patients with popliteal vascular entrapment who have been treated by the operative approach as described remains limited. Initial findings and minimal long-term follow-up of a limited number of patients demonstrate excellent results. Thus, successful results should be achieved in the management of the majority of patients with this problem. A long-term follow-up study will be required to answer the question of what happens to the compressed artery and any potentially damaged or weakened artery distal to the compressed segment after the compression is released.
POPLITEAL VASCULAR ENTRAPMENT: NEW MILLENNIUM UPDATE As the twenty-first century begins, we can reflect on the discovery of an anatomic anomaly by a medical student in Edinburgh 120 years ago. Nevertheless, we also recognize that the clinical management of the anatomic variants has occurred only within the past 40 years. The increasing incidence with notation that the popliteal vein as well as the popliteal artery could be entrapped associated with a variety of anatomic variants was first documented only 20 years ago. Because no center had a significantly large experience, the Popliteal Vascular Entrapment Forum was organized by a small group of individuals who believed that they could evaluate these relatively unusual lesions more effectively by a collective effort. Luca di Marzo of the University of Rome, Italy, as president, organized the first meeting in Rome in September 1998. This was followed by a second
meeting in Washington, D.C., in June 1999. Areas of confusion and controversy have been established to include classification. Areas of needed research have been identified to include a variety of pathophysiologic findings. A database maintained at the University of Rome has been established with continuing refinements for worldwide inclusion. Antonino Cavallaro from the University of Rome serves on the Executive Committee, as does Lewis Levien from Witwatersrand University in Johannesburg, South Africa. Other participants include Sean O’Donnell from Walter Reed Army Medical Center, Washington, D.C., and the Uniformed Services University of the Health Sciences in Bethesda, Maryland, Norman Rich, and Hiroshi Shigematsu from University of Tokyo, Tokyo, Japan. Particular progress has been made by Luca di Marzo and Antionino Cavallaro at the University of Rome in expanding their series. Hiroshi Shigematusu has established a collaborative effort in Japan securing the cases of his colleagues. Norman Rich discussed the largest series of popliteal venous entrapment cases ever presented when this series was presented by Seshadri Raju and Peter Neglen at the American Venous Forum in February 1999. Also, Norman Rich has written a commentary on a recent series from Serbia to be published in the Asian Journal of Surgery. Finally, the largest series of patients with popliteal vascular entrapment ever documented was published in the Journal of Vascular Surgery in October 1999 by Lewis Levien from South Africa. He also repeated the emphasis, adding more validity to the pronouncement in 1979 by Norman Rich that the lesions identified with popliteal vascular entrapment are being recognized with increasing frequency. The Popliteal Vascular Entrapment Forum welcomes collaborative participation, hoping that the twenty-first century will witness early and effective use of the Worldwide Web.
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Little, J.M.; Goodman, A.H. Cystic Adventitial Disease of the Popliteal Artery. Br. J. Surg. 1970, 57, 708. Marzoli, G.P.; Meyer-Burgdorff, G.; Jacquet, G.H. Sulle Pseudocisti Della Parete Arteriosa. Chir. Ital. 1962, 14, 291. Mateo, A.M. Degeneration Quistica de la Tunica Media de la Arteria Poplitea. Angiologia 1974, 26, 331. Mentha, C. Degenerescence Kystique Adventitelle ou Bursite de l’Artere Poplitee. J. Chir. 1965, 89, 173. Miliken, J.C. Cystic Degeneration of the Popliteal Artery in a Female. Br. Med. J. 1971, 2, 769. Morino, F.; Silverstrini, P.; Galli, T. Un Case di Cisti Dissecante Intramurale Dell’Arteria Poplitea. Minerva Chir. 1966, 21, 786. Muller, M.; Rodriguez, J. Obstruccion da la Arteria Poplitca por en Fermedad Quistica Mucinosa de la Pared Arterial. Angiologia 1975, 27, 1. Muller-Wiefel, H.; Papachrysanthou, C. Cystic Wall Degeneration of the Popliteal Artery. Herz/Kriesl 1974, 6, 333. Ohara, I.; Minaguhi, S. Adventitial Cystic Disease of the Popliteal Artery. Operation 1973, 27, 321. Patel, J.; Cormier, J.M. La Degenerescence Kystique on Colloide de l’Adventice Arteriel. Presse Med 1963, 71, 244. Patel, J.; Facquet, J.; Piwnica, A. Degenerescence Kystique on Colloide de l’Adventice. Presse Med. 1958, 66, 1164. Pierangeli, A.; De Rubertis, C. Degenerazione Cistica Avientiziale Dell’Arteria Poplitea. Arch. Ital. Chir. 1966, 92, 108. Powis, S.J.A.; Morrissey, D.M.; Jones, E.L. Cystic Degeneration of the Popliteal Artery. Surgery 1970, 67, 891. Raithel, D.; Hacker, R.W. Die zystische AdventitiaDegeneration der A. Poplitea. Vasa 1975, 4, 353. Robb, D. Obstruction of Popliteal Artery by Synovial Cyst. Br. J. Surg. 1960, 48, 221. Savage, P.E.A. Cystic Disease of the Popliteal Artery. Br. J. Surg. 1969, 56, 77. Schlesinger, A.; Gottesman, L. Cystic Degeneration of the Popliteal Artery. Am. J. Roentgenol. 1976, 127, 1043. Scobie, T.K.; Curry, R.H. Cystic Adventitial Disease of the Popliteal Artery. Can. J. Surg. 1975, 18, 46. Shabbo, F.P. Cystic Disease of the Popliteal Artery. Proc. R. Soc. Med. 1975, 69, 362. Shannon, R. Cystic Degeneraion of the Popliteal Artery. Aust. N.Z. J. Surg. 1971, 40, 290. Shute, R. Degenerescence Colloide de l’Adventice de l’Artere Poplitee Traitee par Prostese en Dacron. Mem. Acad. Chir. 1963, 89, 849. Soots, G.; L’Hermine, C.; Lerche, E.; et al. Degenerescence Colloide Adventicielle de I’artere Poplitee. J. Radiol. Electrol. Med. Nucl. 1972, 53, 85. Sperling, M.; Schott, H.; Ruppell, V. Die zystische Adventitia-Degeneration der Blutgefasse. Chirurgie 1972, 43, 37. Stirling, G.R.; Aarons, B.J. Cystic Myxomatous Degeneration of the Popliteal Artery. Alfred Hosp. Clin. Rep. 1967, 14, 91.
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Suy, R.; Van Osselaer, G.; Pakdaman, A.; et al. The Pseudocyst of the Adventitia of the Popliteal Artery. J. Cardiovasc. Surg. 1970, 11, 103. Taylor, H.; Taylor, R.S.; Ramsay, C.A. Cyst of Popliteal Artery. Br. Med. J. 1967, 4, 109. Tracy, G.D.; Ludbrook, J.; Rundle, F.F. Cystic Adventitial Disease of the Popliteal Artery. Vasc. Surg. 1969, 3, 10. Tytgat, H.; Derom, F.; Galinsky, A. Degenerescence Kystique de l’Artere Poplitee Traitee par Greffe en Nylon. Acta Chir. Belg. 1958, 57, 188. Vollmar, J. Die zystische Adventitia-Degeneration der Schlagadern. Kreis 1963, 52, 1028. Zinicola, N.; Ferrero, S.; Odero, A. Adventitial Cyst of the Popliteal Artery: Case Report. Minerva Cardioangiol. 1973, 21, 474. Albertazzi, V.I. Popliteal Artery Entrapment Syndrome. J. Am. Med. Assoc. 1969, 209, 1087. Albertazzi, V.I.; Elliot, T.E.; Kennedy, J.A. Popliteal Artery Entrapment. Angiology 1969, 20, 119. Amici, F., Jr. Un Raro Caso di Decorso Anomalo con Ostruzione tro Botica Dell’arteria Poplitea. Minerva Ortop. 1965, 16, 427. Baker, W.H.; Stoney, R.J. Acquired Popliteal Entrapment Syndrome. Arch. Surg. 1972, 105, 780. Beebe, H.G. Popliteal Artery Entrapment Syndrome. Vasc. Diagn. Ther. 1981, Feb/Mar, 25. Bouhoutsos, I.; Goulious, A. Popliteal Artery Entrapment: Report of a Case. J. Cardiovasc. Surg. 1977, 18, 481. Brener, B.J.; Alpert, J.; Brief, D.K.; et al. Limb Loss in Young Man Due to Entrapment of the Popliteal Artery. J. Med. Soc. NJ 1977, 72, 47. Brightmore, T.G.J.; Smellie, W.A.B. Popliteal Artery Entrapment. Br. J. Surg. 1971, 58, 481. Carter, A.E.; Eban, R. A Case History of Bilateral Developmental Abnormality of Popliteal Arteries and Gastrocnemius Muscles. Br. J. Surg. 1964, 51, 518. Chavatzas, D.; Barabas, A.P.; Martin, P. Popliteal-artery Entrapment. Lancet 1973, 2, 181. Darling, R.C.; Buckley, C.J.; Abbott, W.M.; et al. Intermittent Claudication in Young Athtetes: Popliteal Artery Entrapment Syndrome. J. Trauma 1974, 14, 543. Delaney, T.A.; Gonzalez, L.L. Occlusion of Popliteal Artery Due to Muscular Entrapment. Surgery 1971, 69, 97. Devin, R.; Salavert, J.P.; Dor, P. Malposition et Stenose Extrinseque de l’Artere Poplitee par Anomalie d’Insertion du Jumeau Interne. Mem. Acad. Chir. 1969, 95, 752. Edmondson, H.T.; Crowe, J.A., Jr. Popliteal Arterial and Venous Entrapment. Am. Surg. 1972, 38, 657. Evans, E.W.; Bernhard, V. Acute Popliteal Artery Entrapment. Am. J. Surg. 1971, 121, 739. Ezzet, F.; Yettra, M. Bilateral Popliteal Artery Entrapment: Case Report and Observations. J. Cardiovasc. Surg. 1971, 12, 71. Fontanetta, A.P.; Kirshbom, E.; Fisher, M.M.; et al. Popliteal Artery Entrapment: Lateral Deviation and Compression of Artery. Vasa 1974, 3, 399. Gallagher, E.G.; Hudson, T.L. Popliteal Artery Entrapment. Am. J. Surg. 1974, 128, 88. Gaylis, H.; Rosenberg, B. Popliteal Artery Entrapment Syndrome. S. Afr. Med. J. 1972, 46, 1071.
526 94. 95. 96.
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Part Four. Peripheral Occlusive Disease Gaylis, H.; Rosenberg, B. The Popliteal Artery Entrapment Syndrome: A Bilateral Case. S. Afr. J. Surg. 1973, 11, 51. Haimovici, H.; Sprayregen, S.; Johnson, F. Popliteal Artery Entrapment by Fibrous Band. Surgery 1972, 72, 789. Hall, K.V. Anomalous Insertion of the Medial Gastrocnemic Head, with Circulatory Complications. Acta Pathol. Microbiol. Scand. 1961, 148 (Suppl), 53. Hall, K.V. Intravascular Gastrocnemius Insertion. Acta Chir. Scand. 1964, 128, 193. Hamming, J.J. Intermittent Claudication at an Early Age, Due to an Anomalous Course of the Popliteal Artery. Angiology 1959, 10, 369. Hamming, J.J.; Vink, M. Obstruction of the Popliteal Artery at an Early Age. J. Cardiovasc. Surg. 1965, 6, 516. Harris, J.D.; Jepson, R.P. Entrapment of the Popliteal Artery. Surgery 1971, 69, 246. Husni, E.A.; Ryu, C.K. Entrapment of the Popliteal Artery and Its Management. Angiology 1971, 22, 380. Inada, K.; Hirose, M.; Iwashima, Y.; et al. Popliteal Artery Entrapment Syndrome: A Case Report. Br. J. Surg. 1978, 65, 613. Insua, J.A.; Young, J.R.; Humphries, A.W.S. Popliteal Artery Entrapment Syndrome. Arch. Surg. 1970, 101, 771. Kessler, H.J.; McCabe, J.S.; Waller, J.V. Popliteal Artery Entrapment Syndrome. N.Y. State J. Med. 1976, 76, 80. Laubach, K.; Trede, M.; Perera, R.; et al. Das Kompressionssyndrom der Arteria Poplitea. Chirurgie 1973, 44, 74. Love, J.W.; Whelan, T.J. Popliteal Artery Entrapment Syndrome. Am. J. Surg. 1965, 109, 620. Mark, L.K.; Kiselow, M.C.; Wagner, M.; et al. Popliteal Artery Entrapment Syndrome. J. Am. Med. Assoc. 1978, 240, 465. Mentha, C. Malposition et Stenose Extrinsique de l’Artere Poplitee par la Compression Musculotendineuse du Jumeau Interne. J. Chir. 1966, 91, 489. Rich, N.M.; Hughes, C.W. Poplitieal Artery and Vein Entrapment. Am. J. Surg. 1967, 113, 696. Schulze-Bergman, G. Zum Kompressionssyndrom der Arteria Poplitea. Vasa 1972, 1, 186. Servello, M. Clinical Syndrome of Anamalous Position of the Popliteal Artery: Differentation from Juvenile Arteriopathy. Circulation 1962, 26, 885. Stuart, T.P.A. A Note on a Variation in the Course of the Popliteal Artery. J. Anat. Physiol. 1879, 13, 162. Turner, G.R.; Gosney, W.G.; Ellingson, W.; et al. Popliteal Entrapment Syndrome. J. Am. Med. Assoc. 1969, 208, 692. Van Bockel, J.H.; Biemans, R.G.M. Popliteal Artery Entrapment. Arch. Chir. Neerl. Fac. 1976, 28, 251. Bergan, J.J. Adventitial Cystic Disease of the Popliteal Artery. In Vascular Surgery; Rutherford, R.B., Ed.; Saunders: Philadelphia, 1977. Bergan, J.J.; Yao, J.S.T.; Flinn, W.R. Surgical Management of Young Claudicants: Adventitial Cyst. In Evaluation and Treatment of Upper and Lower Extremity Circulatory Disorders; Bergan, J.J., Yao, J.S.T., Eds.; Grune & Stratton: Orlando, FL, 1984. Cousin, J.; Leleu-Walle, M.; Cecile, J-P.; et al. Degenerescense Kystique de I’artere Poplitee chez un Garcon de 13 ans. J. Sci. Med. Lille 1973, 91, 85.
118. Flanigan, D.P.; Burnham, S.J.; Goodreau, J.J.; et al. Summary of Cases of Adventitial Cystic Disease of the Popliteal Artery. Ann. Surg. 1979, 189, 165. 119. Biemans, R.G.M.; van Bockell, J.H. Popliteal Artery Entrapment Syndrome. Surg. Gynecol. Obstet. 1977, 144, 604. 120. Ferrero, R.; Barile, C.; Buzzacchino, A.; et al. La Sindrome da Costrizone dell’arteria Poplia. Minerva Cardioangiol. 1978, 26, 389. 121. Ikeda, M.; Iwase, T.; Ashida, K.; Tankawa, H. Popliteal Artery Entrapment Syndrome: Report of a Case and Study of 18 Cases in Japan. Am. J. Surg. 1981, 141, 726. 122. Rich, N.M.; Collins, G.J., Jr.; McDonald, P.T.; et al. Popliteal Vascular Entrapment. Arch. Surg. 1979, 114, 1377. 123. Whelan, T.F., Jr. Popliteal Artery Entrapment Syndrome. In Vascualr Surgery; Haimovici, H., Ed.; McGraw-Hill: New York, 1976. 124. Yao, J.S.T.; Hobbs, J.T.; Irvine, W.T. Ankle Systolic Pressure Measurements in Arterial Disease Affecting the Lower Extremities. Br. J. Surg. 1969, 56, 676. 125. Barnes, R.W.; Strandness, D.E. Isolated Popliteal Artery Occlusion: Physiologic Observations. Vasc. Surg. 1972, 6, 103. 126. McDonald, P.T.; Easterbrook, J.A.; Rich, N.M.; et al. Popliteal Artery Entrapment Syndrome. Clinical Common Nonivasive and Angiographic Diagnosis. Am. J. Surg. 1980, 139, 318. 127. Baumann, G.; Schmidt, F.C.; Becker, H.M.; et al. Zystische Wand-Degeneration der Arteria Ilica External und Arteria Femoralis Communis. Chirurgie 1967, 38, 520. 128. Campbell, R.T.; McCluskey, B.C.; Andrews, M.I.J. A Case of Polycystic Adventitial Disease of the Left External Iliac and Fermoral Artery. Br. J. Surg. 1970, 57, 865. 129. Backstrom, C.G.; Linell, F.; Ostberg, G. Cystic Myxomatous Adventitial Degeneration of the Radial Artery with Development in the Connective Tissue. Acta Chir. Scand. 1965, 129, 447. 130. Richards, R.L. Cystic Degeneration. Br. Med. J. 1963, 3, 997. 131. Ruppell, V.; Sperling, M.; Schott, H.; et al. Pathological Anatomical Observations in Cystic Adventitial Degeneration of Blood Vessels. Beitr. Pathol. 1971, 144, 101. 132. Savage, P.E.A. Arterial Cystic Degeneration. Postgrad. Med. J. 1972, 48, 603. 133. Clark, K. Ganglion of the Lateral Popliteal Nerve. J. Bone Jt. Surg. 1961, 43, 778. 134. McEvedy, B.V. Simple Ganglia. Br. J. Surg. 1962, 49, 585. 135. Parkes, A. Intraneural Ganglion of the Lateral Popliteal Nerve. J. Bone Jt. Surg. 1961, 43B, 784. 136. Sutton, D. Arteriography; Livingstone: London/Edinburgh, 1962. 137. Connell, J. Popliteal Vein Entrapment. Br. J. Surg. 1978, 65, 351. 138. Gibson, M.H.L.; Mills, M.S.; Johnson, G.E.; et al. Popliteal Entrapment Syndrome. Ann. Surg. 1977, 185, 341.
CHAPTER 35
Extraanatomic Bypasses Steven M. Hertz Bruce J. Brener Donald K. Brief Frank J. Veith
Extraanatomic bypass grafts represent an important alternative reconstructive technique to conventional bypass methods in certain clinical situations. Revascularization of the brain, ischemic organs, or ischemic upper and lower extremities is traditionally carried out by a direct anatomic approach to the diseased vessels, relieving the occlusive process by endarterectomy, bypass grafting, or a combination of both. Alternative approaches to reconstruction are necessary when a conventional approach would carry too great a risk because of the poor health of the patient, the presence of infection, or other anatomic factors precluding direct exposure to the diseased vessels. The donor vessel generally provides circulation to a different part of the body than the revascularized area, and the graft may lie in an anatomic plane different from the diseased vessel. Despite the objections of some authors, these grafts have been called “extraanatomic,” not because they are outside the body, but because they are not in the usual location. Commonly used extraanatomic bypass grafts include carotid-subclavian, axilloaxillary, carotid-carotid, and carotid-vertebral bypasses for brachiocephalic occlusive disease and hepatorenal, splenorenal, and iliorenal bypasses for renal artery occlusive disease. Femorofemoral, axillofemoral, transobturator, ascending and descending aortofemoral bypasses are the commonly used extraanatomic procedures for the lower extremity, which is a more common site for atherosclerosis. The principles of revascularization of the brachiocephalic system and the renal vessels are described in Chapters 52, and 58. The present chapter deals primarily with the indications, hemodynamic principles, techniques, and results of the procedures involved in extraanatomic revascularization of the lower extremities.
GENERAL CONSIDERATIONS Indications for Extraanatomic Bypass The choice of anatomic or extraanatomic reconstruction is based on an evaluation of several factors: general health of the patient; ease of the reconstructive procedure; anatomical considerations such as scarring from previous surgery, presence of infection; and long-term patency results. The surgeon must weigh each of these factors; some may be more important than others in a given clinical situation. Axillofemoral and femorofemoral bypasses are most often performed in patients deemed to be at elevated risk for perioperative complications, due to the presumed lower risk of these subcutaneous procedures. The results of electively performed procedures on well-selected patients are excellent, with acceptable patency and mortality rates. Undoubtedly, some patients in whom this route is used would not survive conventional approaches. We have used the subcutaneous route to revascularize patients with acute lower limb ischemia following recent myocardial infarction, prolonged cardiopulmonary bypass procedures, and intraaortic balloon insertions.[1] Evidence of the high-risk nature of the population group undergoing extraanatomic bypass is seen in reports of short and long term mortality rates. Livesay et al.[2] have noted a mortality rate of 10% at 30 days and 52% at 2 years in their patients undergoing axillofemoral bypass. In other extraanatomic procedures, such as transobturator bypass and thoracic aorta-to-femoral bypass, the procedure related risks may be equal or greater than conventional aortofemoral bypass grafting. These bypasses may be prompted by the need to find a non-infected tissue plane or by the presence of a “hostile abdomen.”
Hobson/Wilson/Veith: Vascular Surgery: Principles and Practice, Third Edition, Revised and Expanded DOI: 10.1081/0819-9-120024918 Copyright q 2004 by Marcel Dekker, Inc.
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Hemodynamic Consideration An early concern in the performance of extraanatomic bypass grafting was the production of a “steal” phenomenon, that is, a diversion of blood away from the donor artery and the extremity supplied by it.[3,4] Initial clinical observations by several workers utilizing axillofemoral and femorofemoral techniques suggested that steal did not occur in the absence of a preexisting stenosis in the donor vessel or one produced at the proximal anastomosis to the donor artery. This has been confirmed by the experiments of multiple authors.[5 – 10] In the absence of disease in the donor artery, no decrease in the donor limb blood flow distal to the crossover was observed despite a 10-fold increase in the flow in the donor artery. This principle has been demonstrated in the human femorofemoral graft on numerous occasions by intraoperative flow measurements. If a proximal stenosis is present in the donor artery, the increased flow created by the new bypass distal to it will increase energy losses across the lesion. As a result the pressure will be lower in the distal donor and recipient arteries than in the artery proximal to the stenosis. This will be detected as a fall in donor femoral or ankle pressure or brachial pressure. The greater the stenosis, the greater the fall in donor limb pressure. Furthermore, if the donor limb has a high-resistance “runoff” bed and the recipient limb has a lowresistance outflow bed, the total flow through the donor stenosis may increase more than twofold. This would lead to a greater pressure loss. These physiological changes are not a “steal” of blood from the donor limb through the bypass, but a natural consequence of increasing flow through the previously unrecognized stenosis. It is therefore essential that there be no significant disease in the donor segment and that no stenosis be produced by the proximal anastomosis. The presence of ischemia in the donor limb immediately after the performance of an extraanatomic bypass should alert the surgeon to a technical problem at the donor anastomotic site or to the presence of a stenosis in the donor vessel, the importance of which was unappreciated. An interesting but yet unanswered question is the effect on the donor artery of the markedly increased flow rate proximal to the origin of the extraanatomic bypass. The artery proximal to a large chronic arteriovenous fistula is dilated and often aneurysmal. This has not been observed in donor arteries supplying extraanatomic bypasses followed up to 15 years. Presumably, this is because the flow rates are lower through the donor artery due to the higher resistance of the arterial system, and therefore dilatation and aneurysmal degenerative processes do not occur. Various authors have speculated on the protective effects to the donor artery but supportive data are scant and contradictory.[11 – 15]
GRAFT MATERIALS There is no conclusive evidence that one graft material is preferable for extraanatomic procedures. Long-term patency has been demonstrated with Dacron in multiple series. Expanded polytetrafluoroethylene (ePTFE) has also been used extensively for extraanatomic reconstructions. Both
graft materials are available with external ring reinforcement, which may avoid problems with kinking and compression in some circumstances and may give additional longevity to certain bypasses.[16,17] Crimped grafts have a lower patency rate at reduced flow rates.[18] Autologous saphenous vein has been used successfully in the crossover femorofemoral position. The length of graft necessary for axillofemoral operations makes autologous vein impractical, although its use has been reported.[19] The optimum diameter of synthetic grafts has not been clearly established. Higher blood flow velocities are found with 6- and 8-mm grafts than with larger grafts. These diameters are probably adequate for most extraanatomic grafts, and 6-mm grafts may be superior, particularly in settings where bypass flow rates will be relatively low.[20] It would appear that satisfactory long-term patency rates associated with extraanatomic bypass grafts to the ischemic lower extremity relate more to the proper selection of patients, the status of the donor artery, disease progression, and attention to technical details than to the choice of graft material.
FEMOROFEMORAL GRAFTS The earliest reports of femorofemoral grafting for unilateral iliac occlusive disease were by Freeman and Leeds,[21] Oudot and Beaconfield,[22] McCaughan and Kahn,[23] and Vetto.[24,25] Our (BB, DKB, SMH) current 30 years experience with 277 patients treated for unilateral atherosclerotic iliac occlusive disease continues to support the concept of extraanatomic bypass as a means of dealing with this problem.[26 – 29] Femorofemoral grafts have also been useful in revascularizing a limb after unilateral occlusion of an aortobifemoral graft, in allowing continued support of patients who require intraaortic balloon pumping but whose circulation to the extremity is obstructed by the balloon catheter, and in the management of patients with infected or damaged iliac arteries. The following discussion focuses on the use of femorofemoral grafts for unilateral atherosclerotic occlusive disease since the application of this operation to other clinical settings is obvious and the technical principles are similar to those with occlusive disease. The indication for femorofemoral grafts is the presence of disabling claudication, rest pain, or gangrene. If the patient’s symptoms are primarily unilateral and a strong femoral pulse is present on the unaffected side, the patient can be evaluated for a femorofemoral graft. Angiography and peak systolic pressure determinations in the aorta and distal donor iliofemoral arterial system are necessary before an accurate final decision to perfom this operation can be made. It is often necessary to combine these two studies because conventional arteriography in the anterior-posterior plane may not detect significant obstructive lesions in the iliac system. One can obtain accurate preoperative assessment by performing retrograde transfemoral catheter aortography via the donor femoral artery with oblique views and accurate pressure measurements. Questionable areas of stenosis noted on arteriography may not produce significant pressure gradients at rest. Flow rates in the proposed donor iliac artery can be
Chapter 35.
increased by exercise, vasodilators, or cuff-induced ischemia to elicit or magnify these gradients.[30 – 36] The criteria for a positive femoral artery test has been the subject of some study. We and other authors[37] have accepted a change of less than 15% of the resting aortic pressure during reactive hyperemia or pharmacological vasodilatation as indication of an insignificant stenosis. However, Verhagen and coworkers[38] found that a 20% fall was a better criterion since it was associated with a sensitivity of 87% and a specificity of 78%. Intraoperative pressure measurements may also be useful[39,40] and postbypass pressures and gradients may detect unsuspected or unappreciated stenoses and serve as a guide to their management.[41] Stents have an increasingly important role in such management. Should femorofemoral bypass grafts be inserted if there is a donor iliac lesion? Although this can be expected to compromise the ultimate long term outcome of the graft and subject the donor leg to a decrease in perfusion, a small number of grafts placed in this position[15,32,41 – 42] have fared surprisingly well. Archie has shown a relationship between iliac artery gradients and graft failure, although the wide variability of measurements makes choosing a “cut-off” level difficult.[43] If a hemodynamically significant stenotic lesion is present in the donor artery and the patient is not a candidate for the traditional aortofemoral or axillofemoral bypass, there are three adjuinctive procedures that allow femorofemoral bypass principles to be utilized by modifying the iliac inflow. These are balloon angioplasty, with or without stent
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placement, iliac endarterectomy, and iliofemoral bypass. Multiple series report favorable results utilizing these techniques.[44 – 52]
Technique The technique for the femorofemoral bypass graft has changed little since its original description and is briefly illustrated in Fig. 35-1. The operation can be done under local anesthesia, but regional or general anesthesia may be preferable, if the clinical situation permits. A two-team approach reduces operating time. After appropriate preparation and draping of the lower extremities and groin areas, vertical incisions are made over the femoral vessels. The dissection is carried down to the femoral arteries, ligating the lymphatic tissue to avoid postoperative collections. The vessels are thoroughly dissected, preserving all significant collateral branches, and the deep and superficial femoral arteries are isolated. The subcutaneous suprapubic tunnel is made, and then the patient is given systemic heparin. The tunnel should be carefully constructed so that there is a smooth curve and the graft is not kinked as it approaches the femoral artery (Fig. 35-1). If the superficial femoral artery is occluded and the common femoral artery is patent back to the hypogastric system, the graft is placed in the common femoral artery but carried onto the deep femoral artery to ensure good outflow. If
Figure 35-1. The insertion of a femorofemoral graft. Incisions are made directly over the femoral vessel (left ). Arteriotomics are made (right ) to ensure appropriate inflow and outflow, often involving deep femoral artery reconstruction. The graft must be carefully placed in the subcutaneous tunnel to avoid kinking (lower right ).
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there is significant disease in the orifice of the deep femoral, an appropriate endarterectomy or graft/patch angioplasty is carried out under direct vision. If both the common femoral and the superficial femoral arteries are occluded and the profunda femoral is the only outflow tract for the graft, an end-to-end or end-to-side anastomosis to this vessel is carried out. If the deep femoral is a small vessel or is extensively diseased, a concomitant femoropopliteal bypass may be necessary. In our experience this has been necessary in a small percentage of cases, since the deep femoral artery has usually been adequate. Care must be taken to avoid creating intimal flaps or clamp trauma in either femoral artery since both may be heavily involved with nonocclusive atherosclerosis. Occasionally some form of endarterectomy, interposition, or patch angioplasty on the donor distal iliac or common femoral vessels is required to ensure adequate inflow. We prefer to use 6-mm or 8-mm Dacron or expanded polytetrafluoroethylene with 5-0 or 6-0 sutures for the anastomoses. Optical magnification is helpful. External support may be helpful to avoid problems with angulation and kinking. When bleeding is controlled and no technical problems are noted, heparin is reversed with protamine sulfate and the wounds are closed without drainage. Occasionally an intraoperative arteriogram is performed. It is important to perform a secure layered closure to avoid dead space and minimize wound sepsis. The skin is carefully approximated and light dressings applied. In the recovery room baseline plethysmographic tracings and segmental arterial pressure may be obtained. Although the graft pulse may not be palpable because of edema, its patency can be confirmed by direct Doppler examination or by hearing a bruit in the suprapubic area. Deterioration in the clinical or noninvasive evaluation in the postoperative period demands immediate reoperation. Graft thrombectomy can be performed and technical defects can be corrected. However, delay may lead to failure of the operation and limb loss. When the femorofemoral graft is required to provide circulation to a limb rendered ischemic by an intraaortic balloon, the following technique may be useful if the distance between the arterial entry of the balloon pump and the site for anastomosis of the femoro-femoral bypass is inadequate. The occluded common femoral artery can be divided distal to the ballon insertion site, and the graft is sutured to it end-to-end. The balloon catheter is isolated from the graft so that it can be removed at a later procedure without further contamination of the graft. Alternatives to this operation included removal of the intraaortic balloon with thrombectomy and replacement at another site.
Results Patency rates for femorofemoral crossover grafts have varied considerably. Results of our cumulative 30-years experience and other studies are summarized in Table 35-1. Five-year cumulative patency in about 2000 patients ranged from 45 to 80%. In our series of 277 patients, primary patency was 56% at 5, 42% at 10, and 33% at 15 years. Secondary patency was 69%, 55%, and 43% at 5, 10, and 15 years, respectively (Table 35-2).
Graft failures following femorofemoral bypass are usually a result of progressive disease in the recipient outflow vessels. In 100 cases analyzed in our series[29] there were 43 graft failures; 19 were a results of recipient femoral artery stenosis. There were 12 instances of graft failure due to the development of new lesions in the donor vessels. One stenosis proximal to an aortofemoral graft inserted elsewhere, five iliac lesions proximal to the femorofemoral graft, and six lesions in the donor common femoral artery appeared during the follow-up period and resulted in graft failure. Four infections necessitated graft removal. The most important factor influencing patency was the presence of a previous inflow procedure. Several authors have reported their experience in this subgroup of patients.[41,44 – 51] In our most recent experience primary patency at five years was 64% when no previous surgery had been carried out and 43% when an inflow procedure had been performed previously (see Table 35-2). This correlation has been noted by Rutherford et al.[66] and Kalman and colleagues[65] and probably reflects the fact that the condition which led to failure of the primary procedure affects the longevity of the second operation. Likewise, the need for an adjunctive procedure on the donor limb such as balloon angioplasty, stent or iliac endarterectomy or interposition grafting seemed to compromise the short term success of the femorofemoral graft, reducing the patency at one year from 81% for uncompromised femorofemoral grafts to 66% in our patients. In a report of 18 femorofemoral grafts inserted after angioplasty, Brewster et al.[51] also noted two failures during the period of follow-up. Others report no effect of donor iliac angioplasty or femoral –femoral patency.[71] The effect on graft patency of the status of the superficial femoral artery is unclear. Piotrowski and collegues[72] found an adverse effect of chronic occlusion of the superficial femoral artery, reducing patency from 92% to 35%. Rutherford noted a significant effect of “poor runoff” as well.[73] Our results indicated a reduction in patency from 57% to 42%, but this difference was not statistically significant.[29] Several authors have noted a reduction in donor limb perfusion after femorofemoral grafting.[31 – 32] Harris et al.[32] found a deterioration of either the resting or after-exercise ankle-brachial index in the donor limb in 20 of 44 patients undergoing femorofemoral bypass for claudication. Eighteen of the 20 had patent superficial femoral arteries. Four patients underwent aortofemoral bypass after femorofemoral grafting. Presumably the deterioration in donor limb hemodynamics was not clinically significant in the other patients. This report underlines the importance of careful preoperative evaluation of the donor limb with arteriography including oblique views and intraarterial pressure measurements under conditions of enhanced flow. Preoperative noninvasive tests are usually not adequate to identify iliac lesions in the donor limb, partly because the patient cannot exercise fully due to recipient limb ischemia. Furthermore, standard single-plane angiography can be inaccurate in identifying iliac lesions. The operative mortality and long-term survival rates following femorofemoral grafting depend upon patient selection. The wide varation in operative mortality rate from 0 to 15% (Table 35-1) reflects the use of this operation in both low- and high-risk patients. A 3% perioperative
Chapter 35. Table 35-1.
531
Extraanatomic Bypasses
Mortality and Patency Rates for Femorofemoral Grafts Percent patency at
Plecha and Pories[53] Brief et al.[54] Eugene et al.[55] Mannick and Baini[56] Flanigan et al.[30] Livesay et al.[2] Dick et al.[27] Chang[57] Harris et al.[32] Subram et al.[58] Laurendeu et al.[59] Previous vascular surgery No previous surgery High Risk Low Risk Veith and Gupta[20] Plecha and Plecha[60] Bergqvist et al.[61] Lamerton et al.[62] Bunt[63] Foster et al.[64] Kitka et al.[15] Kalman et al.[65] Previous vascular surgery No previous surgery Rutherford et al.[66] Previous vascular surgery No previous surgery Hepp et al.[67] Fahal et al.[68] Ricco[69] Harrington et al.[70] Authors’ 30-year experience
Year
N
Operative mortality (%)
1976 1976 1977 1977 1978 1979 1980 1981 1981 1983 1983
54 99 33 53 80 36 133 48 44 85
15 3 15 2 4 6 6
2
85 91
19
6
82
66
17 45 61 119 81 61 36 103 27
8 0
88 93 87 98 92
80 89
39 43
0 0
13 47 26 150 74 162 277
0 0 4 4 0 6 3
1984 1984 1984 1985 1986 1986 1987 1987
2 9 4 0
1 year
3 years
5 years
91 84 77 91
76 66
80 62
71 45 80 74 56 73 62
76
63
84 90
84 83
10 years
72 85 60
15 years
55
93 57 79
95
51
47a 90a
1987
1988 1989 1992 1992 1998
75a/90b 90a/95b 100
39a/51b 74a/82b 80
39a/51b 74a/82b 80 86c
84
79 70
52 57 36a/69b
42a/55b
33a/43b
a
Primary. Secondary. c Does not count early failures or deaths. b
mortality rate was seen in our experience. In another study by our group, approximately 80% of our patients were alive 5 years after the operation and 70% after 10 years.[27] The lowest 5-year survival of 42% was reported by Eugene et al.[55] Five-year survival after aortofemoral bypass has remained high, in both our experience (71%) and that of others.[74,75] Should a good-risk patient with hemodynamically significant unilateral iliac disease and a normal contralateral iliac artery have a crossover femorofemoral graft, percutaneous balloon angioplasty, stent, endarterectomy, unilateral aortofemoral, iliofemoral, or aortobifemoral bypass? Balloon angioplasty has excellent long-term results for isolated, short stenoses in the common iliac artery. In a prospective study five year patency varied from 70% for common iliac stenoses in patients with claudication and good runoff to 10 –20% for external iliac occlusions in patients with poor runoff and
Table 35-2.
Authors’ Cumulative Experience 1 year 5 years 10 years 15 years
Total group ðn ¼ 277Þ 18 28 No previous surgery ðn ¼ 177Þ 18 28 Prior inflow procedure ðn ¼ 60Þ 18 28
73 84
56 69
42 55
33 43
82 88
64 76
52 65
47 60
53 72
43 43
17 29
8 19
Adjunctive donor procedure ðn ¼ 40Þ 18 66 28 81
30 51
— —
— —
532
Part Four. Peripheral Occlusive Disease
severe ischemia[76] Iliac angioplasty and stent patency rates can be expected to be excellent in selected patients. A collective review of more than 6000 procedures demonstrates the large variation reported in 5-year patency rates from 32% to 92%.[77] Unilateral iliac endarterectomy and iliofemoral bypass avoid dissection of the normal donor vessels and have excellent patencies in some series[49,64,77 – 80] but poor results in others.[68] Aortofemoral bypass can be performed with low operative mortality and morbidity rates and excellent patency; in a comparison of aortofemoral and femorofemoral bypass we found the five year primary patencies to be 85% and 45% respectively. The mortality and morbidity rates were higher in the aortofemoral group but the differences were not statistically significant.[29] Despite the poorer patency compared to aortofemoral bypass we often prefer to use the femorofemoral graft. This simple operation avoids aortic dissection, produces acceptable secondary patency rates, does not preclude later aortofemoral procedures if they should prove necessary, and avoids bypassing a patent iliac artery. In the most favorable situation, namely a patient without pervious surgery, with acceptable runoff, and with a secure inflow, a primary patency of 64% and a secondary patency of 76% at 5 years can be expected.
AXILLOFEMORAL GRAFTS In 1961, Lewis[81] showed that the axillary artery could supply blood to an ischemic lower half of the body. In 1963 Blaisdell and Hall[82] and Louw[83] reported on the use of axillofemoral grafts to revascularize extremities in poor-risk patients. In 1966 Sauvage and Wood[84] added the femorofemoral extension to the axillofemoral graft for patients with bilateral iliac disease. Subsequent reports by a variety of authors confirm the place of this operation in a variety of clinical settings. Modern indications for axillofemoral grafts include management of aortoiliac occlusive disease in poor-risk patients, aortoenteric fistula, infected aortic grafts, infected aortic aneurysms, and aortic aneurysm in poor-risk patients. The selection of this operation rather than aortofemoral bypass for relief of chronic occlusive disease is based on the estimate of the risk status of the patient as well as a variety of anatomic factors already enumerated. The use of this procedure in patients with chronic iliac occlusive disease is usually limited to patients requiring limb salvage. Most patients too ill to undergo aortic surgery do not require bypass for relief of claudication. Recently, more favorable patency results have led some author’s to broaden their indications for axillo-femoral bypass.[85] Before performing this operation, it is necessary to establish that no occlusive lesion is present in the subclavian or axillary artery. The usual clinical criteria for the absence of subclavian artery stenosis are the absence of a bruit and the presence of equal cuff blood pressures in both arms. However, some surgeons believe routine arteriography of these vessels should precede this operation. Calligaro et al.[86] found that 16% of failed axillofemoral grafts were associated with a stenosis of the axillary artery. Since the left subclavian artery is more frequently the site of disease, some surgeons routinely choose the right subclavian artery as the donor vessel. We
prefer to use the axillary artery ipsilateral to the ischemic leg whenever possible.
Technique The technical principles of axillofemoral bypass for chronic ischemia can be outlined as follows (Fig. 35-2). A wide preparation and draping of the patient is necessary. We favor a circumferential prepping of the donor arm so that it can be moved during the procedure to check on tension of the graft and ensure that kinking of the axillary artery does not occur. Although local anesthesia can be used, we favor general anesthesia and a two-team approach to shorten operating time. A subclavicular incision is made over the donor axillary artery by one team and the groin incisions made in the usual manner by a second team. The fibers of the pectoralis major are separated and the pectoralis minor tendon may be divided to avoid angulation of the graft and facilitate exposure. The first and second portions of the axillary artery are dissected and controlled, and an appropriate area is selected for the donor anastomosis. Blaisdell[87] recommends the use of the first portion of the axillary artery between the chest wall and the medial border of the pectoralis minor muscle since the vessel is fixed in position and there is only one collateral. The third portion of the artery is never used since shoulder motion affects this segment, and this has been implicated in the development of proximal anastomotic pseudoaneurysms and graft separation from the axillary artery.[88,89] When all dissections are complete, the subcutaneous tunnel is made, curving to the mid-axillary line to avoid angulation over the costal margin in the sitting position. The tunnel is then curved medial to the iliac crest to approach the femoral vessels. Ward and his colleagues[90] described placement of the graft throughout most of its length in the subfascial plane under the pectoralis major muscle and the external oblique fascia. They believe this is a more protected position for the graft, particularly in thin individuals. A counterincision is sometimes necessary to tunnel the graft properly and is generally made just inferior to the costal margin. After the vessels are exposed and a suprapubic tunnel is made subcutaneously, the patient is given systemic heparin, and the first anastomosis is carried out to the donor axillary artery. The inferior aspect of the artery is chosen so that no kinking occurs; a beveled anastomosis is preferred. The proximal graft should lay nearly parallel to the axillary artery before sweeping inferiorly. The graft is then tunneled carefully under the pectoralis major muscle to avoid kinking or tension, and the anastomosis to the femoral artery is performed in a standard fashion. Many graft configurations have been used but most authors agree that the crossover component of the graft should originate from the most distal portion of the axillo-femoral graft. Ward et al.[90] and Blaisdell[87] have suggested attaching the femorofemoral limb to the divided proximal common femoral artery. This reduces the bulk of the anastomosis and provides two outflow segments for the axillary femoral graft, one to each leg. This technique requires that there be no stenoses in the common femoral artery. Harris et al.[23] performed the femorofemoral anastomoses first, adding the axillofemoral graft to the hooded portion of the femorofemoral graft. Others have utilized a “lazy S” configuration.[91] Wittens et al. report the use of a “flowsplitter” prosthesis.[92]
Chapter 35.
Extraanatomic Bypasses
533
Figure 35-2. The insertion of an axillobifemoral bypass. (A ) Incisions are made over the donor and recipient vessels. A separate incision for the tunnel is sometimes necessary. (B ) The proximal anastomosis is aided by transection of the pectoralis minor muscle, exposing the first and second portions of the axillary artery. (C ) The graft is tunneled beneath the pectoralis major muscle. (D ) The finished reconstruction is seen. An alternative anastomosis, recommended by Blaisdell,[87] is noted (inset ).
534
Part Four. Peripheral Occlusive Disease
We usually employ an 8-mm graft for the vertical limb and a 6- or 8-mm graft for the horizontal femorofemoral portion. Both Dacron and polytetrafluoroethylene grafts can be used with or without external support. There is no firm evidence that results with one material is superior to the other.[85,86] Externally supported grafts are often pictured to decrease the risks of kinking and compression.[16,93] When an infected groin wound is to be bypassed, the graft is tunneled lateral to the walled off infected wound and is anastomosed to the deep or superficial femoral artery.[94] The axillofemoral wounds are then closed and sealed and the old infected graft removed. When this is done, the femoral artery must be ligated proximally and distally to prevent bleeding.
Results Reported patency rates of axillofemoral grafts for occlusive disease have varied considerably (Table 35-3), with a range in these series of 5-year patency from 36% to 90%. Recent reports of excellent results from the University of Oregon and other authors raise the standards for expected patencies.[17,85,93] Results approaching that of aortofemoral bypass raise the question of extending the role of axillo femoral bypass to treat better risk patients.[85] Patient selection criterion and other specific factors may explain the variation in results seen. Many feel that the addition of the cross-femoral limb extends patency. Five-year primary patency for unilateral axillofemoral bypass noted in three reports is 44%, 19%, and 35%;[84,66,93] Secondary patency for the same procedure is 71%, 37%, and 50%. Five-year primary patency for axillobilateral bypass is 50%, 62%, 85%;[84,66,17] secondary patency is 77% and 82%. In contrast, in a compartive evaluation, Mohan et al.[118] and Ascer et al.[111] found no differences in primary or secondary patencies between axillounifemoral and axillobifemoral grafts. Several authors have postulated that factors which increase flow rates in the graft will increase the likelihood of success. Ray et al.[104] have indicated that a flow rate of over 250 ml/min is necessary for prolonged function. This may explain why the patency in patients with claudication is greater than in those with severe ischemia.[92,104] Similarly, when the iliac flow is severely restricted, there is less competition and therefore a higher flow rate in the graft and increased patency.[104] Further, when the superficial femoral artery was patent, Johnson et al.[101] found a success rate of 95% as compared with 67% when the profunda femoral was the sole runoff vessel. Rutherford et al.[66] found that occlusion of the superficial femoral artery reduced primary patency of axilliounilateral femoral grafts from 54% to zero and for axillobilateral femoral grafts from 92% to 41%. However, Ascer et al.[111] found that although three-fourths of patients with graft occlusions had superficial femoral artery occulusion the same fraction of those with graft patency had superficial femoral artery occlusions. Among the technical factors influencing patency, many feel that graft configuration plays an important role. Several variations of graft geometry have been utilized with variable success. The use of the “inverted C” configuration, as described in the techniques section, is widely used with excellent results. A prospective randomized study demon-
strated the advantage of a “flowsplitter” design over a 908 bifurcation, with 2-year patency improved to 84% from 38%.[119] Others report the use of a “lazy S” configuration with acceptable patency of 73% at 5 years.[117] Other suggestions to increase patency have included using noncrimped or externally supported grafts. Despite the ease of thrombectomy of polytetrafluorothylene grafts, several studies have failed to confirm increased patency rates with this material. Complication associated with these procedures are not unique and include disruption of the axillary anastomosis,[88,89] thrombosis of the graft of donor artery,[120] brachical plexus injuries, false aneurysms, and infection. The operative mortality rate has remained under 10% in most studies. However, as might be expected, the 5-year survival rate has been limited. Although in the study of Johnson et al.[101] two thirds of patients were alive 5 years after surgery, survival after 5 years was as low as 26% in the report of Eugene et al.[55] Schneider found a 3-year survival rate of 35% in a high-risk group.[121] The axillofemoral grafts has been used with great success in the management of infected aortic aneurysms and grafts and aortic enteric fistulas (Chapter 47). It has been combined with iliac ligation and induced thrombosis to treat patients with unruptured aortic aneurysms.[122] However some aneurysms have ruptured after such treatment and other complications have been reported.[123 – 126]
THORACIC AORTA TO FEMORAL ARTERY BYPASS Descending thoracic or supraceliac aorta to femoral artery bypasses have been used in a number of unusual circumstances including infection, previous graft failures, and adhesions.[127 – 138] Descending thoracic aorta to femoral artery bypass was first performed by Sauvage in 1956.[139] Passman has presented a cumulative experience of 50 descending thoracic aorta to ileofemoral bypasses.[140] A low operative mortality of 4% with a 5-year patency of 79% was obtained. Other authors have reported encouraging results in a veriety of clinical settings.[136,141 – 146] Use of the supraceliac aorta through a transperitoneal or retroperitoneal approach is advocated by some and may be helpful in certain circumstances.[134,137,138] Schumaker first described the bypass procedure from the ascending aorta to the femoral artery bypass in 1968[147] in the treatment of abdominal coarctation of the aorta. Frantz et al.[148] applied this principle and reported ascending aorta to femoral artery bypass for the totally occluded infrarenal abdominal aorta in 1974. Others[149 – 155] have successfully employed this operation in the presence of obesity, horseshoe kidney, abnormal renal arteries, large ventral hernias, thoracoabdominal coarctation, failed aortoiliac repair, and multiple laparotomies. Baird et al.[156] have reported 18 cases, five of whom underwent concurrent mediastinal operations. In brief the technique involves a sternal splitting incision and the usual groin incisions using a two-team approach. A small transverse incision above the arcuate line may be helpful to carefully place the graft in the extraperitoneal position deep to the rectus muscle. The
Chapter 35.
Year
N
Mannick et al.[95] Moore et al.[96] Cormier and Bacourt[97]
1970 1971 1971
Krieger et al.[98] Bliss and Barrett[99] Logerfo et al.[100]
1971 1972 1976
Johnson et al.[101] Eugene et al.[55]
1977 1977
Scheiner[102]
1978
37 24 22 29 15 7 64 66 56 35 24 45
DeLaurentis et al.[103] Ray et al.[104]
1978 1979
Livesay et al.[2]
1979
Whittemore et al.[105]
1980
Broome et al.[106]
1980
Burrell et al.[107]
1982
Kenney et al.[108] Courbier et al.[109] Bergqvist et al.[61] Corbett et al.[110]
1982 1982 1984 1984
Ascer et al.[111]
1985
Foster et al.[64]
1986
42 33 21 26 14 54 17 44 36 38
Operative mortality (%) 4 10 10 0 0 8 2 8 2 8 4 10 7
8
Chang
1986
29 220 36 17 13 34 22 40 12 88
Donaldson et al.[113]
1986
100
8
Savrin et al.[114] Christenson et al.[115] Rutherford et al.[66]
1986 1986 1987
Pietri et al.[116]
1987
7 4 13 11 7
Hepp et al.[67]
1988
33 85 15 27 131 10 102 22 17 24 76 184 108 81
[112]
Cina et al.[91] [17]
Harris et al. Taylor et al.[93] Passman et al.[85] Mii et al.[117] b
Primary. Secondary.
535
Mortality and Patency Rates for Axillofemoral Grafts
Table 35-3.
a
Extraanatomic Bypasses
1988 1990 1994 1996 1998
4 14 0 5 12
5 5
5 3 4
Percent patency at Graft Uni Uni Bi Uni Uni Uni Uni Bi Bi Uni Bi Uni Bi Uni/Bi Uni Bi Uni Bi Uni Bi Uni Bi Uni Dacron Bi Dacron Bi PTFE UniBi Uni/Bi Uni Bi Uni Bi Uni Bi Uni Bi Uni Bi Uni/Bi Uni Bi Uni Bi Uni Bi Uni Bi Bi Uni/Bi Bi Uni/Bi
1 year
75 67 87 64 89 83b 60 60 60 90 62 75 90 77
3 years
5 years
80 74 30
54
76b 40 36
37 74 76b 30 36 51 90
75 85 77 75
67
24 30 75 37a/66b 71a/97b 73 100 66 45 57 65a/95b 85a/90b
38 44a/90b 50a/77b 48b 48b
29 42 78 48 78a 64a/74b
b
85
a
93 88 90 89a/95b
19a 62a a 46 /60b
b
73 64a 74a 85a 74 74 81a/88b
44a/71b 50a/77b 32b 33 75 21 34 75 72 19a/37b 62a/82b 35a/50b 46b 73b 69a/72b 85a 71a/79b 74 73a/80b
536
Part Four. Peripheral Occlusive Disease
ascending aortic anastomosis is performed, using 6- or 8-mm PTFE. The graft is sutured to the femoral artery of the more ischemic extremity and crossover 6- or 8-mm graft is inserted to the opposite limb. In an update to his experience, Baird, who has labeled this the “ventral aorta procedure,” reported an 80% 5-year patency in 25 patients.[157] We have found this procedure useful in patients with limb threatening ischemia who require coronary bypass. Occasionally, these patients develop tissue necrosis soon after coronary surgery if the internal mammary collaterals are interrupted or the postoperative course is complicated and a revascularization procedure cannot be carried out promptly. More data are necessary to determine if this extended graft can be combined with coronary bypass with an acceptable operative risk and patency rate.
OBTURATOR FORAMEN BYPASS GRAFTS In 1962 Shaw and Baue[158] used the obturator foramen as an extraanatomic route to bypass groin infection in three patients. Since then over 200 cases have been reported in the literature. VanDet and Brands[159] reviewed results with 66 cases in the literature and added 13 others. Prenner and Rendl’s review included 153 patients.[160] Several recent reports have been published.[161 – 168] The indications for the procedure have included infections of prosthetic grafts; femoral mycotic aneurysms; septic aneurysms after cannulation, catheterization, or balloon counterpulsation; mycotic embolization into the femoral artery with autolysis of the femoral artery; large aneurysm of the ileofemoral system; scar tissue in the groin following previous vascular surgery; loss of covering tissue as a result of injury, irradiation necrosis, or resection of a malignancy; and a need for revascularization despite suppurative lymphadenopathy.
Technique The technique has been detailed by Guida and Moore[169] and Baue and Tilson[170] (Fig. 35-3). The donor artery may be a previously placed aortofemoral limb that is not infected, the aorta, the ipsilateral iliac artery, or the contralateral iliac vessel. The donor vessel is approached either retroperitoneally or transperitoneally through either a vertical incision or preferably a transverse incision. The obturator artery, vein, and nerve penetrate the obturator fascia laterally. The tunnel is created anteromedially to these structures just under the superior ramus of the pubis. The fibers of the obturator internus muscle are separated, and the tough obturator fascia is broken by either blunt or sharp dissection. A tunneling instrument is inserted after the superficial femoral or popliteal artery is dissected near the adductor hiatus. Some authors believe the instrument should be passed from above, but Pearce et al.[164] state that the instrument can be more safely passed from below. The tunneling instrument is placed deep to the adductor longus, and anterior or posterior to the adductor magnus and into the enlarged hiatus. The distal
anastomosis is placed at the appropriate location. Dacron, polytetrafluoroethylene, umbilical vein, and saphenous veins have been used, the latter being preferred in infected cases. Some authors recommend ligation of the external iliac artery below the upper anastomosis and the superficial femoral artery above the lower anastomosis, but we usually prefer to ligate the infected femoral artery directly. This is done after the clean incisions are closed and walled off. Few reports of the long-term fate of obturator bypass grafts are available. Tilson et al.[161] reported 1 late failure at 10 months in 10 grafts followed 6 months to 9 years. VanDet and Brands[159] found failures at 4 and 7 months in 134 grafts followed for up 6 years. Erath et al.[162] noted 3 late failures at 13, 19, and 28 months in 9 grafts observed for up to 52 months. All grafts at risk were patent at least 12 months. Pearce et al.[164] implanted 9 grafts, 8 of which were PTFE and one of which was autogenous vein; 4 grafts failed, 3 within one month and one at 4 months. Rawson[165] presented 5 cases, 2 of which failed. Panetta et al.[167] had success at 112 and 212 years with saphenous vein grafts. The largest series was reported by Nevelsteen et al. from Belgium.[166] Fiftyfive grafts were implantged over a 16-year period. The overall 5-year patency was 37%; above-knee patency was 71% and below-knee patency was 45% at 3 years. Late failure may be corrected by insertion of grafts through normal anatomical planes once the infection has been obliterated. Complications have included graft occlusion, hemorrhage, infection, interval gangrene, injury to the obturator vessels or nerves, and perforation of the rectum and bladder. In summary the obturator foramen provides a satisfactory route for revascularization where an extraanatomic route to the lower extremity is necessary because of the presence of an infected groin wound. Alternatives include femoral artery ligation without reconstruction, immediate or delayed reconstruction through the infected field with autogenous tissue, axillopopliteal bypass,[171] or lateral femoral bypass.[94,163,172,173] This latter technique consists of an extraperitoneal exposure of the aorta or iliac arteries and a lateral subcutaneous tunnel around the infected groin, lateral to the anterior superior iliac spine.[94] We have used all these methods. Induvidual judgments must be made since each technique has its merits.
AXILLOPOPLITEAL AND OTHER EXTENDED EXTRAANATOMIC BYPASS The subject of extraanatomic bypass and its role in revascularization of the lower extremities is limited only by the surgeon’s ingenuity and resourcefulness. Veith and his colleagues[171,174] summarized their experience with a variety of unusual bypasses necessitated by anatomical and risk factors in 61 patients followed for 12 –17 months. These consisted of 11 axillopopliteal, 3 crossover axillopopliteal, 5 crossover femoropopliteal or tibial, 8 femoral-poplitealtibial, and 3 miscellaneous extended extraanatomic grafts. A similar study was reported by Connolly et al.[175] The Montefiore group[176] updated their results with 55
Chapter 35.
Extraanatomic Bypasses
537
Figure 35-3. The insertion of a graft through the obturator foramen. (A ) Incisions are made over the iliac artery, which is exposed retroperitoneally, and over the femoral artery proximal to the adductor canal in this illustration. (B ) The obturator internus muscle and obturator fascia are incised medial to the neurovascular bundle. (C ) The bypass in tunneled superficial to the adductor muscles in this example.
538
Part Four. Peripheral Occlusive Disease
polytetrafluoroethylene axillopopliteal grafts. The primary five-year patency rate was 40%; the secondary patency was 59%. If the axillopopliteal bypass was a sequential graft from the axillary vessel to the femoral vessels and then to the popliteal vessels, the patency rate increased to 74% at 3 years. This is an unusual operation that should be used sparingly and probably as a sequential bypass whenever possible. An axillofemoral left renal bypass was used by McCready et al.[177] to revascularize a left kidney in a patient with an acute aortic occlusion associated with a suprarenal aortic aneurysm. The fact that these operations worked for a significant period of time is indicative of the importance of attention to details of technique and hemodynamic principles as well as the graft materials currently available.
SUMMARY A variety of extraanatomic bypass grafts are available to the imaginative surgeon when standard bypass procedures cannot
be performed safely because the poor operative risk of the patient, the presence of infection, or other anatomic factors obviate standard bypass procedures. In the ischemic lower extremity, axillobifemoral grafts are most commonly used for bilateral lesions and crossover femorofemoral grafts for unilateral disease. Dacron and PTFE grafts, 6 and 8 mm in size, are generally used with nearly equivalent results. The donor artery should be free of a hemodynamically significant lesion, and adequate runoff must be achieved. With meticulous technique and occasional revisions satisfactory long-term results can be achieved with results at 5 years slightly inferior to conventional aortofemoral bypass grafting. Operative morbidity and mortality rates are lower than one would expect if the more extensive intraabdominal operation were carried out in the group of patients. Although infected grafts can be managed by removal without reconstruction or by reconstruction with autogenous material through the infected field, extraanatomic bypass of the infected field will continue to have a major role in the approach to this difficult problem.
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Part Four. Peripheral Occlusive Disease Inahara, T.; Geary, G.L.; Mukherjee, D.; Egan, J.M. The Contrary Position to the Non-Resective Treatment of Abdominal Aortic Aneurysm. J. Vasc. Surg. 1985, 2, 42– 48. Lynch, K.; Kohler, T.; Johansen, K. Nonresective Therapy for Aortic Aneurysm: Results of a Survey. J. Vasc. Surg. 1986, 4, 469– 472. Schwartz, R.A.; Nichols, W.K.; Silver, D. Is Thrombosis of the Infrarenal Abdominal Aortic Aneurysm an Acceptable Alternative? J. Vasc. Surg. 1986, 3, 448– 455. Blaisdell, F.W. Ligation Treatment of an Abdominal Aortic Aneurysm. Am. J. Surg. 1965, 109, 560– 565. Veith, F.J.; Hartsuck, J.M.; Crance, C. Management of Aortoiliac Reconstruction Complicated by Sepsis and Hemorrhage. N. Engl. J. Med. 1964, 270, 1389– 1392. Nunn, D.B.; Kamal, M.A. Bypass Grafting from the Thoracic Aorta to Femoral Arteries for High Aortoiliac Occlusive Disease. Surgery 1972, 72, 749– 755. Cevese, P.G.; Galluchi, V. Thoracic Aorta to Femoral Artery Bypass. J. Cardiovasc. Surg. (Torino) 1975, 16, 432–438. Bowes, D.E.; Keagy, B.A.; Benoit, C.; et al. Descending Thoracic Aorta-Bifemoral Bypass for Occluded Abdominal Aorta: Retroperitoneal Route Without an Abdominal Incision. J. Cardiovasc. Surg. (Torino) 1985, 26, 41– 45. Rosenfeld, J.C.; Savarese, R.P.; DeLaurentis, D.A. Distal Thoracic Aorta to Femoral Artery Bypass: A Surgical Alternative. J. Vasc. Surg. 1985, 2, 747– 750. DeBakey, M.E. Basic Concepts of Therapy in Arterial Disease. Bull. N.Y. Acad. Med. 1963, 29, 707. Elkins, R.C.; DeMeester, T.R.; Brawley, R.K. Surgical Exposure of the Upper Abdominal Aorta and Its Branches. Surgery 1971, 70, 622– 627. Barral, X.; Youvarlakis, P.; Boissier, C.; Cavallo, G. Supraceliac Aorta to Lower Extremity Arterial Bypass. Ann. Vasc. Surg. 1986, 1, 30– 35. Siderys, H.; Graffis, R.; Hilbrook, H.; Kasbechar, V. A Technique for Management of Inaccessible Coarctation of the Aorta. J. Thorac. Cardiovasc. Surg. 1974, 67, 568–570. McCarthy, W.J.; Flinn, W.R.; Yao, J.S.T.; Bergan, J.J. Use of the Descending Thoracic Aorta for Arterial Reconstruction. In Aortic Surgery; Bergan, J.J., Yao, J.S.T., Eds.; W.B. Saunders: Philadelphia, 1988; 403–412. Cancepa, C.S.; Schubart, P.J.; Taylor, L.M.; Porter, J.M. Supraceliac Aortofemoral Bypass. Surgery 1987, 101, 323–328. Taylor, L.M.; Porter, J.M. Supraceliac Aortic Bypass. In Aortic Surgery; Bergan, J.J., Yao, J.S.T., Eds.; W.B. Saunders: Philadelphia, 1988; 403 – 412. Stevenson, J.K.; Sauvage, L.R.; Harkins, H.N. A Bypass Hemograft from Thoracic Aorta to Femoral Arteries for Occlusive Vascular Disease: A Case Report. Ann. Surg. 1961, 27, 632– 637. Passman, M.A.; Marston, W.A.; Criado E. et al. Descending Thoracic Aorto to Ileofemoral Bypass: A Role for Primary Revascularization for Aortoiliac Occlusive Disease. (Abstract) Presented at the International Society for Clinical Vascular Surgery 46th Annual Meeting, San Diego, C.A. 1998 (in press).
141. Bowes, De.; Youkey, J.R.; Pharr, W.P.; et al. Long Term Follow-Up of Descending Thoracic Aorto-Iliac/Femoral Bypass. J. Cardiovasc. Surg. 1990, 31, 430– 437. 142. O’Brien, D.; Waldron, R.P.; McCabe, J.P.; et al. Descending Thoracic Aorto-Bifemoral Bypass Graft: A Safe Alternative in the High Risk Patients. Ir. Med. J. 1991, 84, 58– 59. 143. Branchereau, A.; Expinoza, H.; Rudondy, P.; et al. Descending Thoracic Aorta as an Inflow Source for Late Occlusive Failures Aortoiliac Reconstruction. Ann. Vasc. Surg. 1991, 5, 8 – 15. 144. Kalman, P.G.; Johnston, K.W.; Walker, P.M. Descending Thoracic Aortofemoral Bypass as an Alternative for Aortoiliac Revascularization. J Cardiovasc. Surg. 1991, 32, 443– 446. 145. Criado, E.; Johnson, G., Jr.; Burnham, S.J.; et al. Descending Thoracic Aorto-to-Iliofemoral Artery Bypass as an Alternative to Aortoilic Reconstruction. J. Vasc. Surg. 1992, 15, 550– 557. 146. Branchereau, A.; Magnan, P-E.; Moracchini, P.; et al. Use of Descending Thoracic Aorta for Lower Limb Revascularization. Fur. J. Vasc. Surg. 1992, 6, 255– 262. 147. Schumaker, H.B.; Nahrwald, D.L.; King, H.; Waldhanjen, J.A. Coarctation of the Aorta. Curr. Probl. Surg. 1968, 1, 64. 148. Frantz, S.L.; Kaplitt, M.J.; Beil, A.R., Jr.; Stein, H.L. Ascending Aortobilateral Femoral Artery Bypass for the Totally Occluded Infrarenal Abdominal Aorta. Surgery 1974, 75, 471– 475. 149. Robinson, G.; Siegelman, S.; Attai, L. Recurrent Dissecting Aneurysms of Aorta. NY State J. Med. 1972, 72, 2328– 2331. 150. Siderys, H.; Graffis, R.; Holbrook, H.; Kasbeckar, V. A Technique for Management of Inaccessible Coarctation of the Aorta. J. Thorac. Cardiovasc. Surg. 1974, 67, 568– 570. 151. Favi, P.; Massimo, D.; Diligenti, L.M. Ascending Aorta to Femoral Arteries Bypass Without Opening the Abdominal Cavity: Choce Treatment in Cases of Complete Occlusion of the Infrarenal Aorta. J. Cardiovasc. Surg. 1977, 18, 475– 480. 152. Wukasch, D.C.; Cooley, D.A.; Sandiford, F.M.; Nappi, G.; Reul, J. Ascending Aorta-Abdominal Aorto Bypass: Indiacations, Technique and Report of 12 Patients. Ann. Thorac. Surg. 1977, 23, 442– 448. 153. Cleveland, J.C. Ascending Aorta to Common Femoral Artery Bypass: An Unusual but Successful Method for Revascularization of the Lower Extremity: Report of Case. Cardiovasc. Dis. 1980, 7, 74– 76. 154. Gelfand, E.T.; Callaghan, J.C.; Sterns, L.P. Extended Aortic Bypass. J. Thorac. Cardiovasc. Surg. 1980, 79, 381– 387. 155. Baird, R.J.; Oates, T.K. Ascending Aorta to Bifemoral Artery Bypass. Can. J. Surg. 1981, 24, 415– 418. 156. Baird, R.J.; Ropchan, G.V.; Oates, T.K.; Weisel, R.D.; Provan, J.L. Ascending Aorta to Bifemoral Bypass—A Ventral Aorta. J. Vasc. Surg. 1986, 3, 405– 410. 157. Baird, R.N. Update on the Value of the Ventral Aorta Procedure: Bypass Form the Ascending Aorta. In Current Critical Problems in Vascular Surgery; Veith, F.J., Ed.; Quality Medical Publishing Inc.: St. Louis, MO, 1990; 2.
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Shaw, R.S.; Baue, A.E. Management of Sepsis Complicating Arterial Reconstructive Surgery. Surgery 1962, 53, 75– 86. VanDet, R.J.; Brands, L.C. The Obturator Foramen Bypass: An Alternative Procedure in Ileofemoral Artery Revascularization. Surgery 1981, 89, 543– 547. Prenner, K.V.; Rendl, K.G. Indications and Technique for Obturator Bypass. In Extraanatomic and Secondary Arterial Reconstruction; Greenhalgh, R.M., Ed.; Pitman Books: London, 1982; 201, 221. Tilson, M.D.; Sweeney, T.; Jushey, R.J.; Stansel, H.C. Obturator Canal Bypass Grafts for Septic Lesion of Femoral Artery. Arch. Surg. 1979, 114, 1031– 1036. Erath, H.G., Jr.; Gale, S.S.; Smith, B.M.; Deen, R.H. Obturator Foramen Grafts: The Preferable Alternate Route? Am. Surg. 1982, 48, 65– 69. Feldman, A.J.; Berguer, R. Management of an Infected Aneurysm of the Groin Secondary to Drug Abuse. Surg. Gynecol. Obstet. 1983, 157, 519–522. Pearce, W.H.; Ricco, J.; Yao, J.S.T.; Flinn, W.R.; Bergan, J.J. Modified Technique of Obturator Bypass in Failed or Infected Grafts. Ann. Surg. 1983, 197, 344 – 347. Rawson, H.D. Arterial Grafting Through the Obturator Foramen. Aust. N Z J. Surg. 1986, 56, 127– 130. Nevelsteen, A.; Mees, U.; Deleersnijder, J.; Suy, R. Obturator Bypass: A Sixteen Year Experience with 55 Cases. Ann. Vasc. Surg. 1987, 5, 558– 563. Panetta, T.; Sottiurai, V.S.; Batson, R.C. Obturator Bypass with Nonreversed Translocated Saphenous Vein. Ann. Vasc. Surg. 1989, 3, 56– 62.
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Millis, J.M.; Ahn, S.S. Transobturator Aorto-Profunda Femoral Artery Bypass Using Direct Medial Thigh Approach. Ann. Vasc. Surg. 1993, 7, 384– 390. Guida, P.M.; Moore, S.W. Obturator Bypass Technique. Surg. Gynecol. Obstet. 1969, 128, 1307 –1316. Baue, A.; Tilson, M.D. Obturator Bypasses for Lower Extremity Ischemia. In Vascular Surgery; Rutherford, R.B., Ed.; Saunders: Philadelphia, 1984. Veith, F.J.; Moss, C.M.; Daly, V.; Fell, S.C.; Haimovici, H. New Approaches to Limb Salvage by Extended Extraanatomic Bypasses and Prosthetic Reconstructions to Foot Arteries. Surgery 1978, 84, 764– 772. Smith, R.F.; Szilagyi, D.E.; Calville, J.M. Surgical Treatment of Mycotic Aneurysms. Arch. Surg. 1962, 85, 663– 674. Leather, R.P.; Karmody, A.M. A Lateral Route for Extra Anatomical Bypass to the Femoral Artery. Surgery 1977, 81, 307– 309. Gupta, S.K.; Veith, F.J.; Ascer, E.; Samson, R.H.; Scher, L.A.; Whiteflores, S.A.; Sarayregen, S.; Fell, S.C. Five Year Experiences with Axillopopliteal Bypass for Limb Salvage. J. Cardiovasc. Surg. 1985, 26, 321–324. Connolly, J.E.; Kwaan, J.H.M.; Brownell, D.; McCart, P.M.; Levine, E. Newer Developments of Extra-Anatomic Bypass. Surg. Gynecol. Obstet. 1984, 58, 415– 418. Ascer, E.; Veith, F.J.; Gupta, S. Axillopopliteal Bypass Grafting: Indications, Late Results, and Determinants of Long-Term Patency. J. Vasc. Surg. 1989, 10, 285– 289. McCready, R.A.; Hyde, G.L.; Ernst, C.B. Renal Revascularization by Extraanatomic Bypass. J. Vasc. Surg. 1984, 1, 569–572.
CHAPTER 36
Surgery of the Deep Femoral Artery: Profundaplasty Jonathan B. Towne
course to the superficial femoral artery in the majority of cases. In 10% of the cases, the deep femoral runs medial to the superficial femoral artery, and in 2%, large branches of the profunda femoris are found both medial and lateral to the superficial femoral artery. The medial and lateral circumflex are direct branches of the common femoral artery in 18%, and the lateral femoral circumflex artery is a direct branch of the common femoral in 15%. In those cases where the lateral femoral circumflex arises directly from the common femoral artery, the main trunk of the deep femoral artery takes a more medial or posterior medial course to the superficial femoral artery. In the classic situation, the deep femoral artery passes inferiorly, medial to the femur, giving off three perforating branches, with the terminal portion of the artery—which is sometimes referred to as the fourth perforating branch—connecting to the highest genicular branch of the popliteal artery at the adductor hiatus (Fig. 36-1). The lateral femoral circumflex divides into ascending, transverse, and descending branches. The ascending branch passes superiorly to the lateral aspect of hip, connecting with branches of inferior gluteal artery. The descending branch passes lateral to the superficial femoral artery to the level of the knee and anastomoses with the lateral superior geniculate branch of the popliteal artery (Fig. 36-2). The medial femoral circumflex anastomoses with branches of the obturator artery in the area of the obturator foramen. When the superficial femoral artery is occluded, the principal collateral branches of the deep femoral artery include the descending branch of the lateral femoral circumflex and the third and fourth perforating branches, which anastomose with the highest genicular and lateral superior genicular arteries, to reconstitute the popliteal artery more distally. Where there is inflow occlusion of the distal external iliac or common femoral arteries, the principal collateral connections of the deep femoral artery involve the medial and lateral femoral circumflex artery, which anastomose with the obturator and inferior gluteal arteries, both of which are branches of the hypogastric system (Fig. 36-3).
The deep femoral or profunda femoris arterial system is unique because it is both the principal blood supply of the thigh—one of the largest muscle masses in the body—and also the primary collateral network for iliac and superficial femoral occlusive disease. With occlusive disease of the external iliac artery, connections with the medial and lateral circumflex branches of the deep femoral artery are the principal source of blood supply to the lower extremity. When the superficial femoral artery is involved, the rich collateral connection between the deep femoral and the popliteal arteries maintains distal circulation. Throughout the last decade, the role of deep femoral artery reconstruction has been changing.[1 – 5] As an adjunct to the treatment of inflow disease, the value of performing profundaplasty has been recognized in the execution of inflow procedures such a aortofemoral, femorofemoral, or axillofemoral bypasses. This is particularly true in patients who have preexisting occlusion of the superficial femoral artery. The performance of a concomitant profundaplasty, particularly by way of an angioplasty of the origin of the deep femoral artery, is essential to ensure long-term graft patiency.[6] With outflow disease, there has been an even greater change. Early in the experience with femorodistal bypasses, profundaplasty was a viable alternative to lower limb bypass surgery in patients with occlusive symptoms of the lower leg. However, with the increasing sophistication of bypass techniques with autogenous reconstruction, profundaplasty has assumed a secondary role. Currently, it is the second line of defense and should be considered in patients whose vein is not available, in whom vein bypass surgery has failed, or if there are septic processes involving the groin.
ANATOMY The deep femoral artery usually arises from the posterolateral aspect of the common femoral artery, 3 –5 cm below the inguinal ligament, and takes a lateral or posterolateral
Hobson/Wilson/Veith: Vascular Surgery: Principles and Practice, Third Edition, Revised and Expanded DOI: 10.1081/0819-9-120024919 Copyright q 2004 by Marcel Dekker, Inc.
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Figure 36-1. Angiogram from patient who previously had a femorofemoral bypass and a profundaplasty. The rich collateral network between the distal deep femoral and the proximal popliteal artery is demonstrated.
DISTRIBUTION OF DISEASE Patients with symptomatic ischemia of the lower extremities most commonly have atherosclerotic involvement of the aortoiliac and/or femoropopliteal segments. Although the patterns of arterial involvement are quite variable, diffuse disease of both the superficial and deep femoral arteries is uncommon. In the majority of patients with superficial femoral artery occlusive disease, the deep system is relatively spared. However, Beales et al.[7] reported evidence of some
Figure 36-2. A well-developed descending branch of the lateral femoral circumflex artery. Its connection with the proximal popliteal artery is evident.
deep femoral disease in 59% of ischemic extremities studied by biplanar angiography. Martin et al.,[8] in a similar study, found the atherosclerotic disease to be localized to the proximal deep femoral segment in 74% of affected limbs and to the profunda orifice alone in 55%. In 12%, deep femoral arteries affected by atherosclerosis, the disease was located between the first perforating artery and the terminal segment. Diffuse involvement of the deep femoral artery was seen in 14%. Similarly, Thompson et al.[9] found atherosclerotic disease of the deep femoral artery to be confined to the proximal segment in 76% of cases and to be orificial in 62%.
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artery is rare, and the distal trunk is almost always patient. Atherosclerosis primarily involves the orifice and proximal deep femoral artery, although on occasion the distal artery or its branches can be involved.
ANGIOGRAPHIC TECHNIQUES Angiographic demonstration of atherosclerotic disease of the deep femoral artery has improved with the development of newer techniques. Oblique and lateral views are essential, since the most frequent site of atherosclerotic involvement of the deep femoral artery is near its origin, which often is not apparent on frontal views because this artery arises from the posterior lateral aspect of the common femoral artery. In this position, the proximal portion of the vessel is foreshortened and obscured. In a series of 209 lower extremity angiograms in which frontal, lateral, and oblique views were obtained, Beales et al.[7] demonstrated greater than 50% stenosis of the deep femoral artery or its orifice in 9.3%; in 7.9%, the stenotic segment was recognized only on the oblique or lateral views, demonstrating the necessity of this technique for adequate roentgenographic evaluation. Typically, the common femoral artery is cannulated by the Seldinger technique from a femoral approach. Anteroposterior, right anterior oblique, and left anterior oblique views of the iliac and femoral arteries are obtained using digital substraction or image intensification technique as needed. It is important to visualize the collaterals at the termination of the deep femoral system as well as to assess the amount of occlusive disease in the popliteal and tibial vessels, since these provide important prognostic information as to the potential success of profundaplasty in relieving ischemic symptoms (Fig. 36-4).
INDICATIONS FOR PROFUNDAPLASTY
Figure 36-3. Angiogram from patient with occlusion of the common femoral artery extending into the proximal deep femoral.
When atherosclerosis involves this artery, it is most commonly localized to the proximal portion of the vessel. Haimovici et al.,[10] in a series of 321 arteriograms, found atherosclerotic involvement of the deep femoral artery in 9.5% of nondiabetic patients and 30.5% of diabetic patients. Margulis et al.[11] noted similar atherosclerotic involvement of the deep femoral artery in 18% of 168 limbs undergoing angiography for symptomatic occlusive disease of the lower limb. Nonvisualization of the deep femoral artery by angiography occurs 4 –6% of the time and is usually associated with aortoiliac obstruction and occlusion of the common femoral artery.[11] Complete obliteration of the deep femoral
There are a variety of different clinical situations in which profundaplasty is a useful technique for treating occlusive disease of the lower extremity. The first is as an adjunct to an inflow procedure, such as an aortofemoral, femorofemoral, or axillofemoral bypass. This is of particular importance when one is dealing with synchronous superficial femoral artery and aortoiliac occlusive disease. In patients with combined inflow and superficial femoral occlusive disease, revascularization of the deep femoral collateral system is usually sufficient to relieve the symptoms, obviating the need to perform a simultaneous distal reconstruction. Because of the prevalence of profunda orificial disease, it is often essential to perform a limited proximal profundaplasty in conjuction with the femoral artery revascularization by an inflow procedure. Commonly, the deep femoral occlusive disease is limited to 1–2 cm and rarely goes beyond the origin of the lateral femoral circumflex vessels. In these situations, all that is needed is to extend the tongue of the graft so that it functions as a patch angioplasty.
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Figure 36-5. Angiograms demonstrating well-developed deep femoral thigh collaterals and patent popliteal arteries.
Figure 36-4. Angiography demonstrating only peroneal runoff. The popliteal artery is occluded. This patient is a poor candidate for profundaplasty.
The second clinical situation in which profundaplasty is considered is when a deep femoral arterial reconstruction alone is an option in the treatment of critical limb ischemia. In selecting patients for profundaplasty alone, the most important factors are those related to the extent and distribution of the occlusive disease and the ischemic manifestations in the foot.* Arterial inflow from the iliac system must be unimpaired; it may be determined by clinical
*If gangrene or infection in the foot is extensive, profundaplasty alone is unlikely to solve the problem. If necrosis is minimal or nonexistent and the patient has mild ischemic rest pain, profundaplastly is more likely to be effective.
examination. Qualitative data are obtained by grading the femoral pulses, palpating for thrills, and auscultating for bruits. Physiological testing for subcritical iliac stenosis may also be performed intraoperatively or preoperatively by direct measurement of resting and papaverine-augmented common femoral artery pressures. The most important determinant of the success to the isolated profundaplasty is the adequacy of the deep femoral-to-popliteal collateral system and the severity of the tibial arterial occlusive disease. Angiographic criteria that reliably predict successful outcome include the following: minimal occlusive disease of the distal deep femoral; well-developed deep femoral thigh collaterals; patent popliteal artery (Fig. 36-5), and minimal tibial occlusive disease.[12] Sladen and Burgess[13] identified four roentgenographic signs that were associated with poor results of profundaplasty. These included no obstruction at the origin of the deep femoral artery, a patent superficial femoral artery, poor development of distal deep femoral collaterals, and poor visualization of the tibial vessels (Fig. 36-6). Absence of a pressure gradient across the deep femoral lesion is also an indicator that the procedure will have no beneficial effect. Segmental Doppler pressure measurements can also reliably locate and determine the extent of occlusive disease in each limb segment by providing an estimate of the resistance in each collateral bed. Resistance across the knee joint is the most important determinant of profundaplasty success. It can be evaluated by the measurement of the profunda-to-popliteal collateral index (PPCI), which is calculated by the following formula: Above-knee pressure 2 below-knee pressure Above-knee pressure An index greater than 0.45 implies high resistance across the knee joint, and—as a result—poorly developed collateral
Chapter 36. Surgery of the Deep Femoral Artery: Profundaplasty
Figure 36-6. Angiogram showing poor development of deep femoral thigh collaterals. There is also diffuse disease of the proximal and mid-deep femoral artery.
vessels. This is associated with profundaplasty failure in all cases. A PPCI less than 0.19 indicates that there is excellent collateral development between the distal deep femoral and the patent popliteal artery.[14] Evaluation of our patients undergoing isolated profundaplasty for limb salvage showed that among those whose PPCI was 0.19 or less, salvage was achieved in 10 of 11 patients. Among those with a PPCI above 0.45, however, no salvage was achieved. McCoy et al.[15] found that the low thigh-ankle pressure gradient correlated with the success of profundaplasty. This gradient evaluates the obstruction of flow across the knee as well as that due to tibial artery occlusive disease. The low
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thigh-ankle pressure gradient index (TAGI) is calculated by taking the low thigh pressure minus the ankle pressure and dividing this by the low thigh pressure. The result is termed the TAGI and, as with the PPCI, the lower the number, the less resistance there is to blood flow. In groups with successful outcome, the TAGI was 0.39. In groups that did not do well, however, the TAGI was 0.79. All of these preoperative assessment techniques are just different means of evaluating the same parameter: that is, the adequacy of the collateral channels from the distal deep femoral artery to either patent popliteal or tibial vessels. The clinical presentation in limb salvage patients should also be considered, since it affects the ultimate success of deep femoral revascularization. In general, profundaplasty alone frequently heals chronic ischemic ulcers, but it is less successful in abolishing severe rest pain and does not reliably heal areas of extensive ischemic gangrene. Ankle-brachial indices (ABI) can also help in the selection of patients for isolated profundaplasty. Among patients with critical limb ischemia, those who have lesser degrees of ischemia generally do well with profundaplasty. Such patients have higher ABIs, in the range of 0.30– 0.40 or above. The mean preoperative ABI in our patients who underwent successful isolated profundaplasty for limb salvage was 0.42, compared to 0.27 in patients in whom profundaplasty was unsuccessful. With the more severe forms of vascular occlusive disease, profundaplasty is just not sufficient to salvage extremities. There is a direct correlation with the extent of tibial occlusive disease and the preoperative ABI. Patients who have combined superficial femoral and deep femoral occlusive disease and severe coexisting tibial occlusive disease are more likely to have low ABIs. Patients with common femoral artery occlusion, where the atherosclerotic process extends to the orifice of the profunda artery, generally do well with profundaplasty. The occlusive process in the profunda femoris artery rarely extends to the first perforator. Common femoral endarterectomy with profundaplasty will significantly augment blood flow to the lower extremity. Profundaplasty is also indicated for patients with combined deep and superficial femoral artery disease who have failed previous attempts at femoral-distal bypass. Often, a deep femoral artery stenosis has been overlooked. If this is repaired, one may be able to salvage a leg that would otherwise be doomed to major amputation. Profundaplasty is an excellent alternative in patients who have groin sepsis. This is most commonly seen in those who have infected femoral-distal prostheses that must be removed. Profundaplasty and patch closure with autogenous tissue— with the addition of muscle flap coverage using either the sartorius or the rootus abdomnus muscle—are excellent methods to salvage a patient from a potentially limb- and lifethreatening situation.
OPERATIVE TECHNIQUE Approximately two-thirds or more of patients requiring profundaplasty have the procedure performed as an adjunct to an inflow procedure such as aortofemoral or femorofemoral bypass when the superficial femoral artery is occluded. In
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patients with adequate arterial inflow, restoration of the profunda collateral system is the primary goal. A vertical groin incision is made over the common femoral artery at the level of the inguinal ligament and extended 10 cm distally. Following control of the common femoral artery, the superficial femoral artery is dissected free to facilitate exposure of the deep femoral, which usually courses laterally and posteriorly. A large circumflex femoral vein, which crosses the profunda within 1 – 2 cm of its origin, is identified, ligated in continuity, and divided. The anterior surface of the deep femoral is exposed distally until normal artery is encountered. The disease in the profunda always ends in a branch point, the only variation being at which branch this occurs. The endpoint can be determined either by preoperative angiogram or by palpating the vessel at operation. When profundaplasty is performed with an inflow procedure, the deep femoral system is usually less diseased, with the atherosclerotic plaque usually ending proximal to the first perforator. More distal profunda disease is usually present when an isolated profundaplasty is required. Following systemic heparinization, the common femoral artery and its branches are clamped. A vertical incision is made anteriorly in the common femoral artery and carried on to the profunda to approximately 1 cm distal from the distal end of the occlusive disease, which is usually at a branch point. In cases in which early arborization of the profunda occurs, the arteriotomy is extended distally to the largest branch. Care is taken to avoid the crotch of the common femoral bifurcation and major branches, where the adventitia is often very friable and does not hold sutures well. Endarterectomy of the atheromatous plaque is performed if the luminal surface is friable or if it occludes profunda branches. If the deep femoral is only thickened and its branches are patent, an endarterectomy is not necessary. During endarterectomy, most occluded profunda branches are opened by careful plaque removal, since the occlusive disease rarely involves more than the branch orifices. If a clear inflow break point is not obtained, the distal intima must be tacked with 6-0 or 7-0 sutures to prevent intimal dissection. Rarely, a profunda orifice atheroma is encountered and is easily removed with endarterectomy through the common femoral artery without extending the arteriotomy into the deep femoral artery. The length of profundaplasty and type of disease present will determine how the arteriotomy is closed. An orifice atheroma may sometimes be removed and short profunda arteriotomy closed longitudinally. When an inflow procedure is performed with a short profundaplasty, a Dacron or polytetrafluoroethylene (PTFE) limb is sutured over the arteriotomy for a distance of 3 –4 cm. When short segments of both deep and superficial femoral artery are diseased, endarterectomies are performed and the common femoral bifurcations moved distally by sewing the deep and superficial femoral arteries together. Closure of the profunda arteriotomy usually requires patch angioplasty. In order to provide the best flow characteristics, it is important that a narrow patch be used, so that the final repair approximates the size of the normal artery. There are three options for patch material: autogenous vein, endarterectomized occluded superficial femoral artery, and prosthetics (Dacron, PTFE). When longer arteriotomies are performed, autogenous tissue is the preferred patch material because of its greater
long-term patency and resistance to infection. The author’s preference is to use an endarterectomized segment of the occluded superficial femoral artery to patch the arteriotomy (Fig. 36-7). It is easily prepared, performs as well as the saphenous vein, and preserves the vein for later use in distal arterial bypass or coronary revascularization. Patients with septic groins who require removal of an infected inflow graft and those with heavily scarred groins can have revascularization of their lower extremities done by approaching the mid or distal profunda femoris artery via an anterolateral approach (Fig. 36-8).[16,17] The incision is made at the junction of the proximal and middle third of the thigh parallel and lateral to the sartorius and adjacent to the lateral border of the rectus femoris muscle. A plane of dissection is then developed medially beneath the rectus femoris but superficial to the vastus medialis muscle and to the adductor longus muscle. The fibers of the adductor longus are spread, revealing the middle third of the profunda femoris artery. Alternatively, the mid and distal deep femoral artery can be reached directly inferior to a scarred or infected groin by making an incision medial or lateral to the sartorius muscle and carrying it medial or lateral to the superficial femoral vessels (Figs. 36-9 and 36-10). Splitting the raphe between the vastus medialis and adductor longus muscles exposes the deep femoral vessels.[17] In some patients it is possible to pass an inflow graft just medial to the anterior superior iliac spine without contamination from the infected groin. However, most of the time this is not possible, and we cut a notch in the wing of the ileum to allow a more lateral course of the graft. Nunez et al. also describe a posteriomedial approach where the dissection is carried around the adductor longus muscle (Fig. 36-11).[17] The inflow graft can be tracked either by wedging out the piece of bone on the wing of the ileum (as in the case of axillofemoral grafts) or, if inflow from the abdomen is still required, by going through the psoas tunnel laterally under the inguinal ligament or through the obturator foramen, so that the graft can reach the mid-thigh. Early thrombosis of the deep femoral repair is easily detected by the loss of the femoral pulse and distal ischemia;
Figure 36-7. Preparation of patch from an occluded superficial femoral artery.
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Figure 36-8. One method to expose the mid-deep femoral artery directly. A composite axillofemoral graft has been used. The graft is placed in a notch cut in the wing of the ileum to avoid the infected femoral triangle. (From Towne.[16] Reproduced by permission.)
it is usually due to a technical error that requires prompt reexploration, thrombectomy, and correction. Late occlusion is usually secondary to progression of atherosclerosis in the distal deep femoral artery or the aortoiliac segment or the development of fibrointimal hyperplasia at the suture line. When thrombosis of an inflow graft occurs, occlusive disease is usually present at the site of the distal graft anastomosis; it is most often due to fibrointimal hyperplasia. Graft thrombectomy and a redo profundaplasty is often all that is necessary to establish flow.
RESULTS
Figure 36-9. Direct approach to the mid and distal portions of the deep femoral artery. The incision may be medial or lateral to the sartorius muscle and superficial femoral neurovascular bundle. Incising raphe between vastus medialis and adductor longus muscles provides access to deep femoral vein and artery. (From Nunez et al.[17] Reproduced by permission.)
The efficacy and durability of profundaplasty are primarily determined by the pattern of atherosclerotic disease.When proximal aortoiliac disease is associated with obstruction of the deep femoral, the artery’s collateral system is usually spared from significant atherosclerosis and the flow across the knee joint is often normal. These patients require profundaplasty as an adjunct to inflow procedures for limb salvage, and we have a reported 5-year cumulative limb salvage rate of 80%.[18] In contrast, when adequate arterial inflow is present in the groin, and an isolated profundaplasty is performed to restore its function as a major collateral system, there is often significant involvement of the entire collateral system as well as tibial occlusive disease. Cumulative limb salvage in this group of patients is only 36% at 5 years.[17] When profundaplasty was performed for disabling intermittent claudication, 5-year cumulative patency was 73% in our series.[17] Subjective improvement with
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Figure 36-10. Cross section of thigh showing two alternative direct approaches to the distal two thirds of the deep femoral artery as outlined in Fig. 36-9 and the text. (From Nunez et al.[17] Reproduced by permission.)
complete relief of symptoms was achieved in 72% of patients for the duration of the follow-up, even though objective improvement by noninvasive laboratory techniques was not always present. Unfortunately, when profundaplasty was performed for nonhealing ulceration, rest pain, or ischemic gangrene, results were significantly poorer, as evidenced by a 5-year cumulative patency of only 30%. However, limb retention rates remained at 80% after 5 years in patients who underwent an inflow procedure with profundaplasty for limb salvage indications. Kalman et al.,[19] in a more recent study of isolated profundaplasty, reported excellent results, with a cumulative clinical success rate (considered as both a patent repair and clinical improvement) of 83% at 30 days, 67% at 1 year, 57% at 2 years, and 49% at 3 years. Cumulative limb salvage in this group of patients at 3 years was 76%. The most significant determinant in this series was that good tibial outflow correlated with greater success than did poor tibial outflow. “Good” tibial outflow was defined as 2 to 3 patent tibial arteries; “poor” was defined as 1 or no patent artery. Ouriel et al.[20] reported 1- and 4year patency rates of 83% and 76% when the middle and distal deep femoral arteries were used for the distal anastomosis of an inflow procedure. The long-term mortality for limb salvage patients was 35% at 5 years, with the majority of deaths attributable to atherosclerotic disease.
Figure 36-11. Cross section of thigh showing posteromedial direct route to deep femoral artery. This approach can be used when the subsartorial area is involved with scar or infection. (From Nunez et al.[17] Reproduced by permission.)
To utilize profundaplasty successfully, the surgeon must select patients carefully. This decision can be based on roentgenographic criteria, where the adequacy of the profunda-popliteal collateral system is evaluated and the extent of popliteal and tibial occlusive disease noted. This evaluation can also be done noninvasively by measuring both the popliteal gradient as well as the lower thigh ankle gradient. Much of the frustration of a surgeon doing profundaplasty occurs when too much is expected from the operation. Profundaplasty is not a viable alternative for all patients. When a patient has significant tissue loss of the forefoot and a usable autogenous vein, a femorodistal bypass is certainly the preferred procedure. However, there are patients in whom this is not possible, either because of previous utilization of the vein, a vein of poor quality, or a previously failed distal bypass. It is in these patients that profundaplasty often achieves its greatest value. Likewise, in dealing with septic graft complications, profundaplasty can help the surgeon lead the patient through very trying clinical circumstances to eventual limb salvage. Authors who wholly condemn profundaplasty are guilty of asking too much of this procedure. They generally fail to understand the anatomic requirements of this operation and therefore do not use it in appropriate situations.
Chapter 36. Surgery of the Deep Femoral Artery: Profundaplasty
PROFUNDAPLASTY TO LOWER AMPUTATION LEVEL The amputation level in patients whose limbs cannot be salvaged is directly correlated with deep femoral artery patency. Collateral flow through the profunda system is the major determinant of the healing of below-knee amputations. If the superficial femoral artery is occluded in a
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patient in whom the extent of pedal gangrene precludes limb salvage, the status of the deep femoral circulation should be evaluated. If significant occlusive disease is present, profundaplasty should be performed several days prior to the below-knee amputation. In our experience, deep femoral patency was mandatory to achieve healing of below-knee amputations, and functional rehabilitation was possible in 84% of patients who underwent successful below-knee amputations.[21]
REFERENCES 1.
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3. 4.
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Anderson, C.A.; Rich, N.M.; Collins, G.J.; McDonald, P.T. Limb Salvage by Extended Profunda Femoris Revascularization. Am. Surg. 1978, 100, 44. Taylor, L.M., Jr.; Baur, G.M.; Eldemiller, L.R.; Porter, J.M. Extended Profundaplasty: Indications and Techniques with Results of 46 Procedures. Am. J. Surg. 1981, 141, 539. David, T.E.; Drezner, A.D. Extended Profundaplasty for Limb Salvage. Surgery 1978, 84, 758. Malone, J.M.; Goldstone, J.; Moore, W.S. Autogeneous Profundaplasty: The Key to Long-Term Patency in Secondary Repair of Aortofemoral Graft Occlusion. Ann. Surg. 817, 1988, 1978. Howard, T.R.S.; Bergan, J.J.; Yao, J.S.T.; et al. The Demise of Profundaplasty. Am. J. Surg. 1988, 156, 126. Bernhard, V.M.; Militello, J.P. The Role of Angioplasty of the Profunda Femoris Artery in Revascularization of the Ischemic Limb. Surg. Gynecol. Obstet. 1976, 142, 840. Beales, J.S.M.; Adcock, F.A.; Frawley, J.S.; et al. The Radiological Assessment of Disease of the Profunda Femoris Artery. Br. J. Radiol. 1971, 44, 854. Martin, P.; Frawley, J.E.; Barabas, A.P.; et al. On the Surgery Atherosclerosis of the Profunda Femoris Artery. Surgery 1972, 71, 182. Thompson, B.W.; Read, R.C.; Campbell, G.S.; et al. The Role of Profundaplasty in Revascularization of the Lower Extremity. Am. J. Surg. 1976, 132, 710. Haimovici, H.; Shapiro, J.H.; Jacobson, H.G. Serial Femoral Arteriography in Occlusive Disease: ClinicalRoentgenologic Considerations with a New Classification of Occlusive Patterns. Am. J. Roentgenol. 1960, 83, 1042. Margulis, A.R.; Nice, C.M., Jr.; Murphy, T.O. Arteriographic Manifestations of Peripheral Occlusive Vascular
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Disease: With the Report of Two New Signs. Am. J. Roentgenol. Radium Ther. Nucl. Med. 1957, 78, 273. Mitchell, R.A.; Bone, G.E.; Bridges, R.; et al. Patient Selection for Isolated Profundaplasty: Arteriographic Correlates of Operative Results. Am. J. Surg. 1979, 138, 912. Sladen, J.; Burgess, J.J. Profundaplasty: Expectations and Ominous Signs. Am. J. Surg. 1980, 140, 242. Boren, C.H.; Towne, J.B.; Bernhard, V.M.; et al. Profundapopliteal Collateral Index: A Guide to Successful Profundaplasty. Arch. Surg. 1980, 115, 1366. McCoy, D.M.; Sanchek, A.P.; Schuler, J.J.; et al. The Role of Isolated Profundaplasty for the Treatment of Rest Pain. Arch. Surg. 1989, 124, 441. Towne, J.B. Composite Arterial Grafting. In Operative Techniques in Vascular Surgery; Bergan, J.J., Yao, J.S.T., Eds.; Grune and Stratton: New York, 1980; 163 – 174. Nunez, A.M.; Veith, F.J.; Collier, P.; et al. Direct Approaches to the Distal Portions of the Deep Femoral Artery for Limb Salvage Bypasses. J. Vasc. Surg. 1988, 8, 576. Towne, J.B.; Bernhard, V.M.; Rollins, D.L.; et al. Profundaplasty in Perspective: Limitations in the Long-Term Management of Limb Ischemia. Surgery 1981, 90, 1037. Kalman, P.G.; Johnston, K.W.; Walker, P.M. The Current Rule of Isolated Profundaplasty. J. Cardiovasc. Surg. 1990, 13, 107. Ouriel, K.; DeWeese, J.A.; Ricotta, J.J.; Green, R.M. Revascularization of the Distal Profunda Femoris Artery in the Reconstructive Treatment of Aortoiliac Occlusive Disease. J. Vasc. Surg. 1987, 6, 217. Towne, J.B.; Rollins, D.L. Profundaplasty: Its Role in Limb Salvage. Surg. Clin. N. Am. 1986, 66, 403.
CHAPTER 37
Amputation in the Dysvascular Patient James M. Malone
of Health and Social Security, with 6,000 new patients being referred to limb-fitting centers annually.[12,13]
INDICATIONS FOR AMPUTATION Diabetes mellitus is the primary indication for amputation in more than two thirds of cases. Most patients are male and greater than 60 years of age. In general terms, the indications for amputation in the dysvascular patient are (1) complication of diabetes mellitus, (2) nondiabetic infection with ischemia, (3) osteomyelitis, (4) trauma, (5) failed limb salvage operations, and (6) failed minor amputation.
AMPUTATIONS FOR ACUTE ISCHEMIA Acute ischemia causing tissue necrosis presents a complex surgical management problem. If the patient has presented late, with irreversible tissue loss accompanied by systemic toxicity, with or without myonecrosis, urgent amputation is indicated. Urgent amputation is also the treatment of choice if there is extensive or invasive infection. In elderly patients with sepsis, physiologic amputation rather than urgent surgical amputation may be an important first step in lowering patient mortality.[14] Limbs with lesser degrees of acute tissue ischemia (reversible ischemia) may often be salvageable by arterial bypass or embolectomy, usually combined with compartment fasciotomy. In some of these cases limb salvage is not totally achieved, but the patient may at least become suitable for amputation at a more distal level. If there are no indications for urgent operation and the associated pain is not severe, the ischemic areas may be observed for signs of improvement and heparin anticoagulation or thrombolytic therapy may be employed in selected patients to improve collateral circulation.[15] Determination of the preferred level of amputation is difficult in the presence of acute ischemia.
INCIDENCE AND MORBIDITY OF AMPUTATION In general, the mortality associated with amputation depends not so much on the procedure itself as on the presence or absence of risk factors, especially cardiorespiratory insufficiency. Although above-knee amputation does carry a higher operative mortality risk than below-knee amputation,[1,2] Rush et al.[3] reported a 6% mortality for below-knee amputation and an 11% mortality for above-knee amputation. However, Bunt and Malone[4] reported an overall mortality rate of 1.5% for all major lower extremity amputations. The higher mortality usually associated with above-knee amputation is due to more severe and widespread cardiovascular diseases in that group of patients. More than 70% of patients requiring amputation for peripheral vascular disease have other major systemic manifestations of atherosclerosis. Hospital mortality varies from 2 to 40%.[5 – 8] It has been reported that 50 –75% of amputee patients die within 5 years of amputation;[7,8] however, in nondiabetic patients survival approximates the age-adjusted normal population.[6] The amputation rate in the United States is approximately 30 per 100,000 population but is 15–20 times higher among diabetic patients, who have an incidence of amputation of 600 per 100,000.[9 – 11] Overall, more than 50,000– 60,000 major lower limb amputations are estimated to be performed each year in the United States. In the United Kingdom, approximately 65,000 amputees are known to the Department
Amputation in the Diabetic Patient Diabetics are at special risk of developing leg ischemia and gangrene. In fact, gangrene is more than 50 times more frequent among diabetic patients over 40 years of age than among nondiabetic patients of the same age.[16] Bacterial cultures of infected lesions in diabetic patients usually yield multiple organisms (up to 22 different organisms in one culture have been identified), with a mixture of anaerobes and aerobes.[6] The principal pathogens
Hobson/Wilson/Veith: Vascular Surgery: Principles and Practice, Third Edition, Revised and Expanded DOI: 10.1081/0819-9-120024920 Copyright q 2004 by Marcel Dekker, Inc.
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are usually Staphylococcus, Enterococcus, and other streptococcal organisms, Pseudomonas, Proteus, and Escherichia coli. Underlying osteomyelitis is frequently present at the time of presentation.[17] Because of the virulence and invasiveness of foot infections in the diabetic patient, delay in surgical control can lead to loss of the foot or fatal sepsis.[18] The diabetic foot should always be carefully examined for deep infection. Areas with abscess, suppuration, or invasion of tendon sheaths and plantar fascia should be treated urgently by incision and drainage, wide debridement, or local amputation. If the vascularity of the foot is good, then usually no further procedure will be necessary (Fig. 37-1). However, with irretrievably poor vascularity, definitive amputation should be carried out only after the septic condition has been controlled and drained. In some cases, when the heel or the proximal tissues are already involved, primary below-knee amputation rather than a local foot procedure is indicated (Fig. 37-2). Osteomyelitis in a diabetic foot cannot be adequately treated by antibiotics alone, and surgical excision of the infected bone is always required. In general, surgical wounds in diabetics tend to have a higher incidence of infection[19] and delayed healing[17,20] compared to wounds in nondiabetic patients. However, the presence of diabetes does not significantly affect the rate of stump healing or wound infection after amputation.[6,21]
PREOPERATIVE MANAGEMENT Preoperative care involves treatment of the affected limb and stabilization of the patient’s general medical condition. The patient should not be restricted to bed. Cellulitis and lymphangitis are treated with intravenous antibiotics, while abscesses or closed-space infections require early drainage and debridement. Pain should be treated adequately with narcotic analgesics. The prevention of contractures of the knee and hip is essential in achieving eventual rehabilitation. The presence of contractures more than 158 will preclude successful ambulation on a prosthesis. A thorough assessment of the patient’s cardiac, respiratory, and renal systems is made. Even if urgent amputation is required, a period of 4– 8 hours for the stabilization of diabetes, cardiac failure, and fluid and electrolyte imbalance can be invaluable. If longer preoperative time is available, this process of stabilizing the patient’s general medical condition is a priority. In elderly patients with sepsis, physiologic amputation is a useful adjunct.[14] For all elective major lower limb amputations, preoperative objective amputation level selection, as described below, is an important adjunct to successful surgery and rehabilitation. The patient is informed of the plans for a prosthesis and, if practical, should be seen by the prosthetist and physical therapist before surgery. Limb and joint mobilization exercises and strengthening procedures are commenced prior to surgery if at all possible. A team approach to rehabilitation introduced at this stage fosters a positive attitude among both staff and patient, stressing the expectation that ambulation will be restored. Amputation is a major traumatic experience for the patient and may have far-
Figure 37-1. Local amputation of infected, gangrenous toes in a foot with otherwise good vascular supply resulted in successful salvage of the foot.
Figure 37-2. Ulceration or necrosis of the heel or ankle is a contraindication to local amputation. Below-knee amputation was necessary in this patient.
Chapter 37.
reaching effects on his or her lifestyle and employment. A multidisciplinary approach including comprehensive counseling and an optimistic, enthusiastic outlook from the entire treating team plays an integral role in achieving a successful outcome.[6]
PRINCIPLES OF AMPUTATION SURGERY The commonly used major lower-limb amputations are shown in Fig. 37-3. The main guiding philosophy is that the amputation, when necessary, should be performed at the most distal possible site to remove gangrene, infection, or nonhealing lesions and where healing is likely to occur. The knee joint should be preserved in as many cases as possible. Successful ambulation is achieved after below-knee amputa-
Amputation in the Dysvascular Patient
tion in approximately 85% of patients but after above-knee amputation in only 40%. The primary objective of amputation surgery is to produce a stump that will proceed to primary, uncomplicated wound healing, allowing early limb fitting and complete rehabilitation. In comparison to amputation below the level of the knee joint, above-knee amputation has a higher operative mortality rate,[2] with a far lower rate of patient independence and return to ambulation (with a prosthesis). The loss of mobility caused by absence of the flexible knee joint and the loss of proprioceptive sense from the joint lining renders the use of a prosthesis far more difficult and doubles the amount of energy that must be used for mobilization compared to a below-knee prosthesis.[22] Even when lying in bed, the aboveknee amputee is at a disadvantage, because the added length provided by a below-knee residual limb offers greater leverage for movement and rolling. A list of the principal amputations used in dysvascular patients is given in Table 37-1. A tourniquet should never be used during amputation in the dysvascular patient because of the risk of further compromising the arterial blood supply to the area of the amputation stump. Absolute hemostasis and avoidance of stump hematomas is crucial to achieving maximum healing and rapid rehabilitation. An infected stump hematoma almost always leads to a more proximal amputation and a decrease in patient rehabilitation. Drains are not recommended, as they more often than double the risk of stump infection.[6] Antibiotic prophylaxis is always employed because of the risk of infection in the severely ischemic limb. A firstgeneration cephalosporin is usually adequate, but in patients with infection or gangrene complicated by diabetes, good aerobic and anaerobic coverage is necessary. Significant distal limb infections should be drained up to and including ankle guillotine amputation at an operation prior to definite amputation. At the definite amputation, any open or infected area(s) and necrotic tissue should be well wrapped and protected to prevent direct contamination of the amputation wound. There is evidence from several studies that, in the infected limb, guillotine amputation is the best method of elimination of the infection before definitive amputation is performed as a second-stage procedure.[23,24]
Principal Amputations Used in the Dysvascular Patient
Table 37-1.
Figure 37-3. Common levels for major amputations of the lower limb.
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Toe amputation Transphalangeal Transmetatarsal Forefoot amputation Transmetatarsal Amputation at the ankle Syme amputation Below-knee amputation Through-knee amputation Above-knee amputation Supracondylar Mid-thigh High-thigh Hip disarticulation
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In making the skin incision, the surgeon must take care to avoid undermining and hence devascularizing the skin, especially if a flap technique is being utilized. The tissues should be handled gently at all times, and the use of traumatizing instruments such as firm clamps, retractors, or sharp forceps on the skin and muscle areas should be avoided. Long plantar flaps are used in the hip, calf, foot, and toes because of the superior blood supply to the plantar aspect of the lower leg.[4] A long anterior flap is used at the throughknee level for similar reasons. Bone is always transected several centimeters proximal to the other structures at a level high enough to permit the soft tissue to easily approximate over the bone, producing a good covering without skin tension. Sharp, bony spicules are smoothed from the bone edge with a file or rasp. Proximal stripping of the periosteum should be minimized. Nerves are gently pulled into the wound, ligated (especially large nerves such as the sciatic nerve), and then transected. Surrounding muscle bulk is used to cover and protect the bone end, especially for weightbearing stumps. Coaptation of extensor muscle groups to flexor muscle groups (myoplasty) for all lower limb amputations is important in order to create a physiologic residual limb. The author does not favor true myodesis (muscle fixation to bone) except for long above-knee amputations using a medial adductor– based flap. Hemostasis should be meticulous so that wound drains will not be necessary. Drains probably increase the incidence of wound infection and breakdown.[2,21,25] The skin must never be sutured under tension. The author favors interrupted vertical mattress sutures and does not recommend staples or running skin closures. The latter closure probably further compromises skin blood flow in a dysvascular patient. Postoperatively, intensive efforts are made toward early limb and joint mobilization, and rehabilitation should commence as soon as the patient has recovered from the operation, aided by preoperative instruction, preparation, and exercises.
EFFECTS OF PREVIOUS RECONSTRUCTIVE SURGERY ON AMPUTATION LEVEL Many studies have examined the effects of previous reconstructive arterial surgery on the eventual level of amputation, some demonstrating that the resultant site was higher[26 – 31] and others stating that the eventual level was not affected.[32 – 35] There probably is no definite answer to the effect of prior arterial reconstructive surgery on eventual level of amputation, but delayed healing and local wound complication are more frequent in patients who have amputation after failed reconstruction.[36] A patent bypass graft does not necessarily ensure limb salvage. In a review of 987 patients who had undergone infrainguinal bypass grafts, Dietzek et al.[9] identified 75 patients (7.6%) with patent grafts who failed to achieve healing of ischemic wounds and subsequently underwent a major amputation procedure. Risk factors were the presence of diabetes, extensive pedal necrosis, bypass to an isolated
arterial segment, and lack of improvement as measured by the ankle-brachial pressure index after bypass.
DETERMINATION OF AMPUTATION LEVEL In the ideal situation it would be possible to determine preoperatively whether or not an amputation would heal at a chosen level, so that an inappropriately high level of amputation could be avoided and revision of an amputation to a higher level would never be necessary. In practice, when clinical observation alone is used in choosing the site of amputation, the resultant reamputation rate ranges from 15 to 40%.[6,37] Many special investigative techniques have been advocated for the determination of amputation level (Table 37-2). Of these, the most reliable are transcutaneous P O2 determination and measurement of skin clearance of xenon 133, with helpful, but less dependable information derived from segmental Doppler blood pressures and skin perfusion pressures. Factors that have been shown to have little predictive value include angiographic appearance of the lower limb and level of the most distal pulse.[38]In fact, the use of pulse assessment to determine amputation level has been demonstrated to result in an unacceptably high ratio of above-knee to below-knee amputations.[39] In 1987, Malone et al.[40] published a comparative amputation series with transcutaneous oxygen, xenon (133Xe), and Doppler knee and ankle blood pressures measured at the proposed level of amputation prior to surgery. The only statistically reliable measurement was transcutaneous oxygen. That publication was noteworthy because prior to that time Malone had been a coauthor on many papers suggesting that 133Xe skin clearance was the ideal test for preoperative amputation level selection. Since that time the author has used transcutaneous oxygen as the single best test for preoperative prediction of healing of an amputation level. Blood circulation in the skin is the single most important factor in determining amputation healing. Skin viability is therefore the major factor influencing selection of level in amputations for peripheral vascular disease.[41] Even in experienced hands, clinical judgment (based on factors such as skin viability, nutritional changes, and physical signs of ischemia) has not been shown to be as accurate as noninvasive preamputation level testing.[6] Prediction of the healing
Preoperative Determination of Amputation Level
Table 37-2.
Transcutaneous PO2 measurement Skin clearance of 133Xe Segmental Doppler blood pressures Laser Doppler flowmetry Segmental skin perfusion pressures Skin temperature measurement (thermography) Photoplethysmography and digital plethysmography
Chapter 37.
potential of forefoot amputations may be particularly difficult even with noninvasive techniques. Accurate amputation level success prediction will also allow for correct selection of patients who will require a revascularization procedure to achieve primary healing at a lower amputation level. Burgess and Matsen[42] have pointed out that no single technique can be expected to predict, unfailingly, the outcome of an amputation because of the effects of variables such as surgical technique (tissue handling, flap length, wound tension), alterations in blood flow caused by the procedure itself, and postoperative problems such as pressure from dressings, intercurrent diseases, wound infection, and malnutrition, which may compromise eventual healing. For these reasons, it is easier to predict failure due to circulatory deficiency than it is to predict success. However, Malone has reported greater than 95% success in predicting the healing of below-knee amputation with transcutaneous oxygen measurements.[6,40]
Transcutaneous PO2 Measurement It has been demonstrated that transcutaneous oxygen tension ðPtcO2 Þ measurements, taken with a skin sensor electrode heated to 458C, provide an accurate indication of the severity of vascular disease since blood oxygen content depends on local blood flow.[6,40,43,44] Recent studies have shown that PtcO2 of the anterior and posterior skin at the level of proposed amputation correlates well with eventual healing success or failure. Katsamouris et al.[45] found that healing was very likely if local PtcO2 exceeded 40 mmHg and that failure always occurred for a PtcO2 of ,20 mmHg. Burgess et al.[46] also found that transcutaneous oxygen tension levels correlated well with healing outcome for below-knee amputation, but they did not identify a definite threshold value. However, all patients with a PtcO2 of ,26 mmHg failed to heal. Malone has reported 100% success with belowknee amputation with immediate postoperative prostheses with a PtcO2 of $ 20 mmHg.[40] Ameli et al.[47] used a predetermined threshold of 22 mmHg at the below-knee site in a series of 38 patients and decided on the lower level of amputation dictated by either the PtcO2 or clinical judgment. They found that if PtcO2 readings alone had been used as the basis for selection, 100% healing could have been achieved at the expense of three extra above-knee amputations. Wyss et al.[48] reported that PtcO2 could also be used to predict which patients would require amputation after a vascular reconstruction procedure, with a postoperative PtcO2 of , 20 mmHg at the below-knee site predicting the occurrence of a subsequent amputation. Other research has suggested that the sensitivity of this method is greatly improved by recording the changes in PtcO2 that occur on breathing 100% oxygen.[49,50] In a prospective randomized study, Malone et al.[40] evaluated not only transcutaneous oxygen, but also transcutaneous carbon dioxide. Since there are problems with oxygen diffusion through areas of edema, it was hoped that transcutaneous carbon dioxide might help improve prediction of amputation healing. However, those authors clearly showed that transcutaneous carbon dioxide was less sensitive than transcutaneous oxygen.
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Clearance of 133Xe The rate of clearance of an intradermal injected dose of 133Xe at the proposed site of amputation may be utilized to calculate local skin blood flow. Moore et al.[51 – 53] have reported that when skin blood flow was found to be .2.6 mL/100 g/min by this technique, successful primary wound healing occurred in all cases, whereas only 50% of cases healed when the skin blood flow was between 2.0 and 2.6 mL/100 g/min. Harris et al.[54] reported that no amputation healed if the skin blood flow was ,1.0 mL/100 g/min. However, there was considerable overlap in the skin blood flow measurements of patients with successful and unsuccessful below-knee amputation in the Harris study. Other studies of this technique have shown less correlation with healing rates, with some failures being seen in the presence of blood flow measured up to 7.5 mL/100 g/min.[55] For the most part, this test is no longer utilized except as a research tool, especially after the report by Malone et al.[6] on the superiority of PtcO2 compared to 133Xe clearance for prediction of amputation healing.
Laser Doppler Flowmetry Monochromatic light is reflected back from the skin, and the Doppler shift detected is used to evaluate skin microcirculation. Laser Doppler flowmetry greater than 20 MV was associated with primary healing after below-knee amputation in a study reported by Kram et al.[56] However, the author has found that laser Doppler flowmetry is not as accurate as PtcO2 in predicting successful wound healing after amputation.
Segmental Blood Pressure Segmental blood pressure and flow waveforms as measured by Doppler ultrasound have not in general shown good correlation with healing,[18] probably because of the high proportion of diabetics who tend to have incompressible, calcified arteries, which give false pressure measurements.[57] There is little agreement as to what pressure is necessary for primary healing; Vena et al.[58] reported failure of transmetatarsal amputation with ankle pressures below 35 mmHg, whereas Barnes et al.[59,60] reported that 60 mmHg was the minimal ankle pressure associated with successful healing. When the ankle-to-brachial systolic index is considered, it seems likely that healing will occur with values above 0.35 – 0.45.[58,61] This technique does not give a good indication of the status of circulation in collateral vessels, and there is a significant incidence of successful healing in the presence of extremely low or undetectable segmental pressures and low ankle-to-brachial indicies.[42]
Other Techniques Other techniques that have been reported include skin temperature measurement,[62,63] photoplethysmography,[64] digital plethysmography,[65,66] and skin perfusion pressures.[67,68] Nuclear magnetic resonance (NMR) spectroscopy may become useful as a method of noninvasive assessment of skin perfusion and muscle function,[13] but it is a research tool at the present time.
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Except for PtcO2 ; most of these techniques suffer from lack of widespread availability or excessive variability in results. An example of that problem are the results obtained in skin temperature thermography, which have been found to be dependent on variants other than blood flow, including ambient temperature, patient exercise, and presence or absence of infection.
SURGICAL TECHNIQUES OF AMPUTATION Amputation of the Toe Transphalangeal Level Well-demarcated dry gangrene of the tip of a single toe or of several toes may, in many cases, be allowed to proceed naturally to autoamputation (Fig. 37-4). However, localized amputation is preferable if the involved toe is painful or if there is infection in the form of cellulitis, wet gangrene, discharging ulceration, or osteomyelitis (particularly in the infected diabetic forefoot). This amputation may be done at the transphalangeal level when there is no proximal spread of infection or necrosis into the forefoot and when the arterial blood supply to the rest of the foot is adequate for wound
Figure 37-4. Autoamputation of necrotic toes is the preferred treatment in selected patients who are free of pain or infection.
healing. It is important that all infected, ischemic, or threatened tissue be removed. The skin incision may be circular or may incorporate anterior and posterior or lateral flaps (Fig. 37-5A). Access to the line of incision is provided by retracting adjacent toes with a rolled gauze (rather than traumatizing the tissue with metal retractors) and gripping the toe(s) to be excised with a towel forceps. The initial incision is made to the depth of the bone, avoiding undermining the skin. The bone is then cleared of attached tendons and is usually divided midway through the proximal phalanx, using bone cutters or bone rongeurs. The bone may require further shortening to allow closure of the skin without tension. Under no circumstances should this amputation be completed through the proximal phalangeal metatarsal joint leaving exposed cartilage. In such an event the surgeon should proceed to the next higher level (ray amputation), since exposed cartilage is prone to infection and nonhealing complications. If infection is present, it is preferable not to close the wound; otherwise the skin may be loosely approximated with interrupted sutures, usually nylon or polypropylene. In most cases the patient may commence ambulation on the day following surgery. There are no prosthetic requirements after this amputation, and there is no increase in energy expenditure for ambulation compared to an ageadjusted normal population.
Figure 37-5. (A ) Incisions for transphalangeal and transmetatarsal amputation of the toe (levels of bone division indicated). (B ) Ray amputation incision onto the dorsum of the foot to expose head of metatarsal.
Chapter 37.
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Ray Amputation of the Toe When infection or necrosis of a single toe involves all of the skin on the toe, a small part of the adjacent forefoot, goes past the plantar skin crease, then a ray (or wedge) amputation is indicated. Usually this applies to a single toe alone; however, occasionally two adjacent toes may be amputated using this method. The initial incision should be planned so as to conserve all viable skin to allow for closure of the wound without tension. The plantar skin tends to be spared because of its better blood supply. The incision, often referred to as a racquet incision, skirts the necrotic skin of the toe and is then continued a short distance on the dorsum of the foot to allow exposure of the metatarsal head (Fig. 37-5B). This incision is similarly taken directly down to the bone, dividing tendons and ligaments without undermining the skin. The metatarsal is cleared of tendons, using a periosteal elevator and taking great care to avoid injury to adjacent digital arteries. The bone is then divided through the distal part of the metatarsal, and the affected bone and soft tissues are excised free by a combination of sharp dissection with a scalpel and cutting with heavy scissors. Soft bone is indicative of osteomyelitis in the metatarsal shaft, and more proximal metatarsal shaft resection is required. Occasionally, unsuspected infection of the tendon sheaths or fascial plans may at the time of operation be found to extend into the foot. Such a finding necessitates more proximal amputation or wide debridement and drainage in preparation for a higher level of amputation. At the conclusion of the procedure, the wound is loosely approximated with interrupted sutures, but it should be left open if there has been infection. In most cases the patient may commence ambulation on the day following surgery. There are no prosthetic requirements after this amputation, and there is no increase in energy expenditure for ambulation compared to an ageadjusted normal population.
Transmetatarsal Amputation of the Forefoot Transmetatarsal amputation is usually employed if there is gangrene involving several toes, especially if one of these is the great toe or if the ischemic or infective process extends too far proximally up the foot to allow for the healing of a ray amputation. Once again, the ischemic process is usually more severe on the dorsal surface of the foot, so the skin incision is designed to allow for a longer plantar flap, extending to the line of the heads of the metatarsals (Fig. 37-6). The line of the dorsal aspect of the skin incision is positioned slightly distal to the line of metatarsal division. This anterior or dorsal incision may be adjusted more proximally up the forefoot if resection of the metatarsal heads and part of the shafts is required. The incision is continued down to the metatarsals, and when these are cleared of tendon and ligament, the bones are divided with bone shears or an electric saw. A thick pad of subcutaneous tissue is preserved on the plantar aspect, and the other tissues are dissected away using a scalpel. Further trimming of bone and exposed tendon is performed as necessary to allow for closure of the wound by plantar flap without tension.
Figure 37-6. Incision for transmetatarsal amputation of the forefoot, incorporating a plantar flap.
As with all amputations for vascular disease, the skin should always be handled gently, avoiding the use of forceps wherever possible, and absolute hemostasis is mandatory. Interrupted sutures are placed loosely. The application of an immediate postoperative prosthesis (IPOP) is described later in this chapter. An alternative to IPOP is a non – weight-bearing short leg cast. A walking heel can be added to the cast after wound healing has occurred (10–14 days). Following healing of the transmetatarsal amputation, the patient is usually able to walk satisfactorily without significant disability. After recovery, the patient’s shoe can be modified by distal padding and a steel shank or metatarsal bar for the toe off. Compared to the age-adjusted normal population, there is a 10% increase in energy expenditure for ambulation with this level amputation. Transmetatarsal amputation avoids the equinus and equinovalgus deformities of the more proximal midfoot amputations. However, many of these amputations, although not favored by the author, are once again back in vogue. These amputations include: (1) the Lisfranc amputation, which is a plantar flap based metatarsal/tarsal disarticulation; (2) the Chopart amputation, which is a plantar flap –based calcanealtalus tarsal disarticulation; and (3) the Pirogoff amputation, a formal ankle disarticulation in which the talus is separated from the tibia and fibula, which are then transected immediately above the joint surface. In the opinion of the author, these three midfoot amputations are rarely indicated in the dysvascular patient and are best utilized in traumatic injury.
Amputation at the Ankle (Syme Amputation) This technique, which is a modification of disarticulation through the ankle joint, was originally described by Syme[69] in 1982. The operation involves excision of the distal joint
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surface of the tibia and fibula, with a flap of skin from the heel being used to cover the transected bone. This amputation provides an end weight –bearing stump and leaves a residual limb that is only a few inches shorter than normal, thus allowing the patient to walk for short distances (at home) without a prosthesis. The addition of a prosthesis makes both legs equal in length, but the Syme prosthesis is not cosmetic in appearance and therefore may be contraindicated in women. Because of the great potential for ischemic complication, patients should be selected carefully for this procedure. Contraindications include ischemia, ulceration, or infection of the heel. This is the most technically difficult major lower extremity amputation. This amputation can be performed in one (no transection of the fibular and malleolar flares) stage or two stages (resection of the fibular and malleolar flares at a second minor operation). The main indication is welldemarcated gangrene of the forefoot that extends too far up the foot to allow for a successful transmetatarsal procedure; in addition, the vascularity of the ankle region and heel pad must be well preserved. Presence of the popliteal or posterior tibial pulse is very favorable for healing.[70,71] The author’s experience suggests that this is not a good amputation level in diabetics unless sensation of the heel pad is intact, due to recurrent ulceration on the Syme residual limb requiring below-knee amputation. The incision is shown in Fig. 37-7A. The upper horizontal line begins on the lateral side of the ankle just below the
lateral malleolus and is brought across the front of the ankle joint in a straight line to a point just below the medial malleolus. The lower, vertical part of the incision is carried down across the sole of the foot in front of the heel in a straight line to join the posterior aspects of the ends of the upper incision. The whole of this incision is carried down to bone, carefully avoiding undermining of the skin and preserving a maximum length of posterior tibial artery (the latter of which is crucial for healing). The ankle joint is entered through the anterior aspect, and division of the tendons and ligaments across the front of the ankle allows disarticulation of the talus. The next part of the procedure involves dissecting out the calcaneus, taking great care to avoid damage to the soft tissues and skin of the heel pad. This is performed using sharp dissection with a scalpel around the calcaneus, staying close to the bone, and dissecting off surrounding fibrous tissue, ligament, and fat. This is usually described as a subperiosteal removal of the calcaneus; however, because of the absence of easily identifiable planes, it is very difficult to stay within a true subperiosteal plane. Completion of excision of the calcaneus is best achieved with the partially disarticulated foot reflected down to allow better exposure. Great care must be taken to avoid perforating the skin posteriorly when transecting the insertion of the achilles tendon. When the calcaneus has been excised, the anterior flap is gently retracted, allowing access to the distal ends of the tibia and fibula (Fig. 37-7B). The classic technique describes removal of the articular cartilage with a saw, dividing directly across the lower ends of both bones (fibula and tibia) at a level just above the joint. Hemostasis is achieved and the heel pad rotated up and secured across the cut ends of the bones. The heel pad is held in place by closure of the skin, using interrupted sutures of nylon propylene, which can be left in place for several weeks. The wound may be dressed with layers of gauze held in place by elasticized bandaging. The dressing is applied with gentle compression so as to minimize edema. Alternatively, the stump may be placed within a well-padded plaster-ofParis cast, which can later be fitted with a rubber stop to allow partial weight bearing. The technique of immediate postoperative prosthesis is described later in this chapter. In order to ambulate more than short distances in the house, a definite prosthesis is required. Due to the bulbous nature of the Syme residual limb, construction of the prosthesis requires a medial or posterior window resulting in a noncosmetic prosthesis (“fat ankle”). Compared to an ageadjusted normal population, there is a 10–20% increase in energy expenditure for ambulation at this level of amputation.
Below-Knee Amputation
Figure 37-7. Syme’s amputation: (A ) skin incision; (B ) the disarticulated foot is retracted downward after the joint has been entered and the calcaneus dissected.
The general rule that amputation stumps should be as long as possible does not apply to the below-knee amputation, since fitting a prosthesis is more difficult and stump complications are increased if the below-knee stump is too long. In fact, too long a below-knee residual limb may preclude the fitting of energy absorbing/releasing prostheses such as the FlexfootTM. In addition, the problems of weight bearing and retaining adequate soft tissue to cover the stump are increased with a longer tibia, and since the more distal tissues will tend to have
Chapter 37.
a less adequate blood supply, stump ulceration and pain will be more common. The ideal length for anterior skin incision is one hand’s breadth (10 cm) below the tibial tubercle. After completion of the amputation, the anterior margin of the tibia must be beveled (45–608) and the fibula is usually transected one-quarter inch more proximally than the tibia. The posterior flap must be long enough to cover the residual limb with a good muscle myoplasty and “plastic” skin closure of interrupted vertical mattress sutures. Up until about 20 years ago, most amputations for vascular disease were performed at the above-knee level. Since that time, however, it has been shown that 70– 85% of all vascular amputations may be performed below the knee with satisfactory healing rates.[34,72 – 74] The author would suggest, however, that with proper objective amputation level selection, primary healing may be expected in .95% of below-knee amputations. Clinical judgment concerning the state of the circulation and nutrition of the skin both preoperatively and intraoperatively has been shown not to be a reliable factor in predicting healing of a below-knee stump. However, if good bleeding is noted at the time of operation, the chance of wound healing has been shown to be . 90%.[75] Even where there is little or no bleeding, eventual healing still occurs in 69% of patients.[36,75] It is preferable to decide on the level of amputation by objective investigations (amputation level determination) before the time of surgery, rather than to commence with a below-knee incision with the idea of immediately moving to the above-knee level if necessary. Several conditions dictate that a below-knee amputation should not be performed (Table 37-3). These are: 1.
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Several incisions are described for the below-knee amputation. These include: (1) the circumferential, no-flap incision;[76] (2) short, equal anterior and posterior flaps; (3) skew flaps;[77] and (4) the long posterior flap[41] (“Burgess technique,” which the author favors) (Fig. 37-8). As we have used the long posterior-flap technique in most cases, the following description will be of that method. The scar for endbearing amputation residual limbs should preferably be anterior or posterior to the end of the stump; however, scar placement is not usually a concern for the below-knee amputation, where most prostheses are not of the end-bearing type. We have preferred the long posterior myoplastic flap or myocutaneous flap because of the superior blood supply of the posterior compartment, which leads to a higher rate of primary healing, and because the bulk of the gastrocnemius – soleus muscle mass gives a good cover for the end of the tibia. The incision for this procedure is demonstrated in Fig. 37-9. The operation may be performed with general, spinal, or epidural anesthesia. Following skin preparation and draping, the incision is marked on the skin with a pen. The anterior or horizontal aspect of the incision continues back to a point just behind the fibula laterally and to the corresponding point on the medial side of the leg, level with posteromedial aspect of the tibia. From these (mid-shaft) points, the posterior or vertical lines of the incision are taken down the middle of the distal limb to form a long, curved posterior flap of a length sufficient to cover the stump. The length of the posterior flap usually equals the diameter of the limb at the point of anterior transection plus 2 –3 cm. The skin
Severe joint contractures of the knee or hip. Such contractions make prosthesis fitting virtually impossible. Even if fitting of a prosthesis is possible, the functional result will not be satisfactory. Leg spasticity or rigidity due to previous stroke. Severe arthritic changes of the knee. Painful arthritic knee joint will usually not be worth saving because of the poor functional result. Skin ulceration or infection extending above the below-knee amputation level (expected anterior and/or posterior incisions). Similarly, questionable or borderline skin viability in the patient who is confined to bed should prompt selection of a higher level. Deep infection or necrosis of the muscle compartments extending above the mid-calf level.
2. 3.
4.
5.
In these cases, through-knee or above-knee amputation are often acceptable alternatives. Table 37-3.
Contraindications to Below-Knee
Amputation Joint contracture of knee or hip Leg spasticity or rigidity Severe knee arthritis Skin ulceration or infection at BKAa incision level Infection or necrosis of leg muscle compartment a
BKA = below-knee amputation.
Figure 37-8. Posterior myocutaneous flap incision and level of bone section for below-knee amputation.
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Figure 37-9. Below-knee amputation. The bone is sectioned with a saw while the skin is gently retracted.
incision is deepened through the deep fascia in a single cut perpendicular to the skin so as to avoid undermining. The two saphenous veins and tributaries are ligated as they are encountered. The incision is then deepened through the fascia in all areas of the skin incision. The muscles of the anterior compartment are transected at a level several centimeters distal to the proposed line of division of the tibia, and the anterior tibial vessels are suture ligated. Either the tibia or the fibula may be divided first, depending on the surgeon’s preference. If the tibia is to be divided first, the surrounding muscles are divided in the same line as the skin incision back to the level of the posterior border of the tibia. The anterior tibial neurovascular bundle is identified and the vessels are suture ligated prior to bone section. The bone is cleared of muscle on all sides, using a scalpel and periosteal elevator. Promixal periosteal elevation should be minimized. The tibia may then be divided using a hand-saw, Gigli saw, or electric saw. The upper half of the anterior tibia surface is beveled at 45 –608 after completion of removal of the distal limb. The fibula is similarly cleared of muscle and transected about one quarter of an inch proximal to the tibia. Angled bone-cutting shears aid in dividing the fibula at a higher level than the tibia. The posterior tibial neuromuscular bundle and peroneal vessels are suture ligated when exposed (Fig. 37-10). At this stage the main muscle bulk of the leg will have been divided in a line perpendicular to the skin (Fig. 37-9), and the posterior myocutaneous flap may now be completed using a long amputation knife to divide the soleus and gastrocnemius muscles obliquely. Bleeding vessels and venous sinuses are suture ligated; it is important to achieve
good hemostasis to avoid the formation of postoperative stump hematomas. Nerves are gently stretched down, ligated and divided, and allowed to retract. Absolute hemostasis is essential, especially if an immediate postoperative prosthesis is going to be applied. The bone ends are smoothed with a rasp or file. Then the wound is irrigated and closed in two layers, commencing with myoplasty of the posterior flap by suturing the tendinous cut edge of the gastrocnemius –soleus forward over the ends of the bone to the thinner anterior fascia and the periosteum of the tibia. Finally the skin is closed with interrupted sutures, avoiding tension (Fig. 37-11). Skin apposition must be precise, since delay of epithelialization is likely, because of the reduced vascularity, if there are any gaps between the skin edges. The suture-line scar should be above the beveled anterior edge of the tibia, away from regions of pressure if possible. If no attempt is made to trim the dog ears, then care must be taken with application of the postoperative dressing to not bend or fold over the dog ears, as these will mold into the general shape of the stump after several weeks. The author favors plastic excision of the dog ears with careful closure of the surgical wound at the time of amputation. The resultant hemicylinder provides the prosthetist with a suitable shape for the manufacture of a socket. Closed suction drains may be used if needed but are generally not necessary and increase the incidence of infection.[6] A thick dressing of gauze pads and cotton– wool bandaging is then applied, and the final layer may be elastic Ace bandages or a plaster-of-Paris cast. The techniques of immediate postoperative prosthesis are described later in this chapter.
Chapter 37.
Figure 37-10. structures.
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Cross-sectional anatomy of the leg at level of below-knee amputation, demonstrating position of major neuromuscular
There are many variations of definite below-knee prostheses from a simple pylon with a nonmotion foot to energy-storing prostheses. Prosthetic choice depends on age and the activity level of the patient. Compared to an ageadjusted normal population, there is a 40 –60% increase in energy expenditure for ambulation at this level of amputation.
Through-Knee and Above-Knee Amputation Many techniques of above-knee amputation have been reported; in general, these are all variations of a similar operative procedure. The distal supracondylar amputation and Gritti-Stokes techniques have lost popularity because of the realization that the through-knee amputation has the advantage of preserving proprioceptive areas of the joint and affords greater bone length, which makes manipulation of a prosthesis simpler. Otherwise, the general rule for above-
knee amputation is that maximum bone length should be conserved within the bounds of the patient’s vascular problem. As with the below-knee amputation, myodesis procedures (except as described later), where the muscles are sutured or otherwise fixed to holes drilled in the bone, are generally not encouraged in the dysvascular patient. It is far simpler, just as functional, and probably allows fitting of a more cosmetic prosthesis to divide the muscles distal to the site of bone division and then to suture antagonistic groups over the end of the bone stump, anchoring them to each other and to periosteum. This allows for the preservation of muscle activity (a “physiologic stump”) and gives a good covering for the bone. The skin incision usually employs equal anterior and posterior flaps (fish-mouth incision), as shown in Fig. 37-12; however, a circumferential skin incision is just as effective. A technique using laterally placed flaps is favored for throughknee amputation in some centers,[78] particularly if the anterior skin-flap region is compromised by ischemia.[79]
Through-Knee Amputation
Figure 37-11. The stump is closed without tension allowing “dog cars” to mold into the shape of the stump over several weeks.
The through-knee level gives the amputee the advantage of a long lever with an end-bearing stump. In addition, proprioceptive information coming from the capsular structures of the knee is preserved. The disadvantages to this level amputation are prosthetic. It is hard to get cosmetic or matching knee centers, even with new 4-bar link knees. Since the residual limb is bulbous at the distal femur flares, the prosthesis must be made with a medial or posterior window, and therefore the prosthesis is not often very cosmetic. If a through-knee amputation is to be performed, the skin incision must be distal to the knee joint by 4 –5 cm (level of the tibial tubercle), and the patella and patellar tendon are usually preserved and sutured over the exposed femoral condyles. Preferably the patient is placed prone and an
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for application of an immediate postoperative prosthesis are described later. Compared to the normal age-adjusted population, there is a 100 – 120% increase in energy expenditure for ambulation at this level of amputation.
Above-Knee Amputation
Figure 37-12. Anterior– posterior “fish-mouth” incision for above-knee amputation.
anterior-based skin flap is created. The incision is deepened straight through to the depth of bone, perpendicular to the skin, and the muscles and tendons attached to the upper part of the tibia (sartorius, gracilis, semitendinosus, quadriceps expansion, and gastrocnemius) are divided. The patellar tendon is separated from the tibial tubercle and the knee joint is entered anteriorly. The collateral and cruciate ligaments are divided. The resection continues below the menisci, preserving the capsular attachments to the rims of the medial and lateral meniscus. The described joint incision helps to preserve the rich proprioceptive supply of the knee joint. With the knee bent, the posterior capsule of the joint is divided, giving access to the popliteal neurovascular structures. The artery and vein are suture-ligated, and the nerves are brought down, ligated, and then allowed to retract up into the muscle bulk. The patella is reflected back over the femoral condyles and may be held in place by suturing the infrapatellar tendon to the posterior capsule; however, if there is insufficient patellar tendon length, the tendon may be sutured to the stumps of the cruciate ligaments. The divided hamstring tendons are also sutured to the knee capsule. A satisfactory myoplasty is thus produced. Preservation of the patella and patellar tendon conserves the broad kneeling area of the knee. The wound is closed in two layers. An amputation dressing is then applied, with or without a plaster cast. The techniques
Because ambulation after above-knee amputation is directly related to bone length, this procedure is done with the aim of preserving the maximum possible bone length. The usual level of amputation is just above the terminal flare of the femur, allowing approximately 10 cm for the interposition of an artificial knee joint between the stump and the normal knee axis. We have usually used anterior and posterior flaps, but a circumferential incision is also suitable. Short flaps are preferred because of the possibility of jeopardizing blood supply in long flaps. The incision passes through skin, subcutaneous tissue, and deep fascia without undermining and then is continued obliquely through the muscle layers, in toward the anticipated line of bone section. As the major vessels are almost certainly occluded, hemorrhage is rarely a problem. However, all large vessels should be suture ligated. The main dissection usually commences on the medial aspect of the leg to expose the femoral vessels, which are clamped and suture-ligated as they are encountered (Fig. 37-13). The sciatic nerve is exposed more posteriorly and ligated after being pulled down, so that it will then retract up into the muscle bulk after it is transected and be protected from direct pressure. Ligation of this nerve is important because of the artery that accompanies it. The bone is sectioned using a hand or electric saw, and the ends are smoothed with a file. Opposing muscle groups are then sutured over the end of the bone, with special attention being given to fixation of the rectus femoris and hamstrings to each other and to the periosteum to preserve balance of contractile function. The adductor magnus and fascia lata are sutured to each other transversely over the bone. Careful approximation of muscle layers also obliterates dead space within the wound. The fasciae of the anterior and posterior flap are then approximated with interrupted, absorbable sutures. If necessary, wound drainage may be instituted with a closed suction drain or a Penrose tissue drain placed at the base of the flaps. However, absolute hemostasis is worth the effort since drains increase the possibility of infection. The skin is carefully approximated without tension. The amputation dressing is then applied, and a plaster-of-Paris cast may be added, especially if a prosthesis is to be used immediately. The techniques for application of an immediate postoperative prosthesis are described later. One of the major prosthetic advances in the last two decades has been the move away from the quadrilateral socket (Berkeley Brim) to the Catcam soft plastic socket fit for above-knee amputees. These new prostheses are lighter and more functional than their older counterparts and probably have helped to increase the percentages of ambulatory aboveknee amputees. However, compared to an age-adjusted normal population, the increase in energy expenditure required to ambulate after an above-knee amputation ranges from 140 to 200%. Since use of a wheelchair requires only a
Chapter 37.
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Figure 37-13. Cross-sectional anatomy of the thigh at the level of above-knee amputation.
9% increase in energy expenditure, it is easy to understand why elderly amputees, especially those with cardiovascular impairment, choose a wheelchair over walking with an aboveknee prosthesis. An important new technique for above-knee amputation has been described by F. Gottschalk (personal communication). The above-knee amputation is performed utilizing a long medial flap and shorter lateral flap in order to preserve length of the adductor magnus muscle. The adductor magnus is dissected off the distal medial femur, and after transection of the femur the adductor magnus is wrapped over the end of the femur and then fixed to the lateral femur in a true myodesis. The medial-based skin flap allows closure of the incision on the lateral side of the leg without skin tension. Use of the adductor magnus in this fashion preserves the patient’s ability to keep the residual femur in a more normal weightbearing position relative to the pelvis and knee joint and aids with patient ambulation.
Hip Disarticulation Amputation at the hip level is rarely performed for peripheral vascular disease.[80] Usually, dysvascular patients requiring this level of amputation have had failed above-knee amputations. Most commonly in dysvascular patients, this amputation is performed in the face of occlusion of the common femoral, superficial femoral, and profunda femoral arteries. Because of poor blood supply, healing complications and stump infection are common when this amputation is performed in dysvascular patients. In hip disarticulation amputation, the initial step is control of the femoral artery, followed by division of the musculature of the adductor and anterolateral compartments to expose the hip joint. Anatomic considerations in this dissection have been described in detail by Boyd.[81] After disarticulation, a long posterior flap of gluteal muscle is devised and reflected anteriorly to form a broad muscle base for support of prosthesis.[79] It is important to achieve good cover of the
acetabulum with muscle and soft tissue, and the suture line should be placed so as to avoid direct pressure against the prosthesis.[82] Compared to the normal age-adjusted population, there is a 240–500% increase in energy expenditure for ambulation at this level of amputation. Needless to say, most amputees (except children) do not ambulate at this level of amputation and use a wheelchair for mobility.
POSTOPERATIVE CARE Adequate analgesia is important in achieving early mobility, with exercises aimed at avoidance of flexion contractures. Patients should go to physical therapy for range-of-motion and limb-strengthening exercises starting on the first postoperative day if possible. The dressing is usually not disturbed for 3 or 4 days unless there is significant pain or fever pointing to possible complication. In those instances where drainage tubes are necessary, they are removed as soon as possible, preferably within 24 hours. We prefer not to suture the drains in place, so that they may be removed gently without disturbing the dressing. The elastic stump bandage helps prevent swelling while also allowing for passive and active exercise in order to avoid contractures. If a plaster cast or IPOP has been applied, flexion contractures will not occur, but there may be some loss of joint mobility. Conditions such as diabetes mellitus, hypertension, heart disease, and chronic respiratory disorders require close monitoring and control during the postoperative period. Systemic antibiotics should be continued for several days if infection was present at the time of operation; in the absence of infection several perioperative prophylactic doses of antibiotic are sufficient (24 hours). Early mobilization of the patient is encouraged, either by the use of temporary pneumatic air splint,[83,84] with crutches or a walking frame, or by the technique of immediate postoperative prosthesis
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application, as outlined below. The rehabilitation of the patient commences as soon as possible and is best achieved using a multidisciplinary approach, involving regular instruction and supervision by a physical therapist, occupational therapist, prosthetist, and surgeon.[6] Once wound healing is satisfactory, a stump dressing consisting solely of an elastic Ace bandage can be employed to prevent stump edema and to aid in molding the residual limb shape. The patient is instructed in the proper technique of bandage application and should reapply the bandage several times a day. Correct technique is important in preventing circumferential compression, which may increase edema. In the opinion of the author, aggressive use of temporary removable prostheses after major lower extremity amputation (even if IPOP is not used) not only improves rehabilitation results, but helps control pain and swelling. In the author’s personal series of over 2000 patients treated with either immediate postoperative prosthesis or early temporary prosthesis, the incidence of stump pain and phantom pain problems are , 5%.[6] After the first few days, the patient should not be allowed to lie in bed with the stump propped up on pillows, since that position tends to allow the development of contractures. Sutures should be left in place for at least 2 weeks and sometimes for longer. Narcotic analgesia will usually be required for several days; however, complaints of severe pain after 48 hours suggests a major complication and should precipitate removal of the dressing and inspection of the wound. The possible occurrence of phantom limb pain should be explained to the patient. Postoperative confusion is common because of the generally elderly population that one is dealing with and because of factors such as infection, analgesia, and multiorgan disease. If the patient is confused, steps must be taken to prevent him or her from trying to get out of bed, which often precipitates injury to the amputation stump.
IMMEDIATE POSTOPERATIVE PROSTHESIS FITTING The concept of improved stump healing and accelerated rehabilitation brought about by immediate postoperative prosthesis fitting dates back to the 1960s.[85] The main benefits claimed for this technique are faster rehabilitation of the patient with improved patient morale and motivation, coupled with early acceptance of the procedure and conditioning to accept and use the prosthesis. Other advantages have been noted with early prosthesis fitting, including better control of edema of the stump, less pain, perhaps earlier healing, protection of the wound from trauma, improved rates of rehabilitation, and prevention of contractures. The earlier mobilization is thought to be associated with a lower incidence of venous thromboembolic disease, atelectasis, and pneumonia. Patients have been noted to regain strength and to show earlier learning of balance control due to the increased proprioceptive input from muscles and joints of the involved limb, which occurs
with early mobilization, exercise, and partial weight bearing. Obviously, this technique will not be suitable for all patients, especially those who have been severely debilitated by sepsis or long-term illness. It is possible that there is also the potential problem of compromising wound healing with IPOP use in the patient with severe vascular disease. However, with objective preoperative selection of amputation level, wound-healing problems can be reduced to a minimum. The IPOP technique also works well in diabetics. Because this technique requires the patient to wear a plaster cast over the amputation stump for 2 –3 weeks, it should not be used for those patients who may be vulnerable to wound breakdown or possible infection, since the stump will then not be readily accessible for inspection. Early involvement of the prosthetist is essential. Preferably she or he will see the patient before the operation and will assist at the time of surgery in the application of the IPOP cast. The surgical technique of amputation does not differ from that described above except that, after the initial wound dressing is applied, an IPOP cast is built on the residual limb. The immediate fitting technique (Fig. 37-14) involves application of a rigid cast socket made up of an inner layer (the stump sock), appropriate protection of bony prominences by padding (the relief pads), a polyurethane cap or pad applied over the end of the stump, and application of the plaster cast.[6,86] Depending on the amputation level, a suspension strap with waist belt is incorporated into the plaster cast. An attachment plate is incorporated into the distal end of the plaster, and the pylon tube with prosthetic foot will be fitted to this plate. A window is made in the cast over the patella to protect this area from pressure sores and to allow patellar movement with ambulation. Immediate postoperative prosthetic techniques work well with all levels of major limb amputation (TMA, SYME, BK, or AK) but work best with below-knee amputees. If the patient is well enough, mobilization may commence on the first postoperative day. On the first postoperative day the patient stands at bedside without weight bearing. During the first week the patients progresses to standing without placing weight on the prosthesis while supported by a walking frame or crutches. By the second week the patient advances to 50% weight bearing on the amputated limb, and full weight bearing is achieved by 21– 30 days after surgery. The team of prosthetist, physical therapist, and surgeon supervises and encourages the patient with most of the early exercises and use of the prosthesis. The rehabilitation process is best supervised in the physical therapy department, where special equipment for ambulation, such as parallel bars, is available. The patient progresses from standing and balancing with limited ambulation through progressive weight bearing over several weeks as previously described. The plaster cast is usually changed after 7 –10 days and 14 –21 days. Patients may be discharged to a rehabilitation facility (with IPOP experience) either on the second or third postoperative day or after the first cast change. After the second or third cast change, the patient makes use of temporary removable prostheses until full wound healing and molding of the stump have occurred, at which time measurements for the permanent prosthesis may be taken and the permanent prosthesis manufactured (usually at 6 months).
Chapter 37.
Amputation in the Dysvascular Patient
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Figure 37-14. Techniques of immediate postoperative prosthesis fitting at the back knee level: (A ) stump sock; (B) relief pads to protect bony prominences; (C ) application of plaster cast; (D ) attachment plate incorporated into the plaster, with adjustable-length pylon tube; (E ) complete prosthesis with foot attached; (F ) suspension strap and waist belt attached to prosthesis.
COMPLICATIONS OF AMPUTATION The complications of amputation surgery may be divided into those that are specific for the operation and those that are due to the severe cardiopulmonary disease and diabetes often seen in this patient population. Several follow-up studies have shown that approximately 50% of the diabetic amputee patients die within 2 –3 years of the operation, usually because of cardiac or cerebrovascular problems, and that, of the survivors, a further 30 –50% eventually require amputation of the contralateral leg within the same time span.[6,87 – 90] However, survival for nondiabetic lower extremity amputees approximates the normal age-adjusted population. Until
recent years, the operative mortality rate among those with amputations below the knee was approximately 10%, and among those with through-knee or above-knee amputation, the usual rates were 20 –30%.[2] With recent improvements in patient preparation for surgery, anesthetic techniques, and intensive care, there should now be a mortality rate of ,5% for below-knee and perhaps 10% for above-knee operations. Bodily and Burgess[89] reported a series of 55 patients who had major amputations with an operative mortality rate of only 1.5%, and Fearon et al. reported a 3% mortality rate for below-knee amputation in 100 diabetics. There is also a relatively high incidence of postoperative cardiovascular and cerebrovascular complications such as myocardial infarction, stroke, or respiratory failure.[91] The long-term survival
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prospects for diabetics are significantly worse than for nondiabetics, as previously stated.[92] In a series of 465 amputations, Bunt and Malone[4] reported an operative mortality rate of 1.5%. That series included amputations at all levels of the lower extremity. If the amputation is performed for the treatment of sepsis, infective complications including septicemia and multiorgan failure may be common. A high incidence of postoperative venous thrombosis has been reported, particularly for amputation above the knee.[1] That high incidence of thromboembolic disease is most likely related to prolonged hospitalization both before and after operation and to the generally poor medical condition of patients undergoing above-knee amputation. The success rates with rehabilitation diminish dramatically in any patient who has been at bed rest for more than 30 days prior to major lower extremity amputation.[6] Malone reports that immediate postoperative prosthesis and other such aggressive rehabilitation techniques should not be utilized in patients who have been at extended bed rest prior to amputation, since the eventual successful ambulation rates are unacceptably low. Neurological changes such as confusion, disorientation, and reactive depression frequently occur and may be difficult to manage, while also rendering rehabilitation difficult. Care of the skin wound is compromised in these patients, and they may require special observation to prevent accidents such as falling out of bed, which often leads to breakdown of the stump. Other common general complications include urinary tract infection and urinary retention, sacral-pressure-area bed sores, gastrointestinal bleeding, and renal failure. The main complications of the procedure itself are infections and nonhealing of the wound due to ischemia (Fig. 37-15). These problems can be minimized by good objective selection of amputation level prior to surgery, preoperative treatment for infected ischemic limbs, and the use of antibiotic prophylaxis. However, even with ideal manage-
ment, episodes of skin-flap ischemia and suture-line infection cannot always be avoided. However, amputation level selection by objective tests (such as PtcO2 ) will minimize postoperative healing failures.[6] Wound breakdown due to ischemia may be a primary problem or may occur because of excessive pressure (from the dressing, the plaster cast, a poorly fitting prosthesis, or early weight bearing on a prosthesis). Small areas of wound breakdown will often heal with conservative management. Ischemic failure with or without infection usually requires revision. A failed belowknee amputation may often be revised to a higher level while still retaining the knee joint, or it may necessitate above-knee amputation. Phantom pain occurs frequently, and the patient should be warned of this possibility before surgery. Usually the symptoms are not severe and no specific treatment is necessary, but occasionally narcotic or antidepressant medication may be required. In the author’s experience, there is an inverse correlation between ambulation and problems with postoperative stump pain or phantom pain. Those patients who do not ambulate have a much higher incidence of pain complications, possibly as high as 30 –50%, while those patients who successfully ambulate have a pain complication rate of , 5%. Occasionally painful neuroma formation occurs at the divided nerve endings. Such neuromas require excision. Another important local complication is joint contractures. The main way to avoid contractures is to ensure that joint and leg exercises are commenced early in the postoperative period (and preoperatively too, if possible) and that rehabilitation begins immediately, with the patient being ambulated in a non–weight-bearing fashion with crutches or a walking frame. Adequate treatment of wound and stump pain in the early postoperative period aids early mobility. Failure to rehabilitate should also be regarded as a complication, since a major aim of good amputation is to achieve eventual ambulation and independent mobility. Recent experience suggests that at least 75% of amputees who have been fitted with a prosthesis will make daily use of it, although a significant proportion of these patients do not use their prosthesis outside of the home.[93] Other authors, including Malone, have reported success rates higher than 95% for periods as long as 5–10 years in those patients who were initially treated with immediate postoperative prostheses.[6]
CONCLUSIONS
Figure 37-15. Typical wound edge necrosis of a below-knee amputation stump. This situation can often be salvaged by excision of all the necrotic tissue and primary closure, still at the below-knee level. Severe ischemia or infection usually mandates above-knee revision.
The guiding principle in amputation surgery is to obtain maximal restoration of function. Successful rehabilitation requires preservation of joint wherever such preservation is compatible with healing. Early ambulation is optimal and may best be achieved by the use of immediate prosthesis techniques in suitable patients. Amputation should thus be regarded from the rehabilitation perspective as a reconstructive procedure designed to restore function and allow the patient to return to an independent lifestyle. With the combination of low-level joint-preserving amputations and efficient, light, functional prostheses (Fig. 37-16), amputation
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Figure 37-16. Modern lightweight, functional below-knee prosthetic limb (A ) may be very difficult to differentiate from the contralateral normal limb (B ).
is no longer regarded simply as the removal of dead tissue but as a true reconstructive procedure, which is one alternative among many in the treatment of severe limb ischemia.
Attitudes toward amputation and subsequent rehabilitation should emphasize that return to ambulation is the expected outcome.
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Little, J.M. Major Amputations for Vascular Disease; Churchill Livingstone: Edinburgh, 1975. Otteman, M.G.; Stahlgren, L.H. Evaluation of Factors Which Influence Mortality and Morbidity Following Major Lower Extremity Amputation for Atherosclerosis. Surg. Gynecol. Obstet. 1965, 120, 1217. Rush, D.S.; Huston, C.C.; Bivins, B.A.; Hyde, G.L. Operative and Late Mortality Rates of Above-Knee and Below-Knee Amputations. Am. Surg. 1981, 47, 36. Bunt, T.J.; Malone, J.M. Revascularization or Amputation in the .70 Year Old. Am. Surg. 1994, 60 (5), 349. De Frank, R.D.; Taylor, L.M.; Porter, J.M. Basic Data Related to Amputations. Ann. Vasc. Surg. 1991, 5, 202. Malone, J.M. Lower Extremity Amputation. In Vascular Surgery, A Comprehensive Review, 4th Ed.; Moore, W.S., Ed.; W.B. Saunders: Philadelphia, 1993.
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Kald, A.; Carlsson, R.; Nilsson, E. Major Amputation in a Defined Population: Incidence, Mortality and Results of Treatment. Br. J. Surg. 1989, 76, 308. Finch, D.R.A.; Macdougal, M.; Tibbs, D.J.; Morris, P.J. Amputation for Vascular Disease: The Experience of a Peripheral Vascular Unit. Br. J. Surg. 1980, 67, 233. Dietzek, A.M.; Gupta, S.K.; Kram, H.P.; et al. Limb Loss with Patent Infrainguinal Bypasses. Eur. J. Vasc. Surg. 1990, 4, 413. Bild, D.E.; Selby, J.V.; Sinnock, P.; et al. Lower Extremity Amputation in People with Diabetes: Epidemiology and Prevention. Diabetes Care 1989, 2, 24. Berardi, R.; Keonin, Y. Amputations in Peripheral Vascular Disease. Am. J. Surg. 1978, 135, 231. Yao, J.S.T. Choice of Amputation Level. J. Vasc. Surg. 1988, 8, 544.
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13. Sarin, S.; Sharmi, S.; Shields, D.A.; et al. Selection of Amputation Level: A Review. Eur. J. Vasc. Surg. 1991, 5, 611. 14. Bunt, T.J. Physiologic Amputation for Acute Pedal Sepsis. Am. Surg. 1990, 56 (9), 520. 15. Hargrove, W.C.; Barker, F.C.; Berkowitz, H.D.; et al. Treatment of Acute Peripheral Arterial and Graft Thromboses with Low-Dose Streptokinase. Surgery 1982, 92, 981. 16. Bell, E.T. Atheroselerotic Gangrene of the Lower Extremities in Diabetic and Non-Diabetic Persons. Am. J. Clin. Pathol. 1957, 28, 27. 17. Sizer, J.S.; Wheelock, F.C. Digital Amputations in Diabetic Patients. Surgery 1972, 72, 980. 18. Fearon, J.; Campbell, D.R.; Hoar, C.S.; et al. Improved Results with Diabetic Below-Knee Amputations. Arch. Surg. 1975, 120, 777. 19. Cruse, J.; Foord, R.A. A Five Year Prospective Study of 23,649 Surgical Wounds. Arch. Surg. 1973, 107, 206. 20. Kitter, A. A Technique for Salvage of the Diabetic Gangrenous Foot. Orthop. Clin. N. Am. 1973, 1, 21. 21. Tripses, D.; Pollak, F.W. Risk Factors in Healing of BelowKnee Amputation. Am. J. Surg. 1981, 141, 718. 22. Wu, Y.; Flanigan, D.P. Rehabilitation of the Lower Extremity Amputee. In Gangrene and Severe Ischemia of the Lower Extremities; Bergan, J.J., Yao, J.S.T., Eds.; Grune & Stratton: New York, 1978. 23. McIntyre, K.E.; Bailey, S.A.; Malone, J.M.; Goldstone, J. Guillotine Amputation in the Treatment of Nonsalvageable Lower Extremity Infections. Arch. Surg. 1984, 119, 450. 24. Fisher, D.F., Jr.; Clagett, G.P.; Fry, R.E.; et al. One-Stage vs. Two-Stage Amputation for Wet Gangrene of the Lower Extremity: A Randomized Study. J. Vasc. Surg. 1988, 8, 428. 25. Beraldi, R.S.; Keonin, Y. Amputations in Peripheral Vascular Occlusive Disease. Am. J. Surg. 1978, 135, 231. 26. Sethia, K.K.; Berry, A.R.; Morrison, J.D.; et al. Changing Pattern of Lower Limb Amputation for Vascular Disease. Br. J. Surg. 1986, 73, 701. 27. Ramsburgh, S.R.; Lindenauer, S.M.; Weber, T.R.; et al. Femoropopliteal Bypass for Limb Salvage Operations. Surgery 1977, 81, 453. 28. Kazmers, M.; Satiani, B.; Evans, W.E. Amputation Level Following Unsuccessful Distal Limb Salvage Operations. Surgery 1980, 87, 683. 29. Dardik, H.; Kahn, M.; Dardik, I.; et al. Influence of Failed Vascular Bypass Procedures on Conversion of Below Knee to Above Knee Levels. Surgery 1982, 91, 64. 30. Ellitsgaard, N.; Anderson, A.P.; Fabrin, J.; Holstein, P. Outcome in 282 Lower Extremity Amputations: Knee Salvage and Survival. Acta Orthop. Scand. 1990, 61, 140. 31. Evans, W.E.; Hayes, J.P.; Vermillion, B.D. Effect of Failed Distal Reconstruction on the Level of Amputation. Am. J. Surg. 1990, 160, 217. 32. Bloom, R.J.; Stevick, C.A. Amputation Level and Distal Bypass Salvage of the Limb. Surg. Gynecol. Obstet. 1988, 166, 1. 33. Murdoch, G. Levels of Amputation and Limiting Factors. Ann. R. Coll. Surg. Engl. 1967, 40, 204. 34. Kihn, R.B.; Warren, R.; Beebe, G.W. The Geriatric Amputee. Ann. Surg. 1972, 176, 305.
35. Larsson, P.A.; Risberg, B. Amputations Due to Lower Limb Ischaemia. Acta Chir. Scand. 1988, 154, 267. 36. Rubin, J.R.; Yao, J.S.T.; Thompson, R.G.; et al. Management of Infection of Major Amputation Stumps After Failed Femoro Distal Grafts. Surgery 1985, 98 (4), 810. 37. Barber, G.G.; McPhail, N.V.; Scobie, T.K.; et al. A Prospective Study of Lower Limb Amputations. Can. J. Surg. 1982, 26, 339. 38. Silbert, S.; Haimovici, H. Results of Midleg Amputations for Gangrene in Diabetics. J. Am. Med. Assoc. 1950, 144, 454. 39. Perry, T. Below Knee Amputation. Arch. Surg. 1969, 86, 199. 40. Malone, J.M.; Anderson, G.; Lalika, S.; et al. A Prospective Randomized Comparison of Non-Invasive Techniques for Amputation Level Selection. Am. J. Surg. 1987, 154, 179. 41. Burgess, E.M.; Marsden, F.W. Major Lower Extremity Amputations Following Arterial Reconstruction. Arch. Surg. 1974, 108, 655. 42. Burgess, E.M.; Matsen, F.A. Determining Amputation Levels in Peripheral Vascular Disease. J. Bone Jt. Surg. 1981, 63A, 1493. 43. White, R.A.; Nolan, L.; Harley, D.; et al. Noninvasive Evaluation of Peripheral Vascular Disease Using Transcutaneous Oxygen Tension. Am. J. Surg. 1982, 144, 68. 44. Eickhoff, J.H.; Jacobsen, F. Correlation of Transcutaneous Oxygen Tension to Blood Flow in Heated Skin. Scand. J. Clin. Lab. Investig. 1980, 40, 761. 45. Katsamouris, A.; Brewster, D.C.; Megerman, J.; et al. Transcutaneous Oxygen Tension in Selection of Amputation Level. Am. J. Surg. 1984, 147, 510. 46. Burgess, E.M.; Matsen, F.A.; Wyss, C.R.; Simmons, C.W. Segmental Transcutaneous Measurement of PO 2 in Patients Requiring Below-the-Knee Amputation for Peripheral Vascular Insufficiency. J. Bone Jt. Surg. 1982, 64, 378. 47. Ameli, F.M.; Byrne, P.; Provan, J.L. Selection of Amputation Level and Prediction of Healing Using Transcutaneous Tissue Oxygen Tension (PtcO 2). J. Cardiovasc. Surg. 1989, 30, 220. 48. Wyss, C.R.; Robertson, C.; Love, S.J.; et al. Relationship Between Transcutaneous Oxygen Tension, Ankle Blood Pressure, and Clinical Outcome of Vascular Surgery in Diabetic and Nondiabetic Patients. Surgery 1987, 101, 56. 49. McCollum, P.T.; Spence, V.A.; Walker, W.F. Oxygen Inhalation Induced Changes in the Skin as Measured by Transcutaneous Oxymetry. Br. J. Surg. 1986, 73, 882. 50. Harward, T.R.; Volney, J.; Golbranson, F.; et al. Oxygen Inhalation-Induced Transcutaneous Po2 Changes as a Predictor of Amputation Level. J. Vasc. Surg. 1985, 2, 220. 51. Moore, W.S. Determination of Amputation Level. Measurement of Skin Blood Flow with 133Xenon. Arch. Surg. 1973, 107, 798. 52. Malone, J.M.; Moore, W.S.; Goldstone, J.; Malone, S.J. Therapeutic and Economic Impact of a Modern Amputation Program. Ann. Surg. 1979, 189, 798. 53. Moore, W.S.; Henry, Re; Malone, J.M.; et al. Prospective Use of 133Xenon Clearance for Amputation Level Selection. Arch. Surg. 1981, 116, 86. 54. Harris, J.P.; McLaughlin, A.F.; Quinn, R.J.; et al. Skin Blood Flow Measurement with Xenon-133 to Predict Healing of Lower Extremity Amputations. Aust. N.Z. J. Surg. 1986, 56, 413.
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Holloway, G.A.; Burgess, E.M. Cutaneous Blood Flow and Its Relation to Healing of Below-Knee Amputation. Surg. Gynecol. Obstet. 1978, 146, 750. Kram, H.B.; Appel, P.L.; Shoemaker, W.C. Prediction of Below-Knee Amputation Wound Healing Using Noninvasive Laser Doppler Velocimetry. Ann. J. Surg. 1989, 158, 29. Gibbons, G.W.; Wheelock, F.C.; Siembieda, C.; et al. Noninvasive Prediction of Amputation Level in Diabetic Patients. Arch. Surg. 1979, 114, 1253– 1257. Vena, M.J.; Gross, W.S.; vanBellen, B.; et al. Forefoot Perfusion Pressure and Minor Amputation for Gangrene. Surgery 1976, 80, 729. Barnes, R.W.; Shanik, G.D.; Slaymaker, E.E. An Index of Healing in Below-Knee Amputation: Leg Blood Pressure by Doppler Ultrasound. Surgery 1976, 79, 13. Baker, W.H.; Barnes, R.W. Minor Forefoot Amputation in Patients with Low Ankle Pressure. Am. J. Surg. 1977, 133, 331. Wagner, F.W. Amputation of the Foot and Ankle: Current Status. Clin. Orthop. 1977, 122, 62. Lee, R.Y.; Trainor, F.S.; Karner, D.; et al. Noninvasive Hemodynamic Evaluation in Selection of Amputation Level. Surg. Gynecol. Obstet. 1979, 149, 241. Henderson, H.P.; Chir, B.; Hacken, M.E.J. The Value of Thermography in Peripheral Vascular Disease. Angiology 1978, 29, 65. Abramowitz, H.B.; Queral, L.A.; Flinn, W.R.; et al. The Use of Photo-Plethysmography in the Assessment of Chronic Venous Insufficiency: A Comparison to Venous Pressure Measurement. Surgery 1979, 86, 434. Standress, D.E.; Sumner, D.S. Current Research Review: Noninvasive Methods of Studying Peripheral Arterial Function. J. Surg. Res. 1972, 12, 419. Barnes, R.W.; Thornhill, B.; Nix, L.; et al. Prediction of Amputation Wound Healing: Roles of Doppler Ultrasound and Digit Plethysmography. Arch. Surg. 1981, 116, 80. Holstein, P.; Sager, P.; Lassen, N.A. Wound Healing in Below Knee Amputations in Relation to Skin Perfusion Pressure. Acta Orthop. Scand. 1979, 50, 49. Faris, I.; Duncan, H. Skin Perfusion Pressure in the Prediction of Healing in Diabetic Patients with Ulcers or Gangrene of the Foot. J. Vasc. Surg. 1985, 2, 536. Syme, J. Observations in Clinical Surgery; Edmondson and Douglas: Edinburgh, 1982. Rosenman, C.D. Syme Amputation for Ischemic Disease in the Foot. Am. J. Surg. 1969, 118, 194. McCollough, N.C.; Shea, J.D.; Warren, W.D.; Sarmiento, A. The Dysvascular Amputee: Surgery and Rehabilitation. Current Problems in Surgery; Year Book Medical Publishers: Chicago, 1971. Wray, C.H.; Still, J.M.; Moretz, W.H. Present Management of Amputations for Peripheral Vascular Disease. Am. Surg. 1972, 38, 87.
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Sarmiento, A.; Warren, W.D. A Re-Evaluation of Lower Extremity Amputations. Surg. Gynecol. Obstet. 1969, 129, 799. Lim, R.C., Jr.; Blaisdell, F.W.; Hall, A.D.; et al. Below Knee Amputation for Ischemic Gangrene. Surg. Gynecol. Obstet. 1967, 125, 493. Kiln, R.B.; Warren, R.; Baske, G.W. The Geriatric Amputee. Ann. Surg. 1972, 176, 305. Little, J.M.; Stewart, G.R.; Niesche, F.W.; Williams, C. A Trial of Flapless Below-Knee Amputation for Arterial Insufficiency. Med. J. Aust. 1970, 1, 883. Robinson, K.P. Skew-Flap Below-Knee Amputation. Ann. R. Coll. Surg. Engl. 1991, 73, 55. Kjolbye, J. Prosthetic and Orthotic Practice; Murdoch, G., Ed.; Edward Arnold: London, 1970; 255. Marsden, F.W. Amputation: Surgical Technique and Postoperative Management. Aust. N.Z. J. Surg. 1977, 47, 384. Unruh, T.; Fisher, D.F.; Unruh, T.A.; et al. Hip Disarticulation: An 11-Year Experience. Arch. Surg. 1990, 125, 791. Boyd, H.B. Anatomic Disarticulation of the Hip. Surg. Gynecol. Obstet. 1947, 84, 346. Sugarbaker, P.H.; Chretien, P.B. A Surgical Technique for Hip Disarticulation. Surgery 1981, 90, 546. Little, J.M. A Pneumatic Weight-Bearing Temporary Prosthesis for Below-Knee Amputees. Lancet 1971, 1, 271. Kerstein, M.D. Utilization of an Air-Splint After BelowKnee Amputation. Am. J. Phys. Med. 1974, 53, 119. Burgess, E.M.; Romano, R.L. The Management of Lower Extremity Amputees Using Immediate Postsurgical Prosthesis. Clin. Orthop. 1968, 57, 137. Russek, A.S. Amputation, Immediate Postoperative Fitting, and Early Ambulation. In Vascular Surgery: Principles and Techniques, 2nd Ed.; Haimovici, H., Ed.; AppletonCentury-Crofts: Norwalk, CT, 1984. Couch, N.P.; David, J.K.; Tilney, N.L.; Crane, C. Natural History of the Leg Amputee. Am. J. Surg. 1977, 133, 469. Mazet, R. The Geriatric Amputee. Artif. Limbs 1967, 11, 35. Bodily, K.C.; Burgess, E.M. Contralateral Limb and Patient Survival After Leg Amputation. Am. J. Surg. 1983, 148, 280. Harris, J.P.; Page, S.; England, R.; May, J. Is the Outlook for the Vascular Amputee Improved by Striving to Preserve the Knee? J. Cardiovasc. Surg. 1988, 29, 741. Castronuovo, J.J.; Deane, L.M.; Deterling, R.A.; et al. Below-Knee Amputation: Is the Effort to Preserve the Knee Joint Justified? Arch. Surg. 1980, 115, 1184. Burgess, E.M. The Ischemic Leg; Kempczinski, R.F., Ed.; Year Book Medical Publishers: Chicago, 1985. Finch, D.R.; MacDougal, M.; Tibbs, D.J.; Morris, P.J. Amputations for Vascular Disease: The Experience of a Peripheral Vascular Unit. Br. J. Surg. 1980, 67, 233.
CHAPTER 38
Rehabilitation of the Vascular Amputee Sudesh Sheela Jain Joel A. DeLisa major amputations are living in the United States, yielding a rate of 1.7 major amputations for 1000 people.[2] The National Center for Health Statistics, in 1993, estimated a prevalence of 1,546,000 people with major limb amputations (excluding loss of tips of digits) in the United States.[3] It was estimated that 127,000 amputations were done in acute care nonfederal hospitals, of which 98,000 were lower extremity (LE) amputations. Of these, 29,000 were transtibial (below knee), and 25,000 were transfemoral (above knee); 42,000 were toe or partial foot amputations.[4] Over 75% of all acquired amputations in the LE are due to peripheral vascular disease with or without diabetes mellitus. Trauma is the next most common cause of LE amputation, accounting for about 20% of amputations, followed by tumor at about 5%.[5,6] Cardiovascular disease is the most common cause of morbidity and mortality in the dysvascular amputees. Recognition of the presence and potential impact of concomitant cardiac disease in a patient with amputation is particularly important because common physical activities such as walking place more energy demands on the cardiovascular system of the patient with dysvascular amputation than on able-bodied subjects.[7] Stress testing is indicated for the amputee with serious cardiac compromise to see if the energy level needed for ambulation can be tolerated.[8] Exercise testing can be done with standard ECG-monitored treadmill ambulation,[9] ECG-monitored ergometry,[10] or ECG-monitored arm one leg ergometry and exercise thallium imaging. The decision to use a specific test for an individual patient is based on the level and type of severity of the disease and method available. Roth et al. reported that cardiovascular monitoring provided useful information in a convenient, noninvasive manner in initial postamputation physical therapy.[11] Cardiac patients with dysvascular amputation will likely benefit from a rehabilitation program and appropriate prosthetic training, but they do require cardiovascular conditioning. It is important to maintain enhanced cardiac conditioning in amputation patients to help prevent cardiac complications, improve functional mobility, and promote self-esteem while
REHABILITATION OF THE VASCULAR AMPUTEE Extremity amputation is one of the oldest known surgical procedures. Neolithic man is known to have survived amputation. Ancient amputations were probably done by accident, for punishment, or during ritual sacrifice, rather than with surgical intent. Hippocrates first described the amputation procedure for vascular gangrene. In the sixteenth century, Ambrose Pare´, the great French army surgeon, improved the outcome of amputation by instituting routine ligature of vessels and gentle wound care. Anesthesia and aseptic techniques have reduced complications following surgery, and twentieth-century contributions have emphasized rehabilitation and conceived of amputations as a reconstructive procedure, removing disability and disease, and restoring ability. Restoration of function at most levels of amputation require the use of a prosthetic device, which is attached to the body by various means. Plastics technology has reduced the weight of the prosthesis and improved fitting to the residual limb, thereby providing better function. Successful vascular reconstruction and improved perioperative management has become extremely important in our aging population.[1] Accurate prediction of healing allows better planning and management. Most importantly, a unified team approach provides the expertise of multiple medical disciplines, greater patient acceptance, and optimal prosthetic rehabilitation.
INCIDENCE AND ETIOLOGY In vascular disease, amputation may be needed to save lives, but more often it is required to save function when this has been lost from ischemia. Etiology of limb loss and associated medical conditions are important considerations when developing a management plan for the amputee. In 1977, the National Health Survey found that 358,000 people with
Hobson/Wilson/Veith: Vascular Surgery: Principles and Practice, Third Edition, Revised and Expanded DOI: 10.1081/0819-9-120024921 Copyright q 2004 by Marcel Dekker, Inc.
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enhancing quality of life. Aerobic exercises help reduce depressive symptomotology in deconditioned persons. Treadmill training, ergometry, and mixed exercise training can all be used for cardiac conditioning. Valentine et al. have compared the outcome of younger dysvascular amputees due to premature atherosclerosis with older dysvascular amputees.[12] Their study indicated that younger patients had a higher number of failed bypasses before amputation and died at a younger age, and less than 50% achieved ambulation. They suggested that younger dysvascular amputees should be followed very closely for development of ischemia in the contralateral limb.
PROGNOSIS Roon et al. give an overall 5-year survival rate after LE amputation of about 45% (75% for nondiabetics, and 9% for diabetics) as compared with 85% for the age-adjusted normal population.[13] The majority of deaths are due to associated cardiovascular and cerebrovascular diseases. Dormandy et al.[14] found that at least 15% of LE amputees with peripheral vascular disease develop myocardial infarction, and 5% had cerebral vascular accident within 5 years after the amputation. The major risk factors include smoking, hypertension, and diabetes mellitus. Malone and Goldstone stated that critical limb ischemia will develop in the remaining limb in 18–28% within 2 years of amputation.[15] Changes in surgical techniques and revascularization procedures have allowed preservation of the knee, which decreases energy demands and allows more older patients a chance to undergo rehabilitation after amputation. The shortened longevity emphasizes the need for timely rehabilitation to enhance the quality of the remaining years.
AMPUTATION LEVELS Amputation, being final, is virtually never performed without good indications. Management decisions directly impact on the anesthetic technique, magnitude of perioperative procedures, and ultimate overall risk to the patient. Extensive pressure-related gangrene in the foot or a grossly infected foot is ablated by a staged supramalleolar guillotine residual limb amputation followed by a standard transtibial revision. This approach reduces the rate of residual limb infection from 27% to 3%.[16] Despite the fact that the ratio of transtibial (belowknee) amputation to transfemoral (above-knee) amputation has increased, the overall postsurgical mortality (10 – 30%), long-term survival (2 years, 40–50%; 5 years, 30 –40%), and risk of loss of other limb has not changed significantly since the 1960s.[15] Several caveats are important considerations for a successful amputation. The skin should have adequate perfusion and intact sensation because it is the body component through which forces arising at the prosthetic socket and body interface are transmitted. Ultimate decision on the level of amputation must be made according to the ability of the tissues to heal. Little help can be gained from the
history or the clinical examination, except for observation of the level of pallor, coolness, or gangrene. Buerger’s test has no obvious correlation with eventual level of amputation. Arteriography gives little more information than does the color and temperature of the limb on clinical observation. Doppler evaluation of regional blood flow via large vessels reveals that if the ankle systolic pressure is less than 40 millimeters of mercury (mmHg), transtibial amputation is unlikely to heal. However, in diabetics, ankle pressures are of little value because arteriovenous shunts may be present around the foot and ankle, resulting in false values. If segmental pressures in the thigh are between 50 and 70 mmHg, then transtibial healing does occur. Other methods to assess chances of wound healing include ankle-brachial index and transcutaneous oxygen measurement.[17] The ankle-brachial index (ABI) is used to indicate disease severity and chances of distal wound healing. It is the ratio of the blood pressure values at the ankle and at the brachial artery (see Table 38-1). Transcutaneous oxygen pressure (TcPO2) is another method to predict healing. During this test the skin is heated locally to 448C using a heated electrode. Oxygen tension emitted from the tissue measures its metabolic perfusion and healing capacity. More than 35 mmHg pressure at calf is predictive of healing of the transtibial amputation. If 100% oxygen is inhaled during the TcPO2 test, the sensitivity of the test increases markedly.[18]
REHABILITATION OF AN AMPUTEE The optimal rehabilitation of an amputee requires the interaction of a healthcare team working with the patient to achieve the goals of independency, self-care, mobility, and prosthetic restoration. The rehabilitation phase has been divided into four phases: preoperative management, postoperative management, preprosthetic fit and training, and prosthetic follow-up care.
Preoperative Management The preoperative management begins when the decision to perform an amputation is made and ends with the completion of surgery. Evaluation should include a detailed history and a complete physical examination. Range of motion and strength in the involved as well as in the noninvolved extremities, Table 38-1. Ankle-Brachial Index (ABI) Value as a Prognostic Indicator of Peripheral Vascular Disease ABI value $0.9 0.7– 0.9 0.5– 0.7 #0.45 # 0.3 Note: Calcified vessels skew ABI results.
Prognosis Normal Mild disease Claudication Rest pain Gangrene
Chapter 38. Rehabilitation of the Vascular Amputee
mobility, ambulation, self-care skills, social support, as well as the patient’s reaction to planned surgery should all be documented. Strengthening exercises and breathing exercises to increase vital capacity would put the person in the optimal condition for surgery. Loss of a visible part of one’s body is devastating at any age, and is dreaded by most. The new amputee typically experiences depression, and the response to amputation has been compared to the grieving process, in that the amputee experiences stages of denial, anger, depression, coping, and acceptance.[19] Not every person will go through these stages or ultimately adapt to the limb loss. The patient’s ultimate response to the psychological impact of limb loss is determined by many factors, including etiology of amputation, patient’s life experiences and ways of coping and reacting to catastrophic events, the quality of social support system available to this person, and the comprehensive care provided by the prosthetic team. Amputation should be presented as a constructive option as it will end severe chronic intractable pain. The patient may also be unaware of the prosthetic options for future function and ambulation. It has been suggested that at this stage, a meeting with a successfully rehabilitated amputee who has undergone a similar process is sometimes the most effective first step toward healing.
Postoperative Management The goals of the postoperative period are expediting wound healing, stabilizing the residual limb volume, reducing pain and edema, strengthening muscles, and providing psychological counseling. The physical examination should include evaluation of mental status, vision, peripheral vascular disease status, evaluation of the surgical incision site, skin condition, residual limb skin mobility, edema, induration or tenderness, and any graft donor sites. Range of motion, joint stability, strength and sensation in all extremities should also be documented. Strengthening Exercises: Bilateral hip abductor (gluteus medius), hip extensors (gluteus maximus), and knee extensor (quadriceps) strengthening should be emphasized. Both upper extremity shoulder depressors and wrist and elbow extensors are also strengthened for crutch or assistive device ambulation, to allow improved functional gait ability in LE amputees.[20] Avoid hip flexion, abduction, and knee flexion contractures by using aggressive stretching exercises. In order to avoid contractures, do not put a pillow under the knee or keep the head of the bed elevated for prolonged periods of time. Wound healing: This is maximized by optimizing nutrition, treatment of anemia, provision of diabetic control, and antibiotic use. An open incision or wound should be covered by a Telfaw pad and a sterile soft compressible dressing. The wound should be inspected regularly for odor, drainage, warmth, redness, or dehiscence. For a diabetic patient, if baseline transcutaneous oxygen (TcPO2) is less than 40 mmHg on room air, but exceeds 40 mmHg with 100% oxygen at 18 TM for 20 minutes, the use of postoperative hyperbaric oxygen therapy should be considered. For nondiabetic patients, the critical value for TcPO2 is 30 mmHg.[21]
577
Pinzur et al. have shown that TcPO2 values may be affected by the presence of infection and TcPO2 values increase after treating infection.[22] Residual Limb Management: The residual limb shrinkage and shaping process can be accomplished in one of several ways, all of which can provide shaping without compromising wound healing. Residual limb shrinkage and maturation permits prosthetic fit without requiring frequent changes in the size and configuration of the prosthetic socket. An ideal transtibial residual limb is cylindrical in shape, and an ideal transfemoral residual limb is conical. Postoperative dressings: These are soft, semirigid, or rigid. Soft dressings include elastic bandage wraps, residual limb shrinkers and elastic stockinettes (Compresso-gripw—Knit Rite, Kansas City, MO). Elastic bandages are typically the least effective shrinking device because many patients do not master the wrapping technique, which requires considerable cooperation, skill, and attention on part of the patient, family, or medical staff. These wraps are done in a figure-8 configuration to avoid circumferential constriction with distal edema (Fig. 38-1). These bandages are changed several times a day. Double-length 4-inch bandages are used for the transtibial limb, and double length 6-inch bandages are used for the transfemoral limb. Under this system of management, the time interval from amputation to prosthetic fit may take several months. Elastic shrinker socks (or stump shrinkers) are easy to apply, provide uniform compression, but are more expensive than elastic bandages. They should reach the groin in the transfemoral amputee and should fit snugly. However, if they are not properly fitted and maintained, they can cause skin damage due to constriction. Patients who do not tolerate elastic wrap or shrinker socks may use Compresso-grip socks. These elastic stockinettes are easy to apply and maintain. However, they can also cause skin damage if not properly donned or maintained.
Figure 38-1. Elastic bandage wrapping. (Courtesy of Otto Bock Prosthetic Compendium for lower extremity prosthesis.)
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Part Four. Peripheral Occlusive Disease
Semirigid dressings are made of a fabric material impregnated with Unna paste. These are applied over the residual limb carefully to avoid proximal constriction. Studies have shown that initial immobilization and support with appropriate local pressure and elevation of the injured limb will expedite healing and minimize edema.[23] These dressings should be changed every 2 – 3 days or less frequently, depending upon the condition of the wound. Rigid dressing use in postoperative amputee management was revived by Berlemont[24] in France and Weiss[25] in Poland, and it was popularized in the United States by Burgess.[26] The postoperative plaster of Paris or fiberglass rigid dressing prevents edema, protects from trauma, and decreases postoperative pain. The goal of rigid dressing is to provide a therapeutic degree of terminal pressure and a relatively sterile dry wound surface with no restriction to tissue fluid exchange.[26] Rigid dressings are the preferred method of residual limb care, but require an experienced team. Rigid dressings consist of a plaster cast applied in the operating room immediately after surgery. The distal end is covered with soft absorbent material, and then the entire residual limb is placed in an elastic sock to prevent postoperative edema. Bony prominences are protected by using felt pads and the elastic plaster bandage, then nonelastic plaster is applied. Suspension straps can be secured to the rigid dressing. Postoperative edema occurs within a few minutes so immediate replacement of a dressing is mandatory. Rigid dressing can be nonremovable or removable. The nonremovable rigid dressing is applied immediately after surgery in the operating room and is typically taken off and changed every 5 –10 days after surgery.[27] The rigid removable dressing can be taken off and replaced whenever the wound needs to be viewed. The rigid removable dressing provides good edema control with the advantage of allowing daily inspection. Rigid dressing provides protection to the limb against trauma, e.g., in case of a fall, and it can also serve as a temporary socket to which prosthetic components can be attached to form an early postoperative prosthesis. In dysvascular amputees, early weight bearing may delay wound healing. The amputee should wear the shrinkage device 24 hours a day, except for very short periods of time for bathing or ventilating sores. A shrinkage device can be discontinued after fitting with a definitive prosthesis if the residual limb has become stabilized and the patient is wearing the prosthesis on a regular basis. However, it may still be used at night if nocturnal edema occurs.
Preprosthetic Phase of Management This management can typically last 6 –10 weeks in the dysvascular amputee due to their general debility, skin fragility, and evidence of other complications. The preprosthetic training includes active range-of-motion exercises, positioning, muscle strengthening, skin care, wheelchair mobility, transfer activities, independence in self-care, and patient and family education. To avoid contracture, the patient is asked not to lie on an overly soft mattress or to use a pillow under the back of the thigh. Also, the residual limb should not be resting on a crutch in a transfemoral amputee during standing. The amputee should not place a pillow
between the legs as this may create a hip abduction contracture. The amputee is usually encouraged to lie prone for 15 minutes three times a day to help prevent hip or knee flexion contractures. The amputee who cannot lie prone should lie supine and actively extend the residual limb while flexing the contralateral leg. A transtibial amputee is usually advised to sit with the knee extended on an amputee board, which is placed under the wheelchair cushion, with a towel wrapped over the board for comfort. The amputee should be retrained in the activities of daily living. These include bed activities, dressing, toileting, bathing, safe transfers with and without the prosthesis, and homemaking activities. The residual limb should be washed with nonirritating soap and water when the suture line is healed. It should be patted dry, and emollients should be applied. Soaking of the residual limb should be avoided as it may cause swelling. Crutch walking with large-diameter suction rubber tips should be encouraged, or the patient may use a walker. Virtually all amputees may need a wheelchair at least during the early part of hospitalization, while many may require it for a longer time period. The center of gravity of the seated LE amputee is displaced more posteriorly than in a nonamputee. Therefore, the wheelchair should have its base displaced posteriorly. This can be done either by using regular wheelchair with rear wheel adapters or by using an amputee model wheelchair with rear uprights bent to position rear wheels posteriorly. The wheelchair should have removable footrests for resting the prosthetic foot on one side, and contralateral foot on the other footrest to avoid plantarflexion contracture and provide support in a dysvascular amputee. Self-propulsion of the wheelchair will improve motor strength of both upper extremities, especially of the shoulders and elbows. However, sitting for very long periods of time will encourage flexion contractures of the hip and knee and therefore should be avoided. In the right leg amputee, an accelerator extension is needed to allow the patient to accelerate with the left leg. This can be easily installed in the automobile, and the driver retraining required is minimal. A bilateral LE amputee will require installation of hand controls to drive and will require driver reeducation.
Prosthetic Phase of Management This phase can begin in the immediate postoperative period, when an immediate prosthesis is prescribed, or may merge with the preprosthetic phase for early prosthetic or temporary prosthetic fit. Immediate Prosthesis: In 1963, Marion Weiss reported success in fitting amputees with prostheses immediately after surgery and beginning ambulation training the next day.[25] The usual technique is to apply a rigid plaster of Paris or fiberglass cast in the operating room to prevent edema. It is used as a socket; a pylon and foot is attached to the rigid dressing for immediate postoperative weight bearing. It has been claimed to provide psychological and physical benefits to the patient with less residual limb pain and early residual limb maturity. However, the patient is not allowed to bear full weight on this type of socket for at least 2 weeks. The disadvantages are inability to easily inspect the wound site,
Chapter 38. Rehabilitation of the Vascular Amputee
injurious effects of early weight bearing on the amputated residual limb, and technical difficulties in proper application of a rigid dressing. Wound-healing potential is marginal in the ischemic amputee, and early weight bearing can delay wound healing or cause wound dehiscence. It is therefore recommended that early weight bearing should be individualized, and little or no weight bearing should be allowed until sufficient wound healing has occurred. Provisional (Temporary) Prosthetic Fit: Early functional restoration and fitting of an individual with a provisional or temporary prosthesis 2–3 weeks after surgery is done in patients who may or may not have had an immediate postoperative prosthesis. Early prosthetic fit allows wound healing to have occurred before weight-bearing stresses are placed on the tissues. It consists of a suspension device, socket, pylon, and foot. It includes a knee joint in a transfemoral prosthesis. This prosthesis is used during the period of residual limb shrinkage and may be used for 3 – 6 months, until the residual limb is stabilized. Provisional prosthesis is inexpensive, not very cosmetic, and can be used as a trial in amputees whose ambulation potential with a prosthesis is borderline or uncertain. Permanent (Definitive) Prosthesis: At this stage, amputees should have reasonable skin coverage and wound healing of the residual limb, muscle strength and motor control, adequate cardiovascular reserve, and ability to learn to use the prosthesis.
PROSTHETIC PRESCRIPTION WRITING Prosthetic prescription writing should be done after the following has been taken into consideration: patient’s biographical and functional data, objectives and preferences, and availability of a competent prosthetist and physical therapist.
Patient Data There is no age limitation in writing a prescription. However, attention should be paid to the components chosen for the patient. For example, in a frail and elderly patient, heavy prosthetic components should never be prescribed. The cause and the level of amputation are also important considerations. An elderly, weak patient with cardiac difficulties may not be able to tolerate a prosthetic fit for a transfemoral or higher level amputation, but may be able to tolerate a prosthetic fit at the transtibial level. Other issues to consider are noted in Table 38-2.
Prosthetic Principles A prosthetic device is a collection of component parts. Transtibial and transfemoral prosthetic devices have the following components: 1.
Socket to hold the residual limb and transmit body weight to the floor
Table 38-2.
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Patient Issues to Consider When Prescribing a
Prosthesis Comorbidity factors, such as cardiac, pulmonary Residual limb length—a longer residual limb requires less energy expenditure. Skin and soft tissue/joint contractures, especially of the proximal joints, may preclude prosthetic fit. Musculoskeletal problems. Cognitive function and ability to follow directions Vocation/avocation Premorbid lifestyle, active or sedentary, as this will dictate the components that are chosen for this particular individual
2. 3. 4.
Supporting systems (exoskeletal versus endoskeletal shanks) Suspension systems to keep the prosthetic device on the body Joints that are replaced (foot, ankle in transtibial, and foot, ankle, and knee in transfemoral)
EXOSKELETAL VERSUS ENDOSKELETAL The exoskeletal system, also called a crustacean prosthesis, is characterized by a hard, plastic, laminated outer shell. Its advantage is durability. It is, however, less cosmetically acceptable, and adjustments to the internal surface structure of the prosthesis are very difficult. The exoskeletal prosthesis may also weigh a little more than its endoskeletal counterpart. The endoskeletal system is also called a modular system and is characterized by a metal or plastic pylon covered by a soft polyurethane foam that is contoured to the shape of the sound leg. The advantage of the endoskeletal system is that it is more cosmetically appealing. For example, in transfemoral prosthesis, knee-joint articulations are covered. The internal structures can also be easily accessed by removal of the polyurethane cover, and the components can be easily interchanged. The pylon allows easy length adjustments, and the assembly is quicker because of the prefabricated modules. There is also a very slight decrease in weight, especially for transfemoral and hip disarticulation amputation levels. The disadvantages of the endoskeletal system are that the cosmetic cover is much less durable than the plastic laminate of the exoskeletal construction. The spray-on cosmetic skin can prolong the life of soft covers but is time-consuming to apply and is difficult to maintain.
COMPUTER-AIDED DESIGN – COMPUTER-ASSISTED MANUFACTURING (CAD –CAM) CAD – CAM technology can be used either as an adjunct or as an alternative to traditional methods of prosthetic
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Part Four. Peripheral Occlusive Disease
fabrication. Computerized equipment can provide a positive computer model of the residual limb, which can be modified on the computer by the prosthetist (Fig. 38-2). A computer-controlled milling machine will then manufacture a model, which is used to make a check socket for the prosthesis.[28] This is probably the technology of the future and should expedite prosthetic fabrication and therefore lower the cost.
PROSTHETIC COMPONENTS Foot-Ankle Assembly The primary purpose of the prosthesis is to serve in place of the anatomical parts. Foot-ankle assembly in a prosthesis substitutes for the anatomic foot and ankle. In doing so, the prosthesis should provide the following functions: Joint simulation (plantar flexion, dorsiflexion, inversion, eversion) Shock absorption at heel contact and reach foot flat position rapidly after heel strike Provide a stable weight-bearing base of support Provide cosmesis by resembling the gentle contour of the missing foot There are different types of foot-ankle assemblies offering additional functions such as mediolateral motion or energy storage functions (see Table 38-3). There are essentially two types of foot-ankle designs: nonarticulated and articulated. In the nonarticulated design, the basic structure is a foot-like component with a keel, which is the base supporting structure. The whole foot is made up of a resilient material, and the heel may have a lot more resilience than the rest of the foot. At heel contact, the weight
Figure 38-2.
compresses the heel, simulating plantar flexion and absorbing the shock, and the keel will provide a firm base of support. During the swing phase, the unloaded toe section reverts to a neutral position. Nonarticulated foot ankle assemblies are generally quieter, more durable, and lighter than the articulated foot-ankle assemblies. Two types of nonarticulated foot-ankle assemblies are available: rigid keel and flexible keel. The most commonly used rigid keel foot is the SACH (Solid Ankle Cushion Heel) foot, which is lightweight, durable, low cost, and quite cosmetic. It has a solid wooden keel that extends from the toe break and has an external molded foam with a cushioned heel wedge. It has no movable components so that joint motion is simulated by the rubber surrounding the keel. Plantar flexion is simulated by compression of the heel wedge, but no dorsiflexion is available. The cosmesis is good, as is the stability provided by the SACH foot (Fig. 38-3). The disadvantages include the risk of delay in reaching foot flat in early stance, which may cause some instability. There is limited plantar flexion and dorsiflexion adjustability. However, it is a very popular prosthetic component and is available to accommodate different heel height shoes and can also be ordered with toes, thereby enhancing the cosmesis. Nonarticulated feet with flexible keel include the SAFE (Stationary Attachment, Flexible Endoskeletal) foot and the STEN (STored ENergy) foot. Because the keel is flexible, it allows mediolateral and transverse motion. A small amount of bending of the flexible keel after heel off simulates a little dorsiflexion. However, these are heavier and more expensive than the SACH foot.
Dynamic Response or Energy-Storing Feet The prosthetic feet are primarily designed for walking, yet many amputees would like to be more active and require prostheses that will allow them increased activity. Dynamic response feet incorporate a shock absorption mechanism in
CAD– CAM System. (Courtesy of Seattle Limb Systems, Poulsbo, Washington.)
Smooth rollover; springier gait
Dynamic response Seattle Carbon Copy Quantum
Weight Durability Cannot be used for Syme Weight; durability; cannot be used for Syme
Increased cost; some designs cannot be fitted to very long residua
Rigid keel can produce “jarring” in mid- to late-stance phase Increased weight and cost Limited push-off
Disadvantages
Community ambulator (3); sports participant (e.g., golf) (4)
Household ambulator (1)
Community ambulator (3); child, active adult or athlete (4)
Household ambulator (1); limited community ambulator (2) Community ambulator (3)
HCFA activity levels*
* Numbers in parentheses refer to four increasing levels of anticipated amputee function prepared by the Health Care Finance Administration (HCFA), HEW, Washington, D.C., as a guide to prosthetic prescription. Source: From Ref. [50].
Flex-Foot & derivatives Single axis Provides rapid foot flat and maximum absorption of heel strike impact Readily adjustable Multiple axis Adapts to uneven terrain; permits rotation
Flexible keel Safe STEN
Simple, inexpensive, and durable; can accommodate long residua including Syme Smooth rollover; greater comfort with limited mediolateral motion
Advantages
Rigid keel SACH
Foot
Table 38-3. Foot-Ankle Assemblies
Chapter 38. Rehabilitation of the Vascular Amputee 581
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Part Four. Peripheral Occlusive Disease
Figure 38-3. prosthesis.)
SACH foot with ankle block and assembly bolt. (Courtesy of Otto Bock Prosthetic Compendium for lower extremity
the form of a flexible keel that will dissipate energy and provide a smoother gait. It also provides push-off that the rigid keel cannot provide. As the patient starts to walk faster, the amount of time the patient spends on the heel decreases, while the time spent on the forefoot increases. Because more time is spent on forefoot, more forces are exerted on the forefoot, which increases dorsiflexion momentum. The new materials and new designs allow this dorsiflexion movement to allow the keel to compress, thereby absorbing energy and releasing it during push-off and aiding in propelling the patient forward. The materials currently used for the flexible keel are carbon graphite composite, Delrin, Kavalar, polyurethane elastomer, and
Figure 38-4.
flexible rubber. These feet allow more fluid motion, producing a more natural gait. Some of the newer dynamic response feet are as follows: Seattle Foot — Introduced in 1981, this was the first prosthetic foot, which was able to store energy during stance phase, release it in the late stance, and thereby assist in forward propulsion. This foot has a Delrin spring keel in a C shape and Kavalar-enforced toe pad in a human-looking polyurethane mold (Fig. 38-4). The Seattle Foot is fitted to the patient’s foot size, weight, and level of activity because five degrees of keel flexibility are available. The foot is wide and heavy and has a relatively higher arch that can interfere with mediolateral stability. The Seattle Light Foot has a less
Seattle Foot. (Courtesy of Seattle Limb Systems, Paulsbo, Washington.)
Chapter 38. Rehabilitation of the Vascular Amputee
pronounced medial arch, slimmer profile, and is half the weight of the original Seattle Foot. It is also available in child size (Child Play Foot). A newer version called the Voyager or Seattle Carbon Light Foot (Seattle Limb Systems, Poulsbo, WA) is now available; it provides more springiness and reduced weight. Carbon Copy II — This foot was introduced in 1986 and consists of a solid ankle with a rigid posterior block made of nylon in combination with two flexible anterior deflection plates made of carbon composite. These provide two levels of dynamic response. The first deflector, which ends at the level of distal interphalangeal joints, is used for day-to-day ambulation, and the second, shorter, upper deflector is used for higher level functional activities such as running or jumping. It is encased in an elastomer shell and is available to fit adults, with different heel heights. It is lightweight, durable, and is also available for Symes amputees. Carbon Copy III — This is a newer model of Carbon Copy II, with a shank and ankle-foot system made from carbon fibers with a Kavalar keel. Alignment changes can be done by heating the shank and positioning it as desired. The foot provides some degree of eversion/inversion, and the shank also absorbs rotational forces. The system is modular, permitting selection from two different shanks, light or heavy duty, five different heel durometers, and different stiffness for each deflector plate. Flex-Foot w (and derivatives)—Flex-Foot (Aliso Viejo, CA) feet provide an unique technology in the development of a prosthetic concept where flat carbon graphite feet are extended from the metatarsophalangeal joint lines to proximally into the prosthetic shanks. It takes advantage of the flexibility built into the pylon, storing energy during stance phase, and releasing it during toe-off (Fig. 38-5). Therefore, the keel forms the shank of the prosthesis, and the shank acts as a long leaf spring, bending when loading and straightening forcibly when the load is reduced. Flex-Foot feet store and return more energy than any other foot-ankle assembly, making it suitable for younger or more active amputees who pursue an active lifestyle or participate in track and field sports. The biggest improvement in this design in the achievement of body mass distribution. Also, a prosthesis incorporating the Flex-Foot design is lighter than with any other foot-ankle component. However, Flex-Foot feet require sufficient space between the floor and the end of the residual limb to take advantage of this technology. Other dynamic response feet include Springlite (Salt Lake City, UT), Endolite (Endolite N.A., Centerville, OH), and others.
Articulated Foot-Ankle Assembly In these designs, an articulation is present at the anatomical ankle level and thus allows more mobility at the ankle. Different types of articulated designs are available (see Table 38-3). Single Axis: Available in both exoskeletal and endoskeletal prostheses, the components include a solid wood internal keel, a molded foam rubber shell, and a
583
Figure 38-5. Flex-Foot. (Courtesy of Flex Footw, Aliso Viejo, California.)
single transverse metal axis joint. A rubber plantarflexion bumper allows 158 of plantarflexion, and a rubber dorsiflexion stop permits up to 58 of dorsiflexion. Pushoff is simulated by the flexibility of the rubber toe section. It may be used in transfemoral prosthesis, when stability is highly desirable and very little mobility is needed. Disadvantages are increased weight, less cosmesis, tendency to squeak, and higher maintenance. Multiple Axis Foot/Ankle: This design provides plantarflexion, dorsiflexion, inversion, eversion, and a small amount of rotation, and is therefore very suitable for walking on uneven terrain. It also provides excellent shock absorption in all planes due to the presence of many bumpers, thereby reducing torque on the residual limb (Fig. 38-6). The disadvantages are increased bulk and weight, especially in the older Otto Bock Griessenger foot, need for more maintenance, and decreased stability as compared to other feet, especially in patients with borderline coordination. Newer versions, e.g., Endolite and Multi-Flex Ankle, are made of carbon composite material and hence are much lighter.
584
Figure 38-6.
Part Four. Peripheral Occlusive Disease
Multiaxis ankle with ankle block. (Courtesy of Otto Bock Prosthetic Compendium for lower extremity prosthesis.)
Transtibial Prosthetic Sockets Prosthetic sockets support the residual limb and transmit forces from the residual limb to control the prosthesis. The most commonly used transtibial socket is the patellar tendon bearing (PTB) socket (Fig. 38-7). It consists of a laminated or molded plastic socket with the anterior wall extending proximal to and encapsulating the distal third of the patella. Just below the patella, at the middle of the patellar ligament, is an inner contour or bar, which is one of the major weightbearing surfaces in the socket. However, weight is also borne on the flares of the tibia and on either side of the tibial crest. Medial and lateral walls extend proximally to above the condyles of the femur. The distal portion of the PTB socket may incorporate a soft end pad to prevent distal edema by aiding venous and lymphatic return while walking. The PTB socket can be used as a hard socket, which is less bulky, and easier to clean, and pressure relief can be provided with exactness. However, a soft inner socket liner made of silicone gel or polyurethane foam can be used to provide comfort and skin protection. In 1982, Kristinsson of Iceland proposed a flexible socket design for above-the-knee sockets.[29] It was developed in Sweden, and later a below-the-knee counterpart was developed in New York. In this design, an inner socket is fabricated from flexible polyethylene or a similar material, which is then inserted into a rigid plastic laminated, thermoplastic, or carbon fiber-reinforced frame. The frame covers the primary weight-bearing areas, while the soft tissue and pressure-sensitive areas not requiring rigid support are enclosed in the flexible socket. The advantages of the flexible socket rigid frame are decreased weight, increased comfort, improved heat dissipation, and ease of replacement of the inner socket to accommodate minor anatomical changes. It is, however, more time consuming and difficult to fabricate, more expensive, and is considered by some to be less cosmetic.
Figure 38-7. PTB Socket. (Courtesy of Otto Bock Prosthetic Compendium for lower extremity prosthesis.)
Chapter 38. Rehabilitation of the Vascular Amputee
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SUSPENSION VARIATIONS OF A TRANSTIBIAL AMPUTEE
difficult fabrication and the fact that the entire anterior brim of the SC/SP protrudes while sitting.
A suspension system is required to keep the prosthesis from falling off the residual limb during the swing phase of the gait cycle. Two types of suspension methods are used. Mechanical suspension (cuffs, sleeves, socket modification, or thigh corset) and suction suspension (see Table 38-4).
Suction (Atmospheric) Suspension
Mechanical (Skeletal Grasp) Suspension In cuff suspension, a supracondylar cuff is attached to the medial and lateral socket walls and circles the thigh above the femoral condyles. The attachment points on the socket are slightly posterior to the midsagittal line in order to resist hyperextension forces to the knee and allows them to withdraw slightly from the socket during knee flexion. It does not totally eliminate relative motion between the residual limb and socket, but is simple, easily adjustable, and provides adequate suspension for most amputees. The exception is a very short or painful residual limb, with a tendency toward mediolateral knee instability. Sleeve suspension is a neoprene or a latex material sleeve that is pulled over the prosthesis and extends above the patient’s knee. The suspension sleeves are very effective but do not provide enough stability for a very short residual limb or in patients with mediolateral instability. Other disadvantages include increased perspiration and heat under the sleeve, and the need for good hand dexterity and strength to roll the sleeve up and down for donning and doffing. The thigh corset is attached to the socket and the prosthetic shank by sidebars and knee joints. Sometimes a flexible waist belt and a folk strap assembly are added. Thigh corsets are not very commonly used. Supracondylar suspension employs higher medial and lateral walls than in PTB design, which encompass the femoral condyles fully and has a proximal, smaller mediolateral diameter; therefore the prosthesis does not slip over the epicondyles. The most common method is to build a compressible contoured proximal medial buildup, also called a medial wedge suspension. This wedge can be either removable or nonremovable, and it can be built either into the proximal socket wall or into the soft socket insert. The medial wedge supracondylar suspension eliminates the need for a cuff and provides firmer suspension with less pistoning. It also provides improved mediolateral stability and rotational control because it holds the knee above the epicondyles. This is the preferred suspension for a short residual limb. The disadvantages are that it is more difficult to fabricate and the proximal brim protrudes above the flexed thigh in a seated position, making it less cosmetic. In supracondylar/suprapatellar or SC/SP suspension, medial, lateral, and anterior walls are high and enclose the entire patella. Any tendency for genu recurvatum is resisted because of the enclosure of the patella, and it is therefore used in a very short residual limb. The disadvantages include more
Atmospheric suction suspension methods are considered to be the preferred form of suspension in lower limb prosthetics because they provide the best suspension and virtually eliminate any motion between the residual limb and the socket. The range of motion of the knee is preserved, as is the total contact throughout gait cycle. Because of the intimate fit and suspension, the prosthesis feels lighter, more natural, and easier to control. However, it does require adequate length of the residual limb, stable volume, and healthy skin condition. It is difficult to fabricate and fit. The ICEROSS (ICE landic Roll-On Silicone Socket) was developed in the 1980s. The silicone sleeve is fitted very closely to the amputee’s residual limb so that air is occluded and a very effective suspension is maintained throughout the gait, despite minor changes. The roll-on sleeve is a prefabricated liner that is first turned inside out and is then positioned on the end of the residual limb and rolled on proximally over the knee. It is then secured to the socket by means of a shuttle lock, in which a pin at the end of the silicone liner automatically engages with a spring-loaded plastic mechanism located in the bottom of the prosthetic socket. A release button is placed into the socket, which will permit doffing of the prosthesis. Currently, some other variations or combinations of rollon sleeve and distal locking mechanisms are popular methods to suspend transtibial prosthesis. Fabric socks are sometimes worn over the silicone sleeve to reduce the friction between the sleeve and socket and also provide a means of accommodating changes in volume. The hypobaric suction system consists of a 1-inch-wide silicone band, which is impregnated into the stump sock or stump sheath. It has an automatic air release valve. The band is slightly lubricated and then is placed over the residual limb. The entrapped air is then forced out through the valve, thereby creating a vacuum. As the patient ambulates during the swing phase, the suction developed within the distal liner prevents any displacement. For the hypobaric suspension system to work, the residual limb should be longer than 5 inches, muscular, and the patient should have a nicely contoured residual limb.
TRANSFEMORAL PROSTHESIS A transfemoral prosthesis requires a transfemoral socket, suspension mechanism, knee mechanism, shank, and a foot and ankle assembly. Transfemoral sockets usually are total contact, i.e., providing contact of the socket over the entire residual limb, including the distal end, and are of two types: quadrilateral and ischial containment. The term quadrilateral refers to the appearance of the transfemoral socket when viewed in the transverse plane because it has four distinguishable walls (Fig. 38-8). Weight
Source: From Ref. [50].
Hypobaric
Atmospheric (suction) roll-on sleeve
Supracondylar/suprapatellar
Intrinsic supracondylar
Thigh corset knee joint
Over-the-knee sleeve
Extrinsic cuff
Mechanical (skeletal grasp)
Advantages
Can unload residuum. Maximal mediolateral and hyperextension control Excellent suspension. Adds mediolateral and rotational control As above, but adds recurvatum control Secure suspension with minimal pistoning. Prosthesis feels lighter and more natural As above. Ease of donning. Uses fabric socks which aid hygiene, comfort, and ability to maintain fit
Simple and easily adjustable. Easy to don and doff. Some control of knee. Hyperextension Simple and effective. Good auxiliary suspension
Table 38-4. Transtibial Suspension Methods
Shorter, sharply tapered residua are difficult to fit
May be difficult to don. Some discomfort with knee flexion
As above. Poor sitting cosmesis
No mediolateral or hyperextension control. Heat and perspiration. May interfere with knee flexion. May be difficult to don Pistoning. Heavy, bulky, cumbersome. Thigh atrophy Condylar fit must be precise
Slight pistoning. No mediolateral control
Disadvantages
Preferred suspension but requires residuum of adequate length with stable volume and good skin As above
Painful, sensitive residuum. Unstable knee joint Shorter residua. Mild mediolateral knee instability As above. Recurvatum
Need for auxiliary suspension during sports or other heavy activities
Anticipated volume fluctuation
General indications
586 Part Four. Peripheral Occlusive Disease
Chapter 38. Rehabilitation of the Vascular Amputee
bearing in the quadrilateral socket is achieved primarily through the ischium and the gluteal musculature. The combination of skeletal and muscular anatomy rests on the top of the posterior wall of the socket, which is formed into a wide seat and is parallel to the ground. The anterior wall, especially the medial third, is carefully fitted against Scarpa’s triangle and maintains the ischium and gluteals on the ischial seat. The anterior/posterior diameter of the socket walls is based on the anatomic measurements. The lateral wall is slightly higher than the medial wall, and proximal to the greater trochanter the lateral wall is contoured above the hip abductors to discourage abduction. The entire lateral wall is flattened against the shaft of the adducted femur, with the exception of the laterally projected relief for the terminal aspect of the femur. The medial wall is designed to provide even pressure on adductor muscles and contains all medial tissues to prevent an adductor roll. The quadrilateral socket is designed with initial flexion to improve the ability of the amputee to control knee stability at the heel contact and to help minimize the development of lumbar lordosis at toe-off. The ischial containment socket narrow medial-lateral design, also known as normal shape, normal alignment (NSNA),[30] is narrower mediolaterally and wider anteroposteriorly (Fig. 38-9). In this design, the ischium, and in some cases the ischial ramus, is also enclosed inside the socket. The primary weight bearing in the ischial containment socket is focused primarily through the medial aspect of the ischium and the ramus. Additional weight-bearing support is provided by the gluteal muscles and the lateral aspect of the femur distal to the greater trochanter, as well as the pressure, which is evenly distributed over the entire surface of the residual limb. More residual surface and volume are contained within the ischial containment socket, as compared to the quadrilateral socket, resulting in greater force distribution and lower pressures exerted within an ischial containment design. It has been hypothesized that a quadrilateral socket is displaced laterally during mid-stance and thus results in a shearing force on the perineal tissues. Femoral abduction occurs, decreasing the effectiveness of the gluteus medius muscle.[31] In an ischial containment socket, the medial brim of the socket is extended upwards until the pressure is brought to bear against the ischial ramus, resulting in a bony lock between the ischium, trochanter, and lateral aspect of the femur, providing a much more stable mechanism and resulting in increased comfort in the groin and better control of the pelvis and the trunk. It is generally believed that ischial containment sockets are desirable for short, flabby residual limbs with weak abductors. Many amputees report increased comfort and function with an ischial containment socket. Kristinsson cited the advantages of a flexible brim for sockets, stating that a transition between the necessary rigidity of the socket structure and flexibility of the body tissue at and just proximal to the socket brim is very helpful.[29] The socket brim can be either fully or partially flexible. This type of socket design can be either quadrilateral or ischial containment and uses a flexible thermo-molded plastic inner socket with a rigid or semi-rigid frame.
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Figure 38-8. Quadrilateral socket. (Courtesy of Otto Bock Prosthetic Compendium for lower extremity prosthesis.)
Figure 38-9. Ischial containment socket. (Courtesy of Otto Bock Prosthetic Compendium for lower extremity prosthesis.)
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SUSPENSION VARIATIONS FOR TRANSFEMORAL AMPUTEES Suspension methods in transfemoral amputees are mechanical and suction (see Table 38-5).
Mechanical (Skeletal Grasp) Total Elastic Suspension (TES) Belt: If the residual limb contours and condition or age of the amputee do not allow full suction suspension, supplemental suspension may be indicated. In such cases a total elastic belt, made of a neoprene type of material, can be added over the prosthetic socket. It is easy to don and is comfortable. Silesian Belt: This is a soft belt made of cotton webbing, leather, or Dacron. It is attached to a pivot point on a socket in the area of the greater trochanter and passes around the back as a belt on the opposite iliac crest, where it achieves most of its suspension. Anteriorly, its attachment is either a singular point or, in some cases, double attachment points. Hip Joint and Pelvic Band: This provides rotational stability and a significant mediolateral pelvic stability. However, it is not used very often.
Suction (Atmospheric) Traditional Suction Suspension: This type of suction requires an air seal to make the prosthetic socket airtight and usually includes a distally located one way valve through which the air is expelled. A special fabric sock or elastic bandage is used to pull the residual limb into the socket, and the fabric or sock is pulled through the valve hole, thereby drawing the residual limb into the socket, past the snug proximal brim. In some cases, the patient may use a lubricant on the thigh to reduce the friction, and then push or slide the limb into the socket. This is known as a “wet-fit” socket. The air is then expelled, the valve is replaced, and full suction suspension is achieved. If the air is allowed to enter the socket, the pressure differential disappears and the prosthesis falls from the residual limb. This type of suspension allows greater freedom of movement, increased use of the remaining muscles, decreased pistioning between the residual limb and the socket, and improved comfort and appearance. Traditional Partial or Semi-Suction: If the full suction socket design cannot be utilized because of difficulty in donning or significant volume fluctuation, a partial suction socket can be used. The patient can wear socks inside the full suction socket or use a wet-fit design to push the residual limb in. However, the patient may require an additional Silesian belt or some other auxiliary suspension. Hypobaric and roll-on suction systems can also be used for transfemoral prosthesis (see Table 38-5).
PROSTHETIC KNEES Prosthetic knees can be exoskeletal or endoskeletal. The knee units are fabricated of wood, plastic, or metal. To minimize
weight, aluminum, titanium, and carbon fiber composites can be used. Prosthetic knees provide three functions: support during stance phase, smooth controlled swing phase, and unrestricted knee flexion for sitting, kneeling, stooping, and related activities. Prosthetic knees are divided into four categories: single axis, polycentric, friction control, and locking knees. Single Axis: This consists of a simple hinge mechanism, which provides flexion and extension around the single axis. It provides stance stability but is dependent upon the alignment stability. This joint is low maintenance, but the disadvantage is lack of mechanical stability. Polycentric Axis Knee: It usually consists of four bar linkage that provides more than one point of rotation. The advantage of this knee is that it provides varied mechanical stability during the gait cycle, with enhanced stability during heel strike, and decreased stability during toe-off, thus allowing for easier initiation of swing phase. The greatest advantage is the inherent shortening of the shank during flexion, allowing for better foot clearance in the swing phase and the ability to rotate the shank under the knee during sitting, thereby improving the cosmesis for very long residual limbs and for knee disarticulation amputees. The disadvantages are increased weight and bulk. However, bulk has been reduced with the carbon fiber composite and titanium materials. It is available in both child and adult sizes. Single Axis with Mechanical Friction Control: Most single axis knee units have a friction mechanism, which controls the movement of the shank during the swing phase. The friction mechanism, by applying resistance to rotation about the knee axis, helps dampen any excessive knee flexion and terminal swing impact. The resistance is adjustable with a friction adjustment screw. The single axis constant friction knee is simple, inexpensive, light in weight, quite easy to adjust, and is available in both endoskeletal and exoskeletal versions. However, it does not allow change of cadence. Single or Polycentric Axis with Pneumatic Control: Pneumatic control of the swing of the prosthetic shank is provided by a pneumatic cylinder containing air, which is attached to the knee and is placed in the upper shank. It is more responsive to varied walking speeds and is a more advanced form of swing control than the mechanical friction. The disadvantages are increased necessity for maintenance and increased weight and expense. Single or Polycentric Axis with Hydraulic Control: This is similar to the pneumatic control, but oil is used instead of air. It uses a cylinder and a piston rod arrangement. The oil provides resistance to motion depending on its viscosity and temperature. Silicone is the most commonly used lubricant for prosthetic hydraulic units as it avoids stiffness in cold weather and looseness in hot weather. Hydraulic units provide varied cadence and are indicated for amputees who can take advantage of the cadence response function. The disadvantages are increased weight, maintenance, and expense. Hydraulic and pneumatic controls both swing and stance are also available. However, these units are heavier and more expensive. The weight is applied to the prosthesis while the knee is slightly flexed, thus allowing the unit a slow yielding action of the knee rather than a quick collapse, which in turn allows the young and active amputee to descend ramps and stairs in a step-over-step manner and to recover balance when
See “full suction” above, plus larger, more comfortable socket simplifies donning. Uses fabric socks with air seal, improving hygiene, and adjustability of fit
See “full suction” above, plus very secure retention because of considerable friction in addition to suction
Hypobaric
Roll-on sleeve
Source: From Ref. [50].
Larger socket permits “pushing in,” hence easier donning. Improved hygiene and comfort. Similar to hypobaric
Traditional “partial” suction
No restriction of hip motion by straps or belts around torso. Feels lighter and more natural
Very secure mechanical suspension. Maximum mediolateral and rotational control. Easy to don and doff
Hip joint and pelvic belt
Atmospheric (suction) Traditional “full” suction
Adds to retention security. Some rotational control. Easy to don and doff
Silesian bandage
Simple and effective auxiliary suspension
Advantages
Transfemoral Suspension Methods
Mechanical (skeletal grasp) TES belt
Table 38-5.
Preferred for patients with donning difficulties, especially geriatric. Requires residua of adequate length, strength, and musculature
For patients preferring “roll-on” donning and more intimate feel of sleeve Difficulties in donning especially short, flabby residua. Some problems with adjustability, hygiene, and comfort
An alternative when “full” or hypobaric suction is not practical
Younger, more active and agile amputees. Volumetrically stable residua of adequate length
Simple adjunct to suction. Provides additional physical and/or psychological security For weak, elderly, and/or obese patients. Essentially limited to non–suction wearers
As above
General indications
Shorter, sharply tapered residua are difficult to fit
Requires supplemental mechanical suspension (see below) due to transitory suction
Undersized socket difficult to don requiring “pulling in” or “wet fit.” Some hygiene, comfort, and adjustability problems
Increased pistoning. Restricted hip mobility. Bulky and cumbersome. Some sitting discomfort
No mediolateral control
See “Silesian bandage” above, plus occasional heat and perspiration problems. Limited durability
Disadvantages
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stumbling. By moving a selector switch, the wearer can eliminate the slow yielding stance for control while retaining the swing phase resistance. A flexion lock can be introduced should a particular activity require it. Hydraulic and pneumatic units are also available for polycentric knee designs as well. Newer versions of the knees, e.g., Seattle Power Knee, Otto Bock, C-Leg, and Intelligent Knee, are on the market. One unit uses a tiny, computerized device to enhance the degree of control. A microprocessor with a motor is attached to a pneumatic cylinder of the pneumatic knee. The position and angle of the knees send information to the computer, allowing 12 –13 variations in cadence and provide greater swing control. Locking Mechanism (Weight-Activated Locking Knee or Stance Control Knee): When the weight is applied to the prosthesis, a braking mechanism mechanically prevents the knee from flexing or buckling. The amount of weight required to effectively engage the brake and prevent flexion can be adjusted depending upon the amputee’s weight, activity level, and stance-control needs. It is used very commonly for weak and debilitated individuals. Its disadvantages are increased maintenance and delayed initiation of swing phase if the stance-control brake is set for a higher degree of stance stability. Manual Locking Knee: Manual locks are available for both single axis and polycentric knees in both endoskeletal and exoskeletal configurations. Functional Enhancement Components: These elements add weight, bulk, and cost to the prosthesis. However, they may be used in some patients for specific needs. Torque Absorber: This allows transverse rotation about the long axis of the prosthesis and is useful for bilateral amputees, especially for amputees participating in golf, tennis, and other sports demanding rotational activities. The torque absorber rotator is placed between the lower end of the shank and the foot assembly, allowing rotation of the shank while the foot is placed on the ground. Knee Shank Rotation Adapter: This is useful for sitting cross-legged on the floor by releasing a locking mechanism. The knee and shank are free to rotate. It can also facilitate entry and exit into cars, restaurants, booths, etc. (Fig. 38-10). Multiaxis Ankle Module: This is a modular endoskeletal component that will provide multiple degrees of motion within the ankle, independent of the foot. This is primarily intended for endoskeletal prosthesis, but can also be used for exoskeletal prosthesis by creating a hybrid system. These modules assist in smoothing out the gait pattern and enhancing the stability in a transfemoral amputee.
FOLLOW-UP CARE LE amputees should be followed up at regular intervals to ensure maintenance of optimal prosthetic fit. It is usual for a new amputee to rapidly lose residual limb volume in the initial 1–2 years and require a replacement prosthetic socket. Once the residual limb volume is stabilized and the amputee is functioning well, the follow-ups can be less frequent, and the LE prosthesis may need to be replaced every 3 –5 years.
Figure 38-10. Knee shank rotation adapter. (Courtesy of Otto Bock Prosthetic Compendium for lower extremity prosthesis.)
SPECIAL ISSUES IN AMPUTEE MANAGEMENT Phantom Pain Phantom limb pain was first described by Ambrose Pare´ (1510 – 1590).[32] American neurologist Silas Mitchell (1829 – 1914) published his article on phantom limb anonymously in a nonscientific journal.[33] It is important to differentiate between phantom limb sensation and phantom limb pain because their management strategies are different. Phantom limb sensation is the sensory perception of a missing limb that does not include pain. It is a common occurrence in virtually all amputees. It is usually most prominent in the early postoperative period, and the patient should be reassured that it is a normal occurrence as the cerebral pathways serving the amputated segment are still functioning. Phantom limb sensation involves sensations of willed spontaneous movement, itching, temperature and pressure. The amputee may experience all of the normal limb sensations. It occurs most commonly in distal limbs, which are more richly innervated. The phantom limb usually undergoes a process of telescoping, where it may shrink, and the digits of the phantom foot become attached to the end of the residual limb and may completely dissipate in one year.[34] Residual limb stump pain is distinct from phantom limb pain and is present in the region of amputation. It usually subsides in a few weeks after surgery. Phantom limb pain is a noxious sensory phenomenon of the missing limb. It may be a burning or throbbing pain, or it may be an abnormal ischemic discomfort. In this situation, the phantom limb does not undergo telescoping. According to a recent study, 72% of amputations lead to phantom limb pain
Chapter 38. Rehabilitation of the Vascular Amputee
about a week after amputation, and 60% of amputees still have phantom pain 6 months later.[35] The pathophysiology of phantom pain and sensation is not completely understood, and different mechanisms, as noted below, have been proposed. 1.
2.
3.
Peripheral nerves are involved in the generation of phantom pain, e.g., neuroma from regenerating neurons might contribute to phantom limb sensation. However, this does not explain the phenomenon entirely. The sympathetic nervous system has also been implicated in phantom limb sensation. In the sympathetic efferent –somatic afferent cycle, input from the cortex excites sympathetic neurons in the spinal cord, which excite postganglionic noradrenergic cutaneous vasoconstrictor and cholinergic sudomotor fibers in the residual limb. These result in decreased blood flow to the residual limb and the perception of phantom limb sensation. Pain occurs if certain nociceptors of primary afferents are abnormally activated.[36] It is known that stress and anxiety can exacerbate phantom limb sensation and pain, while distraction, attention, and diversion can reduce phantom limb sensation. Loss of efferent nerves through spinal cord lesions or root avulsion causes disinhibition of dorsal root neurons, allowing transmission of phantom pain.[37] Melzack has proposed a supraspinal (central) origin consisting of a neuromatrix and loops between cortex and thalamus, as well as a cortical and limbic system.[38] The neuromatrix impact is a neurosignature on all sensory inputs or experiences. Sensory inputs modulating the neurosignature are converted to an ever-changing awareness by the sentinent neural hub. Melzack states that without the inhibitory input, increased firing of spinal cells above the amputee level can trigger the neuromatrix. The overactive neuromatrix then interacts with the sentinent neural hub, producing a burning, cramping pain. A corollary for the central origin of phantom limb pain states that the ensuing pain is actually a “memory” of pain in the limb before amputation. It is well known that patients who have protracted pain in the limb before amputation develop phantom limb pain.
Treatment: Treatment of phantom pain is difficult and unsatisfactory. Some aggravating and relieving factors are noted (see Table 38-6). Sherman, in a 1980 review of phantom pain treatment, revealed 68 types of treatment modalities in use for phantom limb treatment, but the success rate was only slightly above 30%, which is near the placebo response.[39] Medical Treatment: Use of low-dose tricyclic antidepressants (amitriptyline, imipramine, doxepin, or other drugs) may achieve symptom reduction in the early postoperative period. Residual limb percussion, vibration, or intense massage can help in desensitization and alleviation of pain. Range-ofmotion exercises and residual limb wrapping in soft elastic or rigid dressing is helpful. Transcutaneous electrical nerve stimulation (TENS) can be successful in some cases.
Table 38-6.
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Factors That Aggravate or Relieve Phantom
Pain Phantom pain– aggravating factors Emotional stress Lack of sleep Cold or warm weather changes Yawning, coughing Ill-fitting prosthesis
Relieving factors Emotional relaxation Rest, sleep Massage, percussion, electrical stimulation Exercise, manipulation of residual limb Well fitted prosthesis
Biofeedback and relaxation training may be beneficial.[40] Wearing a well-fitted prosthesis has been found to alleviate phantom limb pain. Other treatments that have been tried include dorsal column stimulation and various neurosurgical ablative procedures. Bach et al.[41] studied a group of dysvascular patients who were to undergo amputation under epidural anesthesia. All of them had pain for 1–6 months. These patients received continuous epidural analgesia for 3 days prior to amputation. Postamputation, none of these patients had phantom limb sensation, and only 27% had phantom limb pain, which disappeared in 6 months.
Energy Consumption During Gait in Amputees The amount of metabolic energy used during ambulation is an important consideration in dysvascular amputees due to their cardiovascular problems (see Table 38-7). Oxygen (O2) cost is the physiological work required to complete a task. Maximal aerobic capacity (VO2 max) is the highest oxygen uptake during physical work at sea level. O2 cost has been shown to progressively increase with higher levels of amputation.[42] Patients with an amputation walk at a self-selected slower speed to reduce energy expenditure.[43] The average measured gait velocity of dysvascular transtibial amputee is decreased 44% with oxygen consumption increased 33% over the distance walked. Table 38-7.
Energy Expenditure During Gait in an Amputee
Level of amputation Symes amputation Unilateral transtibial amputation Bilateral transtibial Knee disarticulation Unilateral transfemoral Bilateral transfemoral Unilateral hip disarticulation Hemipelvectomy Wheelchair propulsion Crutch walking
% more than nonamputee 25 20 – 25 40 43 65 – 70 80 – 100 82 125 65 65
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Velocity of the traumatic transtibial amputee is decreased only 11% with oxygen consumption increased 7% over the distance walked, as compared with subjects without vascular disease.[43] The longer residual limbs have lower oxygen requirements than shorter residual limbs, ranging from 10% to 40% increase of oxygen consumption measured over the distance walked.[44]
AMPUTATION PREVENTION Good foot care, along with aggressive management of foot ulcers, is an important step towards amputation prevention in diabetic vascular disease. The foot evaluation includes pulses, temperature, nail blanching for venous return, Doppler studies for pulse pressure, and evaluation of skin (shine, atrophy, hyperpigmentation, dryness, presence of calluses or trophic nails). Attention should be paid to pressure points on non – weight bearing areas or to the skin between the toes. Gait should be evaluated with and without the shoes. Evaluate footwear with attention to the depth and width of the shoes, heel height, and wear pattern on the sole of the shoe. Musculoskeletal: Any change in lower extremity range of motion, valgus or varus deformity of the hip or knee will alter the pressure points on the foot. Claw foot, flat foot, varus or valgus of the forefoot or hind foot, missing toes or rays of the foot, Charcot foot, especially dropping of the navicular bone, will all change the weight bearing and pressure points on the foot. Sensation: Protective sensory loss can result in microtrauma. Sensation testing, therefore, is very important.[45] Semmes–Weinstein monofilaments are made of nylon with a diameter ranging from 1.65 to 6.65 units. Consistent perception of a 5.07 monofilament indicates presence of protective sensation.[46] Vibration Sense: If a patient perceives a vibration end point 10 seconds or more before the examiner, there is impairment of vibration sense. Impaired vibration sense is a risk factor for amputation.[47] Muscle Stretch Reflexes: Absent ankle jerks are suggestive of neuropathy. Wasting of extensor digitorum brevis or claw toes are also indicative of neuropathy.
TREATMENT Foot with No Ulceration: Daily foot care includes washing with soap and water; drying, especially between the toes; applying lotion on dry areas; trimming of the calluses; provision of nail care every 6 weeks by a professional; wearing of clean white cotton socks, and change in midday, if moist. Footwear should be a flat, rigid, extra-depth shoe with molded shoe inserts to distribute pressure. Rigid sole with rocker bottom shoes may be used in patients with excessive pressure over metatarsal heads. In Charcot foot, which is not acute, custom-molded shoes are used if significant deformity is present.
Foot with Ulcer: Use antibiotics in case of infection and remove devitalized tissue. Control the edema using support stocking and elevation at rest. Relieve pressure with total contact cast, which will distribute weight-bearing forces across the plantar surface of the foot, protect foot from trauma, control edema, and allow the patient to ambulate. An absorbent plastic cast will absorb the drainage.[48] The cast is applied after cleansing the ulcer. It is changed every 2–3 days in the beginning, and later every week. Complete healing will occur in 6 –12 weeks. The cast may be bivalved after 3–6 months, but only in the most compliant of patients. After the ulcer is healed, continue the cast for another 4 weeks and get appropriate shoes. Once Charcot foot is mature, use a bivalve ankle-foot orthosis for an additional 12 months. Patient education should be provided to prevent recurrence. Charcot Foot: The hallmark of Charcot foot is the absence of history of trauma, and it may or may not be painful. The foot may be warm, swollen, or edematous, which is often confused with cellulitis because erythema decreases with bedrest and antibiotics. However, in this case, erythema recurs when the patient is allowed to walk and switched to oral antibiotics. As the patient walks on the Charcot foot, the bones collapse and the foot gets more and more deformed, predisposing the foot to ulceration.[49] Clinically the foot is warm, swollen, with no ulcers. X-rays in the early stages are not sensitive. Both bone scan and MRI can detect Charcot foot in the early stages, but it may be confused with osteomyelitis by the radiologist. Treatment of Charcot foot involves using a total contact cast and avoiding ulceration of the insensate foot by keeping non– weight bearing for 1–3 months, until the warmth and the swelling have resolved. Advance weight bearing with assisted device and keep casted for 6–12 months until joint contours are recreated on x-rays.
PROSTHETIC PRESCRIPTION: EXAMPLE CASES* Transtibial Amputee .
A 79-year-old retired schoolteacher with type II diabetes and peripheral vascular disease undergoes a transtibial amputation for a gangrenous foot. She likes to go hiking and work outside in her garden.
The prosthetic prescription could include a total contact PTB thermoplastic socket with a soft socket insert, a neoprene sleeve suspension, a lightweight carbon composite titanium shank, and a lightweight multiaxis foot. This lightweight prosthesis would provide for stable support, and the soft liner would add comfort. The multiaxis lightweight foot will allow this patient to be able to walk on an uneven terrain. The sleeve will provide the secure suspension. Other options could *These prosthetic prescriptions are presented for example only, and other options can be used without sacrificing safety or function. Each prosthetic prescription must meet the needs of the individual amputee and should be cost-effective.
Chapter 38. Rehabilitation of the Vascular Amputee
include a silicone suction suspension with PTB socket. An energy-saving dynamic response foot can also be used (see Tables 38-3 and 38-4).
Transfemoral Amputee .
A 72-year-old, elderly, thin man with peripheral vascular disease undergoes a transfemoral amputation and would like to achieve short distance ambulation.
The prescription might include a lightweight total contact ischial containment socket, endoskeletal design with total flexible brim and a rigid frame for comfort, lightweight
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endoskeletal shank design, a weight-activated stance control knee, an energy-storing foot, and TES belt for suspension. This would allow the patient stability as well as mobility. Other options can include a wet-fit suction suspension or silicone suction suspension with ischial containment socket. A polycentric knee can be substituted. A SACH foot can also be prescribed (see Table 38-5). Modern advances in biomechanics, availability of newer materials and computer technology has allowed for availability of newer, smarter knee systems and foot ankle mechanisms.[51,52] These can be used depending upon individual amputee’s functional capabilities and goals to achieve maximum benefit.
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24. Berlemont, M.; Weber, R. Temporary Prosthetic Fitting of Lower Limb Amputees on the Operating Table. Technique and Long Term Results in 34 Cases. Acta Orthop. Belg. 1966, 32 (5), 662– 667. 25. Weiss, M. Myoplastic Amputation; Immediate Prosthesis and Early Ambulation; Department of Health, Education and Welfare, U.S. Government Printing Office: Washington, DC, 1971. 26. Burgess, E.M.; Romano, R.L. The Management of Lower Extremity Amputation Using Immediate Post Surgical Prosthesis. Clin. Orthop. 1968, 57, 137– 146. 27. Wu, Y.; Krick, H. Removable Rigid Dressing for BelowKnee Amputees. Clin. Prosthet. Orthot. 1987, 111, 33– 44. 28. Oberg, T.; Lilja, M.; Johansson, T.; Karsznia, A. Clinical Evaluation of Transtibial Prosthesis Socket: A Comparison Between CAD – CAM and Conventionally Produced Sockets. Prosthet. Orthot. Int. 1993, 17, 164–171. 29. Kristinsson, O. Flexible Above-Knee Socket Made with Low-Density Polyethylene Suspended by a WeightTransmitting Frame. Orthot. Prosthet. 1983, 37, 25– 27. 30. Long, J.A. Normal Shape Normal Alignment (NSNA) Above-Knee Prosthesis. Clin. Prosthet. Orthot. 1985, 9, 9 – 14. 31. Gottschalk, F.A.; Konrosh, S.; Stills, M. Does Socket Configuration Influence the Position of the Femur in Above-Knee Amputation? J. Prosthet. Orthot. 1989, 2, 96– 102. 32. Postone, N. Phantom Limb Pain. Psychiatry Med. 1987, 17, 57– 70. 33. Nathanson, M. Phantom Limbs as Reported by S. Weir Mitchell. Neurology 1988, 38, 504– 505. 34. Jensen, T.; Rasmussen, P. Phantom Pain and Related Phenomena After Amputation. In Textbook of Pain; 2nd Ed. Wall, P.D., Melzack, R., Eds.; Churchill Livingstone: Edinburgh, 1989; 508 – 521. 35. Jensen, T.S.; Krebs, B.; Nielson, J.; et al. Immediate and Long Term Phantom Limb Pain in Amputees: Incidence, Clinical Characteristics and Relationship to Preamputation Limb Pain. Pain 1985, 21, 267– 278. 36. Katz, J. Psychophysiological Contributions to Phantom Limbs. Can. J. Psychiatry 1993, 38, 282– 298. 37. Ribbers, G.; Mulder, T.; Rijken, R. The Phantom Phenomenon: A Critical Review. Int. J. Rehabil. Res. 1989, 12, 175– 186.
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Melzack, R. Phantom Limbs and the Concept of Neuromatrix. Trends Neurosci. 1990, 13, 88–92. Sherman, R.A. Phantom Limb Pain; Mechanism-Based Management. Clin. Podiatr. Med. Surg. 1994, 11, 85– 106. Ludenberg, T. Relief of Pain from a Phantom Limb by Peripheral Stimulation. J. Neurol. 1985, 232, 79– 82. Bach, S.; Noreng, M.F.; Tjellden, N.U. Phantom Pain in Amputees During the First Twelve Months Following Limb Amputation, After Preoperative Lumbar Blockade. Pain 1988, 33, 297– 301. Waters, R.L.; Perry, J.; Antonelli, D.; Hislop, H. Energy Cost of Walking of Amputees: The Influence of Level of Amputation. J. Bone Jt. Surg. (Am.) 1976, 58, 42– 46. Waters, R.L.; Perry, J.; Chambers, R. Energy Expenditure of Amputee Gait. In Lower Extremity Amputation; Moore, W.S., Malone, J.M., Eds.; W. B. Saunders: Philadelphia, 1989; 250– 260. Gonzales, E.G.; Corcoran, P.J.; Reyes, R.L. Energy Expenditure in Below Knee Amputees: Correlation with Stump Length. Arch. Phys. Med. Rehabil. 1974, 55, 111– 119. Caputo, G.M.; Cavanaga, P.R.; Ulbrecht, J.S.; Gibbons, G.W.; Karchmer, A.W. Assessment and Management of Foot Disease in Patients with Diabetes. N. Engl. J. Med. 1994, 331, 854– 860. Birke, J.A.; Sims, D.S. Plantar Sensory Threshold in the Ulcerative Foot. Lepr. Rev. 1986, 57, 261– 267. Boulton, A.J.; Kubrusly, D.B.; Bowker, J.H.; et al. Impaired Vibratory Perception and Diabetic Foot Ulceration. Diabetes Med. 1986, 3, 335– 337. Walker, S.C.; Helm, P.A.; Pullium, G. Total Contact Casting, Sandals and Insoles. Construction and Applications in a Total Foot Care Program. Clin. Podiatr. Med. Surg. 1995, 12, 63– 73. Berger, N.; Fishman, S., (Eds.) The Diabetic Foot; 5th Ed. Mosby Year Book: St. Louis, MO, 1993. Berger, N.; Fishman, S., (Eds.) Lower Limb Prosthetics; Prosthetic-Orthotic Publications: New York, 1998. Michael, J.W. Modern Prosthetic Knee Mechanisms. Clin. Orthop. Rel. Res. 1999, 361, 39–47. Huang, M.E.; Webster, J.B.; Levy, C.E. Acquired Limb Deficiencies. 3. Prosthetic Components, Prescriptions, and Indications. Arch. Phys. Med. Rehabil. 2001, 82, 517– 524.
CHAPTER 39
Lumbar Sympathectomy James S. T. Yao denervates the posterior aspect of the thigh, leg, and foot. Figure 39-1 shows the denervation in relation to level of ablation. In male patients, the control of the function of ejaculation is from L1, and bilateral resection can cause disturbance of ejaculation. Anatomically, there is great variety in the number, size, and location of the lumbar sympathetic ganglia. The first lumbar ganglion lies under the insertion of the crus of the diaphragm and is often inaccessible for removal. Four ganglia are usually found in the lumbar chain, but the number may vary between two and eight. The L2 and L4 ganglia are most constant in position, and the L4 is often located behind the origin of the iliac vessels. Fusion between L1 and L2 can occur, and ejaculation can be disturbed after resection of L2 in such cases. Because of this, it has been recommended that, in male patients, resection of L3 to L4 is sufficient to eliminate vasomotor tone and to cause vasodilation in the foot.[4] Another anatomic variant is crossover fibers. These can be seen in 15% of cases, and this may account for failure of unilateral sympathetic ablation. The distinction between preganglionic and postganglionic fibers is of no surgical importance, because all preganglionic fibers for the lower extremity are interrupted by resection of the ganglia and the intervening sympathetic trunk. Regeneration of sympathetic fibers can occur if only a short segment of the chain is resected. The completeness of sympathetic denervation is best determined by the cessation of the secretory activity of the sweat glands. Instead of the cumbersome iodine –starch test, Benzon et al.[5] have suggested the use of filter paper impregnated with cobalt or triketohydrindene hydrate (Ninhydrin).
The release of vascular tone and dilation of blood vessels under control of the sympathetic nervous system, first observed by du Petit in 1727,[1] has served as the rationale behind numerous procedures designed for sympathetic ablation. In 1924, Royle[2] performed lumbar sympathectomy for the treatment of spastic paralysis. The first lumbar sympathectomy for arterial occlusive disease of the lower extremity was performed in the same year by Julio Diez.[3] Since then, in the 1950s and early 1960s, the procedure has been a popular technique for the treatment of limb ischemia due to atherosclerotic occlusive disease. With the introduction of femorodistal bypass procedures to treat severe limb ischemia in the early 1970s, however, lumbar sympathectomy has declined in favor as an effective revascularization procedure. At present, it is seldom performed in most vascular surgical services. Although lumbar sympathectomy now assumes a lesser role, vascular surgeons must be familiar with this rather simple technique to improve cutaneous blood flow. This chapter attempts to review the indication and techniques for sympathetic ablation.
EFFECTS OF SYMPATHECTOMY Sympathetic ablation abolishes central nervous control of the circulation in a limb and also inactivates the sweat glands in the denervated area. It has been well documented that immediate brisk hyperemia with increase of skin blood flow occurs in patients who have undergone sympathectomy. One week later the flows were one-third of the immediate postoperative values, and a further decline occurred up to the second week. After this time, a stable level only slightly in excess of the preoperative flow was achieved. The effect of lumbar sympathectomy on the large and medium-sized vessels is negligible; therefore, patients with intermittent claudication will not be benefited by this procedure. In general, vasomotor activity in the lower limbs depends essentially on L2 to L4. In practice, resection of these ganglia is sufficient to eliminate vasomotor tone and to cause vasodilation in the foot. The ablation of the L2 and L3 ganglia
SELECTION OF PATIENTS FOR LUMBAR SYMPATHECTOMY In modern practice, indications for lumbar sympathectomy are rather limited. Candidates for this procedure include those with (1) causalgia (reflex sympathetic dystrophy), (2) lower extremity spasm, (3) superficial skin lesions of the foot, and (4) primary hyperhidrosis as well as arterial occlusive disease and no suitable recipient artery for bypass. Concomitant lumbar sympathectomy with aortoiliac or femoropopliteal
Supported in part by the Alyce F. Salerno Foundation.
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reconstructions is no longer considered to be an advantageous adjunctive procedure. In a study of 93 patients who underwent aortofemoral bypass, Satiani et al.[6] failed to find a significant difference in graft patency, need for subsequent distal bypass, or amputation rate between the sympathectomy and nonsympathectomy groups. In an evaluation of sympathectomy in conjunction with infrainguinal bypass, Lee et al.[7] studied 40 patients in whom 50 arterial bypass procedures were done in combination with lumbar sympathectomy. In 32 patients, 40 arterial bypass procedures were performed without concomitant lumbar sympathectomy. As calculated by life-table analysis, there was no difference in cumulative patency between these two groups. From these two studies, one may conclude that despite excellent experimental evidence that sympathectomy improves limb blood flow, there is no concrete evidence in humans that concomitant lumbar sympathectomy improves graft patency in the aortoiliac segment or in the femorodistal arterial segment. The indication for causalgia and lower extremity spasm is clear. However, the procedure must not be done until conservative or pharmacologic management has failed to relieve the symptoms. Causalgia, or reflex sympathetic dystrophy, is a syndrome of burning pain, hyperesthesia, swelling, hyperhidrosis and, in severe cases, trophic changes in the skin and bone.[8 – 10] A trial of sympathetic block may help to predict the response to ablation in these patients. In patients with causalgia, psychiatric counseling may help to determine the need for sympathectomy. The most effective therapy is blocking the sympathetic innervation in conjunction with physical therapy. Lumbar sympathectomy for vasospasm of the lower extremity is rarely needed. Patients with lower extremity vasospasm experience frequent episodes of coldness and numbness of the feet and toes, with bluish discoloration of the skin. Most of these patients will respond to drugs, in particular nifedipine or regional sympathetic block. In a 15-year period during which more than 600 patients with Raynaud’s syndrome were seen, Janoff and his colleagues[11] found only 10 with refractory lower extremity vasospasm. All 10 had relief of their symptoms after lumbar sympathectomy. The indication for lumbar sympathectomy to alleviate tissue ischemia due to atherosclerotic occlusive disease is less clear. Patients with a bypassable artery should be considered for femorodistal graft. The response to sympathectomy depends on the degree of collateral flow. The latter can be simply determined by Doppler ankle pressure measurement. In our previous report,[12] we have found that patients with an ankle pressure index above 0.35 responded favorably to lumbar sympathectomy; the majority of patients with an index below 0.205 had a poor response, necessitating subsequent amputation. Patients with inaudible Doppler fail uniformly. Seeger and his colleagues[13] reported similar results. Using discriminant function analysis, Walker and Johnston[14] have found that patients with ankle systolic pressure above 30 mmHg responded favorably to sympathetic ablation. The critical level of 30 mmHg was also suggested by Nielsen and his colleagues.[15] They found that there was a decrease in subcutaneous blood flow close to gangrenous areas following sympathectomy if the toe pressure was less than 30 mmHg. All these reports suggest that there is a critical level of pressure which determines the success or failure of a lumbar
Figure 39-1. Area of leg denervated by ablation of sympathetic nerves. (Left) Area denervated by removal of L1, L2, and L3. (Right) Area denervated by removal of L2 and L3. (From MacCarty, C. S.: Lancet, 1969. Reproduced by permission.)
sympathectomy. In diabetics, prediction may be complicated by falsely elevated ankle pressure due to calcification and diabetic neuropathy. In the former, the use of Doppler waveform of the pedal vessels and toe pressure measurement will help to determine the degree of ischemia. For neuropathy, it has been suggested that autosympathectomy may occur, especially in those with diabetic neuropathy.[16] As a result, sympathectomy is not effective in these patients.[17] In general, lumbar sympathectomy has played a minimal role in the treatment of tissue ischemia due to arterial occlusive disease. The only certain indication for sympathectomy is the treatment of hyperhidrosis, for which it is outstandingly successful.[18,19]
OPERATIVE TECHNIQUE A retroperitoneal approach is used for performing an isolated lumbar sympathectomy. The patient is placed flat in the supine position. An oblique incision is made parallel to the inguinal ligament, beginning at the tip of the eleventh rib and extending inferiorly to just below the umbilicus (Fig. 39-2A). The muscles of the abdominal wall are opened in the direction of their fibers through muscle-splitting incisions, and the folds are carefully developed until transversalis fascia is encountered (Fig. 39-
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Figure 39-2. Technique for lumbar sympathectomy. (A ) Skin incision. (B ) External oblique muscle opened. (C ) Internal oblique muscle opened. (D ) Blunt dissection with hand. (E ) Sympathetic trunk elevated with nerve hook. (From Bergan, J.J.: Sympathetic Nervous System. In Operative Surgery: Principles and Techniques, 3rd Ed.; Nora, P.F. Ed.; Saunders: Philadelphia, PA, 1990; 986–987. Reproduced by permission.)
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2B and C). The fascia is opened and the opening widened by blunt dissection; the operator’s hand, placed just anterior to the psoas muscle, serves to sweep forward the peritoneal viscera without entering the peritoneal cavity (Fig. 39-2D). Three large Deaver or Harrington retractors are placed in position to carefully retract the underlying viscera. The sympathetic chain is identified first by palpation; it is a firm structure, lies attached to the lateral aspect of the paravertebral fascia, and has a characteristic “violin-string tautness” when palpated. The ureter should not be confused with the sympathetic trunk as it is much larger, is far anterior, and exhibits peristaltic activity when stimulated. Occasionally, lymph nodes may be mistaken for the sympathetic chain. The lumbosacral plexus lies far laterally and is much larger than the sympathetic trunk. The overlying fatty tissue is brushed away with a sponge stick, and the trunk is visualized first at its superior aspect around the first lumbar ganglion. A nerve hook is gently insinuated beneath the trunk at this level (Fig. 39-2E). A silver clip is placed just above the level of the second ganglion at the point of transection. After the trunk is severed at this level, the remaining distal segment is grasped with a long curved hemostat, and, with the back of the nerve hook, the remainder of the trunk together with ganglia is dissected out of its bed. Lumbar veins often pass anterior to the trunk on the right side and are ligated with silver clips. The trunk is followed until it becomes attenuated at about the point where it disappears under the iliac artery or vein. At this point the trunk is cut again, the distal remaining segment again being marked with a silver clip. Removal of L2, L3, and L4 is sufficient to achieve release of sympathetic tone. The bed of the trunk is carefully inspected for signs of bleeding, which can be controlled with silver clips or a small sheath of Surgicel placed on the bed. The retractors are removed and the peritoneal contents allowed to return. The muscles are closed in layers with continuous sutures. The skin is closed with sutures placed in subcuticular fashion; drainage is not necessary. On the right side, special care should be taken to avoid injury to the inferior vena cava, which lies immediately anterior and somewhat medial to the sympathetic trunk. It is gently retracted medially by a blunt dissection while the chain is being removed. On the left side, the major vascular structures of concern are the lumbar veins and the abdominal aorta and iliac artery. If necessary to facilitate removal of the chain, the aorta or iliac artery can be gently retracted with a blunt instrument, much as the vena cava is treated. Lumbar veins, when encountered, are best ligated with hemoclips.
COMPLICATIONS Injury to structures adjacent to the sympathetic chain can range from an annoyance to a catastrophe. Bleeding from lumbar veins or injury to the vena cava, aorta, or iliac vessels demands immediate recognition and treatment. Injury to the ureter through devascularization, transection, or ligation
results in either a urinary fistula or destruction of the involved kidney. Injury to the genital femoral nerve or the lumbosacral plexus resulting from mistaken identification of the sympathetic trunk causes less tragic consequences but at the very least can mean failure of the desired sympathetic effect. Postsympathectomy neuralgia is a constant and annoying feature of sympathectomy, and the patient should be forewarned. It often appears at 10 days to 2 weeks after the operation. The neuralgia manifests itself as a severe pain down the back of the thigh into the foot, particularly at night. Hyperesthesia may often be noted over the anterolateral thigh and in the groin. It lasts for varying periods but typically subsides spontaneously within the first 6 weeks after surgery. Postsympathectomy neuralgia is not accompanied by any sensory or motor deficit; reassurance and analgesics are all the treatment necessary. If there is bilateral removal of L1 ganglion or fusion between L1 and L2 ganglia, disturbance of ejaculatory function can occur. In general, lumbar sympathectomy can be performed with ease and with minimal morbidity by experienced hands. It can, however, become a formidable undertaking in patients who are obese, those with retroperitoneal fibrosis, or those who have had previous abdominal surgery. In a symposium on lumbar sympathectomy,[4] in one series of 1344 lumbar sympathectomies reported at the workshop, the mortality was 0.6% and the morbidity 0.6%. In all instances, this was attributed to the complication of pulmonary embolism. Among these patients, 8.3% had some degree of postsympathectomy pain, and 10% experienced loss of ejaculation.
CHEMICAL SYMPATHECTOMY Chemical lumbar sympathectomy by means of lumbar paravertebral block is an alternative to operative lumbar sympathectomy. The technique is less invasive and has a lower morbidity and mortality. It was first described by Brunn and Mandl[20] in 1924. Following animal experiments, they suggested that phenol might produce a more lasting effect. The technique was then adapted to use in human subjects by Hoxton[21] and became popular in the British Isles.[22,23] The technique is rather simple. Sympathectomy is performed with the patient in a sitting position. Under local anesthesia, a needle is inserted at the level of L3. An injection of radiopaque contrast medium is made to confirm the needle position under x-ray control. Recently, the use of computed tomography has been found helpful for needle guidance. A single injection of 7.5 mL of 7.5% phenol in 50% glycerine is made at the level of the upper border of L3. After injection, the patient is maintained in a sitting position for several hours to allow the heavy phenol solution to track downward and bathe the sympathetic chain. Chemical sympathectomy is not without complication, since damage to nearby somatic nerves is often permanent, and an untoward effect such as paresis has been reported.[24]
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du Petit, F.P. Memoire dan Lequel il est Demontre que les Intercostaux Fournessent des Rameaux que Porter des Esprits dans les Yeux. Hist. Acad. R. Sci. 1727. Royle, N.D. A New Operative Procedure in the Treatment of Spastic Paralysis and Its Experimental Basis. Med. J. Aust. 1924, 1, 77. Diez, J. Un Nuevo Metodo de Simpatectomia Periferica par el Tratamiento de las Affeciones Troficas Gangrenosas de los Miembros. Bull. Soc. Surg. Buenos Aires 1924, 8, 922. Callow, A.D.; Simeone, F.A. The Grimonster Symposium on the Occasion of the 50th Anniversary of the First Lumbar Sympathectomy. Arch. Surg. 1978, 113, 295. Benzon, H.T.; Cheng, S.C.; Avram, M.J.; et al. Sign of Complete Sympathetic Blockade: Sweat Test in Sympathogalvanic Response. Anesth. Analg. 1985, 64, 415. Satiani, B.; Liapis, C.D.; Hayes, J.P.; et al. Prospective Randomized Study of Concomitant Lumbar Sympathectomy with Aortoiliac Reconstruction. Am. J. Surg. 1982, 143, 755. Lee, B.Y.; Thoden, W.R.; Madden, J.L.; et al. Long-Term Follow-up of Bypass Procedures with and Without Lumbar Sympathectomy. Contemp. Surg. 1982, 20, 51. Mockus, M.B.; Rutherford, R.B.; Rosales, C.; Pearce, W.H. Sympathectomy for Causalgia: Patient Selection and LongTerm Results. Arch. Surg. 1987, 122, 668. Horowitz, S.H. Iatrogenic Causalgia: Classification, Clinical Findings, and Legal Ramifications. Arch. Neurol. 1984, 41, 821. Schwartzman, R.J.; McLellan, T.L. Reflex Sympathetic Dystrophy: A Review. Arch. Neurol. 1987, 44, 555. Janoff, K.A.; Phinney, E.S.; Porter, J.M. Lumbar Sympathectomy for Lower Extremity Vasospasm. Am. J. Surg. 1985, 150, 147. Yao, J.S.T.; Bergan, J.J. Predictability of Vascular Reactivity Relative to Sympathetic Ablation. Arch. Surg. 1973, 107, 676.
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Seeger, J.M.; Lazarus, H.M.; Albo, D. Preoperative Selection of Patients for Lumbar Sympathectomy by Use of the Doppler Index. Am. J. Surg. 1977, 134, 749. Walker, P.M.; Johnston, K.W. Predicting the Success of a Sympathectomy: A Prospective Study Using Discriminant Function and Multiple Regression Analysis. Surgery 1980, 87, 216. Nielsen, P.E.; Bell, G.; Augustenborg, G.; et al. Reduction in Distal Blood Pressure by Sympathetic Nerve Block in Patients with Occlusive Arterial Disease. Cardiol. Res. 1973, 7, 577. Grover-Johnson, N.M.; Baumann, F.G.; Imparato, A.M.; et al. Altered Pattern of Innervation of Epineural Vessels in the Lower Limb of Patients with Diabetes Mellitus. Diabetologia 1981, 20, 31. Davalle, M.J.; Baumann, F.G.; Mintzer, R.; et al. Limited Success of Lumbar Sympathectomy in the Prevention of Ischemic Limb Loss in Diabetic Patients. Surg. Gynecol. Obstet. 1981, 152, 784. Shuster, S.; Farr, P.M.; Lawrence, C.M. Measurement of Skin Response to Drugs. In Early Phase Drug Evaluation in Man; O’Grady, J., Linet, O.I., Eds.; Macmillan: London, 1990; 553– 565. White, J.W., Jr. Treatment of Primary Hyperhidrosis. Mayo Clin. Proc. 1986, 61, 951– 956. Brunn, J.; Mandl, F. Die Paravertebral Injektion zur Beka¨ mpfung viscerater Schmerzen. Wien. Klin. Wochenschr. 1924, 37, 511. Hoxton, H.A. Paravertebral Block with Aqueous Phenol in the Treatment of Vascular Disease. Angiology 1953, 4, 268. Reid, W.; Kennedy Watt, J.; Gray, T.G. Phenol Injection of the Sympathetic Chain. Br. J. Surg. 1970, 57, 45. Cross, F.W.; Cotton, L.T. Chemical Lumbar Sympathectomy for Ischemic Rest Pain: A Randomized, Prospective Controlled Clinical Trial. Am. J. Surg. 1985, 150, 341. Smith, R.C.; Davidson, N.M.; Ruckley, C.V. Hazard of Chemical Sympathectomy. Br. Med. J. 1978, 1, 552.
CHAPTER 40
Diabetes and Peripheral Vascular Disease Cameron M. Akbari Frank W. LoGerfo ities at multiple areas within the capillary and arteriolar levels, including the basement membrane, smooth muscle cell, and the endothelium. One of the greatest impediments in understanding vascular disease in patients with diabetes is the misconception that they have an untreatable occlusive lesion in the microcirculation.[9] Many diabetic foot problems have been ascribed to “small-vessel disease,” a common misconception that such an occlusive lesion exists at the arteriolar level. This idea originated from a retrospective histologic study demonstrating the presence of periodic-acid-Schiff (PAS)-positive material occluding the arterioles in amputated limb specimens from diabetic patients.[12] However, subsequent prospective staining and arterial casting studies[13,14] and physiological studies[15] have demonstrated the absence of an arteriolar occlusive lesion. Dispelling the notion of “small-vessel disease” is fundamental to the principles of limb salvage in patients with diabetes, since arterial reconstruction is almost always possible in these patients. Nonocclusive capillary basement thickening may be found in the diabetic microcirculation. However, this does not lead to narrowing of the capillary lumen, and arteriolar blood flow may be normal or even increased despite these changes.[16] Basement membrane thickening theoretically impairs leukocyte migration and the hyperemic response following injury, and thus may increase the susceptibility of the diabetic foot to infection.[17,18] A functional alteration also occurs, in that nonenzymatic glycosylation reduces the charge on the basement membrane. This leads to increases in vascular permeability which may account for transudation of albumin in the kidney, an expanded mesangium, and albuminuria.[19] Similar increases in vascular permeability occur in the eye and probably contribute to macular exudate formation and retinopathy. In the diabetic foot, studies of skin microvascular flow have demonstrated a reduced maximal hyperemic response to heat, which further suggests a functional microvascular impairment and inability to achieve maximal blood flow following injury. Diabetes also affects the axon reflex. Normally, nociceptive C fiber stimulation (by injury) results in both orthodromic
INTRODUCTION Diabetes mellitus is found in as many as 13 million people nationally, or 5.2% of the U.S. population, and more than 650,000 new cases are diagnosed annually.[1] Lower extremity arterial disease is more common among patients with diabetes. The presence of diabetes is associated with a two- to threefold excess risk of intermittent claudication,[2] and the Framingham Study of over 5000 subjects demonstrated that atherosclerotic coronary and peripheral arterial disease is accelerated in diabetes, independent of other atherogenic risk factors.[3] Several other large epidemiological studies have confirmed the role of diabetes in vascular disease. The risk of stroke is at least 2.5-fold higher in patients with diabetes,[4 – 6] and diabetes is strongly associated with atherosclerosis of the extracranial internal carotid artery, thereby imparting an additional risk of stroke.[7]
PATHOPHYSIOLOGY OF VASCULAR DISEASE IN DIABETES MELLITUS Two types of vascular disease are seen in patients with diabetes.[8 – 11] The first is a nonocclusive microcirculatory dysfunction involving the capillaries and arterioles of the kidneys, retina, and peripheral nerves. This microvascular abnormality is relatively unique to diabetes and most likely contributes to the eye (retinopathy), kidney (nephropathy), and nerve (neuropathy) complications of diabetes. The second type of diabetic vascular disease is a macroangiopathy. Morphologically and functionally, this is similar in both diabetic and nondiabetic patients and is characterized by atherosclerotic lesions of the coronary and peripheral arterial circulation. Several biochemical derangements exist in the presence of hyperglycemia and diabetes, and these mechanisms work synergistically to cause the unique vascular abnormalities of diabetes. These produce functional and structural abnormal-
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conduction to the spinal cord and antidromic conduction to adjacent C fibers. This causes the secretion of active peptides, such as substance P, which directly and indirectly (through mast cell release of histamine) cause vasodilation and increased permeability (Fig. 40-1). This neurogenic vasodilatory response is impaired in diabetes, further reducing the hyperemic response when it is most needed, i.e., under conditions of injury and inflammation.[20] The normal endothelium plays an important role in blood vessel wall function and homeostasis by synthesizing and releasing substances, such as prostacyclin, endothelin, and prostaglandins, which modulate vasomotor tone and prevent thrombosis.[21] In addition, arterial vasodilation is at least partially dependent on an intact endothelium and its release of endothelial-derived nitric oxide (EDNO), which causes smooth muscle cell relaxation in response to acetylcholine.[22,23] Endothelial function is abnormal in animal models of diabetes mellitus,[24 – 26] and endothelium-dependent vasodilation is impaired in patients with both insulin-dependent and non – insulin-dependent diabetes mellitus.[27,28] Both oxygen-derived free radicals and advanced glycosylation end products (AGEs) have also been implicated in the pathogenesis of diabetic microvascular complications.[29,30] Increased levels of superoxide anions and other oxygenderived free radicals directly impair EDNO-mediated vasodilatation, and in animal models, administration of superoxide dismutase and other free radical scavengers normalizes EDNO-dependent relaxation in diabetic arteries.[31] In addition, administration of vitamin C, a potent free radical scavenger, restores and improves endotheliumdependent vasodilation, but not endothelium-independent responses, in patients with both insulin-dependent and non – insulin-dependent diabetes mellitus.[32] AGEs are formed from a reversible reaction between glucose and protein to form Schiff bases, which then rearrange to form stable Amadori-type early glycosylation products. Some of these reversible early glycosylation products may undergo complex rearrangements to form irreversible AGEs. In diabetic animal models, AGEs impair the actions of EDNO and cause an impaired endothelium-
dependent response, which is ameliorated by administration of an AGE inhibitor.[33] AGEs may also contribute to the increased vascular permeability of diabetes. Disulfide crosslinkages in collagen and scleral proteins are displaced by these glycosylation products, accounting for the diminished charge in the capillary basement membrane, and blockade of a specific receptor for AGE reverses diabetes-mediated vascular hyperpermeability.[34] Other metabolic abnormalities may also contribute to diabetic vascular disease. Increased levels of vasoconstrictor prostanoids, notably thromboxane (TX) A2 and prostaglandin (PG) H2, have been isolated from segments of diabetic rat aortic tissue, and impaired relaxation to acetylcholine in these segments is restored by treatment with cyclooxygenase inhibitors.[35,36] In humans, however, treatment with aspirin (a cyclooxygenase inhibitor) appears to have little effect on either normal or abnormal endothelium-dependent responses, suggesting that the role of vasoconstrictor prostanoids is less clear.[27,28,37] As noted previously, macrovascular disease is also more common in patients with diabetes. Unlike microvascular disease, which is unique to diabetes and its metabolic alterations, the cause of lower extremity ischemia is similar in both diabetic and nondiabetic patients and is due to accelerated atherosclerosis. A variety of mechanisms have been proposed as the cause of this accelerated atherosclerosis in diabetes.[38,39] The roles of endothelial dysfunction, advanced glycosylation end products, oxygen-derived free radicals, and vasoactive prostanoids and microvascular disease have already been discussed; it is likely that these also contribute to the pathogenesis of macrovascular atherosclerotic disease. Platelet abnormalities are also seen in diabetes and include increased thromboxane release, increased aggregation, and increased interaction with lipoproteins, which may infiltrate the endothelial wall.[40] Elevated fibrinogen levels are also more common among diabetic patients and have been associated with a higher incidence of stroke and cardiovascular disease.[41] As with microvascular disease, it is likely that all of these mechanisms work together in the pathogenesis of macroangiopathy in diabetes.
Figure 40-1. Graphic illustration of the axon reflex (neurogenic inflammatory response). Following injury, antidromic conduction to other axon branches results in peptide secretion (which appears to be mediated by acetylcholine) and vasodilatation. CGRP ¼ C-reactive protein.
Chapter 40. Diabetes and Peripheral Vascular Disease
LOWER EXTREMITY ARTERIAL DISEASE AND DIABETES Problems of the diabetic foot are the most common cause for hospitalization in diabetic patients, with an annual health care cost of over $1 billion.[42] Diabetes is a contributing factor in half of all lower extremity amputations in the United States, and the relative risk for amputation is 40 times greater in people with diabetes.[43] Diabetic foot ulceration will affect 15% of all diabetic individuals during their lifetime and is clearly a significant risk factor in the pathway to limb loss.[44] The principal pathogenetic mechanisms in diabetic foot disease are neuropathy, infection, and ischemia; acting together, they contribute to the sequence of tissue necrosis, ulceration, and gangrene.
Neuropathy Peripheral neuropathy is a common complication of diabetes, afflicting as many as 50 –60% of all patients, and is present in over 80% of diabetic patients with foot lesions.[45 – 47] Broadly classified as focal and diffuse neuropathies, the latter is more common and includes the autonomic and chronic sensorimotor polyneuropathies, both of which contribute to foot ulceration. Sensorimotor neuropathy initially involves the distal lower extremities, progresses centrally, and is usually symmetrical. Sensory nerve fiber involvement leads to loss of the protective sensation of pain, whereas motor fiber destruction results in small muscle atrophy in the foot. Consequently, the metatarsals are flexed, with metatarsal head prominence and “clawing” of the toes. (Fig. 40-2) This leads to abnormal pressure points on the plantar bony prominences without protective sensation, with subsequent high foot pressures, erosion, and ulceration. Meanwhile, autonomic neuropathy in the foot causes loss of sympathetic tone, which results in
Figure 40-2. ulceration.
603
increased arteriovenous shunting and inefficient nutrient flow. Autonomic denervation of sweat and oil glands leads to cracking of dry skin, which further predisposes the diabetic foot to skin breakdown and ulceration.[48] The etiology of diabetic neuropathy is unknown and most likely multifactorial. A combination of metabolic and microvascular defects has been proposed, including impaired nerve myoinositol uptake secondary to increased aldose reductase activity, glycosylated neural proteins, and hypoxia.[49 – 51] In addition, recent clinical studies from the authors’ laboratory have focused on the role of nitric oxide, endothelial-dependent vasodilation, and the altered expression of endothelial nitric oxide synthetase activity in diabetic neuropathic patients with and without lower extremity arterial insufficiency.[52,53] Taken together, it appears that microvascular endothelial dysfunction plays a significant role in the pathogenesis of diabetic neuropathy and that at least part of this is secondary to the metabolic derangements of diabetes.
Infection Prompt control of infection assumes first priority in the management of any diabetic foot problem. The spectrum of infection ranges from superficial ulceration in a neuropathic foot to extensive gangrene with fulminant sepsis. Recognizing that the former may rapidly progress to a potentially fatal infection underscores the importance of a thorough evaluation for infection in these patients. Potential sources of diabetic foot infection include a simple puncture wound or ulcer, the nail plate, and the interdigital web space. Untreated cellulitis may lead to bacterial spread along deeper tissue planes, including tendon sheaths, plantar fascia, and eventual destruction of the interosseous fascia. Edema in the foot is common with untreated infection; this further elevates compartmental pressures and impairs capillary blood flow and recovery.[54]
Multiple functional and anatomic abnormalities result in the biologically compromised diabetic foot, which is prone to
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Classical signs of infection may not always be present in the infected diabetic foot due to the consequences of neuropathy, alterations in the foot microcirculation, and leukocyte abnormalities. Fever, chills, and leukocytosis may be absent in up to two-thirds of diabetic patients with extensive foot infections, and hyperglycemia is often the sole presenting sign.[55] A lack of sensation in the foot and an absence of typical signs of infection often leads to delayed recognition of the problem by both patient and physician. Therefore, a complete examination of the infected areas is mandatory, and the wound should be thoroughly inspected, including unroofing of all encrusted areas, to determine the extent of involvement. Cultures should be obtained from the base or depths of the wound after debridement so that appropriate antibiotic treatment may ensue. Osteomyelitis is common in diabetic foot ulceration and may be demonstrated by bone biopsies in almost 70% of benign-appearing ulcers.[56] Radiographic evaluation for osteomyelitis may include plain radiographs, a three-phase bone scan, labeled leukocyte scans, computed tomography (CT) scans, and magnetic resonance imaging. Indiscriminate use of these tests is both costly and, in the authors’ experience, often unnecessary. A more cost-effective approach involves the use of a sterile probe to detect bone in an open ulcer.[57] With a positive predictive value of nearly 90%, osteomyelitis should be presumed if bone is palpated on probing, thus rendering other specialized and expensive radiographic tests unnecessary. The course of treatment of the infected diabetic foot depends on its severity. Superficial infections with no evidence of deep involvement may be treated at home with a broad spectrum oral antibiotic (pending culture results) and non–weight bearing of the involved extremity, provided there is no systemic toxicity and the patient is compliant. Unfortunately, a more common presentation is the patient with ulceration or gangrene and a deep infection involving tendon or bone. These patients require prompt hospitalization, complete non – weight bearing, correction of systemic abnormalities, and broad-spectrum intravenous antibiotics (which may be narrowed later according to the culture results). Incisions along the entire infected tract and drainage of all infected tissue planes and abscesses are mandatory. Drains and small stab incisions do not provide dependent drainage and are not used. Dressings should consist of gauze sponges moistened with normal saline or 0.25% povidoneiodine solution; full-strength astringents, hot compresses, and whirlpools lead to more harm than good.
Ischemia Ischemia is a fundamental consideration for the vascular surgeon faced with the diabetic foot. Unless recognized and corrected, limb salvage efforts will fail even if infection and neuropathy have been appropriately treated. As noted earlier, there is no evidence for an occlusive lesion at the arteriolar level (“small-vessel disease”) in patients with diabetes. However, diabetic patients are more likely to have atherosclerotic disease affecting the infrageniculate arteries, with sparing of the foot arteries, a finding that allows for successful arterial reconstruction to these distal
vessels.[58] Conversely, the superficial femoral or popliteal artery is less likely to be affected by the occlusive process, allowing these vessels to serve as the origin of arterial bypass grafts. Because the foot vessels are often patent in the diabetic patient, and because of the success of bypass grafting to these vessels, an appropriate evaluation for ischemia is essential in diabetic patients. The most important observation is the presence or absence of a palpable foot pulse; in simplest terms, if the foot pulses are not palpable, it can be assumed that occlusive disease is present.[59] Once active infection in the foot has been controlled, the decision to perform arteriography and perform arterial reconstruction should not be delayed, as this may lead to loss of opportunity to salvage the foot. Noninvasive arterial tests have several limitations in the presence of diabetes. Medial arterial calcinosis occurs frequently in diabetic patients. Although it is associated with an increased cardiovascular mortality, it is not part of the occlusive process and is not associated with the development of peripheral vascular disease. Its presence can result in noncompressible arteries with artifactually high segmental systolic pressures and ankle-brachial indices. Lower levels of calcification in the toe vessels supports the use of toe systolic pressures as a more reliable indicator of arterial flow to the foot.[60] The use of toe pressures is often limited by the proximity of the foot ulcer to the cuff site, but it is still a valuable addition to the evaluation of foot ischemia in the diabetic patient. Segmental Doppler waveforms and pulsed volume recordings are unaffected by medial calcification. However, evaluation of these waveforms is primarily qualitative and not quantitative. In addition, the quality of the waveforms is affected by peripheral edema, and the presence of ulceration precludes accurate cuff placement. Regional transcutaneous oximetry (TcPO2) measurements are also unaffected by medial calcinosis, and recent studies have noted its reliability in predicting healing of ulcers and amputation levels.[61] Its use is limited, however, by a lack of equipment standardization, user variability, and a large “gray area” of values. In addition, TcPO2 measurements are higher in diabetic patients with foot ulcers when compared to the nondiabetic population, which further limits the ability of this test to predict ischemia.[62] The limitations of noninvasive testing emphasize the importance of a thorough bedside evaluation. The absence of a palpable foot pulse strongly suggests ischemia, and arteriography is recommended so that prompt arterial reconstruction may be performed. Because the foot vessels are often spared by the atherosclerotic occlusive process, even when the tibial arteries are occluded, it is essential that arteriograms not be terminated at the midtibial level. The complete infrapopliteal circulation should be incorporated, including the foot vessels, and both anteroposterior and lateral foot views should be included. Concern for contrast-induced renal failure should not mitigate against a high-quality angiogram of the entire lower extremity circulation. The incidence of contrast nephropathy is not higher in the diabetic patient without preexisting renal disease, even with the use of ionic contrast.[63 – 66] The more costly nonionic agents should be reserved for the diabetic patient with compromised renal
Chapter 40. Diabetes and Peripheral Vascular Disease
function. Even in this group, the concern for contrast nephropathy should not delay arteriography, as it seldom requires dialysis for treatment. Microcirculatory and endothelial dysfunction combined with loss of the neurogenic inflammatory response predisposes the diabetic foot to ulceration even with moderate ischemia. In this milieu, maximal circulation is required to heal an ulcer, and correction of even a moderate degree of ischemia will significantly facilitate healing. Therefore, the main principle of arterial reconstruction in the diabetic foot is to obtain maximal perfusion to the foot and to restore normal arterial pressure to the target area. Proximal bypass to the popliteal or tibio-peroneal arteries may restore foot pulses. More often, however, because of the pattern of occlusive disease in the diabetic patient, bypass grafting to the popliteal or even tibial arteries cannot accomplish this goal, due to more distal obstruction. Similarly, although excellent results have been reported with peroneal artery bypass,[67] the peroneal artery is not in continuity with the foot vessels and may not achieve maximal flow, especially to the forefoot, to achieve healing. Autogenous vein grafting to the dorsalis pedis artery represents a technical advance that provides durable and effective limb salvage.[68] The principal indication for the pedal graft is when there is no other vessel that has continuity with the foot, particularly in cases with tissue loss. Dorsalis pedis bypass is unnecessary when a more proximal bypass will restore foot pulses and should not be done if there is an inadequate length of autogenous vein. In addition, if the dorsum of the foot is extensively infected
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and the peroneal artery is of good quality on the preoperative arteriogram, preferential choice should be given to peroneal artery bypass. The distal location of the dorsalis pedis artery theoretically necessitates a long venous conduit, which may not be available. However, by using the popliteal or distal superficial femoral artery as an inflow site, a shorter length of vein may be used, with excellent long-term patency.[69] This is particularly true in the diabetic patient, again due to the pattern of atherosclerotic disease. In the authors’ institutional experience of 384 pedal bypasses over a 7-year period, 60% of grafts utilized the more distal inflow site, usually the popliteal artery.[70] This avoids dissection in the groin and upper thigh, a common location for wound complications. In addition, the shorter length of saphenous vein obviates the need for foot extension of the vein harvest incision, which is parallel to the one required to expose the dorsalis pedis artery; this avoids the resultant skin bridge, which may occasionally become ischemic from undue tension (Fig. 40-3). The vein graft to the dorsalis pedis artery can be prepared as an in situ, reversed, or nonreversed vein graft, without any significant difference in outcome.[71] The in situ technique minimizes size mismatch, eliminates the need to completely mobilize the vein, and may prevent twisting or kinking of the graft. Although the valves may be lysed blindly, we prefer to cut the valves under direct vision with an angioscope using a flexible valvulotome. This allows for concomitant angioscopic assessment of the vein to detect any intraluminal abnormalities.[72] Other technical details include the use of a longitudinal rather than transverse incision in dissecting the
Figure 40-3. Popliteal to dorsalis pedis bypass with translocated nonreversed saphenous vein. Note that the shorter bypass avoids a second foot incision and resultant skin bridge. (From Ref. [70], with permission.)
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dorsalis pedis artery, so that more proximal and distal exposure may be obtained. If the saphenous vein is exposed onto the foot and a skin bridge is created, tunneling of the vein graft should not be made through the skin bridge. Foot and distal leg wounds should be closed with fine plastic surgical technique and not skin staples. Active infection in the foot is not a contraindication to dorsalis pedis bypass, as long as the infectious process is controlled. At the authors’ institution, the results of 56 vein bypasses to the dorsal pedal artery in patients with ischemic foot lesions complicated by infection were recently reviewed.[73] This included 15 patients with severe gangrene, osteomyelitis, and/or deep space abscess. The average duration between admission and bypass was 10 days. Although there was a 12% wound infection rate, the primary graft patency was 92% at 36 months’ follow-up. This aggressive approach to revascularization in the ischemic and infected foot resulted in a limb salvage rate of 98% at the end of 3 years. Because of the presence of medial arterial calcification in patients with diabetes, severe calcification of the outflow artery may be encountered. This should not preclude attempts at arterial reconstruction. A recent series from the authors’ institution reported the results of bypass grafting to severely calcified, unclampable outflow arteries.[74] Over a 6-year period, 101 procedures were performed, including 27 bypasses to the dorsalis pedis artery. At 2-year follow-up, the primary patency, secondary patency, and foot salvage rates were 66, 69, and 77%, respectively, which were not significantly different from procedures performed on patients without severe arterial calcification.
Figure 40-4. permission.)
The authors recently reported the experience with dorsalis pedis arterial bypass in 367 patients over an 8-year period, with a perioperative mortality rate of 1.8%.[70] Tissue loss was an indication for surgery in almost 85% of patients. The actuarial primary and secondary patency and limb salvage rates were 68, 82, and 87%, respectively, at 5-years follow-up (Figs. 40-4 and 40-5). The preoperative digital subtraction arteriogram demonstrated the dorsalis pedis artery in 93% of extremities. In the remaining cases, in which no artery was seen but an audible Doppler signal was present, arterial bypass was successful in 57%, emphasizing that blind exploration is reasonable, especially when amputation is the only other option. Following successful revascularization, secondary procedures may be performed for both limb and foot salvage. Chronic ulcerations may be treated by ulcer excision, arthroplasty, or hemiphalangectomy. In the patient with extensive tissue loss, both local flaps and free flaps may be used. Due to the architecture of the diabetic foot, underlying bony structural abnormalities are often the cause of ulceration and may be corrected by metatarsal head resection or osteotomy. Flexible hammer toe abnormalities with ulceration may be treated by ulcer debridement and flexor tenotomy. Heel ulcers may be treated by partial calcanectomy and local (e.g., flexor tendon) or even free flap coverage. Extensive gangrene of individual toes or the forefoot is best treated by individual toe or transmetatarsal amputation. This aggressive and systematic approach to diabetic foot disease has resulted in improved limb salvage among
Cumulative primary and secondary patency rates of 384 vein grafts to the dorsalis pedis artery. (From Ref. [70], with
Chapter 40. Diabetes and Peripheral Vascular Disease
Figure 40-5. permission.)
607
Cumulative limb salvage and patient survival rates for 384 vein grafts to the dorsalis pedis artery. (From Ref. [70], with
patients with diabetes. At the authors’ institution, there has been a significant reduction in every category of lower limb amputation since 1984 [75] (Fig. 40-6). Concomitant with this fall has been an increase in the number of patients undergoing arterial reconstruction and
a greater application of the dorsalis pedis bypass graft. An understanding of the pathophysiology of the micro- and macrocirculation in diabetes mellitus, combined with an aggressive and orderly treatment plan, will lead to further improvements in foot care and limb salvage in these
Figure 40-6. Since 1984, there has been a decrease in every category of amputation, with a greater application of the dorsalis pedis bypass graft. TMA ¼ transmetatarsal amputation; BKA ¼ Below knee amputation; AKA ¼ Above knee amputation. (From Ref. [75], with permission.)
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patients. Furthermore, understanding the complex pathophysiology of diabetic micro- and macrovascular disease
is critical in reducing the overall morbidity and mortality of diabetes in general.
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63. D’Elia, J.A.; Gleason, R.E.; Alday, M.; et al. Nephrotoxicity from Angiographic Contrast Material: A Prospective Study. Am. J. Med. 1982, 72, 719– 725. 64. Mason, R.A.; Arbeit, L.A.; Giron, F. Renal Dysfunction After Arteriography. J. Am. Med. Assoc. 1985, 253, 1001–1004. 65. Parfrey, P.S.; Griffiths, S.M.; Barrett, B.J.; et al. Contrast Material-Induced Renal Failure in Patients with Diabetes Mellitus, Renal Insufficiency, or Both. A Prospective Controlled Study. N. Engl. J. Med. 1989, 321, 395– 397. 66. Schwab, S.J.; Hlatky, M.A.; Pieper, K.S.; et al. Contrast Nephrotoxicity: A Randomized Controlled Trial of a Nonionic and Ionic Contrast Agent. N. Engl. J. Med. 1989, 320, 149– 153. 67. Plecha, E.J.; Seabrook, G.R.; Bandyk, D.F.; et al. Determinants of Successful Peroneal Artery Bypass. J. Vasc. Surg. 1993, 17, 97–106. 68. Pomposelli, F.B., Jr.; Jepsen, S.J.; Gibbons, G.W.; et al. Efficacy of the Dorsal Pedis Bypass for Limb Salvage in Diabetic Patients: Short-Term Observations. J. Vasc. Surg. 1990, 11, 745– 752. 69. Veith, F.J.; Gupta, S.K.; Samson, R.H.; et al. Superficial Femoral and Popliteal Arteries as Inflow Sites for Distal Bypasses. Surgery 1981, 90, 980– 990.
70. Pomposelli, F.B., Jr.; Marcaccio, E.J.; Gibbons, G.W.; et al. Dorsalis Pedis Arterial Bypass: Durable Limb Salvage for Foot Ischemia in Patients with Diabetes Mellitus. J. Vasc. Surg. 1995, 21, 375– 384. 71. Pomposelli, F.B., Jr.; Jepsen, S.J.; Gibbons, G.W.; et al. A Flexible Approach to Infrapopliteal Vein Grafts in Patients with Diabetes Mellitus. Arch. Surg. 1991, 126, 724– 729. 72. Akbari, C.M.; LoGerfo, F.W. Saphenous Vein Bypass to Pedal Arteries in Diabetic Patients. In Techniques in Vascular and Endovascular Surgery; Yao, J.S.T., Pearce, W.H., Eds.; Appleton and Lange: Norwalk, CT, 1998; 227– 232. 73. Tannenbaum, G.A.; Pomposelli, F.B., Jr.; Marcaccio, E.J.; et al. Safety of Vein Bypass Grafting to the Dorsal Pedal Artery in Diabetic Patients with Foot Infections. J. Vasc. Surg. 1992, 15, 982– 990. 74. Misare, B.D.; Pomposelli, F.B., Jr.; Gibbons, G.W.; et al. Infrapopliteal Bypasses to Severely Calcified Outflow Arteries: Two Year Results. J. Vasc. Surg. 1996, 24, 6 – 16. 75. LoGerfo, F.W.; Gibbons, G.W.; Pomposelli, F.B., Jr.; et al. Trends in the Care of the Diabetic Foot: Expanded Role of Arterial Reconstruction. Arch. Surg. 1992, 127, 617– 621.
CHAPTER 41
Biologic and Synthetic Prosthetic Materials for Vascular Conduits William M. Abbott Thomas F. Rehring A prosthesis is defined as an artificial device to replace a missing part of the body. For the purposes of this chapter the definition of prosthesis will be limited to manmade or manaltered materials used for the repair or replacement of diseased arteries. The quest for the ideal arterial prosthesis continues. Although the currently available prostheses are functional, for many applications the results are imperfect. Nevertheless, they are of paramount importance to the field of vascular surgery and their availability has allowed the field to progress to its prominent state of technical achievement seen today. Modern vascular grafting materials are generally associated with good to excellent results in large-diameter repairs such as aortoiliac artery bypass or replacement. In smaller vessel applications, such as the infrainguinal or coronary arteries, the results are much less satisfactory. Furthermore, prostheses continue to be chronically plagued by problems of thrombosis, anastomotic aneurysm, neointimal hyperplasia, structural deterioration, and infection. In this chapter we will examine the theory behind vascular grafting, the currently available grafting materials and some future considerations. Both the assets and the problems associated with each will be reviewed. The ideal prosthesis should mimic to the greatest extent possible the natural material that it is meant to replace. In this specific instance, it would replicate those of a normal artery. Normal arteries are of the large-elastic, medium-muscular, or small type. The differences are qualitatively governed by the relative amounts of elastin and smooth muscle in each. In this chapter all types will be considered as “artery” generically. A normal artery possesses three anatomic tunics or layers, each of which makes an important contribution to the overall function of the artery. If a prosthetic graft possessed similar physical and biologic properties, the results would be excellent. Unfortunately, that ideal has yet to be realized. The inner or intimal layer of the arterial wall contributes a fundamental thromboresistance within the vascular tree. The
endothelial monolayer of the intima produces both membrane-associated and secreted antithrombotic factors. It also contributes vasoreactive mediators that modify flow distribution through vasoconstriction and vasorelaxation of the smooth muscle of the media. The adventitial layer possesses the majority of the tensile strength of the artery. All three layers thus contribute to both long-term patency and freedom from wall degeneration and aneurysm formation. In addition, the overall vital character of the artery contributes to its general resistance to infection.
GRAFT THROMBOREACTIVITY Many variables contribute to the overall thromboreactivity, the degree and duration of which will govern whether the graft remains patent or undergoes thrombosis and occlusion. Variables inherent to the host include blood flow, blood viscosity, and blood coagulability. As they do not strictly relate to the prosthetic material, they will not be considered further. Thromboreactive variables intrinsic to the graft include its chemical composition, electrochemical charge, surface topography, compliance, and porosity. Each of these parameters contributes separately to the aggregate level of graft thromboreactivity. Knowledge of these can then be used in a predictive nature to determine the outcome of any particular prosthesis. In general, graft thromboses occur over four different time periods and the causes are different in each. Thrombosis immediately following graft placement is generally due to a technical mishap rendered at the time of implantation. As such, thromboreactivity plays a secondary role in these events. In the early-intermediate time frame (days to months), graft thrombogenicity has its greatest contribution to graft occlusion. In the more remote intervals, failures are usually graft wall – related, usually in the form of neointimal
Hobson/Wilson/Veith: Vascular Surgery: Principles and Practice, Third Edition, Revised and Expanded DOI: 10.1081/0819-9-120024924 Copyright q 2004 by Marcel Dekker, Inc.
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hyperplasia. Only very late graft failures (usually 2 years or more after implantation) can be categorized as secondary to disease progression. For the sake of completeness, other desirable graft characteristics will be mentioned here. In general, however, these do not contribute to the overall success or failure of the arterial reconstruction. However, they are important to the implanting surgeon. These would include excellent handling characteristics to allow ease in placement, graft durability, longitudinal suture retention strength, and ease of suture penetration. Finally, general widespread availability, sterility, ease of storage, and reasonable cost are substantial considerations in the overall schema. It must be repeated, however, that no single graft material fulfills all of these criteria.
BIOLOGICAL GRAFTS The autogenous saphenous vein may be considered a biological graft, but it is excluded here by virtue of our original definition. Although modified by harvest and implantation, it nevertheless possesses a privileged position as a graft. For medium- and small-caliber arterial needs, the saphenous vein has generally been regarded as the “gold standard.” That concept needs to be reconsidered, however, as the results for internal mammary artery grafting for coronary artery bypass have been significantly better than that with saphenous vein. It should be unequivocally stated that artery is the gold standard for artery. Excellent recent results with radial artery transposed to the coronary position bear this out.[1,2] Unfortunately, lack of availability limits its applicability. Furthermore, the saphenous vein frequently is of inadequate quality, caliber, or length for use as a bypass graft. It is often diseased and occasionally surgically absent. Hence, alternative materials are essential in the performance of vascular surgery.
ARTERIAL ALLOGRAFTS Arterial allografts (previously termed homografts) have been used intermittently since the early days of arterial reconstruction. The first description of their use in humans was by German surgeons during World War I following Hopfner’s first successful canine allograft implant.[3] Fresh allografts inserted from that time into the late 1940s generally were met with rapid rejection and degeneration. Allograft preservation with formalin, alcohol, glycerine, ethylene dioxide, freeze-drying, or high-voltage cathode ray irradiation produced generally unsatisfactory, although highly variable results.[4] Failure was evidenced by mural degeneration, aneurysm formation, hemorrhage, and death. Yet the biologic characteristics of artery being so highly desirable, this is an area that is worthy of reexamination. This is in light of the generally poor results of small-caliber synthetic bypass grafts, the increasing numbers of infected or redo operations, and limited availability of autogenous conduit. It remains possible that well-handled and well-
preserved arterial grafts may have a role in the modern era. Recent reports from Europe suggest that arterial allografts are useful in the inline repair of aortic graft infection.[5,6] The largest of these trials treated 44 patients with prosthetic graft infections with resection of the infected prosthetic and placement of fresh or cryopreserved arterial allografts (73% aortobifemoral).[7] A reasonable outcome was obtained in this difficult patient population with a 14% operative mortality and 56% actuarial patency rate at 12 months follow-up. Cryopreserved arterial allografts have also been utilized in infrageniculate arterial revascularization of ischemic limbs. Recent European results in 17 patients with limb-threatening ischemia demonstrated a 51% primary patency at 17-month follow-up.[8] Castier et al. obtained a 39% primary patency rate in 35 grafts placed for limb salvage.[9] Previously, Gournier et al. described the placement of 20 cryopreserved arterial allografts for limb threat with a 42% primary patency at 2 years.[10] While these results approximate the results obtained with the below-knee synthetic reconstructions, they have the advantage of native tissue, suggesting a role in the treatment of infected grafts. Other reports continue to raise concern regarding graft degeneration.[11] Once again, longterm follow-up is necessary to determine the durability of these grafts.
VENOUS ALLOGRAFTS The first demonstration of a graft utilized in any position in the arterial circulation was that of a venous allograft. This was performed by Alexis Carrel, who implanted a segment of canine jugular vein into the thoracic aorta of second dog.[12] Venous allografts have been studied more thoroughly than arterial allografts but have had similar results. Satisfactory retention of viability secondary to modern techniques of cryopreservation (attention to cooling curves, novel cryoprotectants) has recently renewed interest in cadaveric venous allografts. Early experiences by Walker and colleagues demonstrated a 28% one-year primary patency in 39 infrageniculate bypasses performed with cryopreserved vein performed largely for limb threat.[13] In a separate study, Harris et al. delineated their results in implanting 25 cryopreserved allograft saphenous vein distal bypass grafts with a 36% secondary patency at one year.[14] More recently, Leseche et al. described 25 patients with cryopreserved vein allografts to the tibial or foot vessels with a 52% secondary patency at one year.[15] Finally, a recent series has suggested that a program of aggressive anticoagulation may improve outcome in these grafts. A preliminary study by Buckley demonstrated a 92% primary patency at 18 months in venous allografts placed in the infrapopliteal position in 22 extremities for limb salvage when perioperative aspirin, dextran, and heparin were administered followed by conservative long-term anticoagulation.[16] Humoral and cellular responses develop to allografts. In the presence of modern immunosuppression, major vessels of transplanted organs are relatively spared from the degenerative results seen previously in allografts.[17] These observations lead several authorities to hypothesize that
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systemic immunosuppression would limit the rejection and thrombosis seen in venous allografts. Support of this hypothesis from animal studies led to several small human trials. Carpenter and Tomaszewski performed a prospective randomized trial of low-dose azathioprine in 40 patients undergoing pedal or crural bypass.[18] No benefit was noted; indeed the one-year primary patency rate was 13% with a mean follow-up of 15.7 months. A conflicting, but rather poorly controlled trial demonstrated that a combination of low-dose cyclosporin A, azathioprine, prednisone, warfarin, aspirin, and oral vasodilators administered to 19 patients receiving a cryopreserved saphenous vein homograft improved patency at one year (16.7% versus 59.4%, mean follow-up 8 months).[19] Some very recent evidence suggests that an immunological privilege may be conferred by cryopreservation, so this idea should not be summarily dismissed at this time.[20] Perhaps the cryopreservation process itself leads to a general proliferative response in the vessel providing results similar to that with synthetic graft materials in the small-caliber application. Currently, however, methods of graft procurement and preservation do not preserve normal endothelial and smooth muscle cell function or eliminate antigenicity. The biologic and economic costs of immune suppression to obtain a successful allograft for an ischemic limb are generally unjustifiable. One exception may be the presence of limbthreatening ischemia in the setting of a graft infection and the absence of autogenous conduit. In this setting, the homograft may serve as a “bridge” to later definitive reconstruction when the infection has cleared.[21]
HUMAN UMBILICAL CORD VEIN ALLOGRAFT Human umbilical vein is a venous allograft but differs from saphenous vein allografts as to its anatomic and embryological origin. Usage of the umbilical vein was introduced in the 1970s and became somewhat popular in the 1980s. The umbilical cord vein, of which there is one, is a long, unbranched conduit, acquired from delivery suites, mechanically or manually stripped of its surrounding tissue, fixed in glutaraldehyde, and encased in a loose mesh of polyester (Dacron). The glutaraldehyde tanning procedure increases tensile strength, masks antigenicity, and sterilizes the tissue. This graft possesses physical, chemical, and mechanical properties that initially seemed superior to that of existing synthetic graft materials. Preliminary studies demonstrated a patency advantage of umbilical vein grafts over polytetrafluoroethylene (PTFE) grafts in a prospective randomized trial of arterial grafts to the below-knee popliteal position.[22] Aalders et al. confirmed this in a prospectively randomized trial of PTFE or umbilical vein for above-knee femoropopliteal bypass in 96 extremities and found that the primary patency of umbilical vein was better than that of PTFE (71.4 vs. 38.7%, respectively) at a median of 76 months follow-up.[23] However, it was somewhat difficult to use due to its size and bulk and was relatively expensive. In addition, it also had an incidence of mural degeneration and aneurysm
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formation as high as 65% over 5 years despite being encased in polyester mesh.[24,25] The largest published retrospective review characterizing this graft detailed its use in 907 lower limb bypasses placed over a 10-year period.[26] Cumulative patency in the popliteal and tibial positions was 53% and 25.7%, respectively. Perioperative graft thromboses occurred in 11% of aboveknee and 22% of crural bypasses. Aneurysm formation occurred in 36% of grafts after 5 years. Although still available, it has dropped out of general favor. Recent attempts to revive this idea with improved glutaraldehyde preservation and an enhanced reinforcing mesh have improved results slightly, but aneurysm formation remains a formidable 17% at up to 6 years follow-up and appears to continue to increase with time.[27]
ARTERIAL AND VENOUS XENOGRAFTS Xenografts are arteries or veins of animal origin. These also have received a great deal of interest over the years, mainly due to their availability. Most of the work on this subject, however, is largely out of date and has received very little attention until recently. Just as in the case of the umbilical cord vein allograft, xenografts have been modified in a number of ways. Moreover, they must be fixed to prevent an aggressive xenogenic immune response that will cause early implant failure and degeneration. The most popular approach of fixation was with some form of chemical digestion to achieve decellularization and removal of foreign animal proteins followed by chemical cross-linking. Although this proved a promising approach for allografts, most evidence suggests that these methods do not effectively blunt the xenogeneic immune response sufficiently to make this approach a viable alternative. Holdsworth et al. placed glutaraldehyde-tanned bovine carotid artery in 55 patients as an above-knee infrainguinal arterial reconstruction.[28] The 5-year cumulative patency was 56%. In another series, Wagner et al. described implantation of 112 glutaraldehyde-fixed bovine carotid artery grafts for infrainguinal reconstruction.[29] Indications for surgery were disabling claudication in 28%, rest pain in 33%, and tissue loss in 39%. Life table primary patencies for all grafts was 48% at 2 years, but rose to 80% if only the above-knee popliteal bypasses were analyzed. Despite these results, no arterial xenografts are currently available for clinical use. Once again, this does not mean that there is no merit in this strategy as an alternative for future investigations. The senior author of this chapter was involved with the development of a very promising arterial xenograft of bovine calf origin which was generated in Switzerland (Solcograft). This graft was decellularized by a complicated chemical reactive step, gently cross-linked using a novel cross-linking agent (adpyl dichloride), enzyme treated, and then recrosslinked using standard glutaraldehyde fixation. Animal results and early clinical results were quite spectacular.[30 – 32] After several years of success, however, the manufacturer seemingly lost control of the chemical process. Aneurysms (which were not a
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problem in the first years of the trial) became quite frequent, and the project was abandoned. Under a clinical investigative protocol, we implanted 24 of these grafts in the mid-1980s. Although the grafts made later in the program did develop aneurysms that prompted discontinuation of the trial, the early results here were as encouraging as they were in Europe. Several patients achieved a 10-year follow-up with patency and perfect appearance on ultrasound and angiography. This information is only provided to show that this approach still has appeal. The investigators have just not been clever (or lucky) enough to find the key to make this approach work consistently and reliably.
SYNTHETIC GRAFTS The development of man-made arterial prostheses is pivotal in the history of vascular surgery. Arterial homografts had limited experimental success, but supply was limited and it was difficult to sterilize and store them. In World Wars I and II, rigid tubes made of gold, paraffined glass, and aluminum or methylmethacrylate were utilized. However, results generally paralleled that of ligation. The modern concept for utilizing porous fabric tubes as arterial conduits is attributed to Voorhees.[33] In 1952, Voorhees was a surgical resident conducting experiments in Blakemore’s laboratory, suspending homograft valve leaflets from silk suture in the right ventricle of the dog. At explantation several months later, he noted a glistening endothelial-like substance coating the silk. This suggested that arterial conduits, made of similar material might be accepted into the circulation. Borrowing a leftover bolt of Vinyon-N cloth, he began implanting handsewn tabular grafts into the abdominal aorta of dogs. Initial success led to the adaptation of a loom utilized for making socks into one capable of making tubular grafts and the subsequent successful implantation of such grafts in 18 patients.[34] This early success lead to the subsequent development of a wide assortment of fabrics. However, a consistently durable prosthetic was not realized until the introduction of knitted Dacron (polyethylene terephthalate) by DeBakey in 1958.[35] Synthetic materials remain the mainstay of graft materials used clinically today. This approach has tremendous advantage as synthetic polymers are uniform and their manufacturing can be highly standardized. They are widely available, can be stored on a shelf, and are reasonably inexpensive. The main problem with all synthetic grafts, however, is the poor long-term patency in the small- and medium-caliber grafts. It is important to understand the fundamental differences between these graft materials in order to gain some rationale in selection and, more importantly, to understand where further development is heading.
POLYESTER GRAFTS Grafts created from polyester (formerly Dacron; the material source has recently become generic) were the first synthetic grafts to achieve widespread utilization. They still maintain
an overwhelming marketshare for graft use in aortoiliac and aortofemoral reconstructions. This synthetic polymer is made into yarn and then fabricated into tubular structures using varied techniques borrowed from the textile industry. Grafts made by both weaving and knitting methods are available. There are a number of variations in filaments and weaving techniques that provide differences in handling characteristics, etc., but are not truly relevant to this discussion. Polyester grafts are generally characterized by their water porosity. Grafts with higher water porosity have better handling characteristics. In addition, the porosity is thought to promote incorporation by surrounding tissue. However, the increase in porosity comes at the obligate cost of an increase in bleeding complications and (at its ultimate extent) may compromise graft integrity. The original woven grafts had a lower water porosity but did not handle well due to their innate stiffness and required heat-sealing to limit fraying at the cut ends of the graft. Currently, however, nearly all polyester grafts are knitted and are coated or impregnated with substances to reduce their implantation porosity to zero. The first of these to be marketed was collagen, but other materials such as albumin and gelatin have been utilized (see below). Collagen remains in the widest use today. In addition to impregnation of the polyester graft, other modifications have been added since their initial introduction. Crimping of the fabric confers flexibility, elasticity, and kink resistance to polyester grafts. Indeed, the clear majority of all polyester grafts currently available espouse this feature. Potential disadvantages of crimping include a decreased inner lumen diameter and increased lumenal fibrin deposition. The addition of a velour finish to the outer, inner, or both sides of polyester grafts is purported to provide improved attachment for fibroblasts to allow better incorporation of the graft. No proven benefit to any velour finish has ever been established, despite their theoretic advantages. Recently, a noncrimped polyester graft with an inner smooth surface of collagen has been introduced for peripheral use. Grafts fashioned of polyester are strong and durable. Nonanastomotic aneurysm or graft degeneration occurs in less than 1% of polyester grafts.[36 – 38] However, in the absence of crimping, they possess no inherent elasticity or compliance. Compliance mismatch at anastomotic sites has been implicated in the development of intimal hyperplasia.[39 – 41] Polyester grafts may have a slightly higher incidence of infection when compared to polytetrafluoroethylene grafts.[42,43] Graft infection, of course, is a problem that all vascular surgeons recognize as a particularly vexing problem (see Chapter 42).
EXPANDED POLYTETRAFLUOROETHYLENE Edwards first introduced PTFE as a vascular prosthesis of Teflon fabric in 1957.[44] In the late 1960s a process for expanding the material was developed, improving many of the characteristics of the material. In the early 1970s, Ben Eiseman at the University of Colorado noted that PTFE was being utilized as insulation around electrical wires in
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computers and began testing it as a replacement portal vein in a porcine model.[45] PTFE, as it is now used, is not a textile, but rather is created by forcible expansion of the solid polymer into a nodular and fibrillar structure. This extrusion confers a porosity greater than that of polyester grafts, but the hydrophobicity of the PTFE limits the excrescence of blood. There are basically two commercial configurations of PTFE utilized in arterial grafts: one has its strength controlled by a chemical processing technique known as sintering (e.g., Impra) and the other has graft strength conferred by an external wrapping of a non-expanded PTFE film (e.g., GoreTex). There is no good study comparing the clinical results of these two PTFE graft materials. Although each manufacturer would have us believe otherwise, there seems to be little difference in performance between the two. Modifications to the original expanded PTFE available today include a graft with thinner wall construction, improved longitudinal extensibility (“stretch”), external support from rings or coils, and lining of the graft with a colloidal graphitecarbon coating. None of the above have consistently demonstrated a significant improvement in overall graft performance. Advantages of current PTFE grafts include strength, minimal chronic graft dilation, and biocompatibility. Furthermore, there is some evidence suggesting a relative resistance to infection over the polyester grafts as noted above.[42,43] Once again, as in polyester grafts, the price of strength of the graft lies in the compliance mismatch between the prosthetic and native artery. Other disadvantages of this material include relative stiffness and the meddlesome proclivity toward needle hole bleeding.
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If the decision to utilize a prosthetic has been made, the surgeon must further determine which material to use. Results comparing the two most clinically relevant graft materials, knitted polyethylene terephthalate and polytetrafluoroethylene, are available. A randomized prospective trial comparing the outcome of PTFE versus Dacron in above-knee femoropopliteal bypass grafts was published in 1997.[51] The data showed that the graft performance was equivalent in both grafts, with a primary patency of 62% for Dacron and 57% for PTFE at 3 years. In the axillofemoral and femorofemoral position, both fabric and PTFE grafts have similar patencies. With the recent data noted above confirming any difference in outcome, it is difficult to choose between polyester and PTFE. Again, these choices should be made on the basis of handling characteristics, surgical preference, and cost.
FUTURE CONCEPTS Development of a better vascular prosthesis is one of the most active and important areas of research in vascular surgery. The majority of research activity involves the development of new and less thrombotic materials for synthetic prostheses. Other work has concentrated on the modification of existing materials with nonthrombotic surfaces. More recently, the addition of vasoreactive proteins to prevent intimal hyperplasia, promote endothelial cell healing, or confer resistance or thrombosis have been studied. Finally, and perhaps most intriguing, is the development of tissue engineering techniques to grow functional arteries in vitro.
CURRENT RECOMMENDATIONS ENDOTHELIAL CELL SEEDING Multiple variables go into the surgeon’s selection of an appropriate prosthesis at the time of implantation. For repair, replacement, or bypass at the aortoiliac level, polyester grafts of woven or knitted configuration with a protein impregnation remain the graft materials of choice. However, the results with all grafts at this location are quite good.[46 – 48] Thus, the surgeon’s selection of grafts for these operations should continue to take into account handling characteristics, surgical preference, and cost. For smaller vessel applications, that is, in anatomic beds distal to the inguinal ligament and smaller arteries, the choices are more difficult. Several general recommendations can be made. Clearly, the more distal the reconstruction, the greater is the need for use of autogenous materials. If saphenous vein is available, it will provide the best overall long-term outcome. However, several authorities suggest the preferential use of synthetic grafts for above-knee bypass reconstructions. In this position, differences in short-term patency are generally small. Furthermore, use of a synthetic allows for a more expeditious operation, smaller incisions, and the preservation of the long saphenous vein for later coronary bypass or a second (and generally more distal) infrainguinal procedure. However, several studies have found that the “reserved” saphenous vein is rarely utilized, casting some doubt on this argument.[49,50]
Seeding an artificial surface with human endothelial cells has great theoretic appeal. Although once thought to be a relatively inert barrier, the endothelium is now well recognized as a multifunctional, selectively permeable interface between the blood and vessel wall. It participates in a wide range of processes through the elaboration of multiple factors including vasoconstrictors, vasodilators, fibrinolytic factors, coagulation factors, growth factors, and surface adhesion molecules. Initial clinical attempts utilized endothelial cells harvested from a short segment of subcutaneous vein and then impregnated into a prosthetic graft. No effect on patency was realized,[52] but some postulated that poor results may have been due to low-density endothelial cell seeding or high detachment rates. Fibronectin, laminin, collagen, and other adhesion-promoting peptides enhance autologous endothelial cell binding to prosthetic grafts.[53] Modern cell culture techniques made possible elective endothelial cell harvest from external jugular or cephalic vein, in vitro cultivation, and subsequent high-density seeding of the prosthesis for later implantation. Early clinical results of in vitro endothelialized femoropopliteal grafts in a randomized trial of 49 patients (76% for claudication) showed improved patency over untreated PTFE.[54] Follow-up of these data, augmented
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with nonrandomized data and published as an extended abstract, demonstrated 81.9% primary patency to the belowknee popliteal artery in endothelialized PTFE grafts.[55] Other studies have demonstrated the usage of genetically modified endothelial cells to improve attachment and replication.[56,57] Logistics and cost presently impede the utilization of this technique and will continue to do so until the results clearly show improvement over current standards.
IMPREGNATED GRAFTS As mentioned before, impregnating the prosthetic graft is not a new idea. Most polyester grafts utilized currently are coated with collagen or gelatin as a mechanical agent to decrease porosity, with added potential benefits of decreased thrombogenicity through decreased platelet and complement activation. An obvious attractive option is to bond a therapeutic material to the lumenal surface of the graft. Grafts have been bonded with anticoagulants,[58,59] thrombolytic agents,[60] or antibiotics[61,62] in order to try to improve results. Others have attempted to manipulate the healing response of grafts with the addition of growth factors as mitogens and chemoattractants for endothelial and smooth muscle cells.[63] Although enticing, none of this work has been shown to confer an advantage in achieving the desired targeted result. A new heparin-bonded PTFE graft is about to enter clinical trials. Preliminary studies supporting this possibility are quite encouraging.
NEW POLYMERS Polymers may be considered in the categories of biodurable or bioresorbable. The most common new biodurable polymers to be utilized for prosthetic grafts are created from polyurethane. The advantage of polyurethane grafts is that they possess mechanical properties approximating that of native artery. These grafts handle quite well, do not fray, have good suture retention strength and have both axial and circumferential compliance similar to that of the natural artery they replace.[64] Structural integrity and durability problems have limited their applicability clinically. Bioresorbable polymers act as a scaffold and allow for a normal healing process to regenerate a “neo-artery.”[65] Tissue engineered vessels based on a bioresorbable framework have been performed in animals.[66] In this study, a vascular graft was derived from biopsy-derived, bovine
smooth muscle and endothelial cells grown on biodegradable polyglycolic acid scaffold under pulsatile stress conditions. These engineered vessels demonstrated rupture strength and suture retention strength similar to native vessels. In addition, they showed contractile responses to vasoconstrictors and have good short term patency when implanted in vivo. Hybrid grafts may incorporate the strengths of several of the above concepts. One such graft was based on a polyurethane prosthesis (to provide arterial compliance), augmented with an artificial basement membrane of collagen and dermatan sulfate (to enhance endothelial adhesion and limit platelet binding) and lined with an autogenous endothelial cell monolayer.[67] Such bioengineering constructs may provide the optimal prosthetic of the future.
PHOTOFIXATION TECHNIQUES The most recent approach to the use of xenografts involves a method of biological graft fixation using light activation of a photoreactive compound. A number of approaches are under investigation for this, and one has resulted in satisfactory results sufficient to warrant a clinical trial in Europe. This is a very intriguing and promising technique. The process uses a photosensitizing agent that causes tissue oxidation and other reactions when radiated with light energy. This strengthens collagen and molecular crosslinks. It also depletes the endothelial smooth muscle cells reducing the antigenicity while not, however, engendering a cellular reaction which is destructive to graft materials. Although promising, these approaches need much more work before it will be known if they are applicable for not.
CONCLUSION In the discussion of the seminal Blakemore and Voorhees study describing their initial trial of Vinyon-N aortic grafts in humans, Dr. Robert R. Linton rose and asked, “. . . one question, namely, how small an artery would it be possible to replace by means of such material?”[34] Now, nearly half a century later, this remains the incisive issue in prosthetic materials for vascular conduits. Current materials perform well in large-caliber positions, but manifest their deficiencies when sewn to small vessels. Future research in this fertile area is likely to lead to improved outcomes in arterial revascularization.
REFERENCES 1. Barner, H.B. Arterial Grafting: Techniques and Conduits. Ann. Thorac. Surg. 1998, 66, S2 –S5, discussion S25– 28. 2. Acar, C.; Ramsheyi, A.; Pagny, J.Y.; Jebara, V.; Barrier, P.; Fabiani, J.N.; Deloche, A.; Guermonprez, J.L.; Carpentier, A. The Radial Artery for Coronary Artery Bypass Grafting:
Clinical and Angiographic Results at Five Years. J. Thorac. Cardiovasc. Surg. 1998, 116, 981– 989. 3. Creech, O.; DeBakey, M.E.; Cooley, D.A.; Self, M.M. Preparation and Use of Freeze-Dried Arterial Homografts. Ann. Surg. 1954, 140, 35–43.
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Callow, A.D. Arterial Homografts. Eur. J. Endovasc. Surg. 1996, 12, 272– 281. Desgranges, P.; Beaujan, F.; Brunet, S.; Cavillon, A.; Qvarfordt, P.; Melliere, D.; Becquemin, J.P. Cryopreserved Arterial Allografts Used for the Treatment of Infected Vascular Grafts. Ann. Vasc. Surg. 1998, 12, 583– 588. Locati, P.; Novali, C.; Socrate, A.M.; Costantini, E.; Morlacchi, E.; Piazzalunga, G.; Costantini, S. The Use of Arterial Allografts in Aortic Graft Infections. A Three Year Experience in Eighteen Patients. J. Cardiovasc. Surg., (Torino) 1998, 39, 735 –741. Chiesa, R.; Astore, D.; Piccolo, G.; Melissano, G.; Jannello, A.; Frigerio, D. et al. Fresh and Cryopreserved Arterial Homografts in the Treatment of Prosthetic Graft Infections: Experience of the Italian Collaborative Vascular Homograft Group. Ann. Vasc. Surg. 1998, 12, 457– 462. Alonso, M.; Segura, R.J.; Prada, C.; Caeiro, S.; Cachaldora, J.A.; Diaz, E.; Lujan, S.; Cal, L.; Vidal, J. Cryopreserved Arterial Homografts: Preliminary Results in Infrageniculate Reconstructions. Ann. Vasc. Surg. 1999, 13, 261– 267. Castier, Y.; Leseche, G.; Palombi, T.; Petit, M.; Cerceau, O. Early Experience with Cryopreserved Arterial Allografts in Below-Knee Revascularization for Limb Salvage. Am. J. Surg. 1999, 177, 197– 202. Gournier, J.P.; Favre, J.P.; Gay, J.L.; Barral, X. Cryopreserved Arterial Allografts for Limb Salvage in the Absence of Suitable Saphenous Vein: Two-Year Results in 20 Cases. Ann. Vasc. Surg. 1995, Suppl., S7– S14. Lehalle, B.; Geschier, C.; Fieve, G.; Stoltz, J.F. Early Rupture and Degeneration of Cryopreserved Arterial Allografts. J. Vasc. Surg. 1997, 25, 751– 752. Carrel, A.; Guthrie, C.C. Uniterminal and Biterminal Venous Transplantations. Surg. Gynecol. Obstet. 1906, 2, 266– 286. Walker, P.J.; Mitchell, R.S.; McFadden, P.M.; James, D.R.; Mehigan, J.T. Early Experience with Cryopreserved Saphenous Vein Allografts as a Conduit for Complex Limb-Salvage Procedures. J. Vasc. Surg. 1993, 18, 561– 568. Harris, R.W.; Schneider, P.A.; Andros, G.; Oblath, R.W.; Salles-Cunha, S.; Dulawa, L. Allograft Vein Bypass: Is It an Acceptable Alternative for Infrapopliteal Revascularization? J. Vasc. Surg. 1993, 18, 553– 559. Leseche, G.; Penna, C.; Bouttier, S.; Joubert, S.; Andreassian, B. Femorodistal Bypass Using Cryopreserved Venous Allografts for Limb Salvage. Ann. Vasc. Surg. 1997, 11, 230–236. Buckley, C.J. Improved Patency of Femoral-Infrapopliteal Cryopreserved Saphenous Vein Allografts Using a Specific Antiplatelet and Anticoagulation Protocol. Abstract American College of Surgeons, South Texas Chapter, San Antonio, TX; 1999. da Gama, A.D.; Sarmento, C.; Vieira, T.; do Carmo, G.X. The Use of Arterial Allografts for Vascular Reconstruction in Patients Receiving Immunosuppression for Organ Transplantation. J. Vasc. Surg. 1994, 20, 271– 278. Carpenter, J.P.; Tomaszewski, J.E. Immunosuppression for Human Saphenous Vein Allograft Bypass Surgery: A Prospective Randomized Trail. J. Vasc. Surg. 1997, 26, 32– 42.
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Posner, M.P.; Makhoul, R.G.; Altman, M.; Kimball, P.; Cohen, N.; Sobel, M.; Dattilo, J.; Lee, H.M. Early Results of Infrageniculate Arterial Reconstruction Using Cryopreserved Homograft Saphenous Conduit (CADVEIN) and Combination Low-Dose Systemic Immunosuppression. J. Am. Coll. Surg. 1996, 183, 208–216. Giglia, J.S., Ollerenshaw, J., Dawson, P., Black, K., Abbott, W.M., A Unique Method of Cryopreservation Inhibits Immune-Mediated Aortic Graft Dilation. Annals of Vascular Surgery, in press. Fujitani, R.M.; Bassiouny, H.S.; Gewertz, B.L.; Glagov, S.; Zarins, C.K. Cryopreserved Saphenous Vein Allogenic Homografts: An Alternative Conduit in Lower Extremity Arterial Reconstruction in Infected Fields. J. Vasc. Surg. 1992, 15, 519– 526. Eickhoff, J.H.; Broome, A.; Ericsson, B.F.; Buchardt Hansen, H.J.; Kordt, K.F.; Mouritzen, C.; Kvernebo, K.; Norgren, L.; Rostad, H.; Trippestad, A. Four Year Results of a Prospective, Randomized Clinical Trail Comparing Polytetrafluoroethylene and Modified Human Umbilical Vein for Blow-Knee Femoropopliteal Bypass. J. Vasc. Surg. 1987, 6, 506– 511. Aalders, G.J.; van Vroonhoven, T.J. Polytetrafluoroethylene Versus Human Umbilical Vein in Above-Knee Femoropopliteal Bypass: Six-Year Results of a Randomized Clinical Trial. J. Vasc. Surg. 1992, 16, 816– 823, (discussion 823–824). Karkow, W.S.; Cranley, J.J.; Cranley, R.D.; Hafner, C.D.; Ruoff, B.A. Extended Study of Aneurysm Formation in Umbilical Vein Grafts. J. Vasc. Surg. 1986, 4, 486– 492. Hasson, J.E.; Newton, W.D.; Waltman, A.C.; Fallon, J.T.; Brewster, D.C.; Darling, R.C.; Abbott, W.M. Mural Degeneration in the Glutaraldehyde-Tanned Umbilical Vein Graft: Incidence and Implications. J. Vasc. Surg. 1986, 4, 243– 250. Dardik, H.; Miller, N.; Dardik, A.; Ibrahim, I.; Sussman, B.; Berry, S.M.; Wolodiger, F.; Kahn, M.; Dardik, I. A Decade of Experience with the Glutaraldehyde-Tanned Human Umbilical Cord Vein Graft for Revascularization of the Lower Limb. J. Vasc. Surg. 1988, 7, 336– 346. Strobel, R.; Boontje, A.H.; Van Den Dungen, J.J. Aneurysm Formation in Modified Human Umbilical Vein Grafts. Eur. J. Vasc. Endovasc. Surg. 1996, 11, 417– 420. Holdsworth, R.J.; Naidu, S.; Gervaz, P.; McCollum, P.T. Glutaraldehyde-Tanned Bovine Carotid Artery Graft for Infrainguinal Vascular Reconstruction: 5-Year Follow-up. Eur. J. Vasc. Endovasc. Surg. 1997, 14, 208– 211. Wagner, W.H.; Levin, P.M.; Treiman, R.L.; Cossman, D.V.; Foran, R.F.; Cohen, J.L. Early Results of Infrainguinal Arterial Reconstruction with a Modified Biological Conduit. Ann. Vasc. Surg. 1992, 6, 325– 333. Guidoin, R.; Domurado, D.; Couture, J.; Dube, S.; Marois, M.; Roy, P.E.; Sigot, M.F.; Martin, L. Chemically Processed Bovine Heterografts of the Second Generation as Arterial Substitutes: A Comparative Evaluation of Three Commercial Prostheses. J. Cardiovasc. Surg. (Torino) 1989, 30, 202– 209. Nemes, A.; Acsady, G.; Fraefel, W.; Lichti, H.; Monos, E.; Oertli, R.; Somogyi, E.; Sotonyi, P. Application of a Vascular Graft Material (Solcograft-P) in Experimental Surgery. Biomaterials 1985, 6, 303– 311.
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32. Schroder, A.; Imig, H.; Peiper, U.; Neidel, J.; Petereit, A. Results of a Bovine Collagen Vascular Graft (Solcograft-P) in Infra-inguinal Positions. Eur. J. Vasc. Surg. 1988, 2, 315– 321. 33. Voorhees, A.B.; Jaretzki, A.; Blakemore, A.H. Use of Tubes Constructed from Vinyon-N Cloth in Bridging Arterial Defects. Ann. Surg. 1952, 135, 332–336. 34. Blakemore, A.H.; Voorhees, A.B. The Use of Tubes Constructed from Vinyon-N Cloth in Bridging Arterial Defects: Experimental and Clinical. Ann. Surg. 1954, 140, 324– 334. 35. DeBakey, M.E.; Cooley, D.E.; Crawford, E.S.; et al. Clinical Application of a New Flexible Knitted Dacron Arterial Substitute. Arch. Surg. 1958, 77, 713– 724. 36. Wilson, S.E.; Krug, R.; Mueller, G.; Wilson, L. Late Disruption of Dacron Aortic Grafts. Ann. Vasc. Surg. 1997, 11, 383–386. 37. Nucho, R.C.; Gryboski, W.A. Aneurysms of a Double Velour Aortic Graft. Arch. Surg. 1984, 119, 1182 –1184. 38. Clagett, G.P.; Salander, J.M.; Eddleman, W.L.; Cabellon, S., Jr.; Youkey, J.R.; Olson, D.W.; Hutton, J.E., Jr.; Rich, N.M. Dilation of Knitted Dacron Aortic Prostheses and Anastomotic False Aneurysms: Etiologic Considerations. Surgery 1983, 93, 9 – 16. 39. Abbott, W.M.; Megerman, J.; Hasson, J.E.; L’Italien, G.; Warnock, D.F. Effect of Compliance Mismatch on Vascular Graft Patency. J. Vasc. Surg. 1987, 5, 376– 382. 40. Ballyk, P.D.; Walsh, C.; Butany, J.; Ojha, M. Compliance Mismatch May Promote Graft-Artery Intimal Hyperplasia by Altering Suture-Line Stresses. J. Biomech. 1998, 31, 229– 237. 41. Wu, M.H.; Shi, Q.; Sauvage, L.R.; Kaplan, S.; Hayashida, N.; Patel, M.D.; Wechezak, A.R.; Walker, M.W. The Direct Effect of Graft Compliance Mismatch per se on Development of Host Arterial Intimal Hyperplasia at the Anastomotic Interface. Ann. Vasc. Surg. 1993, 7, 156– 168. 42. Bandyk, D.F.; Bergamini, T.M.; Kinney, E.V.; Seabrook, G.R.; Towne, J.B. In Situ Replacement of Vascular Prostheses Infected by Bacterial Biofilms. J. Vasc. Surg. 1991, 13, 575– 583. 43. Towne, J.B.; Seabrook, G.R.; Bandyk, D.; Freischlag, J.A.; Edmiston, C.E. In Situ Replacement of Arterial Prosthesis Infected by Bacterial Biofilms: Long-Term Follow-Up. J. Vasc. Surg. 1994, 19, 226– 233, (discussion 233– 5). 44. Edwards, W.S.; Tapp, J.S. A Flexible Aortic Bifurcation Graft of Chemically Treated Nylon. Surgery 1957, 41, 723– 728. 45. Kelly, G.L.; Eiseman, B. Development of a New Vascular Prosthetic: Lessons Learned. Arch. Surg. 1982, 117, 1367 –1370. 46. Corson, J.D.; Baraniewski, H.M.; Shah, D.M.; Kaufmann, J.; Leather, R.P. Large Diameter Expanded Polytetrafluoroethylene Grafts for Infrarenal Aortic Aneurysm Surgery. J. Cardiovasc. Surg., (Torino) 1990, 31, 702– 705. 47. Lord, R.S.A.; Nash, P.A.; Raj, B.T.; Stary, D.L.; Graham, A.R.; Hill, D.A.; Tracy, G.D.; Goh, K.H. Prospective Randomized Trial of Polytetrafluoroethylene and Dacorn Aortic Prosthesis. Ann. Vasc. Surg. 1988, 2, 248– 254. 48. Petrovic, P.; Lotina, S.; Djordjevic, M.; Avramov, S.; Pfau, J.; Velimirovic, D.; Fabri, M.; Stojanov, P.; Savic, D. Results of 132 PTFE (Gore-Tex) Bifurcated Graft
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Comparing Three Antibiotics Bonded to Dacron Vascular Grafts with Collagen Release System. J. Vasc. Surg. 1991, 13, 897– 901. 63. Mikucki, S.A.; Greisler, H.P. Understanding and Manipulating the Biological Response to Vascular Implants. Semin. Vasc. Surg. 1999, 12, 18–26. 64. de Cossart, L.; How, T.V.; Annis, D.A. Two Year Study of the Performance of a Small Diameter Polyurethane (Biomer) Arterial Prosthesis. J. Cardiovasc. Surg., (Torino) 1989, 30, 388– 394.
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CHAPTER 42
Prevention and Management of Prosthetic Graft Infection P. Allen Hartsell Keith D. Calligaro Matthew J. Dougherty Frank J. Veith INTRODUCTION
PATHOGENESIS AND PREVENTION
Infection of arterial prosthetic grafts is one of the most challenging and devastating complications faced by the vascular surgeon. When peripheral arterial grafts are involved, this complication is typically associated with a mortality rate of 9–36% and a limb loss rate of 27 –79%.[1 – 4] When an aortic prosthesis is involved, mortality ranges from 25 to 88% in spite of aggressive management.[1,5,6] Traditionally, this includes total graft excision, debridement of infected tissue and revascularization through noninfected tissue planes if inadequate collateral circulation exists. Veith was one of the first to suggest graft preservation as a possible alternative.[7] While it is fortunately uncommon, graft infection remains a difficult problem in terms of management. This chapter outlines current modalities important in preventing, diagnosing, and treating these serious complications.
Graft infection occurs when the vascular prosthesis is contaminated by bacteria or, more rarely, fungi. The two most common etiologies are direct contamination at operation and hematogenous seeding. By far the most common cause of vascular graft infection is direct contamination at implantation. This may occur with breaks in sterile technique that exposes the graft to bacteria from the surgical team, endogenous flora of the patient, or the patient’s skin. Another potential source of inoculation is through infected lymph that comes into contact with the prosthesis when lymphatics are disrupted during implantation. These lymph vessels that drain infected tissues such as a lower extremity infection or gangrene may predispose the graft to contamination and increase the risk of infection.[13] Liekweg and Greenfield found that inguinal infections developed ipsilateral to foot infections in one third of cases in their series.[1] However, other authors have not found that the presence of concomitant leg infections results in a significant increase in graft infection.[14] Another recently recognized source of bacterial contamination is the artery itself. Positive cultures of intraluminal thrombus have been obtained in normal appearing abdominal aortic aneurysms in 8–20% of cases in some series.[15,16] The organisms cultured were gram positive in 71–83% of cases and gram negative in 17–27%.[15,16] Staphylococcus epidermidis was the most common bacteria isolated.[15] However, the significance of these positive cultures is not clear. Recent prospective data reported by Van der Vliet et al. found positive cultures of aneurysms in 25% of 215 patients.[17] Four (1.9%) patients developed subsequent graft infections, and of these, three had positive aneurysm cultures and only two of those grew the same organism. Therefore, it would seem unlikely that positive aneurysm cultures in an otherwise normal aortic aneurysm are significant.
INCIDENCE The incidence of vascular graft infection varies with graft location and circumstances at the time of implantation. Prosthetic graft infection is more common after emergency operations and when a groin incision is made. Graft infection is estimated to range from 1 to 5%. If aortic operations do not involve the inguinal region, then the incidence of infection is 0.4–1.3%.[8 – 10] The true incidence is not known and may be higher because many graft infections present years later. However, several authors have noted that more than 50% of all graft infections are apparent within 30 days of implantation.[3,11,12]
Hobson/Wilson/Veith: Vascular Surgery: Principles and Practice, Third Edition, Revised and Expanded DOI: 10.1081/0819-9-120024925 Copyright q 2004 by Marcel Dekker, Inc.
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Reoperative wounds may also increase the risk of subsequent graft infection.[14] Patients with failed vascular reconstructions may harbor organisms in former operative sites within scar tissue and on the surfaces of previously implanted grafts. Bandyk reported that bacteria were cultured from 69% of thrombosed grafts and 90% of anastomotic pseudoaneurysms.[18] In addition to direct methods of bacterial graft contamination, the prosthetic may become infected due to hematogenous spread from a distant focus of infection, such as intravascular line sepsis, urinary tract infection, or pneumonia. Using an experimental animal model, Malone, Moore and colleagues[19] demonstrated that intravenous administration of 107 CFU of Staphylococcus aureus immediately after aortic graft implantation resulted in a 100% incidence of graft infection. Further studies[20] demonstrated that there is a gradual decrease in the rate of clinical graft infection over time that correlates with development of the pseudointimal layer inside the graft and ingrowth of a fibrous capsule along the outer surface. During this process of incorporation, the perigraft environment becomes less vulnerable to a bacteremic insult. However, 30% of aortic grafts in a experimental animals still became infected after a bacterial challenge one year after implantation.[20 – 22] Transient bacteremia associated with a damaged or poorly developed pseudointima could theoretically result in a prosthetic graft infection, even years after implantation. This mechanism may explain the phenomenon of late graft infection. Graft infections are commonly associated with preoperative or intraoperative events that lead to bacterial contamination of the graft or selection of more resistant organisms. Prevention of such events is integral to the reduction of vascular graft infection. For example, a prolonged preoperative hospital stay should be avoided if possible to prevent the development of hospital-acquired, resistant strains of skin flora. Additionally, patients tend to have a higher incidence of wound complications and infections if they have concomitant immune or nutritional compromise.[23] Prophylactic administration of antibiotics has been shown to decrease the incidence of wound infections and should be administered intravenously prior to skin incision and at regular intervals during the procedure.[18] Administration of a first-generation cephalosporin, Cefazolin, 1 g intravenously, one hour before incision and then 1 g every 3 –4 hours during surgery, should achieve adequate tissue levels above the minimum bactericidal concentration for most patients. Recent studies suggest that longer periods of antibiotic prophylaxis (over 24 hours) may be beneficial.[24] If the patient is allergic to penicillin or cephalosporin, then vancomycin and gentamicin are adequate. Several clinical studies support the effectiveness of this regimen.[25 – 27] Meticulous sterile technique is paramount. The graft must be handled carefully and avoid contact with the skin and wound edges. Plastic iodine-impregnated drapes should be used to cover the skin. Any lymphatic vessels should be carefully ligated during the dissection, especially in the groin. Careful handling of tissues, good hemostasis to prevent hematoma formation, and closure of the wound in several layers are also important in the reduction of postoperative wound complications. Copious antibiotic irrigation is recommended.
Several other factors that have been shown to contribute to aortic graft infections. These include ruptured aortic aneurysms,[15] prolonged operative time,[28] reoperation at the site of infection, and colon ischemia.[9,29] When placing a prosthetic aortic graft, other simultaneous gastrointestinal operations should generally be avoided due to the increased risk of infection.[9] One exception to this is cholecystectomy. Some vascular surgeons discourage the performance of cholecystectomy at the same time as aortic graft implantation.[28,30] Others have reported incidences of postoperative acute cholecystitis as high as 18% when gallstones were present in patients that had aortic aneurysm repair without cholecystectomy. [31] Removal of the gallbladder should be considered if the patient is stable after completion of vascular grafting and closure of the retroperitoneum. The pathogenesis of prosthetic graft infection involves complex interaction of the graft surface (the biomaterial), the bacterium, inflammatory response to the graft, and host defenses. Prosthetic graft materials incite an immune foreign body reaction that produces a microenvironment in the perigraft space that is conducive to bacterial adhesion and microcolony formation within a biofilm. This foreign body reaction around prosthetic grafts is distinct from autogenous grafts. Prosthetic grafts fail to develop rich vascular connections, and, therefore, host defenses and antibiotics are less likely to be effective in the face of contamination. Neutrophil chemotaxis and bactericidal function are impaired. Indolent perigraft infection may result, and ultimately the infection may progress and manifest as sepsis, anastomotic breakdown with pseudoaneurysm formation, or hemorrhage. This sequence of events has been well described by Bandyk.[18] Additionally, in the case of aortic prostheses, graft-enteric erosions or fistulas can occur and are associated with a high mortality. Bacterial adherence and growth depends on the physical properties of the graft as well as the growth characteristics of the organism. Staphylococcus species adhere in greater numbers to graft materials than do most gram-negative bacteria.[32,33] Products of the bacteria such as slime defend the bacteria from antibiotics and the immune system. Various graft materials have been studied. In the canine model, knitted velour Dacron grafts promised to be more resistant to infection than woven grafts,[34] but a recent clinical series failed to confirm this.[29] Corson and colleagues failed to demonstrate a difference in infection rates between polytetrafluoroethylene (PTFE) and Dacron aortic grafts.[35]
MICROBIOLOGY The vast majority of vascular graft infections are caused by three organisms, Staphylococcus aureus, Staphylococcus epidermidis, and Escherichia coli. These organisms account for 60 –80% of graft infections.[1,36] Bunt’s review of the literature in 1983 reported S. aureus in 43% of aortic and peripheral prosthetic grafts and S. epidermidis in 14% of cases.[5] More recent series have demonstrated that S. epidermidis is becoming more prevalent and is isolated more frequently, as is Pseudomonas.[37]
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Prevention and Management of Prosthetic Graft Infection
S. epidermidis and other coagulase-negative staphylococci are more difficult to isolate and as such are often associated with negative results in cultures of perigraft fluid.[33] S. epidermidis secretes a biofilm with a glycocalyx that prevents its isolation using standard microbiological techniques. Bergamini described the use of high-frequency sonication to mechanically disrupt the biofilm and culture in broth media, which increases the recovery of positive cultures from 30% on agar medium alone to greater than 80%.[32] Prosthetic infections caused by S. aureus and gramnegative bacteria such as Pseudomonas species are more virulent and usually present as an early graft infection within 4 months of implantation. Infections due to Pseudomonas are especially aggressive and are associated with a high rate of anastomotic dehiscence and rupture and must usually be managed with total graft excision.[37] Fungal infections are extremely rare and usually occur in immunocompromised patients.
DIAGNOSIS Diagnosis of graft infection can be difficult and is based on clinical findings, cultures, and various imaging techniques. The vascular surgeon must have a high index of suspicion to make an early diagnosis of an indolent graft infection. Timely diagnosis and management are necessary to avoid the serious consequences of sepsis, bleeding, and death. Any patient with a prosthetic vascular graft that presents with signs of sepsis without an obvious source should be considered to have a graft infection until proven otherwise. Making the diagnosis is frequently challenging because the clinical manifestations may be nonspecific and subtle. While graft infection can be established with positive bacterial cultures from the prostheses, this is not always possible until the graft is removed. The most accurate method of diagnosis is operative exploration and may be required to exclude infection as well.
HISTORY AND PHYSICAL EXAMINATION Graft infections may present as unexplained fever or sepsis. When infection involves aortic grafts confined to the abdomen, septicemia of unknown etiology, prolonged postoperative ileus, or abdominal pain or distention may be the only signs or symptoms. A history of recent illness, infection, or invasive procedure that produces a transient bacteremia can prove important. Unexplained gastrointestinal bleeding in a patient with an aortic graft must be considered to have an aortoenteric fistula or erosion until proven otherwise.[8,38] If the infection involves an extracavitary graft, local signs are usually evident and include cellulitis, draining sinus tracts, tenderness, or a pulsatile mass. Extremities should be examined for evidence of septic embolization.
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LABORATORY STUDIES Routine lab studies including complete blood count, erythrocyte sedimentation rate, urinalysis, urine and blood cultures, and cultures from any other potential sites of infection are obtained. Stool for occult blood is indicated in patients with possible aortoenteric fistula. All laboratory tests may be normal in cases of S. epidermidis graft infection.
IMAGING STUDIES Many modalities are available to diagnose or determine the extent of graft infection. These techniques include ultrasonography, sinography, computed tomography, magnetic resonance imaging, and radionuclide imaging. Contrast angiography is usually necessary in the planning of revascularization when time permits. Ultrasonography is useful in demonstrating perigraft fluid collection and can reliably differentiate hematoma from pseudoaneurysm or fluid collection. Ultrasonography can also be used to guide percutaneous aspiration of a fluid collection for culture. Computed tomography (CT) with contrast enhancement is a very useful tool, for imaging potential graft infections. Intravenous, oral, and rectal contrast may be necessary depending on the suspected site of infection. It is especially sensitive for imaging thoracic and abdominal aortic grafts. CT scan evidence of aortic graft infection includes edema and loss of normal tissue planes of retroperitoneum, persistent perigraft fluid, abnormal collections of fluid or gas around the graft, bowel wall thickening adjacent to the graft, pseudoaneurysm formation, and hydronephrosis.[39,40] Periprosthetic gas is a normal finding within the first few weeks after surgery.[41] One prospective study found CT scans to be more sensitive than indium-labeled leukocyte scans in the detection of graft infection.[42] Magnetic resonance imaging (MRI) is a newer technique for determination of graft infection. It may become the modality of choice in the future. It is useful in distinguishing between inflammation of the perigraft tissues and perigraft fluid collections. Work by Olofsson et al. suggests the superiority of MRI over CT in detection of graft infection.[43] Other authors have shown that T2-weighted images are mildly enhancing in grafts undergoing normal incorporation compared with a greatly increased signal enhancement in active infection.[44] Contrast sinography is a method of percutaneous localization of a communication of the skin to the perigraft space. This study relies on gentle introduction of contrast into the sinus tract. Care must be exercised because forceful introduction of the agent may disrupt a tenuous anastomosis. White blood cell (WBC) scanning techniques using gallium-67, indium-111–labeled WBCs, and indium-111 labeled human immunoglobulin G are radionuclide imaging techniques that are useful for locating sites of leukocyte uptake. They are highly specific for graft infection if positive months or years after graft implantation. False-negative studies are rare. While white blood cell scanning is not as useful early after implantation because of nonspecific
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inflammation, this technique is more accurate 3 –4 months after implantation.[45,46] Indium may be more useful than gallium because gallium has a higher uptake by the gastrointestinal tract and kidney and may obscure the location of the aortic graft. IgG scans are safer and more economical than tagged WBC scans because they have a reduced preparation time and a longer shelf life and health care workers do not need to be exposed to patients’ blood. A new technique using avidin/indium-111 biotin scintigraphy described recently by Samuel et al. may prove to be more useful in the future.[47] In a small series, this agent correctly identified all infected grafts that had confirmed positive graft cultures and had one false positive without any false negatives. This is somewhat better than is seen with other current radionuclide tests. Arteriography is helpful in evaluation of the patient with suspected graft infection to define proximal and distal arterial anatomy so revascularization can be performed either before or after graft excision. Arteriography cannot be used to make the diagnosis of prosthetic infection unless an anastomotic pseudoaneurysm is identified.
ENDOSCOPY Endoscopy is an essential tool used in patients with aortic grafts that present with gastrointestinal bleeding. Graft-enteric fistula or erosion should be suspected in these cases, and endoscopy of the upper gastrointestinal tract is necessary to rule out another source of hemorrhage. Special attention must be paid to the third and fourth portions of the duodenum because these are the most likely locations of aortoenteric fistulas. If the patient has had a recent massive bleed, then endoscopy should be performed in the operating room in the event massive bleeding recurs.[48] The prosthetic may be visualized eroding into the duodenal lumen. If blood clot is visualized in the duodenum, no attempt should be made to dislodge it as this may result in massive exsanguinating hemorrhage.
MANAGEMENT Traditional management of arterial graft infection includes total graft excision. If perfusion to an organ or limb is threatened, then revascularization is indicated, usually by an extra-anatomic route. This treatment remains the standard of care and is the single method to which all other techniques of management are compared. Many authors have described various alternative techniques for addressing these complex issues including selective complete graft preservation, partial excision, and replacement of graft in situ with various autogenous, prosthetic, and allograft conduits.
GENERAL PRINCIPLES We believe that an arteriogram is mandatory to plan a strategy for management of these complications. However, if the
patient is septic or actively bleeding, then emergent intervention is necessary and extensive preparation is not safe. Most patients do not require emergent operation, and more information can be gained regarding the extent of graft involvement and adequacy of run-off vessels. Other preoperative testing can also be obtained to ready the patient for elective surgery. Cultures are taken and systemic antibiotics can be used accordingly. The entire infected graft must be removed if the patient is persistently septic or has complete involvement of the graft with anastomotic bleeding or false aneurysm formation. After graft excision, adequate debridement of the arterial wall and all inflamed perigraft tissues is essential. The artery next to the infected prosthesis must be debrided back to normal noninfected tissue. If local sepsis remains in the area of an aortic stump, then there is an increased risk of stump blowout and death.[49] It is also essential to use monofilament suture to close the arterial defect as a braided, multifibered suture may harbor bacteria between the strands and serve as a nidus for persistent infection.[50] This would increase the likelihood of future arterial anastomotic hemorrhage. Broad-spectrum antibiotics must be administered pre-, intra-, and postoperatively if the identification of the bacteria is not known. Once the organism has been identified, then appropriate, more specific coverage can be given. Wounds should be thoroughly irrigated with a topical antibiotic solution such as bacitracin and kanamycin. Appropriate duration of postoperative antibiotic administration is uncertain. It has been suggested that patients should receive long-term parenteral antibiotics followed by oral antibiotics for 3–6 months based on work by Malone and colleagues.[51] They reported that patients with positive cultures from the arterial wall left behind after aortic graft excision had a much higher incidence of aortic stump blowout. This was significantly decreased with administration of long-term antibiotics.[51] Revascularization of ischemic organs and limbs may prove necessary to prevent limb loss. Occasionally, if the infected graft was occluded and the limb is viable, then no revascularization is needed. It is generally preferred to implant a new graft prior to excision of the infected prosthesis, but this is not always possible if the patient is septic or actively bleeding. If the patient is stable, some authors have recommended a staged procedure with revascularization preceding graft excision by 1 –2 days, especially for aortic graft infection.[52,53] Trout et al. demonstrated a reduced mortality if bypass was performed in this fashion prior to graft excision.[53]
AORTIC OR AORTOILIAC BYPASS GRAFTS Graft infections involving aortic tube or aortoiliac grafts are generally managed with axillobifemoral bypass grafting through noninfected tissue planes, closure of the incisions with placement of plastic adhesive dressings, abdominal exploration with removal of the infected graft, ligation or closure of the aortic stump with monofilament suture,
Chapter 42.
Prevention and Management of Prosthetic Graft Infection
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debridement of infected tissue, and placement of retroperitoneal drains with irrigation of antibiotic solution. This strategy is the “gold standard” treatment because of the admirable results in an analysis of recent series with an average amputation rate of 22.5% and an average mortality rate of 21%.[54] Preoperative arteriography demonstrates the location of the proximal aortic anastomosis in relation to the renal and visceral vessels. If an inadequate infrarenal cuff exists, then supraceliac control is necessary. There may be insufficient uninfected aorta below the renal arteries to allow aortic stump closure. In such cases, renal perfusion is probably best obtained by hepatorenal or splenorenal bypass prior to graft excision.[55] If graft-enteric fistula or erosion is present, debridement of necrotic or inflamed bowel is done. The bowel defect is closed with sutures or a jejunal patch, or a primary anastomosis of the bowel is performed following bowel resection if the small bowel is involved. Aortic stump disruption is one of the most common early and late causes of death in patients who have had total aortic graft excision for an infected prosthesis. This is catastrophic and usually lethal. It typically occurs within 2 –6 weeks of surgery and is caused by residual infection.[53] Other techniques to buttress or support the aortic stump include the use of autogenous vein pledgets,[56] a patch of prevertebral fascia,[57] or an omental flap.[58]
AORTOBIFEMORAL BYPASS GRAFTS Aortobifemoral grafts can be more difficult to treat because involvement of the groin complicates secondary bypasses and mandates lateral or obturator approaches to avoid infected groin wounds when performing secondary distal reconstructions. Via combined abdominal and groin incisions, femoral limbs of the graft are excised, the femoral artery oversewn or ligated, and the wound packed open with antibiotic-soaked dressings.[59,60] If the entire aortobifemoral graft is infected, then total excision with extra-anatomic bypass is indicated as described above (Fig. 42-1). Revascularization may be best achieved with bilateral axillofemoral bypasses to an uninvolved portion of patent superficial or deep femoral arteries or to the popliteal artery. If graft infection is limited to a single patent femoral limb and confined to the groin and there is no infection of the proximal graft, an attempt can be made to save the noninfected portion of the graft by excising the infected graft limb.[9,59] The proximal limb is explored through a suprainguinal, retroperitoneal incision. Graft incorporation is determined and Gram stains and cultures are submitted to prove sterility. Revascularization may be performed by using the proximal uninvolved limb of the graft as inflow with the graft tunneled laterally to an uninvolved segment of patent superficial or deep femoral arteries. Because of the dissatisfaction with the traditional treatment of aortic graft infection with total graft excision with the associated risk of aortic stump blowout and the overall poorer patency rates with axillobifemoral bypass, many investigators have been exploring other methods of
Figure 42-1. Schematic of an infected prosthetic groin graft with a disrupted anastomosis after complete wound excision and debridement, total excision of the graft, and arterial oversewing of the proximal and distal aspects of the common femoral artery. The threatened limb is revascularized with a PTFE graft using the infrarenal aorta (approached retroperitoneally) as an inflow source. The new graft is tunneled medial to the anterosuperior iliac spine under the inguinal ligament, through the psoas canal and lateral to the infected groin. The bypass continues across the anterolateral thigh in a subcutaneous plane to the distal superficial or deep femoral arteries approached lateral to the sartorius muscle, or to the popliteal artery approached laterally. (From Calligaro, K.D.; Veith, F.J.; Gupta, S.; Ascer, E. et al. A Modified Method for Management of Prosthetic Graft Infections Involving an Anastomosis to the Common Femoral Artery. J. Vasc. Surg. 1990, 11, 485– 492.)
graft preservation or in situ reconstruction with various conduits. Kwaan and Connolly described the use of povidoneiodine wound irrigation to allow the healing of postoperative infections and salvage of patent aortofemoral Dacron grafts.[61] In situ replacement with rifampin-impregnated grafts has been described but has not conclusively shown to be the best solution.[62 – 64] Clagett and associates have described a technique of reconstruction of the aortoiliac
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system using autogenous superficial femoral-popliteal veins.[65] Subsequent long-term follow-up suggests that this technique is durable.[66] Darling and colleagues recently described their technique of graft excision through a midline incision after a new PTFE aortic graft is placed through a retroperitoneal approach. Of the 16 patients treated this way, 11 (78%) survived long-term with no evidence of infection.[67] Another technique described by Kieffer et al. that may hold some promise includes human cadaveric allograft placement in situ.[68] However, late deterioration of the allograft wall could be problematic, and further research is necessary to answer this question.
PERIPHERAL BYPASS GRAFT INFECTIONS Traditional management of infected peripheral grafts includes total graft excision with extra-anatomic revascularization of ischemic limbs. However, in many situations this is not optimal because the patient may not have a suitable outflow vessel or adequate autogenous vein for conduit. Accordingly, such management of infected peripheral grafts is frequently associated with high amputation rates.[1 – 4] In spite of these issues, total graft excision is mandatory if the patient is septic or if the patient
presents with acute bleeding. On the other hand, if the infection involves an anastomosis of an occluded graft to a peripheral artery, Calligaro and Veith showed that subtotal excision of the graft can be performed, leaving an oversewn, 2 – 3 mm graft remnant on the artery[59,60] (Fig. 42-2). This patch in most cases becomes progressively covered by granulation tissue and can be allowed to close by secondary intention. Coverage of the graft can also be achieved with the use of muscle flaps. We have also explored various graft-saving techniques to salvage patent, infected prosthetic grafts. These all include aggressive wound debridement and at least 6 weeks of intravenous antibiotics specific to the sensitivity of the organisms cultured. Calligaro and Veith recently reported on a 20-year experience with various graft-preserving techniques in 120 patients with peripheral prosthetic graft infections.[60] This group of patients had a mortality rate of 12% and an amputation rate of 13%. Infections caused by Pseudomonas were more serious and were associated with higher rates of nonhealing wounds and anastomotic hemorrhage.[37,60,69] Bandyk and associates reported their experience with graft excision and in situ placement of a PTFE graft in highly selected cases of localized femoral graft infections only if the infection was secondary to S. epidermidis.[33,49] They reported no deaths and no recurrent infections of the graft segment that was replaced, and all remained patent.
Figure 42-2. (A) Schematic of an occluded infected prosthetic groin graft shown with pus covering an intact anastomosis of the common femoral artery with surrounding necrotic tissue. (B) Schematic of the infected groin after subtotal excision of the occluded prosthetic graft with a 2 –3 mm oversewn graft remnant on the common femoral artery. This technique maintains patency of the underlying artery that is critical to limb survival and potentially avoids the need for complex revascularization procedures. Another essential adjunct is wide, repeated, operative debridement of all infected, necrotic soft tissue and debris. (From Calligaro, K.D.; Veith, F.J.; Westcott, C.J.; DeLaurentis, D.A. New Method for Managing Infected Prosthetic Grafts in the Groin. In: Current Clinical Problems in Vascular Surgery; Veith, F.J., Ed.; Quality Medical Publishing: St. Louis, MO, 1991; 374 – 379.)
Chapter 42.
Prevention and Management of Prosthetic Graft Infection
CONCLUSION Vascular graft infection is one of the most difficult problems vascular surgeons must face. Traditional management of infected arterial grafts includes mandatory excision
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of the entire graft with subsequent revascularization. Due to the high morbidity and the attendant risks of limb loss and even death, investigators continue to research various new methods of complete or partial graft salvage that may be useful adjuncts in the management of these challenging problems.
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Kwaan, J.H.; Connolly, J.E. Successful Management of Prosthetic Graft Infection with Continuous PovidoneIodine Irrigation. Arch. Surg. 1981, 116, 716– 720. 62. Colburn, M.D.; Moore, W.S.; Chvapil, M.; Gelabert, H.A.; Quinones-Baldrich, W.J. Use of an Antibiotic-Bonded Graft for In Situ Reconstruction After Prosthetic Graft Infections. J. Vasc. Surg. 1992, 16, 651– 658. 63. Goeau-Brissonniere, O.; Mercier, F.; Nicolas, M.H.; Bacourt, F.; Coggia, M.; Lebrault, C.; Pechere, J.C. Treatment of Vascular Graft Infection by In Situ Replacement with a Rifampin-Bonded Gelatin-Sealed Dacron Graft. J. Vasc. Surg. 1994, 19, 739– 741. 64. Gupta, A.K.; Bandyk, D.F.; Johnson, B.L. In Situ Repair of Mycotic Abdominal Aortic Aneurysms with RifampinBonded Gelatin-Impregnated Dacron Grafts: A Preliminary Case Report. J. Vasc. Surg. 1996, 24, 472– 476. 65. Clagett, G.P.; Bowers, B.L.; Lopez-Viego, M.A.; Rossi, M.B.; Valentine, R.J.; Myers, S.I.; Chervu, A. Creation of a
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Neo-Aortoiliac System from Lower Extremity Deep and Superficial Veins. Ann. Surg. 1993, 218, 239– 249. 66. Clagett, G.P.; Valentine, R.J.; Hagino, R.T. Autogenous Aortoiliac/Femoral Reconstruction from Superficial Femoral-Popliteal Veins: Feasibility and Durability. J. Vasc. Surg. 1997, 25, 255– 270. 67. Darling, R.C.; Resnikoff, M.; Kreienberg, P.B.; Chang, B.B.; Paty, P.S.; Leather, R.P.; Shah, D.M. Alternative Approach for the Management of Infected Aortic Grafts. J. Vasc. Surg. 1997, 25, 106– 112. 68. Kieffer, E.; Bahnini, A.; Koskas, F.; et al. In Situ Allograft Replacement of Infected Infrarenal Aortic Prosthetic Grafts: Results in 43 Patients. J. Vasc. Surg. 1993, 17, 349–355. 69. Calligaro, K.D.; Veith, F.J.; Schwartz, M.L.; Goldsmith, J.; Savarese, R.P.; Dougherty, M.J.; DeLaurentis, D.A. Selective Preservation of Infected Prosthetic Arterial Grafts—Analysis of a 20-Year Experience with 120 Extracavitary-Infected Grafts. Ann. Surg. 1994, 200, 461–471.
CHAPTER 43
Abdominal Aortic Aneurysms Peter G. Kalman K. Wayne Johnston reported in the surgical literature.[7] As with cardiac disease, it has been suggested that perhaps gender bias exists in patient selection. However, the observed gender difference is not significantly different when a family history for abdominal aortic aneurysms is present.[8] The landmark study in 1966 by Szilagyi et al. reported observations in a large cohort of patients with asymptomatic abdominal aneurysms and concluded that late survival as well as the 5-year risk of rupture were related to aneurysm size.[9] For aneurysms 6 cm or smaller in diameter, the 5-year survival was 48% and risk of rupture was 20%, compared with the 5-year survival of 6% and a rupture incidence of 43% for aneurysms greater than 6 cm in diameter.[9] This report had huge impact on decision making for several years and was the basis for the 6 cm cut-off as the indication for elective repair. This conclusion was made despite the extreme variability by which aneurysms were measured in this study (physical examination, plain x-ray at laparotomy, or autopsy). The next report that affected surgical decision making was by Darling et al. in 1977,[10] when 24,000 consecutive autopsies at the Massachusetts General Hospital were reviewed over a 23-year period. This study supported the theory that aneurysm rupture was related to size, but it was noteworthy that rupture was also found in aneurysms less than 4 cm in diameter. On the basis of these observations, the authors recommended that even small aneurysms should be repaired because they are all potentially lethal. The critical limitation of this and other autopsy studies for the purpose of defining natural history is the inaccuracy of size determination when the aneurysm is not measured under conditions of physiologic blood pressure. This would result in underestimating the actual size of the aneurysm and therefore overestimating the risk at a given size. At present, there is general consensus among vascular surgeons that the most significant predictor of rupture is size: the 5-year risk for aneurysms between 5.5 and 5.9 cm is approximately 20–25% (although this figure may be less), for 6 cm the risk is 35–40%, and for those greater than 7 cm the rupture risk is greater than 75%. Most surgeons agree that repair is indicated when, on balance, the risk of operation is less than the risk of rupture for each size range. Although many surgeons claim to have witnessed rupture of small aneurysms, the risk of rupture is now generally considered to
INTRODUCTION The first reported case of successful replacement of an abdominal aortic aneurysm (AAA), performed by Charles Dubost in 1951, ushered in the era of the current standard of endoaneurysmorrhaphy and intraluminal graft insertion.[1] The impetus for continuing to advance our knowledge regarding the natural history of abdominal aortic aneurysms is the serious risk of rupture. As recently reported in two institutional studies, the overall 30-day mortality rate for patients presenting to hospital with rupture was between 50 and 70%.[2,3] However, these studies derived their mortality rates by including only those patients who arrived at the emergency department after rupture in time for a diagnosis to be made. Undoubtedly, the true mortality for all ruptured aneurysms is higher, potentially reaching 90 –95%. The prevalence of both small and large abdominal aneurysms appears to be increasing, which may be the result of improved imaging techniques and increased physician awareness,[4] but a consensus has yet to be reached regarding the natural history and indications for elective surgery.[5]
PATHOGENESIS, NATURAL HISTORY, AND INDICATION FOR REPAIR According to suggested standards, the definition of a true arterial aneurysm is a permanent, localized (i.e., focal) dilation of an artery with at least a 50% increase in diameter compared with the normal. The most common site for a true arterial aneurysm is the infrarenal abdominal aorta. Arteriomegaly is a diffuse arterial enlargement (i.e., nonfocal) with an increase in diameter of greater than 50% by comparison with the normal diameter. Ectasia is characterized by dilation less than 50% of the normal arterial diameter.[6] Abdominal aneurysms are fusiform dilations that most commonly begin distal to the renal arteries and are either confined to the aorta or extend to involve the iliac arteries. The average age at the time of surgical repair is 69–70 years, with women accounting for 15 – 20% of all patients undergoing both elective and emergency aneurysm repair as
Hobson/Wilson/Veith: Vascular Surgery: Principles and Practice, Third Edition, Revised and Expanded DOI: 10.1081/0819-9-120024926 Copyright q 2004 by Marcel Dekker, Inc.
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be negligible and falls below the expected operative mortality for elective repair.[11 – 16] Reports from population-based studies support this view.[12,15] At the Mayo Clinic, Nevitt et al. found that the risk of rupture for small aneurysms at 5 years was 0%.[12] Similar results were reported from a population-based study from Sweden by Glimaker et al.[15] Improved late survival has also been used as the justification for early repair of small aneurysms, and it has even been suggested to be a cost-effective procedure.[17] Hallett et al. summarized a population-based cohort from the Mayo Clinic and observed that the 5-year survival of patients undergoing aneurysm repair was 62%, compared with the expected survival of 83% for the general population.[16] The decreased survival was primarily due to the prevalence of coronary disease and questions the rationale for elective surgery in this group, particularly in patients with small aneurysms. Almost identical late survival (68% for 5 years) was observed in the Canadian Aneurysm Registry.[18] Because initial aneurysm size has been insufficient to reliably predict risk, the next question to ask is “What is the growth rate for small aneurysms, and is this important?” Bernstein and Chan followed 99 patients who were at high general risk for surgery for an average of 2.4 years (range 1 –9 years) with serial ultrasonography at 3-month intervals.[19] For aneurysms initially less than 6 cm, the mean expansion rate was 0.4 cm/year. The rupture risk for aneurysms less than 6 cm in dimension was less than 5% during the follow-up period, which supported the continuation of conservative therapy. The protocol that was followed dictated that surgery was indicated when the aneurysm reached 6 cm or expanded rapidly (greater than 0.4 cm) at consecutive ultrasound follow-up. This study had long-lasting influence with the conclusion that an expansion rate of 0.5 cm between consecutive 6-month follow-up sessions was a strong indication for elective surgery. Later studies, however, failed to demonstrate the relationship between expansion rate and risk of rupture.[12,20] Whether or not aneurysm expansion is related to rupture risk, there is significant variability observed in growth rate.[19,21,22] In the Kingston aneurysm study, Brown et al. found that the mean growth rate of aneurysms with an initial diameter range of 4.5–4.9 cm was 0.7 cm/year and recommended that lowrisk patients should be considered for elective repair because of the inevitable expansion of 5 cm.[14] Sterpetti et al. observed a mean expansion of 0.48 cm/year, but the rate was found to be extremely variable.[21] Using Cox regression, Cronenwett et al. conducted a multivariate analysis of the variables predictive of small aneurysm rupture[20] and found that the combination of diastolic blood pressure, initial AP diameter, and degree of chronic obstructive pulmonary disease were predictive of aneurysm rupture at 5 years. The growth rate of small aneurysms at The Toronto Hospital was determined from a registry of 430 patients, 214 of whom had more than 3 evaluations at 6-month intervals.[23] Patients were followed on average for 3.3 years, and the initial aneurysm size averaged 4 cm. During follow-up, 58.4% of patients had no change or a decrease in aneurysm size, 25.3% had an expansion between 0.1 and 0.25 cm, 12.6% had an increase greater than 0.25 cm, and only 3.7% enlarged greater than 0.5 cm. There are pitfalls contained in the early studies of the natural history of aneurysm expansion and rupture, not the least of which is the source of the data, which originate from a
variety of designs (autopsy data and referral- and populationbased studies). New information from the large UK and ADAM trials indicate that the rupture rate for aneurysms between 4 and 5.5 cm is approximately 0.6–1% per year. However, this must be monitored at 6-month intervals when observation is selected for management.[24 – 26] The indication for elective aneurysm repair in the elderly should generally follow the same guidelines as repair in younger individuals. It must be emphasized that patient selection is individualized, and the final decision for management should be based on physiologic rather than chronologic age. Numerous reports have claimed that aneurysm repair can be conducted with an acceptable operative mortality and morbidity in the octogenarian, but it must be stressed that these cases are usually highly selected.[27,28] The clustering of abdominal aneurysms in families has been cited in several studies and has raised the possibility that genetic factors may be involved with both X chromosome–linked and autosomal dominant patterns. Although no founder or common link mutation has been identified,[29] this familial association has been found to occur at an estimated incidence of approximately 15–20%.[8,30 – 32] Powell et al. reported the identification of an abnormality on the long arm of chromosome 16 and an association with familial aneurysms.[33] Additionally, molecular defects of Type III procollagen have been identified in Ehlers-Danlos syndrome (Type IV).[34] Type III procollagen is a structural component of arterial walls, and it has been postulated that the defect is related to aneurysm formation. Recent advances in molecular biology have provided evidence that altered gene expression may cause abnormalities in elastin and collagen contents in aneurysms.[35] Because it is presently difficult to determine the populations at risk for the development of significant abdominal aneurysms, identification of familial or genetic tendencies would be invaluable for initiating costeffective screening programs. Comprehensive genetic analysis may serve a useful role in the future by identifying those individuals who have a significant risk for aneurysm development.
DIAGNOSIS Seventy-five percent of abdominal aneurysms are asymptomatic when first detected,[36] either on routine physical examination or as an incidental finding on plain x-ray, ultrasound, or computed tomographic (CT) scan. The majority of those identified are small, usually measuring less than 5 cm in dimension. An important feature to establish when performing a physical examination on a patient with an abdominal aneurysm is to try to determine the upper border of the pulsation. If the palpating hand cannot get between the upper border of the aneurysm and the costal margin, then suprarenal extension should be suspected. The most expeditious way to confirm the diagnosis of an abdominal aneurysm and to accurately determine the size is to obtain an ultrasonographic scan. Similarly, ultrasound is the simplest method for serial follow-up of small aneurysms to detect any change in size. Once it has been decided that surgical intervention is indicated according to the sizing obtained by ultrasound, CT scan provides valuable additional
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Figure 43-1. (A) Spiral CT scan at the level of the renal arteries; left renal vein visualized crossing normal diameter aorta. (B) Threedimensional reconstruction of spiral CT (from A) demonstrating AAA and bilateral iliac aneurysms as well as visceral vessels.
information for operative planning. CT scan accurately delineates the anatomy of the aneurysm and in particular defines the proximal and distal extent of iliac involvement. Operative planning is enhanced by demonstration of the
length of neck, the location of the left renal vein, and the origins of major vessels. More recently, the spiral or helical CT complements and augments the anatomic information provided by conventional CT (Fig. 43-1). Moreover, the
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resolution of spiral CT allows relatively accurate screening of associated renal artery disease with a reported 92% sensitivity and 83% specificity for a stenosis greater than 70%.[37] Associated abnormalities can also be detected by CT scan including venous abnormalities such as left-sided vena cava, caval duplication, retroaortic renal vein or venous collar, as well as nonvascular pathology such as various malignancies, cholelithiasis, horseshoe kidney, and renal tumors and cysts. Contrast aortography is playing a less significant role in the routine preoperative treatment of the patient, although it remains the standard for some vascular surgeons. The majority obtain aortograms only in selected situations—for example, when associated occlusive disease is suspected and the aortogram would assist the surgeon in planning the procedure or in the case of poor definition of the aortic neck as a result of aortic lengthening and buckling. An arteriogram is valuable in the case of internal iliac aneurysms for determining pelvic blood flow because at least one internal iliac artery should be maintained to avoid colon ischemia (and vasculogenic impotence in men). When this is not possible, reimplantation of a large patent inferior mesenteric artery can be performed. Other indications for an arteriogram include juxtarenal or suprarenal aneurysms that require detailed anatomy of visceral arteries and, likewise, clinical suspicion of visceral arterial occlusive disease (i.e., severe hypertension or postprandial pain and weight loss). Less commonly, as with cases of horseshoe and pelvic kidneys, an arteriogram is useful for demonstration of the unpredictable arterial supply or when an aberrant, low renal artery may have been suggested on CT scan. Finally, potential candidates for endovascular repair require detailed mapping of the aorta and iliacs for sizing and positioning of the endoluminal prosthesis. Magnetic resonance imaging has all the benefits of CT scan and aortography combined, and the availability is increasing. The main disadvantages at present include the cost and contraindications in many patients because of metallic devices such as monitoring lines, pacemakers, and surgical clips. A major disadvantage is the slow acquisition time and the resulting claustrophobic distress experienced by some patients.
MEDICAL RISK ASSESSMENT Coronary artery disease (CAD) is the most common cause of death after elective aneurysm repair, and considerable effort is directed toward preoperative detection of cardiac dysfunction and CAD.[38 – 40] Noninvasive evaluations are the most frequently used screening methods because features of the medical history are unreliable for accurately predicting cardiac risk,[41 – 43] and it has been estimated that silent myocardial ischemia occurs in 2.5–10% of asymptomatic patients with no previous documentation of CAD.[44] Unfortunately, the false-positive rates for exercise treadmill testing have been reported to be as high as 40%,[45,46] and echography, radionuclide ventriculography, and dipyridamole-thallium scanning all have low positive predictive value. It has been reported that the latter tests identify 30 – 50% of vascular surgery patients who are at increased risk for a cardiac event, but less than 25% of those identified actually experience adverse cardiac events postoperatively.[47,48]
Guidelines have been established recently for preoperative screening for patients undergoing noncardiac surgical procedures.[49] These guidelines stratify patients into risk groups based on history and symptoms and are designed to help identify patients who may benefit from coronary revascularization before their elective procedure. Cardiac intervention is rarely necessary to simply lower the risk of surgery, and those patients who ultimately undergo coronary revascularization would have done so solely on the merits of their severe symptoms (unstable or severe angina, symptomatic arrhythmias, severe valvular disease). There is no strong evidence demonstrating that prophylactic coronary revascularization improves perioperative mortality or longterm survival rates.
OPERATIVE TECHNIQUES The typical patient undergoing elective AAA repair is monitored intraoperatively with an ECG monitor, radial arterial line, urinary catheter, and selective use of pulmonary artery catheters. A large-bore peripheral intravenous line and a central venous line are available for rapid infusion if required. It is becoming increasingly routine for surgeons to use an autotransfusion device with increasing patient awareness of the uncommon but potential transmission of diseases with blood products. For elective AAA repair, most surgeons favor the midline transabdominal incision, although recently there has been increasing interest in the retroperitoneal approach[50 – 53] (see Chapter 84). Supporters for the transabdominal approach cite surgeon familiarity and the ability to inspect the viscera for potential concomitant pathology. Proponents of the retroperitoneal approach claim less intraoperative hypothermia, less third space fluid loss, and fewer postoperative cases of respiratory problems and ileus. Furthermore, the retroperitoneal approach may be useful in patients who have had multiple abdominal procedures, pararenal aneurysms or those with stomas. Ultimately, the best approach is the one with which the surgeon is most comfortable, although knowledge of both procedures should be part of the surgeon’s armamentarium to ensure that all situations and unusual aortic problems can be managed most appropriately. The feasibility of minimally invasive endoluminal AAA repair has been demonstrated, but the long-term results are unknown. May et al.[54] compared endoluminal versus open repair and found that the endoluminal technique had the disadvantage of a higher early failure rate but, when successful, resulted in shorter hospital length of stay, shorter ICU stay, and less blood loss than open repair. At this point it is fair to say that this technology is still evolving but promising and should still be considered experimental.
RESULTS OF OPEN REPAIR Contemporary operative results are summarized in the multicenter, prospective Canadian Aneurysm Study,[55,56]
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which consisted of 680 consecutive patients who underwent AAA repair performed by 72 participating members of the Canadian Society for Vascular Surgery between March 1 and December 1, 1986. The operative morbidity and mortality is summarized in Table 43-1. Regular follow-up has been maintained at 6- to 9-month intervals through contact with the surgeon, family physician, or patient to update overall status, morbidity, intercurrent illnesses, mortality, and cause of death. This registry is a population-based study because the patients represent a heterogeneous group free from referral center bias; this classification is supported by the fact that the overall operative mortality rate for patients in the study was 4.7% ðn ¼ 32Þ and was unrelated to any surgeon characteristics (i.e., age, community vs. university practice type, city population, or hospital size).
SITUATIONS ENCOUNTERED DURING AAA REPAIR AND THEIR SOLUTIONS Certain situations that are encountered occasionally during AAA surgery make the procedure more difficult and add significant risk to the patient, thus encouraging preoperative recognition and demanding modification of the procedure. A Table 43-1. Operative Morbidity and Mortality in 680 Nonruptured AAA Repairs Postoperative bleeding Transfusion Repeat operation Limb ischemia Graft thrombosis Distal thromboembolism Amputation Graft infection Cerebrovascular event Paraplegia Cardiac event MI CHF Arrythmia New arrythmia Respiratory failure Renal damage requiring dialysis Diarrhea No ischemic colitis With ischemic colitis Prolonged ileus Wound infection Superficial Deep Coagulopathy Mortality (all causes) Cardiac Source: Ref. 56.
2.3% 1.4% 3.5% 0.9% 3.3% 1.2% 1 case 0.6% 1 case 15.1% 5.2% 8.9% 10.5% 8.4% 8.4% 5.4% 0.6% 7.1% 0.6% 11% 1.5% 0.5% 1.1% 4.7% 3.3%
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successful outcome depends on accurate anatomic diagnosis and choosing the optimal exposure and method for proximal aortic control.
JUXTARENAL ANEURYSM AND THE DIFFICULT PROXIMAL ANASTOMOSIS When the proximal anastomosis is technically difficult because it is close to the origin of the renal arteries, suprarenal crossclamping or left renal vein ligation can be used to gain proximal control and improve exposure. It is often safer and simpler to obtain proximal control above the celiac rather than the immediate suprarenal aorta because the risk of embolic debris to the renal arteries is less significant. If a midline incision is used, the stomach is retracted inferiorly and the lesser sac is entered through the gastrohepatic omentum. The right crus of the diaphragm is carefully divided using cautery, and the supraceliac aorta is exposed. With a left retroperitoneal approach, the upper viscera are rotated medially exposing the left crus of the diaphragm, which is then divided with cautery, thus exposing the aorta. In selected cases where a huge juxtarenal aneurysm limits upper abdominal exposure, a low, limited thoracoabdominal incision is helpful to obtain proximal control of the thoracic aorta. Aortic control at each of these sites is used only until the proximal anastomosis is completed, and then the clamp is moved distally to allow visceral perfusion while the distal repair is performed. The proximal anastomosis of a juxtarenal repair often includes the lower margins of the renal arteries, and one of the challenges is preservation of renal function. Patients with preexisting renal dysfunction are at even greater risk. In the Canadian Aneurysm Study[55] a suprarenal clamp was necessary in 6.8% of cases, and this group suffered a higher incidence of renal damage. The mortality rate and incidence of cardiac events was not increased, therefore suprarenal clamping is an option when indicated. For facilitation of the upper anastomosis, the left renal vein was ligated in 7.9% of cases, which resulted in an increased risk of renal damage (i.e., elevation of creatinine and increase in renal failure requiring dialysis). Left renal vein ligation should rarely be performed and only in difficult cases where retraction of the vein gives inadequate exposure.
PLANNING THE DISTAL ANASTOMOSIS An aortic tube graft or bi-iliac graft is recommended unless significant iliofemoral occlusive or aneurysmal disease is present because patients rarely require subsequent reoperation for occlusive or aneurysmal disease of the iliofemoral segment. In the Canadian Aneurysm Study[55] the distal anastomosis was performed as a tube graft in 38.5%, a bi-iliac graft in 30.7%, an iliac/femoral graft in 6.5%, and a graft to both femoral arteries in 24.3%. In contrast to patients with a totally intra-abdominal graft, those with a femoral anastomosis had an increased
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incidence of wound infection (0.9% vs. 3.0%, respectively) and graft thrombosis (0.2% vs. 2.5%, respectively). Other morbidity and mortality rates were the same.
MAINTENANCE OF HINDGUT AND PELVIC PERFUSION There is an increased risk of distal colon ischemia when pelvic blood flow is significantly reduced, and it is an established surgical principle that internal iliac artery flow should be maintained on at least one side, although recently questioned by Mehta and Veith. The criteria for reimplantation of the inferior mesenteric artery is not clearly defined but certainly should be considered in the case of an unusually large inferior mesenteric artery or angiographic evidence of superior mesenteric artery stenosis or if the collateral circulation between the superior and inferior mesenterics is poorly developed. Further considerations while in the operating room include poor backflow from a patent inferior mesenteric artery even after completion of the distal anastomosis, concern that pelvic flow has been reduced by the reconstructive procedure and concern about the appearance of the colon. Methods such as inferior mesenteric stump pressure measurement, intraoperative Doppler, photoplethysmography, or colon pH measurement provide objective assessment, but there is no evidence that these are superior to clinical assessment. In the Canadian Aneurysm Study [55] the inferior mesenteric artery was reimplanted in 4.8% of cases. When internal iliac flow was maintained to one or both sides, the incidence of colon ischemia was 0.3%, whereas, when it was interrupted bilaterally, the incidence increased to 2.6%.
INFLAMMATORY ANEURYSMS Inflammatory aneurysms occur in approximately 5–10% of surgical cases and are therefore usually unexpected until the time of elective repair unless a preoperative CT scan is routinely performed. There are many proposed etiologies for inflammatory aneurysms, but none has been unanimously embraced.[57] They are important to recognize because the periaortic fibrotic tissue can be densely adherent to the duodenum, sigmoid colon and mesocolon, the ureters, vena cava and left renal vein, which may complicate the operative repair. These aneurysms are characterized histologically by extensive adventitial fibrosis and mononuclear cell infiltration with lymphoid follicle formation. The erythrocyte sedimentation rate is frequently elevated and the test for C-reactive protein may be positive. CT typically shows a 1-cm-thick, homogeneous wall with contrast enhancement around the aneurysm, which may be visualized external to the rim of wall calcification (Fig. 43-2). The principles of operative management are now well established: (1) no dissection of the adherent duodenum or sigmoid mesocolon off the aneurysm, (2) perform proximal cross-clamping of the aorta at the diaphragm if impossible below the renal arteries, (3) perform balloon occlusion of the iliac arteries as the inflammatory reaction usually makes iliac
dissection hazardous, and (4) perform the proximal anastomosis by the inclusion method if requrired. In the Canadian Aneurysm Study[48,49] inflammatory aortic aneurysms were observed in 4.5% of cases, and there was no difference in age, sex, or atherosclerotic risk factors. The incidence of pain was not significantly higher in patients with inflammatory aneurysms; unlike previously reported series, however, there was no specific diagnostic feature that distinguished an inflammatory aneurysm from a standard aortic aneurysm. The surgery appeared more difficult as reflected by the higher volume of blood transfused and more frequent use of a cell saver, as well as the higher frequency of renal vein ligation, although morbidity and mortality was not increased.
HORSESHOE KIDNEY The horseshoe kidney is relatively uncommon, occurring with a frequency of 0.25% in the general population. The majority are fused at the lower poles with an isthmus, which may simply be a fibrous band or renal tissue with a separate blood supply. The surgical challenges are the presence of bulky isthmus, anomalous ureters, and renal blood supply.[58] The ureters may be multiple and cross in aberrant places anterior to the isthmus, and preservation of the renal blood supply and collecting system are the goals of reconstruction. Renal ischemia may result if a bulky isthmus is divided, and urine leakage may occur, which may be a serious problem because of the prevalence of coexisting chronic urinary infections. A retroperitoneal approach is ideal because the left kidney and isthmus can be elevated to expose the aorta without division of the isthmus. All patients with the diagnosis made preoperatively should undergo arteriography to define the renal artery anatomy, which can range from single renal arteries to multiple arteries from the aorta, iliac, and visceral arteries. The surgical options include bypass or reimplantation of an artery or cuff of aorta into the graft depending on the individual circumstance.
CONCOMITANT INTRA-ABDOMINAL PATHOLOGY Concomitant intra-abdominal pathology frequently makes surgical judgment more challenging. Important questions arise with respect to priority and performance of a one- or two-stage procedure. As a general rule, AAA repair should not be combined with other procedures that may result in bacterial contamination (e.g., gastrointestinal and genitourinary), and management is dependent on the type and clinical activity of the associated condition, where the symptomatic condition always takes priority.
COLORECTAL TUMORS The priority decision with colorectal tumors depends on the disease that requires intervention most urgently. If the tumor is found incidentally during elective, asymptomatic AAA repair,
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Figure 43-2. Spiral CT scan of inflammatory AAA. Note thick, homogeneous enhancing rind external to the rim of wall calcification.
most surgeons would repair the aneurysm first and recommend colon resection after a 4- to 6-week delay. In the unusual circumstance where the incidental tumor appears obstructive, then colon resection would take priority. If the aneurysm and colon tumor are both detected preoperatively, then the priority is given to the most ominous lesion (e.g., a colon obstruction would be relieved before an asymptomatic AAA, and, similarly, a symptomatic AAA would be dealt with before a nonobstructing colon lesion). Combined procedures would only be entertained on rare occasions when a symptomatic AAA is encountered at the same time as an obstructive colon tumor. In this last scenario, the aneurysm is repaired first followed by the colon resection, after careful retroperitoneal closure.
RENAL TUMORS Renal tumors are occasionally found at the same time as an asymptomatic AAA. In general, there is no contraindication for simultaneous repair unless obvious sepsis is evident from an obstructive lesion.
GALLBLADDER DISEASE Cholelithiasis is the most common abdominal pathology found in the AAA patient, with estimates of prevalence that range from 5 to 20%.[59] Gallstones are most commonly asymptomatic and rarely cause acute symptoms after AAA repair. Ouriel et al. found an incidence of cholecystitis in only 1.1% of 703 elective AAA repairs postoperatively, and the
underlying cause was acalculous in 75%.[59] Asymptomatic gallstones are generally left alone, whereas concomitant cholecystectomy is occasionally considered when symptoms from cholecystitis occurred relatively recently and the AAA repair was entirely uneventful.
RUPTURED AAAS The sudden onset of severe abdominal and/or back pain and syncope should alert one to the presence of a ruptured AAA. Important physical findings include hypotension (measured or a history of syncope, perspiration), tachycardia, abdominal pain, and a mass that may or may not be pulsatile. With symptomatic but intact aneurysms, the severe back and abdominal pain may be indistinguishable from that of a rupture, but the important feature by history is the absence of hypotension and confirmation of an intact aneurysm by CT scan. Symptoms in the latter situation may be related to acute expansion of the aneurysm wall, intramural hemorrhage, or wall degeneration. Symptomatic, intact aneurysms should be considered urgent, but not necessarily emergent because in many cases they can be managed surgically in a more elective manner. With a suspected diagnosis of rupture, the patient is immediately transferred to the operating room. In this setting, insertion of large-bore intravenous access and resuscitation with fluid and blood products can proceed while preparation for operative intervention is begun. If the patient’s condition is stable preparation can proceed in a controlled manner, whereas if the patient suddenly decompensates the surgical team is ready for immediate intervention. Arterial access is
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established to allow accurate blood pressure measurements and for sampling for hematocrit and blood gases. The patient is prepped and draped awake followed by rapid induction and intubation, which frequently causes hypotension when the adaptive sympathetic drive is released. The usual exposure is through a generous midline incision, and rapid control of the aorta is achieved with digital compression or compression with an aortic occluder (against the vertebrae at the supraceliac level), an aortic cross-clamp (infrarenal, suprarenal or supraceliac), and occasionally an intra-aortic balloon. Distal control can usually be obtained by clamping the common iliac arteries, but balloon occlusion catheters are sometimes safer when visualization of the iliacs is poor. Once proximal and distal control is securely achieved, graft placement is performed as in the elective situation once the decision regarding configuration is made (tube vs. bifurcation graft). The immediate and late survival rates after repair of a ruptured AAA remain low in spite of improvements in surgical care. In the Canadian Aneurysm Registry the inhospital survival rate for patients with a ruptured AAA was 50% and 49% at 1 month,[60] which is similar to the 53%
survival rate reported from collected series.[61] The independent predictors of survival in the Canadian Aneurysm Study was aortic cross-clamping above renal arteries, occurrence of a myocardial infarction, respiratory failure, renal damage, and coagulopathy.[60]
SUMMARY Abdominal aneurysms are all potentially lethal and have been estimated to be responsible for about 15,000 deaths annually in the United States.[38] Standard surgical as well as endoluminal repair are the only methods known to be effective in preventing these deaths. Although most vascular surgeons presently adhere to the 5 cm cut-off as the indication for elective repair in patients with an acceptable operative risk, the true natural history of asymptomatic abdominal aneurysms is unknown. Focusing on size alone is insufficient to predict the risk for an individual patient because other important factors such as sex, age, and family history are being increasingly recognized as having a significant impact.
REFERENCES 1. Dubost, C.; Allary, M.; Oeconomos, N. Resection of an Aneurysm of the Abdominal Aorta: Re-Establishment of the Continuity by a Preserved Arterial Graft, with Results After Five Months. Arch. Surg. 1952, 64, 405. 2. Hannon, E.L.; Kilburn, H.; O’Donnell, J.F.; Bernard, H.R.; Shields, E.P.; Lindsey, M.L.; Yazici, A. A Longitudinal Analysis of the Relationship Between In-Hospital Mortality in New York State and Volume of Abdominal Aortic Aneurysm Surgeries Performed. Health Serv. Res. 1992, 27, 517–542. 3. Johansen, K.; Kohler, T.R.; Nicholls, S.C.; Zierler, R.E.; Clowes, A.W.; Kazmers, A. Ruptured Abdominal Aortic Aneurysm: The Harborview Experience. J. Vasc. Surg. 1991, 13, 240– 247. 4. Laroy, L.L.; Cormier, P.J.; Matalon, T.A.S.; Patel, S.K.; Turner, D.A.; Silver, B. Imaging of Abdominal Aortic Aneurysms. Am. J. Roentgenol. 1989, 152, 785– 792. 5. Hollier, L.H.; Taylor, L.M.; Ochsner, J. Report of a Subcommittee of the Joint Council of the Society for Vascular Surgery and the North American Chapter of the International Society for Cardiovascular Surgery. J. Vasc. Surg. 1992, 15, 1046– 1056. 6. Johnston, K.W.; Rutherford, R.B.; Tilson, M.D.; Shah, D.M.; Hollier, L.; Stanley, J.C. Suggested Standards for Reporting on Arterial Aneurysms. J. Vasc. Surg. 1991, 13, 444–450. 7. Johnston, K.W. Influence of Sex on the Results of Abdominal Aortic Aneurysm Repair. J. Vasc. Surg. 1994, 20, 914– 926. 8. Webster, M.W.; St. Jean, P.L.; Steed, D.L.; Ferrell, R.E.; Majumder, P.P Abdominal Aortic Aneurysm: Results of a Family Study. J. Vasc. Surg. 1991, 13, 366– 372.
9. Szilagyi, D.E.; Smith, R.F.; DeRusso, F.J.; Elliott, J.P.; Sherrin, F.W. Contribution of Abdominal Aortic Aneurysmectomy to Prolongation of Life. Ann. Surg. 1966, 164, 678– 699. 10. Darling, R.C.; Messina, C.R.; Brewster, D.C.; Ottinger, L.W. Autopsy Study of Unoperated Abdominal Aortic Aneurysms. Circulation 1977, 56 (Suppl. 3), II161– II164. 11. Sterpetti, A.V.; Cavallaro, A.; Cavallari, N.; Allegrucci, P.; Tamburelli, A.; Agosta, F.; et al. Factors Influencing the Rupture of Abdominal Aortic Aneurysms. Surg. Gynecol. Obstet. 1991, 173, 175. 12. Nevitt, M.P.; Ballard, D.J.; Hallett, J.W. Prognosis of Abdominal Aortic Aneurysms: A Population Based Study. N. Engl. J. Med. 1989, 321, 1009– 1014. 13. Guirguis, E.M.; Barber, C.G. The Natural History of Abdominal Aortic Aneurysms. Am. J. Surg. 1991, 162, 481– 483. 14. Brown, P.M.; Pattenden, R.; Vernooy, C.; Zelt, D.T.; Gutelius, J.R. Selective Management of Abdominal Aortic Aneurysms in a Prospective Measurement Program. J. Vasc. Surg. 1996, 23, 213– 222. 15. Glimaker, H.; Holmberg, L.; Elvin, A.; Nybacka, O.; Almgren, B.; Bjorck, C.G.; et al. Natural History of Patients with Abdominal Aortic Aneurysm. Eur. J. Vasc. Surg. 1991, 5, 125–130. 16. Hallett, J.W.; Naessens, J.M.; Ballard, D.J. Early and Late Outcome of Surgical Repair for Small Abdominal Aortic Aneurysms: A Population Based Analysis. J. Vasc. Surg. 1993, 18, 684– 691. 17. Katz, A.K.; Cronenwett, J.L. The Cost-Effectiveness of Early Surgery Versus Watchful Waiting in the Management
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of Small Abdominal Aortic Aneurysms. J. Vasc. Surg. 1994, 19, 980– 991. Johnston, K.W. Nonruptured Abdominal Aortic Aneurysm: Six-Year Follow-Up Results from the Multicenter Prospective Canadian Aneurysm Study. J. Vasc. Surg. 1994, 20, 163– 170. Bernstein, E.F.; Chan, E.L. Abdominal Aortic Aneurysm in High-Risk Patients. Outcome of Selective Management Based on Size and Expansion Rate. Ann. Surg. 1984, 200, 255– 263. Cronenwett, J.L.; Murphy, T.F.; Zelenock, G.B.; Whitehouse, W.M.; Lindenauer, S.M.; Graham, L.M.; et al. Actuarial Analysis of Variables Associated with Rupture of Small Abdominal Aortic Aneurysms. Surgery 1985, 98, 472– 483. Sterpetti, A.V.; Schultz, R.D.; Feldhaus, R.J.; Cheng, S.E.; Peetz, D.J. Factors Influencing Enlargement Rate of Small Abdominal Aortic Aneurysms. J. Surg. Res. 1987, 43, 211– 219. Delin, A.; Ohlsen, A.D.; Swedenborg, J. Growth Rate of Abdominal Aortic Aneurysms as Measured by Computed Tomography. Br. J. Surg. 1985, 72, 530– 532. Kalman, P.G. Small Aneurysm Growth Rate at the Toronto Hospital. Unpublished Data. Tilson, M.D. Surgery Versus No Surgery for 4 to 5 cm Abdominal Aortic Aneurysms. J. Vasc. Surg. 1992, 15, 871– 872. Lederle, F.A. Management of Small Abdominal Aortic Aneurysms [Editorial]. Ann. Intern. Med. 1990, 113, 731– 732. The UK Small Aneurysm Trial; Mortality Result for Randomized Controlled Trial of Early Elective Surgery or Ultrasonographic Surveillance for Small Abdominal Aortic Aneurysm. Lancet 1998, 352, 1649– 1655. Sterpetti, A.V.; Schultz, R.D.; Feldhaus, R.J.; Peetz, D.J.; Fasciano, A.J.; McGill, J.E. Abdominal Aortic Aneurysm in Elderly Patients: Selective Management Based on Clinical Status and Aneurysmal Expansion Rate. Am. J. Surg. 1985, 150, 772– 776. Ernst, C.B. Abdominal Aortic Aneurysms. N. Engl. J. Med. 1993, 328, 1167– 1172. van der Vliet, J.A.; Boll, A.P. Abdominal Aortic Aneurysm. Lancet 1997, 349, 863– 866. Collin, J.; Walton, J. Is Abdominal Aortic Aneurysm Familial? Br. Med. J. 1989, 299, 493. Powell, J.T.; Greenhalgh, R.M. Multifactorial Inheritance of Abdominal Aortic Aneurysm. Eur. J. Vasc. Surg. 1987, 1, 29. Adamson, J.; Powell, J.T.; Greenhalgh, R.M. Selection for Screening for Familial Aortic Aneurysms. Br. J. Surg. 1992, 79, 897– 898. Powell, J.T.; Bashir, A.; Dawson, S.; et al. Genetic Variation on Chromosome 16 Is Associated with Abdominal Aortic Aneurysm. Clin. Sci. 1990, 78, 13. Superti-Furga, A.; Steinmann, B.; Ramirez, F.; et al. Molecular Defects of Type III Procollagen in EhlersDanlos Syndrome Type IV. Hum. Genet. 1989, 82, 104– 108. Mesh, C.L.; Baxter, B.T.; Pearce, W.H.; et al. Collagen and Elastin Gene Expression in Aortic Aneurysms. Surgery 1992, 112, 256– 261.
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54. May, J.; White, G.H.; Yu, W.; Ly, C.N.; Waugh, R.; Stephen, M.S.; et al. Concurrent Comparison of Endoluminal Versus Open Repair in the Treatment of Abdominal Aortic Aneurysms: Analysis of 303 Patients by the Life Table Method. J. Vasc. Surg. 1998, 27, 213– 221. 55. Johnston, K.W.; Scobie, T.K. Multicenter Prospective Study of Nonruptured Abdominal Aortic Aneurysms. Part I. Population and Operative Management. J. Vasc. Surg. 1988, 7, 69– 81. 56. Johnston, K.W. Multicenter Prospective Study on Nonruptured Abdominal Aortic Aneurysm. Part II. Variables Predicting Morbidity and Mortality. J. Vasc. Surg. 1989, 9, 437– 447. 57. Yonemitsu, Y.; Nakagawa, K.; Tanaka, R.; et al. In Situ Detection of Frequent and Active Infection of Human Cytomegalovirus in Inflammatory Abdominal Aortic
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Aneurysms: Possible Pathogenic Role in Sustained Chronic Inflammatory Reaction. Lab. Investig. 1996, 74, 723 – 736. O’Hara, P.J.; Hakaim, A.G.; Krajewski, L.P.; et al. Surgical Management of Aortic Aneurysm and Horseshoe Kidney: Review of a 31-Year Experience. J. Vasc. Surg. 1993, 18, 586. Ouriel, K.; Ricotta, J.J.; Adams, J.T.; Deweese, J.A. Management of Cholelithiasis in Patients with Abdominal Aortic Aneurysm. Ann. Surg. 1983, 198, 717– 719. Johnston, K.W. Ruptured Abdominal Aortic Aneurysm: Six-Year Follow-Up Results of a Multicenter Prospective Study. J. Vasc. Surg. 1994, 19, 888– 900. Callam, M.J.; Haiart, D.; Murie, J.A.; et al. Ruptured Aortic Aneurysm. A Proposed Classification. Br. J. Surg. 1991, 178, 1126 –1129.
CHAPTER 44
Thoracoabdominal Aortic Aneurysms Larry H. Hollier Marcus D’ayala Alfio Carroccio
INTRODUCTION
ETIOLOGY AND CLASSIFICATION
Thoracoabdominal aortic (TAA) aneurysms can be defined as aneurysms that involve the descending thoracic and abdominal aorta. Although less common than abdominal aortic aneurysms, TAA aneurysms appear to be associated with a worse prognosis.[1,14] In these reports, the 2-year survival rate of untreated patients with these extensive aneurysms was less than 30%, with about half of all deaths occurring as a result of aneurysm rupture.[2] The surgical repair of these complex aneurysms can improve this poor survival rate significantly. As demonstrated by Crawford and colleagues, a 2-year survival rate of about 70% can be expected following operative intervention.[3] However, this operative procedure requires entering both the thoracic and abdominal cavities and is associated with significant morbidity and mortality. Such procedures can challenge even the most experienced vascular surgeons. Although progress in the perioperative care of patients with TAA aneurysms has led to a decrease in the complication rate associated with this procedure, death, paraplegia, and renal failure are still commonly seen. Most authors now quote operative mortality rates of less than 10%, with an overall rate of paraplegia of approximately 4 –20%, depending upon the extent of the aneurysm, and a 5 –30% incidence of renal failure.[4 – 9] The recommendation to proceed with surgical repair must, therefore, take into account this high complication rate, which must be balanced against the risk of aneurysm rupture. Careful preoperative assessment of coexistent comorbidities, standardized surgical techniques, and specific guidelines for postoperative management of these patients can have a favorable impact on the morbidity and mortality associated with this procedure, usually allowing for safe and effective repair.
Most TAA aneurysms are true aneurysms that involve all layers of the aortic wall. They occur most commonly as a result of degenerative disease associated with atherosclerosis but may also be seen as a result of cystic medial necrosis, seen in association with Marfan’s syndrome and other connective tissue disorders such as Ehlers – Danlos syndrome.[10] Another common cause of TAA aneurysms is chronic dissection. Currently, degenerative aneurysms are considered to be multifactorial in nature but are frequently referred to as atherosclerotic. Elastin degradation and collagen failure are believed to be the primary initiating events, and the importance of genetic factors is well recognized.[11] Giant cell arteritis, such as Takayasu’s arteritis, and other arteritides, trauma, and bacterial or fungal infections are etiologies seen less commonly.[10] Risk factors for patients with TAA aneurysms are shown in Table 44-1. When compared to patients with nondissecting aneurysms, patients with dissecting aneurysms differ with respect to several important risk factors. This difference has an effect on the operative mortality, incidence of postoperative complications, and late survival following repair (Tables 44-2 and 44-3).[12,13] Whereas the incidence of hypertension is equally high in both groups, preexisting coronary artery disease, chronic obstructive pulmonary disease (COPD), chronic renal failure, and cerebrovascular disease are more prevalent in patients with nondissecting aneurysms. These patients have a higher incidence of postoperative cardiac, pulmonary, and renal complications, whereas neurologic deficits occur more common in patients with dissecting aneurysms. Additionally, dissecting aneurysms generally are associated with a worse prognosis, with higher operative mortality and lower late survival rates. Regardless of their etiology, TAA aneurysms can be classified according to the extent of aneurysmal involvement
Hobson/Wilson/Veith: Vascular Surgery: Principles and Practice, Third Edition, Revised and Expanded DOI: 10.1081/0819-9-120024927 Copyright q 2004 by Marcel Dekker, Inc.
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642 Table 44-1.
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Comorbid Conditions in Patients with TAA Aneurysms
Author/year Hollier/1988 Golden/1991 Cox/1992 Svensson/1993 Schepens/1994 Safi/1994 Kashyap/1997
COPD (%)
CAD (%)
CVD (%)
Renal failure (%)
Hypertension (%)
DM (%)
Smoking (%)
42 37 41 40 27 36 NA
67 42 63 31 17 13 67
12 NA 15 15 12 12 NA
38 16 16 13 34 29 24
NA 71 77 73 66 67 85
6 NA 8 5 NA NA 8
90 66 84 NA NA NA NA
TAA = Thoracoabdominal aortic. COPD = Chronic obstructive pulmonary disease. CAD = Coronary artery disease. CVD = Collagen vascular disease. DM = Diabetes mellitus. NA = Not applicable.
affecting the descending thoracic and abdominal aorta. Type I TAA aneurysms are those that arise just distal to left subclavian artery and involve the entire thoracic aorta and upper abdominal aorta proximal to the renal arteries. Type II TAA aneurysms involve most of the descending thoracic aorta and the abdominal aorta, from the left subclavian artery to the level of the iliac bifurcation. Type III TAA aneurysms extend from the middescending thoracic aorta and include the abdominal aorta with involvement of the visceral segment. Type IV TAA aneurysms are those that involve the abdominal aorta and extend above the visceral vessels to the level of the diaphragm. This classification system, proposed initially by Crawford and colleagues,[3] has led to uniform reporting standards that allow for meaningful comparisons between series. It is also of prognostic significance because complication rates following surgical repair vary according to the extent and type of aneurysm undergoing repair, with the more extensive type I and II aneurysms carrying a higher postoperative complication rate, particularly with respect to spinal cord ischemia and renal failure.
NATURAL HISTORY Few studies in the literature are available on the natural history of TAA aneurysms. However, it appears that the natural history Table 44-2. Incidence of Postoperative Complications According to Etiology
of these aneurysms is similar to that of aneurysms elsewhere. With time, most TAA aneurysms increase in size and rupture rates, with larger aneurysms expanding at a faster rate and rupturing more frequently. Although aneurysm rupture is seen most commonly in patients with large aneurysms, some large aneurysms can remain stable for years, making expansion rates and rupture unpredictable in any individual patient. TAA aneurysms seem to have a worse prognosis when compared with abdominal aortic aneurysms. In a populationbased study, Bickerstaff and colleagues reported a 2-year survival rate of 29% for untreated patients with large thoracic and TAA aneurysms.[14] Aneurysm rupture occurred in 74% of patients observed during this period, with an associated mortality rate of 94%. Rupture and death were seen more commonly in patients with dissecting aneurysms as opposed to nondissecting aneurysms. The overall 5-year survival rate following diagnosis was only 13%, which compared poorly with the 75% survival rate for an age-matched population of patients without aneurysms. Other reports confirmed the poor results associated with nonoperative management of TAA aneurysms. In a study by Crawford and DeNalale, 76% of patients with TAA aneurysms who remained untreated because of the small size of their aneurysms, advanced age, or associated comorbidities died within 2 years of diagnosis.[2] Fifty-two percent of these deaths occurred as a result of aneurysm rupture.
Table 44-3. Survival Rate Following TAA Aneurysmal
Repair Complication
Nondissecting (%)
Dissecting (%)
Respiratory Cardiac failure Stroke Paraplegia Renal failure
32 11 3 13 21
12 7 4 25 18
Source: Modified with Permission from Panneton, J.M.; Hollier, L.H. Nondissecting Thoracoabdominal Aortic Aneurysms: Part I. Ann. Vasc. Surg. 1995, 9, 503– 514 and Panneton, J.M.; Hollier, L.H. Dissecting Descending Thoracic and Thoracoabdominal Aortic Aneurysms: Part II. Ann. Vasc. Surg. 1995, 9, 596–605.
Year 1 5 10
Nondissecting (%)
Dissecting (%)
80 61 33
74 50 –
TAA = Thoracoabdominal aortic. Source: Modified with Permission from Panneton, J.M.; Hollier, L.H. Nondissecting Thoracoabdominal Aortic Aneurysms: Part I. Ann. Vasc. Surg. 1995, 9, 503–514 and Panneton, J.M.; Hollier, L.H. Dissecting Descending Thoracic and Thoracoabdominal Aortic Aneurysms: Part II. Ann. Vasc. Surg. 1995, 9, 596–605.
Chapter 44.
More recently, Cambria and colleagues evaluated 57 patients with nondissecting TAA aneurysms who were initially managed nonoperatively.[15] Thirty-four of these 57 patients or 60% died during the follow-up period, which averaged 37 months. The most common cause of death was cardiopulmonary disease, accounting for 24% of all mortalities; followed by aneurysm rupture, responsible for 19% of deaths. The 2- and 5-year survival rates for those patients who remained untreated were 52% and 17%, respectively. While these results are more favorable than those reported by other investigators, this study excluded patients with dissecting TAA aneurysms, which are known to have a worse prognosis. Currently, we recommend elective aneurysm repair for those patients in whom the maximum aortic diameter exceeds 6 cm in good risk patients or greater than 7 cm in patients who represent a greater than average risk of surgery.
DIAGNOSIS TAA aneurysms usually cause no specific symptoms and are diagnosed incidentally as a result of imaging studies undertaken for other reasons; occasionally they may present with a number of signs and symptoms depending upon their extent and location. In a recent study of over 1500 patients
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who underwent TAA aneurysmal repair over a 30-year period, only 38% were truly asymptomatic; but while most patients described one or more symptoms, they were not generally thought to be related to their aneurysm.[7] The median age of patients with TAA was 66 years, with males outnumbering females and accounting for 65% of the patients. As TAA aneurysms enlarge, they can compress adjacent structures, which may result in pain that can be referred to the chest, back, flank, or abdomen. However, pain may also be indicative of aneurysm rupture or dissection, which is associated with a high morbidity and mortality. Therefore, the complaint of pain in a patient with a known TAA aneurysm, irrespective of its location, mandates rapid preoperative evaluation and expeditious repair if rupture appears imminent. Other signs and symptoms may include dyspnea, cough, wheezing, or recurrent pulmonary infections, which occur as a result of tracheobronchial obstruction from extrinsic compression in the superior mediastinum. Dysphagia and weight loss from esophageal obstruction have also been reported, and erosion into the tracheobronchial tree or esophagus may lead to hemoptysis or hematemesis. Erosion can also occur into the vena cava, resulting as an aortocaval fistula, presenting with lower-extremity edema and congestive heart failure. A less common complaint is hoarseness, which can occur from stretching of the left recurrent laryngeal nerve by the enlarging aneurysm. Finally, embolization of
Figure 44-1. Chest x-ray showing widening of the mediastinal shadow by an aneurysm of the descending thoracic aorta.
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Figure 44-2.
Operative photography of a thoracoabdominal aneurysm.
thrombotic or atheromatous debris may result in visceral or lower extremity ischemia, or paraplegia may occur from embolization or thrombosis of the spinal arteries. In asymptomatic patients, the presence of a pulsatile abdominal mass or suspicious chest x-ray (CXR) (Fig. 44-l) may suggest the diagnosis of a TAA aneurysm (Fig. 44-2). This diagnosis may be confirmed by computed tomography (CT) scan with intravenous contrast (Fig. 44-3), magnetic resonance imaging (MRI) (Fig. 44-4), transesophageal echocardiography, or conventional angiography (Fig. 44-5). It is our belief that the combination of CT scanning with IV contrast and angiography provide the optimum anatomic information necessary before surgical reconstruction. These imaging studies accurately establish the proximal and distal extent of the aneurysm, and ascertain the presence or absence of dissection, rupture, or associated occlusive disease that might involve the lower extremities, renal or visceral arteries.
PREOPERATIVE EVALUATION Patients with TAA aneurysms frequently have comorbid conditions, such as advanced age, pulmonary dysfunction, cardiovascular disease, cerebrovascular disease, and renal insufficiency (Table 44-1) which increase the morbidity and mortality associated with aneurysm repair. A thorough
preoperative evaluation, therefore, is necessary to improve the overall results associated with operative intervention. A large percentage of patients undergoing TAA aneurysm repair are heavy smokers and suffer from underlying COPD. Respiratory complications have been the most common complications seen in the postoperative period and have been a major cause of morbidity and mortality. Their presence decreased the 30-day survival rate from 98% to 80%. In a study by Svensson and colleagues, only 19% of patients with TAA aneurysms had never smoked. COPD was present in 56% of the patients, and 58% of these developed respiratory failure following surgical repair.[16] Overall, 43% of patients required ventilatory support for more than 2 days after operative intervention and 15% required a tracheostomy. Other studies have also established respiratory failure as the most common complication following TAA aneurysm repair.[17] However, certain measures, such as cessation of smoking for at least one week before surgical repair, the use of bronchodilators, corticosteroids, and antibiotics for treatment of bronchitis, as well as good pulmonary toilet in the postoperative period, can substantially decrease the high incidence of respiratory complications. A history of heavy smoking, productive cough, dyspnea on exertion, or the diagnosis of COPD are generally considered indications for preoperative pulmonary function tests and arterial blood gas analysis. The finding of a significant decrease in forced vital capacity (FVC) or forced expiratory volume over one second (FEV1) is associated with an increase
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Figure 44-3. Computed tomographic scan demonstrating an inflammatory thoracoabdominal aneurysm. Note the contrast-enhancing inflammatory wall of the aneurysm (arrow).
in postoperative pulmonary complications. Preoperative optimization of respiratory function in these difficult patients is of utmost importance and appears to modify the postoperative pulmonary complications. Cardiovascular and cerebrovascular disease are also common comorbid conditions found in patients with TAA aneurysms. As demonstrated by Svensson and colleagues, over 30% of patients with TAA aneurysms will have associated significant cardiac disease, with an additional 15% having cerebrovascular disease defined by the presence of a previous transient ischemic attack, stroke, or carotid endarterectomy.[7] Echocardiography and a dipyridamole thallium scan are obtained routinely in asymptomatic and in sedentary, minimally symptomatic patients, because of the high incidence of underlying silent cardiovascular disease. These studies attempt to assess cardiac risk by evaluating ventricular function, excluding valvular insufficiency, and determining whether a significant segment of myocardium is at risk for ischemia. Patients with more severe cardiac symptoms or those with poor ventricular function or evidence of significant thallium redistribution should undergo coronary angiography.[18] Cardiac revascularization before aneurysm repair is recommended in the presence of severe reconstructible coronary artery disease. Carotid artery duplex studies are also performed routinely as part of the preoperative assessment of patients with TAA
aneurysms, regardless of whether symptoms of cerebrovascular insufficiency are present. Carotid endarterectomy is recommended before aneurysm repair in the presence of a high-grade stenosis. This approach, which is usually well tolerated, will not significantly delay aneurysm repair yet decreases the incidence of postoperative stroke.
OPERATIVE TREATMENT Successful repair of TAA aneurysms requires close cooperation between the anesthesiologist and surgeon. Before induction of general endotracheal anesthesia, a pulmonary artery catheter and right radial arterial catheter are placed to monitor the patient’s hemodynamics and optimize cardiac function. Intraoperative transesophageal echocardiography is also used throughout the procedure to follow the patient’s volume status and detect wall-motion abnormalities suggestive of myocardial ischemia. At least two large-bore IV catheters are inserted, with one connected to a rapid infusion device (RIS, Haemonetics). Additionally, an autotransfusion device (Cell Saver, Braintree, MA) is used to minimize the need for banked blood. An indwelling urinary catheter is placed, and a dose of IV antibiotics is administered before
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Figure 44-4. (A) Magnetic resonance imaging demonstrating an intercostal artery arising from a thoracoabdominal aortic aneurysm. (B) High-resolution magnetic resonance imaging showing the anterior spinal artery originating from the artery of Adamkiewicz.
Chapter 44.
Figure 44-5. Aortogram of a patient with a thoracoabdominal aortic aneurysm.
incision. The patient is then intubated with a dual lumen endotracheal tube, which allows for selective deflation of the left lung, a maneuver that facilitates exposure of the thoracic aorta to the level of the left subclavian artery. Proximal exposure to this level is often necessary, particularly for patients with type I and II TAA aneurysms. For cerebrospinal fluid (CSF) drainage, we also insert a spinal catheter into the 4th lumbar interspace, draining fluid as needed to maintain CSF pressure below 10 mmHg. In both experimental and clinical studies this technique has been shown to decrease the incidence of postoperative paraplegia from spinal cord ischemia.[9,22,23] An epidural catheter is placed above the spinal catheter for postoperative pain control. A decision is then made regarding the need for distal aortic perfusion, which can be achieved through one of several techniques and allows for retrograde perfusion of the intercostal, lumbar, renal, celiac, superior mesenteric, and iliac arteries. This technique reduces the extent and severity of ischemia distal to the aortic cross-clamp while the proximal anastomosis is constructed and critical intercostals are reimplanted. Whereas several authors have reported a decrease in the incidence of postoperative complications (e.g., paraplegia and renal failure) by using distal aortic perfusion to reduce ischemia time to the spinal cord and
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abdominal viscera, others have noted equally good results by using a simple clamp-and-sew technique.[8,9,19,20] We favor distal aortic perfusion for most patients with type I and II aneurysms, reserving a clamp-and-sew technique for those patients with type III and IV aneurysms in whom reconstruction can usually be achieved in under 30 minutes. Distal aortic perfusion has an additional advantage in that it also minimizes the increase in afterload associated with placement of a proximal aortic cross-clamp, decreasing the need for pharmacologic control of proximal hypertension and, therefore, the incidence of cardiac complications. Different options are available for distal perfusion, including femorofemoral bypass, atriofemoral bypass, an external heparin-bonded shunt from the ascending aorta to the descending or abdominal aorta, and axillofemoral bypass. Each has certain advantages and disadvantages. Femorofemoral bypass involves placing a venous cannula through the femoral vein into the right atrium, with an arterial cannula placed into the distal aorta or proximal iliac artery by way of the femoral artery. This approach requires the use of pump perfusion along with a membrane oxygenator and heat exchanger, with full systemic heparinization. Exposure of the femoral vessels through a separate incision is also required. In general, flow rates of about 2–3 L per minute are sufficient to maintain a distal perfusion pressure above 60 mmHg. Atriofemoral bypass may be more beneficial since it does not require full heparinization. Placement of a cannula directly into the left atrium eliminates the need for a membrane oxygenator and heat exchanger, which itself reduces the requirement for full anticoagulation. A separate incision to expose the femoral artery and allow for placement of an arterial cannula is also required with this approach. Both of the techniques mentioned previously involve the use of pump perfusion, which can possibly activate clotting factors and induce a fibrinolytic state. Passively shunting blood from the ascending to descending thoracic or abdominal aorta by means of an external, heparin-bonded shunt is another option available for distal perfusion. However, this technique requires more extensive exposure and is rarely used by us. In some instances, however, we do use a temporary right axillary-to-right femoral artery bypass using 10 mm externally supported polytetrafluorethylene (PTFE) graft, as reported by Comerota and White.[21] This procedure is done with the patient in a supine position just before starting the TAA aneurysmal repair. The graft itself is not tunneled in the subcutaneous tissue and is removed after completing the procedure. This approach avoids the need for heparinization, but has the disadvantage of lengthening the procedure and adding two additional wounds, with the potential for complications. It also requires repositioning the patient before proceeding with aneurysm repair. After completing the above preparatory steps, the patient is positioned on the operating room table right side down. The table is slightly flexed in the lumbar region and the shoulders are placed at a 90 degree angle to the table with the hips at a 30 degree angle. This position is maintained by use of an deflatable beanbag. The left arm is elevated and moved to the right and secured on an overhead arm board. After the patient has been prepped and draped, a left posterolateral thoracotomy incision is performed and carried onto the abdominal wall, curving downwards along the midline or
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extending obliquely across the abdomen. The precise location of this incision depends on the type of aneurysm undergoing repair. For patients with type I and II TAA aneurysms, the thoracotomy incision is centered over the 4th, 5th, or 6th intercostal space, with additional exposure gained by resecting one of these ribs, if necessary. In patients with less extensive disease undergoing repair of type III or IV TAA aneurysms, the thoracotomy incision is made over the 7th, 8th, or 9th interspace. Following entry into the chest, the left lung is deflated and the inferior pulmonary ligament is divided. This procedure permits mobilization of the left lung, which is retracted superiorly and medially. The mediastinal pleura is then incised to expose the underlying descending thoracic aorta. If necessary, this dissection is extended proximally to the level of the left subclavian artery. The left vagus and recurrent laryngeal nerves are identified and preserved. Occasionally, aneurysmal dilatation of the descending thoracic aorta involves the origin of the left subclavian artery, requiring separate control of this vessel and more proximal control of the aortic arch. After completing this proximal dissection, the diaphragm is divided in a circumferential fashion, with marking sutures placed along the edges of the divided diaphragm to facilitate later reapproximation. The crus of the diaphragm is also divided, exposing the underlying aorta. The abdominal dissection is then performed through either a transperitoneal or retroperitoneal route. Dissection proceeds along the left paracolic gutter, elevating the abdominal viscera and rotating these structures medially. Care is taken to avoid splenic injury while dividing the splenophrenic ligament. The left kidney is elevated along with the abdominal viscera, exposing the left renal artery—usually easily identified. The left renal vein is located just below the left renal artery. A lumbar branch originating from the inferior, posterior aspect of the left renal vein must be identified and divided to fully rotate the left kidney medially. The right renal artery is not visualized in this approach, though the celiac and superior mesenteric vessels are usually readily visible. This dissection is carried distally in a plane posterior to the inferior mesenteric artery, exposing the abdominal aorta down to the bifurcation. However, exposure of the distal right common iliac artery is somewhat limited. After proximal and distal control have been obtained, the patient is systemically heparinized, with the extent of anticoagulation determined by the method chosen for distal aortic perfusion. Mannitol and furosemide are administered to induce a brisk diuresis, and mild hypothermia along with a dose of corticosteroids are used as additional means of spinal cord protection. The proximal cross-clamp is then placed, usually distal to the left subclavian artery, with a distal cross-clamp placed a short distance away. This sequential cross-clamping technique permits retrograde distal perfusion. The aneurysmal aorta is opened longitudinally and the proximal descending aorta completely divided to avoid incorporating the esophagus into the anastomosis. A properly sized, collagen-impregnated Dacronw graft is then sewn to the descending aorta with a running stitch of 3-0 prolene suture material. In the presence of a friable aortic wall, this proximal anastomosis is reinforced with a Teflonw felt strip.
After completing this anastomosis, the cross-clamps are moved distally and the suture line is tested for hemostasis. Next, the distal aortic clamp is moved lower on the aorta and the aneurysm is opened more extensively to expose the origins of the distal intercostal arteries and the visceral vessels. Endarterectomy of the origin of the visceral vessels occasionally may be necessary in the presence of associated visceral occlusive disease, but we try never to endarterectomize the intercostal artery orifices because of the high risk of dissection of these vessels. Critical intercostal arteries are then reimplanted using a patchinclusion technique, done by creating a defect in the posterior aspect of the graft and incorporating the segment of aortic wall containing the critical intercostal arteries with a running suture of 3-0 prolene. A similar patch inclusion technique is used to incorporate the celiac, superior mesenteric, and right renal arteries. Usually, the origin of the left renal artery is located too far away from the other visceral vessels to allow for incorporation into this patch, necessitating separate anastomosis of the left renal artery to the graft. However, in some patients a separate graft to the left renal artery may be needed. If the origins of the visceral vessels are widely spaced, or in the presence of dissection, separate grafts to each of the visceral vessels may be necessary. Backbleeding lumbar arteries are oversewn and a decision is made regarding the need to reimplant the inferior mesenteric artery. Finally, the distal anastomosis is completed by suturing the distal end of the graft to the aortic bifurcation. When aneurysmal dilatation extends into the iliac arteries, a bifurcation graft may be needed to accomplish distal perfusion to the lower extremities. Care should be taken to insure that one maintains flow through at least one hypogastric artery to minimize the added risk of colon or cauda equina ischemia. After completing the reconstruction, the aneurysm sac is closed over the graft to prevent contact between the graft and the abdominal viscera. Additionally, closing the sac of the aneurysm over the graft minimizes bleeding from the edges of the aneurysm and aids with hemostasis. If the aneurysm sac cannot be reapproximated over the graft, a PTFE membrane is used for coverage. Platelets, fresh frozen plasma (FFP), and cryoprecipitate are administered while the aneurysm sac is being closed to help ensure adequate hemostasis. Protamine may also be needed, depending upon the amount of heparin administered. The diaphragm is then closed using the marking sutures placed previously as a guide. The chest is closed in multiple layers, leaving two 32 Fr thoracostomy tubes inserted through separate stab wound incisions in the thoracic cavity. Next, the abdominal viscera are inspected, proper positioning of a nasogastric tube is verified, and the abdomen is closed in standard fashion. A closed-suction drain is rarely placed in the retroperitoneum before closure. If distal aortic perfusion was used, all cannula are removed and the femoral vessels repaired. The groin wound is then closed in layers, with the skin closed using a running subcuticular stitch to avoid potential wound complications. Likewise, if a temporary axillofemoral bypass was used, the graft is removed and the axillary and femoral vessels repaired.
Chapter 44.
POSTOPERATIVE CARE Following TAA aneurysmal repair, the patient is transferred to the surgical intensive care unit (SICU). Particularly close attention is given to the patient’s blood pressure, heart rate, respiratory rate, and urine output. The CSF drainage is continued for an additional 2 –3 days to minimize delayedonset paraplegia that may result from progressive spinal cord edema. Central venous pressure, pulmonary capillary wedge pressure, cardiac output, and peripheral vascular resistance are monitored frequently, and laboratory indicators such as a complete blood cell (CBC) count, coagulation studies, serum electrolytes, serum creatinine, and arterial blood gases are checked regularly. Blood products are often necessary in the postoperative period to optimize the patient’s hemodynamics and correct any residual coagulopathy. Electrolyte disturbances, particularly hypokalemia and hypoxemia, are avoided because they may rapidly precipitate a lethal cardiac arrhythmia. No attempts at extubation are made during the first postoperative day; rather, the patient is maintained intubated and sedated. In the presence of significant facial edema, the dual lumen endotracheal tube is not exchanged until the following day for fear of losing control of the airway. A chest x-ray and an electrocardiogram are obtained immediately postoperatively and on a daily basis until the patient is sufficiently stable to leave the SICU. The patient’s sedatives are discontinued on the second postoperative day, when weaning from the ventilator is initiated. At this time it is usually possible to more adequately assess the patient’s neurologic function, which is followed closely. The spinal catheter is discontinued on the third postoperative day. If a delayed neurologic deficit occurs, reinsertion of the spinal catheter is performed rapidly, draining fluid to maintain a CSF pressure of less than 10 mmHg while the patient’s hemodynamics are optimized. In a recent report by Safi and colleagues, this approach resulted in significant improvements in neurologic function in all those patients who developed a delayed deficit.[22] Maintenance fluids initially are given at the rate of 125 mL per hour and additional IV fluids are given to match the urine output on a cc/cc basis. This is necessary
Table 44-4.
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since after the period of intraoperative renal ischemia, there is an obligatory high output loss of fluids while the renal tubules are temporarily dysfunctional. The fluid replacement for urine losses can usually be discontinued the day after surgery and the maintenance IV fluids are usually decreased from 125 mL per hour on the first postoperative day to 100 mL per hour on the second postoperative day and 60 mL per hour on the third day, in anticipation of third-space fluid mobilization. Diuretics are frequently administered on the third postoperative day, when chest tubes, nasogastric tubes, and closed-suction drains can usually be removed. An oral diet is resumed after bowel function has returned. Ambulation is encouraged after the patient has been extubated and the epidural catheter is removed.
RESULTS The morbidity and mortality associated with TAA aneurysm repair has decreased significantly since the procedure was first performed over 40 years ago. Careful preoperative evaluation and advancements in perioperative care and surgical technique, the introduction of the graft inclusion technique, and the use of CSF drainage largely have been responsible for these improved results. Hollier, Safi, Acher, and Brewster now report operative mortality rates of less than 10% and paraplegia rates of less than 10%. Nontheless, despite this progress, mortality, neurologic injury, and renal dysfunction rates are still greater than desirable. The incidence of these devastating complications are still noted to vary according to extent of the aneurysm undergoing repair, cross-clamp times, age of the patient, and presence of comorbid conditions. As seen in Table 44-4, the incidence of paraplegia reported in the literature varies from 5% to 20%, with renal failure rates of 5% to 30%. As described previously, several methods have been used successfully to decrease the incidence of these devastating complications. Spinal cord protection can be improved by CSF drainage, distal aortic perfusion, reimplantation of critical intercostals, mild hypothermia, and IV corticosteroids.[9,19,20,23] Distal aortic perfusion and/or selective visceral artery perfusion can also help decrease renal failure rates and
Postoperative Complications Following TAA Aneurysmal Repair
Author/year Hollier/1988 Golden/1991 Cox/1992 Svensson/1993 Schepens/1994 Safi/1994 Acher/1998
30-day mortality (%)
Paraplegia (%)
Renal failure (%)
Respiratory failure (%)
MI/cardiac failure (%)
15 5 35 8 6 4 10
5 16 21 16 14 9 8
4 29 29 18 14 7 NA
33 26 36 33 26 47 NA
9 5 10 12 23 9 NA
TAA = Thoracoabdominal aortic. MI = Myocardial infarction. NA = Not applicable.
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minimize hemorrhagic complications. Renal dysfunction can be minimized by adequate preoperative hydration, administration of mannitol and furosemide prior to cross-clamping, and endarterectomy or renal bypass in the presence of associated renal artery occlusive disease. Cold perfusion of the kidneys may also useful, and some authors have reported improved results using this technique.[24,25]
CONCLUSION The surgical treatment of TAA aneurysms has improved significantly in recent years. Whereas the operative mortality associated with elective repair has been reduced to under 10%, the morbidity of this procedure still remains high due to the high incidence of postoperative complications. Equally good results have not been attained for patients undergoing repair of ruptured TAA aneurysms. In one recent report, Acher and colleagues documented an operative mortality rate of 1.6% for patients undergoing elective repair, but a 21% mortality rate for a similar group of patients who presented with acute symptoms.[26] Crawford et al. reported operative mortality of about 25% for patients with ruptured
TAA aneurysms,[27] but others report much higher mortality. A review by Johansson and colleagues noted an operative mortality rate of 97 –100% for patients with ruptured TAA aneurysms.[28] This high mortality rate associated with rupture mandates an aggressive approach in the management of these difficult patients. Therefore, for thoracoabdominal aneurysms of significant size, we favor operative intervention for most asymptomatic patients and virtually all symptomatic patients, particularly if they present with rupture. In general, the risks associated with aneurysmal rupture exceed the risk of surgical treatment when aneurysm size exceeds 6 – 7 cm, although the presence of significant comorbid conditions may require deferring surgical reconstruction in extremely high-risk patients. Further experience with endovascular techniques may, in the future, offer the patient additional options for repair of these difficult aneurysms. Until then, however, careful preoperative assessment, optimization of the patient’s overall condition, good surgical technique, and specific guidelines for postoperative care of these patients remains the best approach to achieve successful repair of these complicated aneurysms. It is our hope that future advances in this field may help further decrease the morbidity and mortality associated with this procedure.
REFERENCES 1. Svensson, L.G. Natural History of Aneurysms of the Descending and Thoracoabdominal Aorta. J. Cardiovasc. Surg. 1997, 12 (Suppl.), 279– 284. 2. Crawford, E.S.; DeNalale, R.W. Thoracoabdominal Aortic Aneurysms: Observations Regarding the Natural Course of Disease. J. Vasc. Surg. 1986, 3, 578– 582. 3. Crawford, E.S.; Crawfors, J.L.; Safi, H.J.; et al. Thoracoabdominal Aortic Aneurysms: Preoperative and Intraoperative Factors Determining Immediate and Long Term Results of Operations in 605 Patients. J. Vasc. Surg. 1986, 3, 389– 404. 4. Hollier, L.H.; Symmonds, J.B.; Pairolero, P.C.; et al. Thoracoabdominal Aortic Aneurysm Repair: Analysis or Postoperative Morbidity. Arch. Surg. 1988, 123, 871 – 875. 5. Golden, M.A.; Donaldson, M.C.; Whittemore, A.D.; et al. Evolving Experience with Thoracoabdominal Aortic Aneurysm Repair at a Single Institution. J. Vasc. Surg. 1991, 13 (6), 792– 797. 6. Cox, G.S.; O’Hara, P.J.; Hertzer, N.R.; et al. Thoracoabdominal Aneurysm Repair: A Representative Experience. J. Vasc. Surg. 1992, 15 (5), 780–798. 7. Svensson, L.G.; Crawford, E.S.; Hess, K.R.; et al. Experience with 1509 Patients Undergoing Thoracoabdominal Aortic Operations. J. Vasc. Surg. 1993, 17 (2), 357– 370. 8. Schepens, M.A.; Defauw, J.J.; Hamerlijnck, R.P.; et al. Surgical Treatment of Thoracoabdominal Aortic Aneurysms by Simple Cross-Clamping. Risk Factors and Late Results. J. Thorac. Cardiovasc. Surg. 1994, 107 (1), 134– 142.
9. Safi, H.J.; Bartoli, S.; Hess, K.R.; et al. Neurological Deficit in Patients at High Risk with Thoracoabdominal Aortic Aneurysms: The Role of Cerebral Spinal Fluid Drainage and Distal Aortic Perfusion. J. Vasc. Surg. 1994, 20 (3), 434– 443. 10. Pitt, M.P.; Bonser, R.S. The Natural History of Thoracic Aortic Aneurysm Disease: An Overview. J. Cardiovasc. Surg. 1997, 12 (Suppl.), 270– 278. 11. Patel, M.I.; Hardman, D.T.; Fisher, C.M.; et al. Current Views on the Pathogenesis of Abdominal Aortic Aneurysms. J. Am. Coll. Surg. 1995, 181, 371– 382. 12. Panneton, J.M.; Hollier, L.H. Nondissecting Thoracoabdominal Aortic Aneurysms: Part 1. Ann. Vasc. Surg. 1995, 9, 503–514. 13. Panneton, J.M.; Hollier, L.H. Dissecting Descending Thoracic and Thoracoabdominal Aortic Aneurysms: Part II. Ann. Vasc. Surg. 1995, 9, 596– 605. 14. Bickerstaff, L.K.; Pairolero, P.C.; Hollier, L.H.; et al. Thoracic Aortic Aneurysms: A Population Based Study. Surgery 1982, 92, 1103– 1108. 15. Cambria, R.A.; Gloviczki, P.; Stanson, A.W.; et al. Outcome and Expansion Rate of 57 Thoracoabdominal Aortic Aneurysms Managed Nonoperatively. Am. J. Surg. 1995, 170, 213– 217. 16. Svensson, L.G.; Hess, K.R.; Coselli, J.S.; et al. A Prospective Study of Respiratory Failure After High Risk Surgery on the Thoracoabdominal Aorta. J. Vasc. Surg. 1991, 14 (3), 271– 282. 17. Money, S.R.; Rice, K.; Crockett, D.; et al. Risk of Respiratory Failure After Repair of Thoracoabdominal Aortic Aneurysms. Am. J. Surg. 1994, 168, 152– 155.
Chapter 44. 18.
19.
20.
21.
22.
23.
Hollier, L.H. Cardiac Evaluation in Patients with Vascular Disease—Overview: A Practical Approach. J. Vasc. Surg. 1992, 15, 726– 728. Kouchoukos, N.T.; Wareing, T.H.; Izumoto, K.; et al. Elective Hypothermic Cardiopulmonary Bypass and Circulatory Arrest for Spinal Cord Protection During Operations on the Thoracoabdominal Aorta. J. Thorac. Cardiovasc. Surg. 1990, 99, 659– 664. Frank, S.M.; Parker, S.D.; Rock, P.; et al. Moderate Hypothermia, with Partial Bypass and Sequential Repair for Thoracoabdominal Aortic Aneurysm. J. Vasc. Surg. 1994, 19, 687– 697. Comerota, A.J.; White, J.V. Reducing the Morbidity of Thoracoabdominal Aneurysm Repair by Preliminary Axillofemoral Bypass. Am. J. Surg. 1995, 170, 218– 222. Safi, H.J.; Miller, C.C.; Azizzadeh, A.; et al. Observations on Delayed Neurological Deficit After Thoracoabdominal Aortic Aneurysm Repair. J. Vasc. Surg. 1997, 26, 616– 622. McCullough, J.L.; Hollier, L.H.; Nugent, M. Paraplegia After Thoracic Aortic Occlusion: Influence of Cerebro-
24.
25.
26.
27.
28.
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spinal Fluid Drainage. Experimental and Early Clinical Results. J. Vasc. Surg. 1988, 7, 153– 160. Svensson, L.G.; Crawford, E.S.; Hess, K.R.; et al. Thoracoabdominal Aortic Aneurysms Associated with Celiac, Superior Mesenteric, and Renal Artery Occlusive Disease: Methods and Analysis of Results in 271 Patients. J. Vasc. Surg. 1992, 16, 378– 390. Kashyap, V.S.; Cambria, R.P.; Davison, J.K.; et al. Renal Failure After Thoracoabdominal Aortic Surgery. J. Vasc. Surg. 1997, 26, 949– 957. Acher, C.W.; Wynn, M.M.; Hoch, J.R.; et al. Cardiac Function Is a Risk Factor for Paralysis in Thoracoabdominal Aortic Replacement. J. Vasc. Surg. 1998, 27, 821– 830. Crawford, E.S.; Hess, K.R.; Cohen, E.S.; et al. Ruptured Aneurysm of the Descending Thoracic and Thoracoabdominal Aorta. Analysis According to Size and Treatment. Ann. Surg. 1991, 213, 417– 426. Johansson, G.; Markstrom, U.; Swedenborg, J. Ruptured Thoracic Aortic Aneurysms: A Study of Incidence and Mortality Rates. J. Vasc. Surg. 1995, 21, 985– 988.
CHAPTER 45
Popliteal Artery Aneurysm Timothy P. Connall Samuel E. Wilson Popliteal artery aneurysms are the most common peripheral artery aneurysms, comprising 70% of these lesions. Surgical treatment of these aneurysms dates to Antyllus, a thirdcentury Greek physician who ligated both poles of the aneurysm and incised and packed the aneurysm sac. In 1785 John Hunter treated a coachman with a popliteal aneurysm by simply ligating the superficial femoral artery above the aneurysm (in what today is called Hunter’s canal ).[1] Matas performed endoaneurysmorrhaphy by ligating all branch vessels from within the aneurysm and suturing the walls of the aneurysm together; he performed this surgery on 154 popliteal aneurysms from 1888 to 1920. In the 1950s, aneurysm excision with vein interposition and aneurysm exclusion with venous bypass became the primary methods of treatment.
There is an astonishingly high rate of additional aneurysms in patients with popliteal aneurysm (Table 45-1). Bilateral popliteal aneurysms are found in about 50% of cases. Extrapopliteal aneurysms are found in 40– 75% of patients with a single popliteal aneurysm; if bilateral popliteal aneurysms are present, there is a 68–87% incidence of extrapopliteal aneurysm disease.[5,6,14,17] The abdominal aorta is most often affected, followed by the femoral and iliac arteries. These high rates of associated aneurysms suggest that popliteal aneurysm represents a more aggressive form of “aneurysm disease” than that seen in standard infrarenal aortic aneurysms. The specific genetic defects that lead to end arterial damage are yet to be fully elucidated.[18,19] In the patient with a popliteal aneurysm, a thorough search must be made for additional aneurysms, particularly of the abdominal aorta and contralateral popliteal artery.
EPIDEMIOLOGY CLINICAL FEATURES Though popliteal aneurysm (Fig. 45-1) is the most common peripheral artery aneurysm, its prevalence in the general population is low. In a series from the Henry Ford Hospital, popliteal aneurysm accounted for 1 in 5000 hospital admissions; there was 1 popliteal aneurysm per 15 abdominal aortic aneurysms. Popliteal aneurysm is a disease found almost exclusively in men, most often in the sixth decade of life (Table 45-1). Most popliteal aneurysms are fusiform and associated with atherosclerosis as their presumed primary etiology. Less common etiologies include trauma such as after knee dislocation, knee replacement, or knee arthroscopy,[2] inflammatory arteritides such as Behc¸et’s or Kawasaki disease,[3] infected emboli, and bacteremia such as with Staphylococcus and Salmonella.[4] Nearly all popliteal aneurysms are atherosclerotic. Other etiologies include popliteal artery entrapment syndrome, trauma, and infection, but these causes are uncommon, occurring in less than 10% of cases.[5 – 9] Diseases frequently associated with atherosclerosis are found in patients with popliteal aneurysm. Coronary artery disease and cerebral vascular disease occur, respectively, in 35 and 10% of patients; hypertension is present in 45%; and diabetes mellitus in 13%.[3,7 – 13]
Approximately 70% of patients with popliteal aneurysms will be symptomatic at initial presentation. Popliteal aneurysms present the vast majority of the time with complications of thromboembolic disease ranging from claudication to rest pain and ischemic gangrene. Popliteal aneurysms, in contrast to aortic aneurysms, present with rupture less than 5% of the time.[13,15,17,20] Popliteal aneurysms present with symptoms of compression of neighboring structures such as the sciatic nerve and popliteal vein 10% of the time.[13,15,17,20] Compression may lead to radiculopathy, venous thrombosis, and even arteriovenous fistula.[21]
DIAGNOSIS Physical exam by a person familiar with a normal popliteal pulse is usually an accurate and adequate screening test for low-risk patients. Occasionally a nonvascular mass such as a Baker’s cyst may be mistaken on exam for an aneurysm. When a definitive diagnosis is important, duplex ultrasound is the procedure of choice. A popliteal artery greater than 2 cm
Hobson/Wilson/Veith: Vascular Surgery: Principles and Practice, Third Edition, Revised and Expanded DOI: 10.1081/0819-9-120024928 Copyright q 2004 by Marcel Dekker, Inc.
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Prior to elective operative intervention it is prudent to screen for other aneurysms because of their relatively high coincidence. Depending on the findings of these screening tests, the order of treatment may need to be altered. Ultrasound provides adequate sensitivity and specificity for most clinical situations. Computed tomography (CT) and magnetic resonance imaging (MRI) provide equal and, in some cases, superior images. The CT scan with recent advances to allow three-dimensional reconstruction and luminal “angiographic” reconstruction can provide angiographic quality pictures to the level of the popliteal artery. The tibial vessels are too small to be meaningfuly visualized with current CT technology. The MRI/MRA has higher resolution of small vessels and can often provide enough information regarding popliteal and tibial runoff to obviate the need for arterial angiography, especially when angiographic morbidity is high as with renal insufficiency.
MANAGEMENT Symptomatic Aneurysms Thromboembolic disease from the popliteal arterial aneurysm typically has a progressive natural history. Given the relatively low rates of limb salvage once extensive embolization has occurred, any embolization should be considered a strong indication for surgery. Complete aneurysm and artery thrombosis without embolization may also occur. The natural history of this condition is presumed by some to be more benign and similar to simple atherosclerotic occlusion. Despite surgical intervention, 16– 50% of extremities that present with acute thrombosis or thromboembolism go on to major amputation as either a primary or secondary procedure.[5,12 – 14,16] Figure 45-1.
A typical angiogram of a popliteal aneurysm.
Asymptomatic Aneurysms [14]
in diameter is usually considered aneurysmal. To avoid misinterpretation of a slight dilatation as an aneurysm in patients with arteriomegaly, it is appropriate to compare the diameter of the dilated vessel to the diameter of the distal superficial femoral artery. In such instances a vessel with a diameter 1.5–2.0 times the diameter of the proximal vessel is considered aneurysmal.[12,14] Table 45-1.
The management of asymptomatic popliteal aneurysms is a subject of some controversy. Accumulation of prospective natural history data on asymptomatic popliteal aneurysms is difficult as even large centers usually see fewer than 10 of these lesions per year. The retrospective data available suggest that anywhere from 29 to 59% of popliteal aneurysms will become symptomatic.[6,22 – 24] The variables that will
Epidemiology and Percentage of Additional Aneurysms in Patients with Popliteal Aneurysm Percentage of other aneurysms
Series Reilly et al.[11] (1983) Whitehouse et al.[12] (1983) Vermilion et al.[13] (1981) Shortell et al.[16] (1991) Halliday et al.[5] (1991) a
Abdominal aortic aneurysm.
Number of patients
Mean age
Male: female
AAAa
Iliac
Femoral
Bilateral popliteal
70 61 87 39 40
70 67 60 63 64
15:1 30:1 28:1 39:0 19:1
32 62 40 39 30
8 36 25 18 5
15 38 34 14 22
53 44 68 24 50
Chapter 45. Popliteal Artery Aneurysm
predispose to thromboemmbolism likely include size and intraluminal thrombus, but this is not well defined. Dawson et al.[24] retrospectively followed 42 patients for an average of 6.2 years with asymptomatic popliteal aneurysms with an average aneurysm size of 3.1 cm. At 18 months 59% developed symptoms, culminating in three leg amputations, one peroneal nerve palsy, and eight limbs with claudication. Delaying therapy until the onset of symptoms may avoid operation in high-risk individuals, but it will also adversely effect surgical outcome because of the loss of outflow. Varga et al.[25] followed 137 patients newly diagnosed with popliteal aneurysms to look at variables affecting outcome. Grafts placed emergently had a 10% early bypass failure rate as opposed to 1.2% of those placed electively. Regarding safety and efficacy, in four series reporting operation on patients with asymptomatic aneurysms there were no operative deaths, long-term limb loss was 0–3%, and 89 –97% of patients remained symptom-free.[5,11,13,14] In summary, the indications for repair of popliteal aneurysms requires some surgical judgment. In contrast with aortic aneurysms, the complications of popliteal aneurysms are never life-threatening, and in the high-risk patient a case can always be made for nonoperative management. For most patients elective repair of a popliteal aneurysm (femoral-popliteal bypass with autologous vein) is a definitive, safe operation that has clinical results that rival or exceed similar operations done for occlusive disease.[26] We recommend that an isolated asymptomatic popliteal aneurysm large enough to cause arterial turbulence or thrombus formation be considered for operative repair. These criteria would typically include aneurysms greater than 2.5 cm. In the future, should less morbid methods of treatment be proven, such as endovascular therapy, the indications for repair could be further liberalized. As mentioned above, the presence of thromboembolism defined either clinically or radiologically should be considered a strong indication for surgery to avoid limb loss.
Thrombolytic Therapy Thrombolytics such as urokinase, streptokinase, and t-PA are medications that catalyze endogonous fibrinolytic pathways. They have been shown effective at lysis of thrombus both acute and chronic, venous and arterial, and in situ or embolic. Whether vascular patency will be preserved after thombolytic recanalization depends on the nature of the primary lesion. The use of thrombolytics in the treatment of popliteal aneurysms has strong theoretical appeal where the most frequent cause of graft failure is thomboembolic occlusion of outflow vessels. The use of surgical thrombectomy is not necessarily easier because of frequent concomitant athero-occlusive disease and the difficulty in surgically managing inframalleolar thromboembolism. As was shown in the Topas trial, the use of initial thrombolytics for acute ischemia may be associated with similar limb salvage and lower mortality when compared to initial surgery. Thrombolytics may stimulate additional embolism from the aneurysm sac. Catheter-based infusion directly into the distal embolus may help prevent additional embolization
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from the aneurysm sac. Preoperative thrombolytic use on a known thrombosed popliteal aneurysm without embolization is unnecessary and unwise. The diagnosis of popliteal aneurysm is occasionally made incidentally after therapeutic thrombolysis for presumed atherosclerotic occlusion. The overall effect of thrombolyics in a patient with thromboembolic outflow compromise appears to be beneficial. Hoelting et al.[27] retrospectively compared 11 patients who received primary bypass surgery for acute popliteal aneurysm –related ischemia to 9 similar patients who received thrombolytics prior to bypass surgery. There were 5 “occlusive complications” and one secondary amputation in the primary bypass group as opposed to none in the thrombolytic group. In a similar retrospective review Carpenter et al.[26] compared 38 patients who received primary bypass surgery for acute popliteal aneurysm –related ischemia to 7 similar patients who received thrombolytics prior to bypass surgery. These 7 patients are described as having thrombosis of all three of their run-off vessels. The patients with preoperative thrombolytics had better graft patency ð p , 0:005Þ and limb salvage ð p , 0:01Þ than the patients that underwent emergency primary operation. Varga et al. prospectively compared 23 patients who received thrombolytics to 56 patients who had primary bypass surgery and concluded that “intraarterial thrombolysis is of value in restoring the distal run-off before bypass in popliteal aneurysms presenting with acute limb-threatening ischemia.”[25]
Surgery The procedure of choice for popliteal aneurysm is construction of a reversed saphenous vein arterial bypass and exclusion of the aneurysm. (As a second choice, polytetrafluoroethylene, or PTFE, is used as the arterial conduit.) A medial approach to the popliteal artery is taken, as described by Szilagyi et al.[17] Definitive treatment of popliteal aneurysms consists of aneurysm ligation and bypass. The typical bypass usually consists of an above-knee popliteal to below-knee popliteal bypass, although this can vary considerably in either direction, depending on the extent of aneurysmal disease. The best conduit for bypass is autologous vein. The popliteal aneurysm can be exposed, ligated, and bypassed by either the medial or posterior approach. The medial approach allows exposure of the greater saphenous vein, the above- and below-knee popliteal artery, and the tibial vessels for selective tibial thrombectomy or more distal bypass. Without division of the hamstring tendons, the medial approach does not permit surgery directly on the aneurysm sac. When direct sac exposure is required, as in a patient with compressive symptoms requiring sac debridement, the posterior approach is best. The posterior approach allows a bloodless and superficial dissection of the entire popliteal artery. This exposure readily allows dissection and debridement of the aneurysm off neighboring structures. For aneurysms limited to the popliteal fossa, the posterior approach may also permit a shorter bypass because of better exposure. When necessary an additional 4 –5 cm of superficial
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femoral artery can be exposed posteriorly by division of overlying adductor muscle fibers. Distal tibial exposure through the posterior approach, while possible, is more difficult than from a medial approach. With the posterior approach, unless the lesser saphenous vein is of sufficient size, an additional incision will be required for harvesting of the greater saphenous vein.
Results Patients with asymptomatic aneurysms have higher long-term graft patency rates than do patents with symptomatic aneurysms that have undergone repair.[15,16] Endovascular treatment of aneurysms is currently being aggressively pursued in the treatment of infrarenal aortic aneurysms. Its theoretical advantages include lower surgical morbidity. Such an advantage is especially important in popliteal aneurysm, where many of the lesions are asymptomatic and none are life-threatening. There are currently only case reports describing the endovascular treatment of popliteal aneurysms. Puech-Leaao et al., through a posterior popliteal artery exposure, passed a Palmaz stent sewn to a saphenous vein graft up the superficial femoral artery to perform a proximal anastomosis (stent expansion) beyond the limits of surgical exposure.[28] May et al. reported one case of successful deployment of an endovascular graft to exclude a popliteal pseudoaneurysm caused by knee replacement surgery.[29] Krajcer and Diethrich reported one case of successful
treatment at 8 months of an atherosclerotic popliteal aneurysm treated percutaneously with a Wallstent and PTFE graft.[30] Mercadae reported 6 patients with popliteal aneurysms that were percutaneously treated with an endoluminal graft.[31] In this series with follow-up less than 1 year, there was one case of thrombosis and one case of incomplete exclusion with recurrence. Mercadae concludes that “stent-grafting of popliteal aneurysms seems still to be reserved for elderly and poor condition patients.”
CONCLUSIONS Popliteal aneurysms are relatively rare lesions. Their natural history typically consists of thromboembolic occlusion of the infrapopliteal vessels. It would appear that roughly one third of patients with these lesions will become symptomatic within 3 years. If treatment is delayed until the onset of limb-threatening ischemia, the rate of limb loss is approximately 10 times that when treated electively. The treatments of popliteal aneurysms are ligation and bypass. When outflow vessels are compromised, consideration should be given for preoperative thrombolytic therapy. Popliteal aneurysms can be surgically reached by both the medial and posterior approaches. Endovascular exclusion and bypass is a promising new technology but is yet without significant experience.
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Schechter, D.C.; Bergan, J.J. Popliteal Aneurysm: A Celebration of the Bicentennial of John Hunter’s Operation. Ann. Vasc. Surg. 1986, 1, 118. Potter, D.; Morris-Jones, W. Popliteal Artery Injury Complicating Arthroscopic Meniscectomy. Arthroscopy. 1995, 11 (6), 723. Bradway, M.W.; Drezner, A.D. Popliteal Aneurysm Presenting as Acute Thrombosis and Ischemia in a Middle-Aged Man with a History of Kawasaki Disease. J. Vasc. Surg. 1997, 26 (5), 884. Wilson, P.; Fulford, P.; Abraham, J.; Smyth, J.V.; Dodd, P.D.; Walker, M.G. Ruptured Infected Popliteal Artery Aneurysm. Ann. Vasc. Surg. 1995, 9 (5), 497. Halliday, A.W.; Taylor, P.R.; Wolfe, J.H.; Mansfield, A.O. The Management of Popliteal Aneurysm: The Importance of Early Surgical Repair. Ann. R. Coll. Surg. Engl. 1991, 73, 253. Farina, C.; Cavallaro, A.; Schultz, R.D.; et al. Popliteal Aneurysms. Surg. Gynecol. Obstet. 1989, 169, 7. Jimenez, F.; Utrilla, A.; Cuesta, C.; et al. Popliteal Artery and Venous Aneurysm as a Complication of Arthroscopic Meniscectomy. J. Trauma. 1988, 28, 1404. Gillespie, D.L.; Cantelmo, N.L. Traumatic Popliteal Artery Pseudo-Aneurysms: Case Report and Review of the Literature. J. Trauma. 1991, 31, 412.
9. Rosenbloom, M.S.; Fellows, B.A. Chronic Pseudoaneurysm of the Popliteal Artery After Blunt Trauma. J. Vasc. Surg. 1989, 10, 187. 10. Cole, C.W.; Thijssen, A.M.; Barber, G.G.; et al. Popliteal Aneurysms: An Index of Generalized Vascular Disease. Can. J. Surg. 1989, 32, 65. 11. Reilly, M.K.; Abbott, W.M.; Darling, R.C. Aggressive Surgical Management of Popliteal Artery Aneurysms. Am. J. Surg. 1983, 145, 498. 12. Whitehouse, W.M.; Wakefield, T.W.; Graham, L.M.; et al. Limb-Threatening Potential of Arteriosclerotic Popliteal Artery Aneurysms. Surgery. 1983, 93, 694. 13. Vermilion, B.D.; Kimmins, S.A.; Pace, W.G.; Evans, E. A Review of One Hundred Forty-Seven Popliteal Aneurysms with Long-Term Follow-Up. Surgery. 1981, 90, 1009. 14. Dawson, I.; Van, B.J.; Brand, R.; Terpstra, J.L. Popliteal Artery Aneurysms. Long-Term Follow-up of Aneurysmal Disease and Results of Surgical Treatment. J. Vasc. Surg. 1991, 13, 398. 15. Schellack, J.; Smith, R.B.; Perdne, G.D. Nonoperative Management of Selected Popliteal Aneurysms. Arch. Surg. 1987, 122, 372. 16. Shortell, C.K.; DeWeese, J.A.; Ouriel, K.; Green, R.M. Popliteal Artery Aneurysms: A 25-Year Surgical Experience. J. Vasc. Surg. 1991, 14, 771.
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Szilagyi, D.E.; Schwartz, R.L.; Reddy, D.J. Popliteal Arterial Aneurysms. Arch. Surg. 1981, 116, 724. Kontusaari, S.; Tromp, G.; Kuivaniemi, H.; et al. A Mutation in the Gene for Type III Procollagen (COL 3AI) in a Family with Abdominal Aneurysms. J. Clin. Invest. 1990, 86, 1465. Kuivaniemi, H.; Tromp, G.; Prockop, D.J. Genetic Causes of Aortic Aneurysms: Unlearning at Least Part of What the Textbooks Say. J. Clin. Invest. 1991, 88, 1441. Hands, L.J.; Collin, J. Infra-Inguinal Aneurysms: Outcome for Patient and Limb. Br. J. Surg. 1991, 78, 996. Reed, M.K.; Smith, B.M. Popliteal Aneurysm with Spontaneous Arteriovenous Fistula. J Cardiovasc Surg (Torino) 1991, 32, 482. Gifford, R.W.; Hines, E.A.; Janes, J.M. An Analysis and Follow-Up of One Hundred Popliteal Aneurysms. Surgery. 1953, 33, 284. Wychulis, A.R.; Spittel, J.A.; Wallace, R.B. Popliteal Aneurysms. Surgery. 1970, 68, 942. Dawson, I.; Sie, R.; van Baalen, J.M.; van Bockel, J.H. Asymptomatic Popliteal Aneurysm: Elective Operation Versus Conservative Follow-Up. Br. J. Surg. 1994, 81 (10), 1504.
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Varga, Z.A.; Locke-Edmunds, J.C.; Baird, R.N. A Multicenter Study of Popliteal Aneurysms. Joint Vascular Research Group. J. Vasc. Surg. 1994, 20 (2), 171. Carpenter, J.P.; Barker, C.F.; Roberts, B.; Berkowitz, H.D.; Lusk, E.J.; Perloff, L.J. Popliteal Artery Aneurysms: Current Management Outcomes. J. Vasc. Surg. 1994, 19 (1), 65. Hoelting, T.; Paetz, B.; Richter, G.M.; Allenberg, J.R. The Value of Preoperative Lytic Therapy in Limb-Threatening Acute Ischemia from Popliteal Artery Aneurysm. Am. J. Surg. 1994, 168 (3), 227. Puech-Leaao, P.; Kauffman, P.; Wolosker, N.; Anacleto, A.M. Endovascular Grafting of a Popliteal Aneurysm Using the Saphenous Vein. J. Endovasc. Surg. 1998, 5 (1), 64. May, J.; White, G.H.; Yu, W.; Waugh, R.; Stephen, M.S.; Harris, J.P. Endoluminal Repair: a Better Option for the Treatment of Complex False Aneurysms. Aust. NZ. J. Surg. 1998, 68 (1), 29. Krajcer, Z.; Diethrich, E.B. Successful Endovascular Repair of Arterial Aneurysms by Wallstent Prosthesis and PTFE Graft: Preliminary Results with a New Technique. J. Endovasc. Surg. 1997, 4 (1), 80. Mercadae, J.P. Stent Graft for Popliteal Aneurysms. Six Cases with Cragg Endo-pro System I Mintec. J. Cardiovasc. Surg. 1996, 37 (Suppl. 1), 41.
CHAPTER 46
Splanchnic Artery Aneurysms Russell A. Williams Samuel E. Wilson Splanchnic artery aneurysms involve the celiac, superior mesenteric, and inferior mesenteric arteries and their branches. They occur relatively infrequently when compared to aneurysms of the aorta and iliac vessels, partly because there is a lower overall incidence of atherosclerosis in the splanchnic circulation. Atherosclerosis, responsible for the great majority of aortic and iliac aneurysms, is thought to be responsible for less than half of splanchnic artery aneurysms. While atherosclerosis can be found in the majority of splanchnic artery aneurysms, it is thought to be a secondary process.[1] Splanchnic artery aneurysms have a diverse etiology and a correspondingly diverse natural history. Inflammation is an important primary cause of splanchnic artery aneurysms. It may occur from a primary vasculitis such as polyarteritis nodosum, a metastatic infection such as emboli from endocarditis, or an extravascular process such as pancreatitis or a penetrating peptic ulcer. Peripancreatic pseudoaneurysms are estimated to occur in 10% of patients with chronic pancreatitis.[2] Polyarteritis nodosa is an autoimmune vasculitis which causes multiple aneurysms, typically less than 1 cm in diameter, of the small and mediumsized muscular arteries of the abdominal viscera and kidneys. Due to their small size, intraparenchymal location, and natural history, these aneurysms rupture only occasionally and do not often require surgery. In contrast, embolomycotic aneurysms have a very unpredictable natural history, which often ends in fatal rupture and, unless completely resolved on follow-up angiography, are best treated with surgery. Other important causes of splanchnic artery aneurysms include hemodynamic and connective tissue alterations as well as trauma. Splanchnic artery aneurysms may be single or multiple depending on etiology, and the wall may contain the three layers of the normal arterial wall or they may be false aneurysms. Sixty percent of splanchnic artery aneurysms occur in the splenic artery, 20% in the hepatic artery, 8% in the superior mesenteric artery, 4% in the celiac artery, 4% in the gastric and gastroepiploic arteries, and 4% in the remaining splanchnic branches.[3] Splenic artery aneurysms, the most common splanchnic artery aneurysms, have been variously estimated to occur in 0.8 –4% of patients undergoing angiography,[4] 10% of elderly patients at autopsy; and 0.05% of autopsies of the general population.[5,6]
In general, a majority of splanchnic artery aneurysms are asymptomatic prior to rupture.[7] When pain is present, it often signifies acute aneurysmal growth. Rupture rates and subsequent mortality rates are reported to be 2 –90% and 25–75%, respectively, depending on location and etiology.[4] Rupture may occur into the peritoneal cavity, causing hemorrhagic shock, or, as is common with inflammatory aneurysms, into adjacent structures such as the pancreas or GI tract, causing related symptoms. Angiography provides the anatomical detail necessary for the diagnosis and the planning of treatment of splanchnic artery aneurysms mainly because these aneurysms are often small, multiple, and surrounded by or in direct connection with neighboring vasculature or viscera. Other less invasive modalities, such as x-ray, ultrasound, computed tomography (CT), and magnetic resonance imaging (MRI), are often diagnostic and useful in following aneurysmal growth over time. CT angiography can provide excellent images without arterial injection. Surgical therapy, consisting of ligation or resection of an aneurysm with or without reconstruction, is the most conservative method of treatment and is effective in many instances. Percutaneous embolization is often a less invasive alternative and is considered by some to be the procedure of choice for visceral aneurysms where the risk of end-organ ischemia from embolization is low or where the associated surgical morbidity is substantial, as with peripancreatic pseudoaneurysms.[8,9] In a limited number of situations, as with small atherosclerotic splenic artery aneurysms, these lesions may be safely observed.
SPLENIC ARTERY ANEURYSMS Splenic artery aneurysms (SAA) have been recognized with certainty since 1770, when Beaussier[10] described one in a woman aged 60, at autopsy. Over 50 years ago, the first SAA was successfully treated by operation. A majority of patients with SAA are 50 –70 years of age, but 20% are 20 –50 years of age, and among these younger patients the female-to-male ratio is 20:1.[7] Overall, 87% of patients with SAA are females, and 80% are multiparous
Hobson/Wilson/Veith: Vascular Surgery: Principles and Practice, Third Edition, Revised and Expanded DOI: 10.1081/0819-9-120024929 Copyright q 2004 by Marcel Dekker, Inc.
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females. Ninety-five percent of patients who experience SAA rupture are pregnant.[4] Such epidemiology has led to the common speculation that changes in arterial connective tissue as well as increases in blood volume, portal congestion, and splenic arteriovenous shunting related to pregnancy all contribute to splenic artery medial degeneration and aneurysm formation. One-eighth of women with SAA will also have fibromuscular dysplasia, an arteriopathy which predisposes to aneurysm formation.[1,11] Nonpregnant patients with splenic artery hyperdynamic flow from causes such as cirrhosis, portal-systemic shunts, or liver transplantation are also at increased risk for developing SAA. Splenic artery flow in cirrhotics has been found, on average, to be a least twice that in noncirrhotics. Seven percent of patients with portal hypertension undergoing angiography will have incidental SAA, and additional patients will have generalized splenic artery dilatation. Patients may also develop SAA from trauma, infected emboli, and extravascular inflammatory processes, most notably pancreatic (historical note, President James A. Garfield died secondary to rupture of a traumatic SAA produced by a bullet wound during his attempted assassination).
Clinical Presentation Approximately 80% of patients with SAA are asymptomatic. In these patients the diagnosis is evident from the appearance of typical aneurysmal calcifications seen on a plain radiograph, incidental findings on angiography, or symptoms of spontaneous aneurysmal rupture (Fig. 46-1). Characteristic curvilinear aneurysmal calcifications can be found in 70% of patients with SAA. These findings, while easily identifiable, are not associated with lower incidence of rupture. Spontaneous aneurysmal rupture may cause bleeding into the peritoneal cavity or, as happens with inflammatory aneurysms, into adjoining structures such as the pancreas, GI tract, or (rarely) the splenic vein. Some 25% of the time intraperitoneal rupture is transiently contained within the lesser sac, after which massive uncontained bleeding occurs through the foramen of Winslow or a rupture of the lesser omentum. This clinical phenomenon of “double rupture” provides a window of opportunity for diagnosis and surgical intervention before the onset of hemorrhagic shock. The symptoms of aneurysmal rupture during pregnancy or after delivery may be mistaken for other common obstetric emergencies such as uterine rupture, abruptio placentae, or amniotic fluid embolism especially since SAA rupture may occur during labor. Inflammatory aneurysms rupturing into pancreatic pseudocysts may create symptoms of abdominal pain and hypotension, as these cysts, when large, may sequester a large amount of blood. When such cysts communicate with the pancreatic duct patients may develop acute or chronic GI bleeding. The syndrome, described as hemosuccus pancreatitis, usually requires angiography for a definitive diagnosis.[12] Patients with noninflammatory SAA have a 2–10% incidence of aneurysm rupture. The mortality of rupture may be as high as 70% in pregnancy and up to 25% in those who are not pregnant. The fetal mortality under these circumstances is high. Since the risk of mortality from prophylactic
surgical treatment of noninflammatory SAA is low, patients should undergo surgery if they are or may become pregnant, if the aneurysm is greater than 1.5 –2.5 cm, or if they have referable abdominal symptoms. Operation for SAA due to pancreatitis has an associated mortality of 30% because of the persistent intra-abdominal sepsis presence of extensive inflammatory adhesions, pancreatic pseudocysts, multiple feeding vessels, and enteric erosions as well as the possible need for splenectomy and partial pancreatectomy. Once rupture has ensued, the mortality increases to 50%. Exposure for the surgical treatment of SAA provided by an upper midline incision or, alternatively, a left subcostal incision, which can be extended in a chevron fashion by adding a right subcostal incision, is also useful, especially in the obese or pregnant patient. The latter incision is more time-consuming to perform and inadvisable in an emergency, even if the diagnosis is known. The aneurysm itself is exposed by dividing the gastrocolic ligament to enter the lesser sac. Splenic preservation should be attempted, but this may not be possible if the aneurysm extends into the hilum of the spleen or if emergency surgery is being done for rupture. Splenic artery aneurysms secondary to pancreatitis may be densely adherent to the pancreas or may have ruptured into a pseudocyst or the pancreatic duct. They pose a more difficult technical problem because the dense inflammatory adhesions usually make operation difficult. Double ligation may even be very difficult; percutaneous arterial embolism and thrombosis of the aneurysm is often preferable and safer. Management of the patient who has rupture of a SAA into a very large pseudocyst that extends high under the left diaphragm and liver and which may be adherent to portal vein or even the inferior vena cava can be technically different and hazardous. Opening the pseudocyst to control the bleeding point usually leaves the surgeon with an obscured field that wells full of blood, at times making hemostasis impossible. In this situation the authors have introduced a balloon catheter into the abdominal aorta via the femoral artery to occlude the origins of mesenteric vessels. The gross size and situation of the cyst may preclude the use of a cross clamp of the aorta at the diaphragmatic hiatus. Once control of bleeding within the pseudocyst is achieved, a drain is placed, as many of these cysts communicate with the pancreatic duct and a pancreatic fistula or even pancreatic ascites is likely to ensue. Patients at high operative risk—such as cirrhotics, the elderly, or those with extensive fibrosis from pancreatitis—may benefit from nonoperative percutaneous catheter embolization of the splenic artery and aneurysm. An increasing number of reports of success using this technique are emerging. With the patient under local anesthesia, the catheter is selectively placed within the lumen of the aneurysm.[13] The more commonly used small embolic particles of Teflon, Ivalon, or Silastic are not used to cause thrombosis, as they are not retained in the aneurysm but embolize distally to the spleen. Instead a Gianturco steel coil, which has woolly thrombogenic strands attached, is introduced. This expands after extrusion from the catheter, wedging itself within the lumen and making embolization unlikely. Once in place,
Chapter 46.
Figure 46-1.
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Calcified splenic artery aneurysm in a 60-year-old woman.
the coil acts as a baffle and the other thrombogenic materials can be injected.
causing HAA include pariarteritis nodosa, cholecystitis, and pancreatitis.
Clinical Presentation HEPATIC ARTERY ANEURYSM Hepatic artery aneurysms (HAA) are one-third as common as SAA and affect males two to three times as often as females, which is a reversal of the sex ratio found in SAA. The reversal in gender occurrence may be because medial degeneration, responsible for most SAA, accounts for only 25% of HAP. Other important causes of HAA are trauma, atherosclerosis, and inflammation. Trauma, which may be environmental or iatrogenic, accounts for 22% of HAP. Both blunt and penetrating trauma causes HAA, which may be true or false and intrahepatic or extrahepatic. Twenty percent of all HAA are intrahepatic, and a majority of these are caused by environmental trauma.[14] Iatrogenic trauma typically occurs from biliary surgery such as cholecystectomy, causing extrahepatic aneurysms of the right or common hepatic arteries. Percutaneous transhepatic procedures also can lead to HAA, usually of the intrahepatic type. Inflammation, which accounts for 28% of HAA, occurs most frequently from embolism in a patient with infective endocarditis. Other, less common causes of inflammation
Most patients with HAA are asymptomatic prior to rupture.[15] In these patients the diagnosis is based on vascular calcifications or detection of spontaneous aneurysmal rupture. In patients who have large aneurysms, displacement of neighboring structures such as the biliary and GI tracts provides a diagnostic clue. Pain, when it does occur, is often associated with aneurysmal growth. Spontaneous HAA rupture occurs into the biliary tract as frequently as into the peritoneal cavity. One-third of patients with hemobilia will have the classic triad of hemobilia, pain, and jaundice.[16] Rarely, these aneurysms will rupture into the portal vein, creating acute portal hypertension and bleeding varices. Rupture rates and subsequent mortality rates for HAA are 20– 44% and 35% respectively.[14,17]
Investigations On plain x-rays, atherosclerotic aneurysms will often appear as a rim of eggshell-like calcification; ultrasonography and computed tomography (CT) delineate the aneurysm, showing its relation to the bile ducts or portal vein.
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The definitive study for planning treatment is selective celiac or hepatic artery angiography. Angiography delineates the site and extent of the aneurysm, shows an arteriovenous fistula, and demonstrates any arterial collaterals that have formed or enlarged portal venous collaterals if portal hypertension is present. It also outlines the anatomy of the liver’s blood supply, which is via aberrant vessels in up to 40% of people. This is important information, as the arterial blood supply to the liver should be maintained following treatment, either through collaterals, normal aberrant arteries, or a prosthetic or autologous vein graft to replace the excised, diseased segment of artery.
hepatic aneurysm embolization proving fatal in a 73-year-old man with malignant obstruction of the bile duct who was treated by introducing an endoprosthesis for biliary drainage. A hepatic artery aneurysm complicated the initial procedure and was embolized, resulting in extensive hepatic necrosis.[18] Postoperatively, hepatic viability may be aided by inspired oxygen, bowel rest, and hypertonic dextrose until liver function tests return to normal.
Operations
Unlike SAA and HAA, superior mesenteric artery aneurysms (SMAA) are rarely caused by trauma or medial degeneration, thus their overall incidence is proportionately lower. Most patients have subacute bacterial endocarditis or are intravenous drug addicts. Streptococcus species are commonly grown from the aneurysm, although in drug addicts Staphylococcus is also likely. Approximately 60% of SMAA are caused by embolism from infective endocarditis. Medial degeneration, when present, causes not only SMAA but also dissections. Embolomycotic aneurysms and dissections happen more often in the SMA than in the other splanchnic vessels. In the minority of patients, SMAA are atherosclerotic in origin, and plain radiograph may show ring-like calcification in the upper abdomen near the midline.
Aneurysms located on the main hepatic artery proximal to the origin of the gastroduodenal artery may be excised or ligated, the blood supply to the liver being maintained through collaterals from the superior mesenteric artery entering the gastroduodenal branch of the common hepatic artery. Excision, rather than double ligation, is desirable if the aneurysm is infected, large enough to produce obstructive symptoms of the biliary or intestinal system or if it communicates with part of the GI tract. In some cases it is safer to remove the aneurysm only partially, reducing its size by “debridement” and leaving the sac, which may be adherent to the adjacent vital tissues. Occasionally patients may have had the gastroduodenal artery divided at a previous operation on the biliary system or the duodenum. In these patients, if collaterals are poorly developed, a saphenous vein graft can be used to restore arterial continuity after aneurysmal resection. The 40% of patients who are found on arteriogram to have alternative origins of the hepatic arteries will have the origin of the anomalous artery from the left gastric or superior mesenteric artery. Identification of such vessels on preoperative angiography usually precludes the need to restore hepatic artery continuity. At operation, adequacy of arterial collateral blood flow to the liver is demonstrated if there is profuse backbleeding from the distal, divided end of the hepatic artery. Liver blood flow may also be restored by anastomosing the distal divided stump of the hepatic artery to an artery other than the celiac, such as the splenic, utilizing a segment of prosthetic material or a venous autograft. Invasive angiography has been used to thrombose hepatic artery aneurysms and is the preferred method for treatment of intrahepatic aneurysms that otherwise would be treated by ligation of the right or left hepatic artery or even by hepatic lobectomy. Percutaneous embolization and thrombosis is generally not recommended for the treatment of an extrahepatic aneurysm because of the importance of maintaining the arterial blood supply to the liver. However, there are reports of extrahepatic aneurysms being successfully treated by arteriographic embolization in patients with additional illnesses, such as staphylococcal endocarditis, involving several heart valves where multiple mycotic aneurysms had developed, liver malignancy,[11] or previous surgery at which the diagnosis of leaking hepatic artery aneurysm was missed but subsequently found on an angiogram. There is one cautionary report of percutaneous
SUPERIOR MESENTERIC ARTERY ANEURYSMS
Clinical Presentation Superior mesenteric artery aneurysms are also unique in that the majority of these patients will manifest symptoms, usually of intestinal ischemia, prior to rupture. In patients who have had bacterial endocarditis, the development of a SMAA should be considered, especially if there are complaints of abdominal symptoms, such as epigastric pain unrelated to meals. In some patients, especially those who are thin, a palpable, tender mass which is mobile from side to side may be felt. At times, a pulsation can be appreciated and the patient may have positive blood cultures. Those patients who have a SMAA from another cause can present with similar pain but no antecedent history. The aneurysm will then be discovered during investigation (see Fig. 46-2). With an atherosclerotic aneurysm, a plain radiograph of the abdomen often shows signet-ring – like calcification to the side of the midline with a posterior defect in the circumference, representing the origin of the superior mesenteric artery from the aorta. Otherwise, the aneurysm may be identified only at laparotomy. The natural history of mycotic aneurysms with persistence of infection in the arterial wall is of unrelenting enlargement and ultimately rupture. The history of atherosclerotic or other types of aneurysms is uncertain, though one could expect progressive enlargement and ultimate rupture. Abdominal apoplexy due to rupture into the peritoneal cavity and rupture of a traumatic superior mesenteric artery false aneurysm into
Chapter 46.
Figure 46-2.
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Mycotic superior mesenteric artery aneurysm in an intravenous drug abuser. (Dr. A. Yellin’s case.)
the duodenum some years after an initial penetrating bullet injury to that area has been described.
Operations The first SMAA to be treated successfully was a mycotic aneurysm operated upon by DeBakey and Cooley in 1949 by resection without restoring continuity of the SMAA.[19] Following aneurysmectomy, the viability of the small bowel surprisingly may not be threatened, obviating the need for any additional procedure to restore arterial continuity. Progressive constriction of the aneurysmal lumen of the SMA and other splanchnic arteries is believed to stimulate hypertrophy of arterial collaterals. However, should aneurysmectomy result in an inadequate blood supply, the jejunal continuation of the artery may be anastomosed to the remaining SMA directly or by interposing a saphenous vein graft. Following resection of a mycotic aneurysm, the use of a prosthetic graft or even a venous homograft, especially if it courses through the aneurysm bed, is best avoided. If flow is to be restored, an “extraanatomic” route from adjacent vessel such as the aorta to the jejunal or ileal segment of the superior mesenteric artery is chosen. Other techniques for the treatment of saccular aneurysms include endoaneurysmorrhaphy. After inflow and outflow
control, the aneurysm is opened and its orifice with the main artery, which may be only an ovoid slit several centimeters long, is oversewn from within the aneurysm, maintaining patency of the native vessel. This technique is particularly recommended for mycotic and traumatic false aneurysms, of which both originate from a limited area of weakness in the arterial wall.[20] As part of the management of mycotic aneurysms, the infected aneurysmal sac and contents are excised or debrided without necessarily excising the native vessel. A prolonged course of the appropriate antimicrobial agent is given, starting before operation and continuing for 6 weeks or more after operation. If this is discontinued too early, residual arterial infection may lead to reformation of an aneurysm. A variant of aneurysmorrhaphy may be helpful to treat large saccular or fusiform aneurysms: the sac is opened after control of its inflow and outflow, and the orifices of native artery attached to the aneurysmal segment are oversewn from inside the sac. This, in fact, obliterates the involved segment of the artery, so it should be ascertained that no distal ischemia results. Excision of many of these SMAAs may be difficult, as they can be adherent to important adjacent structures, including the superior mesenteric vein. An injury or deliberate surgical procedure that occludes the superior mesenteric vein is poorly tolerated and may produce ischemia of the small bowel along with ascites. With such an aneurysm, the sac may be excised, leaving the section of its wall adherent to the vein.
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Figure 46-3. (A ) CT scan with enhancement of celiac artery aneurysm (A) compressing the extrahepatic bile ducts (B) producing biliary obstruction. (B ) Angiogram of the same celiac artery aneurysm.
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Operations of the main trunk of the SMA are usually done through a vertical abdominal incision. To expose the artery and its origin more proximally, the duodenojejunal flexure is mobilized, reflected medially, and the pancreas elevated. The patient with a ruptured, freely bleeding SMAA often requires clamp control of the aorta at the diaphragmatic hiatus to stop bleeding and so permit operation on the aneurysm itself. Some very proximally situated aneurysms of the SMA may be operated on by exposing the origin of the artery extraperitoneally, reflecting the left colon and duodenum to the right. In some cases a thoracoabdominal incision facilitates this maneuver.
OTHER SPLANCHNIC ARTERY ANEURYSMS These are very uncommon and include aneurysms of the celiac, gastric, gastroduodenal, and pancreaticoduodenal arteries, the ileal and jejunal branches of the superior mesenteric trunk, and—most rarely of all—the inferior mesenteric artery. The majority are atherosclerotic degenerative aneurysms, but some arise following trauma to the arterial wall or from local inflammation, particularly in the case of the pancreaticoduodenal and gastroduodenal arteries in patients with pancreatitis. The rarity of these aneurysms makes them reportable and has led to many sporadic case reports from which recommendations have been extrapolated. It is thought that they, like aneurysms elsewhere, will all enlarge and, depending on their site, will obstruct adjacent organs, particularly the biliary system, and will ultimately thrombose or rupture (Fig. 46-3A and B). Pancreaticoduodenal and gastroduodenal artery aneurysms caused by pancreatitis usually present as bleeding following rupture into the pancreatic duct, the biliary system, or adjacent bowel. These aneurysms should always be considered as possible points of origin of intestinal bleeding in patients with pancreatitis.
Celiac Artery Aneurysms The celiac artery does not appear to be predisposed to a particular type of aneurysm, although it has been reported that 38% of patients with celiac artery aneurysms (CAA) have other splanchnic artery aneurysms and 18% have abdominal aortic aneurysms.[21] Atherosclerosis is associated with 27% of CAA.[21] Trauma and embolism are unusual causes of CAA. As in the case of SMA, 60% of patients with CAA have abdominal discomfort prior to rupture and 30% have a pulsatile mass.[21] Rupture rates and subsequent mortality rates are 13% and 40% respectively. Operation is successful in about 90% of cases. Surgical exposure, unless the aneurysm is small, will require a thoracoabdominal incision. Also as in the case of SMAA, approximately one-third of patients with CAA will tolerate celiac ligation without reconstruction. Whether ligation is feasible should be determined from temporary intraoperative celiac artery occlusion. In 50% of cases, revascularization is performed.
Figure 46-4. Pancreaticoduodenal artery aneurysm.
Often only the hepatic artery will require revascularization. In other instances complete revascularization, either from celiac artery reapproximation or placement of an interposition graft, is required.
Gastroduodenal and Pancreaticoduodenal Aneurysms The close anatomic relationship of the gastroduodenal and pancreaticoduodenal arteries to the pancreas puts these arteries, like the splenic artery, at risk for development of inflammatory aneurysms (Fig. 46-4). Sixty percent of gastroduodenal and 30% of pancreaticoduodenal aneurysms are caused by pancreatitis.[22] Patients with pancreatitis-related aneurysms may have symptoms prior to rupture, but these may be difficulty to differentiate from symptoms of pancreatitis. When these aneurysms rupture, over half will do so into adjacent structures, including the GI tract, pancreas, and (rarely) the biliary tract, creating symptoms of acute or chronic GI bleeding.[23] Other aneurysms will rupture directly into the peritoneal cavity. Surgical intervention may be complicated and has an associated mortality of up to 30%.[24]
Gastric and Gastroepiploic Aneurysms Aneurysms of the gastric and gastroepiploic arteries occur through various mechanisms, the most common of which are atherosclerosis and medial degeneration. Gastric artery dissection also occurs, with a total of 50 cases reported to date.[22] An unusual cause of gastric artery aneurysms is the so-called caliber-persistent artery of the stomach, also called
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cirsoid aneurysm, miliary aneurysm of the stomach, or Dieulafoy’s vascular malformation. These lesions are probably congenital anatomic variants in which gastric vessels penetrate the submucosa without decreasing in size or joining in the normal submucosal anastomotic plexus of vessels. In the presence of a caliber-persistent artery of the stomach, even the smallest of mucosal disruptions may lead to massive and usually lethal gastric bleeding.[25,26] Gastric artery aneurysms most commonly develop in the gastric and not the gastroepiploic vessels. Unlike other splanchnic aneurysms, the majority of gastric artery aneurysms (70%) will rupture into the GI tract and not the peritoneal cavity.[27] Ninety percent of patients with these lesions present with aneurysm rupture as their initial symptom. The mortality rate for patients after rupture is 70%.[14] Because of the high rate of rupture, emergency surgery is the most common form of treatment. Ligation of the affected gastric vessel will not cause gastric ischemia. Arterial pathology may extend into the gastric wall, in which case local gastric resection should be performed.
INTESTINAL BRANCH ARTERY ANEURYSMS Aneurysms of the jejunal, heart and colic arteries are rare. A total of 6 jejunal arterial branch artery aneurysms and 13 inferior mesenteric artery aneurysms have been reported to date. The etiology of solitary intestinal branch aneurysms is often difficult to ascertain; they may therefore be called “congenital.” Multiple intestinal branch aneurysms are usually associated with a vasculitis, either autoimmune or embolomycotic. Symptoms of these lesions may include a palpable mesenteric mass or symptoms referable to intraluminal or intraperitoneal aneurysm rupture. These aneurysms tend to be small; preoperative angiography, if the patient’s condition permits, is often very helpful in operative localization and in ruling out the possibility of multiple lesions. Surgical treatment can include arterial ligation, aneurysm resection, and, if necessary, resection of involved bowel.
REFERENCES 1.
2.
3. 4.
5.
6. 7. 8.
9.
10.
11. 12.
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Stanley, J.C.; Fry, W.J. Pathogenesis and Clinical Significance of Splenic Artery Aneurysms. Surgery 1974, 76, 898. Hofer, B.O.; Ryan, J., Jr.; Freeny, P.C. Surgical Significance of Vascular Changes in Chronic Pancreatitis. Surg. Gynecol. Obstet. 1987, 164, 499. Deterling, R.A. Aneurysms of the Visceral Arteries. J. Cardiovasc. Surg. 1971, 12, 309. Stanley, J.C.; Fry, W.J. Pathogenesis and Clinical Significance of Splenic Artery Aneurysms. Surgery 1974, 76, 898. Owens, J.C.; Coffey, R.J. Aneurysms of the Splenic Artery, Including a Report of Six Additional Cases. Int. Abstr. Surg. 1953, 97, 313. Foremore, S.W.; Guida, P.M.; Schmacher, H.W. Splenic Artery Aneurysm. Bull. Soc. Int. Chir. 1970, 29, 210. Trastek, V.F.; Bairolero, P.C.; Joyce, J.W.; et al. Splenic Artery Aneurysms. Surgery 1982, 91, 694. Ku, A.; Kadir, S. Embolization of a Mesenteric Artery Aneurysm: Case Report. Cardiovasc. Interv. Radiol. 1990, 13, 91. Mandel, S.R.; Jaques, P.F.; Sanofsky, S.; Mauro, M.A. Nonoperative Management of Peripancreatic Arterial Aneurysms. A 10-Year Experience. Ann. Surg. 1987, 2, 126. Beaussier, M. Sur un Aneurisme de I’artere Splenique Dont les Parios se Sont Ossifees. J. Med. Toulouse 1770, 31, 157. Bedford, P.D.; Lodge, B. Aneurysm of the Splenic Artery. Gut 1960, 1, 312. Lambert, C.J., Jr.; Williamson, J.W. Splenic Artery Aneurysm: A Rare Cause of Upper Gastrointestinal Bleeding. Am. Surg. 1990, 56, 543. Probst, P.; Castaneda-Zuniga, W.R.; Gomes, A.S.; et al. Nonsurgical Treatment of Splenic Artery Aneurysms. Diagn. Radiol. 1978, 128, 619.
14. Stanley, J.C.; Thompson, N.W.; Fry, W.J. Splanchnic Artery Aneurysms. Arch. Surg. 1971, 101, 689. 15. Salo, J.A.; Aarnio, P.T.; Jarvinen, A.A.; Kivilaakso, E.O. Aneurysms of the Hepatic Arteries. Am. Surg. 1989, 5, 705. 16. Contryman, D.; Norwood, S.; Register, D.; et al. Hepatic Artery Aneurysm: Report of an Unusual Case and Review of the Literature. Am. Surg. 1983, 49, 51. 17. Busuttil, R.W.; Brin, B.J. The Diagnosis and Management of Visceral Artery Aneurysms. Surgery 1980, 88, 619. 18. Sjovall, S.; Hoevels, J.; Sundqvist, K. Fatal Outcome from Emergency Embolization of an Intrahepatic Aneurysm. Surgery 1980, 87, 347. 19. Boijsen, E.; Efsing, H.O. Aneurysm of the Splenic Artery. Acta Radiol. Scand. 1969, 8, 29. 20. Olcott, C.; Ehrenfeld, W.K. Endoaneurysmorrhaphy for Visceral Artery Aneurysms. Am. J. Surg. 1977, 133, 636. 21. Graham, L.M.; Stanley, J.C.; Whitehouse, W., Jr.; et al. Celiac Artery Aneurysms: Historic (1745 – 1949) Versus Contemporary (1950 – 1984) Differences in Etiology and Clinical Importance. J. Vasc. Surg. 1985, 5, 757. 22. Eckhauser, F.E.; Stanley, J.C.; Zelenock, G.B.; et al. Gastroduodenal and Pancreaticoduodenal Artery Aneurysms: A Complication of Pancreatitis Causing Spontaneous Gastrointestinal Hemorrhage. Surgery 1980, 88, 335. 23. Gangahar, D.M.; Carveth, S.W.; Reese, H.E.; et al. True Aneurysm of the Pancreaticoduodenal Artery: A Case Report and Review of the Literature. J. Vasc. Surg. 1985, 2, 741. 24. Stabile, B.E.; Wilson, S.E.; Debas, H.T. Reduced Mortality from Bleeding Pseudocysts and Pseudoaneurysms Caused by Pancreatitis. Arch. Surg. 1983, 18, 45.
Chapter 46. 25.
Eidus, L.B.; Rasuli, P.; Manion, D.; Heringer, R. CaliberPersistent Artery of the Stomach (Diculafoy’s Vascular Malformation). Gastroenterology 1990, 99, 1507. 26. Miko, T.L.; Thomazy, V.A. The Caliber Persistent Artery of the Stomach: A Unifying Approach to Gastric
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Aneurysm, Diculafoy’s Lesion, and Submucosal Arterial Malformation. Hum. Pathol. 1988, 19, 914. 27. Thomford, N.R.; Yurko, J.E.; Smith, E.J. Aneurysm of Gastric Arteries as a Cause of Intraperitoneal Hemorrhage: Review of Literature. Ann. Surg. 1968, 168, 294.
CHAPTER 47
Infected Aneurysms Bruce A. Perler Calvin B. Ernst Arterial infection is one of the most demanding problems encountered by the vascular surgeon. Although improvements in surgical technique and better antimicrobial prophylaxis have reduced septic complications of vascular reconstruction, the infected aneurysm continues to pose a threat to life and limb. Even in an era of rapidly expanding diagnostic and therapeutic technology, diagnosis remains difficult and is often delayed, treatment is demanding, and the results, while improving, are far from satisfactory. It is the purpose of this chapter to offer a pragmatic definition of infected aneurysms, to highlight the appropriate diagnostic approach, to provide an overview of the microbiology and anatomic distribution of these lesions, and to outline therapeutic options.
Terminology Confusion exists concerning the classification and nomenclature of infected aneurysms (Table 47-1). Presumably, Osler[4] called these lesions “mycotic” because of the “fresh fungus vegetations” in the mulitple beadlike aneurysms he described. Although mycotic is synonymous with fungal, the term mycotic aneurysm has been used inappropriately to describe any arterial aneurysm caused by microorganisms, fungal or bacterial. To be accurate and minimize confusion, a mycotic aneurysm should be considered a lesion that develops as a complication of bacterial endocarditis, as Osler described. Eppinger[6] introduced the term embolomycotic to describe these aneurysms. Although others postulated that embolization of endocardial vegetations led to aneurysm formation through purely traumatic effects, Eppinger identified the same bacterial strains at the site of emboli as found in endocardial vegetations. He postulated that lodgement of bacteria-laden emboli in the arterial wall initiated the development of an exudative periarteritis with subsequent destruction of the elastic and muscular elements of the wall, with eventual aneurysm formation. The term embolomycotic recognizes both the traumatic and infectious elements in development of these aneurysms.[7] Although over 90% of the mycotic aneurysms reported in the early literature were associated with endocarditis, there were sporadic reports describing patients with infected aneurysms but without endocardial disease.[8] In 1937 Crane[9] described a patient with a multilocular aortic aneurysm who had no evidence of endocardial infection. He coined the term primary mycotic aneurysm to describe this entity. Revell,[10] in a 1943 review of the literature, found only 23 cases of primary mycotic aneurysms and added one of his own. He emphasized that a mycotic aneurysm should be classified as primary if it results from a bacteremia from an obscure focus, reiterating Crane’s definition.[9,10] According to these criteria, Osler’s mycotic aneurysms would be classified as secondary mycotic aneurysms, since they developed as a result of the emobilization of infected vegetations or from the direct spread of aortic valve vegetations to the sinus of Valsalva or the aortic wall. Likewise, direct spread of sepsis from an infected lymph node or osteomyelitis to an adjacent artery would lead to secondary mycotic aneurysm formation.[8]
HISTORY AND EVOLUTION OF TERMINOLOGY Infected aneurysms are among the oldest arterial lesions described in the western literature. As early as the sixteenth century, Ambrose Pare´ recognized that aneurysms could develop secondary to microbial infection, specifically syphilis. In 1844 Rokitansky[1] described abscesses in the walls of arteries and proposed that they resulted from the lodgement of infected emboli. Koch,[2] in 1851, described a 22-year-old man who died suddenly from a ruptured aneurysm of the superior mesenteric artery while being treated for endocarditis. In 1853 Tufnell[3] reported a 25-yearold man with endocarditis and a popliteal aneurysm. It was against this background that Sir William Osler,[4] in the first of his Gulstonian Lectures to the Royal College of Physicians in London in March 1885, coined the term mycotic aneurysm. Osler described several cases in which he believed valvular vegetations characteristic of endocarditis spread directly to the aortic wall and led to aneurysmal degeneration. Osler’s work firmly established mycotic aneurysms as a clinical entity and stimulated other workers to make further observations. By 1923, Stengel and Wolferth[5] had identified 217 cases of mycotic aneurysm from a review of the world literature.
Hobson/Wilson/Veith: Vascular Surgery: Principles and Practice, Third Edition, Revised and Expanded DOI: 10.1081/0819-9-120024930 Copyright q 2004 by Marcel Dekker, Inc.
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Aneurysms
Historical Nomenclature for Arterial Infection
Mycotic aneurysm Primary mycotic aneurysm Secondary mycotic aneurysm Cryptogenic mycotic aneurysm Embolomycotic aneurysm Bacterial aortitis Nonaneurysmal suppurative aortitis Microbial arteritis
Compounding the confusion as to nomenclature was the introduction of the term cryptogenic mycotic aneurysms by Blum and Keefer[11] in 1962. They noted that infected aneurysms resulted from the deposition of organisms upon a diseased intimal surface. In cryptogenic mycotic aneurysms, the source of the bacteremia was unknown, as opposed to a known albeit extravascular or noncontiguous source in the primary mycotic aneurysm.[12] Since pathophysiology, bacteriology, clinical presentation, and proper therapy of these lesions are similar to those of the primary mycotic aneurysms described in most series (see below), this additional terminology seems superfluous. Rokitansky’s observation of abscess formation within the arterial wall remained unnoticed for many years.[7] Eventually, however, cases of arterial sepsis without aneurysm formation were reported. Parkhurst and Decker[12] described 12 patients with bacterial infection of the aortic wall but with aneurysm formation in only 9. In the 3 patients without aneurysms, the disease entity was termed bacterial aortitis. Bardin et al.[13] note that arterial infection without aneurysm formation represents a midpoint on the continuum from asymptomatic bacterial colonization to invasive infection with aneurysm formation; they therefore coin the term nonaneurysmal suppurative aortitis. Microbial arteritis has recently been proposed to describe arterial infection without aneurysm development.[14]
CONTEMPORARY CLASSIFICATION Although most of the nomenclature has been well defined by the respective proponents, the multiplicity of terms has led to Table 47-2.
Mycotic aneurysms Infected aneurysms (nonendocarditis) Microbial arteritis with aneurysm formation Secondarily infected aneurysm Microbial arteritis without aneurysm formation Infected anastomotic aneurysms Colonized aneurysms
MYCOTIC ANEURYSMS Incidence Mycotic aneurysms may occur in a normal or arteriosclerotic artery secondary to embolization or direct extension of septic valvular vegetations in a patient with infective endocarditis.[4,16] Prior to the introduction of antimicrobial drugs, this type represented the most common form of arterial infection.[5,7] In a 1923 review, Stengel and Wolferth[5] identified 217 patients, in 186 (87%) of whom the aneurysms developed secondary to endocardial infection. Pulmonary infection and osteomyelitis were much less frequent causes. It is difficult to ascertain how frequently mycotic aneurysms develop in patients with infective endocarditis. In one report,
Classification of Spontaneous Arterial Infection
I.
Mycotic aneurysm
II. III.
Infected aneurysm Microbial arteritis
IV.
Traumatic infected pseudoaneurysm
V. VI. VII.
confusion regarding the appropriate classification of spontaneous arterial infection (Table 47-1). Patel and Johnston[15] proposed a comprehensive classification in which an infected aneurysm is categorized according to the preexisting arterial condition (normal, arteriosclerotic, aneurysmal, or arterial prosthesis) and the source of infection (intravascular or extravascular). Intravascular sources of infection included septic embolism, septicemia, or extension of adjacent endocardial infection. Extravascular sources included spread from adjacent foci or iatrogenic infection. Wilson and his colleagues[16] classified all forms of spontaneous arterial infection into seven categories (Table 47-2). Review and study of the pathophysiology, bacteriology, and epidemiology of these lesions supports a natural distinction between mycotic aneurysms associated with infective endocarditis as defined by Osler and those arterial infections not associated with infective endocarditis. Therefore, for the purposes of this chapter, these lesions are classified as follows:
Contiguous arterial infection Septic arterial emboli Spontaneous aortoenteric fistula
Source: After Wilson et al.[16]
Aneurysm occurring in a normal or atherosclerotic artery resulting from emboli or endocardial origin. Established aneurysm infected by bacteremia. Infection of normal or atherosclerotic vessel by a bacteremia, often resulting in rupture of the artery and pseudoaneurysm formation. Aneurysm due to trauma (penetrating or blunt); Inatrogenic injury; injection sites in narcotic addicts. Arterial invasion from an adjacent septic focus. Infection seeded from other primary site. Primary erosion.
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13% of patients with endocarditis died of mycotic aneurysm rupture.[16] The introduction of antimicrobial drugs has reduced the mortality and morbidity of bacterial endocarditis, with a consequent reduction in the incidence of mycotic aneurysms. In 20,201 autopsies performed at the Mayo Clinic through 1954, a total of 178 abdominal aortic aneurysms were identified and only 6 (3%) were infected.[17] None were associated with endocarditis. On the other hand, in a 1967 report Perdue and Smith noted that 10 of 16 infected aneurysms were secondary to endocarditis.[18] Furthermore, while mycotic aneurysms secondary to endocarditis compromise a much smaller component of arterial infection than they did in the early part of this century, it must be emphasized that endocarditis has not been eradicated; its potential for septic arterial complications remains an ongoing clinical concern. In a 1986 study, for example, Dean et al. reported 9 patients with bacterial endocarditis and 25 mycotic aneurysms/emboli at Vanderbilt University. Multiple vessels were involved in 7 (78%) of these patients.[19] This experience underscores the necessity for comprehensive cerebral, visceral, and peripheral angiographic examination of the patient who presents with a mycotic aneurysm, since multiple vessel involvement is common and, not infrequently, some lesions are clinically silent. The use of contaminated needles by intravenous drug abusers and the spread of acquired immunodeficiency syndrome (AIDS) in this society may unfortunately contribute to an increase in the prevalence of mycotic aneurysms in the future.[20]
Pathogenesis Mycotic aneurysms develop from infected heart valves either by direct extension or by embolization. Eppinger[6] was the first investigator to isolate identical bacterial strains from mycotic aneurysms and endocardial vegetations in patients with endocarditis, providing circumstantial evidence in support of the embolic mechanism. Direct spread of infection from the aortic valve to the ascending aorta occurs in a substantial number of cases.[21,22] Embolization of infected debris also occurs to the vasa vasorum or to small arterial branches of the main vessel. Finding intact intima in the aorta at sites of the mycotic aneurysm development suggests that these intramural abscesses were seeded from the vasa vasorum.[23 – 25] Infected emboli may cause thrombosis of the vasa vasorum and resulting vessel wall ischemia; compounded by the local sepsis, degeneration of elastic and muscular elements may ensue, resulting in aneurysm development.[26] This is probably the mechanism responsible for aneurysm formation in large vessels such as the thoracic aorta. Lodgement of septic emboli in small peripheral arterial branches and the subsequent destructive infectious process results in infected aneurysms of peripheral vessels. In some patients, histologic examination of mycotic aneurysms has documented intramural abscesses in the intima and inner portions of the media, areas supplied not by the vasa vasorum but by the intraluminal circulating blood.[27] Such transmural inoculation leads to intimal and medial damage, resulting in aneurysmal dilatation. This mechanism is
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probably operative in the smaller, more peripheral arteries. The final common pathway is destruction of the arterial wall, with progressive aneurysmal dilatation and eventual rupture.
Histology The grossly normal vessel adjacent to the aneurysm may harbor microscopic signs of inflammation. Although histologic findings may be quite variable, the inflammatory reaction is less acute in mycotic than in infected aneurysms. The most characteristic findings in mycotic aneurysm are damage and loss of intima, destruction of elastic lamellae—especially the internal elastic lamina—periarteritis, or mesoarteritis. When the inflammatory reaction is less acute, plasma cells and lymphocytes may predominate. Usually, the inflammatory reaction is most prominent around the vasa vasorum, which may be thickened or obliterated in areas of the greatest inflammation. In chronic aneurysms, an infiltration of fibroblasts may be identified as well as calcification.[8,17]
INFECTED ANEURYSMS: MICROBIAL ARTERITIS WITH ANEURYSM; INFECTED ANEURYSM Incidence As our population ages and the incidence of aneurysmal disease increases, more patients are being identified with secondary infection of preexisting arterial aneurysms, usually of the abdominal aorta.[28,29] In addition, microbial inoculation of a diseased but nonaneurysmal arterial wall may result in infection, mural weakening, and aneurysm formation. Such lesions are classified as microbial arteritis with aneurysm. Since pathogenesis and bacteriology of both infected aneurysms and microbial arteritis with aneurysm are similar, histologic differentiation is often impossible, and treatment is the same, these lesions should be considered a variant of the same disease process: infected aneurysms. As with mycotic aneurysms, it is difficult to determine the incidence of infected aneurysms. Most studies have evaluated aortic aneurysms. In an autopsy series from Boston City Hospital covering the years 1902 –1951, a total of 338 aortic aneurysms were noted, and yet only 12 aortic infections (3.5%) were recognized. Of these, 7 were associated with bacterial endocarditis; thus, the incidence of nonendocarditis infected aneurysms was 1.5%.[12] Some have estimated the incidence of infected abdominal aortic aneurysms to be as high as 3–5%.[30] In a recent study, Klontz identified 23 patients with infected aneurysms discharged from all Veterans Administration hospitals from 1986 to 1990.[31] However, in another review of 2585 aneurysm cases, the incidence of infection was only 0.9%.[32] Reddy et al. reported an overall incidence of infected aortic aneurysms of 0.65% at Henry Ford Hospital during the last 30 years, although the incidence had increased from 0.13% in the 1960s to 0.54% in the 1970s and 1.61% in the 1980s.[33]
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Pathogenesis Available data suggest that inoculation of an intimal lesion during transient bacteremia is the mechanism by which both microbial arteritis and infection of a preexisting arterial aneurysm are initiated. Since intact intima is known to be highly resistant to bacterial infection, a defect in the intimal surface appears necessary for microbial arteritis to develop.[34,35] Arteriosclerosis significantly diminishes resistance of the arterial wall to bacterial infection and is the underlying abnormality in the majority of patients with infected aneurysms.[36] Thrombus within arterial aneurysms and the large area of intimal disruption makes these lesions particularly suspectible to infection. Whether the infection develops in a nonaneurysmal atherosclerotic plaque or within an aneurysm, results are similar. Localized sepsis results in a disintegration of mural elastic and muscular elements, with resultant progressive dilatation of the vessel. Once a nidus of infection is established within a plaque or aneurysm thrombus, it becomes difficult or impossible for systemic antimicrobial agents to eradicate the infection. Although atherosclerosis is the most common lesion predisposing to the development of infected aneurysms, any condition that causes irregularity of the luminal surface, such as coarctation, may predispose to secondary bacterial infection.[37] It has been suggested that the thickened intima characteristically located just distal to the coarctation is particularly suspectible to bacterial invasion.[38] Infected aneurysms may also develop secondary to chronic arteriovenous fistulas.[39] Progressive dilatation of the proximal artery and associated degenerative changes of the arterial wall appear to increase susceptibility to bacterial infection.[40] An infected aneurysm may develop at the reentry site of a chronic aortic dissection.[41] Spontaneous arterial infections have also developed in segments of cystic medionecrosis and areas of syphilitic aortitis.[16,42] Some infected aneurysms have been identified with apparently intact intimal surfaces. Under these circumstances it is presumed that hematogenous infection seeded the arterial wall via the vasa vasorum.[25] An association has been demonstrated between infected aortic aneurysms and both lumbar osteomyelitis and infected paraaortic lymph nodes. In one study,[43] 18% of the patients with infected aneurysms of the abdominal aorta also had apparent involvement of adjacent lumbar vertebrae. It is possible that infection within the vertebrae or lymph nodes reaches the aorta via the lymphatic channels or the vasa vasorum, although evidence in support of this mechanism is speculative.[25] Table 47-3.
Aorta Visceral Arm Leg Iliac Other Total
In addition to these anatomic factors, depressed host immunity has been implicated in the genesis of infected aneurysms in at least 25% of cases reviewed.[44] Solid or hematopoietic malignancy, lymphoproliferative disorders, chronic alcoholism, the use of corticosteroids or chemotherapeutic agents, chronic renal insufficiency, autoimmune diseases, and diabetes mellitus have been noted in some patients developing infected aneurysms.[44]
Histology Infected aneurysms can usually be distinguished from the classic mycotic aneurysms histologically. In an infected aneurysm, the inflammatory reaction is very localized, in contrast to the diffuse inflammatory involvement in mycotic aneurysms; it is so localized that the diagnosis may be missed unless multiple microscopic sections are examined. Whereas the intima may be absent in mycotic aneurysms, identifiable fragments of all layers of the arterial wall are usually found in the infected aneurysms. Inflammatory reaction is consistently acute in infected aneurysms, whereas subacute or even more chronic changes may be noted in mycotic aneurysm.[28]
ANATOMIC DISTRIBUTION Mycotic and infected aneurysms have involved almost every artery (Table 47-3).[45 – 48] Excluding intracranial vessels, the most common sites are the aorta, visceral arteries, and upper and lower extremity vessels.
Aorta All segments of the aorta (Fig. 47-1) have been affected, from the ascending thoracic aorta to the bifurcation. When bacterial endocarditis was prevelant, mycotic aneurysms frequently developed in the ascending aorta and arch. As infected arteriosclerotic aneurysms have become more prevalent than true mycotic aneurysms, the infrarenal abdominal aorta, due to its predilection for arteriosclerotic degeneration, has been more commonly involved.[34] To date at least 39 infected aneurysms of the suprarenal abdominal and/or descending thoracic aorta have been reported,[32] and the incidence appears to be increasing.[49 – 53] For example, in a 1998 report of 17 infected aortic aneurysms from Oregon Health Sciences University, 7 (41%) were suprarenal.[53]
Anatomic Distribution of Mycotic and Infected Aneurysms Strengel[5]
Lewis[7]
Revell[10]
Mundth[34]
Anderson[47]
Brown[48]
Total
66 (25%) 69 (26%) 23 (9%) 31 (12%) 10 (4%) 65 (34%) 264
12 (11%) 31 (29%) 13 (12%) 11 (10%) 3 (3%) 37 (35%) 107
21 (75%) 4 (14%) 2 (7%) 1 (4%) 0 0 28
13 (76%) 1 (6%) 0 2 (12%) 1 (6%) 0 17
2 (12%) 0 3 (19%) 7 (44%) 4 (25%) 0 16
3 (30%) 0 1 (10%) 2 (20%) 1 (10%) 3 (30%) 10
117 (27%) 105 (24%) 42 (10%) 54 (12%) 19 (4%) 105 (24%) 442
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Figure 47-1. Lateral (left) and AP (right) aortograms showing typical saccular appearance of a mycotic aortic aneurysm.
Carotid Artery Fortunately, since they represent special problems in management (see below), infected aneurysms involving the extracranial carotid artery are uncommon. In one institution, over an 11-year period during which 23,000 arterial aneurysms were treated, only 11 infected carotid aneurysms were seen.[54] In a review of the literature, Jebara et al. identified 26 cases of infected carotid artery aneurysms.[55] Prior to availability of antimicrobial drugs, many infected carotid aneurysms resulted from pharyngeal or cervical streptococcal infections.[56] Spontaneous carotid artery infections have been reported following dental extractions and carotid angiography, as well as with septic arthritis.[57 – 59] Most recently, infected carotid aneurysms have been associated with intravenous drug use and
Figure 47-2. aneurysms.
other penetrating trauma.[60 – 63] Nevertheless, bacterial endocarditis continues to be a cause of mycotic carotid aneurysm.[64] All age groups have been affected; one report described a pediatric patient who developed an infected carotid artery aneurysm secondary to a chronic immunosuppressive state.[65]
Visceral Arteries Infection remains one of the most common causes of visceral artery aneurysms (Fig. 47-2).[66] In the preantibiotic era, it was estimated that 20% of splenic artery aneurysms were mycotic. Presumably, such aneurysms resulted from emboli from infected cardiac vegetations.[67] In a 1969 review[68] of 350 splenic artery aneurysms, 38 mycotic or infected lesions were
Selective celiac arteriogram of mycotic common hepatic (large arrow) and proper hepatic (small arrow) arterial
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identified. It is not known how often arteriosclerotic aneurysms of the splenic artery become infected. Although superior mesenteric artery (SMA) aneurysms are not common, infection has been responsible for about 60% of these lesions.[65,69,70] Parenteral drug abuse has contributed to the development of infected SMA aneurysms,[71] which may involve the main trunk or branch arteries.[72 – 75] The hepatic artery is rarely aneurysmal (Fig. 47-2). As with the SMA, however, infection is the most common etiology.[76] The majority of hepatic arterial lesions reported have resulted from septic emboli from endocarditis. Since 1960, however, only 16% of hepatic artery aneurysms have been infected.[76] Most recently, infected hepatic artery aneurysms have been seen as a complication of orthotopic liver transplantation. The incidence has been estimated to be 1 – 3%, and previously most cases were identified at autopsy.[70 – 79] Aneurysms have involved the main hepatic as well as the donor gastroduodenal artery.[80] Recently, Fichelle et al. reported successful repair of an infected hepatic artery pseudoaneurysm in a 35-year-old liver transplant patient using a saphenous vein renal-hepatic artery bypass.[81] Deitch et al. recently reported the first case of an infected renal artery pseudoaneurysm secondary to renal artery percutaneous transluminal angioplasty (PTA) and stent placement, with a successful surgical repair.[82] It was postulated that the deposition of platelets and thrombus at the angioplasty site may stimulate a localized arteritis, thus predisposing to bacterial seeding. As is customary in most endovascular procedures, prophylactic antibiotics had not been administered. In view of the increasing performance of percutaneous endovascular procedures in the non –operating room setting, one may see further cases of arterial infection related to this etiology. Although experience to date is anecdotal, prophylactic antibiotic administration may be appropriate peri-procedurally in this scenario.
Extremities Mycotic and infected aneurysms involve arm and leg arteries in about 20% of cases (Table 47-3). Brachial and radial artery infection has resulted from arteriographic catheterization procedures and indwelling arterial cannulas for hemodynamic monitoring.[83 – 85] Parenteral drug abuse appears to be superceding arterial cannulation procedures as the major cause of femoral artery infection.[48,86,87] Due to the widespread nature of the drug problem, some centers now report that infected femoral artery aneurysms are more common than infected aortic aneurysms.[48] There has also been a recent increase in the incidence of infected iliac artery aneurysm as a complication of kidney and pancreas transplantation.[88,89] Finally, sporadic cases of infected iliac artery aneurysms, secondary to PTA and stent placement, are being reported.[90 – 92]
BACTERIOLOGY Numerous organisms have been isolated from mycotic and infected aneurysms (Table 47-4). The organism isolated
47-4. Microbiology of (Excluding Colonized Aneurysms)
Table
Infected
Aneurysms
No. positive cultures Organisms Staphylococcus Salmonella E. coli Streptococcus Pseudomonas Enterobacter Klebsiella Proteus Pneumococcus Mycobacterium Yersinia Arizona hinshawii Enterococcus Campylobacter fetus Citrobacter Haemophilus Edwardsiella Brucella Anaerobes Fungal
Pre-1984
1984 –1990
1991– 1998
23 17 10 7 7 5 4 4 2 2 1 1 1 1 – 1 – – 7 5 97
22 18 5 7 – 3 2 – – 1 – – 1 4 2 3 1 – 9 1 79
13 20 3 19 1 – 2 1 1 1 – – – 3 1 – – 2 9 2 78
Source: Refs. 13,14,29,32–35,39,41,43,47,51,57,60,63,67,71,77,84,88, 89,96–107,111,113,128,135,143,147,150,163,166,200,226,242.
depends upon the etiology of the aneurysm. When bacterial endocarditits was common, nonhemolytic streptococci, pneumococci, and staphylococci were frequently identified.[5] In a 1943 study[10] of 24 aneurysms, pneumococci (33%), streptococci (33%), gonococci (22%), and staphylococci (11%) were identified. In a review of cases recorded prior to 1960, streptococci and staphylococci were found to be the most common offenders (80%), followed by pneumococci and enterococci.[16] As endocarditis has become less prevelant, bacteriologic patterns have likewise shifted. The incidence of staphylococcal infection appears to be increasing (Table 47-4). Salmonella species have also emerged as frequent pathogens of infected aneurysms, particularly in the aorta. In three large reviews[90 – 95] of arotic infection, Staphylococcus (25%) and Salmonella (31%) species predominate. Other reports[34] document isolation of Salmonella from 23 –66% of infected aneurysms. In addition to the emergence of Salmonella and the continued prevelance of staphylococcal species as responsible pathogens, other gram-negative organisms and anaerobic bacteria are being identified with increasing frequency.[47,96 – 106] Aneurysm cultures are not always revealing. In one study,[28] only 53% of aneurysm tissue sampled yielded growth of organisms. In another,[34] 71% of aneurysm cultures were positive. Universal failure to grow organisms from obviously infected aneurysms relates to culture techniques, fagility of the organism, and intercurrent antibiotic therapy.
Chapter 47. Infected Aneurysms
In addition to failure to culture organisms consistently, the source of infection has been determined in only 54–71% of cases.[28,34] Osteomyelitis was formally a common contributing etiology. Bacteremia secondary to gastroenteritis and endocarditis was also frequently noted. Less commonly encountered were urinary tract sepsis, esophageal fistula, diverticulitis, otitis media, pulmonary infection, and cellulitis. Recently, an infected abdominal aortic aneurysm was reported secondary to an appendiceal abscess.[107] Clearly, transient bacteremias from unknown foci are an important factor in the pathogenesis of infected aneurysms. In addition to identifying appropriate antibiotic therapy, culture data may have some prognostic significance. Gramnegative infections of abdominal aortic aneurysms appear more ominous than gram-positive infections. In Jarrett’s review,[43] the mortality rate was 84% among patients with gram-negative infections, contrasted to only 50% when the aneurysm contained gram-positive organsims. Rupture of the aneurysm occurred in 5 of 6 patients with gram-negative infections, compared to 1 of 10 with gram-positive organisms. The greater tendency for rupture with gram-negative infection and, hence, the increased mortality rate may reflect increased organism virulence.
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infection occurring in 10%. In addition to arteritis, meningitis, pleuropulmonary disease, endocarditis, and osteomyelitis, there have been reports of splenic, hepatic, and soft tissue abscesses.[114] The recent increase in Salmonella arterial infection has led to a rethinking of previous dogma concerning antibiotic therapy for Salmonella gastroenteritis. Since antibiotics prolong the fecal excretion of Salmonella and increase the frequency of resistant stool isolates, most investigators recommend no treatment for this otherwise self-limited gastrointestinal ailment.[132] However, in an extensive review[133] of state laboratory records of Salmonella bacteremia in Massachusetts, it is noted that 10 of 105 patients with bacteremia developed endothelial foci of infection. Of these 10 patients, 4 had preexisting untreated gastroenteritis. Furthermore, all 10 were over 50 years of age. Since only 40 patients older than 50 were noted to have Salmonella bacteremia during the study period, the incidence of endothelial infection in this group was 25%. Others have corroborated a predilection of Salmonella arteritis for older individuals.[134] Therefore, it has been suggested that antibiotic treatment of patients over age 50 with Salmonella gastroenteritis might reduce the incidence of endothelial infection.[133]
Salmonella Infection One of the more fascinating yet incompletely understood aspects of infected aneurysms, which deserves special comment, is the tendency for Salmonella species to cause arterial infection. Three types of vascular lesions may result from Salmonella infection. First, a diffuse suppurative arteritis may cause arterial rupture, resulting in a saccular or false aneurysm. Second, Salmonella may initiate a focal arteritis that leads to weakening of the arterial wall and formation of a true infected aneurysm. Third, Salmonella species may infect a preexisting aneurysm. Salmonella arterial infections have been reported in the thoracic and abdominal aorta as well as the iliac, femoral, popliteal, and coronary arteries, although 75% affect the aorta and 50% involve the abdominal aorta.[16,107 – 115] Recent studies continue to demonstrate that Salmonella is a frequent source of arterial infection.[116 – 123] Infection by Salmonella may be faciliated by immunosuppressive diseases such as diabetes, malignancy, human immunodeficiency virus, hemolytic diseases such as sickle cell anemia and malaria, as well as raw gastric acidity and alterations in the intestinal flora.[44,115,124,125] Inoculation of the organisms on a diseased intimal surface appears to be the initiating event in most cases,[126] although invasion of previously healthy intima can occur.[108] Salmonella organisms are gram-negative flagellated bacteria of the family Enterobacteriaceae, with over 2200 serotypes.[115] The most common isolates from infected aortic aneurysms are S. choleraesuis (32%), S. typhimurium (27%), and S. enteritides (9%).[127,128] Organism serotype determines the specific clinical syndrome.[115] The high incidence of Salmonella arteritis due to S. choleraesuis is probably related to its propensity to cause a severe bacteremia.[129 – 131] Fifty percent of all Salmonella bacteremias are due to S. choleraesuis, with localized suppurative
Unusual Bacteria Several unusual organisms have been increasingly isolated from infected aneurysms in recent years. Plotkin and O’Rourke[135] describe a 53-year-old man with an infected aneurysm of the internal carotid artery due to Yersinia enterocolitica, an aerobic and faculatively anaerobic nonencapsulated rod-shaped gram-negative organism. It was presumed that a transient bacteremia in this patient resulted in secondary infection of an arteriosclerotic carotid plaque with eventual aneurysm formation. Arizona hinshawii and Campylobacter fetus have also been isolated from infected aneurysms.[136,137] Bacteremia of the genus Arizona are among the Enterobacteriaceae that have been noted to cause a variety of diseases in humans, including gastroenteritis, urinary tract infection, cholecystitis, septic arthritis, osteomyelitis, and septicemia. Although taxonomically distinct from other Enterobacteriaceae, these organisms were at one time considered to belong to the genus Salmonella, since there are a number of biochemical and serologic similarities between these two groups of organisms.[138] Campylobacter, like Salmonella, lacks the enterotoxin production, cytotoxicity, and invasive properties exhibited by other enteric organisms. Thus, although precise mechanisms of arterial infection are not known, Campylobacter and Arizona infections may share similar characteristics with Salmonella. Clostridium septicum is a relatively uncommon anaerobic pathogen responsible for approximately 1% of all clostridial infections, and often is identified in patients with underlying malignant disease.[139] Over the past two decades 10 patients, ranging in age from 68 to 85, have been reported with infected aneurysms due to Clostridium septicum. At least six of these patients had documented malignancies.[105]
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Fungal Infection Despite the widespread use of the word mycotic (arising from the Oslerian term fungus vegetations ) to describe infected aneurysms, such aneurysms only rarely result from fungal infection. The thoracic and abdominal aorta as well as the major peripheral and intracranial arteries may be affected, however. Histoplasma capsulatum, Aspergillus fumigatus, Candida albicans, Actinomyces, and Penicillium species are the only reported causative agents.[140 – 145] Like systemic fungal infections, these arterial infections tend to be associated with chronic immunosuppressive states, diabetes mellitus, and the use of contaminated needles.[140,145,146] The precise mechanism of arterial infection varies but is similar to that for bacterial involvement. Inoculation of arteriosclerotic plaques by blood-borne organisms has been documented only for Histoplasma.[140] Embolization of infected valvular vegetations and contiguous spread from adjacent foci of infection may also be responsible for some cases.[140,146] Arterial infection via the vasa vasorum, well established for bacterial organisms, has not been conclusively documented for fungi.[140] Fungal infection of arterial aneurysms may occur long after recognition of the original fungal infection. Such aneurysms are usually saccular; when they involve the abdominal aorta, vertebral body erosion is frequently noted. The risk of rupture of these lesions is significant. In a review[140] of aortic aneurysms infected with Histoplasma capsulatum, survival was only 33%. When fungal infection of an aneurysm is suspected at operation, frozen section specimens should be examined for confirmation. Principles of surgical treatment are similar to those for aneurysm infection with bacteria (see below).
having been noted in 28% of the cases in another recent report.[150]
ENDOVASCULAR INFECTION Arterial infection secondary to endovascular stent placement also bridges the gap between pure arterial infection and prosthetic graft sepsis. The true incidence of arterial infection secondary to intravascular stent placement is not known, is probably quite low, but, as noted above, is now being increasingly seen in a variety of anatomic locations.[82,90 – 92,151 – 154] Treatment of this complication should follow the principles of native arterial infection management, as described below.
COLONIZED ANEURYSMS The isolation of positive bacterial cultures from the contents of clinically noninfected arteriosclerotic abdominal aortic aneurysms was first reported by Ernst et al.[155] Several subsequent studies have demonstrated an incidence ranging from 7 to 20%.[156 – 161] Staphylococcal species have predominated. Previous experience has failed to conclusively demonstrate an increased risk of subsequent graft infection and positive aneurysm cultures in the elective setting. Conversely, the incidence of positive cultures is highest in symptomatic aortic aneurysms. This subtle relationship between aneurysm colonization and rupture may be more than coincidental, although the mechanism remains unexplained.
NATURAL HISTORY INFECTED ANASTOMOTIC ANEURYSMS Infected anastomotic aneurysms bridge the gap between pure arterial infection and prosthetic graft infection. Anastomotic aneurysms occur following 2 –5% of bypass grafts, and a majority involve the femoral anastomosis.[147] Traditionally, the development of anastomotic aneurysms has been attributed to a variety of factors such as structural weakness of the artery (often after endarterectomy), suture fracture, graft deterioration, and mechanical stress from patient activity or hypertension. Infection has been considered an infrequent cause. Only 12% of these lesions reported between 1972 and 1982 were infected.[148] However, a recent report suggests that a occult infection may play an etiologic role in many of these aneurysms. In a series of 45 anastomotic aneurysms, Seabrook et al.[149] identified 32 bacterial isolates from 27 (60%) of these lesions. Coagulase-negative staphylococci accounted for 24 (88%) of the isolates. These findings suggested that bacterial contamination and colonization may occur at implantation, resulting in a chronic, low-virulence infectious process at the arterial suture line, with late pseudoaneurysm formation. Furthermore, as the quality of graft and suture materials improves, the incidence of overtly infected anastomotic pseudoaneurysms is increasing,
Complications of infected aneurysms include progressive enlargement and rupture, thrombosis, and embolization. The incidence of rupture is high, averaging 54%, compared to 20% for noninfected aneurysms.[162] In fact, without surgical intervention infected aortic aneurysms were almost always fatal. In one recent review, the mortality among patients with Salmonella aortic aneurysms was 95% when treated medically.[117] Furthermore, ruptured infected aneurysms are usually smaller than ruptured noninfected aneurysms, and progression to rupture occurs rapidly. Less commonly, a slow, insidious course precedes rupture of an infected aueurysm. A febrile illness lasting weeks and even months in some cases has been described prior to eventual rupture.[28] Outcome once an infected aneurysm has ruptured depends upon the vessel involved. Infected aortic aneurysms represent the greatest risk to life. Earlier studies of patients with ruptured infected aortic aneurysms documented a mortality rate approaching 95%.[162] More recent studies have reported a much more favorable outcome, however. Aortocaval and aortoenteric fistulas have also been reported secondary to mycotic and infected aneurysms.[136,162] Limited perforation, particularly of a peripheral vessel, results in pseudoaneurysm formation with persistent sepsis. Prior to rupture, both aortic and peripheral aneurysms may shed emboli, causing septic arthritis and purpura.[163]
Chapter 47. Infected Aneurysms
Although less common than rupture, thrombosis of myocotic and infected aneurysms has been noted both in the aorta and peripheral vessels. It has been suggested that thrombosis of these lesions may result in cure, but evidence in support of this contention is limited.[8]
Table 47-5.
Clinical Characteristics of Infected Aneurysms
Epidemiology
History
DIAGNOSIS Clinical Presentation The clinical presentation (Table 47-5) of patients with mycotic and infected aneurysms depends upon the pathogenesis, underlying etiology, and vessel involved. Septic arterial lesions have been noted in all age groups, from neonates to the elderly.[5,22] Earlier reports documented these lesions most commonly in the second, third, and fourth decades, reflecting the association with bacterial endocarditis.[5] More recently, however, there has been a shift in incidence to the elderly. In a 1967 study,[28] only 9% of infected aortic aneurysms occured in patients younger than age 40, whereas nearly three-fourths occurred in those over age 60. In a 1996 report of patients with infected thoracic and abdominal aortic aneurysms, patients ranged from 57 to 83 (mean, 70) years of age.[164] The increasing age of patients affected with aortic infection emphasizes the importance of diseased arterial intima, usually by arteriosclerosis, in the pathogenesis of microbial arteritis, as well as the rising incidence of infected arteriosclerotic aneurysms. Conversely, the prevelance of drug abuse and the use of contaminated needles—as well as AIDS—may lead to an increased incidence of infectious arterial problems in younger patients in the future.[19,165] Most mycotic and infected aneurysms have been reported in males. Stengel and Wolferth[5] note that approximately two-thirds occurred in men; other studies[10,12,28] document a male predominance ranging from 82 to 91%. In contrast, Jarrett and his colleagues[43] reported infected aortic aneurysms in 7 women and 10 men. Fever or history of a recent febrile illness are the most common complaints in patients with infected arterial lesions; these symptoms have been noted in 70–94% of patients with proven mycotic or infected aneurysms.[34,43,47] The fever may be steady or intermittent and is usually associated with chills and sweats.[14] Frequently, a long history of malaise, weight loss, and increasing weakness is present. Pain is an almost universal complaint. In patients with infected aortic aneurysms, the discomfort may be localized to the abdomen or back. In those with peripheral aneurysms, it is usually localized to the site of the lesion, where there may be overlying erythema, induration, and tenderness. Nearly 90% of infected peripheral aneurysms are palpable, but only 50 – 65% of abdominal aortic aneurysms are.[34] Fever, along with a tender abdominal aortic aneurysm, is presumptive evidence of infection, since temperature elevation is rarely caused by simple expansion or rupture.[43] When pain and tenderness of an infected aortic aneurysm are localized to the flank, differentiation from a perinephric abscess may be impossible.[166] Mistaken diagnosis of inflammatory intraabdominal conditions may lead to confusion and catastrophy.[167] Hepatic artery involvement may cause right-upper-quadrant
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Exam
Laboratory X-ray
Operative findings
Males . females (4 to 1) All age groups Bacterial endocarditis Atherosclerosis; illicit drug use Intermittent febrile episodes Malaise Weight loss Pain Fever with chill (70 – 94%) Pain (2 100%) Rapidly expanding mass (50– 90%) Leukocytosis (65– 83%) Positive blood cultures (50%) Noncalcified aneurysm Lumbar osteomyelitis (AAA) Lobulated, saccular arteriographic appearance Thin-walled aneurysm Surrounding inflammatory reaction Succulent lymph nodes Positive Gram stain
or epigastric pain suggestive of cholecystitis or pancreatitis. Likewise, SMA lesions may be confused with inflammatory diseases of the small or large bowel. Malabsorption has been reported in association with an infected SMA aneurysm.[168] Infected aneurysms of the peripheral vessels may be confused with localized soft tissue abscesses, cellulitis, or lymphadenitis. A thrombosed, infected femoral artery aneurysm may mimic an incarcerated or strangulated groin hernia. Failure to maintain a high index of suspicion can result in surgical disaster if one approaches these lesions without proper exposure and control.[14]
Laboratory Data Leukocytosis is the most consistently abnormal laboratory finding in patients with mycotic or infected aneurysms. A leukocytosis above 10,000/mm3 has been noted in 65–83% of patients with proven infected aneurysms.[28,34,43] Antibiotic tibiotic therapy, however, may blunt this elevation. Furthermore, leukocytosis may be noted following leakage from a noninfected aneurysm. Elevation of the erythrocyte sedimentation rate is a frequent but nonspecific finding. With infected hepatic arterial aneurysms, liver function tests are usually unremarkable.[169]
Bacteriologic Studies Positive preoperative blood cultures provide strong confirmatory evidence for the presence of an infected aneurysm, although negative cultures do not rule out the diagnosis. In one report,[47] only 50% of the patients had positive blood cultures. In another,[34] positive blood cultures were found in 53% of all patients and in only 46% of those with infected aortic aneurysms. In contrast, Jarrett and his colleagues[43]
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report that 70% of patients with infected aortic aneurysms had positive blood cultures, and in each patient the organism cultured from the blood was the same as that isolated from the aneurysm. In a recent report from Henry Ford Hospital, positive blood cultures were obtained from 69% of patients with infected aortic aneurysms, and positive cultures were noted more often in patients with ruptured in contrast to intact aneurysms.[33] As many patients with infected aneurysms may be receiving antibiotics at the time blood samples are drawn, multiple samples may be required before bacteremia is confirmed. Furthermore, the sampling of blood from an arterial site downstream from the presumed focus of infection may improve the yield of positive cultures.[170,171] As with preoperative blood cultures, antibiotics may mask bacterial growth from samples obtained at operation. It is critically important, therefore, to perform a Gram-stain examination in addition to bacterial cultures on material obtained during operation. Positive operative cultures may be obtained in 53 –94% of patients.[28,47] In most patients with negative cultures, however, organisms will be identified on histologic examination of tissue sections.[28] Mundth and his colleagues[34] note that the responsible organism was isolated in 71% of the aneurysm cultures. In the remaining 29%, organisms were identified on Gram-stain examination of the aneurysm wall or its contents. Reddy et al.[33] reported positive intraoperative Gram stains in 50% of patients with rupture but in only 1 of 8 patients with intact infected aortic aneurysms. Operative cultures were positive in all patients with ruptured and 89% of those with intact infected aortic aneurysms.
RADIOLOGIC STUDIES Plain Films Frontal and lateral abdominal x-rays may provide useful information in the patient with a suspected infected aortic aneurysm. An association between osteomyelitis of the lumbar vertebrae and infected aortic aneurysms has been documented.[29,43] Since vertebral body erosion is rarely noted within an arteriosclerotic aortic aneurysm, such findings should raise suspicion of aneurysmal infection. In addition, arteriosclerotic abdominal aortic aneurysms are calcified in about 70% of cases, and this calcification may be noted on standard lumbosacral spine or frontal and lateral abdominal films.[172] Infected aortic aneurysms, however, are less often calcified.[43] Therefore, a noncalcified aneurysm in a patient with fever and leukocytosis is strongly suggestive of an infected aneurysm.
helpful screening procedure. No criteria have been described which confirm aneurysm infection, however. Recently, Harris and colleagues identified aortic wall thickening and false aneurysm formation using transesophageal echocardiography to evaluate two patients with aortic infection.[174]
Computed Tomography The contrast-enhanced computed tomography (CT) scan is extremely helpful in evaluating patients with suspected infected aortic aneurysms. Several findings are highly suggestive of the diagnosis, although none are pathognomonic (Table 47-6).[175 – 181] An irregular, saccular aneurysm noted in a febrile patient is highly suggestive, particularly if there is disruption or absence of intimal calcification. Gas within the aortic wall has been identified by CT in patients with infected aneurysms.[175] More often, air or fluid is identified adjacent to the aortic wall. An encasing or adjacent mass—reflecting either hematoma, abscess, or inflammatory nodal tissue—has also been seen with infected aortic aneurysms. Finally, vertebral osteomyelitis adjacent to an aortic aneurysm should raise the question of aneurysmal infection. Clearly, CT examination may provide strong circumstantial evidence of aortic infection prior to arteriographically detected abnormalities.[181]
Radioisotope Examinations Two new methods are currently available for the evaluation of septic processes, particularly within the abdomen. Labeling of human leukocytes with Indium-111, a gamma-emitting agent, is now possible.[182] Indium-111 leukocyte scanning is based upon external gamma camera detection of labeled leukocytes that have accumulated at sites of infection or inflammation. This technique has been utilized predominantly to detect intraabdominal abscesses and has identified prosthetic graft infection in a limited a number of cases.[144,183] Bell et al.[184] reported the first case of an infected aortic aneurysm detected by Indium-111 leukocyte scanning. Leukocyte scintigraphy may complement CT evaluation of patients with suspected arterial infection. BenHaim and colleagues reported that four patients with infected aneurysms were correctly identified by leukocyte scintingraphy, and the study was negative in 2 of 3 patients with noninfected aneurysms.[185]
Table 47-6. CT Findings of Infected
Aneurysms
Ultrasound Abdominal ultrasound can confirm the presence of an aortic aneurysm and provide a fairly accurate assessment of its size, even in the absence of calcification.[172,173] Ultrasonography is also helpful in documenting intraperitoneal abscesses, a distended gallbladder suggestive of cholecystitis, pancreatic masses, and other intraabdominal inflammatory conditions that must be excluded in evaluating a patient for a possible infected aortic aneurysm. To this end, ultrasonography is a
Saccular aneurysm Irregular aneurysm lumen Absence of calcification Gas within aortic wall Peri-aneurysmal gas Peri-aneurysmal fluid Encasing or contiguous mass Associated para-aortic or psoas abscess Vertebral osteomyelitis
Chapter 47. Infected Aneurysms
Gallium-67 isotopic scans have been used to localize intraabdominal abscessess. Radioactive Gallium-67 collects in areas of inflammation and may be detected by external scanning cameras. Successful use of Gallium-67 scanning in the diagnosis of a Dacron aortic graft infection and aortoenteric fistula has been reported.[186,187] The inflammatory reaction inherent in a mycotic or infected aneurysm should allow these arterial infections to be detected by gallium scanning, although reports to confirm this suspicion are not available.
Arteriography An arteriogram is an essential part of the evaluation of any patient with a presumably infected arterial aneurysm. In addition to providing information for planning reconstruction, arteriography may help confirm the diagnosis of infected aneurysm. An excessively lobulated, saccular aneurysm arising from an otherwise normal-appearing vessel that lacks features of arteriosclerosis is highly suggestive of an infectious etiology (Fig. 47-l).[188] The appearance of localized smooth-walled aneurysmal changes, explained by the rapidly progressive transmural inflammatory destructive process, has been emphasized by others.[29] A particularly eccentric aneurysm with a relatively small mouth in comparison to its widest diameter also suggests infection.[189] Despite these characteristic findings in some cases, the angiographic appearance of many infected aneurysms may be indistinguishable from that of typical arteriosclerotic, traumatic, or congenital aneurysms.[190] Furthermore, angiographic findings characteristic of infection typically occur late in the course of the septic process.[181]
OPERATIVE FINDINGS Certain findings at operation suggest infection within the aneurysm, although such features may be quite subtle. Infected aneurysms tend to be saccular, lobulated, and eccentric.[189] The wall of the aneurysm is typically quite thin and friable.[28] A moderate degree of surrounding inflammation may be noted, and large, succulent lymph nodes adjacent to the aorta or in proximity to a peripheral aneurysm may be encountered. The typical inflammatory aneurysm of the abdominal aorta may also be surrounded by large lymph nodes and be engulfed in an inflammatory reaction. However, the wall of an inflammatory aneurysm is usually thick and pearly white in contrast to the thin-walled, red, mulberrylike infected aortic aneurysm. The operating surgeon must maintain a high index of suspicion when encountering unusual-appearing aneurysms in order to make the diagnosis of infection.
TREATMENT Successful management of the patient with arterial infection remains one of the most difficult challanges encountered by the vascular surgeon. The aim of therapy is to eradicate all infection while maintaining adequate circulation. Principles
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of successful management are independent of the specific lesion (mycotic aneurysm, microbial arteritis with or without aneurysms, and secondarily infected aneurysm), mechanism of infection (transmural bacteremic endothelial inoculation, via vasa vasorum, or direct spread from contiguous sepsis), or organism responsible.
Preoperative Management Establishing the correct diagnosis preoperatively is the first step in treatment. Multiple blood cultures should be obtained, including several samples from a source downstream of the presumed site of the aneurysm. Other potential sources of infection such as urine, sputum, and open wounds should be thoroughly cultured. High-dose intravenous organismspecific antibiotic treatment must be started to prevent continued hemotogenous spread of infection. The goal of sterilization of the patient’s blood is important to prevent possible contamination of a vascular prosthesis that might be required for arterial reconstruction, although one should not inordinately delay operative intervention for this purpose. When attempts at identifying the offending organism(s) prove futile, any combination of broad-spectrum bactericidal antibiotics for both gram-positive and gram-negative organisms (specifically Salmonella ) are appropriate. Although sporadic cases of sterilization and spontaneous healing of these lesions with antibiotics alone have been reported,[34,191] this is the exception, if it occurs at all. Sudden rupture of infected aneurysms has been observed while patients were undergoing intensive antibiotic treatment.[17,28,188,192] Even aneurysmal sterilization does not preclude progressive enlargement and eventual rupture.[188,193,194]
Operative Management Appropriate intravenous lines should be inserted. If necessary, a Swan-Ganz catheter may be placed to monitor pulmonary artery wedge pressure. The insertion of a radial artery cannula in the nondominant wrist or the side opposite anticipated axillofemoral reconstruction provides ready access for blood sampling as well as systemic blood pressure measurements. Once the aneurysm has been exposed, infection must be confirmed. When gross perivascular purulence is encountered, the diagnosis is obvious. In the absence of obvious signs of sepsis, Gram stains should be obtained and frozen sections of the aneurysm wall examined for bacteria or fungi. Identification of microorganisms within the aneurysmal wall or contents in the patient with fever, leukocytosis, positive blood cultures, a particularly friable-appearing aneurysm or an aneurysm surrounded by large lymph nodes is diagnostic of aneurysm infection. Aerobic, anaerobic, and fungal cultures must be obtained and plated immediately in appropriate culture media. Principles for managing infected aneurysms are generally similar to those for dealing with an infected arterial prosthesis. Wide debridement and copious irrigation with antibiotic solution of all involved tissue is required. This includes complete resection of the aneurysm if technically possible. If rupture has occurred, a wider area will be involved
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in the septic process and more aggressive debridement may be required. Ligation of arteries should be performed in clean, healthy-appearing tissue with synthetic monofilament or wire sutures. Preoperative vascular laboratory data combined with arteriography help document adequacy of collateral circulation around the infected lesion. If, at the initial operation, collateral circulation is adequate to support the distal bed without arterial reconstruction, arterial ligation only should be performed. If revascularization is necessary, the method of reconstruction will depend upon the location and extent of arterial involvement and the magnitude of the septic process.[47,195]
Abdominal Aorta Extraanatomic Reconstruction The conventional management of the infected abdominal aortic aneurysm is similar to the treatment of a secondary aortoenteric fistula or an infected aortic prosthesis, namely, excision of all septic tissue and extraanatomic arterial reconstruction. Whether one is dealing with a ruptured or intact abdominal aortic aneurysm, secure closure of the proximal aortic stump distal to the renal arteries is mandatory for a successful result and constitutes one of the more difficult aspects of repair. Postoperative aortic stump dehiscence has been documented in up to 33% of patients.[196] Healthy tissue that will hold sutures may not be readily available. Under these circumstances, temporary suprarenal aortic occlusion, at the diaphragm through the lesser sac, permits complete mobilization of the infrarenal aorta, unencumbered by an infrarenal aortic clamp. A two-layer aortic closure with monofilament suture has been recommended, and prevertebral fascia may be used to strengthen the closure.[14,188,197] Although a pedicle of omentum, transposed through the transverse mesocolon, probably provides no strength, such coverage may facilitate the resolution of periaortic infection (Fig. 47-3). Copious irrigation of the retroperitoneum is performed and irrigatingdrainage catheters may be placed in the aortic bed for drainage
and postoperative through-and-through irrigation with antibiotic or povidone-iodine solutions during the early postoperative period (Fig. 47-4).[115,198] Although antecdotal reports[149,199,200] have described successful management of infected aortic aneurysms by resection without restoring arterial continuity, in the majority of patients arterial reconstruction will be required to prevent distal ischemia. The conventional approach dictates extraanatomic bypass through clean tissue planes. Axillofemoral grafting as a means of extraanatomic bypass has gained popularity since it was first introduced in the United States by Blaisdell and Hall[201] in 1963, although long-term patency is inferior to aortoiliac or aortofemoral reconstruction (Fig. 474). When the infected aneurysm is small and limited to the aorta and when, following excision and distal closure of the aortic bifurcation, there is no significant iliac occlusive disease, unilateral axillofemoral reconstruction is appropriate. Under these circumstances, the contralateral leg will be perfused retrograde around the bifurcation. If the bifurcation must be excised and the common iliac vessels are free of significant disease, they may be mobilized and anastomosed end-to-end to form a neobifurcation, again allowing use of unilateral axillofemoral reconstruction (Fig. 47-5).[29,195] If recurrent occlusion of the axillofemoral graft becomes a late problem, anatomic aortic reconstruction may be performed provided the retroperitoneal infection has completely resolved.[188] At least 6 – 12 months should elapse from the original procedure before this option is considered. In the unstable patient with a suspected leaking or ruptured infected aortic aneurysm, or in the patient in whom infection has not been confirmed preoperatively, the abdomen must be explored as the first step and the extraanatomic bypass carried out with clean instruments after closure of the abdomen. However, in view of the technical difficulty often associated with the abdominal portion of the operation and the time required, which may result in a protracted period of limb ischemia, in the stable patient it appears that overall results have improved most recently by performing the extraanatomic bypass as the initial step.[36,188]
Figure 47-3. Methods of closing infrarenal aorta following aneurysm excision. A proximal row of continuous horizontal mattress sutures is followed by a distal row of continuous over-and-over sutures (left). Prevertebral fascial flap buttress sutured over aortic stump (center). Omental graft passed through transverse mesocolon provides additional protection (right). (From Ernst CB.[198] Reproduced by permission.)
Chapter 47. Infected Aneurysms
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Figure 47-4. Infected aneurysm has been excised. The axillobifemoral bypass maintains pelvic and leg circulation. Irrigation drainage catheters are placed in retroperitoneal space (optional). (From Ernst CB.[198] Reproduced by permission.)
In performing preliminary axillobifemoral reconstruction, Cooke and Ehrenfeld[188] have advocated occluding the common femoral artery proximal to the femoral anastomosis to prevent acute graft thrombosis secondary to competitive flow. However, based upon observations by Blaisdell and his colleagues[202] as well as Ernst [203] it appears that axillofemoral bypass grafts may remain patent for up to 4 months with competitive aortoiliac flow. Therefore, it does not appear necessary to occlude host vessels proximal to groin anastomoses for fear of failure of extraanatomic reconstruction due to competitive parallel blood flow. Bacteremic contamination of the newly placed extraanatomic graft has not been a problem.
In Situ Reconstruction Over the last decade, in view of the continued significant mortality and morbidity associated with the conventional management of aortic infection, increasing numbers of patients have undergone in situ revascularization following resection and debridement of the infected tissues. This strategy has elvolved from the management of patients with suprarenal and thoracoabdominal aortic infection in whom extraanatomic bypass is not an option. There are a number of potential conduits which have been utilized. Several workers have reported in situ reconstruction using prosthetic conduits.[32,49,81,94,204 – 209] In the largest series reported to date, Fichelle and colleagues replaced infected infrarenal abdominal aortic aneurysms in 21 patients with either Dacron[21] or polytetrafluoroethylene (PTFE)[2] grafts. There were three (14%) deaths and no cases of recurrent infection with a mean follow-up of 53 months[81] (see below). In contrast, Pasic et al. reported an operative mortality of 33% among 6 patients undergoing in situ prosthetic repair of infected aortic aneurysms, and one survivor presented with a late aortoenteric fistula.[204] Most recently, Gupta and
Figure 47-5. After resection of infected aortic aneurysm and ligation of infrarenal aortic stump, common iliac arteries have been anastomosed and unilateral axillo-femoral bypass has been performed. (From Scher LA, et al. [29] Reproduced by permission.)
colleagues reported 2 patients who underwent in situ replacement of infected aortic aneurysms with rifampinbonded Dacron grafts.[210] This preliminary clinical experience was based on prior studies demonstrating antistaphylococcal bactericidal activity on graft surfaces for at least 2 days after aortic replacement as well as the lack of thrombogenicity associated with rafampin bonding and the absence of evidence suggesting the emergence of rifampinresistant organisms.[211 – 213] Another novel approach recently reported has been the implantation of gentamicin-methylmethacrylate-methylmethacrylate beads in the bed of the in situ prosthetic graft in 4 patients with infected aneurysms of the carotid, innominate, ascending, and infrarenal aorta.[214] Review of this largely antecdotal experience highlights several principles which should guide the clinician contemplating in situ replacement of an infected aneurysm with a prosthetic conduit. Aggressive soft tissue debridement is absolutely necessary, and the graft anastomoses must be performed to uninvolved vessels.[81] Gross purulence, rupture, and gram-negative infection are relative contraindications to attempting in situ reconstruction.[33,53] An alternative strategy for performing in situ reconstruction which is being increasingly undertaken today is the use of freshly harvested or cryopreserved homograft vessels.[215 – 221]
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This approach is based upon the cardiac surgical experience utilizing homograft tissue in managing patients with valvular infection and associated problems.[222,223] This represents a more theoretically appealing approach than placing a synthetic conduit in the bed of the infected artery. While freshly harvested vessels might avoid some of the potential long-term degenerative complications associated with cryopreserved vessels, the limited number of organ donors and the frequently urgent or emergent nature of these infectious problems makes cryopreserved conduits, which are more readily available, appealing. Preliminary experience has been favorable, and it is speculated that more refined techniques of homograft preparation and preservation will reduce the incidence of long-term graft calcification and aneurysmal degeneration.[220]
Endovascular Repair The most innovative, and perhaps controversial, approach to the management of patients with infected aortic aneurysms has utilized currently evolving stent-graft technology. Semba and colleagues[224] recently reported 3 patients with infected thoracic aortic pseudoaneurysms who underwent placement of polyester fabric-covered Z stents delivered from the femoral artery under fluoroscopic control. There were no periprocedural deaths. One patient suffered a cardiac arrest 25 months later, without evidence of recurrent infection. The other 2 patients were alive and without signs of recurrent infection at 4 and 24 months, respectively, following the procedure.
Visceral Arteries The relatively small size and frequency of multiple visceral aneurysms emphasizes the importance of arteriography for diagnosis and preoperative planning (Fig. 47-2).[16] The surgical approach required for treatment depends upon the size and location of the lesion, as well as the adequacy of collateral development. Goals of operative management are to prevent rupture of the aneurysm while preserving adequate distal perfusion.
Superior Mesenteric Artery DeBakey and Cooley[225] performed the first successful resection of a mycotic aneurysm of the SMA in 1949. By 1987, a total of 19 patients with infected SMA aneurysms had been successfully treated by ligation with or without aneurysm excision.[71,226] Attempts to excise these aneurysms completely may be hazardous, since they are usually densely adherent to important adjacent structures. With adequate drainage and long-term antibiotic therapy, recurrent infection should not be a problem even with only partial excision and endoaneurysmorrhaphy.[227] Following ligation of the vessel, the bowel should be observed for 30 minutes to assess viability. Use of the sterile Doppler probe or injection and detection of sodium fluorescein dye may prove useful in assessing bowel viability.[228,229] These two techniques are clearly superior to using clinical parameters of mesenteric arterial pulsations, peristalsis, and color to assess viability. Short segments of apparently nonviable intestine must be resected. If long
segments of bowel appear compromised, mesenteric revascularization will be required, preferentially utilizing autogenous artery or vein conduits through noninfected tissue planes if possible.[227] The use of synthetic graft material has been associated with persistent infection and anastomotic disruption;[47,230] it is therefore contraindicated. Endoaneurysmorrhaphy, another method of treating arterial aneurysms, has proven successful in managing infected SMA aneurysms.[69,70,227] Restorative endoaneurysmorrhaphy requires obtaining proximal and distal control of the involved artery, opening the aneurysm, and oversewing the aneurysm orifice; that is, performing an arteriorrhaphy which preserves the vessel lumen. An intraluminal shunt facilitates vessel repair by maintaining bowel circulation and provides a stent around which the arteriorrhaphy is performed. The shunt is removed before placing the last few sutures. If the aneurysm is not saccular and involves both afferent and efferent vessels, obliterative endoaneurysmorrhaphy may be performed by oversewing the orifices of these vessels from within the open aneurysmal sac. By limiting dissection and working from within the aneurysm, maximum collateral circulation is preserved. Use of intraluminal balloon occlusion of the inflow and outflow vessels facilitates endoaneurysmorrhaphy because the extensive dissection required for proximal and distal clamp occlusion is not required.
Hepatic Artery Most infected hepatic arterial aneurysms can be successfully managed by ligation or ligation with aneurysm excision.[231] When the aneurysm involves the proper hepatic artery (the segment distal to the gastroduodenal branch) or when preoperative angiography documents poor collateral development, an attempt at arterial reconstruction should be made to prevent liver ischemia.[169] Saphenous vein or autogenous hypogastric arterial segments are the preferred bypass materials. Infected aneurysms of intrahepatic arteries have, until recently, been considered curable only by hepatic lobectomy. Porter and colleagues[32] describe a 29-year-old man with staphylococcal endocarditis who developed a mycotic aneurysm in a posterior intrahepatic branch of the right hepatic artery. The vessel was selectively catheterized, and several methicillin-soaked pieces of Gelfoam were embolized into the aneurysm, resulting in occlusion. Arteriography performed 2 months following embolotherapy confirmed obliteration of the aneurysm. It is suggested that transcatheter arterial embolization may prove useful for treatment of infected visceral arterial aneurysms when surgical intervention is not advisable or technically possible.
Other Visceral Vessels Mycotic or infected aneurysms involving the celiac, splenic, or inferior mesenteric arteries (IMA) have been successfully treated by the surgical options described.[232] Most splenic arterial lesions may be ligated or excised, with or without splenectomy. Likewise, rich mesenteric collateral circulation may permit IMA ligation and aneurysm resection.[233] Measurement of IMA stump pressure or use
Chapter 47. Infected Aneurysms
of a sterile Doppler helps document adequacy of colonic collateral blood flow, permitting safe IMA ligation.[234]
Carotid Artery Infected aneurysms of the carotid artery are very uncommon. In a 1995 review only 27 cases of extracranial carotid artery infected aneurysms were reported.[235] The principals of management of infected aneurysms of the extracranial carotid arteries are the same as those for infected arterial lesions elsewhere, namely excision, wide debridement and drainage, and intensive antibiotic therapy. The necessity for and optimal methods of restoring carotid arterial continuity have provoked debate. Risks of neurologic deficit after ligation must be balanced against risks of recurrent infection, arterial disruption, and potentially fatal hemorrhage following arterial reconstruction in a contaminated field. Sir Astley Cooper performed the first common carotid artery ligation for an extracranial aneurysm in 1805. This patient became hemiplegic and died. However, he performed a second common carotid arterial ligation 3 years later and the patient survived for 13 years.[236] Mont Reid[237] reported on 10 patients treated by ligation; 4 died and 2 of the 6 survivors developed hemiplegia. Moore and Baker[238] recorded mortality and morbidity rates of 17 and 28%, respectively, among 104 patients undergoing carotid ligation associated with head and neck tumors. In contrast to these disastrous results, Rogers[239] reported transient hemiplegia developing in only one of 19 patients undergoing carotid ligation. Also, James and colleagues[240] recorded only one transient deficit among 13 patients after common carotid ligation performed using local anesthesia. Monson and Alexander[57] reported the first successful autogenous saphenous vein interposition graft after resection of an infected carotid arterial aneurysm in 1980. Several other workers[61 – 63] have also reported successful saphenous vein bypass grafts after resection of infected carotid aneurysms. Successful primary end-to-end anastomosis following excision of an infected carotid aneurysm has also been reported.[241] The question of arterial reconstruction versus ligation for infected carotid artery aneurysm remains unsettled. Historically, most workers have favored ligation.[242,243] Conversely, in a recent review of patients with infected carotid artery aneurysms, Jebara and colleagues noted a 25% mortality among 12 patients who underwent ligation, and reoperation was required for recurrent cerebral ischemia in one survivor of ligation.[55] As an index of adequacy of collateral cerebral blood flow, Ehrenfeld and his colleagues[244] have successfully employed measurement of carotid stump pressure when ligation was required. After analysis of data obtained from 24 patients in whom carotid ligations were performed, they concluded that patients whose stump pressure exceeds 70 torr systolic tolerated acute carotid ligation, especially if systemic blood pressure was maintained at the same levels as when stump pressure measurements were obtained. Those with intermediate stump pressures of 52–68 torr were vulnerable to post-ligation stroke. It appeared, however, that safety of carotid ligation in these patients was enhanced by systemic anticoagulation with heparin sodium and maintence of high systemic blood pressures. Furthermore, 7 patients also had preoperative stump pressure estimates using ocular
683
pneumoplethysmography (OPG-Gee) with common carotid compression. Close correlations of all operative and preoperative measurements were observed in all cases. Another alternative to ligation historically has been the application and progressive tightening of a Selverstone clamp around the common or internal carotid arteries. Avellone et al.[245] described a 24-year-old woman in whom the clamp was applied to the internal carotid artery proximal to the aneurysm and progressively tightened over a 72-hour period. This procedure proved successful. If, however, neurologic symptoms had developed, the clamp would have been opened. If the patient does not tolerate carotid occlusion—as documented by EEG changes, stump blood pressure measurements, or neurologic instability while awake—a possible alternative for cerebral revascularization is extracranial– intracranial bypass using autogenous saphenous vein.[246]
Extremity Vessels The subclavian or axillary artery between the thyrocervical and supscapular branches can usually be safely ligated because of profuse protective collateral circulation around the shoulder. Resection of lesions involving the distal axillary artery, however, may require reconstruction. When reconstruction is required, autogenous tissue should be used and the grafts should be placed through clean tissue planes.[14,247] The brachial artery distal to the profunda branch may be safely ligated. Aneurysms of the radial and ulnar arteries can usually be excised without reconstruction. Documentation of adequacy of collateral circulation through the superficial and deep volar arches by Allen’s test or Doppler assures safe ligation of these vessels. The femoral artery is the most common site of infected peripheral aneurysms, and today the incidence may be increasing as a result of iatrogenic trauma as well as the prevelance of drug abuse in our society. The management of these lesions continues to generate debate. The most conservative approach, especially in the setting of gross purulence, is excision and arterial ligation. In young individuals common or superficial femoral artery ligation usually results in a viable extremity, although these patients will often experience claudication. If these symptoms are disabling, subsequent reconstruction, after infection has resolved, is appropriate. In one series of 18 infected femoral pseudoaneurysms secondary to intravascular drug injections, no deaths and no complications occurred among 6 patients who underwent ligation alone. The mean ankle-brachial index after ligation in this group was 0.63.[244] There were 12 patients who underwent revascularization procedures, and among this group there were 13 reoperations for vascular complications and 3 (25%) major amputations.[248] When aneurysm resection also requires sacrifice of the profunda femoris artery, arterial reconstruction will often be necessary to maintain limb viability, although this is not always the case. For example, in one recent report the mean anklebrachial index was 0.41 among patients undergoing ligation of the common femoral, superficial femoral, and profunda femoris arteries and 0.58 among patients in whom only single vessel ligation was required for management of infected femoral pseudoaneurysms secondary to drug abuse.[249] In the largest series reported to date the mean ankle-brachial index
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Aneurysms
was 0.43 and 0.52 among those undergoing triple and single vessel ligation, respectively.[250] It is clear that ligation and extensive debridement offers the best chance of controlling the septic process and minimizing the risk of subsequent hemorrhage. Intraoperative documentation of an audible Doppler signal at the ankle is highly predictive of limb viability after arterial ligation.[240] Among patients in whom limb perfusion is inadequate, a number of reconstructive options exist. An anatomic reconstruction may be performed through the bed of the resected aneurysm in the absence of gross purulence and if the proximal and distal anastmoses can be performed in clean tissue planes to vessels not directly involved in the septic process. The use of an autogenous conduit, usually saphenous vein, is mandatory. There is some evidence that coverage of the graft with a sartorius muscle flap may reduce the likelihood of recurrent infection in this setting (Fig. 47-6).[251 – 253] In the presence of gross contamination or if a prosthetic graft must be placed, an extraanatomic route for the bypass should be selected. Several authors[254,255] advocate the lateral circumflex iliopopliteal bypass. Since this graft by definition must pass through a portion of the femoral triangle, secondary graft infection by contiguous spread is a possible complication and represents a shortcoming of this approach. Therefore, most workers advocate placing the iliopopliteal or ilioprofunda graft through the obturator foramen (Fig. 47-7).[256 – 259] Alternatively, recent studies have suggested that in situ reconstruction may be successfully performed, even with a synthetic conduit, by covering the graft and closing the wound with a formal rotational muscle flap. Rotating a muscle from a separate bed, based upon a pedicled blood supply that is independent of the site of infection, ensures maximum vascularity of the rotated muscle. A well-vascularized muscle bundle will deliver a high level of antibiotics and immunocompetent cells to the wound and will raise the oxygen tension within the wound, which may promote eradication of residual infection through stimulation of leukocyte function and thus promote healing.[260] For these reasons and others, it has been suggested that performance of a formal rotational muscle flap procedure is a superior approach when compared to local sartorious transfer.[261,262]
POSTOPERATIVE MANAGEMENT Regardless of the surgical procedure performed, prolonged postoperative antibiotics are mandatory to protect arterial suture lines and vascular grafts from potential reinfection. Although the duration of antibiotic coverage required has not been firmly established, most authors[34,47] recommend at least 6 weeks of intravenous organism-specific antibiotic treatment. When prosthetic grafts are placed in situ, some have advocated life-long antibiotic therapy.[263] Conversely, Malone has suggested that 6 weeks of intravenous followed by 6 months of oral antibiotic therapy is most appropriate.[264] This recommendation is predicated on the observation that graft surface coverage stabilizes at 6 months.[264] Although long-term chronic therapy seems
Figure 47-6. Sartorius muscle has been transposed to cover interposition sapheneous vein graft, after resection of infected femoral artery aneurysm. (From Reddy DJ, et al.[265] Reproduced by permission.)
reasonable in dealing with fungal infections, its necessity in bacterial infection has not been conclusively established.
RESULTS OF TREATMENT Prior to the advent of antimicrobial drugs, mycotic or infected aneurysms were invariably fatal. The natural history of these lesions was one of rapid enlargement and early rupture. It has been estimated that the average time from diagnosis to death was approximately 3 months.[135] With the introduction of antibiotics, better understanding of the pathophysiology of these lesions, and greater appreciation of the proper therapeutic principles, survival has improved.
Chapter 47. Infected Aneurysms
685
Aortic Aneurysms
Figure 47-7. Bypass graft placed from right external iliac artery to superficial femoral artery through obturator canal. (From Patel KR, et al.[256] Reproduced by permission.)
Peripheral Aneurysms Infected aneurysms of peripheral vessels are more easily diagnosed; consequently, mortality is less than for lesions in the aorta or the visceral circulation. Mundth and his associates[34] recorded a 25% operative mortality for patients with infected peripheral aneurysms. In the report of Anderson et al.,[47] of 14 patients with infected peripheral aneurysms, 5 were treated by ligation alone and all survived, although 1 required amputation. Of the 14 patients, 9 underwent aneurysm resection and arterial reconstruction. Only 2 of these patients were cured. The other 7 developed bleeding or recurrent sepsis within 1 week. Of these patients, 2 expired and leg amputation was required in another 2 after reoperation. Recent studies of infected peripheral aneurysms have reflected increasing number of lesions secondary to parenteral drug abuse. Reddy et al.[265] performed selective revascularization in 54 patients with no mortality and an 11% amputation rate. In another report,[256] routine revascularization was carried out with prosthetic grafts in 15 patients, with 1 postoperative graft infection and no operative mortality. Padberg et al.[248] reported 18 patients with infected femoral pseudoaneurysms secondary to ilicit drug abuse, including 6 patients who underwent ligation alone, with no deaths and no amputations. Among 12 patients who underwent attempted reconstruction, there were 3 (25%) amputations and 13 reoperations for arterial complications.
Infected aortic aneurysms present a much greater risk to life than peripheral aneurysms, although results are improving. In one early report, among 13 patients undergoing operation for an infected aortic aneurysm, 60% died.[34] A 67% operative mortality was reported among patients with Salmonella-infected aortic aneurysms.[35] In a 1983 review of the English literature,[115] only 34 survivors were identified after operation for infected abdominal aortic aneurysms. In 89% of the successfully treated patients, the diagnosis was made before operation. Likewise, in 88% of these patients, operation was performed prior to rupture. In Mundth’s study[34] of infected aortic aneurysms, 67% of patients with nonruptured aneurysms survived, whereas none with ruptured aneurysms did so. It appears that accurate preoperative diagnosis, before rupture has taken place, is crucial to successful results. In addition, bacteriology has an important impact on survival with gram-negative organisms portending a more omnious prognosis.[43] There is less agreement today, however, concerning the optimal method of revascularization, namely, in situ versus extraanatomic bypass. In the earlier experience,[115] the majority of survivors had undergone extraanatomic bypass. Clearly, surgical outcome continues to improve among patients who undergo the conventional management of aneurysm excision and extraanatomic bypass. In a 1997 report 5 (83%) of patients who underwent extraanatomic bypass for infected infrarenal aortic aneurysms survived,[266] and in a 1998 review of 10 cases, survival was 90% after extraanatomic reconstruction.[53] In another center 5 patients underwent extraanatomic reconstruction following resection of an infected aortic aneurysms without mortality.[95] Nevertheless, it is clear that even in the most experienced hands the conventional managment of aortic infection is still associated with considerable morbidity. Operative mortality is not insignficant, and survivors continue to be at risk of aortic stump rupture and extraanatomic bypass graft thrombosis.[33,106] In view of this, there has been increasing enthusiasm in recent years for performing in situ revascularization following resection of infected aortic aneurysms. While experience with in situ revascularization is largely anecdotal, preliminary reports suggest a reduced operative mortality when compared to historical series of patients undergoing extraanatomic bypass (Table 47-7). Furthermore, reinfection has been noted infrequently, even when prosthetic conduits have been utilized. It is clear that careful patient selection is crucial in undertaking in situ reconstruction. For example, in one study reinfection occurred three-times more often among patients with gram-negative infection.[115] Presently, it appears that in situ repair is most appropriate among patients with gram-positive arterial infection and minimal contamination at operation, and clearly for patients with suprarenal aortic involvement. If available, homograft conduits, at least theoretically, should be preferable to prosthetic grafts. In each case, the risk of subsequent graft infection must be weighed against the operative morbidity, risk of aortic stump blowout, and morbidity of recurrent graft thrombosis when extraanatomic bypass is performed.
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Part Five.
Table 47-7.
Aneurysms
In Situ Reconstruction for Aortic Infection: Acute and Long-Term Results
Author
Year
No. Cases
Conduit
% Mortality
% Recurrent infection
Follow-up
Fichelle[106] Pasic[204] Yokoyama[206] Ahad[219] Vogt[217] Knosella[221] Illuminati[208] Codero[207] Pagamo[218] Moriyana[205]
1993 1993 1994 1995 1995 1996 1996 1996 1996 1998
21 6 1 1 2 8 2 3 1 1
P P P CH CH CH P P H P
14 33 0 0 0 12 0 33 0 0
0 25 N.A. 0 0 0 N.A. 0 0 N.A.
12 – 172 ðx ¼ 53 mÞ 7 m – 9 yr ðx ¼ 5:5 yrÞ N.A. 2m 6 m/12 m ,1 – 40 m ðx ¼ 13 mÞ N.A. 2 yr 18 m N.A.
P = prosthetic graft; H = homograft; CH = cryopreserved homograft, yr = year, m = month.
Visceral Artery Aneurysms Results of treatment of infected visceral artery lesions are unclear, since individual experiences are limited and only anecdotal reports are available for study. In 1981, Howard and Mazer[226] collected 24 patients from the literature who had survived operative treatment for an infected SMA aneurysm. In 10 patients, ligation of the SMA without arterial reconstruction was performed, and 6 of these underwent aneurysm resection. Only 30% of this group required
bowel resection. Of the 24 patients, 9 were successfully treated by aneurysmorrhaphy alone and 5 underwent aneurysm resection with some form of revascularization. In 2 of these patients, a prosthetic graft was used, and recurrent infection developed in 1, necessitating replacement with a vein graft. Although the incidence of infected and noninfected lesions was not defined, Stanley and coworkers[66] reported an operative mortality of 32% for hepatic artery aneurysms, of which 85% were ruptured at the time of operation.
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Gomes, M.N.; Choyke, P.L. Infected Aortic Aneurysm: CT Diagnosis. J. Cardiovasc. Surg. 1992, 33, 694. Thakur, M.L.; Coleman, R.E.; Welch, M.J. Indium-111 Labeled Leukocytes for the Localization of Abscesses: Preparation, Analysis, Tissue Distribution and Comparison with Gallium-67 Citrate in Dogs. J. Lab. Clin. Med. 1977, 89, 217. Stevick, C.A.; Fawcett, H.D. Aortoiliac Graft Infection. Arch. Surg. 1981, 116, 939. Bell, D.; Jackson, M.H.; Stevenson, A.J.M.; Nicholl, J.J. Intrathoracic Mycotic Aneurysm Detected by Indium-111 Labeled Autologous Neutrophils with Single Photon Emission Computed Tomography. Thorax 1987, 42, 397. Ben-Haim, S.; Seabold, J.E.; Hawes, D.R.; Rouhalamini, S.A. Leukocyte Scintingraphy in the Diagnosis of Mycotic Aneurysm. J. Nucl. Med. 1992, 33, 1486. Causey, D.A.; Fajman, W.A.; Perdue, G.D.; et al. Ga Scintingraphy in Post-Operative Synthetic Graft Infections. Am. J. Roentgenol. 1980, 134, 1041. Perdue, G.D.R.; Smith, R.B. III; Ansley, J.D.; Constantino, M.J. Impending Aortoenteric Hemorrhage: The Effect of Early Recognition on Improved Outcome. Ann. Surg. 1980, 192, 327. Cooke, P.A.; Ehrenfeld, W.K. Successful Management of Mycotic Aortic Aneurysms: Report of a Case. Surgery 1974, 75, 132. Felson, B.; Akers, D.U.; Hall, G.S.; et al. Mycotic Tuberculous Aneurysm of the Thoracic Aorta. J. Am. Med. Assoc. 1977, 237, 1104. Weintraub, R.A.; Abrams, H.L. Mycotic Aneurysms. Am. J. Roentgenol. 1968, 102, 354. Nabseth, D.C.; Deterling, R.A. Surgical Management of Mycotic Aneurysms. Surgery 1961, 50, 347. Currens, J.H.; Faulkner, J.M. Gonococcal Mycotic Aneurysm of the Aorta: Report of a Case Superimposed upon a Syphilitic Aorta. Ann. Intern. Med. 1943, 19, 155. Javett, S.M.; Kahn, E. Rupture of Mycotic Aneurysm of the Thoracic Aorta. Arch. Dis. Child. 1952, 27, 294. Robb, D. Surgical Treatment of Mycotic Aneurysm. Surgery 1962, 52, 847. Ehrenfeld, W.K.; Wilbur, B.G.; Olcott, C.N., IV.; Stoney, R.J. Autogenous Tissue Reconstruction in the Management of Infected Prosthetic Grafts. Surgery 1979, 85, 82. O’Mara, C.S.; Ernst, C.B.; Williams, G.M. Secondary Aortoenteric Fistula. Am. J. Surg. 1981, 142, 203. Fry, W.J.; Lindenauer, S.M. Infection Complicating the Use of Plastic Arterial Implants. Arch. Surg. 1967, 94, 600. Ernst, C.B. Aortoenteric Fistulas. In Vascular Emergencies; Haimovici, H., Ed.; Appleton-Century-Crofts: New York, 1982; 365 – 385. Park, I.; Pinsky, W.M.; Baker, C.J. Ruptured Mycotic Aneurysm of Abdominal Aorta: Successful Treatment in a Child. Am. J. Dis. Child. 1981, 135, 570. Bridges, R.A.; McTamaney, J.P.; Barnes, R.W. Recognition and Management of Ruptured Infected Aneurysm of the Abdominal Aorta. Vasc. Surg. 1981, 15, 360. Blaisdell, F.W.; Hall, A.D. Axillary-Femoral Artery Bypass for Lower Extremity Ischemia. Surgery 1963, 54, 563.
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Blaisdell, F.W.; Hall, A.D.; Thomas, A.N. Ligation Treatment of Abdominal Aortic Aneurysm. Am. J. Surg. 1965, 109, 560. Ernst, C.B. Axillary-Femoral Bypass Graft Patency Without Aortofemoral Pressure Differential. Ann. Surg. 1975, 181, 424. Pasic, M.P.; Carrel, M.; Tonz, M.; Vogt, P.; von Segesser, L.; Turina, M. Mycotic Aneurysm of the Abdominal Aorta: Extra-Anatomic Versus In-Situ Reconstruction. Cardiovasc. Surg. 1993, 1, 48. Moriyana, Y.; Toda, R.; Iwamura, H.; et al. Infected Atherosclerotic Ulcer of the Abdominal Aorta as a Cause of Mycotic Aneurysm Treated by In-Situ Prosthetic Graft Reconstruction. Report of a Case. Surg. Today 1998, 28, 325. Yokoyama, H.; Maida, K.; Takahashi, S.; Tanaka, S. Purulently Infected Abdominal Aortic Aneurysm: In Situ Reconstruction with Transmesocolic Omental Transposition Technique. Cardiovasc. Surg. 1994, 2, 78. Cordero, J.A., Jr.; Darling, R.C. III; Chang, B.B.; Shah, D.M.; Paty, P.S.; Leather, R.P. In Situ Prosthetic Graft Replacement for Mycotic Thoracoabdominal Aneurysms. Am. Surg. 1996, 62, 35. Illuminati, G.; Calio, F.G.; Bertagni, A.; Mangialardi, N.; Vietri Infectious Arterial Aneurysms: Patterns and Treatment. Riv. Eur. Sci. Med. Farmacol. 1996, 18, 53. Quinones-Baldrich, W.J.; Nene, S.M.; Gelabert, H.A.; Moore, W.S. Rupture of the Perivisceral Aorta: Atherosclerotic Versus Mycotic Aneurysm. Ann. Vasc. Surg. 1997, 11, 331. Gupta, A.K.; Bandyk, D.F.; Johnson, B.L. In Situ Repair of Mycotic Abdominal Aortic Aneurysms with RifampinBonded Gelatin-Impregnated Dacron Grafts: A Preliminary Case Report. J. Vasc. Surg. 1996, 24, 472. Gahtan, V.; Esses, G.E.; Bandyk, D.F.; Nelson, R.T.; Dupont, E.; Mills, J.L. Antistaphylococcal Activity of Rifampin-Bonded Gelatin-Impregnated Dacron Grafts. J. Surg. Res. 1995, 58, 105. Sardelic, F.; Ao, P.Y.; Fletcher, J.P. Rifampin-Impregnated Dacron Grafts: No Development of Rifampin Resistance in an Animal Model. Eur. J. Vasc. Endovasc. Surg. 1995, 9, 314. Lundell, A.; Bergqvist, D.; Lindblad, B.; Leide, S. The Acute Thrombogenicity of an Infection-Resistant Rifampin Soaked Dacron Graft: An Experimental Study in Sheep. Eur. J. Vasc. Endovasc. Surg. 1992, 6, 403. Pasic, M.; von Segesser, L.; Turina, M. Implantation of Antibiotic-Releasing Carriers In Situ Reconstruction for Treatment of Mycotic Aneurysm. Arch. Surg. 1992, 127, 745. Schuch, D.; Wolff, L. Repair of Mycotic Aneurysm of the Innominate Artery with Homograft Tissue. Ann. Thorac. Surg. 1991, 52, 863. Vogt, P.; Pasic, M.; von Segesser, L.; Carrel, T.; Turina, M. Cryopreserved Aortic Homograft for Mycotic Aneurysm. J. Thorac. Cardiovasc. Surg. 1995, 109, 589. Vogt, P.R.; von Segesser, L.K.; Goffin, Y.; Pasic, M.; Turina, M.J. Cryopreserved Arterial Homografts for In Situ Reconstruction of Mycotic Aneurysms and Prosthetic Graft Infection. Eur. J. Cardiothorac. Surg. 1995, 9, 502.
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Aneurysms
Pagano, D.; Guest, P.; Bonser, R.S. Homograft Replacement of Thoraco-Abdominal Aorta for a Leaking Mycotic Aneurysm. Eur. J. Cardiothorac. Surg. 1996, 10, 383. Abad, C.; Hurle, A.; Feijoo, J.; Gomez-Marrero, J.; Abdallah, A. Total Aortic Arch Replacement by Cryopreserved Aortic Homograft. Eur. J. Cardiothorac. Surg. 1995, 9, 531. Pasic, M. Mycotic Aneurysm of the Aorta: Evolving Surgical Concept. Ann. Thorac. Surg. 1996, 61, 1053. Knosalla, C.; Weng, Y.; Yankah, C.; Hofmeister, J.; Hetzer, R. Using Aortic Allograft Material to Treat Mycotic Aneurysms of the Thoracic Aorta. Ann. Thorac. Surg. 1996, 61, 1146. Kirklin, J.K.; Smith, D.; Novick, W.; et al. Long-Term Function of Cryopreserved Aortic Homografts. A TenYear Study. J. Thorac. Cardiovasc. Surg. 1993, 106, 154. Doty, D.B.; Michielon, G.; Wang, N.-D.; Cain, A.S.; Miller, R.C. Replacement of the Aortic Valve with Cryopreserved Aortic Allograft. Ann. Thorac. Surg. 1993, 56, 228. Semba, C.P.; Sakai, T.; Slonim, S.M.; et al. Mycotic Aneurysms of the Thoracic Aorta: Repair with Use of Endovascular Stent-Grafts. J. Vasc. Interv. Radiol. 1998, 9, 33. DeBakey, M.E.; Cooley, D.A. Successful Resection of Mycotic Aneurysm of Superior Mesenteric Artery: Case Report and Review of Literature. Ann. Surg. 1953, 19, 202. Howard, T.C.; Mazer, M.J. Mycotic Aneurysm of the Superior Mesenteric Artery: Report of a Successful Repair. Ann. Surg. 1981, 47, 89. Olcott, C.; Ehrenfeld, W.K. Endoaneurysmorrhaphy for Visceral Artery Aneurysms. Am. J. Surg. 1977, 133, 636. Bulkley, G.B.; Zuidema, G.D.; Hamilton, S.R.; et al. Intraoperative Determination of Small Intestinal Viability Following Ischemic Injury. Ann. Surg. 1981, 193, 628. O’Connell, J.A; Hobson, R.W. III. Operative Confirmation of Doppler Ultrasound in Evaluation of Intestinal Ischemia. Surgery 1980, 87, 109. Smith, R.F.; Szilagyi, D.E.; Colville, J.M. Surgical Treatment of Mycotic Aneurysms. Arch. Surg. 1967, 85, 663. Kirklin, J.W.; Shocket, E.; Comfort, M.W.; Huizenga, K.A. Treatment of Hepatic Artery Aneurysm by Excision. Ann. Surg. 1955, 142, 110. Zeppa, R.H.; Petrou, P.; Womack, N.A. Collateral Circulation to the Liver: A Case of Mycotic Aneurysm of the Celiac Artery. Ann. Surg. 1966, 163, 223. Lau, J.; Mattox, K.K.; DeBakey, M.E. Mycotic Aneurysm of the Inferior Mesenteric Artery. Am. J. Surg. 1979, 138, 443. Ernst, C.B.; Hagihara, P.F.; Daugherty, M.E.; Griffent, W.O. Inferior Mesenteric Artery Stump Pressure: A Reliable Index for Safe IMA Ligation During Abdominal Aortic Aneurysmectomy. Ann. Surg. 1978, 187, 614. Naik, D.K.; Atkinson, N.R.; Field, P.L.; Milne, P.Y. Mycotic Cervical Carotid Aneurysm. Aust. N.Z. J. Surg. 1995, 65, 620. Cooper, A. Account of the First Successful Operation, Performed on the Common Carotid Artery for Aneurysm
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in the Year 1808: With the Post-Mortem Examination in 1921. Guy’s Hosp. Rep. 1936, 1, 53. Reid, M.R. Aneurysms in the Johns Hopkins Hospital: All Cases Treated in the Surgical Service from the Opening of the Hospital to January, 1922. Arch. Surg. 1926, 12, 1. Moore, O.; Baker, A.W. Carotid Artery Ligation in Surgery of the Head and Neck. Cancer 1955, 8, 712. Rogers, L. Ligation of the Common Carotid Artery: Report of 19 Personal Cases. Lancet 1949, 1, 949. James, N.J.; Stuteville, O.H.; Tasche, C. Elective Carotid Artery Ligation in the Treatment of Advanced Cancer of the Head and Neck. Plast. Reconstr. Surg. 1971, 47, 243. Shea, P.C.; Glass, L.F.; Reid, W.A.; Harland, A. Anastomosis of Common and Internal Carotid Arteries Following Excision of Mycotic Aneurysm. Surgery 1955, 37, 829. Howell, H.S.; Baburao, T.; Graziano, J. Mycotic Cervical Carotid Aneurysm. Surgery 1977, 81, 357. Lueg, E.A.; Awerbuck, D.; Forte, V. Ligation for the Common Carotid Artery for the Management of Mycotic Aneurysm of an Extracranial Internal Carotid Artery. A Case Report and Review of the Literature. Int. J. Pediatr. Otorhinolaryngol. 1995, 33, 67. Ehrenfeld, W.R.; Stoney, R.J.; Wylie, E.J. Relation of Carotid Stump Pressure to Safety of Carotid Arterial Ligation. Surgery 1983, 93, 299. Avellone, J.C.; Ahmad, M.Y. Cervical Internal Carotid Aneurysm from Syphilis: An Alternative to Resection. J. Am. Med. Assoc. 1979, 241, 238. Samson, D.S.; Gewertz, B.L.; Beyer, C.W., Jr.; Hodosh, R.M. Saphenous Vein Interposition Grafts in the Microsurgical Treatment of Cerebral Ischemia. Arch. Surg. 1981, 116, 1578. Yellin, R.E. Ruptured Mycotic Aneurysm. Arch. Surg. 1977, 112, 981. Padberg, F., Jr.; Hobson, R. III; Lee, B.; et al. Femoral Pseudoaneurysm from Drugs of Abuse: Ligation or Reconstruction? J. Vasc. Surg. 1992, 15, 642. Cheng, S.W.; Fok, M.; Wong, J. Infected Pseudoaneurysms in Intravenous Drug Abusers. Br. J. Surg. 1992, 79, 510. Ting, A.C.; Cheng, S.W. Femoral Pseudoaneurysms in Drug Addicts. World J. Surg. 1997, 21, 783. Kaufman, J.L.; Shah, D.J.; Corson, J.D.; et al. Sartorius Muscle Coverage for the Treatment of Complicated Vascular Surgical Wounds. J. Cardiovasc. Surg. 1989, 30, 479. Meyer, J.P.; Durham, J.R.; Schwarz, T.H.; et al. The Use of Sartorius Muscle Rotation-Transfer in the Management of Wound Complications After Intra-inguinal Vein Bypass: A Report of Eight Cases and Description of the Technique. J. Vasc. Surg. 1989, 9, 731. Laustsen, J.B.S.; Christensen, J. Transposition of the Sartorius Muscle in the Treatment of Infected Vascular Grafts in the Groin. Eur. J. Vasc. Surg. 1988, 2, 111. Trout, H.H.; Smith, C.A. Lateral Iliopopliteal Arterial Bypass as an Alternative to Obturator Bypass. Am. Surg. 1982, 48, 63. Louw, J.H.; Birkenstock, W. Circumflex Arterial Bypass for Ischemia of the Lower Limbs: Another Imitation of Natural Collaterals. Br. J. Surg. 1974, 61, 104.
Chapter 47. Infected Aneurysms 256.
Patel, K.R.; Semel, L.; Clauss, R.H. Routine Revascularization with Resection of Infected Femoral Pseudoaneurysms from Substance Abuse. J. Vasc. Surg. 1988, 8, 321. 257. Jarrett, F.; Darling, R.C.; Mundth, E.D.; Austen, W.G. The Management of Infected Arterial Aneurysms. J. Cardiovasc. Surg. 1977, 81, 361. 258. Fromm, S.H.; Lucas, C.E. Obturator Bypass for Mycotic Aneurysms in the Drug Addict. Surg. Gynecol. Obstet. 1970, 130, 82. 259. Guida, P.M.; Moore, S.W. Obturator Bypass Technique. Surg. Gynecol. Obstet. 1969, 128, 1397. 260. Mixter, R.C.; Turnipseed, W.D.; Smith, D.J., Jr.; et al. Rotational Muscle Flaps: A New Technique for Covering Infected Vascular Grafts. J. Vasc. Surg. 1989, 9, 472. 261. Perler, B.A.; Vander Kolk, C.A.; Dufresne, C.A.; Williams, G.M. Can Infected Prosthetic Graft Be Salvaged with Rotational Muscle Flaps? Surgery 1991, 110, 912.
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CHAPTER 48
Symptomatic Extracranial Vascular Disease: Natural History and Medical Management William S. Fields James C. Grotta
19th century there was considerable interest in both the clinical and pathological features of embolism, but these were for the most part disregarded during the first half of the 20th century. Excellent descriptions of embolism from the heart can be found in the reports of several authors[2 – 4] and of embolism from the extracranial arteries in others.[5,6] Traditionally, the source of a “cerebral embolus” has been considered to be the heart. Embolism from this source produces up to 25% of all cerebral infarcts.[7 – 9] Cardiac emboli vary considerably in size but are commonly large and tend to obstruct major arteries. One variety of large cardiac embolus is seen in association with mitral stenosis; when this valvular disorder is accompanied by atrial fibrillation, the incidence of embolism is said to be markedly increased.[10] Patients with major cerebral emboli originating from the heart have a poor prognosis, with 1 in 3 dying immediately.[10] There appears to be a greater risk of recurrence during the first year or two after the initial embolus than is present thereafter. Mural thrombus associated with myocardial infarction is an important cause of cerebral embolism, occurring within 6 weeks of the acute ictus in perhaps as many as 5% of patients suffering myocardial infarction. About one-third of the patients die during the immediate postischemic period. However, unless there is recurrent myocardial infarction, the risk of further embolization decreases rather quickly after about 4–6 weeks.[11] Notwithstanding these cardiac causes of embolic TIA; most TIAs are related to embolism from lesions in the extracranial cerebral arteries. The link between thrombosis at the common carotid artery bifurcation and embolic occlusion of the distal part of the internal carotid artery is clearly described by Chiari,[5] who appears, however, to have been unaware of previous references in the English literature to this connection between
Thromboembolic stroke is a serious health problem in virtually all developed countries. Approximately one of every five persons who suffer such a stroke will die within the first 30 days, and of those who survive for a longer period, half will require special care, which places a tremendous economic burden both on the family and on society. Arteriographic studies of patients entered into the Joint Study of Extracranial Arterial Occlusion[1] demonstrated the frequency with which multiple atherosclerotic lesions were observed and emphasized the importance of extracranial versus intracranial vascular lesions and of the frequent embolic origin of intracranial vascular occlusions (see Table 48-1). It is estimated that about 50% of ischemic strokes have an embolic basis, either of cardiac or arterial origin, and that the remainder will have some hemodynamic factors underlying the infarction. These factors include thrombosis, sometimes augmented by orthostatic hypotension or hypotension secondary to myocardial infarction.
TRANSIENT ISCHEMIC ATTACKS Episodes of transient stroke-like symptoms, which have a rapid onset and pass in a matter of minutes or hours or occasionally in a day or more, have been recognized at least since the middle of the 19th century. A variety of terms have been employed to describe such episodes, including cerebral intermittent claudication, little strokes, and transient cerebral insufficiency. However, in the last four decades the term transient ischemic attack (TIA) has displaced all others and has become generally accepted. The concept of embolism to the eye or brain antedates even the first clear descriptions of TIA. In fact, during the
Hobson/Wilson/Veith: Vascular Surgery: Principles and Practice, Third Edition, Revised and Expanded DOI: 10.1081/0819-9-120024931 Copyright q 2004 by Marcel Dekker, Inc.
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Part Six. Cerebrovascular Disease Table 48-1. Sites of Arterial Stenosis and Occlusion Incidence of lesionsa Stenosis Site Extracranial arteries Internal carotid bifurcation Internal carotid (distal to bifurcation) Vertebral Intracranial arteries Carotid siphon Basilar Middle cerebral a
Occlusion
Right
Left
Right
Left
33.8 8.0 18.4
34.1 9.1 22.3
8.5 8.6 4.0
8.5 8.7 5.7
6.6
9.0
6.7 (7.7) 3.5
9.2 (0.8)
4.1
2.2
2.1
Percent of lesions at designated sites in 4478 patients subjected to angiography.[3]
extracranial arterial disease and distal thromboembolism. In Albutt’s A System of Medicine,[12,13] embolism from the heart or from “diseased and roughened” arteries supplying the brain is described, and it is noted that “in a number of cases recovery from the paralysis which follows embolism is both rapid and complete.” In another important article, published in 1914, Hunt[6] emphasized that strokes could be caused by extracranial arterial disease. He describes the syndrome of internal carotid occlusion and makes the following observations: The object of the present study is to emphasize the importance of obstructive lesions of the main arteries of the neck in the causation of softening of the brain, and more especially to urge the routine examination of these vessels in all cases presenting cerebral symptoms of vascular origin. In other words, the writer would advocate the same attitude of mind toward this group of cases as towards intermittent claudication, gangrene, and other vascular symptoms of the extremities, and never omit a detailed examination of the main arterial stem. Unfortunately, after 1914 this knowledge appears to have been largely ignored, only to be revived 40 years later by Fisher.[14,15] His theory that embolism could sometimes be a cause of TIA or stroke was soon supported by evidence coming from other workers,[16,17] and the prognostic implications of TIA were emphasized by Marshall.[18] It is remarkable that only in the last 40 years have the symptoms of TIA become generally recognized and their prognostic implications with respect to both stroke and coronary heart disease generally understood.
Defining and Diagnosing TIA The classification and nomenclature of cerebrovascular disease has never been completely satisfactory, and this is particularly apparent when one attempts to define a TIA. The recognition of TIA is almost invariably dependent upon the patient’s recollection of an event during which apprehension and anxiety may be more prominent features than the focal
neurological symptoms. It is rare indeed for a physician to be present when the symptoms occur, and unless the episodes are sufficiently frequent to concern the patient and the doctor has a receptive mind and is familiar with the symptomatology of TIA, transient cerebral or ocular symptoms can be completely missed or disregarded. The diagnosis of TIA is almost always based on clinical history, uncommonly on focal signs, and not on any diagnostic tests. It is therefore not too surprising that the definition of TIA is less than satisfactory. The World Health Organization (WHO)[19] proposed in 1978 a definition of TIA as follows: Episodes of temporary and focal cerebral dysfunction of vascular origin; rapid in onset (no symptoms to maximum symptoms in less than five minutes and usually less than a minute); and variable in duration, commonly lasting from two to fifteen minutes but occasionally lasting as long as a day (twenty-four hours). The resolution or disappearance of each episode is swift (ordinarily a few minutes at most). A prolonged attack may take longer to clear up. An attack leaves no persistent neurological deficit. This WHO definition is complex; it does not address the issue of transient disturbances of ocular function (amaurosis fugax), which represent a specific type of carotid territory TIA, does not specifically exclude focal cerebral dysfunction of other vascular pathology such as hemorrhage, and is rather ambiguous. It is not clear what is implied by dysfunction and deficit, and if both words mean the same thing, it would be more satisfactory to use only one or the other. Furthermore, it is not clear whether it is the neurological symptoms, the neurological sings, or both, that should resolve in 24 h. Most physicians comprehend the meaning of symptoms and signs rather than dysfunction and deficits, and it is not uncommon to find minimal neurological signs of no functional significance, such as reflex asymmetry or a Babinski sign, that persist for some hours, days, or even weeks after the symptoms have disappeared. Whether or not such signs are noted will depend upon the thoroughness of the examiner and the length of time that has elapsed after the symptoms have subsided. If these minimal signs are observed, or if the CT scan shows a small
Chapter 48.
Symptomatic Extracranial Vascular Disease: Natural History and Medical Management
hypodensity consistent with infarction in the appropriate vascular territory, should the episode be called a stroke rather than a TIA? If so, a cohort of patients with focal symptoms lasting less than 24 h will, if they are adequately examined within a few days, include a large number of individuals who must be classified as having suffered a cerebral infarct. If, on the other hand, they are examined less carefully several weeks after an episode, the same cohort may be considered to contain only TIA patients. The WHO definition would not include a patient with a “persistent neurological deficit” or “minimal residual deficit,” leaving uncertainty as to what is really meant by persistent or residual. Does this imply that, according to the WHO definition, patients with neurological signs lasting beyond the 24-h time limit must be excluded from the TIA classification? The 24-h time limit dividing TIA from stroke is now generally accepted, although it is arbitrary and has no special pathogenetic significance. The limit could just as easily have been 1 h or 48 h. Amaurosis fugax, for example, never lasts for more than a few minutes, and most cerebral hemispheric episodes last less than 1 h. Furthermore, there is no clearly established evidence that, even when both symptoms and signs have disappeared by 24 h, infarction of the brain has not occurred. Evidence obtained from computed tomography makes it obvious that in some cases infarction and even hemorrhage have occurred. In these cases, prospective studies have shown that while overall long-term prognosis may be worse, the incidence of subsequent ipsilateral stroke is no different than if such lesions are not found.[20 – 24] In the final analysis, there is no definitely established knowledge that the pathogenesis, natural history, and clinical management is substantially different in patients whose symptoms have lasted a few minutes, hours, or days. Whatever difference may be present is probably one of degree. Common practice dictates that in whatever way one defines a TIA, patients whose episodes last somewhat longer than 24 h tend to be managed in much the same fashion. Whether it is correct to have similar treatment policies for TIA patients and for patients with small cerebral infarcts is not established. From the foregoing, the reader might suspect that it is not necessary or desirable to define a TIA at all. This is certainly not so, inasmuch as a consensus definition is required if one is to make comparisons between reports from different centers or to undertake epidemiological surveys. A less ambiguous and simpler definition has been suggested by Warlow and Table 48-2.
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Morris:[25] “an acute loss of focal, cerebral or ocular function, with symptoms lasting less than twenty-four hours and which, after adequate investigation, is presumed to be due to embolic or thrombotic vascular disease.” If minimal, functionally insignificant physical signs are noted subsequently, the patient can still be deemed to have has a TIA. There will always be difficulty with the TIA definition until the pathogenesis in each individual case can be determined. Any definition must be kept simple; care must be exercised in excluding other causes for transient neurological episodes, particularly nonfocal episodes, and one should direct attention to the duration of symptoms as well as the physical signs. In clinical practice generally, there has been an unfortunate tendency to diagnose TIA in middle-aged or elderly patients suffering transient focal neurological episodes, with little concern for the possibility of other etiologies such as migraine and epilepsy. Many general physicians tend to include under the TIA rubric patients who have cardiac arrhythmias with associated transient neurological episodes as well as those persons with transient nonfocal neurological symptoms. The tendency to utilize the TIA diagnosis for almost any transient neurological dysfunction has resulted in overprescribing socalled vasoactive and antithrombotic medications as well as performing unnecessary examinations for possible surgical intervention. However, the resurgence of medical interest in the whole question of cerebrovascular disease has to some extent offset this trend toward overdiagnosis and overtreatment. Transient ischemic attacks occur in both the territories of the carotid and the vertebrobasilar arteries. The main distinguishing feature between the two is the presence of lateralized symptoms in the carotid syndrome (e.g., monocular blindness, hemiparesis) versus nonlateralized symptoms (bilateral or alternating) in patients with the vertebrobasilar syndrome. Care must be taken, however, to differentiate isolated symptoms such as recurrent vertigo, “drop attacks,” transient amnesia, and episodes of unconsciousness from TIA. However, such symptoms, when observed together and/or with other brainstem manifestations, suggest a diagnosis of vertebrobasilar TIA. It is generally considered that a TIA is an indicator of threatened stroke and must be recognized and appropriately treated in order to reduce the risk for stroke. Antecedent TIAs occur in up to 50% of strokes caused by atherothrombosis, 10–30% of cardioembolic stroke, and even 10 –15% of lacunar strokes (Table 48-2).[26] A TIA in the presence of 90 – 95% stenosis of the ipsilateral carotid artery is a particularly
Transient Ischemic Attacks in Various Cerebrovascular Syndromes in Recent Series
Series Harvard Stroke Registry (1978) Michael Reese Stroke Registry (1983) Stroke Data Bank (1988) Lausanne Stroke Registry (1988) University of California, San Diego Stroke Registry (1993)
Atherothrombosis (%)
Embolism (%)
Lacune (%)
Hematoma (%)
SAH
50 41.5 20 29 23
23 11 13 30 12
11 – 13 14 12
8 – 3 6 –
7 – 1 – –
Numbers represent percentage of each stroke type preceded by transient ischemic attack. SAH indicates subarachnoid hemorrhage. Source: Ref. [26].
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ominous event with a 35% likelihood of ipsilateral stroke over the next year, with the greatest risk in the first week.[27] Frequent or prolonged TIAs also are associated with increased risk of subsequent stroke.[28,29] These considerations mandate the urgent screening of the carotid bifurcation, usually by ultrasound, and prompt institution of some form of antithrombotic therapy, usually aspirin, in all TIA patients.[26] If severe carotid stenosis is identified, further diagnostic studies including arteriography are indicated in preparation for carotid endarterectomy. In other patients, particularly those with prolonged TIAs, a cardiac source should be sought and treated. The pathogenesis of TIA falls into one of two major categories: thromboembolic or hemodynamic. Unfortunately, the distinction is not always readily apparent.
Thromboembolic Pathogenesis As has already been stated, thrombi can form at the site of an ulcerated atheromatous plaque or in an artery either in or beyond a stenotic segment. Some of these thrombi will not be large enough to constitute a major problem. Others will result in symptoms of TIA or completed stroke by passing downstream into intracranial branches. A thrombus in combination with an obstructing atheroma obliterating the arterial lumen will characteristically propagate downstream to the next point of arterial branching. This pathogenetic mechanism is considered to be exceedingly important for TIA because of the potential for instituting corrective medical or surgical management. Pathologists have known for many years that obstructing atheromata in the cervical portion of the carotid arteries are associated with cerebral infarction. However, it was not until the introduction and widespread use of arteriography as a diagnostic procedure that clinicians began to realize how frequently atherosclerotic lesions in these arteries are associated with cerebral infarction. More recently, there has been increased awareness that stenotic and ulcerated atheromatous lesions, particularly at the cervical carotid bifurcation, may be the site of thrombosis or the source from which emboli may pass into the distal intracranial portions of the cerebral circulation. The term cerebral embolism is used to include emboli from an intraarterial as well as a cardiac course. Artery-to-artery emboli are of two main varieties, which may exist either alone or in combination.
Platelet-Fibrin Emboli White bodies have been observed passing through or lodging in the retinal arterioles during an attack of amaurosis fugax.[30] Subsequently, this material has been studied and shown to contain both platelets and fibrin. Identification of platelet-fibrin emboli in the vertebrobasilar arterial territory is more difficult, since the distal portion of this circulation is not accessible to direct visual examination, as is the case in the territory of the ophthalmic branch of the internal carotid artery. However, it seems reasonable to postulate that a similar mechanism operates in both major arterial circulations to the brain, although the validity of this theory remains to be established in the posterior intracranial circulation.
Atheromatous Material Fragments of atheromatous debris, when observed in the retinal arterioles, have been referred to as “bright plaques” and are usually associated with the ulceration of a plaque upstream in the carotid artery.[31,32] Irregular atheromata and formation of ulcers are readily observed in arteriograms of the cervical arteries of patients with TIAs. Such lesions may also be identified by more noninvasive imaging techniques such as ultrasound. Ulcerated lesions at the cervical carotid bifurcation are located most often on the posterior aspect of the lumen in the distal portion of the common carotid artery, the proximal portion of the internal carotid artery, or both. Such lesions may also be observed, but less frequently, in the carotid siphon or in the vertebral arteries. The importance of extracranial versus intracranial vascular lesions has been shown by the previously mentioned results of Hass et al.[1] (Table 48-1). Finally, atheroscleotic debris and embolism may arise from the aortic valve and proximal aorta imaged most readily by transesophageal echocardiography. The clinician, however, even with support provided by noninvasive imaging and/or arteriography, frequently encounters difficulty in deciding whether a specific patient has extracranial arterial disease with embolization into the intracranial arteries, intracranial disease with or without embolization from the aorta or heart, or primary occlusive disease occurring simultaneously in both the extra- and intracranial arteries. It is necessary to examine these diagnostic possibilities carefully in order to select appropriate therapy. In spite of thorough study, the physician may still be led to the conclusion that although there is ischemia in a certain vascular territory, the exact cause of such ischemia is not readily identifiable. In general, if it is concluded that TIAs are due to platelet-fibrin emboli from an atherosclerotic plaque in the carotid artery, then antiplatelet therapy is the first-line strategy. If thromboembolism from the heart chambers or valves is suspected, then anticoagulation is usually employed. These therapies will be described in more detail in a later section.
Hymodynamic Pathogenesis Whenever a clinician is confronted with TIA, he or she should attempt to exclude factors that could be responsible for ischemia on a hemodynamic basis such as orthostatic hypotension, carotid sinus hypersensitivity, low perfusion states, or vascular compression by musculoskeletal structures. Many of these entities, which are accompanied by diminished cardiac output and/or reduced distal blood flow, are likely to be associated with diffuse disturbances of cerebral function such as impaired awareness or loss of consciousness. Episodes of transient focal ischemia are rare in individuals who are at high risk for stroke unless there is marked stenosis in one or more of the aortocranial arteries. The possibility that vasospasm produces TIA has not proved to be important in the etiology of ischemic stroke. It is clear, however, on rare occasions that sudden elevation of systemic blood pressure to an excessively high level (diastolic above 130 mmHg) may be associated with transient ocular or
Chapter 48.
Symptomatic Extracranial Vascular Disease: Natural History and Medical Management
cerebral ischemic attacks. Intensive retinal arteriolar narrowing may be observed by ophthalmoscopic examination during such as vascular crisis. Management of the hypertension alone usually brings about cessation of symptoms and disappearance of the ocular changes. The scientific literature is full of reports of TIA induced by extravascular compression of the vertebral arteries during extreme rotation or hyperextension of the neck by bilaterally situated osteophytes on the cervical vertebrae.[33] Tortuous, coiled, or kinked internal carotid arteries have also been suspected. Despite the large number of reports on the subject, extravascular compression is an uncommon cause of TIA.[34] When it is clear that the pathogenetic mechanism of the cerebral ischemia is hemodynamic, therapy must be directed at the responsible circulatory mechanisms rather than the thrombotic process. It is absolutely necessary to make this clinical distinction. The impaired circulation resulting from altered hemodynamic phenomena may result secondarily in the initiation of thrombosis, especially in the presence of atherosclerosis. Severe forms of hemodynamic disturbance lead to massive cerebral infarction, and white thrombi made up largely of platelets appear in the pial arteries of the “watershed areas” in patients who are near death from cardiac failure, cardiac arrhythmia, and severe hypotension.
Natural History and Prognosis The natural history of TIA and the prognosis for patients suffering from this disorder may take one of four possible forms: (1) the attacks may cease spontaneously, (2) the attacks may continue unabated, (3) cerebral infarction may ensue, or (4) the attacks may be associated with some other major vascular catastrophe, such as myocardial infarction, because the affected population is generally at high risk for vascular disease. In retrospective studies of patients who have had a completed cerebral infarction, a substantial number are reported as having had one or more previous TIAs.[26,35] Data from prospective series indicate that TIAs may precede any type of stroke and their incidence ranges from 10 to 50%, depending on pathogenesis (Table 48-2). Such information may not always be available, however, since many patients are unable to relate their prior experience after they have suffered a completed stroke. Prospective studies with follow-up ranging from 1 to 5 years suggest that approximately 35% of individuals suffering TIAs will have a completed stroke within 5 years. The first month following the onset of TIAs is the period of most serious risk, and a disproportionate number of the completed strokes will have occurred within the first year.[36] The best data on this topic are from the nonsurgical (medical) arms of recent trials of surgical carotid endarterectomy for carotid stenosis.[37,38] These trials clearly demonstrate an association between risk of subsequent stroke and increase in degree of stenosis and document the steadily increasing incidence of stroke (while on aspirin) over the next 2 years after enrollment into the study (Fig. 48-1). However, since enrollment was up to 90 days from the onset of symptoms, data on the incidence of stroke in the first few days after TIA occurrence are not available. In one retrospective study, 6 of 578 patients (1%)
699
admitted to hospital for TIA or stroke suffered a new inhospital cerebral infarction.[39]
PROGRESSING STROKE This is a clinical state that has never been described with precision. According to the definition suggested by several authors, a progressing stroke is one in which the neurological deficit is still increasing in severity or in distribution after the patient has been admitted to the hospital. Further historical information will often reveal that the progression has been going on during the period just preceding admission.[40] Increasing experience with urgent stroke treatment has allowed more frequent observation of hyperacute stroke; frequent fluctuations in clinical course with either worsening or improvement are commonly observed in the first few hours after symptom onset.[41] This is a fascinating phenomenon which begs for more detailed description, and the etiology of these fluctuations remains unknown but suggests the dynamic nature and potential reversibility of hyperacute stroke. Movement of an offending embolus downstream, with intermittent reperfusion followed by relodging of the embolus, or perhaps electrophysiologic (spreading depolarizations) or biochemical (overwhelming of cellular homeostatic mechanisms) phenomena leading to incorporation of penumbral tissue into the infarct core are possibilities. Frequently, hemodynamic factors may play a role, particularly if symptoms are associated with fluctuating mean arterial blood pressure, cardiac output, or high-grade arterial stenosis. These considerations would lend support to certain therapies in these hyperacute patients including thrombolysis, cytoprotective strategies, and hemodynamic measures such as vasopressors or volume expanders aimed at improving marginal perfusion. On the other hand, one common explanation for stroke progression, namely “propagating thrombus,” while possible, has rarely been described in the literature except in cases of basilar stenosis/occlusion. The failure of recent trials of anticoagulation for acute stroke[42,43] would speak against this as a common mechanism for deterioration except in basilar or carotid thrombosis.
COMPLETED STROKE The term completed stroke is ordinarily employed to describe a focal neurologic deficit that is abrupt in onset and has become stabilized. The variability in symptoms and the extent of initial disability, as well as the variability in recovery of function, is dependent upon a number of factors, including the adequacy of collateral circulation, the state of cardiorespiratory function, and the presence or absence of major systemic disorders that might critically alter cerebral metabolism. It is useful to subdivide ischemic stroke by pathogenesis in order to guide appropriate therapy, which will be discussed in the next section. One classification gaining wide acceptance was formulated by the investigators carrying out the recently completed trial of heparinoid for acute stroke.[44] They subdivided stroke into small artery, cardioembolic, large
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Figure 48-1. Kaplan – Meier curves showing the probability of surviving free of various endpoints in NASCET. The numbers of patients who remained event-free in each treatment group is shown at 6 month intervals at the bottom of each graph. Note the steadily increasing evidence of stroke in medical patients over the first 2 years after randomization (A and B). (From Ref. [37]).
artery, other, or undetermined based on a combination of clinical and laboratory criteria (Table 48-3). The only therapy scientifically shown to be effective in treating acute ischemic stroke of any subtype is thrombolysis. For secondary stroke prevention, in general, the first-line therapy to prevent subsequent strokes caused by small vessel disease is antiplatelet therapy and risk factor reduction. Anticoagulation is employed to prevent subsequent cardioembolic stroke, and carotid endarterectomy plus antiplatelet therapy is used for high-grade carotid stenosis. The various medical therapies for primary and secondary stroke prevention and for treating acute stroke will now be discussed in detail. Surgical treatment for extracranial arterial stenosis will be discussed in subsequent chapters.
EVALUATION OF ANTITHROMBOTIC THERAPY Acceptance of the concept that thrombosis or thromboembolism is pathogenetic in many cerebral ischemic events has led to the design of therapeutic approaches for the specific purpose of influencing the thrombotic process. These have included the administration of anticoagulant, plateletsuppressant, or thrombolytic agents, depending upon clinical circumstances and therapeutic objectives. The potential for these various modalities to prevent or alter the outcome of an ischemic stroke can best be assessed by review of the available data gathered in controlled clinical trials.
Chapter 48. Table 48-3.
Symptomatic Extracranial Vascular Disease: Natural History and Medical Management
701
Features of TOAST Classification of Subtypes of Ischemic Stroke Subtype
Features Clinical Cortical or cerebellar dysfunction Lacunar syndrome Imaging Cortical, cerebellar, brain stem, or subcortical infarct . 1.5 cm Subcortical or brain stem infarct , 1.5 cm Tests Stenosis of extracranial internal carotid artery Cardiac source of emboli Other abnormality on tests
Large-artery atherosclerosis
Cardioembolism
Small-artery occlusion (lacune)
Other cause
+ 2
+ 2
2 +
+/ 2 +/ 2
+
+
2
+/ 2
2
2
+/ 2
+/ 2
+ 2 2
2 + 2
2 2 2
2 2 +
TOAST, Trial of Org 10172 in Acute Stroke Treatment. Source: Ref. [44].
The basic principles that must be taken into consideration in designing and executing clinical trials include a clear statement of objectives, a detailed explanation of the criteria for eligibility and exclusion, a clear description of the methods to be used, a delineation of the outcome variables of interest, and a statement of the methods of analysis that will provide accurate information regarding statistical significance. Sample size and randomization are of particular importance in the evaluation of any antithrombotic therapy.[45] Unless there is a very strict assignment to each treatment modality in accordance with a predetermined table of randomization, there is grave risk that bias, on the part of either the observer or the subject, may affect the long-term outcome of the trial. The large number of subjects required to achieve statistical significance in the evaluation of antithrombotic therapy in ischemic cerebrovascular disease is an especially difficult problem. Long-term follow-up and large-scale multicenter trials are required. Moreover, the overall frequency of stroke in patients with TIA is approximately 7% per year, and if a drug brought about 50% reduction in incidence of stroke, more than 1000 patient-years would be necessary for a study to be statistically meaningful.[46]
Anticoagulant Therapy Indications for anticoagulant therapy for cerebral ischemia remain controversial. For primary prevention, there is excellent evidence that anticoagulation reduces the incidence of stroke and other embolic events in higher risk patients with nonvalvular atrial fibrillation. Atrial fibrillation is a common cause of stroke, especially in the elderly; its prevalence is 6% among those older than 65 years, and it accounts for a quarter of all strokes in those over 80 years. Five randomized trials have shown that warfarin is associated with a 66% reduction in the risk of stroke.[47] Current guidelines call for treatment to an INR of 2.0–3.0 in patients over 60 years.[48]
The evidence in favor of anticoagulation for secondary prevention, i.e., to prevent stroke after a TIA or to prevent recurrent stroke, is much less persuasive, partly because large randomized trials have not yet been completed. No scientific evidence supports the routine use of heparin as emergency therapy for all patients with a history suggestive of recent TIA. In a population-based study of the initial management of TIAs of recent onset, 102 patients treated with heparin fared the same in terms of probability of death, stroke, and either stroke or TIA during the 30 days after initial examination as did those 187 who did not receive heparin.[49] Fifty-five patients were randomized to heparin or aspirin after recent TIAs in another study. Though the incidence of subsequent TIA was the same, only one stroke occurred with heparin vs. 4 with aspirin. It is of interest that three of the aspirin strokes occurred in patients with vertebrobasilar TIAs.[50] There is also suggestive evidence of the value of heparin in patients with “crescendo TIAs,” i.e., those with frequently recurring attacks most likely signifying imminent stroke often associated with critical arterial stenosis in the carotid or vertebrobasilar system.[51] Chronic anticoagulation for secondary prevention after completed stroke has recently been studied.[52] Aspirin 30 mg daily was compared to warfarin (INR 3.0– 4.0) in 1316 randomized patients after TIA or noncardiac minor stroke. The study was stopped prematurely because of excessive bleeding in the warfarin group without evidence of a reduction in ischemic events. Bleeding was clearly related to the intensity of anticoagulation. A trial of lower intensity anticoagulation compared to aspirin has recently completed enrollment and includes subgroups of patients with conditions such as antiphospholipid syndrome and patent foramen ovale, who may be at increased risk of stroke and consequently might particularly benefit from warfarin. Follow-up should be completed and the results published within the next few years.[54] Another subgroup who may benefit from chronic anticoagulation are those with stroke due to intracranial arterial stenosis. In a retrospective analysis of 151 patients
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with stroke or TIA in the distribution of a 50 –99% stenosis of an intracranial carotid, anterior, middle, posterior cerebral, vertebral, or basilar artery, the rate of stroke was 10.4/100 patient-years in patients who were treated with aspirin compared to 3.6/100 patient-years in those prescribed warfarin. Only 3 patients had major bleeding on warfarin.[54] A larger prospective study to confirm these results is planned. Heparin is the drug most frequently prescribed for the treatment of acute or progressing ischemic stroke; its use has been recommended by many experts in cerebrovascular disease.[55] In a 1988 survey,[56] neurologists from four academic services reported its use in 73% of patients with large-artery atherothrombotic strokes, 54% with cardioembolic strokes, 31% with lucunar infarctions, and 38% with strokes of undetermined etiology. Despite the widespread use of heparin, its role in the management of ischemic stroke is still controversial, and recent data from large randomized trials have cast doubt on the benefit of anticoagulation for most acute stroke patients. In the large International Stroke Trial, 19,333 patients were randomized within 48 hours of stroke onset to 10,000 or 25,000 units of heparin subcutaneously daily (vs. no heparin). The rate of death of recurrent ischemic or hemorrhagic stroke at 14 days was not significantly different (11.7% with heparin compared to 12% without heparin). As expected, hemorrhagic recurrences were increased and ischemic ones decreased in the heparin group.[41] In a trial carried out in Hong Kong, the low molecular weight heparin nadroparin reduced the rate of 6-month death and severe disability, but these results were not confirmed in a follow-up study.[57] Finally, an American study of a low molecular weight heparinoid vs. placebo in 1281 ischemic stroke patients within 24 hours of stroke onset showed no beneficial effect on good outcome, recurrent stroke, or stroke progression, and there was a higher incidence of cerebral hemorrhage. Post hoc analysis, however, suggested that good outcome might occur after use of this drug in patients with strokes due to large artery atherosclerosis such as those with carotid stenosis.[42] These results in patients with large artery atherosclerosis need to be confirmed by further prospective analysis. In summary, however, until further data are available, the routine use of either full-dose heparin or low molecular weight heparin is not indicated in patients with acute ischemic stroke. When heparin is used, the regimen for its administration in patients with ischemic stroke has not been standardized. Recent evidence suggests that weight-adjusted administration reduces the risk of hemorrhagic complications. The recommended dose is 18 units/kg/h by continous intravenous infusion. The activated partial thromboplastin time (APTT) should be measured after 6 hours and the infusion rate adjusted up or down based on the result aiming for an APTT of 46– 70. In most stroke patients, an initial bolus of heparin to achieve more rapid induction of anticoagulation is avoided, but if given, the dose is 80 units/kg. If chronic anticoagulation is indicated, then coumadin 5.0 mg daily can be started on the second day.[58] The most feared complication of heparin therapy is hemorrhagic transformation (HT). HT occurs spontaneously in patients with large infarcts and by itself may not be harmful.[59] However, in association with heparin anticoagulation, HT may progress to hematoma formation.
The risk of this complication can be minimized by delaying or deferring altogether starting anticoagulation in patients with large infarcts and maintaining strict control over blood pressure and the level of anticoagulation by avoiding intermittent bolus dosing and carefully maintaining the APTT between 46–70. Heparin-induced thrombocytopenia can be a mild reaction occurring during the first 48 h of the infusion or a more serious event that develops later after initiation of therapy, usually between 5 and 10 days.[60 – 62] Thrombocytopenia is a direct effect of the heparin; its incidence and severity seem unrelated to the type of heparin used—whether porcine or bovine.[63] Defractionation of heparin into low molecular weight heparins or heparinoids has made possible a dissociation between the antithrombotic and the anticoagulant effects of the drug.[64,65] Low molecular weight heparins have a selective antithrombotic effect by inhibiting factor Xa without some of the other actions of heparin, and they prevent thrombosis and fibrin formation at least as well as conventional heparin. Hemorrhage associated with reversible platelet aggregation independent of antithrombin III is lacking with these compounds, unlike heparin. In addition, these agents do not have the antiplatelet aggregation or thrombocytopenic effects of conventional heparin and thereby mitigate the “white clot” syndrome and resultant risk for further cerebral ischemia.[65,66] While initial studies of routine use of low molecular weight heparins in acute stroke have been negative, it would be logical to consider these agents as an alternative to unfractionated heparin if anticoagulation is to be carried out. Furthermore, since deep venous thrombosis (DVT) in the lower extremities occurs in about half of patients with acute ischemic stroke, and pulmonary embolism accounts for about 5% of deaths, routine prophyl axis against DVT is indicated in most stroke patients. In the International Stroke Trial,[41] the best outcomes were obtained in patients who received lowdose heparin (5000 units subcutaneously every 12 hours) combined with aspirin. With this combination, the incidence of pulmonary emboli was reduced without increased risk of bleeding. The aforementioned heparinoid substances, lacking the hazards of more established anticoagulants, may be a safe alternative.[67]
Thrombolytic Therapy The brain is so sensitive to hypoxia that the catastrophic consequences of thrombotic occlusion are almost entirely the result of reduction in blood flow and deprivation of oxygen. However, the viability of brain tissue is also dependent upon the adequacy of collateral circulation. Irreversible tissue damage occurs within 10 min of total interruption of blood flow and after 1–3 h if blood supply is decreased to 20% of normal. Therapy directed toward dissolution of obstructing thrombotic material provides a very seductive approach from the theoretical point of view, since it provides the opportunity to restore flow promptly at a time when the tissue is still salvageable. Treatment of this nature should enable one to dissolve both single and multiple thrombi in extracranial and intracranial vessels. Unfortunately, one seldom sees patients
Chapter 48.
Symptomatic Extracranial Vascular Disease: Natural History and Medical Management
within 60 min of the onset of an ischemic stroke. By the time most patients arrive in the emergency department, changes have already taken place, not only in the brain parenchyma but also in the blood vessels within the ischemic area. This latter change will result in a breach of the blood-brain barrier if and when pulsatile flow is stored. Consequently, the administration of a thrombolytic agent at this point introduces the serious hazard of converting a “white infarct” into a “red or hemorrhagic infarct” and subsequently into a cerebral hemorrhage, particularly in patients who are hypertensive. This set of circumstances is comparable to what frequently occurs when a thrombotic occlusion of the carotid artery is removed surgically. Despite these concerns, recombinant tissue plaminogen activator (rtPA) was approved by the FDA in June 1996 for the treatment of acute ischemic stroke within 3 hours of symptom onset, following publication of the first and only scientific demonstration of effective therapy for this condition.[68] The NINDS rtPA stroke study was in fact two consecutive randomized comparisons of rtPA vs. placebo. Study design was influenced by animal stroke models demonstrating that damage could be limited if reperfusion occurred within 3 hours, negative clinical experience with delayed treatment, the occurrence of brain bleeding after thrombolysis for myocardial infarction, and several previous small randomized clinical studies of rtPA in stroke patients including a dose-escalation pilot trial that demonstrated intracranial hemorrhage at doses above 0.9 mg/kg,[69,70] and one angiographically based study that showed a high prevalence of arterial occlusion in acute stroke patients and
the ability of intravenously administered rtPA to recanalize a substantial number of these occlusion depending on the size and location of the thromboembolism.[71] Therefore, the NINDS group used an rtPA dose of 0.9 mg/kg given intravenously over 1 hour (10% given as a bolus over the first minute) and based treatment on the clinical diagnosis of stroke without requiring angiographic demonstration of the occlusion. Most importantly, all patients were treated within 3 hours of symptom onset based on careful interview of witnesses. Patients were excluded who did not have careful review of a brain CT scan prior to treatment to exclude hemorrhage or who had elevation of blood pressure above 185/110 or other conditions likely to increase the risk of bleeding. The criteria used by the NINDS group were adopted by the FDA and other organizations endorsing the use of rtPA (Table 48-4). In the NINDS study, the treatment was relatively safe; symptomatic intracranial hemorrhage occurred in 6% of patients. At 3 months after treatment, the NINDS investigators found a highly significant ðp ¼ 0:008Þ increase in the odds of a favorable outcome on a global statistic embodying four different clinical scales. For instance, the percentage of patients demonstrating complete recovery on their neurological exam increased from 20% to 31%, and complete recovery to full independence increased from 38% to 50%. Furthermore, despite the increased bleeding risk, the likelihood of death or severe disability was reduced by rtPA, as was length of hospital stay. This benefit was seen in all stroke subtypes. Patients with advanced changes of ischemia on the baseline CT scan had higher rates of bleeding and
Table 48-4 Inclusion Criteria Patients 18 years or older with a clinical diagnosis of ischemic stroke and a measurable neurologic deficit should be considered for rtPA treatment if time of symptom onset is well established to be less than 180 minutes before treatment would begin. Exclusion Criteria Patients should be excluded from treatment if with any of the following: 1. Evidence of intracranial hemorrhage on pretreatment CT 2. Only minor or rapidly improving stroke symptoms 3. Clinical presentation suggestive of SAH, even with normal CT 4. Active internal bleeding 5. Known bleeding diasthesis: ! platelets , 100,000/mm3 ! heparin treatment last 48 hours with elevated APTT ! current use of oral anticoagulants or recent use with an elevated PT . 15 seconds 6. Patient has had major surgery or serious trauma excluding head trauma in the previous 14 days 7. Within three (3) months of any intracranial surgery, serious head trauma, or previous stroke 8. History or gastrointestinal or urinary tract hemorrhage within 21 days 9. Recent arterial puncture at a noncompressible site 10. Recent lumbar puncture 11. Patient requires aggressive treatment to decrease BP to systolic ,185 or diastolic , 110 12. History of intracranial hemorrhage 13. Abnormal blood glucose (, 50 or .400 mg/dL) 14. Post– myocardial infarction pericarditis 15. Seizure at stroke onset 16. Known AVM or aneurysm Source: Ref. [68].
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probably should not be treated even if within the 3-hour limit. While not definitely established by the NINDS study, it is likely that the earlier within the 3-hour time frame that the patient is treated, the higher the rate of good outcome. Conversely, patients with very severe strokes due to total occlusion of the carotid or basilar artery are less likely to respond to intravenous thrombolysis. The positive results found in the NINDS study must be reconciled with negative results from other trials. Two consecutive European trials of intravenous rtPA found that results were negative if drug administration was delayed up to 6 hours. However, in patients with advanced CT ischemic changes were eliminated and with early therapy, results were similar to the NINDS trial.[72 – 74] Other trials, also negative, demonstrating increased risk of bleeding and death following thrombolysis differed from the NINDS trials in several important respects; they used streptokinase in high doses, often combined with heparin or aspirin, and treated patients 5–6 hours after stroke onset.[75 – 77] These negative trials underscore the risks of thrombolytic therapy and emphasize the need to adhere to published guidelines particularly regarding drug, dose, and time to treatment. Implementation of rtPA therapy within 3 hours of symptom onset into community practice has been slow because of logistic problems in streamlining emergent medical care for stroke patients, lack of patient awareness of symptoms and that treatment is available, and numerous other concerns including physician misinformation and legitimate concerns about risk. Nevertheless, where implemented, results have largely reflected the NINDS trial experience.[78,79] Finally, alternative approaches to the NINDS rtPA guidelines may improve on efficacy or safety; these include alternative doses and drugs, intraarterial administration of lytics, either alone or following intravenous rtPA,[80] and selection of patients based on newer imaging techniques. However, these approaches remain investigational.
Platelet-Suppressant Therapy The most striking property of platelets is their ability to aggregate. When platelets interact with collagen, they first adhere to the collagen fibers. Aggregating agents are then released from and synthesized by the platelets, and aggregation ensues. Collagen is present in the subendothelial layer in the walls of blood vessels and is largely responsible for platelet deposition on blood vessels once the endothelial layer has been removed.[81] It is widely believed that exposure of subendothelium is a relevant factor in intraarterial thrombosis.[82] Once platelets have been induced to aggregate or when they have adhered to collagen or other foreign surfaces, they undergo the “platelet release reaction.” This is a secretory process in which the contents of intracellular storage granules are specifically discharged from the platelets into the surrounding plasma.[83] The released materials include adenosine diphosphate (ADP), catecholamines, and serotonin. The process is, therefore, one of the mechanisms through which platelets amplify their own aggregation. The same agents that induce aggregation in the release reaction also induce platelets to synthesize prostaglandins and thromboxanes.[84 – 86] This is another mechanism through
which platelets can amplify their own aggregation, because some of the intermediate prostaglandins and thromboxanes that are synthesized are potent though short-lived aggregating agents.[87 – 90] Although observations in vitro allow us to speculate on the involvement of platelets in thrombus formation, it is important to appreciate the limitations of such studies. Although valuable biochemical information has been obtained by studying isolated platelets in artificial media, the ways in which platelets behave under such conditions do not fully reflect the ways in which they behave either in anticoagulated plasma or in vivo. Consequently, studies to determine the influence of antiplatelet agents on platelets suspended in artificial media, in the absence of plasma proteins, do not give accurate information on the amount of drug required to affect platelet behavior. Most drugs are highly protein-bound; to effect a given degree of inhibition, higher concentrations are needed in plasma than in a proteinfree system. The walls of blood vessels contain enzymes that convert ADP into materials that do not induce platelet aggregation. Prostacyclin (PG1,2) is a potent inhibitor of platelet aggregations.[91,92] Vessel walls, therefore, have the capacity to limit any amplification of platelet aggregation that might occur once platelets have been activated. Studies in vitro cannot take account of the modulating effect of the vessel wall. A considerable number of pharmaceutical agents alter platelet function in vitro, but only a few have potential clinical usefulness when one considers their toxicity, the length of time during which they will affect certain platelet functions, and the dose required to produce a satisfactory clinical response. At the time of writing, four pharmacologic agents have been extensively evaluated and shown to be effective in clinical trials for stroke prevention or treatment: acetylsalicylic acid (aspirin), dipyridamole, ticlopidine, and clopidogrel. Several aspects of platelet behavior are affected by aspirin, both when the experiments are done wholly in vitro or when the platelets are studied ex vivo after the drug has been ingested. Because of the ease with which the effects of aspirin can be demonstrated, the drug has received a great deal of attention from researchers, and considerable strides have been made toward understanding the mode of action of this agent. The major effects of aspirin on platelets are on the events that follow stimulation of platelets by an aggregating agent. Aspirin completely inhibits the synthesis of prostaglandins and thromboxanes irrespective of the nature of the aggregating agent. It also inhibits the release reaction that accompanies the aggregation induced by such agents as ADP, norepinephrine, and low concentrations of collagen.[93 – 95] The effects of aspirin on prostaglandin and thromboxane synthesis, both in platelets and in the vascular wall, and on the platelet release reaction probably explain most if not all of the other effects of aspirin that have been observed in in vitro and ex vivo experiments.[93 – 97] Aspirin produces gastrointestinal symptoms in approximately 10% of patients on long-term treatment. Although prolonged use is associated with continuing low-grade blood loss from the gut, the evidence that aspirin ingestion produces acute gut blood loss in the absence of peptic ulcer
Chapter 48.
Symptomatic Extracranial Vascular Disease: Natural History and Medical Management
is inconclusive. Furthermore, at the dose levels that have been used in clinical trials to date, neurotoxicity and interaction with other drugs such as anticoagulants have not posed any serious problems. In spite of the fact that aspirin markedly prolongs bleeding time in persons with preexisting hemorrhagic disorders, it prolongs the bleeding time of normal subjects only minimally without producing a clinical hemorrhagic tendency. Consequently, only those persons with a hemorrhagic diathesis, specific aspirin idiosyncrasy, or active peptic ulcer would be considered ineligible for such treatment. For these reasons, aspirin has been the most attractive drug to employ in controlled clinical trials in patients with ischemic cerebrovascular disease. Unfortunately, it has one serious drawback as an investigational tool because of its widespread use and availability as a nonprescription drug. For these reasons it is difficult to maintain the “double-blind control” unless the taste of both the aspirin and the placebo is disguised.
Clinical Trials of Platelet Antiaggregant Drugs During the past 15 years, several large-scale multicenter trials have been conducted to determine the clinical benefits, if any, of platelet-suppressant therapy in both TIA and ischemic stroke. A controlled trial conducted in the United States compared aspirin 650 mg (2 tablets) twice daily with placebo in subjects who had a definite history of one or more carotid territory TIAs within 12 weeks of entry.[99,100] There was a clearly demonstrated marked reduction in transient events, particularly in individuals who had had multiple attacks before entering the trial. An even more striking result was obtained in those subjects who had arteriographically demonstrated lesions in the cervical portion of the carotid artery on the side appropriate to their presenting symptoms. Among those individuals treated medically throughout the duration of the trial, 51% had atherosclerotic lesions in the cervical carotid bifurcation. In this particular trial, no significant difference was noted in the effect on males versus females with regard to the reduction of TIAs, but there was a trend, although not statistically significant, toward less effective protection in females when cerebral infarction was considered. Coincident with conduct of the trial in the United States, another multicenter controlled trial was carried out under the auspices of the Medical Research Council of Canada, in which aspirin, sulfinpyrazone (Anturane), and a combination of the two active agents were tested against placebo. The published data from this clinical trial clearly indicate a 50% reduction in stroke morbidity and mortality in the aspirintreated group; however, this reduction appeared to be confined to male subjects.[101] The exact reason for this difference in response between the sexes was not clear. However, it was thought by some reviewers that the apparent sex bias resulted from a statistical artifact produced by the small number of females in the study. Sulfinpyrazone was shown to be about as effective as placebo and a combination of aspirin and sulfinpyrazone about as effective as aspirin alone.
705
Another multicenter controlled trial of aspirin alone and in combination with dipyridamole (Persantine) was reported from France in 1983.[102] These investigators reported a beneficial response with aspirin which did not appear to be enhanced by dipyridamole. The results of these three separately conducted trials when considered together clearly demonstrated a positive effect by aspirin in a total dosage of 1.3 g daily with respect to reduced morbidity and mortality from cerebral infarction and with respect to a reduction or cessation of TIA. A fourth trial conducted in Denmark and reported in 1983 failed to show a positive response to aspirin.[103] However, all patients referred for carotid surgery were excluded from the trial. If one accepts the conclusion of the American trial that the patients most likely to benefit were those with carotid lesions appropriate to their cerebral symptoms, it would appear that many, if not most, of the individuals who might have been expected to benefit from aspirin were excluded from the trial and submitted to surgical intervention. The European Stroke Prevention Study, completed in 1987, included 2500 patients with a clinical diagnosis of TIA, RIND, or stroke.[104] All subjects were randomly allocated to either (1) aspirin 325 mg plus dipyridamole (Persantine) 75 mg daily or (2) placebo. Neither drug was given alone. It was concluded that there was a 33% reduction in stroke morbidity and mortality in this study population. Between 1979 and 1985, a total of 2435 patients were entered into the United Kingdom–TIA Aspirin Trial.[105] They were assigned randomly to one of three treatment groups: aspirin 600 mg twice daily, aspirin 300 mg once daily, or placebo. It was reported that the likelihood of suffering one or more of four categories of endpoint events—namely, nonfatal myocardial infarction, nonfatal major stroke, vascular death, or nonvascular death—was 18% less in the two groups that received aspirin. No definite difference in response was noted between the groups receiving 300 and 1200 mg of aspirin. However, the lower dose produced far fewer gastrointestinal complaints. In humans a single aspirin tablet (325 mg) will reduce the cyclooxygenase activity of platelets by 90%, and this effect only begins to disappear 2 days later, presumably with the introduction into the bloodstream of new, unaffected platelets. These observations suggest that smaller daily doses of aspirin alone or combined with another antithrombotic agent might be of greater therapeutic benefit based on the hypothesis that there is a lesser effect of aspirin against the cyclooxygenase activity in the vessel wall than in the platelet or a more rapid recovery from the effect on the vessel wall.[106] Two trials have evaluated very-low-dose aspirin for stroke prevention. No difference was seen when 30 mg daily was compared to 283 mg, but there was no placebo group.[107] In another study, 75 mg daily was only 16% better than placebo.[108] Recent data from NASCET indicate that perioperative stroke was no higher in patients receiving lower-dose aspirin. While it is possible that there is no advantage to aspirin doses higher than 325 mg, it has yet to be proven that doses less than 325 mg are as effective for stroke prevention. Lower doses of aspirin (325 mg or below) are now the most frequently prescribed for stroke prevention, but it must be kept in mind that individual patients vary in their
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response to aspirin doses, and some patients may need higher doses, perhaps only once weekly, to achieve maximal antiplatelet effect from aspirin.[109] The use of aspirin in completed stroke has been clarified in recent clinical studies. In 19,331 patients in the International Stroke Trial randomized to aspirin 300 mg vs. no aspirin within 48 hours of acute stroke, mortality was no different, but recurrent stroke (ischemic or hemorrhagic) was reduced by aspirin from 4.2% to 3.5%. A reduction in the risk of recurrent ischemic stroke was offset by a slight increase in intracranial bleeding.[41] In a Chinese trial,[110] 6776 stroke patients given aspirin 160 mg within 48 hours demonstrated a trend toward less mortality and dependency compared to 6170 controls (31.8% vs. 30.3%). Again, aspirin was associated with a reduced incidence of recurrent (in-hospital) ischemic strokes (2.3% vs. 1.7%), but a slight increase in intracranial bleeding. The aspirin arm of a European trial of streptokinase, aspirin, or both vs. placebo also demonstrated reduction of long-term mortality.[111] Therefore, the routine use of aspirin within 48 hours of stroke onset will reduce the number of early recurrent ischemic strokes by approximately 7 per 1000 patients treated, increase the number of intracranial hemorrhages by approximately 2/1000, and reduce the risk of all recurrent strokes and early death by approximately 11/1000 ðp , 0:001Þ: Dipyridamole, another platelet suppressant, has been marketed and widely employed as an antithrombotic agent in vascular human disease, but its mode of action is still not clearly understood. Current evidence suggests, however, that its effect in vitro is mediated by inhibition of phosphodiesterase.[112] This inhibition has been said to potentiate the effect of prostacyclin on the platelets – a reaction that depends on platelet generation of cyclic adenosine monophosphate (cAMP). When used alone, it did not conclusively have more than a placebo effect.[113] Early trials showed no benefit of an aspirin/dipyridamole combination over aspirin alone.[102,104] However, a recent study was more promising, showing a substantial additional benefit when high-dose (200 mg bid) dipyridamole was added to low-dose (50 mg qd) aspirin.[114] There is debate whether the differences between this trial and the previous studies was because of a more effective (higher) dose of dipyridamole or a lower (ineffective) dose of aspirin. Ticlopidine hydrochloride is a novel platelet antiaggregant that functions primarily as an inhibitor of the adenosine diphosphate pathway of platelet aggregation. In contrast to aspirin, ticlopidine inhibits most of the known stimuli to platelet aggregation when they are tested at physiological concentrations. Ticlopidine does not inhibit the cyclooxygenase pathway and does not block the production of thromboxane by platelets or the production of prostacyclin by endothelial cells. Like aspirin, ticlopidine alters platelet function for the normal life span of the platelet. In a controlled trial in 56 North American centers,[115] the effects of ticlopidine hydrochloride (500 mg daily) were compared with aspirin (1300 mg daily). Because aspirin in a daily dose of 1300 mg had been approved by the U.S. Food and Drug Administration as a stroke-preventive agent, it was used as a drug for comparison rather than as a placebo in assessing the risk of stroke or death. These medications were randomly assigned to 3069 patients with recent TIAs or with
a mild persistent focal or retinal ischemia. The rates of fatal or nonfatal stroke at 3 years were 10% for ticlopidine and 13% for aspirin. Ticlopidine was moderately more effective than aspirin in both sexes. Unfortunately, severe but reversible neutropenia was encountered in 1 of every 100 patients (1%), dictating that close monitoring of this hematological parameter be undertaken during the initial 3 –4 months of treatment. This has been reinforced by post-marketing experience. There may be subgroups of patients for whom ticlopidine is particularly advantageous, i.e., African Americans, women, diabetics, and those who cannot tolerate aspirin.[116] Finally, the combination of ticlopidine and aspirin has been found to be highly effective when used short term in patients following coronary stenting.[117] The most recent addition to the antiplatelet armamentarium is clopidogrel, which was compared to aspirin 325 mg daily in patients with recent stroke, myocardial infarct, or symptomatic peripheral vascular disease. For the combined patient population of 19,185, the yearly incidence of subsequent stroke, myocardial infarct, or vascular death was reduced from 5.8% with aspirin to 5.3% with clopidogrel ðp ¼ 0:04Þ:[118] Though the study was not powered for subgroup analysis, there was no significant effect in the 6054 patients who qualified for the study because of stroke. The main disadvantage of clopidogrel compared to aspirin is its cost. Its advantages over ticlopidine, to which it is closely related pharmacologically, are that it is given once daily and has fewer side effects. In particular, there are fewer gastrointestinal symptoms and thrombocytopenia has not been observed. Combination therapy with clopidogrel and aspirin has not yet been formally studied but is being increasingly used clinically.
CONCLUSIONS 1.
2.
3.
4.
Stroke is a very important cause of death and disability in most developed countries. Among the various categories of stroke, the ischemic variety related to thrombosis or thromboembolism is by far the most common. The clinician should make every effort to distinguish between cerebral hemorrhage and cerebral infarction by whatever diagnostic procedures are available. An attempt should also be made to categorize the stroke according to the currently accepted classification, i.e., transient ischemic attack (TIA), progressing stroke (stroke in evolution), or completed stroke, and small artery, large artery, cardioembolic, other, or cryptogenic. The clinician should have basic knowledge of the mechanisms of blood clotting and the contraindications when one of the various types of antithrombotic therapy is considered in the patient who either has had or is at risk of having a stroke. To date, there are no conclusive data supporting routine use of anticoagulant therapy after TIA, though heparin is generally recommended if TIAs are repetitive while ruling out a high-grade carotid stenosis requiring surgery or severe intracranial
Chapter 48.
5.
6.
Symptomatic Extracranial Vascular Disease: Natural History and Medical Management
stenosis, in which case long-term anticoagulation may be useful. In patients with completed stroke, present evidence indicates that routine treatment with anticoagulant drugs is not useful. The best available current information suggests that embolism of cardiac origin can be prevented by employing anticoagulants. Warfarin should be given in high-risk patients with underlying cardiac conditions such as atrial fibrillation. The use of intravenous thrombolytic therapy (rtPA) within 3 hours of ischemic stroke symptom onset in appropriately selected patients has been shown to significantly increase the chance of recovery and
7.
8.
9.
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lessen the risk of death or severe disability despite an increased risk of symptomatic hemorrhagic changes. Aspirin reduces the frequency of recurrent TIAs and stroke in both male and female patients who have suffered TIA or stroke. Daily doses of 50 –325 mg of aspirin are effective in the prevention of stroke and produce fewer side effects than higher doses. Dipyridamole, ticlopidine, and clopidogrel are alternatives to aspirin in selected patients, and may amplify the effect of aspirin when used in combination. Further studies of combinations of antiplatelet agents are needed.
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Part Six. Cerebrovascular Disease Hemostatic Defect Due to Platelet Cyclo-oxygenase Deficiency. Proc. Natl. Acad. Sci. USA 1975, 72, 1446. Roth, G.J.; Stanford, N.; Majerus, P.W. Acetylation of Prostaglandin Synthetase by Aspirin. Proc. Natl. Acad. Sci. USA 1975, 72, 3073. Smith, J.B.; Ingerman, C.; Kocsis, J.J.; Silver, M.J. Formation of an Intermediate in Prostaglandin Biosynthesis and Its Association with the Platelet Release Reaction. J. Clin. Invest. 1974, 53, 1468. Lieberman, G.E.; Lewis, G.P.; Peters, T.J. A Membrane Bound Enzyme in Rabbit Aorta Capable of Inhibiting Adenosine Diphosphate Induced Platelet Aggregation. Lancet 1977, 2, 330. Evans, G.; Packham, M.A.; Nishizawa, E.E.; et al. The Effect of Acetylsalicylic Acid on Platelet Functions. J. Exp. Med. 1968, 128, 877. O’Brein, J.R. Effects of Salicylates on Human Platelets. Lancet 1968, 1, 779. Weiss, H.J.; Aledort, L.M.; Kochwa, S. The Effects of Salicylates on the Hemostatic Properties of Platelets in Man. J. Clin. Invest. 1968, 47, 2169. Zucker, M.B.; Peterson, J. Inhibition of Adenosine Diphosphateinduced Secondary Aggregation and Other Platelet Functions by Acetylsalicylic Acid Ingestion. Proc. Exp. Biol. 1968, 127, 547. MacMillan, D.C. Effect of Salicylates on Human Platelets. Lancet 1968, 1, 1151. Fields, W.S.; Hass, W.K., (Eds.) Aspirin Platelets and Stroke Background for a Clinical Trial; Warren H Green: St. Louis, 1971. Fields, W.S.; Lemak, N.A.; Frankowski, R.F.; et al. Controlled Trial of Aspirin in Cerebral Ischemia. Stroke 1977, 8, 301. Fields, W.S.; Lemak, N.A.; Frankowski, R.F.; et al. Controlled Trial of Aspirin in Cerebral Ischemia: Part 11. Surgical Group. Stroke 1978, 9, 309. Canadian Cooperative Study Group; A Randomized Trial of Aspirin 110 and Sulfinpyrazone in Threatened Stroke. N. Engl. J. Med. 1978, 299, 53. Bousser, M.G.; Eschwege, E.; Haguenau, M.; et al. “AICLA”: Controlled Trial of Aspirin and Dipyridamole in the Secondary Prevention of Atherothrombotic Cerebral Ischemia. Stroke 1983, 14, 5. Sorensen, P.S.; Pedersen, H.; Marquardsen, J.; et al. Acetylsalicylic Acid in the Prevention of Stroke in Patients with Reversible Cerebral Ischemic Attacks: A Danish Cooperative Study. Stroke 1983, 14, 15. European Stroke Prevention Study Group. European Stroke Prevention Study: Principal End Points. Lancet 1987, 2, 1351. UK-TIA Study Group. United Kingdom Transient Ischaemic Attack (UK-TIA) Aspirin Trial: Interim Results. Br. Med. J. 1988, 296, 316.
106. Masotti, G.; Poggesi, L.; Galanti, G.; et al. Differential Inhibition of Prostacyclin Production and Platelet Aggregation by Aspirin. Lancet 1979, 1, 1213. 107. The Dutch TIA Trial Study Group; A Comparison of Two Doses of Aspirin (30 mg vs. 283 mg a Day) in Patients After a Transient Ischemic Attack or Minor Ischemic Stroke. N. Engl. J. Med. 1991, 325, 1261. 108. Antiplatelet Trialists’ Collaboration; Collaborative Overview of Randomised Trials of Antiplatelet Therapy—I: Prevention of Death, Myocardial Infarction, and Stroke by Prolonged Antiplatelet Therapy in Various Categories of Patients. Br. Med. J. 1994, 308, 81. 109. Valles, J.; Santos, T.; Aznar, J.; Osa, A.; Lago, A.; Cosin, J.; Sanchez, E.; Broekman, J.; Marcus, A. Erthrocyte Promotion of Platelet Reactivity Decreases the Effectiveness of Aspirin as an Antithrombotic Therapeutic Modality. Circulation 1998, 97, 350. 110. Chen, Z.M.; Xie, J.X.; Peto, R.; et al. Chinese Acute Stroke Trial (CAST): Rationale, Design and Progress. Cerebrovasc. Dis. 1996, 6 (Suppl. 2), 23. 111. Candelise, L.; Motto, C.; Aritzu, E.; et al. Aspirin Given Within 6 Hours Reduces Long Term Case Fatality but Not Stroke Related Disability. Cerebrovasc. Dis. 1996, 6 (Suppl. 2), 23. 112. Moncada, S.; Korbut, R. Dipyridamole and Other Phosphodiesterase Inhibitors Act as Antithrombotic Agents by Potentiating Endogeneous Prostacyclin. Lancet 1978, 1, 1286. 113. American – Canadian Cooperative Study Group. Persantine Aspirin Trial in Cerebral Ischemia. Stroke 1983, 14, 99. 114. Diener, H.C.; Cunha, L.; Forbes, C.; Sivenius, J.; Smets, P.; Lowenthal, A. European Stroke Prevention Study 2. Dipyridamole and Acetylsalicylic Acid in the Secondary Prevention of Stroke. J. Neurol. Sci. 1996, 143, 1. 115. Hass, W.K.; Easton, J.D.; Adams, H.P., Jr.; et al. A Randomized Trial Comparing Ticlopidine Hydrochloride with Aspirin for the Prevention of Stroke in High-Risk Patients. N. Engl. J. Med. 1989, 321, 501. 116. the TASS Baseline and Angiographic Data Subgroup; Grotta, J.C.; Norris, J.W.; Kamm, B. Prevention of Stroke with Ticlopidine: Who Benefits Most? Neurology 1992, 42, 111. 117. Schomig, A.; Neumann, F.J.; Kastrati, A.; Schuhlen, H.; Blasini, R.; Hadamitzky, M.; Walter, H.; Zitzman-Roth, E.M.; Richardt, G.; Eckhard, A.; Schmitt, C.; Ulm, K. A Randomized Comparision of Antiplatelet and Anticoagulant Therapy After the Placement of CoronaryArtery Stents. N. Engl. J. Med. 1996, 17, 1084. 118. CAPRIE Steering Committee; A Randomised, Blinded, Trial of Clopidogrel Versus Aspirin in Patients at Risk of Ischaemic Events (CAPRIE). Lancet 1996, 348, 1329.
CHAPTER 49
Carotid Pathology Anthony M. Imparato
Atherosclerotic plaques are the most commonly encountered cerebral circulatory lesions associated with ischemic stokes, and they cause an even higher incidence of transient cerebral ischemic symptoms.[1 – 3] Atherosclerotic cerebral plaques are frequently associated with atherosclerotic lesions in other regions of the body; therefore a decision is often required as to whether a single therapeutic modality will suffice to treat the underlying vascular disorder or whether individual organ systems threatened by ischemia must be dealt with individually, combining medical with surgical therapies. Where surgical intervention is contemplated, the question is in what order the multiple surgeries should be done.[4 – 10] The problem is further complicated by the fact that lesions of the carotid bifurcation differ markedly from patient to patient. In some, morphologic components of the plaques suggest that there is marked instability of the pathologic process, indicating possibly imminent cerebral ischemia either through embolization, progression to total occlusion, or even propagation of thrombus to occlude collateral arteries. Even seemingly identical and advanced lesions may be markedly different in their ability to cause cerebral ischemia.[11,12] Carotid lesions are often associated with other lesions of intra- and extracranial cerebral arteries, which significantly influence the effects of individual arterial occlusions.[13,14] Clinically, there are marked variations in syndromes resulting from carotid bifurcation lesions, and “the precise mechanism of cerebral infarction may be uncertain clinically.”[15] Symptoms may vary markedly and may be easily characterized as cerebral hemispheric or, less obviously, as vertebrobasilar. They may be as difficult to define as transient global amnesia.[16] Indeed, advanced lesions and even total occlusions of carotid arteries are encountered in asymptomatic individuals, some of whom, nevertheless, at postmortem examination, are found to have cerebral infarcts. The spectrum of pathologic changes found at the carotid bifurcations depends upon the population from which specimens are retrieved, whether from surgical patients subjected to carotid endarterectomy, from patients examined postmortem who were suspected to be suffering from cerebrovascular disease, or from asymptomatic patients of various age groups who came to autopsy for unrelated
causes. It seems ironic that, in view of the very great interest in stroke, the largest series of carotid plaque studies have been based on arterial specimens retrieved at carotid endarterectomy and x-ray, ultrasound, and nuclear magnetic resonance arteriography performed on living patients.[17 – 20] Appreciation of the characteristic pathologic components of carotid plaques and their evolution is essential to planning therapy, performing safe operations, and evaluating the numerous conflicting viewpoints regarding how best to manage related clinical situations.
CAROTID PLAQUE—SURGICAL PATIENTS The predominance of extracranial arterial involvement in patients presenting with a wide range of cerebral ischemic symptoms is exemplified by the prospective randomized Joint Study of Extracranial Arterial Occlusions (1962 – 1972),[21] in which 4748 symptomatic patients had extensive cerebral angiographic studies. Nearly half were found to have extracranial arterial lesions; these predominated over intracranial lesions, with stenoses far more numerous than occlusions. The carotid bifurcations were the most frequently involved sites, followed by the origins of the vertebral arteries (Fig. 49-1). This general pattern has since been encountered repeatedly in studies of the cerebral arteries and seems to vary only in the North American black population, wherein extracranial lesions appear less frequently than the intracranial type.[22] Characteristically, grossly, carotid plaques involve the distal 2 – 3 cm of the common carotid and the proximal 2 – 3 cm of the internal carotid arteries. Thus, the entire carotid sinus, which is the bulbous dilatation of the proximal part of the internal carotid artery, and the distal common carotid are involved by plaque. There is variable extension into the external carotid, usually to just beyond its origin but sometimes also to beyond the linguofacial trunk. The thickest portion of a plaque is usually on the outer lateral wall of the carotid sinus opposite the ostium of the external carotid, extending about 1 –2 cm into the proximal part of the internal and thereby having an
Hobson/Wilson/Veith: Vascular Surgery: Principles and Practice, Third Edition, Revised and Expanded DOI: 10.1081/0819-9-120024932 Copyright q 2004 by Marcel Dekker, Inc.
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Figure 49-1. Frequency distribution of arterial lesions at surgically accessible (A ) and inaccessible (B ) sites encountered during the Joint Study of Extracranial Arterial Occlusions in 4748 symptomatic patients who had four-vessel cerebral angiographic studies. (From Hass WK, et al.[21] Reproduced by permission.)
eccentric distribution (Fig. 49-2A and B; see also color plate). The luminal surface may be glistening white, smooth, and firm to the touch, exhibiting varying degrees of impingement on the lumen, from minimal to nearly complete, with or without attached salmon-colored flow thrombus. Microscopically, the entire lesion may be composed of fibrous tissue alone, which may thicken the intima to produce preocclusive stenosis (Fig. 49-3A and B; see also color plate). If the thinner portions of the plaque appear yellow, foam cells will be found on histologic examination, usually in proximity to the site of greatest proliferation, but not appearing to be a part of it (Fig. 49-4; see also color plate). The “simple fibrous plaque” is usually totally avascular and devoid of fat, although there may be some fat in neighboring foam cells. Complex or compound plaques, grossly viewed, achieve complexity by containing encysted red/maroon clot, totally within a fibrous shell, with no discernible breaks in the luminal surface, which, however, may be stained by the contained hemorrhage (Fig. 49-5A and B; see also color plate). In many plaques there are breaks in the overlying fibrous cap, with exposure of the contained hemorrhage to the flowing blood. The largest encysted collections are found on the outer wall of the carotid sinus and proximal internal carotid artery, sites where the most pronounced fibrous intimal thickening is also encountered. On occasion, even on gross inspection, there is visible clearly recognizable hemorrhage with areas of brown granular amorphous material-hemorrhage, which is undergoing degradation (Fig. 49-6; see also color plate). Totally encysted collections of amorphous toothpastelike atheromatous debris having the same configuration and location as encysted hemorrhage may be found (Fig. 49-7A and B; see also color plate) and may also have areas of fracture of the overlying fibrous luminal cap or frank ulceration, as found with encysted hemorrhage. Microscopically, these complex “compound plaques” have a spectrum of histologic changes. These range from hemorrhage alone, which may appear to be massive and of recent occurrence, to older hemorrhages, in which still clearly recognizable collections of red blood cells intermingle with areas of amorphous debris and cleftlike spaces, identifiable as cholesterol clefts. Finally, there is only amorphous debris with multiple cholesterol clefts (Fig. 49-8A and B; see also color plate). The intrinsic vascularity of plaques, visible as thin-walled vascular spaces, is quite variable. Ulcerations consist of usually large, up to 1 cm, defects over once-encysted intraplaque hemorrhages or over encysted atheromatous debris (the “cholesterol abscess”). On rare occasions, the remains of a unicameral evacuated hematoma with collapsed filmy side walls may be recognized. At other times flattened, saucerlike defects, which may be partially or totally healed, indicate one outcome of even massive ulceration (Fig. 49-9A, B, C, and D; see also color plate). If less than total occlusion is produced by the plaque, thrombus—when encountered (unpredictably)—is characteristic of “flow thrombus,” being smooth, adherent, and usually pink. It may be found in the bases of shallow or deep ulcers; at sites of preocclusive stenoses, which may be smooth, fibrous, and nonulcerated; or, unaccountably, in only moderately
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Figure 49-2. (A ) Typical carotid bifurcation plaque removed by endarterectomy, showing the major involvement at the bifurcation with limited extension to the internal and external carotid (see also color plate). (B ) Diagrammatic representation of typical carotid bifurcation plaque. (From Hass WK, et al.[16] Reproduced by permission.)
stenotic plaques. When complete occlusion occurs, it usually appears to have started with the deposition of pink flow thrombus at the site of maximal stenosis caused by a complex or compound plaque at the carotid sinus. The ostium of the external carotid may be free of occluding thrombus. Beyond the flow thrombus of total occlusions, when of relatively recent deposition, is found glistening maroon-colored stasis clot extending various distances into the internal carotid artery. This eventually extends to the intracavernous portion and beyond. Even recently symptomatic though remotely occurring total occlusion of the internal carotid may be from a fibrous cord resulting from fibrous organization of stasis clot. This remains loosely adherent to otherwise normal intima of the distal internal carotid artery and may extend to the intracavernous portion (Fig. 49-10A; see also color plate).[23 – 26] In a recent study to determine the local factors in the arterial wall that precipitated thrombosis, Torvick et al.[27] examined histologically, specimens removed from 11 patients with clinical histories suggesting recent cerebral infarction in the territory of the middle cerebral artery. Severe atherosclerotic stenosis was found to be frequent but was not a prerequisite for thrombus formation. Half the patients had moderate (,60%)
narrowing of the lumen. Ulcerations in 3 patients, intraplaque hemorrhage in 1, and massive plaque rupture in 1 were thought to have played roles in thrombogenesis. Specimens from half the patients showed no such complications.[27] The above findings, in a Norwegian population, may be compared with those of an older study of Castaigne et al.[28] in a French population. In the latter, at postmortem, 60.6% of 61 internal carotid occlusions in 50 patients were ascribed to atherosclerotic thromboses and 21.3% to embolism. The variability between these two sets of findings may be related to the changing pattern of heart disease. The observation, however, that all atherosclerotic occlusions occurred in or near preexisting stenoses and, further, that 72.9% occurred in relation to tight stenoses (. 50%) might be due to methodological differences in the study protocols. But it could also have been due to rheologic differences in the blood of different populations related to diet, activity, or medication as it might affect blood coagulability. These rheologic differences have become subjects of great interest to a number of investigators[29 – 35] and may help explain, at least in part, some of the remarkable differences in the evolution of plaques and the varieties of clinical syndromes they produce.
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Figure 49-3. (A ) Fibrous carotid bifurcation plaque in situ at operation. The luminal surface is white and smooth. (B ) Fibrous nature of plaque shown microscopically, with marked thickening of the intima overlying normal media. (See also color plate.)
CAROTID PLAQUE PATHOLOGY— POSTMORTEM Postmortem examinations of asymptomatic persons as well as those suspected of having cerebrovascular disorders amplify the relationship between extracranial cervical occlusive arterial disease and strokes. Rodda and Path[36] found, in 20 necropsies with 15 stenosed and 17 thrombotic occluded internal carotid arteries, that there were 46 cerebral infarcts larger than 1 cm. Massive infarcts involving the territories of two major arteries were associated with distal internal carotid artery occlusions and ineffective cervical and circle of Willis anastomoses. Isolated infarcts of the middle cerebral artery’s territory were associated with internal carotid artery occlusions or stenosis and impairment of circle of Willis anastomoses.[36] Hutchinson and Yates[37] concluded, on the basis of postmortem studies, that fatal cerebral infarction was usually associated with combined carotid and vertebrobasilar arterial lesions, further emphasizing the role of the collateral circulation in the pathogenesis of ischemic strokes. Svindland and Torvick[38] performed histologic examinations of the carotid bifurcations retrieved at 53
consecutive autopsies in patients over age 65 who were neurologically asymptomatic and showed no carotid-related brain infarcts. They found that about half of their cases had stenoses of more than 50%. With increasing stenosis there was an increasing frequency of plaque compounding—due to plaque hemorrhage, ulcerations, and mural thrombi. When stenoses exceeded 60%, most had small recent and old plaque hemorrhages, while half had ulcerations and mural thrombi. Numerous healed ulcerations were also found; their pit-like defects are illustrated in Fig. 49-9D.
CAROTID PLAQUE PATHOLOGY— POPULATION SURVEYS Population surveys[39 – 43] of asymptomatic individuals above age 50, using noninvasive methods such as ultrasonic arteriography and spectral analysis, indicate an appreciable incidence of carotid bifurcation stenosis and even internal carotid occlusion, which varies somewhat with the incidence of risk factors (e.g., diabetes mellitus, hepertension, heart disease, smoking, and peripheral vascular disease) in the
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Figure 49-4. Foam cells in media and at junction of media and intima from portion of yellow-stained carotid plaque removed by carotid endarterectomy. Overlying thick intima is at a “noncritical” area of the plaque, where there are none of the changes associated with plaque “compounding” (i.e., intraplaque hemorrhage, “cholesterol abscess,” ulceration, or thrombosis). (See also color plate.)
populations surveyed. Generally about 10% or more of those studied were found to have detectable stenoses, half of which could be considered to be hemodynamically significant. Of additional interest is the fact that the dynamic nature of carotid plaques, deduced from observations made on surgical specimens,[23 – 26] appears to be confirmed by these studies, which indicate that both plaque progression and, seemingly, regression can be detected on long-term follow-up.
SYMPTOMATIC VERSUS ASYMPTOMATIC PLAQUES Mechanism of Cerebral Infarction The most feared complication of cerebrovascular arterial disease is stroke. Most of a voluminous literature relating to cerebrovascular insufficiency, however, relates to mechan-
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isms by which usually transient ischemic symptoms are produced and how they should be treated. By implication, these mechanisms are invoked to explain the occurrence of strokes.[44 – 46] There may, however, be additional factors which contribute to cerebral infarctions. As examples, Pessin et al.,[47] Lhermitte et al.,[48] and Gunning et al.[49] have each shown that internal carotid thrombosis secondary to carotid bifurcation atherosclerosis causes cerebral infarction. This may result from embolization of thrombus from the occluded artery, propagation of thrombus from the internal carotid to its branches (middle cerebral artery), or from territorial ischemia due to inadequate compensatory collateral circulation. Transcranial Doppler flow studies have documented this failure of collateral circulation in the presence of even mildly symptomatic internal carotid occlusions. [50] Positron emission tomography (PET) measures regional cerebral blood flow, cerebral metabolic rate of oxygen, and oxygen fraction. It therefore allows quantification of regional hemodynamics in patients with internal carotid occlusions who are clinically well compensated. That is, PET can reveal the hemodynamic vulnerability of the cerebral watershed areas after internal carotid artery occlusion in persons who nevertheless have good collateral circulation through the circle of Willis. These findings emphasize the importance of systemic hemodynamic factors—such as blood pressure and blood volume—as well as rheologic factors affecting blood viscosity in the precipitation of cerebral infarction. Total red cell mass and fibrinogen levels may be additional important elements in the genesis of cerebral ischemia in the presence of hemodynamically significant cerebrovascular occlusive lesions.[51 – 53] A number of studies indicate the role of embolism in the genesis of cerebral ischemia, starting with the observations of Chiari[54] and Hunt[55] and culminating with the more recent reports of Fisher,[56] Russel,[57] and Hollenhorst.[58] Their observations have had a profound influence on the medical and surgical treatment of strokes and impending strokes. The sometimes bright, doubly refractile bodies and at other times gray, relatively dull filling defects seen in retinal arteries have led to the concepts of atheroembolization and platelet fibrin embolization, respectively, as underlying the occurrence of transient visual as well as cerebral hemispheric symptoms. The significance of these symptoms was recognized even by Hippocrates, who wrote: “Unaccustomed attacks of numbness and anesthesia are signs of impending apoplexy.”[59] Less dramatic but nevertheless devastating effects are produced by minute emboli from carotid bifurcation atherosclerosis. These may cause a multi-infarct dementia simulating Alzheimer’s disease.[60 – 63] The finding of healed ulcers at the carotid sinus[23,38] in even asymptomatic patients attests to the insidious and subtle manner in which cerebral damage may occur from carotid bifurcation embolization. Numerous studies have compared carotid plaque characteristics in symptomatic and asymptomatic patients. However, these have failed to achieve unanimity as to the relative importance of various plaque characteristics in association with symptoms. A critical difference of opinion exists with regard to the significance of intraplaque hemorrhage in relation to symptoms. While Imparato
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Figure 49-5. (A ) Massive intraplaque hemorrhage at operation, at the usual location on the outer lateral wall of the carotid sinus, enclosed within a fibrous shell. (B ) Microscopic section through encysted intraplaque hemorrhage. (See also color plate.)
et al.,[23] Persson et al.,[24] Ammar et al.,[64] and Fisher et al.[65] conclude, on the basis of examination of surgical specimens of carotid plaques, that there is a correlation between intraplaque hemorrhages and symptoms, Bassiouny et al.[66] fail to find such a correlation and report that hemorrhage may be found in the absence of severe stenosis. It is perhaps this last part of their conclusion that is significant, for it is the finding of grossly visible hemorrhage which often results in significant stenosis that forms the basis for the correlation.[67] Fisher and Ojemann[68] have emphasized severe stenosis or occlusion in the occurrence of symptoms. Norris and Bornstein,[42] on the basis of follow-up duplex studies of carotid arteries, emphasize progressive stenosis over time as correlating with symptoms. Carr et al.[69] and Bassiouny et al.[70] emphasize plaque rupture as responsible for symptoms. It should be remembered, however, that the conversion of a fibrous plaque to one with hemorrhage indicates the potential for that plaque to develop additional pathologic changes— ulceration, hemodynamically significant stenosis, and thrombosis—which may lead to strokes. The study by Imparato et al.[23] refers to large, grossly visible hemorrhages which make up at least 50% of each plaque. These were found to correlate
with the occurrence of symptoms and susceptibility to devastating strokes. Ulcerations—as diagnosed by angiography, duplex scanning, or pathologic examination—implying that embolization has occurred correlate less clearly with symptoms.[67,71,72] The study of Moore et al.,[73] however, which implicates massive ulceration with the occurrence of stroke, is somewhat analogous to that of Imparato et al.,[23] in which gross hemorrhages are correlated with the symptoms, indicating that advanced pathologic changes at the bifurcation of the carotids are dangerous. Although focal transient ischemic symptoms such as short-lived strokes or amaurosis fugax may occur with minimal carotid lesions, they nevertheless serve as markers for impending strokes when associated with hemodynamically significant lesions of the carotid arteries. The marked stenoses are simply markers of advanced and complex pathologic changes in the carotid arteries. These can result in embolization of large portions of the plaque to intracranial vessels, as opposed to the microemboli which may cause transient symptoms. Marked stenosis can lead to early thrombosis of the artery. The relationship between stroke and advanced carotid pathology has been demon-
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Figure 49-6. Encysted gross intraplaque hemorrhage in situ, with areas of brown discoloration indicating breakdown of intraplaque hemorrhage. (See also color plate.)
strated, as well, in asymptomatic patients. The study of Roederer et al.,[43] in which carotid bifurcation plaques were followed over time by duplex scans, achieved a high statistical correlation with symptoms—transient ischemic attacks (TIAs), strokes, or vessel occlusions—when the degree of stenosis progressed to more than 80%. Norris and Bornstein’s[42] association of plaque progression with stroke, as will be evident when plaque evolution is discussed, introduced a similar concept. Amaurosis fugax and transient focal ischemic cerebral episodes may also be the result of acute carotid thrombosis. These symptoms may occur either through embolization or through regional hemodynamic insufficiency and may even result from chronic long-standing carotid occlusion.
EVOLUTION OF CAROTID PLAQUES A striking feature of atherosclerotic lesions, not only in humans[74] but in animals as well,[75] is their stereotyped, patchy distribution in different parts of the arterial tree, albeit with wide differences in their degrees of develop-
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ment. The geometry of individual arteries as it affects local hemodynamics appears to determine the occurrence of the initial pathologic lesion, whose progression, however, may be intermittent and episodic, influenced by as yet poorly understood factors.[24,76 – 84] Of critical importance and quite controversial is the question of whether the complex, compound atherosclerotic plaque develops from fatty streaks or from intimal fibrous plaques. Both are found as early as neonatal life in close proximity to each other, so that some have concluded that fatty streaks evolve to complex plaques.[85 – 87] There are subtle differences in their distributions, however, such that flow characteristics at the sites of predilection of each may be quite different in this regard. Schwartz and Mitchell[74] describe the distribution of flat sudanophilic lesions found at postmortem examination in the aorta and carotid arteries, comparing this to the distribution of raised white fibrous plaques. They find significant differences between them, including the fact that the ostia of the intercostal arteries are spared by fatty streaks but are nearly always involved by raised, fibrous, non–fat-containing plaques. The predilection for fibrous plaques to occur in the abdominal aorta rather than the thoracic segment correlates with the finding of advanced complex atherosclerotic lesions later in life in the abdominal aorta. Similarly, their studies and the studies of Grottum et al.,[86] of the sudanophilic staining of the carotid bifurcation, reveal fatty streaks to be distributed slightly at variance with the stereotyped finding of advanced atherosclerotic plaques on the outer wall of the carotid sinus. These observations point to the conclusion that fatty streaks occur at sites of high shear, while fibrous intimal plaques which progress to complex atherosclerosis occur at sites of flow separation and stagnation—flow conditions which are suspected to occur in vivo from study of flow in glass models of the carotid bifurcations.[76 – 78] Our observations of carotid plaques surgically removed from symptomatic as well as asymptomatic patients would favor the view that the carotid bifurcation plaque begins as fibromuscular intimal thickening, most pronounced on the outer wall of the carotid sinus and totally free of foam cells. In reaction to specific hemodynamic factors,[88] similar to those which can be produced in experimental animals whose blood vessel geometry is altered to generate specific abnormalities of flow,[89 – 91] fibrous proliferation may continue until the lumen at the carotid sinus is reduced to a pinhole. Thereupon thrombosis may occur, still free of foam cells, hemorrhage, or “encysted” atheromatous debris. How fibrous plaque becomes complex is variously described as resulting from atheromatous degeneration of fibrous fatty plaques and subsequent hemorrhage or fissuring of the surface overlying the “cholesterol abscess,” with dissection of blood into the plaque.[92] Our observations led to a quite different conclusion and are based upon finding hemorrhages of different ages completely enclosed in fibrous stroma without encysted lipid or fatty streaks. It has been suggested and seems quite likely that intraplaque hemorrhage results from rupture of the dilated vascular spaces[93] often found in association with hemorrhages and at other times in simple fibrous plaques,[94] similar to what has been postulated as
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Figure 49-7. (A ) Encysted collection of atheromatous debris, the “cholesterol abscess,” having the same location and configuration as large intraplaque hemorrhage. (B ) Transition of intraplaque hemorrhage to cholesterol abscess, showing elements of both (in situ at operation). (See also color plate.)
occurring in coronary arteries.[95,96] Subsequently, hemorrhages are associated with increasing numbers of cholesterol clefts in amorphous debris surrounded by hemorrhages of different ages, culminating in the “pure cholesterol abscess,” which may have no residual signs of hemorrhage except hemosiderin-laden macrophages. The shapes and locations of the large hemorrhages and of encysted atheromatous debris coincide completely and are usually found on the outer wall of the sinus. These developments can result in marked luminal stenosis, flow impairment, rupture with ulceration, and thrombosis of the internal carotid artery.[94,97,98] It seems unlikely, then, that hemorrhage occurs into “cholesterol abscesses”; instead, cholesterol abscesses probably result from intrafibrous plaque hemorrhages. Furthermore, if dissection of blood through minute fissures were occurring, one would not expect to find the massive localized collections of hematoma material wherein all the elements of the blood are evenly dispersed. This differs markedly from the platelet-fibrin flow thrombus found in the bases of some deep ulcers, characteristic of thrombus which forms when blood is in motion.
Grossly visible and recent ulcerations of plaque almost always occur over encysted hemorrhages or cholesterol abscesses. Intermediate stages to ulceration are marked thinning of the fibrous cap overlying these collections of blood or lipid. Fissures, cavities obviously evacuated of blood or of atheromatous debris, and, rarely, the thinned-out remains of fibrous caps may still be visible, resembling the collapsed walls of a roofless chamber. The process leading to this massive ulceration has been likened to a volcanic eruption. The encysted hemorrhagic or atheromatous debris literally explodes from its confinement. Embolization, therefore, is of portions of the arterial wall, after marked stenosis has resulted from the accumulation of intraplaque hematomas or of cholesterol abscesses.[39,92] Such embolization may be massive, resulting in debulking of plaque. This may explain some instances of “plaque regression” detected on repeated duplex scanning of highly stenotic plaques which suddenly become less so.[39,42] Ulcers may attract platelet fibrin thrombi and be the source of platelet microemboli, or they may heal completely, becoming resurfaced with flattened cells. Indeed, the finding of multiple smooth pits at the carotid sinus suggests that
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Figure 49-8. (A ) Transition of intraplaque hemorrhage to cholesterol abscess showing recent hemorrhage and amorphous debris, a stage beyond that shown in Fig. 49-5B. (B ) Cholesterol abscess—microscopic, totally “encysted” within an overlying fibrous cap, surrounded by degenerating hemorrhage. (See also color plate.)
ulceration may be a recurring phenomenon. Conversely, it is conceivable that, following massive ulceration and debulking, highly stenotic plaques may fail to re-form, because of changes in either hemodynamics (change in vessel geometry, medication for cardiovascular disorders), blood rheology, or metabolism. The thrombosed internal carotid artery is usually found in association with marked stenosis, ulceration, or otherwise complex plaques containing hemorrhage or atheromatous debris. Thrombosis begins with platelet fibrin flow thrombus accumulation until flow stasis occurs in the distal carotid artery, whereupon stasis clots form. Eventually, over varying periods of time, sometimes longer than a month, these clots propagate to the carotid siphon origin of the ophthalmic artery and even beyond to the middle cerebral artery. Fibrous organization of such clots eventually occurs. Retrograde propagation of thrombus to the external and common carotids from carotid sinus plaques occurs infrequently and appears to reflect the fact that “compounding” of the plaque at the origin of the external carotid does not usually occur. Therefore runoff for the common carotid flow into the external carotid persists even after internal carotid thrombosis occurs.
POST – CAROTID ENDARTERECTOMY RECURRENT STENOSIS Arterial revascularization procedures are subject to both early and late failures.[99 – 103] Those which occur within hours or days are usually ascribed to operative technical factors,[104,105] which lead to thromboses and occur in both endarterectomy and arterial substitutions, whether with autologous tissue or with artificial prostheses. After the second or third postoperative week, exuberant proliferative intimal or neointimal lesions occur, which then assume dominant roles in causing failures. As applies to post –carotid endarterectomy recurrent proliferative lesions, there is remarkable resemblance to the lesions that first led to operation. During the first year or two postendarterectomy, recurrent stenotic lesions are entirely fibrotic on microscopic examination while grossly presenting smooth, usually white and glistening surfaces (Fig. 49-11; see also color plate). Their distribution varies from focal, at sites of taper in the internal carotid at the distal ends of arteriotomy closures, whether primarily sutured or closed with autologous vein patches, to generalized, and involve the entire endarterectomy
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Figure 49-10. (A ) Recent total occlusion of an internal carotid artery showing pink flow thrombus at the carotid sinus and maroon stasis clot distally (endarterectomy specimen). (See also color plate.) (B ) Organized thrombus in intimal carotid artery with carotid siphon plaque removed by thrombectomy (surgical specimen).
sites. They may be localized to the common carotid arteries at sites of transection of often thick intima, which results in a pronounced ledge which causes hemodynamic abnormality leading to neointimal proliferation. These fibrotic lesions can be reproduced experimentally in animals,[106,107] in arterial models which mimic the sites of spontaneously occurring atherosclerosis as well as sites where postoperative exuberant proliferation occurs (Fig. 49-12; see also color plate). The experimental lesions are thought to occur at sites of disordered flow and result primarily from migration of smooth muscle cells from the media to lumenal locations and their subsequent proliferation, termed myointimal hyperplasia. These, too, bear a remarkable resemblance to the early fibrotic, stenotic carotid bifurcation atherosclerotic plaques. On occasion also mimicking the original carotid pathology, a
recurrent lesion at the carotid bifurcation will contain intrafibrous plaque hematoma (Fig. 49-13; see also color plate). Late lesions, as much as 25 years post – carotid endarterecromy, resemble the complex spontaneously occurring atherosclerotic plaques, usually involve the endarterectomy sites in their entirety, and exhibit the hallmark findings of the original lesions with stenoses, intraplaque hemorrhages, ulcerations, and thromboses (Fig. 49-14A and B; see also color plate.) Laminated thrombus resembling that found in aneurysms and distributed along the entire endarterectomy site may cause marked stenosis leading to reoperation. It occurs usually associated with patch closures of arteriotomies in which the patches are too large, resulting in marked dilatation of the vessels.
Figure 49-9. Examples of evolution of ulceration of carotid plaques. (A ) Partially evacuated intraplaque hemorrhage showing the thin fibrous film overlying encysted hemorrhage remaining after its eruption through the overlying fibrous cap. (B ) Ulcerated area overlying cholesterol abscess and thrombus in base of ulcer (microscopic). (C ) Excised plaque with deep ulcer crater, partially healed. (D ) Multiple pits in excised carotid plaque resulting from previous ulcerations and subsequent healing. (See also color plate.)
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Figure 49-11. Myointimal hyperplastic lesion recovered from a 62-year-old old woman 1 year post – carotid endarterectomy with autologous saphenous vein patch arteriotomy closure. She developed marked carotid stenosis at the endarterectomy site and amaurosis fugax, for which reendarterectomy was done. (See also color plate.)
Figure 49-12. (A ) Anastamotic myointimal hyperplasia in a model of carotid interposition between the aorta and inferior vena cava at 3 weeks (canine). (B ) Myointimal hyperplasia in the canine carotid artery 2 mm below an occluding ligature 3 weeks postoperatively. (See also color plate.)
The findings of recurrent carotid stenosis indicate the need for close postoperative follow-up for the remainder of the patients’ lives. They also suggest that the criteria for operability for primary lesions might be applicable to recurrent lesions.
SUMMARY The problem of evaluating different therapeutic modalities for the treatment of ischemic stroke syndromes is complicated by the fact that there is great variability in the pathologic findings at the most commonly involved
sites in the arterial system—the carotid bifurcations. The variability with which the pathologic process may progress is dependent upon as yet poorly understood factors related to blood rheology and other risk factors. [108] The variability with which end-organ ischemia develops may additionally be related to collateral circulation. Marked flow-impeding stenoses of the carotid bifurcations, denoting advanced pathologic changes related to intramural hemorrhages and encysted atheromatous debris,[43,109,110] are the hallmarks of plaques that may eventually and unexpectedly cause ischemic strokes or death. These may occur either through embolism of large
Chapter 49. Carotid Pathology
723
Figure 49-13. (A ) Intrafibrous plaque hematoma at carotid endarterectomy site 7 years postoperatively. (B ) Same lesion with removal of the fibrous cap covering the hematoma. (See also color plate).
segments of plaque or by producing sufficient stenosis or luminal ulceration to precipitate thrombotic occlusion of the internal carotid arteries. Even asymptomatic occlusion of the internal carotid artery must be considered a potential stroke-producing lesion, as demonstrated by PET of the brain. The hallmarks of “dangerous” carotid plaques which may lead to frank strokes are flow-impeding stenosis and complexity resulting from intraplaque hemorrhage,
encysted atheromatous debris, ulceration, and/or thrombus. Whether hemodynamics, blood rheology, and collateral circulation will eventually be factored into the evaluation of the potential of individual carotid plaques for stroke is uncertain. Sophisticated studies of brain physiology, such as PET and magnetic resonance imaging to detect early signs of cerebral ischemia, will undoubtedly be utilized in the evaluation of otherwise asymptomatic plaques.
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Figure 49-14. (A ) Symptomatic recurrent carotid stenosis 12 years post – carotid endarterectomy and autologous saphenous vein patch showing typical ulcerated atherosclerotic plaque superimposed on healed endarterectomy site appearing as proximal and distal glistening white, smooth surfaces (in situ). (B ) Same plaque excised. (See also color plate.)
Since highly stenotic plaques were once less so, it will be necessary to identify those early plaques that will progress to significant stenosis before they do so. Then, perhaps,
corrective measures can be applied before the risk for stroke becomes significant. Such prophylaxis is necessary since not all strokes are heralded by premonitory transient symptoms.
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CHAPTER 50
Management of Ulcerative Lesions of the Carotid Artery: Symptomatic and Asymptomatic Hugh A. Gelabert Wesley S. Moore
development, and secondary embolization. The embolic theory of cerebrovascular ischemia is reviewed and placed in the context of carotid ulceration. The clinical presentations as well as data regarding the natural history of these lesions are presented in order to formulate a cogent approach to the patient with a carotid ulcer.
INTRODUCTION The reports of both the ACAS and NASCET trials have resulted in reaffirmation of principles of carotid surgery long held by vascular surgeons: that high-grade carotid stenosis and symptomatic lesions present a risk of stroke and that this risk may be reduced by carotid endarterectomy. The embolic theory of stroke—that emboli originating from carotid lesions result in clinical symptoms of transient ischemic attack, amaurosis, and stroke-has been reinforced by these trials. Furthermore, the recognition that the development of a carotid ulcer represents the footprint of repeated emboli has lent support to endarterectomy for carotid ulcerations. The current discussion regarding carotid ulceration revolves not about whether these lesions should be repaired, but when they should be repaired. Ulcerative lesions of the carotid artery represent the result of disruption and fragmentation of an atherosclerotic plaque. The plaque fragments which are lost when the ulcer forms become emboli. These emboli may be silent, or they may present with symptoms. In either event, the presence of an ulcerated lesion of the carotid artery signifies that two events have occurred: first, that the plaque has progressed to the stage of becoming a complex lesion with plaque degeneration, fragmentation, and disruption, and, second, that a patient with an ulcerative lesion is suffering carotid arterial embolic disease. At the center of the debate regarding the management of carotid ulcers is our understanding of the natural history of the ulcerated carotid lesion. This reflects three issues: what happens to a degenerating plaque over a period of time, how significant is the thromboembolic risk of the denuded arterial wall, and what is the risk of further degeneration. The primary risk of the carotid ulcer is recurrent embolization. This chapter will focus on the management of carotid ulcers by reviewing the process of plaque growth, ulcer
HISTORICAL DEVELOPMENT The development of the embolic theory of cerebrovascular disease spans over a century of medical progress. The theoretical basis of these emboli was first postulated in 1861 by Panum.[1] He described atherosclerotic plaque degeneration and proposed that the degenerating plaque was capable of downstream embolization. In 1905, Chiari[2] further advanced the theory of cerebrovascular embolic disease by specifically suggesting that atherosclerotic plaques of the carotid arteries might produce emboli. These theories were not to be demonstrated clinically until the late 1940s. First, Florey[3] reported in 1945 on a series of autopsies in which emboli were removed from arterial beds downstream from degenerating atheromatous plaque. These observations confirmed the general contention that degenerating plaque was able to produce downstream emboli. Proof that carotid plaques produced cerebrovascular symptoms required more time. The initial clinical observations along these lines were made by Handler,[4] who, in 1947, described the concomitant occurrence of encephalomalacia and atheroemboli to other organs. In 1961, Russell[5] described two patients with transient monocular blindness and suggested that these symptoms were caused by retinal emboli. In the same year, Hollenhorst[6] described “bright plaques” in retinal vessels and suggested that these represented emboli from atheromatous plaques.
Hobson/Wilson/Veith: Vascular Surgery: Principles and Practice, Third Edition, Revised and Expanded DOI: 10.1081/0819-9-120024933 Copyright q 2004 by Marcel Dekker, Inc.
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The initial surgical correlation of the presence of plaque ulceration on operative specimens and neurologic symptoms was made by Julian et al.[7] in 1963, with the suggestion that the patient’s symptoms might be related to embolization from the ulcerative lesions. Gunning and his associates[8] noted a high incidence of mural thrombus in symptomatic patients with cerebrovascular disease. This led them to propose that many instances of cerebrovascular symptoms could be attributed to emboli from the carotid bifurcation. In 1966, Ehrenfeld and associates[9] reported a series of patients whose transient monocular blindness was relieved by carotid endarterectomy of stenotic ulcerative lesions. While these observations appeared to support the concept of carotid emboli, the investigators could offer no definitive proof. The accepted explanation of cerebrovascular symptoms at the time rested on the hemodynamic theory. Accordingly, patients undergoing endarterectomy for symptomatic disease were selected on the basis of having carotid artery stenosis. Thus, all patients with ulceration in their carotid arteries also had what were considered to be significant stenoses, and the two theories could not be clearly separated. The first report which separated embolic and hemodynamic causes of transient ischemic attacks was presented in 1968 by Moore and Hall.[10] They reported a series of patients suffering transient monocular blindness or cerebral transient ischemic attacks (TIAs) in whom angiography revealed both the absence of a hemodynamically significant lesion and the presence of ulcerative lesions. These patients’ symptoms were dramatically stopped by carotid endarterectomy to remove the ulcerative lesions. This observation led to a dramatic proposal: that, in the absence of hemodynamically significant lesions, these patients’ symptoms were the result of carotid emboli.[11]
DEFINITIONS The definition of a carotid ulcer is an apparently simple task. It is complicated by limitations in our ability to identify ulcers and by our limited understanding of the physiology of ulceration.[12] If ulceration were to be defined on the basis of diagnostic modalities, an angiographic and sonographic definition could be formulated. Angiography has been the primary means of identifying ulceration preoperatively. Accordingly, ulcers have been described as excavations in the arterial wall as seen on profile view.[13] Ultrasonography has recently been applied to the identification of carotid ulcers, and, while the characteristics of an ulcer in these studies have not been clearly defined, several features have been described. Principal among these are irregularities of the arterial lumen and excavation of the plaque as seen on B-mode imaging. The pathologic definition of a carotid ulcer presents a different series of problems. There is some disagreement as to the minimal size of intimal disruption which would qualify as an ulceration. If the specimens are subjected to microscopic observation, the definition of ulceration becomes a histologic question and is defined according to the presence or absence of endothelium and basement membrane and loss of plaque substance.[14]
If the definition of ulceration is approached from a pathophysiologic perspective, it becomes evident that a carotid ulcer must contain several elements. It is, at the least, a defect of the arterial wall consisting of the loss of endothelial surface and excavation of the sclerotic arterial wall. This presumes the presence of atherosclerotic plaque within the arterial wall as well as disruption of the plaque and its overlying endothelium. The disruption may be caused by intraplaque hemorrhage or by plaque infarction and degeneration.
PATHOPHYSIOLOGY The pathophysiology of carotid ulceration is the consequence of the natural growth and degeneration of atherosclerotic plaques. The normal pattern of plaque development is that of growth by increase in the number of foam cells and deposition of matrix. The composition of the matrix material appears to vary between plaques, some being soft and friable and others firm and brittle. The determinants of these differences in plaque consistency are not clearly understood. In part they reflect the rate of deposition of lipid metabolites, fibrous strands, and calcium salts. These differences in the composition of plaque play an important role in determining the course of the plaque growth and its subsequent embolic potential. The limits of a plaque’s growth are defined by its nutrient supply. Thus, when an artery is occluded, the plaque will not continue to grow. Some plaques are similarly affected by the loss of the adventitial blood vessels. Thus, when the nutrient supply is outstripped by the plaque’s growth, the plaque becomes ischemic. At a further point, the plaque may begin to degenerate. Plaque degeneration follows two principal paths. First, the plaque may hemorrhage and expand. This leads to a rapid increase in the plaque’s size and is frequently accompanied by the development of symptoms referable to the plaque. As the expanding plaque stretches the overlying endothelium, it may rupture into the arterial lumen, releasing emboli and forming an ulcer.[15] The second degenerative path followed by some plaques is that of infarction and erosion. A portion of the plaque may outgrow its blood supply and infarct. Instead of developing an intraplaque hemorrhage, it may simply degenerate, losing its cellular elements. The endothelial layer above the plaque may simultaneously undergo degenerative changes, possibly as a consequence of the plaque infarction. This combination of events leaves the infarcted plaque exposed to the bloodstream, and erosive forces then hollow out the infarcted plaque remnants, creating an ulcer. The ulcerated plaque represents a thrombotic surface. By virtue of the loss of the endothelial surface, the ulcerated plaque provides a nidus for platelet aggregation and thrombus formation. Loss of the endothelium means loss of the endothelial antithrombotic properties. Exposure of the basement membrane and collagenous components of the arterial wall and plaque allows initiation of the coagulation cascade as well as the platelet aggregation and release reactions. Finally, the ulcer crater itself forms an eddy in
Chapter 50. Management of Ulcerative Lesions of the Carotid Artery: Symptomatic and Asymptomatic
the bloodstream, which may promote the accumulation of platelets and thrombus. The accumulated platelet and fibrin meshwork may grow until portions of the mass extend into the bloodstream and are broken off by the flowing blood. These fragments become emboli and may be responsible for the spectrum of cerebrovascular symptoms associated with embolic phenomena. Further emboli may arise from continued erosion of loose fragments of plaque. As these are washed into the current of blood, they become plaque emboli. When one of these cholesterol crystals becomes lodged in the retinal arterioles, it may be recognized as a Hollenhorst plaque. The initial disruption of the plaque with disgorgement of its contents into the arterial lumen is referred to as the primary embolic event. It is the consequence of plaque degeneration and may be characterized by the composition of the embolic material. The material discharged from the primary ulcer is principally made up of calcium salts, plaque matrix, and cholesterol crystals. The primary embolic event is differentiated from secondary events, which occur at a later time and are the consequence of both plaque degeneration and the thrombotic properties of the exposed plaque surface. Accordingly, the embolic material generated by the secondary plaque is composed of degenerating plaque, fragments of thrombus, and platelet aggregates. The significance of a plaque ulcer is twofold. First, by virtue of its presence, it is an indication that a primary embolic event has occurred. While the affected patient may not recall having experienced embolic symptoms, the presence of an ulcer signifies that an embolic event has occurred. The second point signaled by the presence of an ulcer regards the composition of the plaque in which the ulcer occurred. The ulcer indicates that the composition of the host plaque makes it susceptible to further erosion and the creation of more emboli. The pathophysiologic consequence of a plaque ulcer includes the formation of arterial emboli in the cerebral circulation. These emboli may be of varied composition and may affect any territory supplied by the carotid circulation. The symptoms created by the emboli may be transient or permanent. The duration of the symptoms and the consequent neurologic sequellae are related in part to the nature of the embolic material. The various types of emboli differ widely with regard to their biologic fate. Heavily calcified fragments of plaque are virtually insoluble and will remain within the vessel lumen almost indefinitely. Similarly, cholesterol emboli may persist for long periods. Platelet aggregates are quite variable with regard to their solubility. While some are very friable and ephemeral, others are tenacious and may be persistent enough to produce an infarction. In a similar manner, fibrin and platelet thrombi may either dissolve quickly or persist and cause a stroke. The nature of the symptoms produced by the emboli will be determined mainly by the vessel into which the embolus flows and the area of the brain supplied by this vessel. Emboli which do not appear to produce symptoms may have occluded very small arterioles—or arterioles which had adequate collateral supply—and thus did not result in significant cerebral ischemia. Alternatively, an embolus may have occluded the vessel leading to a silent portion of the cerebrum and thus have had no apparent symptomatic impact. Finally,
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an embolus which fragments upon lodging within a vessel may not have had sufficient time to generate a significant ischemic event. The balance between the distribution of the emboli, the solubility of the embolic material, the area of the brain affected by the embolus, and the collateralization of the affected area of brain will determine the type and duration of embolic symptoms. The fate of the ulcerative lesions remains unclear. While some will be resurfaced by endothelial regrowth, others will remain open and will gradually expand. The factors regulating these two paths are still not clearly understood.
PRESENTATION As with most lesions of the carotid system, carotid ulcers may present with cerebrovascular symptoms, or they may remain asymptomatic. The symptomatic presentations will span the entire spectrum of neurologic manifestations. The afflicted patient may suffer from hemispheric TIA, amaurosis, or stroke. The neurologic lesion will be in the distribution of the affected carotid artery. Accordingly, ulcers will not account for posterior fossa symptoms or symptoms referable to the contralateral hemisphere except in circumstances where the cerebral circulatory pattern has been dramatically altered. Asymptomatic carotid ulcers are almost always discovered in the course of investigating another lesion. Most commonly, these ulcers are found in the contralateral carotid during investigation of a symptomatic plaque or a high-grade asymptomatic stenosis. As noted in the discussion of the pathophysiology of these ulcers, the presence of an ulcer denotes the fact that a primary embolic event has occurred. In keeping with this principle, it is possible that some patients may display signs of embolic disease yet be unaware of any related symptoms. Close attention to the physical examination is of great importance in this regard, since it may confirm the presence of deficits unknown to the patient.
CLASSIFICATION In addition to the presence or absence of symptoms, it is important to classify carotid ulcers according to specific anatomic features. Most important of these is the presence or absence of an associated hemodynamically significant stenosis. When an ulcer is associated with a large plaque, it may be difficult to differentiate between symptoms related to the stenosis and those related to the ulcer. Ulcers which are not associated with large plaques are termed low-profile ulcers. These lesions may also be either symptomatic or asymptomatic. In the absence of other lesions, symptomatic presentations may be attributed to the ulcer. By combining symptomatology and anatomic features, it is possible to generate four subclassifications of carotid ulcers: symptomatic, asymptomatic, low-profile, and stenosis-related. Of these four groups, asymptomatic low-profile ulcers would be expected to present the least risk. By studying
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this low-risk group, a lower limit of risk may be defined for carotid ulcers in general.
Table 50-1. Stroke Rate (Percent) by Symptom and Lesion First year
NATURAL HISTORY Carotid ulcers were long thought to be innocuous lesions. Indeed, there is evidence to suggest that some of these lesions may be of minimal significance. There is, however, also considerable evidence suggesting that some carotid ulcers may be very dangerous. The natural history of the low-profile asymptomatic lesion has been the subject of several studies which have sought to settle this question of risk. Moore and colleagues[16] have reported a group of 141 patients with low-profile asymptomatic ulcers followed for 10 years. They were stratified according to the size of their ulcers and the outcomes were reported in a life-table analysis. In their most recent report, these investigators noted a variation in the stroke rate of the patients with ulcers of different sizes. Patients with the smallest ulcers (A ulcers) had the lowest annual stroke rate: 0.9%. Patients with the intermediate-sized ulcers (B ulcers) had an annual stroke rate of 4.5%. Finally, those patients with the largest and most complex ulcers (C ulcers) had an annual stroke rate of 7.5% (Table 50-1). The authors conclude that the presence of the large ulcers represents a marker of significant risk of stroke. Unfortunately, their study is unable to clearly reveal the exact cause of the strokes in their patients. The subsequent strokes could have been the result of further growth of the plaque, the development of other ulcers, or the further growth of the index ulcer.
ANGIOGRAPHY Angiography plays a central role in the diagnosis and management of carotid ulcers. It is the only reliable means of preoperative diagnosis of these ulcers and has also provided the information by which ulcers may be classified into the three groups mentioned above and shown in Fig. 50-1.[17] This, in turn, provides an indication of the patient’s risk of cerebrovascular events. Accordingly, angiography allows not only the diagnosis but also the staging of carotid ulcers. The studies which have provided information regarding the natural history of carotid ulcers relied upon unmagnified biplanar arteriography to detect and classify the ulcers. The basis of this classification is the measure of the ulcer’s size. Using these unmagnified arteriograms, the maximal depth and length of the ulcer is measured in millimeters. These dimensions are then multiplied to provide the “ulcer area” in square millimeters. Ulcers whose product is 10 or less are called type A ulcers. Those whose product is between 10 and 40 are classified as type B ulcers. Those whose product is greater than 40 are type C ulcers.[16] Certain technical details of angiography are important in determining the yield of the study. Single-view radiographs may allow the ulcer to be hidden by the overlying,
Stenosis, no ulcer Asymptomatic TIA Stroke Ulcers, no stenosis A B C Postoperative
Annual
5 10 9 0.9 4.5 7.5 3
5-Year
5 6 9
25 34 45
0.9 4.5 7.5 1
4.5 22.5 37.5 7
Source: Adapted from Moore, W. S., et al.[16,19]
intraarterial contrast. It is therefore necessary to obtain biplanar views to ensure that the ulcer is seen in maximum profile. This will also affect the classification of the ulcer. If it is not in maximum profile, it may be underestimated. The angiographic method is of greatest importance with regard to the diagnosis and classification of carotid ulcers. Newer techniques, such as digital studies, have been promoted with the promise of increased case of use, safety, and accuracy. The use of digital arterial and venous studies has affected our ability to evaluate ulcers in an unexpected manner. While it may be argued that the sensitivity of the digital technique is similar to that of conventional arteriography, the ability to enhance the images may generate some misleading artifacts. Further, the ability to derive significant measures of the ulcer size is impaired with the digital techniques. The size of the angiographic film is also important in the classification and comparison of ulcers. Since all the data regarding the natural history of carotid ulcers have been generated on the basis of unmagnified arteriographic images, these remain the basis for comparison and classification. Arteriograms which make use of magnification and reduction will impair the ability to classify the ulcers, since this will distort estimates of the size of the ulcer. No data exist which compare the fate of ulcers diagnosed by digital angiography to those detected by conventional techniques. Furthermore, no large series have been compiled using the digital techniques alone. Accordingly, if one were presented with an ulcer diagnosed by digital angiography, it would be impossible to formulate more than a guess as to the correct management of the lesion. Magnetic resonance angiography (MRA) has gained increasing popularity for cerebrovascular studies. These images are similar in appearance to those obtained by conventional angiography. The advantage of these angiograms resides in the noninvasive nature of the studies (no puncture is required, stroke risk is lower). Additionally, the images may be digitally manipulated and expressed in three dimensions as well as multiple projections. This ability would theoretically facilitate the identification of ulcerative lesions. Technical limitations may constrain the success of such efforts since the presence of turbulent blood flow may generate signal variations resulting in erroneous images. Thus the current reliability of this technique remains below that of
Chapter 50. Management of Ulcerative Lesions of the Carotid Artery: Symptomatic and Asymptomatic
conventional angiography. Given the rapid pace of novel developments of MRA, reliable studies correlating ulcer characteristics with stroke potential or clinical outcomes are not yet been available.
NONINVASIVE TESTING Several noninvasive tests have been used in an attempt to diagnose carotid ulcers. Radiolabeled platelets have been used in the hope that they would adhere to the ulcerated surface of the artery and be detectable on nuclear scan. While some adherence did occur, the test was unable to clearly distinguish the areas of ulceration from the background arterial wall activity. Duplex scanning has also been applied to the detection of carotid ulcers. Early results have been disappointing: the Bmode images have lacked sufficient resolution to allow the identification and measurement of ulcers. Most recently, Comerota and associates[18] have been able to report improved results. According to their report, the diagnostic sensitivity of B-mode scanning and angiography are statistically equal. While this is a promising report, it does not represent the bulk of current experience. In most instances, the ability of angiography to detect carotid ulcers is far greater than that of duplex scanners. A further limitation to duplex scanners is their inability to measure the size of ulcers. Since there are no data correlating the results of duplex scanning with those of angiography, it is not possible to formally classify carotid ulcers on the basis of ultrasonography. A duplex scan alone is insufficient evaluation prior to surgery for carotid ulceration. If an ulcer is detected by sonographic technique, it is necessary to obtain an arteriogram to confirm and classify the ulcerated lesion. It is important to recognize that ulcers may be found in association with arterial stenoses or may be related to lowprofile nonstenotic plaques. Patients who present with embolic symptoms in the absence of a hemodynamically significant stenosis require conventional arteriography in order to exclude nonstenotic ulcerations.
MEDICAL MANAGEMENT The medical management of carotid ulceration is directed primarily toward the use of antiplatelet and anticoagulant drugs in an effort to prevent secondary embolic phenomena. The theoretical grounds for these interventions lie in the assumption that these medications may prevent the aggregation of platelets or the deposition of fibrin on the ulcerated arterial surface. This is the same rationale as that behind the studies in which patients suffering transient ischemic attacks were treated with aspirin or persantine in an attempt to control their symptoms and reduce their stroke rate. No specific study has been designed to treat carotid ulcers with aspirin, persantine, coumadin, or any of their analogues. Accordingly, all information regarding the use of these agents
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in this setting is derived by extrapolation from the TIA trials. From these, we know that the use of aspirin will reduce the number of TIAs and may also reduce the number of strokes that patients will suffer. None of the major studies have compared the results of antiplatelet treatment with surgical intervention; therefore, the comparative benefit must be established by historical methods. Warfarin has been used in symptomatic patients in an attempt to control ischemic symptoms and to reduce the stroke rate. In randomized studies, it reduced the incidence of TIAs but had no effect on the stroke rate. Finally, it resulted in increased overall mortality. Again, these data proceed from studies of symptomatic patients with carotid stenoses and may not be directly applicable to patients with asymptomatic nonstenotic ulcers. The efficacy of both antiplatelet and the anticoagulant medication would appear limited to the prevention of platelet or fibrin emboli. These medications would not be expected to protect against plaque emboli, which occur as a consequence of plaque degeneration. Ironically, some authors have suggested that the use of these medications may accelerate the degenerative process, specifically by facilitating intraplaque hemorrhage. Until these suspicions are confirmed, however, antiplatelet therapy remains the cornerstone of the nonoperative management of carotid ulcers.
SURGICAL MANAGEMENT The role of surgery in the management of carotid ulcers should be based on a clear appreciation of the natural history of these lesions. Symptomatic patients generally should be treated surgically. When the larger, type C ulcers are symptomatic, the patient should undergo carotid endarterectomy. Low-profile type A or B ulcers are treated initially with aspirin. If breakthrough symptoms appear during aspirin therapy, such patients are considered for surgery. The management of asymptomatic patient is somewhat different from that of patients with symptoms. From the data presented by several groups, it would appear that the smallest of the carotid ulcers, the type A lesions, pose minimal risk and may be safely managed without surgery. At the other end of the spectrum, the very large carotid ulcers would appear to present a considerable risk. Most authors would agree that these patients should undergo endarterectomy. The intermediate lesions are the most controversial, since they generally have a moderate course and by some estimates may not be as dangerous as the larger lesions. In their study, Moore and associates[16] identified a stroke rate of 4.5% per year in these cases. This rate represents a significant risk and would indicate carotid endarterectomy if the operation can be performed with a low morbidity and mortality. While critics hold that this study may have overestimated the risk of these lesions, their point is yet to be clearly demonstrated. As in all surgery, the combined operative morbidity and the expected surgical result must clearly exceed the risk represented by the natural course of the disease being treated.
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Chapter 50. Management of Ulcerative Lesions of the Carotid Artery: Symptomatic and Asymptomatic
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Figure 50-1. (A, B, and C) Types A, B, and C ulcers, respectively. (D) Schematic illustration of ulcer measurement. (From Dixon, S.; Pais, S. O. and Raviola, C., et al: Natural history of non-stenotic asymptomatic ulcerative lesions of the carotid artery: A further analysis. Arch. Surg. 1982, 117, 1993. Copyright 1982, American Medical Association. Used with permission.)
In terms of carotid endarterectomy performed for stenotic lesions, this requires that the perioperative stroke and death rates should be less than 5% for symptomatic patients and less than 3% for asymptomatic patients. While the exact risk limits of endarterectomy for ulcerative lesions have not been defined, it would be safe to assume that these limits would be similar to those mentioned above. The technical aspects of carotid endarterectomy performed for ulcerative lesions are not dissimiliar from those associated with surgery for stenotic lesions. Emphasis is placed on careful disection, with an intent to minimize the risk of emboli. The endarterectomy itself may be slightly more difficult in a nonstenotic lesion, since the thinner plaque may not offer as clear an endarterectomy plane. The decision regarding the use of carotid shunting or patch closure should be guided by the principles of cerebral monitoring, prior history, and arterial size. These decisions are not directly influenced by the presence or absence of an ulcer. Endarterectomy should lower the risk of stroke to the range of 1% per year. The perioperative rate of combined neurologic morbidity and operative mortality should be less than 3% for asymptomatic lesions and less than 5% for symptomatic ulcers. This should result in a net reduction of the stroke risk at 5 years from almost 40% to about 8% in the case of asymptomatic class C ulcers. Similarly, the risk for asymptomatic class B ulcers would fall from 22% to about 8%.
CONCLUSIONS The pathophysiologic significance of an ulcer is a most important point. By virtue of its presence, it denotes two important facts. First, that an embolic event has occurred. Whether the event was silent or whether it produced symptoms, the presence of an ulcer is indisputable evidence that the patient has suffered embolic disease. The second point is that the plaque from which the ulcer developed is of such a consistency that it is susceptible to ulceration. This suggests that further ulceration is more likely in these plaques than in other, harder plaques. Again, it would suggest that this individual is at an increased risk of further embolic attacks. To reduce the risk of stroke in these patients, it is important that they be studied with unmagnified conventional arteriography. This is the best method of detecting and the only method of classifying ulcerative lesions. Patients with symptomatic ulcers with or without significant stenosis should undergo carotid endarterectomy. Patients with asymptomatic class B or C ulcers are at significant risk of stroke and should be considered candidates for prophylactic carotid endarterectomy. Surgeons performing these procedures must be able to demonstrate an operative mortality and stroke rate of less than 3% for asymptomatic lesions and less than 5% for symptomatic ones.
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REFERENCES 1. Panum, P.L. Experimentelle Beitrage zur Lehre von der Embolie. Virchows Arch. (Pathol. Anat.) 1862, 25, 308. ¨ ber das Verhalten des Teilungswinkels der 2. Chiari, H. U Carotis Communis bei der Endartenitis Chronica Deformans. Verh. Dtsch. Ges. Pathol. 1905, 326. 3. Florey, C.M. Arterial Occlusions Produced by Emboli from Eroded Aortic Atheromatous Plaques. Am. J. Pathol. 1945, 21, 549. 4. Handler, F.P. Clinical and Pathological Significance of Atheromatous Embolization, with Emphasis on an Etiology of Renal Hypertension. Am. J. Med. 1956, 20, 366. 5. Russell, R.W.R. Observations on the Retinal Blood Vessels in Monocular Blindness. Lancet 1961, 2, 1422. 6. Hollenhorst, R.W. Vascular Status of Patients Who Have Cholesterol Emboli in the Retina. Am. J. Opthalmol. 1966, 61, 1159. 7. Julian, O.C.; Dye, W.S.; Javid, H.; Hunter, J.A. Ulcerative Lesions of the Carotid Artery Bifurcation. Arch. Surg. 1963, 86, 803. 8. Gunning, A.J.; Pickering, G.W.; Robb-Smith, A.H.T.; Russell, R.R. Mural Thrombosis of the Internal Carotid Artery and Subsequent Embolism. Q. J. Med. 1964, 33, 155. 9. Ehrenfeld, W.H.; Hoyt, W.F.; Wylie, E.J. Embolization and Transient Blindness from Carotid Atheroma: Surgical Considerations. Arch. Surg. 1966, 93, 787. 10. Moore, W.S.; Hall, A.D. Ulcerated Atheroma of the Carotid Artery: A Cause of Transient Cerebral Ischemia. Am. J. Surg. 1968, 116, 237.
11. Moore, W.S.; Hall, A.D. Importance of Emboli from Carotid Bifurcation in Pathogenesis of Cerebral Ischemic Attacks. Arch. Surg. 1970, 101, 708. 12. Wechster, L.R. Ulceration and Carotid Artery Disease. Stroke 1988, 19, 650. 13. Thicle, B.L.; Young, J.V.; Chikos, P.M.; et al. Correlation of Arteriographic Findings and Symptoms in Cerebrovascular Disease. Neurology 1980, 30, 1041. 14. Hertzer, N.R.; Beven, E.G.; Benjamin, S.P. Ultramicroscopic Ulcerations and Thrombi of the Carotid Bifurcation. Arch. Surg. 1977, 112, 1394. 15. Imparato, A.M.; Riles, T.S.; Gorstein, F. The Carotid Bifurcation Plaque: Pathologic Findings Associated with Cerebral Ischemia. Stroke 1979, 10, 238. 16. Moore, W.S.; Boren, C.B.; Malone, J.M.; et al. Natural History of Nonstenotic Asymptomatic Ulcerative Lesions of the Carotid Artery. Arch. Surg. 1978, 113, 1352. 17. Dixon, S.; Pais, S.O.; Raviola, C.; et al. Natural History of Nonstenotic Asymptomatic Ulcerative Lesions of the Carotid Artery: A Further Analysis. Arch. Surg. 1982, 117, 1493. 18. Comerota, A.J.; Katz, M.I.; White, J.V.; Grosh, J.D. The Preoperative Diagnosis of the Ulcerated Carotid Atheroma. J. Vasc. Surg. 1990, 11, 505. 19. Gelabert, H.A.; Moore, W.S. Carotid Endarterectony: Current Status. Curr. Probl. Surg. 1991, 28, 249.
CHAPTER 51
Cerebral Protection During Carotid Artery Surgery Allan Callow
surprising that a number of years had to elapse before sample sizes of primary and secondary risk factors, reported by many clinicans, became large enough to permit reasonable conclusions.
What should have been apparent a decade or more ago, certainly at the time this chapter was revised, is now becoming more widely appreciated, namely, that most brains can withstand carotid cross clamping during carotid endarterectomy without suffering clinically detectable ischemic damage. This is another way of stating that most peri- and immediate postoperative strokes are the result of something other than diminished ipsilateral carotid flow. A derivative of this observation is that, for the majority of patients and the majority of experienced carotid surgeons, special measures for cerebral “protection” during surgery are unnecessary. Reinforcement for this position is provided by the rarity of neurologic deficits occurring among patients operated upon under local/regional anesthesia. What then explains the continuing and seemingly irreducible number of post- and perioperative neurological deficits that accompany carotid operations? An absolute answer is not available and may never be, but more and more evidence indicates technical errors during the operation. Nonetheless, mature clinical judgment, and recent precise sophisticated intraoperative studies provide substantial insight. First, let me present my personal biases. With that baggage put aside, let us then look at the data.
High-Risk Conditions High-risk conditions include the following: 1. 2. 3. 4.
5.
6. 7.
PERSONAL BIASES
8.
Patient Selection
Occlusion, or near-occlusion stenosis, of the contralateral carotid artery Previous stroke, in whichever arterial territory, by history, physical examination, or scan Objective evidence of cerebral or cerebellar infarction, old or new Coexisting occlusive disease in the carotid and vertebral arterial systems, by history, neurologic examination, or angiography Change in affect or state of consciousness accompanying a previous neurologic episode of whatever territory, severity, duration, and residual deficit Coexisting hypertension not easily controlled with medication Coexisting coronary artery occlusive disease, compromise of renal function, and pulmonary insufficiency, separately or combined Scarring of the anticipated operative field by previous surgery, thermal, radiation, or other trauma
Each of the above conditions may exist separately or in various combinations. Undoubtedly other additive factors operate, but relative values are unreliable. Age, of itself, does not constitute a high risk.[1 – 3]
In almost all writings and lectures on this subject patient selection is strongly emphasized. Unfortunately, most guidelines are soft and highly personal. The reality is that in the last analysis one develops one’s own guidelines. These are predominantly based on one’s own experiences with some input from others. It follows that the larger a surgeon’s experience and the more rapidly it is accumulated, the faster he or she becomes an expert. Many subsets of coexisting clinical conditions are seen in the carotid patient. This explains the large volume of patients required to develop reliable correlations. The lower the power of a given risk factor the greater must be the sample size. Thus, it is not
PERIOPERATIVE STROKE IS DUE TO SEVERAL FACTORS In decreasing order of frequency, factors in perioperative stroke are plaque and thrombus fragmentation during carotid dissection, with embolization to the intracranial circulation as
Hobson/Wilson/Veith: Vascular Surgery: Principles and Practice, Third Edition, Revised and Expanded DOI: 10.1081/0819-9-120024934 Copyright q 2004 by Marcel Dekker, Inc.
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the artery is being exposed or otherwise manipulated; formation of thrombus on the highly thrombogenic endarterectomized segment with local and distal progression and possible embolization; ipsilateral hemispheric ischemia during interruption of carotid flow; and reduced carotid flow secondary to reduced cardiac output or hypotension of whatever cause. We performed a literature review of the carotid experience of known centers of excellence in an attempt to identify shared practice patterns.[4] Did these centers of excellence utilize similar criteria for patient selection and evaluation of operative risk? Anesthesia technique preference, cerebral perfusion monitoring methods, and minutiae of operative technique were ascertained. Surprising variation was found in each of these items except one: operative technique. Here, too, some variation was present. Common to all series, however, was meticulous, compulsive attention to the smallest detail of whatever technical step or technique was favored. Variations of choice were numerous. Meticulous attention to detail and care in performing the dissection of the artery and in its subsequent handling was common to all teams. Scrupulously detailed grooming of the endarterectomy site and precise placement of each suture of the arteriotomy closure, with or without tacking sutures and with or without a patch, characterized the performance of the operative procedure in these centers of excellence. Equal attention was directed to monitoring the patient’s cardiorespiratory status, careful sedation and anesthesia, and avoidance or prompt treatment of pre- and postoperative hypo- and hypertension. Thus, cerebral protection begins with accurate patient evaluation and selection and extends through the period of anesthesia induction, operation, and awakening, if general anesthesia is used. It continues through the immediate postoperative period. On our service every possible candidate for carotid endarterectomy was seen in consultation with a neurologist with experience in the carotid stroke problem. This single item enhanced the understanding of cerebrovascular disease and the complexities of neurologic disease for every member of our service. In today’s world the most important factor of all remains the care and skill of the surgeon. In an attempt to determine the precise onset and cause of cerebral ischemia during carotid endarterectomy, the specific activity being performed by the surgical and anesthesia team at the time of initial appearance of symptoms was considered to be the cause of the ischemia in a series of 192 consecutive carotid endarterectomies performed with regional anesthesia by Dobrin and his associates.[5] Nine patients (4.6%) required a shunt for clamp-induced ischemia manifested by loss of consciousness in four patients, mental confusion in two, dysarthria and confusion in one, and contralateral motor weakness in two. In four of the nine patients cerebral ischemia developed within one minute of cross clamping. Ischemia appeared in five patients after 20 –30 minutes of cross clamping and before unclamping. In these five patients cerebral ischemia was related to systemic hypotension, with a mean reduction in systolic blood pressure of 35 mmHg. All awake patients in whom cerebral ischemia developed had complete resolution of symptoms following shunt placement. All patients who were converted to general anesthesia
awakened without a neurological deficit. Postoperative complications within 5 days of surgery included one TIA, one mild stroke, and one worsening of a preexisting stable stroke. Patients especially vulnerable to flow-related ischemia were those with contralateral stenosis or occlusion. “Although 80% of patients with contralateral occlusion will still tolerate carotid cross clamping, 20% will not.”[6] Reinforcing earlier statements in this essay, these authors practice a meticulous operative technique: “dissecting the patient away from the artery,” removal of all debris and “floaters,” visualization of the distal plaque endpoint, copious flushing and backbleeding of the internal carotid artery to remove air as well as particulate debris, and antegrade reperfusion of the external branch as the first step in flow restoration. These precautions undoubtedly reduce the incidence of cranial embolization.
INTRAOPERATIVE MONITORING Most if not all of the quasi-physiologic measures developed over the past three to four decades for assisting or measuring cerebral perfusion and oxygenation have been abandoned as too cumbersome and unreliable. These include induction of hypercarbia, hypothermia and hypertension, estimation of internal carotid back-bleeding, and somato-sensory evoked potentials. Transcranial Doppler sonography and single positron emission tomography yield interesting but not always applicable information. Although they have become valuable research tools, they are not available in most hospitals.
ELECTROENCEPHALOGRAPHY We continue to believe that mastering the few details of encephalography necessary for detecting reduced cerebral blood flow characteristic of carotid cross clamping is a valuable and occasionally critically useful skill. It has been criticized as cumbersome to set up, difficult to interpret, unreliable, and expensive. Under certain circumstances these may be true, especially the added expense in these days of zealous cost-cutting. Nonetheless, it can be of great reassurance and safety in situations where general anesthesia is required and where difficulty with shunt insertion is possible or actual as with high distal plaque endpoints, redo operations, and for small caliber internal carotid arteries. EEG monitoring, together with routine and/or selective shunting, more than any other technique, made possible the safe and widespread expansion of carotid endarterectomy as practiced today.[7] With adequate cerebral perfusion, the basic symmetric pattern consists of sustained rhythmic activity of 10 – 14 Hz and ranges between 25 and 100 mV. Four major frequencies—alpha, beta, theta, and delta, named in order of their discovery—are customarily identified. These are illustrated in Fig. 51-1. The most prevalent finding in the normal EEG is an alpha rhythm of from 8 to 13 Hz. The beta band, in excess of 13 Hz, becomes depressed and even absent with cerebral hypoxia.
Chapter 51.
Figure 51-1.
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The four major EEG frequencies. (From Hess, R.[8] Reproduced by permission of Sandoz Ltd.)
Hypoxia is also associated with an increased prominence of the delta band, sometimes referred to as slow-wave activity, which is under 4 Hz. Increasing depth of anesthesia will also cause the delta band to become predominant. Slowing of the EEG occurs when the cerebral metabolic rate is decreased by about 30%, and it rapidly deteriorates with further decrease. With progressive anoxia, as striking as the appearance of the delta band is the gradual suppression and eventual loss of the beta band. If anoxia is severe and prolonged, electrical silence ensues. These two changes, diminution and eventual disappearance of fast-wave activity, the beta band, and a simultaneous appearance of the slow wave, the delta band, are taken as urgent and absolute indications for a temporay shunt. In general, the more severe the changes in the EEG, presumably reflecting a greater degree of ischemia, the longer the recovery period required for the EEG to return to its preocclusion pattern. This is illustrated in Fig. 51-2. In our experience utilizing continuous EEG monitoring in a series of 1262 operations over a 5-year period, transient deficits occurred in 36 instances, for an incidence of 2.8%. However, permanent or prolonged, but not always severe neurologic deficits, lasting beyond the fourth or fifth postoperative day, occurred in 1.3%. Mortality was 0.48%. Each of the deaths was cardiac in origin. None was a primary stroke death. In our experience of some 3000 operations, positive features of EEG monitoring included provision for close correlation between cerebral perfusion and electrical activity as well as continuous surveillance of cerebral blood flow, elimination of reliance on a single back or stump pressure of the internal carotid artery measured at the beginning of the operation and not easily available thereafter, avoidance of
haste in the conduct of the procedure, and provision of protection throughout the operation for all patients, irrespective of undetected variations in collateral flow, depth of anesthesia, and transient or prolonged cardiac malfunction. The EEG is an accurate indicator of cortical ischemia during general anesthesia provided that the depth of anesthesia is closely monitored.
REGIONAL ANESTHESIA Although the choice of anesthesia technique has been controversial for many years, local/regional anesthesia is now favored for most patients and by most surgeons. Clinical behavior, change of affect, inability to carry out simple response requests such as finger motion and speech are all reliable detectors of even subtle changes in cerebral blood flow. Two studies[9,10] have demonstrated that for patients in the American Society of Anesthesiologists (ASA) Categories III and IV, the outcome is better for those receiving regional anesthesia/cervical plexus block than for those receiving general anesthesia. These categories include patients who are aged, have a history of myocardial infarction, angina, congestive heart failure, severe cardiomyopathies, substantial pulmonary dysfunction, diabetes, or any other disease that significantly alters their lifestyle and life expectancy. Three contraindications for regional anesthesia are: (1) the combative or confused patient who may require heavy sedation, (2) the patient who refuses, because of claustrophobia or other reason, to be awake, and (3) a relative contraindication such as contralateral phrenic nerve paralysis.
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Figure 51-2. Two tracings from the same patient under general anesthesia: normal baseline tracing on the left and an abnormal tracing on the right. The right tracing demonstrates diminution of amplitude, marked depression of beta frequency, and emergence of the slow or delta band with cross clamping of the carotid artery. Compare with Fig. 51-1.
The patient is placed with the head slightly elevated and rotated away from the operative side.[11] The tranverse processes of C-2 to C-4 are located by palpation 1.5 –2 cm below the mastoid process. The patient is lightly sedated with a short-acting agent (fentanyl/midazolam) prior to injection in three locations with 5.0 mL of local anesthetic (bupivacaine, 0.5% plain). A superficial block along the posterior border of the sternocleidomastoid muscle is done with 10.0 mL of a local agent. This is displayed in Figs. 51-3–51-5. Complications of cervical plexus block include inadvertent injection into the external jugular vein, Horner’s syndrome, vertebral artery injection presenting as a transient seizure, subarachnoid injection resulting in total spinal block and secondary apnea, embolization from trauma to the carotid artery, and transient phrenic and recurrent laryngeal nerve paralyses. It is probably true that none of the currently available techniques for assessing cerebral blood flow during carotid cross clamping is entirely without some shortcomings. Regional anesthesia eliminates the need for any of these techniques because the patient’s state of consciousness is the monitor. Insofar as lessening the possibility of intra- or perioperative stroke due to embolism, however, regional anesthesia is no better than other methods. An advantage of
a different sort, other than avoidance of perioperative stroke, is the alleged reduction in morbidity and mortality in the patient who is at high risk because of coexisting cardiac and respiratory disease, although only one randomized controlled study exists to support this belief.[12,13]
SUMMARY We continue to favor continuous 20 lead electroencephalography in those special situations and for those special patients for which general anesthesia may be needed or the risk of cardiovascular or cerebrovascular complications may be high. The reported experience of lesser cardiovascular stress experienced by patients under regional as opposed to general anesthesia is an example of the first risk. An old cerebral infarction illustrates the second. No discussion of cerebral protection can be considered complete without mention of proper selection of patients. Classification into various risk groups is facilitated by the neurologic status, coexistence of cardiovascular disease, including hypertension and diabetes mellitus, and by delineation of collateral
Chapter 51.
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Figure 51-3. Depiction of anatomic landmarks for deep cervical plexus block. The local anesthetic is injected 1 – 2 mm from the anterior cornu of the transverse process of C-2 to C-4. (Reprinted with permission from Williams and Wilkins, Media, PA.)
channels, the status of the contralateral carotid artery, the posterior circulation, and the presence of an old or silent infarct. Diagnostic pursuit of these possibilites is by no means needed as a routine workup, but where indicated, or suspected, ascertaining their presence adds a measure of safety. The need for continuing accumulation of data— clinical, angiographic, and intraoperative—among the many
subsets of patients still exists. We do not find justification, for the present at least, for recent reports advocating carotid endarterectomy without a shunt with no monitoring support and no preoperative assessment—by some means—of the cervical and cerebral circulations. Effort must continue to be made to strive to reduce reported postoperative neurologic deficits and stroke from their current 1 –2 and 4 –6%,
Figure 51-4. Anatomic landmarks for a superficial cervical plexus block. The midpoint of the posterior border of the sternocleidomastoid muscle is identified, and 5 mL of the anesthetic agent are deposited along its superior half and 5 more along its inferior border. Care must be taken not to inject into the external jugular vein, vertebral artery, or the apex of the lung. (Reprinted with permission from Williams and Wilkins, Media, PA.)
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Figure 51-5. (A) Segmental distribution of nerves providing cutaneous innervation of the head and neck. (B) Anesthetic result following deep and superficial cervical block showing areas of skin anesthesia. (Reprinted with permission from Williams and Wilkmins, Media, PA.)
respectively. For the average low-risk patient we must adopt an attitude of zero tolerance for these complications. For the present, withholding arteriographic assessment and ignoring
the need for cerebral protection seem unwarranted and unnecessarily hazardous. Operating with no monitoring whatsoever denies the patient a better chance of safe conduct.
REFERENCES 1. Callow, A.D. Surgery of the Carotid and Vertebral Arteries for the Prevention of Stroke; Williams & Wilkins: Media, PA, 1996; 435. 2. Callow, A.D.; Rosenthal, D.; Cossman, D.; Ledig, C.B. Results of Carotid Endarterectomy for Vertebrobasilar Insufficiency: An Evaluation Over Ten Years 1978, 113, 1361. 3. O’Donnell, T.F.; Callow, A.D.; Willet, C.; et al. The Impact of Coronary Artery Disease on Carotid Endarterectomy. Ann. Surg. 1983, 705–712. 4. Callow, A.D.; Mackey, W.C. Optimum Results of the Surgical Treatment of Carotid Territory Ischemia. Circulation 1991, 83, I-190. 5. Lawrence, P.F.; Alves, J.C.; Jocha, D.; Dobrin, P.B. Incidence, Timing and Causes of Cerebral Ischemia During Carotid Endarterectomy with Regional Anesthesia. J. Vasc. Surg. 1998, 27, 329– 337. 6. Callow, A.D.; Mackey, W.C. Long Term Follow-Up of Surgically Managed Carotid Bifurcation Atherosclerosis:
7.
8. 9.
10.
11.
Justification for an Aggressive Approach. Ann. Surg. 1989, 210, 308. Callow, A.D. Fact or Fancy—a Twenty Year Personal Perspective on the Detection and Management of Carotid Occlusive Disease. The Leriche Memorial Lecture. J. Cardiovasc. Surg. 1980, 21, 641. Hess, R. EEG Handbook; Sandoz Monographs, EEG Laboratory of University Hospital, Sandoz Ltd.: Zurich, 1996. Palmer, M.A. Comparison of Regional and General Anesthesia for Carotid Endarterectomy. Am. J. Surg. 1989, 157, 329– 330. Allen, B.T.; Andersen, C.B.; Rubin, B.G.; et al. The Influence of Anesthetic Technique on Perioperative Complications After Carotid Endarterectomy. J. Vasc. Surg. 1994, 19, 834– 843. Young-Beyer, P.A. Anesthetic Management for Carotid Endarterectomy. In Vascular Surgery, Theory and Practice; Callow, A.D., Ernst, C.B., Eds.; Appleton & Lange: Stamford, CT, 1995; 1440.
Chapter 51. 12.
Zuccarello, M.; Yeh, H.S.; Tew, J.M. Morbidity and Mortality of Carotid Endarterectomy Under Local Anesthesia. Neurosurgery 1988, 23, 445– 450.
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Forrsell, C.V.; Takolander, R.; Berquist, D.; et al. Local Versus General Anesthesia in Carotid Surgery: A Prospective, Randomized Study. Eur. J. Vasc. Surg. 1989, 3, 503–509.
CHAPTER 52
Extracranial Carotid Artery Occlusive Disease Samuel E. Wilson Robert W. Hobson II
from smoking, regulation of blood lipids and improved physical fitness has been credited for the decline in mortality from cerebrovascular diseases in recent decades. Patients who fit into the high-risk profile described above, however, continue to have a substantial risk for stroke. The Framingham Study on patients aged between 30 and 62 at the time of entry into the program indicates that the 5% who developed cerebrovascular disease had predominately atherothrombotic disease rather than subarachnoid hemorrhage or intracerebral hemorrhage.[5] The Rochester population study performed between 1955 and 1969 reported that the incidence of cerebral ischemia increased with age, so that patients over age 75 had a rate of 1786 per 100,000 population per year in contrast to those aged 55 –64, who had a rate of 277.[6] One fifth to one third of patients die as a consequence of a first stroke. Over the ensuing 2 years, about 60% have another stroke. Eventual causes of death after the first stroke are recurrent stroke (50% of patients), other cardiovascular disease (30%), and a miscellaneous group of causes (20%).[2] Two weeks after the onset of an acute progressing stroke in the carotid region, some 60% of patients have been found to be still hemiparetic, 14% are dead, 15% have a residual monoparesis, and only 12% are neurologically normal. After a stroke, treatment of existing hypertension has proven useful in preventing recurrent cerebral ischemia. Anticoagulants have also been used to reduce future embolic complications in patients who have had cerebral emboli from a cardiac source. Management of hyperlipidemia, cessation of smoking, and control of other medical risk factors contribute to further reduction in stroke. Strokes associated with large-artery thrombosis develop suddenly in about 40% of patients and in a stepwise or stuttering fashion in another 33%; only in the remainder is the onset gradual. Unfortunately, many patients develop strokes with no preceding cerebral symptoms. In one clinical trial on asymptomatic carotid artery stenosis,[7] one half of all neurologic events were first-time strokes unassociated with warning transient ischemic attacks (TIAs). The likelihood of
INTRODUCTION A stroke is the result of direct or indirect interference with the blood supply to the brain. The number of cerebrovascular deaths annually in the United States is about 150,000, making stroke the third leading cause of death after heart disease and cancer. Approximately 700,000 new strokes occur each year, and 200,000 recurrent strokes are documented.[1] If the stroke is not fatal, rehabilitation of the majority of patients who have a permanent neurological deficit is protracted and costly. Thromboembolic disease accounts for the major cause of stroke[2] (Fig. 52-1), and carotid atherosclerosis is a direct cause of brain infarction in 10 –20% of cases.[3] Although epidemiologic evidence has confirmed a 50% reduction in mortality rate from stroke over the last two decades (Fig. 52-2), neurologic deficits after stroke constitutes a major cause of disability among elderly Americans.[4] About 40% of the patients who survive required special nursing care and another 10% are disabled to such an extent that they need to be institutionalized. Approximately 2 million persons in the United States who have survived a stroke are alive. One can readily see how the acute and chronic care required by stroke victims consumes billions of dollars of the health care budget annually.
RATIONALE FOR THE SURGICAL PREVENTION OF STROKE Currently, there are limited measures the physician can employ to influence the recovery of infarcted brain tissue; accordingly, emphasis is placed on prevention. Epidemiologic studies suggest typical risk profiles that would identify patients at risk of developing stroke. In this higher-risk group are individuals with hypertension, coronary artery disease, diabetes or prior history of stroke. Management of risk factors through widespread treatment of hypertension, abstinence
Hobson/Wilson/Veith: Vascular Surgery: Principles and Practice, Third Edition, Revised and Expanded DOI: 10.1081/0819-9-120024935 Copyright q 2004 by Marcel Dekker, Inc.
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Figure 52-1.
Decline in age-adjusted mortality rates for cardiovascular disease, United States, 1972 –1986. (From Ref. 4.)
finding a focal TIA with other etiologies for stroke is 23% in lacunar strokes, 11% in embolism, 8% in hemorrhagic strokes, and 7% in strokes of aneurysmal origin. There is general agreement that patients who have TIAs should undergo duplex scanning, followed by angiographic evaluation and possibly operative correction if associated pathology is identified in the extracranial carotid system. In the Mayo Clinic Study in Rochester, Minnesota, 31 patients per 100,000 population per year developed TIAs, the incidence increasing with age, so that in persons aged 65–74 the incidence reached 200 patients per 100,000 population per year.[6] About one third of patients who had TIAs developed a stroke due to cerebral infarction, and 50% of these strokes occurred within the first year following the onset of the TIAs. The Canadian Cooperative Study of patients who had TIAs showed that in the control group of 139 men and women, 20 (14%) developed stroke.[8] The likelihood of developing cerebral infarction is higher in patients who have multiple hemispheric TIAs rather than a single, isolated attack. Prospective randomized trials comparing aspirin and other antiplatelet agents with placebo have shown a tendency toward reduced stroke in persons treated with the antiplatelet medications.[9] Benefits of aspirin therapy as compared to placebo have been confirmed by meta-analysis of the data
accumulated for patients presenting with TIAs, amaurosis fugax, and nondisabling stroke. A 23% relative risk reduction in the incidence of stroke and death has been reported for aspirin therapy in comparison to placebo.[10] The beneficial effects of aspirin in reducing the risk of recurrent myocardial infarction is also achieved. New antiplatelet agents have been introduced to further improve the results of medical therapy. An earlier clinical study demonstrated that ticlopidine was significantly better than aspirin in preventing stroke and death.[11] However, clopidogrel (Plavix) has now replaced ticlopidine as the preferred antiplatelet agent[12] because of its clinically positive results and absence of bone marrow depression reported with ticlopidine. The incidence of surgically correctable disease in the ipsilateral carotid artery in persons with hemispheric TIAs has been shown angiographically to be as high as 72%.[13] In the medical treatment group from the North American Symptomatic Carotid Endarterectomy Trial (NASCET),[14] patients presenting with TIAs and ipsilateral carotid stenoses and receiving no treatment had an incidence of stroke of approximately 8.5% per year. With aspirin therapy, this may be reduced to 5.9% per year; following uncomplicated carotid endarterectomy, it would be further reduced to 2.3% per year.[15]
Figure 52-2. Frequency of stroke by type in men and women: 36-year follow-up. ABI, atherothrombotic brain infarction; CE, cerebral embolism; TIA, transient ischemic attack; SH, subarachnoid hemorrhage; IH, intracerebral hemorrhage. (From Ref. 2.)
Chapter 52.
Randomized clinical trials comparing carotid endarterectomy and medical therapy versus best medical therapy alone in patients with transient monocular blindness, TIAs, or recent nondisabling strokes in the presence of ipsilateral carotid stenosis, greater than 70% have shown a highly significant reduction in fatal and nonfatal strokes in patients undergoing operation. NASCET recommended that patients in the above category be referred for carotid endarterectomy. Surgical intervention provided a 71% risk reduction for fatal and nonfatal strokes and a 58% mortality reduction when compared with optimal medical management, including antiplatelet medication (aspirin), after a mean follow-up of 18 months.[14] Symptomatic patients with severe carotid stenosis were also reported to derive significant benefit from operation in the European Carotid Surgery Trial (ECST), where results showed a twofold reduction of stroke risk in patients treated with carotid endarterectomy and medical therapy when compared to medical therapy alone.[16] The third trial on symptomatic carotid disease associated with ipsilateral carotid stenoses of $50% was conducted in the Department of Veterans Affairs Medical Centers. A significant reduction in stroke and crescendo TIAs was observed in patients in the surgical group as early as one year after randomization.[17] Patients who have TIAs in the carotid distribution but no correctable vascular disease—suggesting another etiology for their symptoms, such as an embolic or hypercoagulable condition—also have a heightened risk of stroke. For those who continue to have TIAs on aspirin therapy, treatment with other antiplatelet medications has been reported to be beneficial. Although other anticoagulants such as warfarin have been suggested, no demonstrably greater clinical benefit has been reported than that observed with aspirin.[18]
HISTORICAL PERSPECTIVE The ancient Greeks understood the importance of the carotid arteries, since the term carotid is derived from the Greek word karoo, which means to stupefy. Compression of the carotid arteries was known to cause “sudden sleep.”[19] Occlusive disease of the carotid and vertebral arteries was recognized and described by John James Wepner as a postmortem finding in 1658.[19] His contemporary Thomas Willis encountered similar findings in postmortem examinations but felt that the communication between the carotid and vertebral vessels (circle of Willis) would render total occlusion of the extracranial arteries insignificant. For the next 200 years, strokes were attributed to intracranial rather than extracranial vascular disease. By the late nineteenth century, astute clinicians had recognized the relationship of stroke to extracranial vascular disease. Savory and Gowers described patients with symptoms of ocular and cerebral ischemia who were found to have cervical carotid disease on postmortem examination.[19] Ramsay Hunt,[20] a neurologist at Columbia University, in an address to the American Neurological Association in 1913, emphasized the relationship of extracranial disease to stroke. He urged that, in all cases of cerebral symptoms of vascular origin, the main arteries of the
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neck be carefully examined for diminution or absence of pulsation. The definitive antemortem diagnosis of cerebrovascular disease became possible when Egaz Moniz of Lisbon developed cerebral angiography as a method for localizing cerebral tumors in 1927. Ten years later, Moniz and colleagues[21] described four cases of internal carotid occlusion associated with hemiplegia confirmed by angiography. In 1951, Miller Fisher, a Canadian neurologist, performed 373 postmortem examinations of the brain from patients who had died of cerebrovascular disease.[22] He made several salient observations. Hemorrhagic infarcts were present in fewer than 20% of his specimens; he therefore concluded that most cases of stroke were embolic in origin. Fisher also reported that atheromas tended to form at the extracranial carotid bifurcation, and he observed that arteries distal to the cervical carotid disease were frequently spared. He correctly indicated that extracranial carotid disease was an important cause of strokes, and he went on to speculate that vascular surgeons would find a way to bypass the occluded carotid segment in the neck by direct vascular anastomosis of the internal and external carotid systems above the area of stenosis. Carrea, Molins, and Murphy,[23] three Argentinean surgeons, acknowledged the importance of Fisher’s speculations. On cerebral angiography, they diagnosed a 41-yearold man who had recently developed aphasia and right hemiparesis as having a severe left internal carotid stenosis. Then, on October 20, 1951, they performed the first successful vascular reconstruction for cerebral ischemia. Carrea and his colleagues resected the diseased portion of the left internal carotid and performed an end-to-end anastomosis between the external and distal internal carotid arteries. Their report was not published until the patient had made an uneventful recovery and after a 39-month follow-up, which showed him to be neurologically intact. On January 28, 1953, Strully and colleagues[24] attempted a thromboendarterectomy of a totally occluded internal carotid artery without success, but they went on to predict that endarterectomy would be feasible prior to thrombosis if the distal vasculature were patent. The first successful carotid endarterectomy was performed in this country by Michael DeBakey on August 7, 1953.[25] The patient was a 53-year-old bus driver with a 30month history of intermittent weakness in the right arm and leg. A thromboendarterectomy of the common and internal carotid arteries was undertaken and the arteriotomy closed primarily. An intraoperative arteriogram confirmed patency of the distal circulation. The patient survived 19 more years without any recurrence of symptoms. However, it was the report in 1954 by Eastcott, Pickering, and Rob[26] that captured the imagination of the surgical world. Their patient was a 60-year-old housewife with recurrent ocular and cerebral TIAs. On angiography, a near occlusion of the internal carotid was observed. She underwent resection of the left internal carotid, ligation of the external carotid artery, and an end-to-end anastomosis between the common and internal carotid arteries. Twenty-six years after her operation, she was still symptom-free. The success of these early operations accompanied by long symptom-free periods of survival has made carotid endarterectomy one of the most commonly performed vascular
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operations in the United States, currently in excess of 140,000 procedures per year.[27] Data from randomized clinical trials resolved controversy over the efficacy of carotid endarterectomy combined with best medical care versus optimal medical care alone in the management of extracranial carotid occlusive disease. With the acceptance of uniform indications for the operation and expected results, carotid endarterectomy can be recommended for the treatment of symptomatic and now asymptomatic extracranial carotid occlusive disease.
PATHOGENESIS The pathophysiology of stroke as a result of carotid artery disease is the subject of ongoing research and much spirited debate. A detailed understanding of the pathogenesis of cerebral ischemia is as essential as an accurate knowledge of the natural history of carotid artery stenosis in developing a rational therapeutic program for extracranial vascular occlusive disease. In the early 1950s, Fisher[22] described a variety of pathologic changes occurring in the carotid arteries of patients dying of stroke. He recognized the two basic mechanisms by which a carotid artery lesion produced ischemia: (1) embolization from irregular luminal surfaces, usually but not exclusively associated with an ulcerated plaque; and (2) decreased flow from a narrowed or occluded internal carotid artery. These observations were verified clinically by the 1968 report of the Joint Study of Extracranial Arterial Occlusions,[28] which showed that approximately 75% of the more than 4000 patients studied had significant extracranial arterial lesions, producing greater than 30% stenosis as shown by aortic arch and cerebral angiography. Stenosis occurred more frequently than occlusion, and the carotid arterial bifurcation was the most frequently involved site (34%), followed by origins in the vertebral artery (20%). These findings, together with the then newly recognized significance of cholesterol emboli to the retina (Hollenhorst plaques),[29] indicated that cerebral ischemia could occur from either of the two previously mentioned mechanisms. Atherosclerosis, the most common cause of extracranial carotid artery stenosis in humans, is an intimal disease, with secondary changes occurring in the media of the artery. Several theories concerning the formation of these plaques have been proposed and modified during the last century. Ross and Glomset [30] postulated a “reaction-to-injury hypothesis,” which proposed that injury to the endothelium was the initiating event in atherogenesis. They reported that the endothelium responds to injury in a variety of ways, including endothelial desquamation, with loss of its nonthrombogenic character and local secretion of growth factors with minimal or no morphologic alteration of the involved endothelium. Platelets adhere to the exposed subendothelial connective tissue and release the contents of their granules. Chemotactic and mitogenic factors such as platelet –derived growth factor (PDGF), epidermal growth factor (EGF), and other cytokines induce the proliferation of smooth muscle cells and their migration from the media to the intima.
The specific injuries that precipitate atherogenesis are not known, although risk factors have been identified. One of these is high serum cholesterol—specifically elevation of its low-density lipoprotein (LDL) fraction. In vitro exposure of an arterial segment to cholesterol perturbs the fluidity of the cell membrane and alters calcium influx, permeability, and cellular secretion. Oxidized LDL cholesterol appears to be most injurious to endothelial cells and may induce the release of cytokines and growth factors as well as the elaboration of specific binding sites for monocytes.[31] It has recently been postulated that the earliest lesion in plaque development, the fatty streak, may develop under a structurally intact endothelium. The appearance of foam cells, which characterize the fatty streak microscopically, occurs secondarily to an attachment of circulating monocytes to an intact endothelium under the influence of local factors. Oxidized LDL appears to be most injurious to endothelial cells and may induce the release of cytokine and growth factors as well as the elaboration of specific binding sites, leading to monocyte attachment, migration, and subendothelial localization. Monocytes, upon entering the arterial wall, undergo a complex series of phenotypic alterations to become macrophages, which “scavenge” oxidized LDL and become foam cells.[32] This subendothelial migration leads to further secretion of PDGF by all major cell types present in the arterial wall, inducing smooth muscle cells to travel to a subendothelial plane, proliferate under the influence of a variety of mitogenic factors, and subsequently to form a fibrous plaque. Atherosclerosis also shows a predilection for developing in specific vascular sites, including the circle of Willis and the extracranial carotid artery system. In particular, these sites include points of bifurcation and areas of anatomic arterial curvature. The carotid bifurcation is particularly prone to plaque formation, since it is a branching point and it enlarges to form the carotid bulb. The combination of these two circumstances leads to enhanced flow-field changes and prominent hemodynamic alterations. Hydrogen bubble flow visualization and velocity profile studies (Fig. 52-3) have demonstrated that flow in the common carotid artery is laminar.[33] Laminar flow is defined as a column of flowing blood traveling in concentric layers along a vascular tube. The core layers travel at the highest velocity, with each adjacent layer moving more slowly until a stationary fluid layer is encountered at the vascular wall. This decrease in the velocity of blood flow from core to periphery is known as the velocity gradient. Since each fluid lamina travels at its own speed, it exerts a force on an immediately adjacent lamina traveling at a different speed; this force is referred to as shear stress. When a column of blood traveling with laminar flow reaches the carotid bifurcation, it separates at the flow divider formed by the internal and external carotid branches (Fig. 52-4). Flow streamlines are compressed toward the flow divider, and flow remains laminar, with a high-velocity profile and an associated high wall shear stress. Flow patterns, nonetheless, retain their axial and unidirectional alignment. Along the outer wall of the widened carotid bulb, however, flow patterns become complex and include areas of flow separation and reversal with the development of counterrotating helical trajectories. In this region, the wall shear stress is low. In the distal bulb and the distal internal carotid, flow resumes
Chapter 52.
Figure 52-3. Hydrogen bubble flow visualization technique in a glass model human carotid bifurcation shows laminar flow in the inner wall of the bulb and area of flow separation in the outer wall where the atherosclerotic plaque localizes. (From Ref. 33.)
laminar conditions linked to a high velocity and high wall shear stress.[34] Contrast media washout and particle tracking studies have also shown decreased clearance of particles opposite to the flow divider in the region of low velocity and shear stress. These flow properties are thus associated with an increased residence time of atherogenic bloodborne cellular
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elements that are given an increased probability of adhering, interacting, and possibly injuring the endothelium leading to atherogenic plaque formation. Increased residence time of particles such as platelets in the outer wall of the carotid bulb and internal carotid also has local hemodynamic implications. Thromboxane A2 synthesized by platelets from endogenous arachidonic acid is released upon platelet aggregation. Released thromboxane A2 is a potent vasoconstrictor and also stimulates further platelet aggregation. A hypercholesterolemic environment also leads to a reduction in the activity of endothelial-derived relaxing factor (EDRF), which is a potent vasodilator released from the endothelium. Since EDRF, subsequently shown to be nitric oxide, also inhibits platelet adherence and aggregation and suppresses vascular smooth muscle proliferation in vitro, a deficiency of EDRF would enhance vasoconstriction, promote platelet –vessel wall interactions, and lead to the proliferation of smooth muscle cells.[35] Hemodynamic changes secondary to the unique geometry of the carotid bifurcation result in the creation of an environment susceptible to atherogenic plaque formation. At first, the arterial stenosis caused by atherosclerotic plaques was thought to cause cerebral infarction by simply decreasing cerebral blood flow—arterial stenosis being regarded as “critical” if it was flow-limiting and “subcritical” if flow volume was maintained. Brice et al.[36] measured the pressure gradient and flow in the carotid artery and concluded that the amount of constriction required to limit flow corresponds to an average reduction of luminal area by 80–85%. A significant drop in pressure does not occur distal to a stenosis of less than 72% luminal reduction. Conversely, studies have confirmed plaque ulceration and thrombus formation with arterial stenoses in the range of 50 –80% area reduction. Additional factors influence the development of a critical stenosis: pressure and adequacy of the collateral circulation of the territory supplied by the affected artery, increased metabolic demands of the tissue being perfused, a reduction in systemic blood pressure, or decreased cardiac output. Imaging techniques such as slow-motion angiography and real-time B-mode imaging have shown arterial wall movement at the level of the carotid bifurcation to be greater than
Figure 52-4. Dye flow visualization technique in an acrylic model human carotid bifurcation shows boundary layer separation at the level of the outer wall of the bulb where the atherosclerotic plaque localizes. HS: Flow divider between internal (below) and External (above) carotid arteries. SEP: Boundary layer separation. (From Ref. 34.)
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previously appreciated. Lusby and colleagues[37] observed greater distensibility at the carotid bulb as compared to the common carotid artery, resulting in varying stress at the bifurcation with pulsatile flow. A significant amount of plaque movement with the cardiac cycle has also been demonstrated.[38] Furthermore, the cardiac pulse cycle creates an oscillatory (changes in direction) shear stress in the carotid bulb, which correlates strongly with early plaque formation at this site.[39] The variations in distensibility found at the carotid bulb indicate differences in compliance. It then follows that pulsatile flow creates a greater circumferential stress at the carotid bulb, which contributes to endothelial injury and the development of atheromas. In addition, a change in elastin and collagen content secondary to atheroma formation may further contribute to alterations in the mechanical properties of the arterial wall at the carotid bifurcation and proximal internal carotid artery. These changes in wall structure and the asymptomatic nature of atheroma deposition produce imbalances in wall tension in the atherosclerotic plaque that forms at this location. Sudden alterations in systemic blood pressure may cause further abrupt changes in wall tension, leading to intraplaque hemorrhage, rupture of the plaque’s fibrous cap, or luminal thrombosis. All the above factors contribute to the formation of an atherosclerotic plaque at the carotid bifurcation, which leads to a variety of complications, depending on whether the plaque ulcerates and creates emboli or hemorrhages or fractures, leading to increasingly severe arterial stenosis and possible thrombosis. Imparato et al.[40] (see color insert for color figures appearing in chapter 49) analyzed the histologic and gross morphology characteristics of 69 carotid plaques from 50 symptomatic patients; these investigators reported that even though great variability in plaque morphology was found, 65% of the specimens exhibited some degree of intraplaque hemorrhage. A prospective study of 376 carotid plaques (275 symptomatic, 101 asymptomatic) obtained as endarterectomy specimens in 280 patients demonstrated a correlation between plaque morphology and symptoms. Ulceration was found to be the most frequent gross morphologic characteristic encountered, but hemorrhage was the only gross characteristic that was significantly more frequent in plaques from symptomatic patients than in those from asymptomatic patients. Intraplaque hemorrhage also correlated significantly with the degree of stenosis present.[41] More contemporary studies in asymptomatic patients with greater than 60% carotid stenosis have found intraplaque hemorrhages in nearly all the specimens and ulcerations and/or recent mural thrombi in half of them.[42] Eleven specimens from patients presenting with carotid thrombosis were recovered at autopsy and examined. Again, greater than 60% stenosis was found in nearly all, plaque ulceration in only three, and intraplaque hemorrhage in only one.[43] Atherosclerotic stenoses with or without plaque ulceration, rupture, and hemorrhage remains the greatest risk factor for carotid atheroemboli or thrombosis. Recently, analysis of carotid plaques by pixel distribution analysis of B-mode ultrasonograms has demonstrated its potential to identify plaque components more characteristic of asymptomatic or symptomatic plaques.[44]
CLINICAL PRESENTATION The symptomatology of carotid artery occlusive disease manifests a variety of neurologic deficits, depending on the duration of cerebral ischemia. The clinical presentation may be a TIA, which is usually secondary to thromboembolic events. It is classically defined as a stereotypic and temporary loss of sensory or motor function or loss of vision in one eye (transient monocular blindness), usually lasting less than 15 minutes and resulting in recovery of neurologic function without deficits at 24 h. If the deficit persists longer than 24 h but full recovery of neurologic function is again achieved, it is defined as a nondisabling stroke or by some clinicians a reversible ischemic neurologic deficit (RIND). The persistence of a neurologic deficit, such as hemiplegia, for longer than 30 days is defined as a permanent fixed deficit. Pathologically, the difference between a TIA and a fixed neurologic deficit relates to the degree and persistence of ischemia and is indirectly related to the adequacy of the collateral circulation. Fixed neurologic deficits are associated with actual infarction of brain tissue. In the region of the carotid artery, TIAs result from ischemia in the terminal branches of the anterior and middle cerebral arteries, which supply the motor and sensory cortex, as well as the speech center of the dominant hemisphere. Typical motor symptoms include clumsiness, weakness, or paralysis in the contralateral side of the body. These may also be associated with isolated sensory symptoms such as paresthesias or anesthesia. A motor or perceptive aphasia may also be present if the dominant (commonly the left) hemisphere is involved. Dysarthria may occur if the nondominant hemisphere is involved. Patients with carotid artery disease may also present with a variety of eye symptoms.[45] Amaurosis fugax is a transient monocular blurring or visual loss ipsilateral to the diseased artery. It is commonly described as a curtain or window shade coming down over the visual field or as a quadrant field defect. Rarely does it last longer than 30 minutes or cause a residual visual deficit. Ischemia of the optic radiations posterior to the optic chiasm may result in homonymous hemianopsia, a loss of vision in the ipsilateral temporal and contralateral nasal visual fields. Ischemic optic neuropathy may arise due to emboli or thrombosis of the short posterior ciliary arteries, resulting in hypoperfusion of the central retinal artery and subsequent blindness due to infarction of the optic nerve. Routine ophthalmoscopic examination may confirm presence of Hollenhorst plaques—bright yelloworange cholesterol crystals originating from ulcerative atherosclerotic carotid lesions.[29] Severe flow restriction to the ophthalmic artery can also lead to neovascularization of the iris, which is known as rubeosis. Extensive bilateral carotid disease can also manifest itself as retinal “claudication,” or loss of vision upon exposure to bright light. Presence of any of the above findings or symptoms warrants a thorough evaluation of the carotid arterial system. Turbulence due to altered flow patterns secondary to carotid artery stenosis can manifest itself as a cervical bruit. However, only 47% of patients with cervical bruits evaluated by angiography are found to have a hemodynamically significant lesion.[46] Furthermore, nearly 40% of patients
Chapter 52.
with a significant lesion of the carotid bifurcation will have no audible cervical bruit.[47] Presence or absence of significant carotid artery disease cannot be predicted accurately by the finding of a cervical bruit on physical exam. Patients may also present with rotating, poorly localized motor or sensory deficits as well as bilateral homonymous hemianopsia, ataxia, vertigo, diplopia, or dysarthria—usually in a variety of combinations but not alone. These symptoms have been designated as nonhemispheric, since they are not stereotypic, are poorly localized, and implicate hypoperfusion rather than emboli as their etiology.[48] Frequently, symptoms secondary to vertebrobasilar disease are incorrectly attributed to carotid pathology. The clinical characteristics of vertebrobasilar symptoms are related to the specific portion of the hindbrain that is affected and include a combination of the following: dysarthria, dysphagia, diplopia, nystagmus, visual field defects, hoarseness, ataxia, and syncope.[49] Headaches, seizures, loss of memory, and confusion should not be ascribed to carotid or vertebrobasilar disease. Patients presenting with a pure motor or sensory deficit associated with hypertension and the presence of small filling defects within or near the internal capsule on computed tomography (CT) are diagnosed as suffering from lacunar infarction. A lacuna is defined as a small cerebral infarct that becomes a cavity when macrophages scavenge the infarcted tissue. In the past, it has been attributed to a combination of hypertension and small-vessel disease.[50] Recently, this etiology has been challenged, and small emboli have been implicated as a potential source of lacunae. Thus, a complete cardiac and carotid artery assessment should be undertaken to rule out these sites as potential sources of emboli.[51] The final and most devastating clinical presentation of carotid disease is fixed neurologic deficit secondary to brain infarction. Stroke can be the initial manifestation of extracranial carotid artery disease. Asymptomatic patients with a carotid artery stenosis greater than 75% were found to have a 1-year stroke rate of 5%.[52] One should also not forget that stroke survivors are at high risk for subsequent stroke and that the leading cause of their mortality is recurrent stroke.[53]
ANGIOGRAPHY Cerebral angiography is the most complete preoperative study for anatomic delineation of the carotid arteries and their intracranial branches. In the patient considered a candidate for carotid endarterectomy, a full angiographic examination includes bilateral visualization of the extracranial arteries, evaluation of hemispheric blood flow, and aortic arch imaging. Selective views are added to aid in the diagnosis of ulcerative lesions and provide additional information on the vertebrobasilar system. Angiography can also help rule out other causes of neurologic symptoms, such as siphon and branch stenoses, cerebral aneurysms, tumors, and arteriovenous malformation. The invasive nature of cerebral angiography—with its associated complications and high cost—has led to the increasing use of duplex ultrasound for the selection of
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patients for carotid endarterectomy.[54] Angiography also requires needle puncture of an artery, which may be diseased in many of these patients, making the procedure painful and technically difficult. The injection of a contrast medium can cause transient renal dysfunction or lead to dependency on renal dialysis in high-risk patients.[55] Mechanical injury from catheter manipulation can result in acute arterial occlusion, distal embolization, arterial dissection, and hematoma formation. Furthermore, neurovascular complications such as TIAs and strokes have also been reported.[56] Carotid artery thrombosis can occur in patients with plaque dissection or a “string sign” (greater than 90% luminal narrowing) at time of angiography. The overall incidence of complications following angiography ranges from 0.2 to 2% of cases. Magnetic resonance angiography (MRA) has been introduced to overcome the limitations seen with duplex scanning. It is not operator-dependent, it can assess the intracranial circulation and aortic arch, and calcified vessels do not obstruct its signals. A comparison study of MRA, duplex scan, and angiography has shown 100% sensitivity and 92% specificity between MRA and angiography when lesions with greater than 70% stenosis were studied.[57] The greater cost and limited patient access associated with MRA are the principal objections to this test being used as a screening tool of cerebrovascular disease rather than duplex scanning. Recently, computed tomographic angiography (CTA) has also been used effectively to measure arterial cross-sectional reduction and characterize plaque composition.[58]
DESCRIPTION OF CAROTID ENDARTERECTOMY Preparation of the patient for carotid endarterectomy includes the establishment of an adequate intravenous route for fluid replacement, invasive monitoring in selected cases, and strict pharmacologic control of blood pressure. An intra-arterial catheter in the radial artery is employed for continuous monitoring of arterial blood pressure. The systolic arterial blood pressure is regulated within 20– 30 mmHg of the patient’s baseline pressure to prevent systolic hypo- or hypertension. General anesthesia is preferred by the authors; however, local anesthesia or cervical block anesthesia may be employed based on the surgeon’s or anesthesiologist’s preference. Surgical accessibility of the carotid arteries and accuracy of diagnostic tests for prediction of severity of disease have stimulated performance of carotid endarterectomy for extracranial carotid occlusive lesions. The skin incision may follow the anterior border of the sternocleidomastoid, or alternatively, a transverse incision may provide a better cosmetic result. The incision is extended through the platysma and superficial cervical fascia, and the sternocleidomastoid is mobilized along its anterior border. Next, the anteromedial border of the internal jugular vein is mobilized for its length and the common facial vein, which usually marks the carotid bifurcation, is ligated and divided along with any other medial venous tributaries. A well-placed
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self-retaining retractor is used to displace the sternomastoid muscle and the internal jugular vein laterally and posteriorly, which allows unobstructed visualization of the bulb and surrounding sheath (Fig. 52-5). Division of the ansa hypoglossi, which supplies the strap muscles of the neck, may be unavoidable and does not result in noticeable residual weakness. It also becomes useful in retracting the hypoglossal nerve atraumatically. The common, external, and internal carotid arteries are isolated by sharp dissection. Manipulation of the carotid bulb and proximal internal carotid artery is avoided to preclude dislodging any intraluminal debris. Should bradycardia or hypotension be reported by the anesthesiologist during the dissection of the carotid bulb, 0.5–1.0 mL of 1.0% Lidocainew is injected at the bifurcation into the area of the carotid body nerve.[59] Generally, dissection is carried superiorly on the internal carotid artery until the hypoglossal nerve is identified. In case of a low-lying carotid bifurcation, the hypoglossal nerve may cross the internal carotid artery more inferiorly than usually expected. Surgical dissection is more difficult when the bifurcation of the common carotid is anatomically high in the neck and distal exposure of the internal carotid artery is restricted by the overlying ramus of the mandible. In such cases, mobilization of the 12th nerve is aided by transecting the descending ansa hypoglossi as well as arterial and venous branches supplying the sternocleidomastoid muscle, which tether the nerve posteriorly. Division of the posterior belly of the digastric muscle and gentle downward traction of the internal carotid are also used to facilitate its exposure. Mandibular subluxation, accompanied by nasotracheal intubation, can be used in the unusual patient with a high distal exposure, generally at or above the second cervical vertebra.[60,61] After systemic heparinization, atraumatic vascular clamps are applied to the distal internal carotid, common carotid, and external carotid arteries. The superior thyroid artery, a first branch of the external carotid artery, can be temporarily controlled with a vessel loop. The arteriotomy is begun in the common carotid artery in its anterolateral location and continued into the internal carotid artery for approximately 3–4 cm, avoiding the region of the carotid body (Fig. 52-6).
The arteriotomy should be extended beyond all grossly visible disease present in the internal carotid artery. When a shunt is used, the distal end is inserted first to observe collateral backbleeding and expel air or atheromatous debris from the tubing (Fig. 52-7). The shunt is then gently secured using an appropriate atraumatic vascular clamp, a vessel loop, or a Rummel tourniquet. The proximal end of the shunt is then carefully inserted into the common carotid along its central axis to avoid arterial dissection. The time for arteriotomy and insertion of the shunt (ischemia time) is kept to a minimum. The endarterectomy is begun at the site of greatest disease generally the posterolateral carotid bulb, using a freer elevator, and carried distally into the internal carotid artery. A plane is developed between the diseased intima and the circular medial fibers to achieve a feathering of the plaque at its distal end on the internal carotid artery (Fig. 52-8). If the observed end point is irregular or associated with an intimal flap, the arteriotomy must be extended beyond the limit of the established end point and a new end point established. The distal intima can also be secured by use of interrupted tacking sutures. Proximally, the plaque is transected sharply with Pott’s scissors in the common carotid artery. The plaque is extracted from the external carotid artery by eversion endarterectomy. The endarterectomized surface of the carotid artery is inspected carefully, irrigated with heparinized saline, and shreds of residual tissue removed by gentle teasing in a transverse direction. Meticulous irrigation and debridement of this surface prevents residual atheromatous material or thrombus from being washed upstream upon resumption of blood flow. Primary arterial closure can be performed with the shunt still in place using fine monofilament vascular suture (5-0 or 6-0) from each direction and continued until approximately two thirds of the arteriotomy is closed. The shunt is then removed, the arteries are flushed, vascular clamps are reapplied, and the closure is completed within another 1–3 min. However, during the last 15 years, patch closure with saphenous vein has been recommended for the purposes of reducing perioperative stroke and death[62,63] as well as restenosis.[64,65] AbuRahma et al.[66] reported a randomized clinical trial in which carotid endarterectomy with patch angioplasty (vein or PTFE) was less likely than
Figure 52-5. Exposure of the carotid bifurcation. A small clip has been placed on the superior thyroid artery. The hypoglossal nerve is seen crossing the internal carotid artery.
Figure 52-6. An arteriotomy has been made exposing the ulcerative plaque.
Chapter 52.
Figure 52-7. A Javid shunt has been placed prior to endarterectomy.
primary closure to cause perioperative stroke. Although some authors[67] have expressed concern about the higher incidence of perioperative stroke and recurrent stenosis observed with use of Dacron patches, O’Hara and colleagues[68] recently reported no significant differences in patch closure with vein or Dacron. If satisfactory hemostasis is achieved, heparin reversal with protamine is unnecessary prior to closure of the skin incision. Early adherence of fibrin and platelets may be retarded by heparin’s residual effect.[69] Reversal of heparin by protamine sulfate has also been reported to increase the incidence of postendarterectomy stroke.[70] Consequently, care must be exercised in deciding to reverse the effects of heparin. Intraoperative Doppler assessment of the internal carotid artery is performed to check adequacy of flow. If there is any doubt about the adequacy of flow, intraoperative ultrasonography or arteriography is obtained. Any unsuspected technical defect visible on arteriogram must be repaired, which generally then indicates patch closure, if primary closure was used initially. The skin incision is closed in layers using interrupted sutures in the platysma muscle and subcutaneous tissue and a continuous subcuticular suture for
Figure 52-8. The operative specimen illustrates the fine tapering of the distal plaque removed from the internal carotid artery.
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the skin. A closed suction drain may be employed at the surgeon’s discretion. Upon completion of the operation, the patient is monitored in the recovery room or intensive care unit for abnormalities in blood pressure, arrhythmias, or the development of neurologic deficits. If stable after 3 –4 h, the patient may be transferred to a surgical floor without need for further intensive unit care. Antiplatelet therapy (aspirin) is begun perioperatively and maintained postoperatively. Most patients are discharged on the first (80%) or second postoperative day.[71,72] Cerebral embolization of platelet aggregates or atheromatous material from carotid plaque is probably the most important cause of neurologic deficits or strokes in the postoperative period (Table 52-1). Rough or excessive handling of the carotid bifurcation, inadequate removal of loose medial fibers after endarterectomy, and the technically improper use of a shunt all increase the likelihood of emboli. The second most important cause of operative neurologic deficits is cerebral ischemia from inadequate or impaired collateral circulation. Cerebral ischemia may also result from hypotension during the operative procedure, leading to arterial thrombosis of intracerebral arteries. A reliable method to ensure adequate cerebral blood flow during carotid clamping is the use of a temporary indwelling shunt. However, most patients can tolerate temporary carotid clamping without deleterious effects, as has been determined by judging the patient’s conscious response to carotid clamping during endarterectomies performed under local anesthesia.[73] In addition, use of shunt may be associated with its own set of technical misadventures, such as embolization of atheromatous debris or air bubbles at the time of shunt introduction, mechanical intimal injury, and an inadequate end point due to poor visualization, which, if not recognized, can result in arterial thrombosis. To maximize benefits and minimize complications, a temporary shunt may be used routinely or selectively based on neurologic testing
Table 52-1.
Complications of Carotid Endarterectomy
1. Wound a. Hematoma b. Infection 2. Surgical technique a. Carotid artery Disruption False aneurysm Carotid-cavernous arteriovenous fistula Graft infection b. Cranial nerve injury c. Embolism d. Cerebral ischemia 3. Postoperative period a. Stroke Thrombosis of endarterectomized segment Hypotension Hypertension b. Myocardial infarction c. Recurrent stenosis
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Figure 52-9. Mechanisms responsible for postoperative stroke have been classified in great detail. Most of these events could be assigned to three broad etiologic categories: (1) stroke resulting from inadequate cerebral perfusion or embolization during the carotid endarterectomy; (2) stroke due to embolization or fresh thrombus or thrombotic occlusion after restoration of flow in the carotid artery; (3) stroke from intracerebral hemorrhage probably associated with reperfusion injury. More than 50% of the postendarterectomy neurologic events are related to the first two of these three categories. On careful review of the VA Study, four of five postoperative strokes were associated with technical errors at the endarterectomy site. The mechanism of stroke will obviously influence postoperative management, but at the outset the cause may be suspected but is unknown. Therefore, clinical decisions are best keyed initially to the time of stroke discovery and to the findings of appropriate imaging studies. (B) If general anesthesia is used, patients should be awakened in the operating room so that neurologic status can be assessed. If it is apparent that the patient has experienced a postoperative stroke, we recommend reintubation and exploration of the wound. If there is no carotid artery pulse or if the Doppler signal is abnormal, the arteriotomy is reopened and appropriate corrective measures are carried out. If the pulse and Doppler interrogation are normal, an intraoperative arteriogram is performed including intracranial views. The management of specific findings is discussed below. If the arteriogram is normal, the arteriotomy and neck incision are closed and a CT scan of the brain is obtained later. If ambiguity exists concerning the presence or absence of lateralizing signs or symptoms, the patient is transferred to the recovery room. (C) If a stroke occurs or is discovered during the first 1 – 3 h postoperatively, a duplex ultrasound scan is obtained expeditiously. If the scan reveals occlusion, stenosis, or low flow, reexploration is performed. If the scan is negative, a CT scan is performed to evaluate the presence or absence of intracerebral hemorrhage, which, if present, would indicate medical management. If the CT scan is negative, percutaneous (transfemoral) arteriography is recommended to direct further therapy. (D) The details of immediate or early reexploration for a thrombosed or technically defective carotid endarterectomy are beyond the scope of these comments, but briefly they involve (1) gentle removal of any thrombus present, (2) correction of technical defects, and (3) closure with vein patch angioplasty. A completion arteriogram is indicated to confirm a good result and to exclude distal emboli. (E) For delayed strokes, a CT scan is obtained to evaluate the presence or absence of intracerebral hemorrhage, which for delayed stroke is generally a part of the reperfusion injury syndrome. If no
Chapter 52.
with the patient under local anesthesia, when the internal carotid artery back stump pressure is low (less than 50 mmHg), or when electroencephalographic changes occur following carotid clamping.[74] Patients with a past history of stroke, bilateral carotid disease, or contralateral occlusion are also generally considered shunt candidates. Technical errors, cerebral emboli, and carotid thrombosis—not inadequate collateral flow—account for most of the neurologic deficits after carotid endarterectomy. Therefore, in the patient who awakens with a neurologic deficit or a suspected stroke in the early postoperative period, immediate surgical reexploration may be indicated.[75] Noninvasive carotid artery assessment is less reliable postoperatively, and angiography delays the potential therapeutic correction of cerebral ischemia. At reoperation, carotid blood flow is assessed using Doppler examination. If the internal carotid is found to be patent, an arteriogram is obtained through a common carotid puncture proximal to the endarterectomy site. If a pulseless thrombosed carotid is found or significant irregularities are noted on operative angiography, the patient is heparinized, and the endarterectomy site explored. The arteriotomy is opened and the internal carotid is allowed to backbleed to remove any thrombus that may have formed distally. If no backbleeding is observed, a Fogarty catheter may be introduced and a thrombectomy restricted to the extracranial cervical carotid artery is performed. Once backbleeding is established, a temporary shunt is inserted to ensure restoration of cerebral blood flow. If technical errors are observed, revision of the operative site is indicated. Patch angioplasty with saphenous vein is recommended and a completion arteriogram obtained to confirm a technically satisfactory result. An algorithm[75] for the management of stroke after carotid endarterectomy (Fig. 52-9) has been helpful. Thrombosis is the most common cause of postoperative stroke following carotid endarterectomy, and prompt reexploration is associated with significant neurologic improvement as compared to those patients who are not reexplored.[76] Transient postoperative dysfunction of the hypoglossal, recurrent laryngeal, or marginal mandibular branch of the facial nerve has also been reported following carotid endarterectomy.[77] Injury to either the vagus nerve or recurrent laryngeal nerve produces paralysis of the ipsilateral vocal cord, hoarseness, and loss of an effective cough
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mechanism. In the patient with a history of prior carotid endarterectomy or thyroidectomy, preoperative laryngoscopy is useful to evaluate vocal cord function. Bilateral recurrent laryngeal or vagal nerve injuries may be life-threatening because of airway obstruction, and tracheostomy may be required. Vagal nerve injury may also occur during dissection of the carotid artery or by entrapment of the nerve by incorrect placement of a clamp or retractor at the time of common carotid occlusion. Due to its proximity to the carotid bifurcation, the hypoglossal nerve is also at high risk for injury. Trauma to this nerve results in paralysis of the ipsilateral tongue and deviation of the tongue to the side of injury. If the injury is severe, clumsiness during speech and mastication can occur. The marginal mandibular branch lies between the platysma and the deep cervical fascia and may be injured due to pressure from a self-retaining retractor or a poorly placed incision. Injury to the nerve is associated with a temporary or at times a permanent drooping of the corner of the mouth on the operated side. Alterations of blood pressure after carotid endarterectomy are associated with transient and permanent neurologic deficits as well as myocardial infarction. Hypertension and hypotension have been reported in up to 66% of patients following carotid endarterectomy,[78] making their management an important overall aspect of patient care. Transient hypotension and bradycardia are occasionally observed due to stimulation of the carotid body nerve[79] and can be controlled with injection of 0.5– 1.0 mL of 1% Lidocaine into the nerve at the bifurcation. Persistent postoperative hypotension usually responds to fluid administration if the patient’s central venous pressure is low, but a few require administration of a vasoconstrictor such as neosynephrine or phenylephrine. Careful cardiac monitoring is a must if vasopressors are employed. Postoperative hypertension probably occurs secondary to a loss or alteration of cerebrovascular autoregulation. Cerebral hyperperfusion, subclinical cerebral edema, and elevated intracranial pressure, alone or in combination, lead to an increase of central and peripheral norepinephrine levels and a subsequent elevation of the systemic blood pressure.[80] Good preoperative blood pressure control aids in the prevention of postoperative hypertension, but if the systolic blood pressure rises above 180 mmHg or the diastolic pressure exceeds 100 mmHg, intravenous vasodilators or short-acting beta blockers must be
hemorrhage is found, a duplex scan is performed to direct further therapy. If a technical defect or significant thrombus is found, it can be dealt with by reoperation if the evaluation has been expeditious, as it may be for an early in-hospital event. If the delay exceeds 3 h after the occurrence of stroke, however, observation becomes appropriate. If the CT and duplex scans are normal, transfemoral arteriography is recommended to exclude an intimal flap, intracranial embolism, or other cause. (F) Arteriographic evidence of an intracranial carotid branch occlusion should stimulate consideration for selective thrombolytic therapy delivered to the area of thrombus distal to the endarterectomy via microcatheter. With the decision to proceed with thrombolytic therapy, it should be recognized that its value in the postoperative patient versus its associated complications has not been rigorously evaluated and its use is based on anecdotal case experience. However, in institutions with rapid response evaluation of stroke victims within 3 h of the event, this option can be considered. (G) Most agree that operating in the presence of a dense neurologic deficit may be associated with higher risk. The area between a mild and severe deficit will continue to be unclear in the absence of better early markers of ischemic damage to the cerebral microcirculation and definitive comparative studies. Elapsed time after a stroke may also influence the choice of operative or conservative therapy. Beyond a certain short interval (3 h), the risk of operation on acute strokes and exacerbating the ischemic injury or risking intracranial hemorrhage escalates.
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utilized to bring the blood pressure into the range of 140–160 mmHg. Oral preoperative antihypertensive agents should be restarted as soon as the patient can tolerate them. Postoperative hypertension is associated with a 10% incidence of neurologic deficits and lasts longer than 24 h in 20% of patients.[81] Headaches and seizures are unusual neurologic complications associated with carotid endarterectomy. Although minor headaches are occasionally encountered in the postoperative period, severe headaches are rare. They may be attributed to increased flow following endarterectomy and subsequent cerebral vessel distension. This hypothesis is supported by the increased incidence of headaches in patients with preoperative high-grade carotid stenosis or severe hypertension postoperatively. Severe headaches localized to the operated side have also been found to correlate with the onset of seizures. Seizures are also found with increased incidence in patients with high-grade carotid stenosis or presence of prior strokes. Since their CT scans are normal or unchanged and carotid repairs are patent in these patients, a loss of autoregulation in the cerebral blood flow seems to be the most likely cause of these seizures. Furthermore, an increase of more than 100% in cerebral blood flow has been documented in patients with postoperative seizures following carotid endarterectomy.[82] The patient with a high-grade stenosis or prior stroke who develops a severe ipsilateral headache following carotid endarterectomy should be started prophylactically on phenytoin. The patient who develops seizures should also be started on anticonvulsants, and CT scan or magnetic resonance imaging (MRI) of the head must be obtained to rule out the presence of cerebral hemorrhage.[83]
RANDOMIZED CLINICAL TRIALS The key issue is whether the risks of stroke and stroke/death are reduced after carotid endarterectomy in patients also receiving optimal medical care versus optimal medical management alone. Prior to 1991, the only large randomized prospective study that compared operative and medical treatment appeared in 1970.[28] This study demonstrated that while patients randomized to carotid endarterectomy had a lower incidence of stroke and death during long-term followup, this benefit was offset by a high perioperative stroke rate of 12%. Previously, the appropriateness of carotid endarterectomy was criticized when the Rand Corporation randomly reviewed 1302 Medicare claims received for the performance of this operation in three different geographic areas in 1981.[84] Two thirds of the patients were judged to have had the operation for equivocal or inappropriate reasons. Equally alarming was the finding that 9.8% of the patients suffered a major complication: stroke with residual deficit at the time of discharge or death within 30 days of surgery. These authors concluded that carotid endarterectomy was overused in this country and that the procedure should be limited to the hospitals and surgeons with high standards and low rates of complications.[85] These concerns led to the initiation of multicenter randomized trails evaluating the efficacy of carotid endarterectomy combined with best medical care
versus medical therapy alone in the prevention of stroke and death. Results of these clinical trials determined indications for carotid endarterectomy and its role in the prevention of stroke.
CLINICAL TRIALS ON EFFICACY OF CAROTID ENDARTERECTOMY FOR SYMPTOMATIC STENOSIS The NASCET trial was conducted at centers primarily located in the United States, Canada, and Europe.[14] Participating surgeons reported a less than 6%, 30-day peri-operative morbidity and mortality (the average for participating surgeons was 3.4% by their audited past records). Patients were eligible for the trial if less than 80 years of age with a hemispheric TIA or a non-disabling stroke within 180 days of entering the trial and angiographic evidence of an ipsilateral carotid stenosis of 30 –99%. All patients receive optimal medical management, including control of risk factors and aspirin therapy. A group of 659 patients with a 70 –99% stenosis of the internal carotid artery and either a nondisabling stroke (32%) or one or more TIAs (68%) underwent randomization into optimal medical therapy alone (331 patients) or medical management combined with operative intervention (328 patients). The perioperative stroke morbidity and mortality rate was 5.8% for the surgical group, with a mortality rate of less than 1%. During a period of similar duration, there was just over a 3% stroke morbidity and mortality for the medical group. After a 2-year follow-up by life-table analysis, 26% of the medically treated patients but only 9% of the surgical patients had experienced a fatal or nonfatal ipsilateral stroke. This yields an absolute risk reduction of 17% at 2 years for any ipsilateral stroke if the patient undergoes carotid endarterectomy.[14] A secondary analysis of these patients with high-grade stenosis showed that those with less severe stenosis (70 – 79%) had a lower risk of stroke; therefore, their gains from surgical intervention were smaller than those of patients with more severe stenoses (90–99%). Among patients with stenoses of 50–69%, efficacy of carotid endarterectomy was also confirmed.[86] The 5-year rate of any ipsilateral stroke (failure rate) was 15.7% among patients treated surgically and 22.2% among those treated medically ( p ¼ 0.045). Carotid endarterectomy was less effective in this group of patients with moderate stenoses. Conversely, among patients with less than 50% stenosis, carotid endarterectomy was not effective, with a reported failure rate in the surgical group (14.9%) that was not significantly different than the medically treated group (18.7%, p ¼ 0.16). Complementary beneficial results were observed in the ECST[16] and the Veterans Administration Symptomatic Endarterectomy Trial.[17] The ECST was initiated in 1981 and involved 80 centers in 14 European countries. It was designed to randomize patients who had experienced a TIA, transient monocular blindness, or nondisabling ischemic stroke attributable to ipsilateral proximal carotid occlusive disease to carotid endarterectomy combined with best medical care
Chapter 52.
(60% of the patients) versus best medical care alone. Best medical care included aspirin administration, treatment of any essential hypertension and advice to quit smoking. The patients were stratified into three groups: mild (less than 30%), moderate (30–69%), or severe (70–99%) carotid stenosis. An interim report issued in 1991, 10 years after the initiation of this trial, showed that 778 symptomatic patients with severe (70–99%) carotid stenosis underwent randomization into immediate operative intervention (455 patients) or medical therapy alone (323 patients). The total risk of surgical death, surgical stroke, ipsilateral ischemic stroke, or any other stroke was 12.9% for the surgical group and 21.9% for the medical group at a follow-up of 3 years ( p , 0.05), confirming the efficacy of carotid endarterectomy, despite a 30-day stroke and death rate of 7.5%. In the same report, 374 patients who had mild carotid stenosis (0 – 29%) were randomized into surgical (219 patients) or medical (155 patients) therapy. At a 3-year follow-up, there was little risk of ipsilateral stroke in either the medical or surgical group; the perioperative stroke morbidity and mortality rate of carotid endarterectomy erased any benefit that surgical intervention provided to this cohort of patients.[13] The Veterans Administration Symptomatic Trial Cooperative Studies Program was designed to determine the role of carotid endarterectomy in preventing stroke from symptomatic carotid stenosis and was initiated at 13 VA medical centers in 1986.[17] Only men presenting within 120 days of onset of symptoms that were consistent with TIAs, transient monocular blindness, or recent nondisabling strokes were medically screened. Patients with ischemic symptoms attributed to a greater than 50% stenosis of the ipsilateral carotid artery were randomized to either carotid endarterectomy plus best medical care versus best medical care alone. Best medical care in this study included daily aspirin administration and treatment of all coexisting medical disorders. The primary end points selected as evidence of treatment failure included cerebral or retinal infarction, crescendo TIAs, or death from any cause within 30 days of randomization. A total of 189 patients were entered into the trial after initial screening of nearly 5000 patients. Carotid endarterectomy was performed in 90 of the 91 patients randomized to surgical treatment; one patient suffered a stroke prior to operation. The trial was terminated early because of the NASCET and ECST results. However, at a mean follow-up of 11.9 months, there was a significant reduction in the combined incidence of stroke and crescendo TIA in the patients who underwent carotid endarterectomy (7.7%) versus nonsurgical patients (19.4%). Among the 129 patients with carotid artery stenosis greater than 70%, the benefit of carotid endarterectomy was even more pronounced. The surgical group had a stroke and crescendo TIA rate of 7.9%, versus 25.9% for the medical group. Discounting the one preoperative stroke, carotid endarterectomy was performed with a perioperative stroke and mortality rate of 5.5% in multiple centers and among relatively high-risk patients.
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CLINICAL TRIALS ON EFFICACY OF CAROTID ENDARTERECTOMY FOR ASYMPTOMATIC STENOSIS The Veterans Administration Asymptomatic Trial Cooperative Studies Program was initiated at 11 VA medical centers in 1982 to assess the effect of carotid endarterectomy on the combined incidence of neurologic events, TIA, and stroke in patients with asymptomatic carotid stenosis.[87,88] The trialists randomized 444 male patients with documented angiographic diameter-reducing stenoses of 50% or greater, which, when coupled with a positive ocular pneumoplethysmography (OPG) or duplex scan, constituted area-reducing stenoses of $ 75%. Patients were randomized to optimal medical management and carotid endarterectomy (211 patients) versus optimal medical management alone (233 patients). The 30-day postrandomization permanent stroke and death rate was 4.3% for the surgical group[89] and 9.7% including neurological complications of angiography for the entire group. The combined incidence of all neurological events[89] was 24.5% for the medical group, which was reduced significantly ( p , 0.002) in the surgical group to 12.8%. If only ipsilateral events were considered (75% of all neurologic events), the incidence was 20.6% in the medical group and 8.0% in the surgical group ( p , 0.001). Reduction in ipsilateral stroke alone favored the surgical group by a trend of 2:1, however, the data lacked statistical significance because of the surgical morbidity and mortality as well as the small sample size. The Asymptomatic Carotid Atherosclerosis Study (ACAS), sponsored by the National Institutes of Health,[54] investigated patients with asymptomatic carotid stenosis in a trial with many similarities to the VA trial. The threshold stenosis for randomization was a 60% diameter-reducing lesion. In addition, precise duplex scanning criteria permitted randomization to the medical group without arteriography. A total of 1662 patients with asymptomatic carotid stenosis were randomized to aspirin therapy and best medical care versus aspirin, best medical care, and carotid endarterectomy. After a median follow-up of 2.7 years, the aggregated risk over 5 years of ipsilateral stroke and any perioperative stroke or death in the surgical group was estimated to be 11.0% for patients treated with medical therapy alone as compared with 5.1% for patients treated with medical therapy plus carotid endarterectomy. Although this represented a relative risk reduction of 53%, absolute risk reduction in stroke was noted to be approximately 1.2% per year. The overall 30-day stroke and death rate for the surgical cohort was 2.3%. However, of the 414 patients in this surgical cohort who underwent arteriography prior to carotid endarterectomy, the arteriographic stroke complication rate was 1.2% which was included in the overall perioperative complication rate of 2.3%. These data have formed the basis for modern recommendations on the use of carotid endarterectomy in asymptomatic patients in this country. The VA trial established that overall neurological events including TIA and stroke could be reduced significantly after carotid endarterectomy,[88] while the larger ACAS trial established this goal for stroke alone.[54] Some clinicians are cautious
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about the selection of patients for operation, particularly in the 60 –79% stenosis category due to the anticipated absolute benefit of only 1.2% per year.[89] Unfortunately, the ACAS investigators did not have adequate arteriographic data from the medical treatment arm of the study to categorize differential neurological event rates in patients with 60–79% stenosis as compared with 80– 99%. Nevertheless, our current recommendation favors endarterectomy, particularly in patients with stenoses of 80–99% in institutions that have audited 30-day stroke and death rates of less than 3%. In studying the natural history of asymptomatic stenosis, it should be acknowledged that only one fifth of the patients in the medical group developed neurological symptoms. Although presence of a high-grade stenosis (arteriographic diameter reduction of .50% or a calculated area reduction of .75% in the VA trial and 60% diameter stenosis angiographically in ACAS), the degree of stenosis may be only one of several factors determining incidence of stroke. The current clinical challenge is to identify factors such as ultrasonic plaque morphology, incidence of silent CTconfirmed cerebral infarction, status of collateral cerebral circulation, and combinations of clinical risk factors such as hypertension, coronary artery disease, smoking, and peripheral vascular disease, which then superimposed upon a highgrade threshold stenosis will result in an increased risk of stroke as a first event. These data support the selective use of carotid endarterectomy in centers with low complication rates[90] among better-risk patients whose life expectancy is 5 or more years.
INDICATIONS FOR CAROTID ENDARTERECTOMY: SPECIAL CONSIDERATIONS Recommendations regarding the use of carotid endarterectomy were carefully reviewed by consensus panels of the American Heart Association in 1995[91] and again in 1998.[92] Indications were categorized into the following groups: proven, acceptable but not proven, uncertain, and proven inappropriate. For patients with symptomatic disease including recent TIA and nondisabling stroke who are good risks with a surgeon whose surgical morbidity and mortality is less than 6%, current indications include the following: 1.
2.
3.
Proven: One or more TIAs in the past 6 months and carotid stenosis $70% or mild stroke within 6 months and a carotid stenosis of $70%. Recent recommendations from the NASCET trialists have also included patients with moderate carotid stenosis, 50 –69% in this group of indications for carotid endarterectomy.[86] Acceptable but not proven: Progressive stroke and stenosis $70% or carotid endarterectomy ipsilateral to TIAs and a stenosis $ 70% combined with required coronary artery bypass grafting. Uncertain: TIAs with stenosis , 50% or TIAs with stenosis of , 70% combined with coronary artery
4.
bypass grafting or symptomatic acute carotid thrombosis. Proven inappropriate: Moderate stroke with stenosis .50%, not on antiplatelet therapy; single TIA .50% stenosis, not on antiplatelet therapy; high-risk patient with multiple TIAs not on antiplatelet therapy, stenosis .50%; high-risk patient, mild or moderate stroke stenosis .50%, not on antiplatelet therapy; global ischemic symptoms with stenosis of .50%; acute dissection, asymptomatic on heparin.
For patients with asymptomatic carotid occlusive disease whose surgical risk is , 3% and life expectancy exceeds 5 years, the following indications are recommended: 1.
2.
3.
4.
Proven: Ipsilateral carotid endarterectomy is acceptable for stenotic lesions ($60% diameter reduction) with or without ulceration and with or without antiplatelet therapy, regardless of contralateral disease status. Acceptable but not proven: Unilateral carotid endarterectomy simultaneously with coronary artery bypass grafting for stenotic lesions ($60%) with or without ulceration and with or without antiplatelet therapy, regardless of contralateral artery status. Uncertain: Unilateral carotid endarterectomy for stenosis .50% with B or C ulcers irrespective of contralateral internal carotid artery status. Proven inappropriate: Patients with stenoses . 60% or patients whose risk of operation exceeds 3% or life expectancy is . 5 years.
Crescendo TIAs are defined by a change in symptom pattern in the patient with symptomatic carotid disease. There must be an increase in the frequency of symptoms over a period of one to several days, an increase in the duration of symptoms with episodes lasting longer than the primary event, and/or increased severity of ischemia with the development of greater or new transient motor, sensory, or visual defects. An evaluation of 12 of the 189 patients in the VA symptomatic trial[17] identified as having an internal carotid stenosis greater than 50% developed crescendo TIAs (Fig. 52-10) (see color plate). All 12 of these patients were in the medical group and were treated with intravenous heparin and underwent emergent carotid endarterectomy within 24 h of onset of symptom progression. None suffered a postoperative complication.[17] Other reports in the surgical literature of patients with crescendo symptoms have also shown that carotid endarterectomy can be undertaken with good results.[94] The patient with crescendo TIAs constitutes a neurologic emergency and should undergo immediate anticoagulation and prompt carotid endarterectomy by an experienced surgical team. Completed stroke with recovery and a minimal to modest neurologic deficit is an indication for operation if accompanied by appropriate ipsilateral carotid disease, as confirmed in the symptomatic trials.[14,16,17] Other potential sources of infarction—such as intracranial small or large arterial disease, emboli arising from the heart, and other
Chapter 52.
Figure 52-10. Preoperative arteriogram of a 64-year-old man who developed crescendo TIAs. Note the typical extensive plaque of internal, external, and common carotid arteries in the operative specimen (see color plate).
systemic disorders—must be ruled out. CT scan or MRI is also indicated to determine the extent of the infarct, whether it is hemorrhagic or ischemic in nature, and to exclude tumors or vascular malformations as their cause. In the presence of a fixed neurological deficit or larger central cerebral infarct (CT/MRI), operative intervention generally is delayed 4 – 6 weeks or until the patient’s neurologic improvement reaches baseline. The use of a shunt is also recommended, since the status of cerebral flow autoregulation is difficult to determine at the time of operation. A preoperative angiogram (contrast or MRA) may be obtained after noninvasive tests have been performed and the patient is considered to be a good surgical candidate. The operative team must be able to perform an endarterectomy in this group of higher-risk patients with a morbidity and mortality rate of less than 6%. Stroke in evolution or progressive stroke occurs when an acute neurologic deficit progresses within hours or days in a sequential series of acute exacerbations to a major stroke.[93] In Mentzer et al. series,[94] 12 of 17 patients who underwent emergent carotid endarterectomy for fluctuating and progressive neurologic deficits improved, but only 3 of 26 patients treated medically improved. Furthermore, only 1 patient in the surgical group deteriorated, compared to 14 in the medical group. At 6 months, 80% of the nonoperated patients had some degree of neurologic deficit, as opposed to 53% in the operated patients. Moderate or severe deficits were considerably more common in the nonoperative group. Patients should undergo a rapid diagnostic workup, which should include a carotid duplex scan to document the presence of a high-grade carotid stenosis or an irregular plaque with soft thrombus, followed by CT scan or MRI to exclude a hemorrhagic stroke. Prompt anticoagulation and operative intervention should follow if the patient is medically fit. Angiography carries a higher risk in these patients and further delays the initiation of surgical therapy. An acute stroke due to acute occlusion and associated with a neurologic deficit lasting longer than 24 hours continues to be a challenging problem in surgical management. Patients are generally considered neurologically unstable, morbidity
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or mortality is high, and reperfusion of ischemic tissue can result in hemorrhagic transformation of an originally ischemic stroke. Carotid endarterectomy may be applicable only under extremely limited circumstances, depending on the time of onset of the deficit and the timeliness of surgical intervention.[95] Concurrent carotid endarterectomy and coronary artery bypass are performed in patients with existing comorbid factors, and each procedure carries its own set of risks.[96 – 98] As originally presented by Bernhard and associates,[96] the combined procedure has been associated during more recent years with a somewhat higher combined stroke, myocardial infarction, and mortality than when either procedure is performed alone.[97] Brener et al.[98] performed a meta-analysis on three operative strategies: simultaneous carotid and coronary bypass grafting, carotid surgery followed by coronary artery bypass grafting (CABG), and CABG followed by carotid surgery. The analysis reported that perioperative stroke rate was similar if the carotid and coronary procedures were combined or if carotid endarterectomy preceded CABG. However, the frequency of stroke was significantly greater if CABG preceded the carotid operation. Conversely, the frequency of myocardial infarction ( p ¼ 0.01) and death ( p ¼ 0.02) was greater when carotid endarterectomy preceded CABG. In the absence of a randomized clinical trial comparing these various options, each institution and surgical group must audit their results and determine the best mode of operative intervention. More recent publications on the combined procedure[99] have demonstrated moderately reduced 30-day stroke and death rates from the combined procedure. If an institution audits its results appropriately and is able to achieve complications in the 5– 7% range, combined procedures are generally indicated. This would be particularly true of a high-grade symptomatic lesion with CABG for which the combined procedure is routinely recommended in our service as well as the patient with bilateral high-grade asymptomatic lesions or unilateral occlusion and contralateral asymptomatic high-grade stenoses. The exception to the combined procedure would be the unilateral high-grade asymptomatic stenosis with a more normal contralateral artery, which on our service would be treated by CABG and then a delayed carotid endarterectomy well after recovery from the cardiac surgical procedure. In the future, a cooperative trial to evaluate these various options will become essential. It is also possible that carotid artery stenting may be used in this group if stenting is proven to be efficacious in its randomized trials. Operation on patients with tandem extracranial and intracranial lesions may carry an increased risk.[100] The course of the internal carotid artery in the neck extends from its bifurcation to the base of the skull, where it continues intracranially as the petrous segment through the carotid canal in the petrous portion of the temporal bone; the cavernous segment follows the sphenoid bone to emerge intradurally at the circle of Willis. In the cerebral circulation, the carotid siphon is said to be the second site, after the carotid bulb, most likely to develop atherosclerotic changes. Roederer et al.[101] concluded that patients with severe carotid bulb lesions should be referred for carotid endarterectomy.
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Accompanying siphon stenoses did not result in greater risk for recurrent symptoms. Thus, nonoperative management should be considered only when the degree of siphon stenosis exceeds that of the lower carotid bulb lesion. External carotid endarterectomy has specialized indications. The combined stroke and TIA rate for those patients with an ipsilateral occluded internal carotid artery is as high as 20%.[102] In the presence of an internal carotid artery occlusion, the external carotid artery supplies blood flow to the ipsilateral hemisphere from a rich source of collaterals originating through the internal maxillary artery.[103] Tributaries from these collaterals provide a route for emboli. Strokes may occur due to emboli originating from external carotid arterial plaque, from the stump of the occluded internal carotid artery, or because of decreased flow from the available collateral circulation. In Gertler and Cambria’s[103] collective review, 48 of 52 patients who had external carotid endarterectomies for amaurosis fugax or hemispheric TIAs in the presence of an occluded internal carotid artery but a patent external carotid artery became asymptomatic; the other 4 were improved. There were no deaths and no perioperative strokes. Zarins et al.[104] have also reported increased ipsilateral and contralateral cerebral blood flow in patients who had undergone external carotid endarterectomy. In the symptomatic patient with an occluded internal carotid artery and a diseased external carotid artery, endarterectomy of the external carotid artery can be undertaken with good results. The more complex extracranial-intracranial (EC-IC) bypass previously had been recommended in selected patients with symptomatic internal carotid occlusions or distal occlusive disease. However, the cooperative trial results[105] demonstrated no benefit in stroke prevention over optimal medical management. In recent years, selection of patients using positron emission tomography (PET) scanning has identified a subset of patients who may benefit from EC-IC bypass.[106]
CAROTID ARTERY STENTING: AN ALTERNATIVE TO CAROTID ENDARTERECTOMY Although carotid endarterectomy (CEA) currently has been established as the preferred means for managing symptomatic[14,16,17] and asymptomatic[88,90] extracranial carotid stenosis, use of carotid artery stenting (CAS) has been expanded during recent years.[107 – 109] Three[110 – 112] randomized clinical trials comparing the efficacy of CAS and CEA have been conducted. In Europe, the Carotid and Vertebral Artery Transluminal Angioplasty Study (CAVATAS) investigators are comparing surgical intervention and angioplasty for treatment of carotid and vertebral occlusive lesions.[110] Among 504 patients randomized primarily to angioplasty alone (only 25% received stents) and considered suitable candidates for CEA, the 30-day disabling stroke and death rates were comparable—6.3% for CEA and 6.4% for the CAS group—with overall 30-day stroke and death of 9.8% for CEA and 10.0% for CAS. Phase II is now active and will utilize CEA versus CAS in symptomatic carotid
cases. The influence of these recently published data on cases randomized to CEA or CAS may be blunted by the somewhat higher than expected complication rate in the CEA group. A smaller clinical trial[111] was halted prematurely because of a higher than expected complication rate in the CAS arm of the study. However, concerns have been raised as to the investigators’ choice of an unacceptably small sample size, inadequate credentialing of the interventionalists performing CAS, and unrealistic complications from CAS before the trial was halted. Alberts and coauthors[112] described the methodology of another randomized clinical trial comparing CAS and CEA in 219 randomized symptomatic patients (stenoses 60–99%). The stated aim of the trial was to determine whether or not CAS was equivalent to CEA in the prevention of ipsilateral stroke, peri-procedural death (within 30 days), or vascular death within one year of treatment. However, this trial was discontinued by the manufacturer due to procedural and recruitment difficulties. Data from this clinical series, however, demonstrated a 30-day stroke and death rate for CEA of 4.5% and CAS of 12.1% and a primary endpoint rate of 3.6% for CEA and 12.1% for CAS ( p ¼ 0.022). In an equivalency analysis, this trial did not find that CAS was equivalent to CEA in symptomatic patients. Methodological flaws included limited experience with the procedure by some interventionalists, nonuniform antiplatelet regimens, absence of supervision by a designated principal investigator, and apparent lack of input to the trialists from an independent data monitoring and safety board (oversight committee). Conclusions regarding the results of these initial clinical trials await further review and do not provide conclusive data. However, as confirmed at a recent consensus conference,[113] CAS is recommended to treat extracranial carotid stenosis in selected subsets of patients with periprocedural complications that approach those reported for CEA. Nevertheless, a well-designed clinical trial is urgently required, particularly for good risk patients with primary atherosclerotic occlusive disease, if we are to advise our patients about the comparative efficacy of these two new procedures. Current practice suggests consideration for CAS in several areas: anatomically high internal carotid stenoses, carotid restenosis following prior CEA, radiation-induced carotid stenosis, and occasional high-risk patients due to severe medical co-morbidities. These indications were considered and approved by a multidisciplinary consensus panel[113] and represent a reasonable approach in view of the American Heart Association’s position[114] against use of CAS for symptomatic carotid stenosis, unless part of an approved randomized clinical trial. One author’s clinical experience with CAS in these subjects of patients was recently published.[115] Overall 30-day stroke and death was 2.8% and in-stent restenosis ($ 80%) was observed in 3.8% of cases. A definitive comparison of carotid endarterectomy and carotid artery stenting in better risk patients has not been conducted. However, the Carotid Revascularization Endarterectomy vs. Stent Trial (CREST) was funded by the National Institute of Neurological Disease and Stroke (NINDS 1-R01 NS38384-01, 1999 –2004) for the purpose of comparing these two treatment modalities in symptomatic patients with extracranial carotid stenosis of $ 50%. Several
Chapter 52.
challenges have been overcome to initiate this trial in 2001– 02.[116] These included negotiations with the Center for Medicare and Medicaid Services on reimbursements for the stent arm of the trial, obtaining FDA approval for the use of an antiembolic device to reduce the incidence of peri-procedural atheroemboli and stroke, and finally to gain FDA approval of a recent modification in the recovery catheter of the filter device. The CREST trial is also unique because of its partnership with industry (Endovascular Technologies, Guidant Corporation, Santa Clara, CA) for supply of
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the stents and antiembolic devices. CREST was reinitiated in June 2002 and approved for randomization of patients. After a credentialing period for interventionalists, 2500 patients will be recruited over 3 years. The study will compare the efficacy of the two procedures, anticipating a 1.2% per year differential in primary end points of stroke, myocardial infarction, and death. Other trials and registries are also underway, which should contribute to conclusions regarding the efficacy and effectiveness of these two procedures.
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Part Six. Cerebrovascular Disease Eastcott, H.H.G.; Pickering, G.W.; Rob, C. Reconstruction of Internal Carotid Artery in Patients with Intermittent Attacks of Hemiplegia. Lancet 1954, 2, 944. Cronenwett, J.L.; Birkmeyer, J.D Carotid Artery Disease. The Dartmouth Atlas of Vascular Health Care; AHA Press, Division of Health Forum, Inc.: Chicago, IL, 2000, 41– 64. Fields, W.S.; Maslenikov, V.; Meyer, J.S.; et al. Joint Study of Extracranial Arterial Occlusion: Progress Report of Prognosis Following Surgery or Non-Surgical Treatment for Transient Cerebral Ischemic Attacks and Cervical Carotid Lesions. JAMA 1970, 211, 1993. Hollenhorst, R.W. Significance of Bright Plaques in the Retinal Arterioles. JAMA 1961, 178, 23. Ross, R.; Glomset, J.A. The Pathogenesis of Atherosclerosis. N. Engl. J. Med. 1976, 295, 369. Brown, M.S.; Goldstein, J.L. Lipoprotein Metabolism in the Macrophage: Implications for Cholesterol Deposition in Atherosclerosis. Annu. Rev. Biochem. 1983, 52, 223. Steinberg, D.; Witztum, J. Lipoproteins and Atherogenesis: Current Concepts. JAMA 1990, 264, 3047. Zarins, C.K.; Giddens, D.P.; Bharadvaj; et al. Carotid Bifurcation Atherosclerosis: Quantitative Correlation of Plaque Localization with Flow Velocity Profiles and Wall Shear Stress. Circ. Res. 1983, 53, 502. LoGerfo, F.W.; Nowak, M.D.; Quist, W.C. Structural Details of Boundary Layer Separation in a Model Human Carotid Bifurcation Under Steady and Pulsatile Flow Conditions. J. Vasc. Surg. 1985, 2, 263– 269. Furchgott, R.F.; Vanhoutte, V.M. Endothelium Derived Relaxing and Contracting Factors. FASEB J 1989, 3, 2007. Brice, J.A.; Dowsett, D.J.; Lowe, R.D. The Effect of Constriction on Carotid Blood Flow and Pressure Gradient. Lancet 1964, 1, 84. Lusby, R.J.; Woodcock, J.P.; Machleder, H.I.; et al. Transient Ischemic Attacks: The Static and Dynamic Morphology of the Carotid Bifurcation. Br. J. Surg. 1982, 69, 941. White, A.; McCarty, K.; Morgan, R.; et al. Investigation of Carotid Plaque Motility: Proceedings of BES Meeting, Glasglow, Scotland, 1987. Ku, D.N.; Giddens, D.P.; Zarins, C.K.; et al. Pulsatile Flow and Atherosclerosis in the Human Carotid Bifurcation: Positive Correlation Between Plaque Localization and Low and Oscillating Shear Stress. Arteriosclerosis 1985, 5, 293. Imparato, A.M.; Riles, T.S.; Gostein, F. The Carotid Bifurcation Plaque: Pathological Findings Associated with Cerebral Ischemia. Stroke 1979, 10, 238. Imparato, A.M.; Riles, T.S.; Mintzer, R.; et al. The Importance of Hemorrhage in the Relationship of Gross Morphological Characteristics and Cerebral Symptoms in 379 Carotid Artery Plaques. Ann. Surg. 1983, 197, 195. Svindland, A.; Torvik, A. Atherosclerotic Carotid Disease in Asymptomatic Individuals: A Histological Study of 53 Cases. Acta Neurol. Scand. 1988, 78, 506. Torvik, A.; Svindland, A.; Lindboe, C.F. Pathogenesis of Carotid Thrombosis. Stroke 1989, 20, 1477. Lal, B.K.; Hobson, R.W., II; Pappas, P.J.; Kubicka, R.; Hameed, M.; Chakhtoura, E.Y.; Jamil, Z.; Padberg, F.T.
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CHAPTER 53A
Occlusive Disease of the Branches of the Aortic Arch Ramon Berguer
This chapter reviews the clinical presentation, diagnosis, and treatment of occlusive lesions of the branches of the aortic arch. Proximal left subclavian lesions which give rise to vertebrobasilar ischemic syndromes are addressed in Chapter 54. There are variations and anomalies in the anatomy of the branches of the arch which are relevant to both the presentation and the treatment of the occlusive disease of these vessels. The standard anatomic arrangement is a leftsided aortic arch from which the innominate, left common carotid, and left subclavian take off in succession. In 16% of cases the origins of the left common carotid and that of the innominate artery are close enough that the two share some part of the circumference of their ostia. In 8% of cases a common trunk exists for the innominate and left common carotid artery. In 6% of patients the left vertebral arises from the arch between the left common carotid and the left subclavian arteries. In 0.5% of patients the right subclavian arises as the last branch of the arch and reaches the right upper extremity following a retroesophageal route: a retroesophageal right subclavian artery.
DIAGNOSIS Occlusive arterial disease may involve one or multiple trunks. The best clue to the physical diagnosis of occlusive disease of the branches of the arch is abnormal pulse waveforms or unequal blood pressures[1] in the upper extremities. Bruits at the base of the neck are frequent in these patients. In individuals presenting with symptoms, the diagnosis is usually reached after having completed the common work-up for the more frequent carotid bifurcation syndrome. Duplex scans may visualize lesions in all three branches of the arch, but generally the standard duplex examination does not extend to, or may not resolve, the retrosternal segments of the branches of the arch. Magnetic resonance angiography (MRA) can be a valuable tool for outlining the branches of the arch, but this may require special coils and sequencing: a routine brain and neck MRA is unlikely to provide adequate visualization of the branches of the arch. Computed tomography (CT) angiography is time-consuming, heavily dependent on operator manipulation of images, and it does not provide a clear picture of the hemodynamics around occlusions. To this date arteriography provides the best visualization, and, in cases of multiple occlusion, it offers valuable information regarding the collateral patterns that have been established. This information may be relevant to the sequencing of surgical reconstructions to be done.
AORTIC ARCH SYNDROMES Occlusive disease of the branches of the aortic arch results in either embolization or blood flow restriction to the territories they supply: the head and the upper extremities. Lesions of the left common carotid artery will give rise to left hemispheric or left eye symptoms; those of the left subclavian could give rise to both vertebrobasilar and left upper extremity symptoms; those of the innominate artery can involve any or all of three territories—right carotid, vertebrobasilar, and right upper extremity. The occlusive lesions that involve the branches of the aortic arch are generally atherosclerotic. Less commonly arteritis (Takayasu’s, radiation) and dissection, either spontaneous or traumatic, can be the source of symptoms. Aneurysmal disease of the branches of the arch is usually associated with aneurysmal disease of the ascending aorta.
SURGICAL MANAGEMENT The indications to repair lesions of the innominate and common carotid arteries are inferred from those we use in the carotid bifurcation territory. The occlusion of a subclavian artery rarely results in a stroke and is frequently asymptomatic. Critical lesions of the innominate and common carotid arteries may progress to occlusion. The probability for stroke in acute common carotid occlusion is substantial. Asymptomatic patients may be found to have a critical (greater than 75% diameter) lesion of either the carotid or the innominate artery. If these patients are a reasonable surgical risk, a reconstruction should be considered. Support for this position derives from
Hobson/Wilson/Veith: Vascular Surgery: Principles and Practice, Third Edition, Revised and Expanded DOI: 10.1081/0819-9-120024936 Copyright q 2004 by Marcel Dekker, Inc.
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Figure 53A-1. Transposition of the left subclavian to the left common carotid artery. (From Berguer, R. Reconstruction of the Supra Aortic Trunk and Vertebrobasilar System. In Vascular Surgery, A Comprehensive Review; Moore, W., Ed.; W.B. Saunders: Philadelphia, 1998.)
the observation that the histology and behavior of the plaques in the common carotid and innominate arteries is similar to that of the plaques found in the internal carotid artery bulb. Since all three arteries contribute to the same hemispheric territory, we may infer that the outcome of common carotid and innominate lesions is similar to those found in the internal carotid bulb. There is not, and probably will never be, a prospective series with sufficient numbers to tell us the natural history of isolated common carotid or innominate lesions because they are rare. If symptomatic patients, whose etiology may be embolic or hemodynamic, are found to have an appropriate lesion in the artery supplying the symptomatic territory, the surgical indication is straightforward. Once a decision to proceed with a surgical reconstruction has been made, the next step is to decide whether it will be done by means of a cervical or a thoracic operation. Cervical reconstructions[2] are less risky than transthoracic reconstructions,[3] but in the more complex cases with two- or three-vessel involvement the long-term prognosis of a cervical reconstruction is inferior to that of a transthoracic one. The thoracic route should be avoided if possible in patients who have had myocardial revascularization because of the possibility of injury to functioning coronary bypass grafts. Lesions of the innominate artery deserve special consideration when they are emboligenous because the proximal innominate artery needs to be surgically excluded from the path of flow, and this may be a difficult thing to accomplish through a cervical approach. There is a clear indication of necessity for each of the approaches. Patients with a single subclavian or common
Figure 53A-2. A left common carotid to left subclavian bypass. The internal jugular vein is retracted laterally, showing the proximal anastomosis of the bypass to the common carotid artery. (From Berguer, R. Reconstruction of the Supra Aortic Trunk and Vertebrobasilar System. In Vascular Surgery, A Comprehensive Review; Moore, W., Ed.; W.B. Saunders: Philadelphia, 1998.)
carotid lesion who have a good ipsilateral carotid or subclavian artery should undergo a transposition (Fig. 53A1) or bypass (Fig. 53A-2) by means of a cervical operation. This type of reconstruction has outstanding patency rates and very low morbidity. At the other end of the spectrum there is the patient with extensive disease and involvement of all three branches of the arch. In this latter case the source of the bypass has to be the aorta and a transthoracic reconstruction through a midsternotomy is the best solution (Fig. 53A-3). Between these two extremes lies the patient with involvement of the innominate and another vessel in whom the advantages and risks of cervical reconstruction have to be weighed against those of thoracic reconstruction.
CERVICAL RECONSTRUCTIONS The most common and probably the most frequently performed surgical reconstruction for disease of the supraaortic trunks is a carotid-subclavian or a subclavian-carotid bypass. This operation uses a neighboring artery as inflow source. In whatever direction the bypass is placed, the proximal end of the recipient vessel must be obliterated if the operation is done for embolic disease. In subclavian-carotid bypasses the proximal end of the common carotid artery is obliterated even though the operation may be done for hemodynamic disease. The reason for the latter is that the ensuing decrease in flow rate through this diseased proximal portion may result in its thrombosis and the tail of the thrombus may grow across the anastomosis of the bypass and embolize distally.
Chapter 53A. Occlusive Disease of the Branches of the Aortic Arch
Figure 53A-3. A typical transthoracic reconstruction consisting of a bypass from the ascending aorta to the bifurcation of the innominate artery. A side branch to revascularize the left carotid bifurcation has been attached to the main graft.
The technique of carotid-subclavian or subclavian-carotid bypass usually requires a single supraclavicular incision when the common carotid is used at either end of the bypass.[4] If, because of concomitant disease, the operation has to extend to the bifurcation of the carotid (Fig. 53A-4), two incisions are made: a supraclavicular and a short carotid incision. The segment of subclavian which is either the donor or receiving artery for the bypass is generally the second or retroscalene portion. For the last 4 years, however, we have frequently used the segment of subclavian that transverses the space between the outer border of the scalenus anticus and the medial border of the brachial plexus. In individuals who are thin, this segment of subclavian can be accessed without completely dividing the scalenus anticus or for that matter mobilizing the phrenic nerve. The standard approach to the retroscalene subclavian is through an incision above the clavicle going through the prescalene fat pad.[4] The phrenic nerve is identified and the underlying scalenus anticus muscle is divided. The segment of subclavian chosen for anastomosis is usually lateral to the thyrocervical trunk. The common carotid artery is exposed in the medial edge of the wound by retracting the jugular and vagus nerve forward, and an appropriate segment of the common carotid is isolated. Fifteen years ago a vein graft was considered to be the best choice for bypass in this location, but
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Figure 53A-4. A bypass from the left subclavian to the left carotid bifurcation.
this is no longer the case. Vein grafts are often too small to substitute for these arteries; they also kink and angulate more frequently than prostheses. Our preference is to use a prosthetic graft; either PTFE or Dacron, which have excellent long-term patency rates. The donor artery is clamped and the prosthetic graft is anastomosed to it. Flow is then reestablished through the donor artery while the anastomosis to the receiving artery is made. As mentioned above, when doing a subclavian-carotid bypass it is a simple matter to ligate the common carotid artery below the anastomosis to decrease the chance of thromboembolization from the proximal common carotid artery. In the subclavian artery this step requires exposure of the prevertebral subclavian and its ligation via a transcervical incision: this is demanding technically and sometimes impossible. The exclusion of the proximal subclavian can be performed as an endovascular procedure by placement of an intravascular occluding balloon in it.
CROSS-OVER BYPASSES In patients with common carotid and/or subclavian disease who do not have an ipsilateral companion vessel appropriate as a donor, it is necessary to go to the other side of the neck to obtain adequate inflow for a bypass graft from the common carotid or subclavian arteries. Traditionally these bypasses crossed
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Figure 53A-5. The distance between the two common carotid arteries is 50 mm through the retropharyngeal tunnel and 100 mm through the pretracheal path.
the midline in front of the trachea, sometimes partially hidden behind the clavicular heads. This may result in some unsightly deformity. The more relevant criticism, however, is that they are quite long and present a problem if the patient is to have a tracheostomy or a midsternal incision or coronary bypass in the future. In our practice we have used for 15 years the retroesophageal route to cross the midline.[5] The resulting bypass is more direct and shorter than a pretracheal one (Fig. 53A-5). The exposure of the donor and receiving arteries for a crossover bypass is the same on both sides regardless of whether a pretracheal or retroesophageal bypass is planned. Usually a supraclavicular incision is made if the donor artery is the subclavian and an oblique incision is made if the donor is the common carotid artery. Similar choice of incisions exists on the opposite side depending on which artery will receive the bypass. To run the bypass in front of the trachea, a tunnel is made behind the sternal head of the sternomastoid using blunt dissection until we meet the finger from the opposite side. For the retroesophageal tunnel the plane of dissection is anterior to the longus colli and to the sympathetic chain and posterior to the common carotid artery. The plane of dissection goes towards the anterior body of the vertebra and slides over the lamina prevertebralis (Fig. 53A-6) to meet the exploring finger from the opposite side in the midline. The space in front of the vertebra and behind the pharyngoesophageal tube is a virtual space which admits a finger easily. In our experience bypasses placed in this space have never caused esophageal indentation or pressure symptoms in spite of their prevertebral location (Fig. 53A-7). The complications of cervical reconstruction are different for the two separate groups of patients. In our entire series of cervical reconstructions the combined mortality/morbidity was 4% (3.8% nonfatal stroke, 0.5% fatal stroke). However, in the asymptomatic patients with single trunk disease, no
mortality/morbidity was noted. Four of the seven strokes in the symptomatic/complex group could be attributed to perioperative graft occlusion. The other strokes were secondary to anastomotic bleeding (1 case) and to hypertensive crisis (2 cases). All but one complication occurred in patients who had multiple trunk disease. Only one stroke (1%) occurred in the group with single carotid or subclavian lesion in a patient with preoperative symptoms.
Figure 53A-6. A retropharyngeal bypass from the right common carotid to the left carotid bifurcation. (From Berguer, R. Reconstruction of the Supra Aortic Trunk and Vertebrobasilar System. In Vascular Surgery, A Comprehensive Review; Moore, W., Ed.; W.B. Saunders: Philadelphia, 1998.)
Chapter 53A. Occlusive Disease of the Branches of the Aortic Arch
Figure 53A-7. Arteriogram of a retropharyngeal bypass from the right subclavian to the left carotid bifurcation. (From Ref. [5] with permission from publisher.)
TRANSTHORACIC RECONSTRUCTION Practically all the transthoracic reconstructions are done through a midsternotomy. In rare cases of severe calcification of the entire arch of the aorta, one may look for an inflow source in the descending aorta using a left thoracotomy combined with cervical incisions.[4] The midsternotomy need not to be complete in patients in whom the operation is limited to the innominate artery. The most common procedure used for transthoracic reconstruction is a bypass based on the ascending aorta to the innominate bifurcation with limbs to the left common carotid and/or left subclavian as needed (Fig. 53A-8). These bypasses are done with prosthetic material and the best arrangement is a single tube arising from the ascending aorta generally anastomosed to the innominate bifurcation to which side branches are attached as needed.
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Figure 53A-8. Schematic drawing of a bypass from the ascending aorta to the innominate bifurcation and left common carotid artery. (From Berguer, R. Reconstruction of the Supra Aortic Trunk and Vertebrobasilar System. In Vascular Surgery, A Comprehensive Review; Moore, W., Ed.; W.B. Saunders: Philadelphia, 1998.)
Endarterectomy of the innominate artery is hardly ever used. Indications for innominate endarterectomy are restricted to individuals with disease of the distal half of the innominate artery or to reconstructions done in patients who have had previous aorto-coronary bypasses where there may not be enough room in the ascending aorta for safe placement of an exclusion clamp. The standard bypass technique is done through a full midsternotomy, we now prefer to use an upper midsternotomy as a better tolerated approach (see below). The midsternotomy is prolonged with a short arm to the right side of the neck to gain individual access to the two branches of the innominate artery. If the left carotid bifurcation is to be reconstructed, a separate incision is used for it. The ascending aorta is exposed in its intrapericardial portion. All the receiving arteries are exposed. Prior to clamping, the systolic pressure is dropped to 100 –110 mmHg. A partial exclusion clamp is placed on the ascending aorta where an aortotomy is made. The graft, usually a No. 8 or 10 prosthetic tube, is anastomosed end-to-side to the ascending
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aorta without systemic heparinization. After completing the anastomosis, the graft is vented and hemostasis ensured. With the graft clamped, the patient is heparinized while we attach any side branches that may be needed to the main graft. The distal anastomosis of the main graft is usually to the bifurcation of the innominate. The side branches may go to the left common carotid in the mediastinum or to the left carotid bifurcation in the neck (Fig. 53A-9). Revascularization of the left subclavian artery through a midsternal incision requires division of the brachiocephalic vein. This may result in left jugular and subclavian vein thromboses and mild neck swelling postop. If the revascularization of the left subclavian is needed, we now prefer to revascularize the left common carotid low in the mediastinum and then, as a secondary procedure and at an ulterior date, do a transposition of the left subclavian to the left common carotid or a bypass between the left subclavian and common carotid arteries.
UPPER MIDSTERNOTOMY This incision provides access to the innominate artery and to the ascending aorta comparable to that obtained with a standard midsternotomy. Since only the upper sternum is divided, the chest is more stable in the postoperative period and there is considerably less postoperative pain. The incision starts with the same short oblique arm that is customary over the right supraclavicular area in order to expose the bifurcation of the innominate artery. It then continues over the midsternal line down to the fourth sternal segment. The sternal saw is advanced down to the end of the third sternal segment. At this point a pediatric sternal retractor is inserted and opened gradually to cause a subperiostial fracture of the sternum. The ascending aorta is exposed after opening the pericardium in the same manner as was done with a standard midsternotomy.
TRANSTHORACIC RECONSTRUCTION The direct approach to the supraaortic trunks is usually reserved for individuals with severe innominate disease usually associated with disease of the other trunks. This type of reconstruction carries a higher mortality/morbidity as a group than in those patients undergoing cervical reconstructions.
Figure 53A-9. Arteriogram following a transthoracic reconstruction. Both the main graft and its left branch terminate at each carotid bifurcation.
The operative mortality for transthoracic reconstruction of the supraaortic trunks is 6% in our total experience. The combined stroke/death rate was 16%. Most of the deaths were due to cardiac causes, and none occurred in 13 asymptomatic patients who were operated in our series. Most of the deaths were due to cardiac and pulmonary complications, although two of them were due to stroke.
REFERENCES 1.
Berguer, R.; Higgins, R.F.; Nelson, R. Noninvasive Diagnosis of Reversal of Vertebral Artery Flow. N. Engl. J. Med. 1980, 302, 1349– 1350. 2. Berguer, R.; Morasch, M.D.; Kline, R.A.; Kazmers, A.; Friedland, M.S. Cervical Reconstruction of the Supraaortic Trunks: A Sixteen Year Experience. J. Vasc. Surg. 1998, In Press. 3. Berguer, R.; Morasch, M.D.; Kline, R.A. Transthoracic Repair of Innominate and Common Carotid Artery
Disease: Immediate and Long-Term Outcome for 100 Consecutive Surgical Reconstructions. J. Vasc. Surg. 1998, 27, 34 – 42. 4. Berguer, R.; Kieffer, E. Surgery of the Arteries to the Head; Springer-Verlag: New York, 1992;. 5. Berguer, R.; Gonzalez, J.A. Revascularization by the Retropharyngeal Route for Extensive Disease of the Extracranial Arteries. J. Vasc. Surg. 1994, 9 (2), 217 – 226.
CHAPTER 53B
Vertebrobasilar Ischemia: Reconstruction of the Vertebral Artery and Proximal Portion of the Subclavian Artery Ramon Berguer
The symptoms of VBI are dizziness, vertigo, diplopia, blurring of vision, drop attacks, perioral numbness, and alternating paresthesia. Patients with VBI secondary to hypoperfusion usually have transient and repetitive symptoms induced by changes in body attitude (orthostatism) or head and neck movements (aggravation of extrinsic compression), which nearly always occur while the patient is sitting up or standing and are relieved by lying down. Hypoperfusion of the vertebrobasilar system may be due to several central causes, such as low cardiac output, orthostatism, hypotension from inappropriate antihypertensive medication, and anemia. Peripheral arterial causes are obstruction of the proximal SA, VA, basilar artery, and even some of the branches of the latter, as well as reversal of flow or arteriovenous fistula of the VA. These arterial obstructions may be due to intrinsic disease of the arterial wall, usually atherosclerotic plaques, or to extrinsic compression of the VA by bony or ligamentous structures (see below). These patients seldom have infarctions in the vertebrobasilar territory, but their symptoms create functional disabilities and may lead to traumatic injuries from falls or driving accidents. In thromboembolic VBI, the mechanism is repeated thromboembolization of the branches of the VA, usually from a cardiac or arterial source. These patients present with transient ischemic attacks from focal ischemia or with fixed neurologic deficits secondary to an infarction. Their symptoms are often not repetitive but rather arise from the different areas where thromboembolization has occurred. Because of progressive damage due to infarctions in the brainstem, cerebellum, and occipital lobes—as seen in magnetic resonance images—heir prognosis is serious. While the large majority of patients undergoing corrections of lesions of the VA or proximal SA have a history of transient ischemia attacks or stroke in the vertebrobasilar territory, 1–3% will be asymptomatic. In these patients, surgical reconstruction is advised for lesions such as a large
We use the term ischemia as opposed to insufficiency, which is more traditionally attached to vertebrobasilar symptoms, because in approximately a third of cases the symptoms are secondary to thromboembolic disease rather than to hypoperfusion secondary to stenosis or occlusion. The proximal subclavian artery (SA) is discussed within the context of vertebrobasilar ischemia (VBI) because disease of this segment of the SA may result in vertebrobasilar ischemia and operations on this artery are part of the surgical correction of the VBI syndrome. The same applies to lesions of the innominate artery, which are described elsewhere in the book.
THE SYNDROMES OF VERTEBROBASILAR ISCHEMIA The concept of VBI secondary to disease of the vertebral artery (VA) or proximal SA has traditionally been considered a hemodynamic problem resulting in hypoperfusion of the vertebrobasilar territory.[1] Available evidence suggests that about 30% of patients presenting with symptoms of VBI suffer thromboembolization from either the SA, VA, or basilar artery.[2 – 4] Rancurel et al.[5] defined two types of VBI: hypoperfusion and thromboembolic. The hypoperfusion syndrome may be due to a blockage in the SA or VA, causing a drop in perfusion pressure in the basilar artery by reducing blood flow into it and, occasionally, by diverting flow from the basilar artery, as in the reversal of VA flow, the so-called subclavian steal syndrome. The symptoms of VBI arise from the territory supplied by the vertebrobasilar arteries, including the brainstem, the cerebellum, and—in patients where the basilar artery gives rise to the posterior cerebral arteries—the occipital lobes and posterior portion of the temporal lobes.
Hobson/Wilson/Veith: Vascular Surgery: Principles and Practice, Third Edition, Revised and Expanded DOI: 10.1081/0819-9-120024937 Copyright q 2004 by Marcel Dekker, Inc.
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aneurysm of the VA, which, though asymptomatic, have a high potential for disastrous complications.
ANATOMY The SA is a branch of the innominate artery on the right side and of the aorta on the left. The right SA may exit at the last branch of the arch: a retroesophageal right subclavian artery. This anomaly is associated with nonrecurrence of the inferior laryngeal nerve on the side of the anomalous subclavian and a thoracic duct emptying on the right side of the neck. In patients with a right-sided aortic arch, it is the left SA that may exit as the last branch of the arch and follow a retroesophageal course. Occasionally the abnormal origin of the retroesophageal right subclavian artery is associated with a dilatation known as a diverticulum of Kommerel. This diverticulum may evolve as an aneurysm, extending behind the tracheoespohageal axis and sometimes reaching a very large size. The right SA is shorter than the left SA and less susceptible to atherosclerotic disease and to traumatic disruption. Its
Figure 53B-1. Relationships of the first segment of the right subclavian artery. The low middle cervical ganglion (intermediate ganglion) sends connections to the stellate ganglion in front and behind the vertebral artery. An ansa subclavia also connects the intermediate ganglion with the stellate ganglion in front of the subclavian artery. The right recurrent inferior laryngeal nerve loops behind the subclavian artery and the distal portion of the innominate artery bifurcation.
anterior wall is in contact with the vagus nerve (Fig. 53B-1), which sends a recurrent inferior laryngeal nerve under the SA and behind the origin of the common carotid artery. Sympathetic branches known as the ansa subclavia also cross the anterior wall of both SA. The left SA is a common site for atherosclerotic disease and may also be involved in decelerating injuries. In its intrathoracic segment, the SA travels with the vagus and phrenic nerves, which cross in front of it in the form of an elongated X (Fig. 53B-2). Further up in the neck, the artery comes in posterior proximity to the thoracic duct, which emerges from the posterior mediastinum high in the common carotid artery to curve outward and drain into the jugulosubclavian venous confluent. The first segment of the SA ends at the takeoff of the VA. Past this level, the SA has two branches that have relevance to the surgical reconstruction of the SA: the internal mammary artery, which is of prime interest in revascularization of the coronary arteries, and the thyrocervical trunk, which may be used in some techniques of proximal reconstruction of the VA. The VA is often asymmetrical, the left side more often being the larger one. Any of the VA may be hypoplastic and end in a posterior –inferior cerebellar artery without joining with the VA in the opposite side to form the basilar artery. The VA originates from the subclavian artery, although in 6% of cases the left VA may originate from the aorta. The first segment of the VA normally extends from its origin in the SA to the level of C6, where it enters the cervical spine. In 7% of cases, the VA is shorter and enters the spine at the level of C7.
Figure 53B-2. View of the first segment of the left subclavian artery through a fourth intercostal posterolateral thoracotomy. The vagus and phrenic nerves cross in front of the origin of the subclavian artery. The superior intercostal vein runs between the vagus and phrenic nerves.
Chapter 53B. Vertebrobasilar Ischemia: Reconstruction of the Vertebral Artery
As we will mention later, this may create problems when one is trying to do a transposition to the common carotid artery. In those cases where the VA originates from the arch of the aorta between the left common carotid and the left SA, it generally enters the spine one or two vertebral levels above C6 and therefore has a long first segment. In its first segment (Fig. 53B-3), the VA courses behind the vertebral vein and is in close relationship to the sympathetic chain. Either the top of the stellate ganglion or the so-called intermediate (midcervical) cervical ganglion may be in close proximity to the wall of the VA. Communicating branches between the stellate and middle cervical ganglia run in front and behind the SA (ansa subclavia). The second segment of the VA extends from its entry in the cervical spine, usually at C6, and extends up to its exit from the transverse process of C2. The artery here travels in an osteomuscular canal surrounded by a plexus of veins and in front of the anterior rami of the various cervical nerves. It is also in close relationship to the uncovertebral joints and can be displaced by osteophytes developing in them. The third segment of the VA extends from the top of the transverse process of C2 up to the point where the artery penetrates the atlantooccipital membrane. As the VA exits the C2 transverse foramen, it moves outward toward the more lateral foramen of C1. This segment of the VA is often elongated to allow for the considerable rotational motion of the C1–C2 intervertebral joint. After it exits through the foramen of C1, the artery rests on the posterior arch of the atlas, and, after penetrating the atlantooccipital membrane, it becomes intradural. In the space between C1 and C2 the artery lies behind the anterior ramus of corresponding (C2) cervical nerve. In its third segment, the VA receives important collateral branches from the occipital artery and occasionally from the cervical ascending artery. These branches preserve patency of the third and fourth segments of the VA when its proximal segments are occluded. In its fourth segment, the VA has two important branches, the anterior spinal artery and the posterior inferior cerebellar artery. The distal part of the fourth segment is incompletely developed when the VA ends in the posterior inferior cerebellar artery.
ARTERIAL PATHOLOGY AND ITS CONSEQUENCES In the SA, atherosclerotic disease is the most common pathology. Plaques in the SA may be simple or complex (with hemorrhage and ulceration). These plaques may also be the source of embolization into the vertebrobasilar or upper extremity territories. Aneurysmal disease of the proximal SA is relatively uncommon. Severe stenosis or occlusion of the SA may cause reversal of VA flow, the so-called subclavian steal phenomenon. Other anatomic conditions, such as occlusion of the innominate artery or of the origin of the external carotid artery, may result in blood flow being diverted away from the VA. The latter condition results in a vertebral to external carotid steal via the occipital artery.
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Figure 53B-3. Relationships between the cervical spine, the vertebral artery, and the sympathetic chain.
The most common lesion found in the VA is a stenosis of its origin. Although the stenosing plaques in the VA are traditionally considered fibrous and smooth, this is not always the case. In fact, the few pathologic studies done on atherosclerotic VA have shown that these plaques may contain hemorrhage, thrombus, or ulceration. Exceptionally, the VA may be compressed in its first segment by the cervical sympathetic chain and, as it is about to enter C6, by the stout tendon of the longus colli muscle. In its second segment, the VA is most commonly involved by extrinsic pressure from osteophytes in the cervical spine, which may cause compressions of the artery during neck movements. This chronic trauma may also result in damage to the wall, with formation of mural thrombus or intramural dissection. In its third segment, the artery is rarely affected by atherosclerotic disease. This segment, however, is a common site for spontaneous arteriovenous fistulas, false aneurysms, and intramural dissections. This is most likely related to the mobility of the C1 –C2 intervertebral joint. The few lesions found in the fourth segment of the VA are usually atherosclerotic plaques.
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ULTRASOUND AND RADIOLOGIC IMAGING Ultrasound and Doppler studies may document occlusion of the SA and its hemodynamic consequences and may visualize portions of the VA. None of these noninvasive methods provides an assessment of the VA complete enough to establish an etiologic diagnosis for the symptoms or to decide if a surgical reconstruction is indicated. Selective arteriography remains the method of choice for the anatomic diagnosis of the cause of VBI and for planning its surgical management. A four-vessel arteriogram provides the best information on the existence of disease in the intra- and extracranial segments of the carotid and VA and in the SA. Plaques in the SA may be difficult to see in the usual arch injections. Usually the SA is seen clearly in only one (right posterior oblique) of the two oblique projections normally used in arch injections. Superimposition of the origin of the VA by an overlying SA may require additional oblique views lest a severe lesion at the ostium of the VA be missed. Patients who have symptoms related to head movement require a dynamic arteriogram. For this a selective injection of the subclavian arteries is obtained after positioning the head in the rotation, extension, or flexion views that cause the symptoms. The anatomy of the cervical spine changes when the patient is sitting up or standing and therefore supporting the weight of his or her head.[6] These dynamic arteriographic views are obtained either with the patient sitting up (through a brachial approach) or with the patient in the Trendelenburg position, supporting part of the body’s weight on a head rest (through a femoral approach). The importance of dynamic arteriography is not sufficiently recognized. Studies comparing the incidence of significant lesions using standard and dynamic arteriography[6] have show that the yield of the latter is up to five times greater than the former.
CLINICAL INDICATIONS FOR VERTEBRAL/PROXIMAL SUBCLAVIAN ARTERY RECONSTRUCTION In patients who have symptoms of VBI it is imperative to rule out other causes for the symptoms not arising from the arteries in question. Such causes include cardiac arrhythmias, orthostatic hypotension, anemia, brain tumors, and some degenerative neurologic disease. Once these potential causes for the symptoms have been ruled out, indications for reconstruction of the VA or proximal SA are based on the arteriographic demonstration of a lesion compatible with the patient’s symptoms. The VA and proximal SA may bear other lesions that, although asymptomatic, may constitute an indication for a surgical reconstruction because of their disastrous potential (arteriovenous fistulas, aneurysms) or because of the need for cardiac revascularization (revascularizing an internal mammary artery in a patient with a blocked proximal SA). In patients undergoing reconstruction of the VA for stenosing disease not of the thromboembolic type, it is
accepted that both vessels must be stenosed by at least 75% of their diameter to be considered critical lesions from a hemodynamic viewpoing. Naturally, if the VA is hypoplastic or absent, a 75% stenosis of a single dominant VA is considered significant. Lesions at the origin of a VA that ends in a posterior-inferior cerebellar artery (PICA) are not considered indications for a surgical reconstruction, unless there is evidence of embolization in the territory of the ipsilateral PICA.
SURGICAL RECONSTRUCTION OF THE PROXIMAL SUBCLAVIAN ARTERY Most repairs in the SA are done through a cervical approach. When the SA repair is part of a reconstruction involving other supraaortic trunks, the transsternal route is used. In the 1960s, the left transthoracic route was the standard approach for endarterectomy of the left SA in the rare reconstructions of this vessel then done. Today, this route is still used occasionally for a bypass from the descending thoracic aorta to the SA in cases where the cervical route is not advisable because of previous surgical explorations or radiation injury. To correct lesions in the first portion of the SA through a cervical approach, the techniques used are either a carotid-SA bypass or a transposition of the SA to the common carotid artery. The latter technique has been our preference for the last decade. Another cervical technique for reconstruction of the proximal SA is the axilloaxillary or SA-to-SA bypass, which is rarely used nowadays. The patency rates of these “crossover” reconstructions are inferior,[7] therefore this technique is only indicated in exceptional anatomic situations and usually in debilitated patients.
Bypass for the Common Carotid to the Subclavian Artery The incision in the neck is a transverse, slightly oblique one. The clavicular head of the sternomastoid muscle is divided. The common carotid artery is exposed medial to the jugular vein. The second or third segment of the SA is exposed lateral to the jugular vein (Fig. 53B-4). If there is enough SA of good quality between the scalenus anticus and the brachial plexus, there is no need to completely divide the former. On the contrary, if the second portion of the SA must be exposed, the phrenic nerve is carefully dissected and the scalenus anticus muscle cut. The material we use for bypass is a synthetic tube, either polytetrafluoroethylene (PTFE) or Dacron. The patient is given systemic heparin. The carotid anastomosis is done first. For this, the common carotid artery is cross-clamped. Partial exclusion clamping of the common carotid artery is to be avoided. The common carotid artery anastomosis is done to an elliptical defect, created by an aortic punch in the lateral wall of the artery. After completing the anastomosis with a continuous suture of 5-0 or 6-0 polyproplylene and bleeding it through the bypass, the latter is clamped close to the anastomosis and flow is resumed through the common carotid
Chapter 53B. Vertebrobasilar Ischemia: Reconstruction of the Vertebral Artery
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Figure 53B-5. Subclavian-to-carotid transposition. After transection of the subclavian artery, an eversion endarterectomy leads to the ostium of the vertebral artery and clears the plaque remaining in the distal segment of the subclavian artery. Figure 53B-4. A carotid subclavian bypass. The course of the phrenic and vagus nerves is outlined in solid black.
artery. The bypass, which lies behind the jugular vein and vagus nerve, is then anastomosed to an elliptical defect created in the superior wall of the SA with an aortic punch. If the operation is done for embolic disease of the vertebrobasilar or hand territories, the SA proximal to the VA must be exposed and ligated. This maneuver requires careful technique and knowledge of the adjacent anatomy, since it may be a potential cause of morbidity (bleeding, Horner’s syndrome, and lymphatic leaks).
Transposition of the Subclavian Artery to the Common Carotid Artery The incision is similar but is not carried out as far laterally as the previous one. The common carotid artery is dissected into the mediastinum after ligation of the thoracic duct and the vertebral vein. The dissection of the SA is kept medial to the scalenus anticus, exposing the origins of the VA and the internal mammary artery. The VA is fully dissected throughout its first segment, and this may require dividing the sympathetic nerves connecting the intermediate and stellate ganglion that lie in front of the VA. This dissection of the first segment of the VA is needed to avoid kinking of the VA as the SA is moved to its site of transposition in the common
carotid artery. The internal mammary artery is left intact. Systemic heparin is given. The proximal and distal SA, the VA, and occasionally the internal mammary artery are clamped. The SA is divided approximately 1 cm proximal to the VA takeoff. The clamp that occludes the proximal SA is maintained in place while its stump is oversewn with a 5-0 polypropylene (Fig. 53B-5). In addition, we place a more proximal ligature of heavy silk. Care must be taken not to cut through the SA when tying this ligature, since control of the artery in the mediastinum through this incision is difficult. If the SA is occluded, it is oversewn in the same manner. There is often plaque in the stump of the distal SA, which extends into the ostium of the VA. This plaque is cleared by an eversion endarterectomy. A site is selected in the common carotid artery for anastomosis. The common carotid artery is cross-clamped, and, using an aortic punch, an elliptical arteriostomy is made in its lateral wall at a site that can be reached by the distal SA with case. Care must be taken to avoid axial rotation of the SA at the anastomosis, since this will result in kinking of the VA. The anastomosis is done end to side with continuous 6-0 polypropylene.
Transthoracic Repair of the Left Subclavian Artery This technique is nowadays reserved for situations where the transcervical approach is deemed unsafe because of previous
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operations in the supraclavicular artery or neck changes due to radiation. The patient is intubated with a Carlens tube and placed in the lateral decubitus position. A thoracotomy is made through the fourth intercostals space and the left lung is collapsed. The intrathoracic portion of the left subclavian artery is exposed by incising the pleura and avoiding injury to the phrenic and vagus nerves, which accompany the SA (Fig. 53B-2). The SA is dissected up to the level of the VA, which is separately looped at its origin for eventual temporary clamping. An appropriate segment in the descending thoracic aorta is selected for implantation of a prosthetic graft (Fig. 53B-6). The patient is given systemic heparin. The aortic site is isolated with a partial exclusion clamp and the prosthetic tube is anastomosed in an end-to-side fashion using 3-0 or 4-0 polypropylene. After completion of the aortic anastomosis, the partial exclusion clamp is released and the graft allowed to distend to determine where it will comfortably reach the site elected for its anastomosis to the SA. The SA is cross-clamped, and a small clamp is placed in the VA. After division of the SA, the proximal stump is ligated and oversewn with 5-0 polypropylene. The end of the prosthetic graft is anastomosed end to end to the SA with continuous 6-0 polypropylene, and flow is reestablished first into the arm and then into the VA.
RECONSTRUCTION OF THE VERTEBRAL ARTERY There are two levels for reconstruction of the vertebral artery: one at the proximal VA to treat lesions of its ostium and another at the C1–C2 level for lesions of the intraspinal segment. The techniques for reconstruction of the VA have evolved over the years. The original operations in the proximal VA were endarterectomies with patch or transsubclavian endarterectomies.[8] Vein bypass was introduced in the 1970s,[9] but nowadays most proximal VA reconstructions are done by transposition. Bypass between the SA and the VA is a technique limited to cases where transposition is not feasible because the VA is too short or it is unsafe to clamp the common carotid artery (during the transposition) in patients who have a contralateral internal carotid artery occlusion. Occasionally a VA has enough redundancy in its first portion that it can be transposed to another subclavian site, leaving the ostial stenosis behind. Reconstruction of the distal VA has been done mostly through the use of a vein bypass tended between the common carotid and the distal VA. However, a number of transposition techniques can be used when a saphenous vein of good quality and caliber is not available.
Transposition of the Proximal Vertebral Artery to the Common Carotid Artery The incision is oblique and the dissection is carried between the two bellies of the sternomastoid muscle. The common carotid artery is retracted medially and the jugular vein and vagus laterally. The common carotid artery is dissected into the mediastinum, ligating, on the left side, the thoracic duct. The vertebral vein is divided and ligated (Fig. 53B-7).
Figure 53B-6. bypass.
Descending aorta to left subclavian artery
Figure 53B-7. Transposition of the proximal vertebral artery to the common carotid artery. Division of the vertebral vein permits visualization of the underlying artery. Note the sympathetic fibers surrounding the vertebral artery.
Chapter 53B. Vertebrobasilar Ischemia: Reconstruction of the Vertebral Artery
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The VA can be found below its homonymous vein, and its first segment is dissected from its origin to the tendon of the longus colli muscle, preserving the sympathetic nerve trunks that cross the artery. After dissection, an estimate is made to determine if there is enough length of VA to reach the site of implantation in the common carotid artery. The patient is given systemic heparin and the VA is divided above its ostium, oversewing its origin with 5-0 polypropylene. After the division, it is often necessary to pull the artery from under the sympathetic nerves that surround it so as to avoid injury to the latter. The end of the VA is spatulated for anastomosis. The common carotid artery is cross-clamped, and an arteriostomy is made with an aortic punch in its posterior wall (Fig. 53B-8). The VA is then anastomosed end to side to the arteriostomy in the common carotid artery, using 7-0 polypropylene in a continuous suture.
Subclavian to Vertebral Artery Bypass This technique is used in cases where the VA is too short for transposition (entering the spine at C7) or when the internal carotid is occluded on the opposite side, making ipsilateral cross-clamping of the remaining carotid a risky proposition. This operation requires a good proximal SA and a good-sized saphenous vein. The SA is isolated in its retroscalene portion lateral to the jugular vein. The vertebral vein is divided and the underlying VA is identified. There is no need to divide sympathetic nerves. The artery is usually slung above the crossing of the sympathetic fibers, as near to the tendon longus colli as possible. After systemic heparin is given, the VA is cross-clamped, using microsurgical clips; an end-to-side anastomosis is then constructed between the end of the vein graft and the arteriotomy in the VA using 7-0 polypropylene (Fig. 53B-9). This end-to-side anastomosis will be transformed later into an end-to-end type by applying a hemoclip proximal to it. The vein is then brought under appropriate tension to the elected site of anastomosis in the SA. An aortic punch is used to make an arteriostomy in the SA, to which the proximal end of the vein graft is anastomosed with 6-0 polypropylene.
Transposition of the Vertebral Artery to Another Subclavian Site The requirement for this operation is disease of the VA limited to the ostium, a redundant VA, and a good-quality SA, which must be free of disease in its proximal portion. The incision and approach is the same as described for the bypass. The elected site of implantation is often the stump of the thyrocervical trunk after its division (Fig. 53B-10). The VA is transposed by end-to-side anastomosis using 7-0 polypropylene.
Reconstruction of the Distal Vertebral Artery Reconstructions of the distal VA are usually done at the C1 – C2 level and only exceptionally above the transverse process of C1. Different techniques are available.[10] The approach to the VA at this level, is common to all these techniques.
Figure 53B-8. Transposition of the proximal vertebral artery to the common carotid artery. The anastomosis is constructed in an open manner after spatulation of the vertebral artery.
The incision is anterior to the sternomastoid and is carried up to the earlobe. In about half the patients, it is necessary to divided the greater auricular nerve. The approach is behind the jugular vein and in front of the sternomastoid. By dissecting between these structures, the accessory spinal nerve is identified and then dissected to the level where it crosses over the jugular vein, in front of the transverse process of C1. The levator scapula muscle is identified and its anterior and posterior edges are dissected. The anterior ramus of the C2 nerve root is seen emerging under the levator scapula. With this nerve serving as a guide, the muscle is cut above it (Fig. 53B-11). The anterior ramus of C2 crosses perpendicular to and over the artery. It is divided and the VA is identified below it (Fig. 53B-12). The artery is surrounded by a venous plexus, from which it is isolated by careful dissection. The reconstruction of the artery can now be done through any of the following techniques.
Common Carotid to Distal Vertebral Artery Bypass This technique requires the availability of a good-sized vein, a matter that should be determined preoperatively by ultrasonic mapping. Because the technique involves clamping of the common carotid artery, it may represent a risk if the opposite internal carotid artery is occluded. Upon deflection of the vagus nerve and jugular vein anteriorly and over the carotid, the common carotid artery is exposed below the bifurcation and a proper site is selected for the proximal anastomosis of the vein graft. With the distal vertebral artery already dissected and
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Figure 53B-9. A subclavian-to-proximal vertebral artery bypass. In the right frame, the proximal anastomosis of the graft is to the stump of the thyrocervical trunk. Although the distal anastomosis is represented here as an end-to-end, our preference today is different (see text).
Figure 53B-10. Transposition of the proximal vertebral artery to a different subclavian site.
Figure 53B-11. Exposure of the distal vertebral artery (right side). The levator scapula is divided between C1 and C2. The right angle clamp rests on the anterior ramus of C2, which can be seen bifurcating at the anterior edge of the levator scapula muscle. The accessory spinal nerve is seen coursing through the posterior and superior parts of the incision.
Chapter 53B. Vertebrobasilar Ischemia: Reconstruction of the Vertebral Artery
Figure 53B-12. Exposure of the distal vertebral artery. The levator scapula muscle has been divided. The anterior ramus of C2 has also been divided, and its distal stump is held out of the way by a stay suture. The vertebral artery is looped. Note entry of posterior collateral artery, which will connect with the occipital artery. The plexus of vertebral veins that surrounds the artery has been dissected away and rests behind it.
the site of implantation of the common carotid artery selected, the patient is given systemic heparin. The distal VA is clamped above C2 and immediately below C1. The distal end of the vein graft is anastomosed to the distal VA with continuous 7-0 or 8-0 polypropylene (Fig. 53B-13). This anastomosis is constructed end to side and will ultimately be transformed to an end-to-end anastomosis by application of a hemoclip immediately below its heel. The distal anastomosis is tested by releasing the microsugical clamp below C1. The vein graft is then brought into opposition to the common carotid artery, where the end-toside anastomosis to an elliptical defect created by a punch in the posterior wall of the common carotid artery is done using 6-0 polypropylene. If a graft has valves, it can be bled by making a small arteriotomy in the VA below the end-to-side anastomosis and above C2. This allows forward-bleeding of the graft and back-bleeding of the distal VA. The application of an additional hemoclip above the arteriotomy will control the bleeding from the small arteriotomy and transform the end-toside anastomosis into a functional end-to-end junction. It is advisable to place a stitch in the arteriotomy itself in case one of the clips escapes. If there is not enough room below the anastomosis to do this type of purging, it can be done by the introduction of a soft plastic cannula proximally in the graft, which will keep the valves of the vein graft from closing during backbleeding.
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Figure 53B-13. Right common carotid to right distal vertebral artery bypass. The jugular vein has been displaced anteriorly over the carotid. The distal end-to-side anastomosis has been transformed into an end-to-end by the application of a clip proximal to the heel of the anastomosis.
Transposition of the External Carotid to the Vertebral Artery This operation requires a normal carotid bifurcation and a good-sized external carotid artery trunk. The incision is anterior to the sternocleidomastoid. After exposure of the distal VA as described above, the bifurcation of the common carotid is exposed in front of the jugular vein and the superior thyroid artery is ligated. The distal common carotid artery and the external carotid artery are dissected. The posterior part of the carotid blub is also freed to allow for some axial rotation of the carotid bifurcation. Care is taken to identify and spare the superior laryngeal nerve behind the carotid bulb. The external carotid artery is progressively skeletonized, minding the hypoglossal nerve and continuing the dissection above it. The digastric muscle is dissected and either retracted or cut. This makes it possible to dissect a sufficient length of internal carotid artery. Infiltration with papaverine may be needed to avoid spasm of this muscular artery during its dissection. Once an appropriate length has been obtained and the size of the external carotid artery has been found to be adequate to be anastomosed to the VA, all the intervening branches of the external carotid artery are divided and ligated. The external carotid artery is then pulled from under the hypoglossal nerve and transposed in front of the internal carotid artery by rotating the bulb from posterior
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to medial. The external carotid artery is brought through the tetrojugular space into the proximity of the distal VA. The distal end of the external carotid artery is denuded of adventitia, as is standard procedure in microsurgical techniques. The anastomosis of the distal segment of the external carotid artery to the distal VA is done (Fig. 53B-14) as an end-to-side anastomosis and then eventually transformed into an end-to-end anastomosis by applying a hemoclip below its heel. Usually 7-0 or 8-0 polypropylene is used for the anastomosis.
Transposition of the Occipital Artery to the Distal Vertebral Artery This operation takes advantage of the natural collateral pathway that keeps the VA open through branches of the occipital artery when the proximal VA is occluded. In most adults, the hypertrophy of the occipital artery is not sufficient to provide a good match, the VA being 2 – 2.5 times larger. In some individuals, specifically children who have had traumatic or surgical occlusions of the proximal VA (e.g., a left subclavian artery patch to correct a coarctation), the collaterals between the occipital and distal VA are well developed and the occipital artery is large. In these cases a simple and direct anastomosis between the occipital artery in its premastoid portion and the distal VA provides direct blood flow to the latter. Needless to say, this technique requires an external carotid artery and a carotid bifurcation free of disease. The incision is similar to the one used for exposure of the distal VA, but it does not need to be prolonged into the lower portion of the neck, since no exposure of the carotid artery bifurcation is needed. After identification of the distal VA, the digastric muscle is either elevated or cut and the occipital artery is identified behind this muscle and dissected for approximately 1.5 in. Small branches that arise behind the digastric muscle are ligated. Once the length and caliber of the exposed occipital artery are judged adequate, the distal end of the occipital artery is divided and its proximal end is prepared for anastomosis by removing the adventitia. The anastomosis between the occipital and the distal VA is done using 8-0 polypropylene, usually with interrupted sutures (Fig. 53B-15). The anastomosis is also constructed end to side and then made end to end by application of a clip in the VA below the anastomosis.
Transposition of the Distal Vertebral Artery to the Cervical Internal Carotid Artery This technique has the appeal of a direct anastomosis between two arteries of comparable size and structure (Fig. 53B-16). The disadvantage of this technique is that is requires crossclamping of the ipsilateral internal carotid artery during the anastomosis and therefore previous assurance that there is good collateral flow from the opposite internal carotid artery. This technique is contraindicated in patients who have a contralateral internal carotid artery occlusion. The exposure of the distal VA is in the same field as the exposure of the distal cervical internal carotid artery: both are approached through a retrojugular dissection. Dissection of the
Figure 53B-14. Schematic drawing of the transposition of the external carotid artery to the distal vertebral artery.
high portion of the cervical internal carotid artery between C2 and C1 often requires papaverine infiltration to overcome spasm during manipulation. The division of the VA is done as low as possible near the top of the transverse process of C2, since it will have to be moved to the neighboring internal carotid artery. This distance is very small, since this high cervical segment of the internal carotid artery literally rests on the transverse process of C1. The selected spot for implantation of the VA into the internal carotid artery is devoided of adventitia. The distal cervical internal carotid artery is crossclamped using microsurgical occluders. An arteriotomy is made in its posterior wall and the VA is anastomosed to the arteriotomy in an end-to-side fashion. Depending on the size of the vessels, continuous or interrupted sutures of 7-0 or 8-0 polypropylene are used.
RESULTS We have used nearly exclusively, for the last 10 years, the technique of subclavian to carotid transposition for reconstruction of the subclavian artery.[11] The patency rate
Chapter 53B. Vertebrobasilar Ischemia: Reconstruction of the Vertebral Artery
Figure 53B-15. Schematic drawing of the transposition of the occipital artery to the distal vertebral artery.
in 45 transpositions has been 100% with a mean follow-up of 53 months. Three complications have been recorded: a phrenic nerve injury with paralysis of the hemidiaphragm and two acute postoperative bleeds requiring transfusion, which were repaired without further problems. There were no deaths or strokes in this group during the 30-day postoperative period. In 137 isolated proximal vertebral reconstructions there was no mortality or central neurologic morbidity. However, there have been 2 deaths among 39 patients undergoing simultaneous VA and internal carotid artery repair: one myocardial infarction and one stroke from an atheromatous embolus through a temporary shunt. Complications of proximal VA reconstruction include lymphocele in 5 cases
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Figure 53B-16. Transposition of the distal vertebral artery to the upper cervical internal carotid artery.
and, in 2 cases, thrombosis of the reconstruction requiring reoperation. A temporary Horner’s syndrome was noted in 15% of the cases. Among 100 distal reconstructions,[12] the mortality has been 4% and the combined mortality and morbidity 5%. Most complications were due to postoperative thrombosis, which has been largely avoided since we introduced routine intraoperative arteriograms to correct technical flaws. Cumulative secondary patency rates were 84% and 80% at 5 and 10 years, respectively. Of the symptomatic patients discharged with patent proximal and distal VA reconstructions who were alive at 5 years, 85% had their symptoms relieved by the operation.
REFERENCES 1.
Millikan, C.; Sickert, R. Studies in Cerebrovascular Disease. The Syndrome of Intermittent Insufficiency of the Basilar Arterial System. Proc. Staff Meet. Mayo Clin. 1955, 30, 61.
2.
Carterigue, P.; L’Hermitte, F.; Garetier, J.; et al. Arterial Occlusion in the Vertebrobasilar System. Brain 1973, 96, 133. 3. Caplan, L.R. Top of the Basilar Syndrome. Neurology 1980, 30, 72.
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4. Hacke, W.; Zemmer, H.; Ferbest, A.; et al. Intraarterial Thrombolytic Therapy Improves Outcome in Patients with Acute Vertebrobasilar Occlusive Disease. Stroke 1989, 19, 1216. 5. Rancurel, G.; Kieffer, E.; Arzimanoglu, A.; et al. Hemodynamic Vertebrobasilar Ischemia: Differentiation of Hemodynamic and Thromboembolic Mechanisms. In Vertebrobasilar Arterial Disease; Berguer, R., Caplan, L., Eds.; Quality Medical Publishing: St. Louis, MO, 1991. 6. Ruotolo, C.; Hazan, H.; Rancurel, G.; Kieffer, E. Dynamic Arteriography of the Vertebral Artery. In Vertebrobasilar Arterial Disease; Berguer, R., Caplan, L., Eds.; Quality Medical Publishing: St. Louis, MO, 1991. 7. Criado, F.J. Extrathoracic Management of Aortic Arch Syndrome. Br. J. Surg. 1982, 69 (Suppl.), 545.
8. Crawford, E.S.; DeBakey, M.E.; Fields, W.S. Roentgenographic Diagnosis and Surgical Treatment of Basilar Artery Insufficiency. J. Am. Med. Assoc. 1958, 149, 711. 9. Berguer, R.; Andaya, L.; Bauer, R. Vertebral Artery Bypass. Arch. Surg. 1976, 111, 976. 10. Berguer, R.; Kieffer, E. Surgery of the Arteries to the Head; Springer-Verlag: New York, 1992. 11. Berguer, R.; Morasch, M.D.; Kline, R.A.; Kazmors, A.; Friedland, M.S. Cervical Reconstruction of the Supraaortic Trunks: A Sixteen Year Experience. J. Vasc. Surg. 1998, In Press. 12. Berguer, R.; Morasch, M.D.; Kline, R.A. A Review of 100 Consecutive Reconstructions of the Distal Vertebral Artery for Embolic and Hemodynamic Disease. J. Vasc. Surg. 1998, 27, 852.
CHAPTER 54
Carotid Arterial Tortuosity, Kinks, and Spontaneous Dissection J. Timothy Fulenwider Robert B. Smith III the arterial tree is an appreciation of the development and retrogression of the dorsal aortas, appearing initially as symmetrical and parallel conduits destined to transform into the adult vascular form by as early as the 14-mm embryo stage. The dorsal aortas run parallel to the primitive foregut and fuse with the truncus arteriosus, forming the aortic sac, which contributes branch arteries to each developing pharyngeal arch. The third aortic arch ultimately forms the common carotid artery and the proximal internal carotid artery; the distal internal carotid system is formed by the cranial portion of the dorsal aorta. The external carotid artery sprouts from the third aortic arch, which joins with remaining portions of the first and second arches. Early in development, the communication between the third and fourth aortic arches—the carotid duct—becomes obliterated, and the extracranial carotid system assumes its adult configuration. These primordial vascular changes and cardiogenesis occur in the cephalad region of the embryonic pharynx. Developmental elongation of the fetal neck subsequently leads to descent of the heart into the mediastinum, with elongation of the innominate and carotid arteries. Maldescent of the heart or persistence of embryonic anatomy is felt responsible for subsequent looping and redundancy of the internal carotid artery.[3] Evidence for the congenital origin of the carotid loop is based upon its identification in fetal postmortem examinations. The anomaly is found in approximately 15% of children studied, with the prevalence rising to 25% of adults.[10] Degenerative changes of the arterial wall with secondary elongation are probably responsible for the higher prevalence in aging populations. Others have identified elastic tissue dysplasia of the tunica media of the carotid artery, a finding supportive of the congenital origin of carotid loops and tortuosities.[11,12] The etiologic significance of degenerative changes secondary to arteriosclerosis—with accentuation by chronic arterial hypertension and other hyperdynamic circulatory states— remains speculative.
The overwhelming majority of carotid-related ischemic brain and retinal syndromes confronting the vascular surgeon are secondary to artherosclerosis. Initiated either by intraplaque hemorrhage or by accretion of platelets and fibrin in an ulcer niche, carotid emboli are presumed responsible for most target-organ ischemic events. However, carotid stenoses reducing the lumen’s cross-sectional area to 25% of normal may also precipitate distal ischemic events, especially during periods of systemic hypotension or reduced cardiac output. A heterogeneous group of extracranial carotid arteriopathies, both congenital and acquired, occur relatively infrequently and may produce ischemic central nervous syndromes virtually indistinguishable from those of atherosclerotic origin. The symptomatic loop or coil, carotid kink, and spontaneous carotid dissection are among these unusual entities potentially responsible for carotid flow impairment or embolization. This chapter examines the carotid loop or coil, carotid kink, and spontaneous dissection, emphasizing anatomic and pathophysiologic details, diagnostic dilemmas, and contemporary medical or surgical management controversies.
THE CAROTID LOOP Extracranial internal carotid tortuosity is a relatively common angiographic finding.[1 – 3] The carotid loop, defined as a 360degree coil or spiral configuration or as an elongation and redundancy resulting in a sigmoid curvature, is felt to be congenital in origin (Fig. 54-1).[4 – 8] Development of this anomaly is best explained by defective embryogenesis of the carotid artery.[9] Normally, extensions of the endocardial heart tubes form the embryonic dorsal aortas, which assume an arched configuration in the fetal pharyngeal region due to rotation of the cardiogenic plate and fusion of the endocardial heart tubes. Central to an understanding of the development of
Hobson/Wilson/Veith: Vascular Surgery: Principles and Practice, Third Edition, Revised and Expanded DOI: 10.1081/0819-9-120024938 Copyright q 2004 by Marcel Dekker, Inc.
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Figure 54-1. Artist’s rendition of a 360-degree loop of the internal carotid artery and of marked tortuosity without coiling: (A ) elongation (loop): (B) tortuosity.
Although anatomists of the mid – eighteenth century accurately described elongation of the carotid arteries in autopsy examinations, Kelly, in the Glasgow Medical Journal in 1889, was among the first to observe the condition and to forewarn unwary surgeons of the significance of the bulging pharyngeal wall behind the posterior tonsillar pillar.[13] Edington, in an autopsy of a 34-year-old man who had died from chronic Bright’s disease, identified bilateral, tortuous internal carotid arteries abutting each ipsilateral posterior pharyngeal wall. He speculated that the condition was secondary to the arteritis of chronic nephritis; however, he noted that abnormal persistence of portions of the embryonic arches could not be excluded etiologically.[13] In 1925, Kelly reported 150 consecutive cases of tortuous or redundant internal carotid arteries and ascribed the condition in young individuals to developmental abnormalities.[5] He stressed the infrequency of progressive enlargement and alleviated fears of spontaneous rupture. On a number of occasions, tortuous internal carotid arteries have been misdiagnosed as peritonsillar abscesses, with fatal exsanguination following surgical drainage. Since the first successful surgical correction of a tortuous extracranial artery by Riser in 1951, controversy has persisted concerning the potential association of tortuous or coiled internal carotid arteries and the risk of cerebral ischemia and infarction.[14,15] While precise figures are unavailable, the relatively high prevalence of tortuosity, looping, and coiling of the cervical internal carotid artery is noteworthy. In patients with cerebral symptoms undergoing carotid arteriography, 4–31% of adults and 15 –43% of children have demonstrated extracranial internal carotid tortuosity, coiling, or looping.[1,10,16,17] The tortuosity frequently occurs in association with atheromatous plaques in adults. It is probable that tortuosity or carotid looping alone is rarely a primary cause of neurologic symptoms in adults; however, Sarkari et al.[8] described several children with seizures, transient
hemiparesis, hemianopia, and dysphasia in association with an ipsilateral internal carotid loop. Unfortunately Sarkari, who theorized that the carotid anomaly was responsible for the severe neurologic deficits, provided no pathologic studies of the vessels involved. Additionally, most other series affirming the association of carotid tortuosity and coiling with cerebral ischemia have not provided convincing evidence of such a cause-and-effect relationship. The available data suggest that carotid coiling, whether unilateral or bilateral, rarely accounts for cerebral ischemic sysmptoms in the absence of atherosclerotic occlusive disease in the carotid, vertebral, or basilar arteries.[1,18] Thus far, proof is lacking that the risk of stroke in unselected patients with carotid tortuosity and coiling exceeds the risk of neurologic injury or death associated with operative intervention.[1] Most patients presenting with cerebral ischemic symptoms who are found to have redundancy or looping of the extracranial carotid artery are middle-aged, with peak incidence at approximately 60 years. Approximately one fourth of adults have bilateral lesions, whereas up to 50% of children with tortuous vessels have bilateral coiling or elongation, which may be associated with other arterial anomalies such as aortic coarctation. For unknown reasons, women with elongation of the common carotid artery are four times more likely than age-matched men to have this vascular anomaly.[19] Presenting symptoms mimic those from extracranial carotid atherosclerotic lesions and include both focal and global transient ischemic events, fluctuating deficits, and fixed neurologic damage of variable severity.[20,21] Not infrequently, symptoms are most intense when the patient is supine in bed or has just woken up. Symptoms are usually considered to be secondary to hemodynamic consequences; most frequently, they are provoked by ipsilateral cervical rotation. However, contralateral cervical rotation, flexion, and extension may also lead to impairment of carotid flow. As demonstrated arteriographically, cervical rotation maneuvers may reduce or stop carotid flow by causing critical angulation or compression of the vessel by parapharyngeal soft tissue or osseous structures.[22] While extrinsic compression by the atlas, mandible, vertebral bodies, or fibrous bands is thought to limit carotid flow with cervical motion, the possibility of distal embolization has not been excluded in these cases. Albanese et al.[11] recently reported finding elastic tissue dysplasia of a coiled internal carotid artery in a 48-year-old man who suffered two episodes of transient left cerebral hemispheric ischemia prior to the development of a left hemispheric infarction. The extracranial carotid coil demonstrated a paucity of elastic fibers in the tunica media; however, in addition to focal areas of intimal hyperplasia, a small area of endothelium was covered by recent thrombus—a possible source of cerebral embolus. Theoretically, flow disturbances in looped arteries may occur, creating areas of high and low luminal surface shear stress potentially sufficient to promote deposition of platelet-fibrin aggregates with cerebral embolic potential. Although there are no pathognomonic neurologic changes attributable to carotid tortuosity and coiling, symptoms of either hemispheric or global neurologic deficits and vertebrobasilar insufficiency provoked by cervical rotation, extension, or flexion are important clues. Moreover, transient
Chapter 54.
Carotid Arterial Tortuosity, Kinks, and Spontaneous Dissection
or permanent cerebral hemispheric signs in children should always arouse suspicion of the presence of internal carotid coiling. There are also no pathognomonic signs of internal carotid tortuosity. A prominent cervical pulsation below the mandibular angle that becomes more pronounced with head turning may rarely be found and is best appreciated using bidigital, peritonsillar palpation. Rarely, a bruit or thrill may be appreciated during cervical rotation maneuvers. Carotid compression tests, as recommended by Derrick,[23] add little diagnostically and are potentially hazardous, since four of his patients developed acute neurologic deficits with these compression maneuvers. Perhaps the simplest, most sensitive noninvasive test to identify the presence of the tortuous, looped, or coiled internal carotid artery is the Doppler colorflow mapping technique. The experienced technologist may be able to delineate these carotid anatomic variants with realtime, B-mode ultrasonography of the duplex scanner. Both of these ultrasound imaging techniques may also provide important adjunctive information (e.g., atherosclerotic plaque formation). Nonetheless, these imaging techniques alone, as with arteriography, provide insufficient physiologic data and will not clarify the hemodynamic significance of the loop or coil. Additionally, the interpretation of flow data based upon Doppler spectral analysis may be difficult because of severe flow disturbances related to the geometry of the loop or coil. Oculopneumoplethysmography (OPG) may be more useful in determining the hemodynamic significance of these carotid anomalies. Currently, the most popular OPG testing technique is the positional OPG: determination of ophthalmic systolic pressures (OSP) with the neck in the neutral, flexed, extended, and laterally rotated positions. A reduction of ipsilateral OSP with changes of cervical position suggests that the carotid loop or coil may be reducing carotid flow, particularly if the patient’s symptoms are reproduced during the test. Most authorities agree that complete four-vessel cerebral angiography is essential and should include multiple views taken with cervical flexion, extension, and bidirectional rotation.[1,18,23,24] Examples of typical internal carotid tortuosity and looping are presented in Figs. 54-2 and 54-3. Prior to assignment of the carotid loop as causal in producing cerebral symptoms, other possibilities must be excluded. The most common of these include carotid atherosclerotic disease, cerebral neoplasm, intracranial vascular disease, cardiogenic emboli and arrhythmias, subdural hematoma, and orthostatic hypotension. The natural history of the tortuous, or coiled, extracranial internal carotid artery is unknown; yet it is generally agreed that these anomalies, if asymptomatic and discovered coincidentally, may be safely observed without significant threat of cerebral ischemia. Once the decision is made that the tortuous carotid is responsible for cerebral symptoms, operative correction should be considered, since the roles of systemic anticoagulation and antiplatelet compounds have not been determined. The goal of operative therapy should be to eliminate the tortuosity or loop of the carotid artery and also to remove any intrinsic obstruction from coexisting atherosclerotic plaque. Restoration of unimpeded carotid arterial flow is essential. Originally described by Riser et al.,[15] carotid arterioplexy to the sternocleidomastoid muscle to straighten the elongated artery has been abandoned. Presently,
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Figure 54-2. Lateral view angiogram of the extracranial carotid system, demonstrating a smooth atheromatous plaque of the proximal internal carotid artery and sigmoid curve in the vessel at the level of the angle of the mandible.
resection of the elongated artery is the operation of choice and demands proper assessment of the redundant arterial length. This determination is facilitated by complete mobilization of the distal internal carotid artery, with lysis of all fibrous bands that tether the artery near the base of the skull. Gentle manipulation of the thin-walled, friable internal carotid artery is mandatory to prevent possible dislodgment of atherothrombotic material and to minimize endothelial injury. Endarterectomy of associated bifurcation atheromas is as essential as complete mobilization and precise geometric planning to eliminate possible kinking. In order to minimize the dangers of suture line disruption of the friable internal carotid artery, some authors have advocated resection of a sleeve of common carotid artery, placing the anastomosis in this vessel of larger caliber and greater structural integrity. However, this technique frequently necessitates sacrifice of the external carotid artery— potentially an important route of cerebral collateral blood flow. To preserve the external carotid artery, others have recommended ligation at the origin of the internal carotid artery, with translocation of the orifice of the internal carotid artery more proximally onto the anterolateral common carotid artery.[25] The authors prefer instead to excise a segment of proximal internal carotid artery, to apply caudad traction and detorsion in order to eliminate the tedundancy, and then to construct a new anastomosis over an indwelling shunt, as previously recommended by Najafi et al.[26] Caution is essential during insertion of the internal carotid shunt; the redundant length of internal carotid artery must be
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Figure 54-3. Lateral angiogram showing an ulcerated atheroma in the proximal internal carotid artery and a 360-degree loop just cephalad to the plaque.
straightened prior to shunt insertion to minimize the risk of creating an endothelial flap. The internal and common carotid arteries are spatulated to create an elliptical anastomosis that is twice the length of the diameter of the internal carotid artery. The anastomosis is constructed with continuous monofilament suture, and the shunt is removed immediately prior to completion of the anastomosis. Because of the extensive dissection necessary, general anesthesia is frequently employed, but local or regional block anesthesia is also suitable for some patients. In properly selected subjects, the results of carotid arterioplasty for congenital loops and coils are quite acceptable, with approximately 80% of patients completely relieved of symptoms. Perioperative combined neurologic morbidity and mortality rates should be under 5%.[21]
THE CAROTID KINK Kinking of the extracranial internal carotid artery is defined as an acute bending or angulation of the artery, often described as “buckling.” Acute angulation of the internal carotid artery is almost invariably associated with atherosclerosis, with the
distal tip of the atheroma corresponding to the vertex of the carotid angle.[17] Kinking of the carotid is most frequently an acquired condition, which appears later in life and occasionally coexists with tortuous changes of the internal carotid.[10] The relative fixation of the proximal common carotid artery by the aortic arch and the distal internal carotid artery at the base of the skull predisposes the more flexible internal carotid to angulation, particularly when elongation of the artery occurs as a result of congenital lengthening or acquired degeneration secondary to chronic hypertension. The exact incidence of acute angulation of the carotid artery is unknown; however, in selected patients with cerebral symptoms, the incidence varies from 4 to 20%.[1,2,16,17] Even more confusing is the matter of stroke risk from carotid kink alone, since the overwhelming majority of patients with carotid kinks also demonstrate significant extracranial carotid atherosclerotic disease. Nevertheless, most authorities agree that a demonstrated carotid kink represents a greater threat of ischemic stroke than does elongation or coiling of the internal carotid artery. The first direct operation for correction of an internal carotid artery kink was performed by Hsu and Kistin[27] in 1956 but was unsuccessful. In 1959, Quattlebaum, Upson, and Neville[28] successfully resected the common carotid artery in three symptomatic patients with kinked internal carotid arteries. In 1962, Derrick and Smith[29] postulated that carotid kinking was more frequently causal of cerebral infarction than previously recognized and endorsed a more aggressive attitude toward the investigation and operative correction of carotid kinks. More recently, Vannix et al.[3] reemphasized the potential lethality of cerebral complications associated with the internal carotid artery kink and urged operative correction of this potentially disabling condition. Contrariwise, others have deemphasized the importance of carotid kink alone in the production of neurologic symptoms and have correctly pointed out the high prevalence of concomitant atherosclerosis and other coexisting nonvascular pathology as potentially responsible for the apparent cerebral ischemia.[1] The role of the noninvasive vascular laboratory in screening for significant carotid kinks remains controversial. Stanton et al.[30] were among the first to popularize OPG during cervical rotation, flexion, and extension as potentially useful in screening. These authors—utilizing the electromagnetic flowmeter intraoperatively with recordings obtained during bidirectional rotation, hyperextension, and flexion—confirmed the hemodynamic significance of the carotid kink with reductions of arterial flow from 30 to 80% during testing. According to their report, correction of the kink by segmental resection restored normal OPG scores with positional testing. Interestingly, each of the 16 patients undergoing operation had atherosclerotic stenoses and presumably underwent concomitant endarterectomy of an associated carotid atheroma. While positional OPG testing for the screening of carotid kinks has not been universally accepted, these data indicate that internal carotid kinks may account for symptomatic flow impairment. As elaborated by Metz et al.,[16] however, it is difficult to be certain of the relevance of any given factor in the production of cerebrovascular symptoms. These investigators have stated that the cessation of symptoms after the removal of a suspected cause does not necessarily establish a direct relationship between the two.
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In fact, some believe that removal of carotid plaque by endarterectomy alone is sufficient to relieve cerebral symptoms and that correction of redundant length is rarely necessary. Symptoms produced by the kinked internal carotid artery are virtually indistinguishable from the transient and permanent neurologic deficits that are of atherosclerotic origin. It is generally accepted that the hemodynamic theory of cerebral hypoperfusion is operative in the majority of symptomatic cases; however, microembolic events cannot be excluded with certainty. Kinking of the vertebral or innominate arteries also may coexist. Historical clues suggestive of the presence of a carotid kink typically include the precipitation of cerebral symptoms with extremes of cervical motion. Development of an audible bruit with cervical rotation may be observed, but physical examination of the cervical region is most often entirely normal.[28] The definitive diagnostic test is the four-vessel carotid and vertebral angiographic examination with complete intracranial views (Fig. 54-4). Positional angiography may confirm the anatomic significance of carotid kinks, whereas physiologic information may be obtained by using positional OPG. Parenthetically, it must be stated that while positional OPG may support the hemodynamic significance of the carotid kink, operative correction may not be curative; also, negative positional OPG testing does not necessarily preclude successful operative correction. While most would agree that correction of an incidental, asymptomatic carotid kink is not indicated, some have recommended corrective arterioplasty if positional OPG testing suggests a significant reduction in carotid flow, if the carotid angulation is less than 60 degrees,
or if there is the functional equivalent of less than 25% residual lumen area. The authors endorse the more conservative approach to the isolated asymptomatic kink, for it appears that the natural history of this lesion is less morbid than operative correction. Generally accepted indications for the correction of internal carotid artery kinks are the following: (1) evidence that the kink may be responsible for cerebral ischemia by reproduction of symptoms on head rotation, flexion, or extension, and (2) exclusion of other craniocerebral vascular, neoplastic, or developmental abnormalities which might account for similar symptoms. In actual practice, most patients with extracranial carotid kinks undergo operation primarily for correction of ulcerostenosing atheromas of the carotid with coincidental angulation of the artery noted at the apex of the rigid atheroma. Following endarterectomy and primary or patch closure of the arteriotomy, the acute angulation is frequently relieved. On other occasions, acute angulation of 90 degrees or less is observed after performance of the endarterectomy. If such a kinked vessel creates a harsh thrill or produces significant intraoperative pressure reduction in the distal internal carotid artery, the angulation should be corrected. A variety of shortening techniques have been advocated, but direct arteriopexy is rarely indicated. The authors’ preferred technique of arterioplasty for correction of acute angulation is similar to that described earlier for the correction of the internal carotid artery loop (Figs. 54-5–5410). Following endarterectomy, if required, resection of a cuff of proximal internal carotid is performed over an indwelling shunt, which serves additionally as a reconstruction stent. In the absence of intraluminal shunt utilization, careful internal
Figure 54-4. Anteroposterior carotid arteriogram showing an incidental kink or lateral angulation of the internal carotid artery.
Figure 54-5. Operative repair of a carotid bifurcation atheroma with associated redundancy and kinking: location of the arteriotomy.
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Figure 54-6. Following mobilization of the internal carotid artery and cautious shunt insertion, a standard bifurcation endarterectomy is performed.
carotid detorsion and spatial orientation are required to minimize anastamotic flow disturbances. An elliptical end-toend anastomosis (length-to-diameter ratio of 2:1) is then constructed with running monofilament vascular sutures. Despite the infrequent need for correction of a carotid kink, operative morbidity and mortality rates are acceptably low and should parallel those of simple carotid endarterectomy in experienced hands.
SPONTANEOUS DISSECTING HEMATOMA OF THE INTERNAL CAROTID ARTERY Dissecting hematomas of the extracranial internal carotid artery are rare yet potentially devastating causes of cerebral ischemia. The term spontaneous implies the occurrence of internal carotid dissection without recognizable traumatic antecedent, although—not infrequently—spontaneous dissections are observed in association with fibromuscular dysplasia, Erdheim’s cystic medial necrosis, arteriosclerosis, arterial tortuosity, Marfan’s syndrome, and Ehlers-Danlos syndrome.[31 – 35] Since the original description by Anderson and Schechter in 1959,[36] over 200 cases have been reported,
Figure 54-7. An appropriate length of redundant internal carotid is excised, taking care to prepare the ends for an oblique reanastomosis.
with the largest series from Ehrenfeld and Wylie,[37] Fisher et al.,[38] and Bogousslavsky et al.[39] Blunt and penetrating cervical trauma and acceleration-deceleration cervical injuries are well recognized causes of arterial dissection but are excluded from this consideration. Likewise excluded are dissecting aneurysms of the ascending and transverse aorta, which may extend into the proximal carotid system and, rarely, into the internal carotid artery. Whether dissection of the extracranial internal carotid artery is ever clearly spontaneous remains controversial. As emphasized by Trosch et al.,[40] antecedent trauma may be trivial and either not recalled or too embarrassing to disclose. Such trauma as coughing, vigorous nose blowing, shaving, brushing teeth, head turning while leading a parade, neck flexion while scolding a child, and “head banging” during punk rock dancing have been recorded prior to “spontaneous” carotid dissections.[40,41] In the majority of patients, however, the etiology is unknown. Males and females appear to be afflicted at similar rates, with the mean age at diagnosis being 46 years (range, 11–74 years). Both internal carotids appear to be affected with similar frequency.[34,35,39] Presenting clinical manifestations of internal carotid dissection include focal cerebral neurologic deficits—whether transient or permanent—in over 80% of cases, but it appears that the regional extent of neurologic complaints in this condition is often greater than that attributable to atherosclerotic embolization.[38] Thus, many patients present with
Chapter 54.
Carotid Arterial Tortuosity, Kinks, and Spontaneous Dissection
Figure 54-8. With gentle traction while the indwelling shunt is being advanced, the internal carotid stump is positioned at the cut edge of the common carotid artery.
signs of both retinal ischemia and contralateral hemiparesis or hemihypesthesia, in addition to multiple cranial nerve palsies. Noteworthy physical symptoms and signs of carotid dissection may include the rapid onset of severe hemicrania; Horner syndrome; Raeder trigeminal syndrome; scalp hyperalgesia; dysgeusia; central sixth, seventh, and eighth cranial nerve palsy; as well as contralateral focal sensory and motor deficits. These neurologic features may occur singly or in variable combinations or may be preceded by transient cerebral ischemia in about 20% of patients.[39] Dysgeusia is felt to result from involvement of the chorda tympani branch of the seventh cranial nerve. Importantly, the evolution of a complete Horner oculosympathetic palsy may occur asynchronously or may be incomplete. The acute onset of ipsilateral head and facial pain in the frontal, parietal, or periorbital area may be followed in 24– 72 hours by the development of one or more features of Horner syndrome, with anhydrosis most frequently absent. The headaches are typically nonthrobbing and fluctuating in intensity; they frequently require 2 –6 months to resolve completely. During this interval, rarely is there complete relief of the cephalalgia. Other complaints include pulsatile or machinery vascular tinnitus.[37,38,42,43] Physical findings of carotid dissection vary enormously. The multiplicity of neurologic findings mentioned above—in addition to tenderness over the carotid bulb, carotidynia, and an evolving cervical bruit—are strongly suggestive of the
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Figure 54-9. Reanastomosis is performed by use of a continuous monofilament vascular suture, producing a “Tshaped” closure.
diagnosis. The origin of the internal carotid dissecting hematoma is usually 2 –3 cm distal to the carotid bulb. Through the usually vertically oriented intimal rent, the hematoma pulsates deep into the tunica media, creating a subadventitial cleavage plane.[37,38] The entire arterial circumference is rarely involved; however, thrombosis of the false channel severely compromises the true lumen, leading either to markedly reduced flow or to secondary complete thrombosis. The dissection seldom extends beyond the base of the skull, but cavernous sinus extension has been reported. On rare occasions, reentry of the hematoma into the true lumen may occur acutely, restoring arterial flow. The experience of Ehrenfeld and Wylie[37] in 10 patients with dissecting aneurysms has provided the best description of the typical gross pathology. Consistent in their experience was a sharp transition between the normal color and size of the internal carotid artery and the dark-blue discoloration and moderate cylindrical dilatation produced by the dissection. Only 4 patients of their series experienced termination of the dissection at a level easily visualized from the cervical incision, whereas the other 6 experienced dissections beyond the limits of surgical accessibility. Three patients had an arteriotomy performed, and each demonstrated the short vertical intimal rent marking the origin of the dissection. Microscopically, the typical features included organizing hematoma in the deeper layers of the tunica media with
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Figure 54-10. Completed endarterectomy and internal carotid shortening procedure. Note that the continuity of the external carotid is preserved by this technique.
reduction of elastic tissue and fragmentation of internal elastic laminae. Smooth-muscle cells were widely separated and diminished in number. Mucopolysaccharide stains demonstrated the deposition of mucoid material indicative of degenerative changes. Atherosclerosis was consistently absent.[37] In 1972, Ojemann et al.[44] suggested that the long stenotic segment of extracranial internal carotid artery visualized angiographically (“string sign”) might be a reliable indicator of carotid dissection (Figs. 54-11 and 54-12). Adopting this radiographic feature, radiologists became convinced that spontaneous carotid dissection was clearly not as rare as previously suspected. Typically, the angiogram of the carotid dissection reveals an irregular, extremely narrow column of contrast beginning slightly above the carotid bulb, with a gradual taper ending at the base of the skull. Usually there is little or no evidence of atherosclerotic plaque. These radiographic features are highly suggestive of carotid dissection, but the “string sign” may also occur with other types of vascular disease such as atherosclerosis, fibromuscular dysplasia, arteritis, moya moya, and vasospasm.[38] Although the degree of stenosis is usually high-grade, the length of the angiographic stenotic segment can be variable. Occasionally a small cul-de-sac projecting cephalad and posteriorly is identified and is thought to represent the residual lumen at the origin of the intimal tear. If spontaneous organization of the false channel hematoma develops, retraction of the intima occurs at variable rates, producing scalloped or undulating angiographic margins of the recanalizing carotid artery walls. Traditionally, contrast arteriography remains the diagnostic standard of carotid dissection; however, confidence in magnetic resonance angiography in establishing the diagnosis is increasing. The
Figure 54-11. Lateral carotid arteriogram of a young patient with carotid dissection, showing severe tapering of the internal carotid lumen and a “string sign” extending cephalad. Note the absence of atherosclerotic changes.
role of helical computerized tomography in the detection and surveillance of carotid dissections is presently unclear. Carotid duplex imaging with color flow mapping is being used with increasing frequency in the screening of patients with possible carotid dissections. B-mode ultrasound findings of a double internal carotid lumen with intimal flap, intramural thrombus with overlying intact intima, and minimal atherosclerotic changes are typical of carotid dissection. Spectral analysis data may show a high resistance waveform with short systolic flow signal or temporal fluctuations of systolic signals. Color flow mapping may suggest severe arterial luminal encroachment or occlusion. The accuracy of carotid duplex scanning in the diagnosis of carotid dissection is technologist-dependent; therefore, the most reliable technique for the diagnosis of carotid dissection remains contrast arteriography. Bilateral and recurrent carotid dissections are unusual.[35,38,39] Early experience with this condition resulted in a variety of urgent attempts to restore cerebral arterial flow. These included resection of the involved segment with saphenous vein interposition grafting, dilation, balloon catheter thrombectomy, or ligation of the internal carotid artery, provided a stump
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Carotid Arterial Tortuosity, Kinks, and Spontaneous Dissection
Figure 54-12. Later film from the same angiographic sequence demonstrating eventual filling of the carotid siphon and suggesting patency of the severely narrowed lumen.
pressure of greater than 65 torr was identified.[37] The majority of these operations were unsuccessful due to technical difficulties with exposure of the distal point of dissection, the presence of residual thrombus with cerebral embolic potential, or progression of frank stroke as a result of acute revascularization of a bland cerebral infarct. In 1976, taking a new approach, Ehrenfeld and Wylie[37] described experience with 7 patients in whom the carotid artery was not disturbed surgically. Of these patients, 3 underwent cervical exploration only and 4 were managed nonoperatively. Surprisingly, none of the patients had further progression of neurologic symptoms with up to 3 years follow-up. Repeat arteriography was obtained in 6 of these
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patients from 2 to 16 months following the original arteriogram. One carotid had progressed to total occlusion, whereas the remaining five had increased to essentially normal caliber. Others have since reported favorable results with nonoperative therapy;[45] however, the optimum therapeutic protocol is presently unknown. One of the larger, more contemporary clinical series of 30 spontaneous carotid dissection and stroke patients was reported by Bogousslavsky et al.[39] This group represented 2.5% of stroke patients admitted to their unit. Bogousslavsky emphasizes that acute carotid dissection is frequently followed by severe, permanent neurologic impairment or even death: 7 (23%) expired within 7 days of the neurologic event and 11 of 23 survivors (48%) had severe physical limitations or required total custodial care. Maximal functional recovery was achieved within 6 months by the survivors. Of the 23 survivors, 13 (57%) demonstrated recanalization of the carotid artery, which usually occurred within 30 days of the acute dissection. The authors conclude that carotid thrombosis and distal cerebral embolization account for the larger hemispheric infarctions and that early heparin anticoagulation may favorably influence clinical outcome by maintaining carotid patency and preventing luminal thrombosis until natural clot retraction can occur. They also caution against heparin therapy whenever the dissection extends intracranially, because of commonly associated subarachnoid hemorrhage. Although the exact role of heparin, warfarin, and antiplatelet drugs is uncertain, a consensus of the recent literature suggests that the initial approach should be nonsurgical.[39] In the absence of massive cerebral infarction or intracranial hemorrhage, systemic heparinization should be initiated and, theoretically, may facilitate resolution of the dissecting hematoma and minimize the threat of distal cerebral embolization. It has been suggested that a minimum of 3 weeks of heparin therapy is necessary;[46] however, continuing heparinization and subsequent warfarin (Coumadin) therapy until there is normalization of the ophthalmic systolic pressure by OPG testing or recanalization—as determined by duplex carotid scanning or arteriography—is a logical approach.[45] Operative intervention is reserved for medical failures. Persistence of transient ischemic neurologic events with failure of recanalization may necessitate graft replacement of the diseased carotid artery or ligation, preferably preceded by extracranial-intracranial bypass. Bilateral extracranial carotid dissections may require extracranial-intracranial bypass grafting for low-flow symptoms that endanger the brain. Recently, the technical feasibility for immediate endovascular stent recanalization of a carotid dissection has been demonstrated.[47] At present, the propriety, timing, risks, and outcome of endovascular stent procedures for carotid dissections await future trials. Very rarely, the spontaneous dissection originates in the common carotid artery, permitting reconstruction by subclavian-carotid bypass to preserve ipsilateral cerebral perfusion.[48]
REFERENCES 1.
Perdue, G.D.; Barreca, J.P.; Smith, R.B. The Significance of Elongation and Angulation of the Carotid Artery: A Negative View. Surgery 1975, 77, 45.
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Brosig, H.-J.; Vollmar, J. Chirurgische Korrektur der Knickstenosen der A Carotis Interna. Munch. Med. Wochenschr. 1974, 116, 969.
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3. Vannix, R.S.; Joergenson, F.J.; Carter, R. Kinking of the Internal Carotid Artery: Clinical Significance and Surgical Management. Am. J. Surg. 1977, 134, 82. 4. Desai, B.; Toole, J.F. Kinks Coils and Carotids: A Review. Stroke 1975, 6, 649. 5. Kelly, A.N. Tortuosity of the Internal Carotid in Relation to the Pharynx. J. Laryngol. Otol. 1925, 40, 15. 6. Gass, H.H. Kinks and Coils of the Cervical Carotid Artery. Surg. Forum. 1958, 9, 721. 7. Ohara, I.; Iwarbrehi, T.; Yaegashi, S. Abnormally Twisted Cervical Internal Carotid Artery, Probably Congenital. Vasc. Surg. 1969, 3, 1. 8. Sarkari, N.B.S.; Holmes, J.M.; Bickerstaff, E.R. Neurological Manifestations Associated with Internal Carotid Loops and Kinks in Children. J. Neurol. Neurosurg. Psychiatry 1970, 33, 194. 9. Gray, S.W.; Skandalakis, J.E. The Thoracic Aorta. In Embryology for Surgeons, the Embryological Basis for the Treatment of Congenital Defects; Saunders: Philadelphia, PA, 1972; 809–857. 10. Weibel, J.; Fields, W.S. Tortuosity, Coiling, and Kinking of the Internal Carotid Artery: I. Etiology and Radiographic Anatomy. Neurology 1965, 15, 7. 11. Albanese, V.; Spadaro, A.; Iannotti, F. Elastic Tissue Dysplasia of Coiled Internal Carotid Artery in an Adult. J. Neurosurg. 1983, 58, 781. 12. Ochsner, J.L.; Hughes, J.P.; Leonard, G.L. Elastic Tissue Dysplasia of the Internal Carotid Artery. Ann. Surg. 1977, 185, 684. 13. Edington, G.H. Tortuosity of Both Internal Carotid Arteries. Br. Med. J. 1901, 2, 1526. 14. Robicsek, F.; Daugherty, H.K. Redundancy of the Carotid Artery Combined with Intrinsic Occlusion. Vasc. Surg. 1970, 4, 101. 15. Riser, M.M.; Geraud, J.; Ducoudray, J. Dolicho-carotide Interne avec Syndrome Vertigineux. Rev. Neurol. (Paris) 1951, 85, 145. 16. Metz, H.; Murray-Leslie, R.M.; Bannister, R.G. Kinking of the Internal Carotid Artery in Relation to Cerebrovascular Disease. Lancet 1961, 1, 424. 17. Bauer, R.; Sheehan, S.; Meyer, J.S. Arteriographic Study of Cerebrovascular Disease: II. Cerebral Symptoms Due to Kinking, Tortuosity and Compression of Carotid and Vertebral Arteries in the Back. Arch. Neurol. 1961, 4, 119. 18. Weibel, J.; Fields, W.S. Tortuosity, Coiling, and Kinking of the Internal Carotid Artery: II. Relationship of Morphological Variation to Cerebrovascular Insufficiency. Neurology 1965, 15, 462. 19. Schecter, D.C. Dolichocarotid Syndrome: Cerebral Ischemia Related to Cervical Carotid Artery Redundancy with Kinking: Parts I and II. N.Y. State J. Med. 1979, 79, 1391 –1542. 20. Harrison, J.H.; Davalos, P.A. Cerebral Ischemia: Surgical Procedures in Cases Due to Tortuosity and Buckling of the Cervical Vessels. Arch. Surg. 1962, 84, 85. 21. Quattlebaum, J.K., Jr.; Wade, J.S.; Whiddon, C.M. Stroke Associated with Elongation and Kinking of the Carotid Artery: Long-Term Follow-up. Arch. Surg. 1973, 177, 572. 22. Freeman, T.R.; Lippitt, W.H. Carotid Artery Syndrome Due to Kinking: Surgical Treatment in Forty-Four Cases. Am. Surg. 1962, 28, 745.
23. Derrick, J.R. Carotid Kinking and Cerebral Insufficiency. Geriatrics 1963, 17, 272. 24. Robicsek, F.; Daugherty, H.K.; Sanger, P.W. Intermittent Cerebrovascular Insufficiency: A Frequent and Curable Cause of Stroke. Geriatrics 1967, 22, 96. 25. Rundles, W.R.; Kimbrell, F.D. The Kinked Carotid Syndrome. Angiology 1969, 20, 177. 26. Najafi, H.; Javid, H.; Dye, W.S. Kinked Internal Carotid Artery. Arch. Surg. 1964, 89, 134. 27. Hsu, I.; Kistin, A.D. Buckling of the Great Vessels. Arch. Intern. Med. 1956, 98, 712. 28. Quattlebaum, J.K., Jr.; Upson, E.T.; Neville, R.L. Stroke Associated with Elongation and Kinking of the Internal Carotid Artery. Ann. Surg. 1959, 150, 824. 29. Derrick, J.R.; Smith, T. Carotid Kinking as a Cause of Cerebral Insufficiency. Circulation 1962, 25, 849. 30. Stanton, P.E.; McClusky, D.A.; Lamis, P.A. Hemodynamic Assessment and Surgical Correction of Kinking of the Internal Carotid Artery. Surgery 1978, 84, 793. 31. Mettinger, K.L.; Ericson, K. Fibromuscular Dysplasia and the Brain. Observations on Angiographic, Clinical and Genetic Characteristics. Stroke 1982, 13, 46. 32. Bostro¨m, K.; Liliequist, B. Primary Dissecting Aneurysm of the Extracranial Part of the Internal Carotid and Vertebral Arteries: Report of Three Cases. Neurology 1967, 17, 179. 33. Luken, M.G.; Ascherl, G.F.; Carrell, J.W. Spontaneous Dissecting Aneurysms of Extracranial Internal Carotid Artery. Clin. Neurosurg. 1979, 26, 353. 34. Treiman, G.S.; Treiman, R.L.; Foran, R.F. Spontaneous Dissection of the Internal Carotid Artery: A Nineteen-Year Clinical Experience. J. Vasc. Surg. 1996, 24, 597. 35. Bassetti, C.; Caruzzo, A.; Sturzeneggel, M. Recurrence of Cervical Artery Dissection: A Prospective Study of 81 Patients. Stroke 1996, 27, 1804. 36. Anderson, R.; Schechter, M. A Case of Spontaneous Dissecting Aneurysms of the Internal Carotid Artery. J. Neurol. Neurosurg. Psychiatry 1959, 22, 195. 37. Ehrenfeld, W.K.; Wylie, E.J. Spontaneous Dissection of the Internal Carotid Artery. Arch. Surg. 1976, 111, 1294. 38. Fisher, C.M.; Ojemann, R.F.; Roberson, G.H. Spontaneous Dissection of Cervicocerebral Arteries. Can J. Neurol. Sci. 1978, 5, 9. 39. Bogousslavsky, J.; Despland, P.; Regli, F. Spontaneous Carotid Dissection with Acute Stroke. Arch. Neurol. 1987, 44, 137. 40. Trosch, R.; Hasbani, M.; Brass, L. “Bottoms up” Dissection (letter). N. Engl. J. Med. 1989, 320, 1564. 41. Jackson, M.A. “Headbanging” and Carotid Dissection. Br. Med. J. 1983, 287, 1262. 42. Waespe, W.; Niesper, J.; Imhof, H.-G. Lower Cranial Nerve Palsies Due to Internal Carotid Dissection. Stroke 1988, 19, 1561. 43. Maitland, C.G.; Black, J.L.; Smith, W.A. Abducens Nerve Palsy Due to Spontaneous Dissection of the Internal Carotid Artery. Arch. Neurol. 1983, 40, 448. 44. Ojemann, R.D.; Fisher, C.M.; Rich, J.C. Spontaneous Dissecting Aneurysm of the Internal Carotid Artery. Stroke 1972, 3, 434. 45. Gee, W.; Kaupp, H.A.; McDonald, K.M. Spontaneous Dissection of Internal Cartotid Arteries: Spontaneous
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Resolution Documented by Serial Ocular Pneumoplethysmography and Angiography. Arch. Surg. 1980, 115, 944. 46. McNeill, D.H.; Dreisbach, J.; Marsden, R.J. Spontaneous Dissection of the Internal Carotid Artery: Its Conservative Management with Heparin Sodium. Arch. Neurol. 1980, 37, 54.
47.
48.
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Hong, M.K.; Satler, L.F.; Gallino, R. Intravascular Stenting as a Definitive Treatment of Spontaneous Carotid Artery Dessection. Am. J. Cardiol. 1997, 79, 538. Graham, J.M.; Miller, T.; Stinnett, D.M. Spontaneous Dissection of the Common Carotid Artery. Case Report and Review of the Literature. J. Vasc. Surg. 1988, 7, 811.
CHAPTER 55
External Carotid Endarterectomy Karl A. Illig Richard M. Green James A. DeWeese
There is abundant evidence that patients with occlusion of the internal carotid artery have the potential for ipsilateral hemispheric or ocular symptoms due either to thromboemboli passing through natural connections between the external and internal carotid arteries or to hemodynamic abnormalities from reduced blood flow.[1 – 3] In certain situations, operation on the carotid bifurcation which both removes atherosclerotic plaque and remodels the stump of the occluded internal carotid artery, producing a smooth tapering of the common carotid artery into the external carotid artery, can prevent these symptoms. In a similar fashion, patients with diseased or occluded external carotid arteries can suffer thromboembolic events through an open internal carotid. Endarterectomy or remodeling of the stump of the diseased external carotid artery can similarly relieve such symptoms and prevent late stroke.
laboratory. New occlusions occurred in 24 patients with previously unoperated arteries. The occlusions were associated with ipsilateral strokes in 6 patients (25%), ipsilateral transient ischemic attacks (TIAs) in 4 patients (16%), and nonhemispheric symptoms in 1 patient (5%). Thirteen patients (54%) had no symptoms. Fritz et al.[8] found a similar incidence of stroke (22%) coincident with ICA occlusion in their series of patients, although they did not have preocclusion data for analysis. The external carotid artery (ECA) becomes important in the setting of a chronic ICA occlusion regardless of the occlusion’s immediate clinical efffect. The natural history of this lesion has been a topic of great interest and some variability, but it is certainly not a benign condition. Fields and Lemak[9] found that 359 patients with ICA occlusion followed for an average of 44 months had a 25% incidence of new strokes. New lateralizing strokes ipsilateral to the occlusion occurred in 8% of the patients. Cote et al.[10] followed a similar group of patients in the Canadian Cooperative Study for 34.4 months and found that 23.5% suffered new strokes and 15% of the strokes, or 5% when adjusted annually, were ipsilateral to the occlusion. The largest experience was reported by Nichols et al.,[11] who found a 5-year cumulative stroke rate of 25% (15% ipsilateral) and an annual ipsilateral stroke rate of 3%. Finally, the incidence of all new strokes in the group of patients with chronic ICA occlusion followed in the medical arm of the EC/IC Bypass Study Group was 29% over 55.8 months, or 6% per annum.[12] The incidence of ipsilateral stroke in this group of patients was 22% at 5 years. The variability in these studies may be explained by differences in study design. A prospective study will have a higher stroke-recognition rate than a retrospective study, and studies that include patients with common carotid artery occlusions may be examining a different population with less risk of embolizing up a collateral pathway.
INTERNAL CAROTID ARTERY OCCLUSION Natural History A significant number of patients who present with an acute stroke are found to have an occluded internal carotid artery (ICA) ipsilateral to the hemispheric lesion. Since the timing of the occlusion is not known, the relationship between the occlusion and the neurologic deficit is a matter of conjecture. Data on the immediate sequelae of ICA occlusion have been derived from either autopsy or ligation series, which may not be applicable to the atherosclerotic patient.[4 – 6] Nichols et al.[7] gathered prospective data before and after ICA occlusion from a group of 2700 patients evaluated over a 7year period with serial duplex scanning in the vascular
Hobson/Wilson/Veith: Vascular Surgery: Principles and Practice, Third Edition, Revised and Expanded DOI: 10.1081/0819-9-120024939 Copyright q 2004 by Marcel Dekker, Inc.
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Hemodynamics The external carotid artery accounts for approximately 3% of the blood flow in the internal jugular veins.[13] The contribution of the external carotid system can increase in the setting of an ICA occlusion.[14] A variety of hemodynamic data are available before and after external carotid revascularization to further support the role of these important collateral pathways. Machleder and Barker[15] demonstrated that the placement of an indwelling shunt into the external carotid artery during carotid endarterectomy increased the ICA stump pressure an average of 10.8 mmHg. Schuler et al.[16] used ocular pneumoplethysmographic (OPG) pressure measurements to assess the effectiveness of external carotid endarterectomy in improving cerebral perfusion and found that significant increases in the OPG pressure occurred. In similar clinical circumstances, Zarins et al.[17] and McIntyre et al.[18] found that external carotid endarterectomy resulted in a 15 –39% ipsilateral increase and a 0 –52% contralateral increase in cerebral blood flow measured by xenon-enhanced computerized tomography (CT) imaging. However, in a study using transcranial Doppler, Norris et al.[19] raised questions about the role of the external carotid artery as an important source of cerebral blood flow. They demonstrated—with carotid compression in a group of patients with ICA occclusion and contralateral severe stenosis—that flow through the middle cerebral artery was normal in 95% of the group and only slightly reduced in the remaining 5%. They concluded that the primary collateral sources of cerebral blood flow when the ICA is occluded are vertebrobasilar communications and that the external carotid artery stenosis causes stroke by embolic, not hemodynamic, means.
Anatomy of Collaterals The collateral network of the adult cerebral circulation is a remnant of intrauterine development. The collateral vessels develop primarily from the facial branches of the external carotid artery.[20] There are three major networks:[21] (1) large interarterial connections such as the circle of Willis, (2) intracranial to extracranial anastomoses based on the external carotid artery through the periorbital plexus and the vertebral artery, and (3) small interarterial connections on the surface of the brain, called the leptomeningeal collaterals. The collateral vessels derived from branches of the external carotid artery can be visualized angiographically. The accompanying figures demonstrate filling of the distal ICA from the orbital collaterals in a patient with ICA occlusion at the carotid bifurcation (Fig. 55-1). The sequence demonstrates filling of the ophthalmic artery from the facial branches of the ECA and then filling of the internal carotid siphon from the ophthalmic artery. The size of these collaterals ranges from 0.1 to 0.3 mm.[22] In the early stages of embryologic development, the ophthalmic artery and the branches of the ECA, originally separate, become connected via a rich anastomotic network. As the ophthalmic artery develops, there is a partial regression of the ECA component of the orbital perfusion, but the potential of this collateral network remains.[23] The role of the ophthalmic artery can be evaluated by the direct, noninvasive technique of transorbital Doppler ultrasonography. A 2-MHz pulsed-wave Doppler probe can be
placed over the orbit to insonate the ophthalmic artery, usually at a depth of 35–40 mm. The angle of insonation is less than 15 degrees.[24] The use of this technique may help select those patients who might benefit from external carotid endarterectomy. Transorbital sonography can delineate the direction and quantify the velocity of ophthalmic artery flow through established extracranial to intracranial collaterals through which emboli might pass.[25]
CLINICAL PRESENTATION Symptoms that occur in the setting of an ICA occlusion can be due to a variety of pathologic mechanisms. Some patients will present with an ulcerative and/or stenotic lesion in the proximal ECA or distal common carotid artery. These lesions can be a source of atheroembolic material, causing ischemic events in the territory perfused by the collateral vessels.[26,27] Second, a “stump” may be present at the origin of the occluded ICA, which is a potential source for embolic material via the ECA and its collaterals. Third, emboli may arise from the tail of a thrombus distal to an occluded ICA and travel beyond the circle of Willis.[28] Finally, hemodynamic factors may cause symptoms due to lack of perfusion. Baron et al.[29] describe a condition in which perfusion does not match oxygen requirements and thereby causes ischemic symptoms. This has been called the “misery-perfusion syndrome” and may be reversed by increasing flow to that region. It was initially felt that the extracranial-to-intracranial (EC-IC) bypass would best treat this entity, but the large cooperative study has refuted that possibility.[12] The failure of EC-IC bypass may be further confirmation that symptoms in the setting of a chronic ICA occlusion are embolic, not hemodynamic. Other indirect observations that support the embolization hypothesis are (1) the presence of a source of emboli in the stump of the ICA or at the level of the common carotid or ECA and retinal plaques[30] and (2) the relief of symptoms after ECA reconstruction and closure of the ICA stump even in the absence of an ECA stenosis.[31]
Results of Operative Series There have been a number of clinical reviews on external carotid revascularization,[32 – 36] which have been summarized by Gertler and Cambria.[20] Although over 200 cases have been reported, relatively few patients with ICA occlusions will require further operative therapy. Data on operative indications in the collected series are incomplete, but it appears that the most common reasons for operation are hemispheric TIAs and amaurosis fugax. Less common indications are nonhemispheric symptoms and prior stroke. In general, results after routine ECA reconstruction are quite good, without significant operative morbidity or mortality. In 24 published series, there were 192 ECA endarterectomies with no operative deaths and a stroke rate of 1.6%.[16,17,30 – 36] These same series examined long-term results (range, 1 month to 5 years) and found that there were 8 deaths from cardiac events (4%) and 21 neurologic events (10%), including 7 strokes (3%). None of the strokes was ipsilateral
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Figure 55-1. (A ) An arteriogram in an asymptomatic patient with an occluded ICA. There is a large internal maxillary artery. (B ) The arrows show a faint view of the ophthalmic artery filling from the collateral network fed by the internal maxillary artery. (C ) The ophthalmic artery is clearly seen in this late-phase arteriogram. (D ) The carotid siphon (Car) is visualized as it fills from the ophthalmic artery (Ophthal).
to the ECA reconstruction. The other neurologic events were TIAs or seizures. Roughly 90% of patients had either no further symptoms or marked improvement in symptoms following operation. Patients with embolic events did better than patients with hemodynamic events. Several authors have reported a significant morbidity and mortality associated with ECA reconstruction. In the series of O’Hara et al.[32] and Halstuk et al.,[33] however, a significant number of strokes were reported after ECA reconstruction, but these events occurred in patients with complicated ECA operations such as reoperation, bypasses from the subclavian artery, or EC-IC
bypass. The EC-IC bypass study indicates with strong statistical power that fatal and nonfatal strokes were not prevented by anastomosis of the superficial temporal artery to the middle cerebral artery.[12] The subgroup of patients with symptoms after ICA occlusion fared worse with operation than without. This does not mean that external carotid revascularization is without merit. It might mean that the creation of an anastomosis between the external and internal carotid arteries may just create another pathway for embolization in the setting of atherosclerotic debris and abnormal flow dynamics at the carotid bulb.
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Case Reports Case 1 This is a 68-year-old white woman with a known left ICA occlusion. She previously underwent a right carotid endarterectomy but presented again with left-sided amaurosis fugax. Her symptoms occurred several times per day. A funduscopic examination with dilated pupils did not reveal atheroemboli. The ocular plethysmograph (OPG) was abnormal on the left. An arteriogram was performed, which showed a left ICA occlusion and a tight stenosis of ECA (Fig. 55-2). At operation there was a critical stenosis of the ECA extending to just beyond the lingual artery. There was no loose material in the “stump,” and the ECA plaque was not ulcerated. The ICA was transected at the bifurcation and oversewn. An endarterectomy of the ECA through a separate arteriotomy with patch closure was performed. The postoperative OPG was increased from preoperative levels but still below the line. This patient was followed for 24 months and had no further ocular symptoms.
Case 2 This is a 72-year-old white man who presented with sudden left-eye blindness. He was known to have a chronic occlusion of his left internal carotid artery and a stenosis of his left ECA. A funduscopic examination revealed an ischemic optic nerve and a central retinal artery embolus. An arteriogram was done, which showed an irregular stenosis of the ECA and an occlusion of the ICA (Fig. 55-3). This arteriogram points out the severe geometric distortion that occurs at the carotid bifurcation when the ICA occludes. At operation, a chronic ICA occlusion was found, and there was an ECA stenosis with fresh thrombus extending into the ECA. Endarterectomy and thrombectomy were performed, but the patient’s eyesight never returned to normal.
Figure 55-2. Arteriogram showing an occluded ICA and a stenosis of the ECA extending to the lingual artery in a patient with amaurosis fugax. At operation, a plaque beginning at the carotid bulb and extending up to the lingual artery was removed. There was no ulceration in the plaque. These symptoms may have been hemodynamic.
Case 3 This is an 80-year-old white man who presented with TIAs in the distribution of his left middle cerebral artery. Four years prior to the onset of these symptoms, he had suffered a left hemispheric CVA with almost complete resolution. A duplex scan at that time documented a left ICA occlusion. The patient was evaluated with an arteriogram, which showed an ICA occlusion with a large ulceration in the distal common carotid artery (Fig. 55-4).
Figure 55-3. Arteriogram showing an occluded ICA with an irregular surface at the orifice of the ECA and a significant ECA stenosis. This arteriogram demonstrates the significant geometric abnormality that occurs when the ICA occludes. The correction of the hemodynamic abnormality in the area of distorted geometry should be a primary aim of operation.
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arteriogram, revealed an occluded ICA with a long stump (Fig. 55-5). The patient was placed on aspirin with no relief of the neurologic symptoms. The patient underwent exploration of the carotid bifurcation. At operation there was a chronically occluded ICA with loose thrombus in the stump. The stump was obliterated from within and a patch closure extending onto the ECA was performed. The patient was followed for 30 months with complete relief of symptoms.
Operative Technique
Figure 55-4. Arteriogram showing a giant ulceration in the distal common carotid artery. The fluoroscopic image of this lesion showed recirculation of contrast in this pouch. This looks like a saccular aneurysm. In fact, at operation it proved to be a large crater filled with loose debris.
At operation, there was a giant ulceration of an atheromatous plaque involving the distal common carotid artery with debris extending into the ECA. An endarterectomy of the common carotid artery extending well into the ECA with patch closure was required. This patient was followed for 12 months, until he died of a myocardial infarction. There were no further neurologic events.
Case 4 This is a 57-year-old white man who presented with a history of left hemispheric TIAs. Workup, including an
The technical goals of ECA reconstruction include removal of any potential clot or debris, correction of any stenosis, and obliteration of the ICA stump. The same care utilized with standard carotid endarterectomy must be employed here. We use either general anesthesia with continuous electroencephalographic (EEG) monitoring[37] or cervical block anesthesia. The dissection must isolate the first few branches of the ECA and care must be taken to avoid injury to the hypoglossal nerve. Our preferred technique has been division of the occluded ICA so that any stump can be obliterated flush with the common carotid and a smooth tapering flow surface into the ECA established. We prefer to close the ICA separately and to repair the endarterectomy incision with a patch of either saphenous vein or prosthetic material (Fig. 55-6). Another satisfactory method of closure of the arteriotomy on the common and external carotid arteries is by the technique of “flap” angioplasty. This utilizes a segment of disobliterated ICA, which is swung onto the ECA and applied as a flap (Fig. 55-7). Sterpetti et al.[38] examined three ways to reconstruct the ECA and emphasized that it is important to construct a smooth tapering of the common carotid artery into the ECA. They also found that there was a correlation between the type of reconstruction performed and recurrent disease. Those patients whose ICA stump was not eliminated had a much higher incidence of recurrent stenosis.
Figure 55-5. Arteriogram showing an occluded ICA with a long “stump.” The stump appears to be filled with debris. At operation, this debris proved to be fresh thrombus.
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been treated with less concern than the internal one during conventional endarterectomy, which may not be warranted.
Background Data
Figure 55-6. A line drawing showing our preferred method of ECA reconstruction. The occluded ICA is transected at the bifurcation, and this arteriotomy is closed separately. Another arteriotomy is made from the common carotid artery onto the ECA up to the lingual artery. The endarterectomy is performed and repaired with a patch angioplasty.
EXTERNAL CAROTID ARTERY OCCLUSION By contrast, the opposite situation—an occluded or diseased external carotid in the setting of an open internal carotid artery—can also be of clinical concern. Cerebral or retinal emboli through the ICA can occur in this setting by one of two mechanisms: dislodgement of debris or thrombus from the stump of the chronically occluded or diseased ECA, or extension of thrombosis from an acutely occluded ECA into the bulb.[39 – 41] Traditionally, the external carotid artery has
Figure 55-7. (A ) An alternative method of ECA reconstruction employs the technique of “flap” angioplasty. The occluded ICA is divided 1 – 2 in. above the bifurcation. A V-shaped incision is made, with the apex in the common carotid artery extending into the ECA and the occluded ICA, which is then disobliterated. The inner walls of the ECA and ICA are sewn together, and the outer wall of the disobliterated ICA is rotated over to the outer wall of the ECA and anastomosed. (B ) The finished appearance of the flap closure.
Although ECA flaps have long been noted by angiography after endarterectomy, their significance has been unclear. Countee et al.[39] first reported such a problem in 1982, describing a patient who experienced clear recurrent hemispheric symptoms 312 years after an otherwise successful carotid endarterectomy. Angiography revealed an open ICA but occluded ECA stump, and operation, which consisted of ECA obliteration in a fashion apparently exactly analogous to ICA obliteration discussed above, revealed extensive friable atherosclerotic debris within the stump. Symptoms did not recur. Moore et al.[40] added to this experience in 1990, describing 3 patients with symptomatic, acutely thrombosed ECAs and open ICAs 7 hours to 2 years after endarterectomy and another with an acute, on-table ECA thrombus due to an intimal flap during endarterectomy, and coined the term “external carotid artery stump syndrome.” Hewitt [41] similarly described two additional cases: one due to atherosclerotic emboli from a true ECA stump and the other due to acute ECA thrombosis with extension into the bulb.
Prevention The best solution to postendarterectomy ECA problems is, of course, prevention, by addressing the ECA during the initial operation. Two solutions are possible: careful ECA endarterectomy or transection of the plaque flush with the ECA orifice. Archie[42] describes results using the former technique. After blind eversion ECA endarterectomy in the usual fashion, the ECA is locally reexplored, maintaining flow through the newly opened ICA, in cases where on-table continuous-wave Doppler signals (analyzed both audibly and by visual inspection of strip recordings) were abnormal. Using this method, 7% of patients required formal ECA endarterectomy through a separate ECA arteriotomy for residual ECA disease. Postoperatively, only 1% of these patients had “significant” (not defined) late ECA duplex stenoses, as compared with 5% of patients (2.5% stenoses, 2.5% occulusions) treated previously without special attention to the ECA ( p , 0.05). None of these patients, however, became symptomatic. The opposite tack is suggested by Ascer et al.,[43] who advocate simply transecting the plaque flush with the ECA orifice, suggesting that it is better to not disturb it at all. In 114 cases, no patient experienced neurologic problems during operation or at follow-up (90 patients with a mean of 20 and range of 4–36 months). Although no ECA occlusions were noted, 5 patients (6%) progressed to 75% or greater ECA stenoses. Therefore, although good results are claimed by both groups, the rate of late ECA stenosis can probably best be minimized by careful eversion endarterectomy, intraoperative interrogation, and separate ECA endarterectomy via a separate ECA arteriotomy when problems are found, maintaining flow through the newly endarterectomized ICA
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as Archie suggests.[42] Because ECA stump problems are so rare, however, whether or not either method yields superior clinical outcome remains unknown.
Diagnosis and Treatment Because ECA stump syndrome is such a rare event, diagnosis will be difficult. It should be suspected in the setting of a focal embolic neurological event ipsilateral to an open ICA and occluded or diseased ECA, especially when a stump is present. While this situation will probably require angiography for definitive diagnosis (to exclude a diseased but nonstenotic ICA as well), either an occluded or a stenotic ECA should be easily detected by routine duplex ultrasonography. If the above criteria are met and suspicion is low for another source, operation is indicated. In a fashion exactly analogous to that used to treat ICA stump syndrome, the carotid bifurcation should be exposed and the stump of the occluded ECA remodeled, while a diseased ECA should be treated with ECA endarterectomy.
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CONCLUSIONS Chronic occlusion of the internal carotid artery is not a benign condition. The geometry of the carotid bifurcation in this setting as well as the likelihood of atheromatous disease in the common carotid and external carotid arteries may create a situation in which embolization can occur via the ophthalmic artery collaterals into the eye and brain. Patients with embolic symptoms in the setting of an ICA occlusion should therefore be evaluated for this possibility. Operation, when indicated, must take into account both the abnormal geometry and the atheromatous problem so that a smooth, tapering flow surface into the ECA is achieved. Although apparently rare, atherosclerotic or thrombotic debris can arise from an occluded or stenotic ECA and embolize through a patient ICA. The ECA should be treated with respect during conventional carotid endarterectomy, and in the appropriate clinical setting, remodeling or endarterectomy of the ECA in an analogous fashion may similarly be required. Operation can be performed with low morbidity and mortality rates and excellent long-term results.
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Barnett, H.J.M. Delayed Cerebral Ischemic Episodes Distal to Occlusion of Major Cerebral Arteries. Neurology (Minneapolis) 1982, 28, 674. Barnett, H.J.M.; Peerless, S.J. Collaborative EC/IC Bypass Study: The Rationale and a Progress Report. In Cerebrovascular Diseases; Mossy, J., Reinmuth, O.M., Eds.; Raven Press: New York, 1981; 271 – 288. Watts, C. External Carotid Artery Embolus from the Internal Carotid Artery “Stump” During Angiography. Stroke 1982, 13, 515. Torvik, A.; Jorgensen, L. Thrombotic and Embolic Occlusions of the Carotid Arteries in an Autopsy Series: Part 2 Cerebral Lesions and Clinical Course. J. Neurol. Sci. 1966, 3, 410. Castagine, P.; Lhermitte, F.; Gautier, J.C. Internal Carotid Artery Occlusion: A Study of 61 Instances in 50 Patients with Post-Mortem Data. Brain 1970, 92, 231. Landolt, A.M.; Millikan, C.H. Pathogenesis of Cerebral Infarction Secondary to Mechanical Carotid Artery Occlusion. Stroke 1970, 1, 52. Nichols, S.C.; Bergelin, R.; Strandness, D.E. Neurologic Sequelae of Unilateral Carotid Artery Occlusion: Immediate and Late. J. Vasc. Surg. 1989, 10, 542. Fritz, V.U.; Voll, C.L.; Levien, I.J. Internal Carotid Artery Occlusion: Clinical and Therapeutic Implications. Stroke 1985, 16, 940. Fields, W.S.; Lemak, N.A. Joint Study of Extracranial Arterial Occlusion. J. Am. Med. Assoc. 1976, 235, 2734. Cote, R.; Barnett, H.J.M.; Taylor, D.W. Internal Carotid Occlusion: A Prospective Study. Stroke 1983, 14, 898. Nichols, S.C.; Kohler, T.R.; Bergelin, R.O.; et al. Carotid Artery Occlusion: Natural History. J. Vasc. Surg. 1986, 4, 479.
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The EC/IC Bypass Study Group; Failure of ExtracranialIntracranial Arterial Bypass to Reduce the Risk of Ischemic Stroke: Results of an International Randomized Trial. N. Engl. J. Med. 1985, 313, 1191. Danziger, J.; Bloch, S. The Value of the External Carotid Circulation in Intracranial Disease. Clin. Radiol. 1975, 26, 261. Webster, M.W.; Steed, D.L.; Yonas, H.; et al. Cerebral Blood Flow Measured by Xenon-Enhanced Computed Tomography as a Guide to Management of Patients with Cerebrovascular Disease. J. Vasc. Surg. 1986, 3, 298. Machleder, H.I.; Barker, W.F. External Carotid Artery Shunting During Carotid Endarterectomy. Arch. Surg. 1974, 108, 785. Schuler, J.J.; Flanagan, D.P.; DeBord, J.R.; et al. The Treatment of Cerebral Ischemia by External Carotid Revascularization. Arch. Surg. 1983, 118, 567. Zarins, C.K.; DelBeccaro, E.J.; Johns, L.; et al. Increased Cerebral Flow After External Carotid Revascularization. Surgery 1981, 89, 730. McIntyre, K.E.; Ely, R.L.; Malone, J.M.; et al. External Carotid Artery Reconstruction: Its Role in Treatment of Cerebral Ischemia. Am. J. Surg. 1983, 150, 58. Norris, J.W.; Krajewski, A.; Bornstein, N.M. The Clinical Role of the Cerebral Collateral Circulation in Carotid Occlusion. J. Vasc. Surg. 1990, 12, 113. Gertler, J.P.; Cambria, R.P. The Role of External Carotid Endarterectomy in the Treatment of Ipsilateral Carotid Occlusion: Collective Review. J. Vasc. Surg. 1987, 6, 158. Alksne, J.F. Collateral Circulation. In Collateral Circulation in Clinical Surgery; Strandness, D.E., Ed.; Saunders: Philadelphia, PA, 1969; 595 –609.
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22. Weinberger, J.; Robbins, A.; Jacobson, J. Transient Ischemic Attacks with External Carotid Artery Stenosis and a Normal Internal Carotid Artery. Angiology 1983, 34, 764. 23. Vignaud, J.; Hasso, A.N.; Lasjaunias, P.; Clay, C. Orbital Vascular Anatomy and Embryology. Radiology 1974, 111, 617. 24. Spencer, M.P.; Whisler, D. Transorbital Doppler Diagnosis of Intracranial Arterial Stenosis. Stroke 1986, 17, 916. 25. Schneider, P.A.; Rossman, M.E.; Bernstein, E.F.; et al. Noninvasive Assessment of Cerebral Collateral Blood Supply Through the Ophthalmic Artery. Stroke 1991, 22, 31. 26. Bogousslavsky, J.; Regli, F.; Hungerbuhler, J.-P.; Chrzanowski, R. Transient Ischemic Attacks and External Carotid Artery Occlusion. Stroke 1981, 12, 627. 27. Street, D.L.; Ricotta, J.R.; Green, R.M.; DeWeese, J.A. The Role of External Carotid Revascularization in the Treatment of Ocular Ischemia. J. Vasc. Surg. 1987, 6, 280. 28. Finklestein, S.; Kleinman, G.M.; Cuneo, R.; Baringer, J.R. Delayed Stroke Following Carotid Occlusion. Neurology 1980, 20, 84. 29. Baron, J.C.; Bousser, M.G.; Rey, A.; et al. Reversal of Focal “Misery-Perfusion Syndrome” by Extra-Intracranial Arterial Bypass in Hemodynamic Cerebral Ischemia: A Case Study with 150 Positron Emission Tomography. Stroke 1981, 12, 454. 30. Torvik, A.; Jorgensen, L. Thrombotic and Embolic Occlusions of the Carotid Arteries in an Autopsy Material: Part I. Prevalence, Location and Associated Diseases. J. Neurol. Sci. 1964, 1, 124. 31. Barnett, H.J.M.; Peerless, S.J.; Kaufmann, J.C.E. “Stump” of Internal Carotid Artery—A Source for Further Cerebral Embolic Ischemia. Stroke 1978, 9, 448. 32. O’Hara, P.J.; Hertzer, N.R.; Beven, E.G. External Carotid Revascularization: Review of a Ten-Year Experience. J. Vasc. Surg. 1985, 2, 709.
33. Halstuk, K.S.; Baker, W.H.; Littooy, F.N. External Carotid Endarterectomy. J. Vasc. Surg. 1984, 1, 398. 34. LaMuraglia, G.M.; Darling, R.C.; Brewster, D.C.; Abbott, W.M. Neurologic Sequelae with Internal Carotid Artery Occlusion. Arch. Surg. 1987, 122, 432. 35. Connolly, J.E.; Stemmer, E.A. Endarterectomy of the External Carotid Artery. Arch. Surg. 1973, 106, 799. 36. Karmody, A.M.; Shah, D.M.; Monaco, V.J.; Leather, R.P. On Surgical Reconstruction of the External Carotid Artery. Am. J. Surg. 1978, 136, 176. 37. Green, R.M.; Messick, W.J.; Ricotta, J.R.; et al. Benefits, Shortcomings and Costs of EEG Monitoring. Ann. Surg. 1985, 201, 785. 38. Sterpetti, A.V.; Schultz, R.D.; Feldhaus, R.J. External Carotid Endarterectomy: Indications, Technique and Late Results. J. Vasc. Surg. 1988, 7, 31. 39. Countee, R.W.; Vijayanathan, T.; Wu, S.Z. External Carotid Occlusion as a Cause of Recurrent Ischemia After Carotid Endarterectomy. Neurosurgery 1982, 11, 518. 40. Moore, W.J.; Martello, J.Y.; Quinones-Baldrich, W.J.; Ahn, S. Etiologic Importance of the Intimal Flap of the External Carotid Artery in the Development of Postcarotid Endarterectomy Stroke. Stroke 1999, 21, 1497. 41. Hewitt, R.L. Importance of the Occluded External Carotid Artery After Carotid Endarterectomy (Letter). J. Vasc. Surg. 1995, 21 (4), 706. 42. Archie, J.P. Management of the External Carotid Artery During Routine Carotid Endarterectomy. J. Cardiovasc. Surg. 1992, 33, 62. 43. Ascer, E.; Gennaro, M.; Pollina, R.M.; Salles-Cunha, S.; Lorenson, E.; Yorkovich, W.R.; Ivanov, M. The Natural History of the External Carotid Artery After Carotid Endarterectomy: Implications for Management. J. Vasc. Surg. 1994, 23, 582.
CHAPTER 56
Extracranial Carotid Artery Aneurysms James A. Gillespie Samuel E. Wilson
reports of carotid aneurysms in the literature have been concerned with only one or two new examples, however, and it is therefore a relatively rare condition, which has a special importance because of the threat of hemorrhage, stroke, or death that it poses.
Carotid artery aneurysms are uncommon, but their clinical significance has long been recognized. Indeed, surgical treatment was first employed successfully in 1808 by Sir Astley Cooper,[1] a London surgeon, using the technique of proximal ligation, even then widely practiced in dealing with peripheral aneurysms. His patient lived for another 13 years. Since that time, reports of carotid aneurysms have appeared regularly in the literature, Winslow[2] collecting some 106 cases up to 1925. However, it was not until 1952 that a reconstructive surgical technique was used to deal with a carotid aneurysm,[3] and since that time the number of cases reported has increased considerably. Reconstructions, by maintaining carotid blood flow, reduce the risk of a cerebrovascular accident, so often the sequel of simple ligation, and the various surgical techniques are now fairly well standardized. Approximately 1% of carotid extracranial operations are for aneurysms.[4]
PATHOLOGY OF CAROTID ARTERY ANEURYSMS Many causes of carotid aneurysms have been described, but the two most important are undoubtedly atherosclerosis and trauma. Before considering these in more detail, some of the other less common etiologies may be noted. Syphilis was an important cause in the last century and the first part of this one, but rarely is today. Loss of elastic tissue in the arterial wall in Marfan’s syndrome has been the cause of some reported carotid aneurysms, as has cystic medial necrosis, where carotid aneurysms are frequently associated with other peripheral aneurysms. Similarly, carotid aneurysms may occur with renal artery aneurysms in fibromuscular hyperplasia. Congenital carotid aneurysms, perhaps bilateral, have been reported, and so also have primary or spontaneous dissecting aneurysms, as opposed to traumatic dissecting ones, though their etiology is somewhat obscure.[9] Carotid aneurysm has also been associated with polyarteritis nodosa. Mycotic carotid aneurysms are occasionally caused by infected emboli in bacterial endocarditis but more usually result from spread of infection from a nearby area of cellulitis or from a peritonsillar or mastord abscess. Mycotic aneurysms may also follow a septic penetrating injury, perhaps from a heroin injection in an addict.[10] In one series of 10 postoperative aneurysms, 5 were caused by infection.[11] Diabetes seems to have been only rarely mentioned in patients with carotid aneurysms. Finally, carotid aneurysms have been described after irradiation for cervical malignancy.[12]
THE INCIDENCE OF CAROTID ARTERY ANEURYSMS The actual total incidence of extracranial carotid artery aneurysms is relatively small, and this is perhaps best indicated by Schechter’s[5] detailed survey. He found reports of a total of only 853 carotid aneurysms in the literature up to 1977. The low incidence of carotid artery aneurysms compared to that of other extracranial aneurysms is also well demonstrated, for example, in figures from DeBakey’s[6] unit in Houston, where there were only 37 carotid aneurysms out of a total of 8500 aneurysms which they treated surgically in the 20 years up to 1977. Another group in Ohio reported 41 carotid aneurysms from a total of 1118 peripheral aneurysms which they evaluated over a 30-year period.[7] Yet another report states that while 500 patients with occlusive carotid disease had been dealt with over a 24-year period, only 19 carotid aneurysms were treated in the same period.[8] Most
Hobson/Wilson/Veith: Vascular Surgery: Principles and Practice, Third Edition, Revised and Expanded DOI: 10.1081/0819-9-120024940 Copyright q 2004 by Marcel Dekker, Inc.
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Atherosclerotic Carotid Aneurysms These aneurysms usually occur in elderly patients and are frequently associated with atherosclerotic aneurysmal or occlusive arterial disease elsewhere. Many of these patients are hypertensive, and the aneurysm wall is frequently calcified. These aneurysms may be bilateral, are usually fusiform rather than saccular, and tend to occur in the region of the carotid bifurcation.
Traumatic Carotid Artery Aneurysms These aneurysms are the second most common type after atherosclerotic aneurysms. They may result from blunt trauma, penetrating injuries, sudden neck hyperextension and rotation, or they may follow previous carotid artery surgery for stenotic or occlusive disease. Penetrating injuries may lead occasionally to arteriovenous aneurysms, and, if infection enters, mycotic aneurysms. Traumatic aneurysms are often of saccular type, but dissecting ones occasionally may result. Blunt trauma may cause intimal tears and medial disruption with consequent weakening of the arterial wall. Traumatic carotid aneurysms can also result from damage to the arterial wall from bone splinters, and examples in association with mandibular fractures are reported. While traumatic aneurysms involve mostly the common carotid artery, some occur in the high internal carotid artery, often extending up to the base of the skull. It is likely that fixation of the internal carotid artery as it passes into the bony carotid canal in the base of the skull base is an important factor when the more distal part of the artery is deformed and twisted by blunt trauma. Many posttraumatic aneurysms are actually false aneurysms, especially those occurring as a result of penetrating injuries and after surgery for carotid stenosis. The latter most commonly occurs when the original arteriotomy was closed with a patch graft, and seldom when it was closed directly. False aneurysms have also, very rarely, been reported after needling the carotid vessels in arteriography. Aneurysms of any type involving the external carotid artery are rare, just over 2% of all.[13]
EFFECTS OF CAROTID ARTERY ANEURYSMS Like other peripheral aneurysms, carotid aneurysms may occlude spontaneously, may liberate emboli distally, or, less commonly, may rupture. Their special danger lies in the effect of emboli or sudden ischemia on the brain, while rupture and hemorrhage may occur into the oropharynx with desperate airway consequences. Carotid aneurysms pose a very real threat to life, and Winslow,[2] in his extensive early survey of these lesions, made the point that four out of every five patients treated conservatively eventually died from a complication of their aneurysm, though few authorities would put the figure so high today.
Figure 56-1. Traumatic high internal carotid aneurysm (arrow) in a 28-year-old male patient. He was briefly unconscious following an auto accident, but made an apparently complete recovery. Two months later he presented with transient strokes. Computed tomography (CT) scan showed small brain infarcts.
CLINICAL PRESENTATION The most common presentation of a carotid aneurysm is a swelling in the neck, which is usually felt to be pulsatile. Pain in the area is also a frequent complaint, especially when the aneurysm is expanding or dissecting, and here the mass is likely to be tender to palpation. Reports on brain damage vary greatly, some suggesting that perhaps up to half of all patients present with some neurological feature, such as a stroke, transient cerebral ischemic attacks (Fig. 56-1), or a visual defect due to embolization.[14] The patient sometimes complains of a buzzing in the ear, and auscultation over the neck may reveal a loud systolic bruit. Hoarseness can result from vagal or recurrent laryngeal nerve compression, or from Horner’s syndrome from similar compression of the cervical sympathetic nerves. The hypoglossal nerve may also be involved.[15] Some internal carotid aneurysms project into the oropharynx (Fig. 56-2), occasionally giving dysphagia or dyspnea. It has long been recognized that here a carotid aneurysm may resemble a peritonsillar abscess and disaster
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attends attempted lancing. Fatal spontaneous rupture into the oropharynx has occurred. Small, high internal carotid aneurysms may not be palpable in the neck and can be a rare cause of unexplained facial pain. Occasionally they may rupture to give rise to profuse epistaxis or to bleeding from the ear. For these reasons otolaryngologists especially recognize the importance of carotid aneurysms.[16]
DIFFERENTIAL DIAGNOSIS In most cases the diagnosis can be made clinically without much difficulty. However, enlarged cervical lymph nodes, branchial cysts, and carotid body tumors may occasionally be confused, and if the aneurysm bulges into the oropharynx, it may be misdiagnosed as a peritonsillar abscess. Perhaps the greatest difficulty in differential diagnosis arises where the carotid artery in an elderly and often hypertensive patient is elongated and kinked outward, pulsation and swelling being both visible and easily palpable. Here it may only be possible to prove or refute the diagnosis of aneurysm with ultrasound scanning or computed tomographic arteriogram.
INVESTIGATION OF CAROTID ANEURYSMS While diagnosis often is certain on clinical examination, it can sometimes be difficult, for example, with high, small internal carotid aneurysms. Investigations include plain xrays of the neck to show a soft tissue mass and perhaps calcification in the aneurysm wall. Ultrasound scanning demonstrates aneurysms well and is the best noninvasive investigative method. Examination of the fundi may reveal retinal artery emboli in patients with aneurysms complicated by transient visual field defects or transient cerebral ischemia. Flow-through aneurysms can be measured by the Doppler flowmeter. Arteriography, however, is the essential investigative method when surgical intervention is planned. The proximal and distal carotid artery, as well as the aneurysm, must be visualized. Arteriography can be performed by selective carotid catheterization. The aneurysm itself should not be needled. Arteriography shows dissecting aneurysms well (Fig. 56-3), a common appearance being a tapering narrowing with a line string of contrast extending distally. Duplex ultrasound can be used for postoperative follow-up.
TREATMENT OF CAROTID ANEURYSMS Treatment is essentially surgical, there being little to offer of a nonsurgical nature that is likely to be helpful. Patients who are for other reasons unfit for operation, those who have small and symptomless aneurysms discovered by chance, and those whose aneurysms extend right to the base
Figure 56-2. Three weeks after an apparently trivial injury to the left side of his neck, this 15-year-old male patient presented in the ear, nose, and throat unit with a mass in the left tonsillar region. Arteriography showed a large, false internal carotid artery aneurysm. This ruptured into the esophagus immediately before surgery was to be undertaken, but he was resuscitated and the common carotid artery ligated. He made a complete recovery.
of the skull may merely be observed. However, a conservative approach to carotid aneurysms in general is likely to result in a considerable morbidity, mainly because of neurological complications, but occasionally from rupture. For example, Winslow[2] found that of 106 patients treated conservatively, 71% died as a result of a complication of their aneurysms. Even though the only active treatment then was proximal ligation, he concluded that carotid aneurysm was “strictly a surgical problem.” Perhaps an occasional exception to this rule of active treatment arises in dealing with the rather rare dissecting aneurysms without cerebral embolic complications. Here reports suggest that the caliber of the arterial lumen may return spontaneously to normal in time, as has been shown arteriographically.[11] Long-term anticoagulation or aspirin therapy with the aim of preventing cerebral embolic symptoms in conservatively treated patients does not appear to have been employed, and it seems unlikely that it would be effective. Mycotic aneurysms require intensive antibiotic therapy but also need urgent surgical treatment because of the high risk of rupture, and the same applies to false aneurysms, which in general are liable to continue to expand and possibly to rupture.
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which there is a symptom-producing high internal carotid aneurysm with no possibility of making a distal anastomosis. Two methods have been employed to try to reduce the risk of neurological sequelae following ligation in those patients in whom it has to be employed. One is to occlude the artery slowly over several days using a Selverstone clamp in the hope of allowing an adequate collateral circulation to develop before occlusion is complete. The patient is anticoagulated throughout this period to reduce the risk of embolization. When the clamp is finally removed, a ligature is applied in its place.[17] If ischemic signs appear at any time, the clamp is slackened. The other method is to try to estimate the likely risk of brain damage by preligation investigations and only to subject the patient to ligation if it seems likely to be safe. These investigations will be described later. Simple proximal ligation is of course a good technique for dealing with the uncommon external carotid aneurysms, where there is no risk of producing cerebral ischemia. McIvor reported that ligation of the internal carotid artery in 16 patients after negative balloon test occlusion led to five strokes, two of which were fatal.[18]
Reconstructive Approach to Carotid Aneurysm Surgery
Figure 56-3. Right carotid angiogram showing a partial occlusion due to dissection of the proximal part of the right internal carotid artery in a patient who developed hemiplegia following a traffic accident. He sustained multiple facial fractures including a fracture of the right mandibular ramus.
TECHNIQUES OF SURGICAL TREATMENT The techniques for surgical treatment fall into two main types, namely simple ligation and reconstructive surgery.
Simple Ligation As has been noted, treatment of a carotid aneurysm by ligation was carried out successfully over 175 years ago, and ligation remained virtually the only surgical option available until the advent of reconstructive arterial techniques. Ligation may be done just proximal to the aneurysm or both proximal and distal to it, or the common carotid may be ligated. Wherever the ligature is placed, however, it has long been recognized that there is a high risk of cerebral infarction postoperatively. In the early literature, for example, death rates of over 50% were reported as a sequel to common carotid ligation. However, more recent reports put the incidence of serious neurological damage at a lower figure, and ligation is still the only feasible surgical treatment in certain patients. The best example of this situation is that in
However carefully simple ligation is performed, the risk of cerebral damage remains sufficiently high to make those techniques by which carotid blood flow can be maintained the first choice, and reconstruction was first employed successfully in 1952. Several procedures have now been described, the most preferable being excision of the aneurysm with primary end-to-end reconstruction of the artery. This is quite often feasible, but it does require the availability of a sufficient redundant length of artery. If there is not a sufficient length, interposition of a vein or prosthetic tube graft is necessary. Sise et al.[19] reported a favorable experience with PTFE interposition grafts in six patients with extracranial carotid aneurysm changes. An occasionally applicable technique for avoiding the use of an interposition graft in dealing with low internal carotid aneurysms is to divide the external carotid artery at such a level that its proximal end can be anastomosed to the distal end of the internal carotid after excision of the aneurysm (Figs. 56-4 and 56-5). Saccular aneurysms often have a relatively narrow neck, especially those saccular false aneurysms arising after previous carotid endarterectomy. Here the small defect in the arterial wall left after excision of the aneurysm may be closed with a vein or prosthetic patch graft. Mycotic aneurysms require special additional measures including antibiotic cover, vein rather than prosthetic graft material, and complete excision of all the infected aneurysm wall. A vein bypass rather than an interposition graft may occasionally be feasible when removing mycotic aneurysms to avoid having suture lines in the infected area.[20] In conclusion, two other surgical techniques may be mentioned. One is wrapping carotid aneurysms with cellophane or plastic sheets. This is now obsolete because reconstructive methods are technically no more difficult, the results are superior, and wrapping cannot prevent embolization. The other is Matas’s endoaneurysmorrhaphy. Perhaps
Chapter 56. Extracranial Carotid Artery Aneurysms
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Figure 56-4. Operative exposure of a 4-cm aneurysm of the internal carotid artery. The common carotid artery is to the left in the photograph and the hypoglossal nerve to the right. This aneurysm was replaced by interposition of a PTFE graft. (See also color plate.)
the only situation in which this may still usefully be employed is in dealing with high internal carotid aneurysms where a distal anastomosis at the base of the skull is not technically possible. In these patients a Matas repair is done over a temporary internal shunt. This shunt may be a tapered one to allow better wedging of it into the distal internal carotid artery as it passes through the bony carotid canal in the base of the skull.[21] Much ingenuity has also been displayed in planning the distal anastomosis of grafts even in this very difficult situation.[22] Endovascular placement of a covered stent graft has been attempted cautiously.[23]
Measures to Minimize the Risk of Cerebral Embolization and Ischemic Damage During Surgery Cerebral embolization may occur during surgery as a result of handling an aneurysm which contains laminated and loose thrombus. It is therefore essential to disturb aneurysms as little as possible during their dissection. When an internal shunt is to be used, a clamp is first applied distal to the aneurysm, which is then incised so that the thrombotic material inside can be removed quickly before the shunt is inserted. Intravascular clotting during surgery can be minimized by the use of heparin, and heparin therapy is essential for the whole period of gradual occlusion during which a Selverstone clamp is applied postoperatively. This clamp should, of course, be tightened only when the patient is fully conscious. Many techniques for avoiding cerebral ischemic injury, or predicting its likely occurrence, have been described, and it is also generally agreed that cerebral protection during the operation is essential routinely. The degree of risk of cerebral ischemic damage after simple ligation or during reconstructive procedures has been assessed preoperatively by such procedures as oculoophthalmodynamometry with carotid compression, or intraoperatively by continuous electroencephalographic monitoring,
Figure 56-5. Method for reconstruction of an aneurysm of the internal carotid artery by interposition of a PTFE graft. (Reprinted with permission from Sise et al.[19])
xenon cerebral blood flow measurements,[24] and carotid stump pressure measurements. In the latter a pressure of 50 – 70 mmHg probably indicates an adequate cerebral collateral circulation. Anesthetic measures to try to protect the brain from ischemia during operation include using hypercarbia and a hypertension-producing technique. Hypothermia has also been used. However, by far the best way of avoiding brain ischemia is to insert an internal shunt during any reconstructive procedure, and, indeed, this is now standard practice, if anatomically feasible. Where an interposition vein or prosthetic graft is to be used, this is passed over the shunt before the shunt is inserted. The distal anastomosis is then completed first and the shunt is removed just before the last sutures are placed in the proximal anastomosis. Occasionally an external shunt is more applicable. However used, a shunt means that internal carotid blood flow is only arrested for 3–5 minutes.
Surgical Anatomy of the Carotid Arteries The left common carotid artery is intrathoracic in its lower part on the left side, and in the neck each common carotid artery is covered by the sternomastoid muscle. Surgical exposure is achieved by an incision through the skin and platysma in line with the anterior border of the sternomastoid or by an oblique, transverse incision. The vagus nerve and cervical sympathetic chain lie behind the common carotid, as does the jugular vein. The internal carotid artery is closely related to the ninth to twelfth cranial nerves, as well as to the internal jugular vein and the carotid body. The uppermost third of this artery is deeply
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placed below the base of the skull, the temperomandibular joint, and the parotid gland. It is crossed superficially by the stylohyoid ligament, the posterior belly of the digastric muscle, and the styloglossus and stylopharyngeus muscles. The mastoid and styloid processes lie behind it, as do the longus capitis muscle and the prevertebral fascia. The external carotid artery lies behind the stylohyoid muscle and the posterior belly of the digastric muscle and passes up toward the parotid gland. It is closely related to the superior laryngeal, facial, hypoglossal, and glossopharyngeal nerves and to the pharyngeal branch of the vagus. Care must be taken to avoid injury to all these nerves during exposure of aneurysms. To lessen the risk of nerve damage when dealing with large nonmycotic aneurysms, portions of the aneurysm wall with adherent nerves can safely be left in situ when the bulk of the aneurysm is removed.
Results of Surgery for Carotid Aneurysms Apart from damage to adjacent nerves and the risk of local infection, the only serious complication of surgery is cerebral damage from ischemia or embolization. If this does not occur, the operation can be judged successful. However, the risk of neurological damage in association with surgery remains significant, though just exactly how significant it is difficult to say because widely varying figures appear in the literature. Simple ligation appears to be followed by cerebral damage in
about 30% of patients in collected series,[25] while its reported incidence after reconstructive operations is less. Moreau et al. reported the outcome of 38 patients who had primary closure of the defect, reanastomosis or grafting with only 2 transient neurologic events and 8 cranial nerve injuries.[26] The severity of this neurological damage ranges from the massive fatal stroke to lesser defects with later partial or complete recovery. Occasionally, evidence of neurological damage does not appear immediately after operation but becomes manifest after several days, presumably because of late distal thrombosis of the internal carotid or its intracranial branches, occlusion of the reconstruction, or late embolization.
CONCLUSIONS Aneurysms of the extracranial carotid arteries are uncommon, but they have a special significance because of the threat they pose of cerebral embolic phenomena and, less commonly, of rupture. They appear to have been increasingly recognized, and to have generated much interest, over the last 10 or 15 years, judging by the number of case reports and reviews which have appeared in the surgical literature. The present tendency is to treat them actively, preferably by reconstructive vascular techniques.
REFERENCES 1. Cooper, A. Account of the First Successful Operation Performed on the Common Carotid Artery for Aneurysm in the Year of 1808 with Post Mortem Examination in the Year 1821. Guy’s Hosp. Rep. 1836, 1, 53. 2. Winslow, N. Extracranial Aneurysm of the Internal Carotid Artery. Arch. Surg. 1926, 13, 689. 3. Dimtza, A. Aneurysms of the Carotid Arteries. Report of Two Cases. Angiology 1956, 7, 218. 4. Pulli, R.; Gatti, M.; Credi, G.; Narcetti, S.; Capaccioli, L.; Pratesi, C. Extracranial Carotid Artery Aneurysms. J. Cardiovasc. Surg. 1997, 38 (4), 339– 346. 5. Schechter, D.C. Cervical Carotid Aneurysms. N.Y. State J. Med. 1979, 79, 892. 6. McCollum, C.H.; Wheeler, W.G.; Noon, G.P.; DeBakey, M.E. Aneurysms of the Extracranial Carotid Artery. Am. J. Surg. 1979, 137, 196. 7. Welling, R.E.; Taha, A.; Goel, T.; et al. Extracranial Carotid Artery Aneurysms. Surgery 1983, 93, 319. 8. Busuttil, R.W.; Davidson, R.K.; Foley, K.T.; et al. Selective Management of Extracranial Carotid Arterial Aneurysms. Am. J. Surg. 1980, 140, 85. 9. Campbell, F.C.; Robbs, J.V. Spontaneous Dissecting Aneurysm of the Internal Carotid Artery. J. R. Coll. Surg. Edinb. 1981, 26, 286. 10. Ledgerwood, A.M.; Lucas, C.E. Mycotic Aneurysm of the Carotid Artery. Arch. Surg. 1971, 109, 496.
11. Krupski, W.C.; Effeney, D.J.; Ehrenfeld, W.K.; et al. Aneurysms of the Carotid Arteries. Aust. N.Z. J. Surg. 1983, 53, 521– 525. 12. McCready, R.A.; Hyde, G.I.; Bivins, B.A.; et al. RadiationInduced Arterial Injuries. Surgery 1983, 93, 306. 13. Kaupp, H.A.; Haid, S.P.; Jurayj, M.N.; et al. Aneurysms of the Extracranial Carotid Artery. Surgery 1972, 72, 946. 14. Boddie, H.G. Transient Ischaemic Attacks and Stroke Due to Extracranial Aneurysm of Internal Carotid Artery. Br. Med. J. 1972, 3, 802. 15. Morki, B.; Sundt, T.M., Jr.; Houser, O.W.; et al. Spontaneous Dissection of the Cervical Internal Carotid Artery. Ann. Neurol. 1986, 19, 126– 138. 16. Lane, J.R.; Weisman, R.A. Carotid Artery Aneurysms: An Otolaryngologic Perspective. Laryngoscope 1980, 90, 897. 17. Webb, R.C.; Barker, W.F. Aneurysms of the Extracranial Internal Carotid Artery. Arch. Surg. 1969, 99, 501. 18. McIvor, N.P.; Willinsky, R.A.; TerBrugge, K.G.; Rutka, J.A.; Freeman, J.L. Validity of Test Occlusion Studies Prior to Internal Carotid Artery Sacrifice. Head Neck 1994, 16 (1), 11 – 16. 19. Sise, M.J.; Ivy, M.E.; Malanche, R.; Ranbarger, K.R. Polytetrafluoroethylene Interposition Grafts for Carotid Reconstruction. J. Vasc. Surg. 1992, 16, 601.
Chapter 56. Extracranial Carotid Artery Aneurysms 20.
Monson, R.C.; Alexander, R.H. Vein Reconstruction of a Mycotic Internal Carotid Aneurysm. Ann. Surg. 1980, 191, 47. 21. Rhodes, E.L.; Stanley, J.C.; Hoffman, G.L.; et al. Aneurysms of Extracranial Carotid Arteries. Arch. Surg. 1976, 111, 339. 22. Pellegrini, R.V.; Manzetti, G.W.; DiMarco, R.F.; et al. The Direct Surgical Management of Lesions of the High Internal Carotid Artery. J. Cardiovasc. Surg. 1984, 25, 29. 23. May, J.; White, G.H.; Waugh, R.; Brennan, J. Endoluminal Repair of Internal Carotid Artery Aneurysms: A Feasible
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but Hazardous Procedure. J. Vasc. Surg. 1997, 26 (6), 1055– 1060. 24. Mokri, B.; Piepgras, D.G.; Sundt, T.M.; Pearson, B.W. Extracranial Internal Carotid Artery Aneurysms. Mayo Clin. Proc. 1982, 57, 310. 25. Rittenhouse, E.A.; Radke, H.M.; Summer, D.S. Carotid Artery Aneurysm. Arch. Surg. 1972, 105, 786. 26. Moreau, P.; Albat, B.; Thaevenet, A. Surgical Treatment of Extracranial Internal Carotid Aneurysm. Ann. Vasc. Surg. 1994, 8 (5), 409– 416.
CHAPTER 57
Carotid Body Tumors Frank T. Padberg, Jr. Alfred V. Persson
Vascular surgeons will rarely encounter this treacherous neoplasm, but all should be familiar with its management. Carotid body tumors are rarely malignant, usually asymptomatic, and have generally been associated with substantive procedural complications. However, the low incidence of morbidity from small tumors, improved preliminary noninvasive diagnosis, and better appreciation for the tumor’s natural history now provide the basis for a rational surgical approach. Advocates of nonsurgical management once emphasized the high incidence of devastating neurologic sequelae incurred by carotid ligation. Refinement of carotid arterial reconstruction, now safely performed on a routine basis, has significantly reduced the need for such drastic measures. Precise description of the natural history of the untreated carotid body tumor has been hindered by the difficulty in establishing the initial diagnosis. Color Doppler flow imaging and magnetic resonance imaging (MRI) offer improved screening of suspicious masses. Arteriography will correctly identify the neoplasm prior to operative exploration. Prolonged observation and development of strict clinicopathologic criteria for malignancy now permit more accurate description of the growth patterns and potential for mortality from tumors of the carotid body.
seen only infrequently. Since the diagnosis was rarely made prior to operative exploration, no surgeon or clinic could develop a large experience. At the beginning of the twentieth century, surgical resection, which included the carotid bifurcation, was recommended.[1 – 3] Enthusiasm for this procedure was soon tempered, however, by the high complication rate. [4] A 1929 review by Bevan and McCarthy[5] concluded that nonresective treatment was preferable if ligation of the carotid arteries were required. In support of this approach, they cited a single case of tumor regression following radiation. Unfortunately, neither histologic confirmation of the lesion nor subsequent long-term follow-up was included in this influential report. In 1940 Harrington et al.[6] described microscopic malignancy in 50% of their patients. On the basis of these pathologic findings, they again recommended routine surgical resection. The surgical options had been expanded and now included subadventitial dissection of the tumor with carotid preservation. This report described an overall reduction in the incidence of complications from tumor resection, but the mortality for those patients who required carotid ligation remained unacceptably high. Although a greater number of these tumors could be removed without sacrificing the carotid arteries, predicting which lesions would receive carotid ligation was not possible until virtually the entire dissection had been completed. In 1947, Lahey and Warren[7] reported a 33% mortality and a 50% incidence of neurologic sequelae in their patients who required carotid ligation. LeCompte[8] thoroughly reviewed these tumors for the Armed Forces Institute of Pathology and reported that he could find no conclusive evidence of malignancy. Since the available information suggested that the natural history of this tumor was generally benign and since the risks of ligation were unacceptable, these authors again recommended that resection be abandoned if carotid ligation were required. Martin,[9] succinctly reiterating this philosophy, stated that “since the carotid body tumor is rarely malignant, little benefit is conferred on the patient by removing it except to establish the diagnosis.” Subsequently, advances in vascular surgical practice have significantly reduced the risks of excision. Successful resection and reanastomosis of the carotid bifurcation for
HISTORICAL ASPECTS In 1743, Van Haller published an anatomic description of the carotid body. The first surgical resection of a tumor of the carotid body was attributed to Reigner in 1880; his patient succumbed to hemiplegia 3 days following resection with carotid ligation. Tumor excision with survival was reported in 1886, as was resection without significant neurologic sequelae.[1] The carotid body tumor excised in 1887 by Gay was probably both the first to be excised in the United States and the first to be removed without sacrificing the carotid artery. Lund[2] recorded the first uncomplicated bilateral resection on the same patient in 1917. Evolution of an appropriate approach to this neoplasm developed slowly because tumors of the carotid body were
Hobson/Wilson/Veith: Vascular Surgery: Principles and Practice, Third Edition, Revised and Expanded DOI: 10.1081/0819-9-120024941 Copyright q 2004 by Marcel Dekker, Inc.
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carotid body tumor was first reported in 1938.[10] Most large series have noted a reduction in cerebrovascular complications concurrent with the maturation of vascular reconstructive techniques during the last 20–25 years.[11 – 14] Improved screening is offered by the recent development of color Doppler flow imaging and MRI. Accurate diagnosis prior to operation is provided by arteriography. In addition to facilitating appropriate perioperative planning, precise identification of the lesion permits more accurate description of the natural course of the carotid body tumor. Reports of fatal outcomes directly related to continued growth of carotid body tumors demonstrate that this lesion is not invariably benign in terms of either local extension[15 – 17] or metastasis.[12,18 – 21] Accordingly, a primary surgical approach is now the recommended therapy.[11,14,15,22]
PATHOPHYSIOLOGY The surgical literature most commonly refers to this entity as a carotid body tumor. Confusion with respect to nomenclature arises because many similar terms have been applied and because pathologic classification has related it to other paraganglionic tumors. In the Atlas of Tumor Pathology, Glenner and Grimley[23] refer to this lesion as a carotid body paraganglioma; as such, it is the most common of the extraadrenal paraganglionic tumors. LeCompte,[8] in a previous edition of the atlas, classified the tumor of the carotid body as a separate entity because of its chemoreceptor function. Glenner and Grimley’s return to the unified paraganglionic system of tumor classification was supported by electron microscopic data confirming that its structures were derived from neuroectoderm. Less commonly used terms ( perithelioma, glomus caroticum, endothelioma, chemodectoma, chromaffinoma, and nonchromaffin paraganglioma ) have been deleted from general usage. Thus, preferred nomenclature for this neoplasm includes both carotid body tumor and carotid body paraganglioma. The normal carotid body is a small ð3 £ 6 mmÞ organ of neuroectodermal origin located between the bifurcating vessels of the carotid artery. Embryologically, the carotid body develops between the adventitia and media of the arterial wall, deriving its blood supply predominantly from the external carotid artery.[24] It is highly vascular, with a blood flow proportionally greater than that of the brain.[25] The cells are responsive to changes in PO2, PCO2 and pH and probably function primarily in the control of respiration. The described pathology of this organ encompasses hypertrophy and tumor development. Physiologic hypertrophy of the carotid body may occur with chronic hypoxia and has been associated with habitation at high altitude, cyanotic heart disease, and chronic obstructive lung disease.[26 – 29] Carotid body tumors have been reported in patients with cyanotic congenital heart disease.[28] These tumors also occur with greater frequency in populations residing at altitudes above 6000 feet.[29] Thus, although a correlation is established between chronic hypoxic stimulation and tumor development, the majority of these lesions have no such predisposing factors. On gross examination, the carotid body tumor has a firm consistency with a poorly defined capsule.
Histologically, the characteristic appearance is that of clumps of cells (Zellballen ) contained in a stroma richly interspersed with capillary endothelium. There is no histologic criterion that reliably defines malignancy. This determination is made only by clearly documented nodal or distant metastatic foci. The reported incidence of malignancy has ranged from 0%[8] to 50%.[6] However, there is no longer any reasonable doubt that this tumor is capable of metastatic behavior.[23] The highest estimates have often been based on histologic criteria that are not generally accepted.[6,30] Since metastases may not become apparent for 10–20 years, length of patient observation may be an important factor in explaining the observed variation.[15,16,23] Local recurrence occurs in 6 – 10% of patients and is distinguished from metastatic disease.[20,30,31] The differentiation of true metastatic tumors from multicentric primary paraganglioma presents a significant problem when one is attempting to define the incidence of malignancy accurately. An 87-year review[21] of the literature on metastatic carotid body tumor estimated the incidence at approximately 11–13%. This assessment was based upon strict criteria of distinct regional metastasis and/or distant metastasis. Distant metastases occurred most commonly in the skeleton and lung. The true incidence is probably between 2.5%[11,31] and 11%[21,30] when local recurrence, multifocality, bilaterality, and referral patterns are factored into these data. Although local extension does not fulfill the above criteria for malignancy, the net effect on the patient can be equally significant. Death has been described from asphyxia[15] and intracranial extension.[16,17] Several authors[15,17,32] have estimated that a 25 –30% overall mortality rate results from the combined effects of metastatic and local tumor growth.
CLINICAL PRESENTATION Almost all patients present with an asymptomatic cervical mass. Complaints of pain or discomfort vary greatly, but if these are present, they are generally mild and nonspecific. A history of slow enlargement is frequently elicited. Usually the mass has been present for approximately 6 years at the time of surgical intervention.[18,19,33] Although tumors have been described in infants[17] and in patients over 70 years of age,[15] most patients will be in their late forties at the time of presentation. Hormonally active carotid body tumors are very rare, even though extraadrenal paraganglionic tumors are often associated with symptoms of excess catecholamine secretion. There is no predisposition to either sex. Bilaterality occurs most frequently when the tumor is familial.[34] Specific physical findings with this lesion are limited. The diagnosis should be considered with any lateral cervical mass. Due to its attachment to the underlying artery, the carotid body tumor tends to be more mobile in the horizontal than in the vertical plane. It is usually firm and rubbery on palpation. Due to its intimate arterial attachment, it is often pulsatile. Although absent in the majority of cases, a bruit may be audible; this finding will often indicate other more common conditions, such as atherosclerotic occlusive disease. Cranial nerve dysfunction from a previously unoperated carotid body tumor is present in less than 10%;[11,14] vagal, hypoglossal, and sympathetic involvement has been described.[11,13]
Chapter 57.
Differential diagnosis is that of the solitary lateral cervical mass. Branchial cleft cysts may be distinguished by fluctuation on palpation or a dimple produced by tension on the sinus tract. Most inflammatory adenopathies will initially be tender; usually size and tenderness will decrease slowly when the lesion is observed. Tubercular adenopathy, which can be mistaken for a lesion of the carotid body, is fortunately rare. Lymphoma rarely presents as a solitary cervical node, but when present it is indistinguishable from the carotid body tumor on physical examination. Epithelioid carcinomas may metastasize to a single cervical node; however, they possess a distinctive hardness, and a diligent search will often identify a primary in the oropharyngeal cavity. Thyroid carcinoma may also present as a solitary lateral cervical mass. A true carotid artery aneurysm is very rare and may be characterized by an expansile quality. Solid tumors, which may present as a solitary mass in this location, include neurofibroma, schwannoma, salivary gland tumors, and other cervical paragangliomas (jugular, vagal, and sympathetic). Although the carotid body tumor is the most common, the vascular surgeon may also be consulted for other cervical paraganglionic neoplasms. The vagal body tumor arises from the upper or lower cervical vagal ganglion and also presents as a lateral neck mass. Cranial nerve involvement is more common, and arteriography may show anterior displacement of the carotid bifurcation rather than splaying; however, larger vagal body tumors may also splay the carotid bifurcation.[35] The incidence of malignancy is similar to that of the carotid body tumor.[30,36] Multiple ipsilateral cervical paragangliomas may also occur concurrently.[35] Jugular body tumors and glomus tympanicum primarily involve the structures of the middle ear, presenting with tinnitus and invasion of the skull base.[30] The operative procedures for these neoplasms may require a multidisciplinary surgical team and imply a greater risk; the vascular surgeon may be consulted when revascularization of the internal carotid artery is required. Bilateral carotid body tumors and multicentric paragangliomas[15,19] are most commonly encountered with tumors that have occurred in a familial pattern. Bilaterality is noted in 25% of familial carotid body lesions and in 4% of randomly occurring tumors.[34] The genetic locus has been mapped, and the mode of inheritance is thought to be autosomal dominant with genomic imprinting; paternal offspring of either sex are most likely to express the gene clinically with paragangliomata.[37] The multicentric potential is present in any patient with a paraganglioma. The vast majority of carotid body tumors do not secrete circulating hormones; however, when symptoms are produced by cervical palpation, the diagnosis should be entertained.[38,39] Symptoms of hypertension, palpitations, dizziness, headache, and flushing are associated with functional paragangliomas and confirmed by measurement of increased catecholamine metabolites. These findings should stimulate the search for additional concurrent paraganglioma, particularly pheochromocytoma.
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that has been present for several months. Substantial risks from needle or incisional biopsy techniques probably exceed their benefit. Noninvasive evaluation with color flow Doppler and MRI has improved substantially. However, arteriography remains the most accurate modality and is recommended prior to surgical intervention.[11 – 13,15] The importance of clearly establishing the diagnosis of carotid body tumor preoperatively cannot be overemphasized. Excision of this tumor requires extensive preoperative and intraoperative preparation, which is usually not necessary for most other midlateral neck masses. Contrast arteriography is invaluable. Its diagnostic accuracy is excellent,[11] even though the characteristic appearance may not always be present.[38] An early tumor blush (Fig. 57-1) located at the bifurcation of the common carotid artery will characteristically splay apart the origins of the internal and external carotid arteries (Fig. 57-2). The extent of the tumor blush, unusual feeding vessels, and concomitant atheroma may also be delineated. The diagnosis of a second cervical paraganglioma (usually contralateral) has often been made during complete bilateral cerebral arteriography. Recent advances in imaging technology are useful in evaluating paragangliomas. Color flow Doppler imaging of cervical paraganglioma demonstrates hypervascularity with a low resistance flow pattern, which is complemented by the
DIAGNOSTIC CONSIDERATIONS The diagnosis of carotid body paraganglioma should be considered in patients with a solitary, midlateral neck mass
Figure 57-1.
Carotid arteriogram showing tumor blush.
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functioning carotid body tumor using I123 metaiodobenzylguanidine scintigraphy, which is used for localization of pheochromocytoma. Percutaneous needle biopsy or incisional biopsy under local anesthesia is ill advised and inaccurate.[13,43] Arterial injuries reported from these procedures have produced lifethreatening hemorrhage,[15,44,45] pseudoaneurysm,[11] and carotid thrombosis.[43] B-mode ultrasonic imaging has been helpful in identifying branchial cleft cysts, thyroid cysts, or the widened lumen of the rare carotid aneurysm, but it is of little value in definitive diagnosis of this tumor. Although other noninvasive vascular studies are not helpful in establishing the diagnosis, they are uniquely suited to preoperative assessment of the physiologic consequences of carotid ligation. Gee et al.[46] have accurately predicted successful, uncomplicated carotid ligation by oculoplethysmography (OPG) during common carotid compression. Thus, these noninvasive studies provide an objective assessment of the patient’s ability to withstand acute carotid occlusion.
THERAPEUTIC CONSIDERATIONS
Figure 57-2. Carotid arteriogram showing displacement of carotid arteries.
anatomic feature of splaying at the carotid bifurcation. Color Doppler flow imaging is considerably better than B-mode for distinguishing both the hypervascularity and the splayed arterial bifurcation.[40] The color Doppler images are highlighted by an increase in vascularity between the internal and external carotid arteries (Fig. 57-3) (see also color plate), which is characteristic of these highly vascular tumors (Fig. 57-4) (see also color plate). A recent study comparing color flow Doppler imaging to MRI/CT/angiography identified 11 of 11 palpable carotid body tumors; of 3 impalpable tumors, only one was missed. Color flow Doppler imaging of vagal body tumors was less accurate; 6 of 11 were identified. The high cervical location of the vagal body tumor makes them less accessible to both palpation and ultrasound imaging.[35] Magnetic resonance imaging defines the magnitude of local extension and involvement of adjacent structures. MRI will detect a carotid body tumor 5 mm in diameter and will define the position of the common, internal, and external carotid arteries.[41] Magnetic resonance imaging has been favorably compared with computed tomography (CT) but is not recommended as a replacement for angiography.[42] As familiarity with these modalities develops, their importance in screening patients with lateral cervical masses will undoubtedly increase. A recent report also describes localization of a
Primary surgical excision is the preferred treatment for the carotid body tumor. These neoplasms were once thought to be largely benign, relatively innocuous lumps in the neck.[5,7,8,16] More recent reports have now described delayed appearance of distant metastases, an incidence of local recurrence, and significant local extension in 20–30% of carotid body tumors.[15 – 17,21,23,30] Rarely these uncommon tumors will be hormonally active. Inability to predict which patients would require carotid ligation and the prohibitive mortality accompanying this surgical procedure once provided the most cogent argument against routine resection. Significant reductions in operative mortality have been attributed to advances in surgical technique.[11 – 14] The development of a reliable technique for carotid reconstruction has provided a superior alternative to ligation. It is unwarranted to assume that all these lesions are malignant, but since differentiation of malignancy is not possible histologically, complete resection is indicated when carotid body tumor is diagnosed. The risk of surgical morbidity is directly related to tumor size at the time of diagnosis. Although the risk of stroke and arterial complications has been minimized, the probability of cranial nerve injury is little changed. The incidence of cranial nerve involvement is directly related to tumor size for both spontaneous and postoperative occurrences. Complete resection is more likely when the neoplasm can be removed without requiring neurolysis or arterial reconstruction. Thus, the ideal time for resection is when the carotid body tumor is small. A low threshold for diagnostic evaluation in the lateral neck mass is essential for early identification. Alternative treatments are not curative and have not generally been efficacious. Radiation therapy has been applied to the carotid body tumor sporadically but with little substantive benefit.[48] However, radiation may have a role with other craniocervical paragangliomata such as the jugular body tumor, in which intracranial extension is frequent,[47,48] and surgical excision involves complex and morbid skull base
Chapter 57.
Carotid Body Tumors
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Figure 57-3. Color Doppler flow image of a left carotid body tumor. Note increased vascularity between internal and external carotid arteries (see color plate).
procedures.[49] Chemotherapy has not been widely applied. Selective intravascular embolization of the external carotid has been advocated for reduction of tumor bulk prior to surgery and to decrease intraoperative blood loss.[44,50,51] Although potentially offering an attractive alternative in the
Figure 57-4.
difficult situation, the procedure is not without risk of mortality.[52] A recent study demonstrated no advantage from embolization in 22 patients with 4 –5 cm tumors equally divided into groups treated with embolization and those without embolization.[53] Partial resection of tumors deemed
Color Doppler flow image of left carotid body tumor. Note vascularity of the tumor (see color plate).
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unresectable has been followed by persistent enlargement, intracranial extension, and metastases.[13,54] However, some patients will still present with tumors of such bulk that reconstruction is not feasible; when collateral arterial flow is not adequate to consider ligation, these therapeutic options may need to be reconsidered. Preoperative preparations for resection of the carotid body tumor differ from those for other cervical lesions. Angiography, which is not usually required for other masses in this vicinity, is accurate for establishing the diagnosis and essential for planning the operation. Physiologic evaluation of the collateral cerebral circulation is recommended when it is anticipated that carotid reconstruction or ligation may be required. When the rare functional tumor is encountered, perioperative adrenergic blockade is appropriate. Rational therapeutic decisions can then be based on knowledge of the tumor’s natural history and the relative risks of surgery. Arrangements for adequate supplies of bank blood and the autotransfusion system are made. Preoperative preparation should include both the neck and the lower extremity, so that the saphenous vein can be harvested if required.
SURGICAL TECHNIQUE Small carotid body tumors can generally be excised with modest blood loss and without interruption of cerebral blood flow. Accordingly, the risk of excision in these patients is relatively low. However, larger tumors more commonly come to surgery. Extensive blood loss, averaging 2000 mL,[11,15] can be anticipated by preparation of the autotransfusion system. Although most of these tumors can be excised through a subadventitial plane, the surgeon must be prepared to replace the internal carotid artery if it cannot be spared. Therefore, it is important to have an adequate conduit available, and the saphenous vein is mapped prior to the procedure. The neck is explored through an S-shaped incision made along the anterior border of the sternomastoid muscle. First, the common and then the internal carotid arteries are exposed, and Dacron umbilical tape is placed around each for control. Control of the external carotid artery may not be sought when the tumor involves the entire artery. An intraluminal arterial shunt is prepared prophylactically. As the dissection progresses, the hypoglossal and vagus nerves (Fig. 57-5) are identified and preserved. When the tumor has been exposed and arterial control established, resection is begun. A subadventitial plane is developed on the common carotid artery and the dissection proceeds upward. The external carotid artery is ligated at its origin and the tumor freed from the internal carotid artery in the same plane (Fig. 57-6). The various branches of the external carotid artery are identified and ligated. At the end of the dissection, the common and internal carotid arteries should be left intact and the hypoglossal and vagal nerves undamaged. After the tumor has been excised, meticulous care should be taken with hemostasis. Resection of the carotid bifurcation is often necessary when very large tumors are encountered. In such patients, as much of the tumor as possible is exposed. The upper end of
Figure 57-5. The carotid body tumor is shown in relationship to the carotid artery, the vagus nerve (V), and the hypoglossal nerve (H). (Reprinted with permission of the Lahey Clinic.)
the internal carotid artery is carefully dissected. A segment of saphenous vein is harvested, and an internal shunt is placed in its lumen. Supplemental heparin may be required to maintain patency of the shunt. The internal carotid artery is transected above the tumor, an arteriotomy is made in the common carotid artery, and the shunt is inserted expeditiously. The internal carotid artery is anastomosed to the saphenous vein end to end with a running 5-0 or 6-0 vascular suture. The next step varies with the logistics of the tumor and its relationship to the arteries. Because the tumor usually blocks the surgical field, the vein must be draped over the tumor to connect it to the common carotid artery. Therefore an attempt is made to complete the resection prior to constructing the proximal
Chapter 57.
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OUTCOME AND PROGNOSIS Primary surgical excision of the carotid body tumor is generally curative. The majority of patients will have no further complaints following successful resection of the tumor. There is, however, a small but definite incidence of contralateral tumors, recurrence, and malignancy. At the present time, color flow duplex and/or MRI examinations have been recommended for postoperative follow-up and for screening examinations of the patients’ relatives. Periodic clinical observation is warranted for detection of multicentric paragangliomas, local recurrence, and delayed appearance of metastatic lesions. Because histologic criteria are inaccurate for diagnosis of malignancy and because the presentation may not occur for decades, regular clinical evaluation assumes a significant role in defining this threat. Descriptions of malignant carotid body tumors are characterized by low-grade malignancy, delayed appearance of metastatic foci often occurring after the standard 5-year interval observed with most neoplasms.[30] Although tumor expansion has been responsible for a number of deaths, such extensive growth has also taken many years. Similarly, patients may also live for more than 5 years following identification of metastatic deposits.[32] The true incidence of malignancy with these lesions is difficult to define accurately but is probably between 2.5 and 11%. Recurrence may be difficult to detect by physical examination when it occurs deep in the neck. Thus, CT becomes a valuable examination for follow-up evaluation. However, CT scans obtained within 8 weeks of resection will often demonstrate a mass at the base of the skull. This is the result of scar and should not be confused with residual or recurrent tumor. Figure 57-6. The carotid body tumor being removed from below. The external carotid artery has been sacrificed. Care has been taken to spare the vagus (V) and hypoglossal (H) nerves. (Reprinted with permission of the Lahey Clinic.)
anastomosis. If the tumor can be excised first, the length of saphenous vein can be adjusted properly. Proximal anastomosis between saphenous vein and common carotid artery is also fashioned end to end. The saphenous vein is cut tangentially because of the discrepancy in the size of the two vessels. In very large tumors that have grown up to the base of the skull, vascular reconstruction may be impossible because the distal internal carotid artery is rendered inaccessible (Fig. 57-7). In such cases, the internal carotid artery must be sacrificed if the tumor is resected. Preoperative assessment of the collateral capabilities of the cerebral circulation is important, as it is better to leave the patient with a large tumor than to leave her or him hemiplegic. Although no preoperative test is 100% reliable, intracerebral cross-filling on the arteriogram and Gee OPG during carotid compression have been employed for this assessment.[11,46]
COMPLICATIONS With modern diagnostic and technical expertise, complications from treatment of carotid body tumor may be minimized. Color flow Doppler imaging and MRI offer noninvasive screening and should help to avert premature attempts at biopsy. Contrast arteriography remains the most accurate and useful diagnostic modality. Despite the rarity of this neoplasm, the solitary lateral cervical mass should be evaluated by arteriography prior to the use of other invasive diagnostic methods. Thus, percutaneous needle biopsy or local excisional biopsy can be avoided, along with their attendant potential for significant hemorrhage and pseudoaneurysm formation (Fig. 57-8). When these problems occur, treatment of the tumor becomes significantly more complex. The unprepared surgeon is faced with a difficult decision when a carotid body tumor is diagnosed at the time of cervical exploration; closure of the wound, aborting of the procedure, and elective rescheduling have been recommended.[55] However, when the lesion is recognized preoperatively, the surgeon can make necessary preparations for resection. Blood
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Part Six. Cerebrovascular Disease
Figure 57-7.
(A and B ) Arteriograms of patients with large carotid body tumors. Note relationship to the carotid vessels.
Chapter 57.
Carotid Body Tumors
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Figure 57-8. (A and B ) These carotid body tumors demonstrate splaying of the carotid bifurcation. The typical tumor blush (B ) appears behind a pseudoaneurysm (A ) which resulted from direct biopsy.
loss can be anticipated as well as carotid arterial reconstruction. Cranial nerve injury is more commonly associated with excision of the carotid body tumor than with other cervical procedures, such as carotid endarterectomy. The precise incidence is difficult to determine, because most reports describe multiple procedures at multiple institutions. However, the incidence of cranial nerve involvement approaches 35% when abnormalities noted both at presentation and following treatment are considered together.[11,12,33] The probability of injury increases in proportion to the size of the tumor and with prior attempts at resection. Injuries of the vagal and hypoglossal nerves are the most frequently encountered; however, accessory, facial, and cervical sympathetic nerve damage has also been reported. Earlier series reporting tumor resection without
arterial reconstruction were characterized by a prohibitive incidence of major cerebral deficits. In more recent reports emphasizing arterial reconstruction, this problem has virtually been eliminated.
SUMMARY OF KEY POINTS IN JUDGMENT The innocuous presentation of the carotid body tumor subtly disguises the potential for significant complications from treatment of these uncommon, highly vascular tumors. Preoperative diagnosis is essential for counseling the patient and planning appropriate management. Accurate identifi-
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cation is achieved by maintaining a high level of suspicion, screening with color flow duplex or MRI, and a low threshold for angiography, which confirms the diagnosis. Early identification requires a high level of suspicion and a low threshold for angiography, which confirms the diagnosis. Although the incidence of malignancy is low, insidious local growth has also proved life threatening. Surgical compli-
cations are less likely when the tumor is relatively small and preoperative preparation has been complete. Refinement of vascular surgical techniques has facilitated safe excision of larger tumors and those that require arterial reconstruction. Surgical resection is the recommended treatment for the carotid body tumor and is preferably undertaken before the lesion has attained excessive bulk.
REFERENCES 1. Gratiot, J.M. Carotid Body Tumors: Collective Review. Surg. Gynecol. Obstet. (Int. Abstr. Surg.) 1943, 77, 177. 2. Lund, F.B. Tumors of the Carotid Body. J. Am. Med. Assoc. 1917, 69, 48. 3. Scudder, C.L. Tumor of the Intercarotid Body. Am. J. Med. Sci. 1903, 126, 84. 4. Chase, W.H. Familial and Bilateral Tumors of the Carotid Body. J. Pathol. Bacteriol. 1933, 6, 1. 5. Bevan, A.D.; McCarthy, E.R. Tumors of the Carotid Body. Surg. Gynecol. Obstet. 1929, 49, 764. 6. Harrington, S.W.; Clagett, O.T.; Dockerty, M.B. Tumors of the Carotid Body. Ann. Surg. 1941, 114, 820. 7. Lahey, F.H.; Warren, K.W. Tumors of the Carotid Body. Surg. Gynecol. Obstet. 1947, 85, 281. 8. LeCompte, P.M. Tumors of the Carotid Body and Related Structures (Chemoreceptor System). In Atlas of Tumor Pathology, sec 4, fasc 16; Armed Forces Institute of Pathology: Washington, DC, 1951. 9. Martin, H. Surgery of Head and Neck Tumors; HoeberHarper: New York, 1957; 20. 10. Enderlen, E. Originalmitteilungen, Operation der Carotisdrusengeschwulste. Zentralbl. Chir. 1938, 46, 2530. 11. Padberg, F.T., Jr.; Cady, B.; Persson, A.T. Carotid Body Tumor. Am. J. Surg. 1983, 145, 526. 12. Lees, G.D.; Levine, H.L.; Beven, E.G.; Tucker, H.M. Tumors of the Carotid Body. Am. J. Surg. 1981, 142, 362. 13. Farr, H.W. Carotid Body Tumors: A 40 Year Study. Cancer J. Clin. 1980, 30, 260. 14. Hallett, J.W.; Nora, J.D.; Hollier, L.H.; et al. Trends in Neurovascular Complications of Surgical Management for Carotid Body and Cervical Paragangliomas: A Fifty-Year Experience with 153 Tumors. J. Vasc. Surg. 1988, 7, 284. 15. Dent, T.L.; Thompson, N.W.; Fry, W.J. Carotid Body Tumors. Surgery 1976, 80, 365– 372. 16. Martin, C.E.; Rosenfeld, L.; McSwain, B. Carotid Body Tumors: A 16-Year Follow-Up of Seven Malignant Cases. South. Med. J. 1973, 6, 1236. 17. Monro, R.S. Natural History of Carotid Body Tumors and Their Diagnosis and Treatment. Br. J. Surg. 1950, 37, 445. 18. Lahey, F.H.; Warren, K.W. A Long-Term Appraisal of Carotid Body Tumors with Remarks on Their Removal. Surg. Gynecol. Obstet. 1951, 92, 481. 19. Shamblin, W.R.; ReMine, W.H.; Sheps, S.G.; Harrison, E.G. Carotid Body Tumor (Chemodectoma). Am. J. Surg. 1971, 122, 732. 20. Merino, M.J.; LiVolsi, V.A. Malignant Carotid Body Tumors: Report of Two Cases and Review of the Literature. Cancer 1981, 47, 1403.
21. Zbaren, P.; Lehmann, W. Carotid Body Paraganglioma with Metastases. Laryngoscope 1985, 95, 450. 22. Javid, H.; Chawla, S.K.; Dye, W.S.; et al. Carotid Body Tumor: Resection or Reflection. Arch. Surg. 1976, 111, 344. 23. Glenner, G.G.; Grimley, P.M. Tumors of the Extraadrenal Paraganglion System (Including Chemoreceptors). In Atlas of Tumor Pathology, second series, fasc 9; Armed Forces Institute of Pathology: Washington, DC, 1973. 24. Boyd, J.H. The Development of the Human Carotid Body. Contrib. Embryol. 1937, 26, 1. 25. Daly, M.D.; Lambertsen, C.J.; Schweitzer, A. Observations on the Volume of Blood Flow and Oxygen Utilization of the Carotid Body in the Cat. J. Physiol. 1954, 125, 67. 26. Heath, D.; Edwards, C.; Harris, P. Post-Mortem Size and Structure of the Human Carotid Body. Thorax 1970, 25, 129. 27. Edwards, C.; Heath, D.; Harris, P. The Carotid Body in Emphysema and Left Ventricular Hypertrophy. J. Pathol. 1971, 104, 1. 28. Hirsh, J.M.; Killien, F.C.; Troupin, R.H. Bilateral Carotid Body Tumors and Cyanotic Heart Disease. Am. J. Roentgenol. 1980, 134, 1073. 29. Pacheco-Ojeda, L.; Durango, E.; Rodriques, C.; Vivar, N. Carotid Body Tumors at High Altitudes: Quito, Ecuador, 1987. World J. Surg. 1988, 12, 856. 30. Lack, E.E.; Cubilla, A.L.; Woodruff, J.M.; Farr, H.W. Paragangliomas of the Head and Neck Region: A Clinical Study of 69 Patients. Cancer 1977, 39, 397. 31. Nora, J.D.; Hallett, J.W.; O’Brein, P.C.; et al. Surgical Resection of Carotid Body Tumors: Long-Term Survival, Recurrence, and Metastasis. Mayo Clin. Proc. 1988, 63, 348. 32. Gaylis, H.; Mieny, C.J. Incidence of Malignancy in Carotid Body Tumors. Br. J. Surg. 1977, 64, 885. 33. Krupski, W.C.; Effeney, D.J.; Ehrenfeld, W.K.; Stoney, R.J. Cervical Chemodectoma: Technical Considerations and Management Options. Am. J. Surg. 1982, 144, 215. 34. Rush, B.F., Jr. Familial Bilateral Carotid Body Tumors. Ann. Surg. 1963, 157, 633. 35. Jansen, J.C.; Baatgenburg de Jong, R.J.; Shipper, J.; van der Mey, A.G.L.; van Gils, A.P.G. Color Doppler Imaging of Paragangliomas in the Neck. J. Clin. Ultrasound 1997, 25, 481. 36. Gill, P.S.; Valentine, R.J.; Oller, D.W.; Rob, C.G. Intravagal Paraganglioma: Report of a Case and Discussion of Vascular Parapharyngeal Masses. Surgery 1988, 103, 432.
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38.
39.
40. 41.
42. 43.
44.
45.
Heutink, P.; van der Mey, A.G.; Sandkuijl, L.A.; et al. A Gene Subject to Genomic Imprinting and Responsible for Hereditary Paragangliomas Maps to Chromosome 11q23qter. Hum. Mol. Genet. 1992, 1, 7. MacGillivray, D.C.; Perry, M.O.; Selfe, R.W.; Nydick, I. Carotid Body Tumor: Atypical Angiogram of a Functional Tumor; Report of a Case and Review of the Literature. J. Vasc. Surg. 1987, 5, 462. Ikejiri; Muramon; Takeo, S.; Furuyama, M.; Yoshida; Saku, M. Functional Carotid Body Tumor: Report of a Case and a Review of the Literature. Surgery 1996, 119, 222. Steinke, W.; Hennerici, M.; Aulich, A. Doppler Color Flow Imaging of Carotid Body Tumors. Stroke 1989, 20, 1574. Vogl, T.; Bru¨ning, R.; Schedel, H.; et al. Paragangliomas of the Jugular Bulb and Carotid Body: MR Imaging with Short Sequences and Gd-DTPA Enhancement. Am. J. Roentgenol. 1989, 153, 583. Olsen, W.L.; Dillon, W.P.; Kelly, W.M.; et al. MR Imaging of Paragangliomas. Am. J. Roentgenol. 1987, 148, 201. Engzell, U.; Franzen, S.; Zajicek, J. Aspiration Biopsy of Tumors of the Neck: II. Cytologic Findings in 13 Cases of Carotid Body Tumor. Acta. Cytol. 1971, 15, 25. Muhm, M.; Polterauer, P.; Gsttner, W.; Temmel, A.; Richling, B.; Undt, G.; Niederle, B.; Staudacher, M.; Ehringer, H. Diagnostic and Therapeutic Approaches to Carotid Body Tumors: Review of 24 Patients. Arch. Surg. 1997, 132, 279. Fruhwirth, J.; Och, G.; Hauser, H.; Gutschi, S.; Beham, A.; Ainz, J. Paragangliomas of the Carotid Bifurcation: Oncological Aspects of Vascular Surgery. Eur. J. Surg. Oncol. 1996, 22, 88.
46.
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48. 49.
50.
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53.
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Gee, W.; Mehigan, J.T.; Wylie, E.J. Measurement of Collateral Cerebral Hemispheric Blood Pressure by Ocular Pneumoplethysmography. Am. J. Surg. 1975, 130, 121. Konefal, J.B.; Pilepich, M.V.; Spector, G.J.; Perez, C.A. Radiation Therapy in the Treatment of Chemodectomas. Laryngoscope 1987, 97, 1331. Mitchell, D.C.; Clyne, C.A.O. Chemodectomas of the Neck: The Response to Radiotherapy. Br. J. Surg. 1985, 72, 9023. Jackson, C.G.; Harris, P.F.; Glasscock, M.E.; et al. Diagnosis and Management of Paragangliomas of the Skull Base. Am. J. Surg. 1990, 159, 389. Schick, P.M.; Hieshima, G.B.; White, R.A.; et al. Arterial Catheter Embolization Followed by Surgery for Large Chemodectoma. Surgery 1980, 87, 459. LaMuraglia, G.M.; Fabian, R.L.; Brewster, D.C.; PileSpellman, J.; Darling, R.C.; Cambria, R.P.; Abbott, W.M. The Current Surgical Management of Carotid Body Paragangliomas. J. Vasc. Surg. 1992, 15, 1038. Pandya, S.K.; Nagpal, R.D.; Desai, A.P.; Purohit, A.T. Death Following External Carotid Arterial Embolization for a Functioning Glomus Jugulare Chemodectoma. J. Neurosurg. 1978, 48, 1030. Litle, V.R.; Reilly, L.M.; Ramos, T. Preoperative Embolization of Carotid Body Tumors: When Is It Appropriate? Ann. Vasc. Surg. 1996, 10, 464. Warren, K.W. Some Observations on Carotid Body Tumors. Surg. Clin. N. Am. 1959, 39, 621. McPherson, G.A.D.; Halliday, A.W.; Mansfield, A.O. Carotid Body Tumors and Other Cervical Paragangliomas: Diagnosis and Management in 25 Patients. Br. J. Surg. 1989, 76, 33.
CHAPTER 58
Renovascular Disease Richard H. Dean Kimberley J. Hansen associates[1] suggested an even lower prevalence. Likewise, Shapiro et al.[2] suggested that the identification and successful operative treatment of RVH in patients over the age of 50 years is so unlikely that diagnostic investigation for a correctable cause in that group should be undertaken only when hypertension is severe and uncontrollable. Estimates of the prevalence of hypertension in the United States from all causes vary from 15 to 30 million people, and it may be present in 10–15% of the adult population. Indeed, the incidence of RVH is undoubtedly low in this general hypertensive population if all patients with even mild hypertension are included. Since RVH tends to produce relatively severe hypertension, its prevalence in the large subpopulation of mildly hypertensive patients (diastolic blood pressure , 105 mmHg) is probably negligible. In contrast, however, it is a frequent cause of hypertension in the smaller group of severely hypertensive people. Hollifield[3] investigated 137 patients with previously unrecognized hypertension who were uncovered in a shopping center screening program. Diagnostic study in these patients included arteriography and, when appropriate, renal vein renin assays and split renal function studies. None of the 102 patients with a diastolic blood pressure between 90 and 115 mmHg had RVH. In contrast, 9 of the 35 patients (26%) with a diastolic blood pressure of 118 mmHg or higher had RVG. Similarly, Davis et al.[4] have shown a 31% incidence of RVH in 85 patients initially evaluated in our center for malignant hypertension. In our experience, the presence of severe hypertension at the two extremes of life carries the highest probability of being RVH. Our review of the causes of hypertension in 74 children admitted for diagnostic evaluation over a 5-year period showed that the hypertension in 78% of those who were less than 5 years old had a correctable renovascular origin.[5] Interestingly, after childhood, the age group which has the next highest probability of having RVH is the elderly. In the 1996 academic year, the authors’ center screened 629 hypertensive adults for renovascular disease (Table 58-1). Overall, 25% of subjects screened demonstrated significant renal artery disease. However, 52% of subjects greater than 60 years of age with a diastolic pressure . 110 mmHg had significant renal artery stenosis or occlusion. When elevated serum creatinine was present in conjunction with these age and blood pressure characteristics, 71% of subjects demonstrated
Although hypertension has been recognized for centuries, the importance of its identification and treatment has been appreciated only during the past 150 years. Most commonly, hypertension is a silent process and is manifested only by sequelae of acceleration in the rate of atherogenesis and the frequency of cardiovascular morbidity and mortality rates. Uncommonly, the hypertension may be so severe that the elevated pressure itself produces vessel wall injury and the clinical picture of malignant hypertension. Although most physicians appreciate the potentially lethal nature of this malignant variety and the importance of its control, physician apathy toward the merits of aggressive diagnostic evaluation and management of asymptomatic patients with less severe hypertension continues to limit the impact of current knowledge on the populationwide success of treatment of this disorder. The incidence of renovascular hypertension (RVH), the necessity for its identification, and the value of operative management remain poorly defined. Some centers are routinely evaluating hypertensive patients for renovascular origin and are submitting suitable candidates to operative treatment. Other centers seldom study patients for RVH and even more uncommonly select operative management for this form of hypertension. Several factors have led to this disparity in approaches. Among these reasons are reports emphasizing a low frequency of a renovascular cause of hypertension, the low costeffectiveness of diagnostic investigation, the infrequent cure of hypertension by operation, and improvements in management by drug therapy. Unfortunately, the inappropriately biased collection of data and conflicting results of studies in these areas have perpetuated the lack of uniformity in concepts regarding the value of diagnostic study and merits of operative treatment. In this chapter, diagnostic studies and methods of management of the respective causes of renovascular disease and RVH will be reviewed with emphasis on the current status of their value and results of their use.
PREVALENCE OF RENOVASCULAR HYPERTENSION Renovascular hypertension is generally thought to account for 5 – 10% of the hypertensive population. Tucker and
Hobson/Wilson/Veith: Vascular Surgery: Principles and Practice, Third Edition, Revised and Expanded DOI: 10.1081/0819-9-120024942 Copyright q 2004 by Marcel Dekker, Inc.
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hemodynamically significant renovascular disease. Certainly, the elderly age group admitted for evaluation is skewed toward the more severe spectrum of hypertension, for less severe levels likely would not have led to referral of such patients to our center. Based on these data it is inappropriate to view hypertensive patients as a homogeneous group with respect to the prevalence of RVH. Rather, the probability of finding RVH correlates with the severity of hypertension. Accordingly, the search for RVH should be directed to the subset of patients who have the more severe degree of hypertension. It must be remembered, however, that severity of hypertension is based on its level without medication interference and does not refer to the difficulty of control by drug therapy.
PATHOPHYSIOLOGY OF RENOVASCULAR HYPERTENSION The kidney is a dominant site of blood pressure regulation because of its influence on circulating plasma volume as well as its activity in modulation of vasomotor tone. To examine the pathophysiology of renovascular hypertension, it is appropriate to first review the normal homeostatic activities of the kidney in the regulation of blood pressure.[6] The renin-angiotensin-aldosterone system is a complex feedback mechanism which, in its normal state of activity, maintains a stable blood pressure and blood volume under varying conditions. Richly innervated, modified smoothmuscle cells located along the afferent arterioles in juxtaposition to the renal glomerulus (juxtaglomerular apparatus) are sensitive monitors of perfusion pressure. Diminished perfusion pressure stimulates these cells to release renin, a proteolytic enzyme. Renin, in turn, interacts with an alpha2-globulin (angiotensinogen) manufactured in the liver to produce angiotensin I. Angiotensin I, an inactive and labile decapeptide, is converted to the potent vasoconstrictor angiotensin II by a converting enzyme found primarily in the lungs. In addition to its potent vasoconstrictor properties, angiotensin II also increases blood pressure through its stimulation of aldosterone release from the zona glomerulosa of the adrenal cortex. This, in turn, increases plasma volume by increasing sodium and water resorption in the renal tubules. Through these actions of angiotensin II, blood pressure, plasma volume, and plasma sodium content are increased. In addition, the adjacent cells of the distal convoluted tubule (macula densa) may play a role by acting as a sensor of sodium concentration in the distal tubules and thereby exerting a positive feedback Table 58-1.
mechanism on renin release. As these mechanisms increase perfusion pressure to the juxtaglomerular cells, further renin production and release is suppressed and blood pressure is modulated within a narrow range. Potentially, two forms of hypertension may be produced by the development of renovascular disease. These are (1) renin-dependent hypertension and (2) volume-dependent hypertension. Through the mechanisms just described, decreased perfusion activates the renin-angiotensin-aldosterone axis of vasoconstriction and volume expansion. Current information regarding the nature of renovascular hypertension suggests that a functionally significant unilateral renal artery stenosis activates both the angiotensin II –mediated increase in peripheral resistance and blood pressure as well as aldosterone-mediated volume expansion. When the contralateral renal artery and kidney are normal, the normal feedback mechanisms in the normal kidney produce an effective natriuresis and compensatory reduction in circulating plasma volume. In this scheme, an angiotensin II– vasoconstrictive source of hypertension is created. In contrast, when the contralateral renal artery or kidney is also diseased, this compensatory diuresis is lost and volume expansion occurs, producing an angiotensin-aldosterone – mediated volume-dependent hypertension. Modification of renal perfusion by renal revascularization can effectively diminish or abolish the underlying mechanism producing either of these two varieties of renovascular hypertension.
CHARACTERISTICS OF RENOVASCULAR HYPERTENSION Due to the relative infrequency of RVH in the entire hypertensive population, many reports have focused on the value of demographic factors, physical findings, and screening tests as discriminants between essential hypertension (EH) and RVH on which to base the decision for further diagnostic study. The most frequently quoted discriminating factors that suggest the presence of RVH and a need for further study are the recent onset of hypertension, a young age, a lack of a family history of hypertension, and the presence of an abdominal bruit. In the review of the first 200 patients with RVH treated in our center, 56% had a family history of hypertension, 51% had no audible bruit, and ages ranged from 5 to 80 years (mean age: 56 years).[7] Since RVH can be secondary to any of several processes affecting the renal artery and since each of these diseases has its own clinical characteristics, it is not
Renal Duplex Sonography in 629 New Hypertensive Adults
All patients . 60 years & DBP $ 100 mmHg DBP $ 110 mmHg & SC $ 2.0 mg/dL DBP ¼ diastolic blood pressure. SC ¼ serum creatinine.
RVD present (%)
RVD absent (%)
Total
154 (24) 98 (52) 53 (71)
475 (76) 91 (48) 22 (29)
629 (100) 189 (30) 75 (12)
Chapter 58.
surprising that the use of demographic or physical findings such as age, abdominal bruit, and duration of hypertension as discriminants to exclude patients from study has a high risk of inappropriately excluding patients with RVH. Therefore, one should base the decision for diagnostic study primarily on the severity of hypertension. Mild hypertension has a minimal chance of being renovascular in origin. In contrast, the more severe the hypertension, the higher the probability that it is from a correctable cause. With this in mind, we submit all patients with diastolic blood pressures greater than 105 mmHg who would be acceptable operative candidates to evaluation for a correctable origin of hypertension.
DIAGNOSTIC EVALUATION The general evaluation of all hypertensive patients is shown in Table 58-2. Electrocardiography is important to gauge the extent of secondary myocardial hypertrophy or associated ischemic heart disease. Serum electrolytes and serial serum potassium determinations can effectively exclude patients with primary aldosteronism if potassium levels are greater than 3.0 mg/dL. One must remember, however, that hypokalemia is most often due to salt-depleting diets and previous diuretic therapy. Estimation of renal function is mandatory. Preexisting renal disease may reduce renal function and cause hypertension. Further, hypertension from any cause may produce intrarenal arteriolar nephrosclerosis and subsequent depression of renal function. Finally, assessment of the urinary 17-hydroxy- and ketosteriod and vanillylmandelic acid (VMA) levels in young patients and patients with paroxysmal hypertension will effectively identify the rare patient with a pheochromocytoma or a functioning adrenocortical tumor.
Screening Studies A number of screening diagnostic studies have been advocated for the recognition of the patient with RVH. Each of these studies is useful in the evaluation of hypertensive patients. With the exception of renal arteriography, however, none of these screening tests has the necessary sensitivity to serve as the single study on which the necessity for more definitive diagnostic evaluation is based. Previous review of the results of these other proposed screening studies has shown that over 30% of patients with RVH would have been missed if further evaluation had been undertaken solely on the basis of these results.[8]
Renal Duplex Sonography The authors’ center has chosen renal duplex sonography as the preliminary screening study of choice for both renovascular hypertension and insufficiency (i.e., ischemic nephropathy).[9] As a screening study, preparation is minimal (an overnight fast) and there is no need to alter antihypertensive medications. The examination poses no risk to residual excretory renal function, and overall accuracy is not adversely affected by concomitant aorto-iliac disease—
Table
58-2.
General
Renovascular Disease
Evaluation
of
Patients
825
with
Hypertension History and physical examination Hemogram; SMA-12; urinalysis, urine culture; serum K, 3 times Electrocardiogram and chest x-ray Analysis of 24-h urine collection for creatinine clearance, electrolytes, catecholamines, VMA, and 17-OH-steroids and ketosteriods
important considerations since over 70% of contemporary patients have at least mild renal insufficiency in combination with aorto-iliac atherosclerosis. The utility of renal duplex sonography is demonstrated by the results from our first prospective validity analysis in 74 consecutive patients who had 70 conventional cut-film angiograms to 148 kidneys for comparison.[9] Among 122 kidneys with single renal arteries, renal duplex sonography provided 95% sensitivity, 98% specificity, 98% positive predictive value, 94% negative predictive value, and overall accuracy of 96%. From this experience and more than 6000 renal duplex studies performed at the authors’ center, the technique appears to be valuable for lesions of the main renal artery when the screened population demonstrates a 20 –40% prevalence of renovascular disease. However, renal duplex does not accurately define multiple or polar renal arteries or their associated disease. Seventeen percent of patients treated for RVH at our center have polar disease, and in 11% of patients, polar disease is the sole source of renin-mediated hypertension. Consequently, the authors proceed with renal angiography in children and young adults when hypertension is severe or poorly controlled despite a negative duplex result.
Renal Arteriography There continues to be controversy over the use of aortography and renal arteriography in the routine screening of hypertensive individuals. Some feel it should be reserved for select groups of patients. We do not share this conservative view and proceed with arteriography in any patient who would be a candidate for renal artery revascularization if a lesion were found, irrespective of other screening tests. As a general rule, we have required that the patient have documented diastolic blood pressures in excess of 105 mmHg, and the majority have had pressures in excess of 120 mmHg. Both aortography and selective renal arteriography using multiple projections are necessary to adequately examine the entire renal artery. The proximal third of the left renal artery usually courses anteriorly, the midthird transversely, and the distal third posteriorly, whereas the right renal artery pursues a more consistent posterior course. Previous review of these factors has underscored the necessity of oblique aortography and oblique selective renal arteriography to project these portions of the vessels in the profile and identify the stenosis.[10] Through the introduction of computer-assisted subtraction angiography, one can now obtain anatomic definition of
826
Part Seven. Visceral Arterial Disease
the renal vasculature as an outpatient screening procedure. Unfortunately, further technologic refinements are required before this study can replace conventional arteriography. Currently, it does not identify fibromuscular dysplastic lesions with accuracy and frequently provides a picture which erroneously exaggerates the severity of atherosclerotic lesions. Nevertheless, further instrumental development is awaited with enthusiasm.
Functional Studies Renal Vein Renin Assays When an obstructive lesion is found by renal arteriography, its functional significance should be evaluated. Most centers now rely solely on renal vein renin assays (RVRA) to establish the diagnosis of RVH. The unfortunate consequence of this trend is that one must presume that all patients with RVH will have lateralizing RVRA. The results of evaluation of this study in our center underscore the fallacy of this presumption. Many factors affect the results of RVRA, which, if not properly managed, will lead to erroneous results. The effect of antihypertensive medications and unrestricted sodium intake on renin release and, thereby, RVRA is widely recognized. Many antihypertensive medications, especially those that function through beta-adrenergic blockade, suppress renin output and can lead to false nonlateralization of RVRA. Likewise, the chronic use of angiotensin-converting enzyme inhibitors dramatically stimulates renin release from both kidneys and destroys lateralization of renin ratios. Before one can consider that there is no drug interference in the release of renin, all such medications must have been withheld for at least 5 days prior to the measurement of RVRA. Similarly, suppression of renin levels is seen when sodium intake is not restricted. For this reason, the patient must be on no more than a 2-g sodium diet for at least 2 weeks prior to the study. The preparation of patients for RVRA in our center is summarized in Table 58-3. Vaughn et al.[11] have stressed the importance of expressing RVRA in relation to the systemic renin activity rather than simply evaluating the ratio of renin activity between the two renal veins. In patients with RVH secondary to unilateral renal artery stenosis, one should find hypersecretion of renin from the ischemic kidney and suppression of rennin secretion from the normal kidney. Through application of this hypothesis, Stanley and Fry[12] have shown a statistically significant difference in the renal-systemic renin indices in patients who were cured of RVH by operation when compared to those who were only improved. Although this method has appeal as
Table 58-3.
Patient Preparation for Renal Vein Renin Assays
1. Chronic salt restriction (2-g sodium diet) 2. Discontinue all antihypertensive drugs except diureties and vasodilators for at least 5 days prior to study 3. Oral furosemide (40 mg) diuresis night before the study 4. Nothing by month for 8 h prior to study 5. Strictly flat bed rest for 4 h before and during study 6. Prestudy sedation with intramuscular diazepam (Valium) (5 mg)
a predictor of the extent of benefit, its value in patients with bilateral renal artery lesions is limited. Since both lesions may be producing RVH, both this method and RVR ratios have reduced validity as predictors of response to operation. Further, the risk of hypertension is more directly related to its severity than to its absolute presence or absence. If one bases the decision for operative management solely on whether or not absolute cure is to be expected, then many patients who would receive the benefit of reduction in severity of hypertension to a mild, easily controlled level would be dropped from consideration as operative candidates. Therefore, this method of RVRA interpretation should be considered only as an additional predictive tool and not an alternative to the evaluation of RVR ratios. We consider a 1.5:1 ratio between the involved and uninvolved sides to be a positive test and, when positive, to have functional proof that the renovascular lesion is causing RVH.
Split Renal Function Studies With the advent of RVRA, most centers have stopped using split renal function studies (SRFS) because of the associated discomfort, possible complications, and confusing results. Valuable information can be obtained from SRFS that is not obtained from RVRA. Information regarding the likelihood of viability and retrievability of a severely ischemic kidney can be acquired from this study. Classically, a positive test shows a 40% reduction in urine volume, a 50% increase in creatinine concentration, and a 100% increase in para-aminohippuric acid concentration on the involved side. Further experience with this test, however, shows that these criteria are much too rigid.[13] We now feel that this test is positive if there is consistent lateralization in each of three samples with a decrease in urine volume and an increase in para-aminohippuric acid and creatinine concentration. When either the RVRA or the SRFS is positive, the diagnosis of renovascular hypertension is established.
TREATMENT OF RENOVASCULAR HYPERTENSION Therapeutic Options Medical Therapy Identification of the optimal method of treating patients with RVH remains an elusive goal. Advocates of drug therapy, operative management, and, more recently, percutaneous transluminal angioplasty (PTA) cite selective data to support their respective views. A majority of the medical community still only evaluate patients for RVH when medications are not tolerated and hypertension remains severe and uncontrolled. The study by Hunt and Strong[14] is the most informative one currently available to assess the comparative value of drug therapy and operation. They compared the results of operative treatment in 100 RVH patients with the results of drug therapy in 114 similar patients. After 7–14 years of follow-up, 84% of the operated group were alive, as compared to 66% in the drug therapy
Chapter 58.
group. Furthermore, of the 84 patients alive in the operated group, 93 were cured or significantly improved, while 16 (21%) of the patients alive in the drug therapy group had required operation for uncontrollable hypertension. Another 7 patients remained uncontrolled without operation. Death during follow-up was twice as common in the medically treated group. These differences were statistically significant ðp , 0:01Þ in both patients with atherosclerotic lesions and those with fibromuscular lesions of the renal artery. Additional information influencing the decision for operative management of RVH in the atherosclerotic patient is the anatomic and renal function changes that occur during drug therapy. Dean et al. reported the results of serial renal function studies performed on 41 patients with RVH secondary to atherosclerotic renal artery disease who had been randomly selected for nonoperative management (Table 58-4).[15] In 19 patients, serum creatinine levels increased between 25 and 120%. The glomerular filtration rates dropped between 25 and 50% in 12 patients; 14 patients (37%) lost more than 10% of renal length; and in 4 patients (12%) a significant stenosis progressed to total occlusion. In addition, 17 patients (41%) had deterioration of renal function or loss of renal size that led to operation, and 1 patient required removal of a previously reconstructible kidney. Of the 17 patients with deterioration, 15 had acceptable blood pressure control during the period of nonoperative observation. Therefore, we feel that progressive deterioration of renal function in nonoperatively treated patients with atherosclerotic renal artery stenosis and RVH is common and occurs even in the presence of blood pressure control with drugs. The detrimental changes that occur during drug therapy and the current excellent results of operative management[16] argue for an aggressive attitude toward renal revascularization in the treatment of RVH. Our indications for operative management of RVH have been outlined in detail elsewhere.[6,17] Nevertheless, in brief, all patients with severe, difficult-to-control hypertension should be considered for operation. This includes patients with complicating factors such as branch lesions and extrarenal vascular disease and patients with associated cardiovascular disease that would be improved by blood pressure reduction. Young patients with moderate hypertension and no complicating diseases who have an easily correctable atherosclerotic or fibromuscular main renal artery stenosis are also candidates for operation. The chance for cure of moderate hypertension is quite good in such patients who have no complicating factors. It remains to be proved that drug control is ever as good as the complete cure of
Table 58-4.
Renovascular Disease
827
hypertension. In fact, one might argue that reduction in the driving pressure of blood flow across the stenosis by successful drug therapy might accelerate deterioration in renal function by further reducing renal perfusion. Finally, there is no clear evidence that age (at least under 60 years), type of lesion (whether atherosclerotic or fibromuscular), duration of hypertension, or the presence of bilateral lesions by themselves have proven value as determinants of operative risk or likelihood of successful operative management.[6] Therefore, they should not be used as deterrents to such management. Certainly the atherosclerotic patient with a 20-year history of easily controlled, mild hypertension who experiences acceleration in severity secondary to the development of renovascular hypertension is unlikely to be cured by operation. We believe, however, that removal of severe, difficult-to-control hypertension by operation with reversion back to a mild, easily controlled variety is equally valuable in reducing the risk of cardiovascular morbid events secondary to hypertension. In addition, risk of operation must be considered when determining the most appropriate therapeutic option. This consideration is of greatest pertinence when both renal and aortic disease must be managed simultaneously. In our center, renal revascularization, when done alone, is associated with a risk of less than 1%. Similarly, elective repair of infrarenal abdominal aortic aneurysms or aortoiliac occlusive disease alone also has an associated operative mortality rate of less than 1%. These risks are in contrast to a 5.3% risk when performing combined aortic and renal procedures. To assess preoperative factors possibly predictive of operative risk for combined procedures, we reviewed the 33 patients who underwent such procedures over an 8-year period.[18] Sixty-one women and 72 men (mean age: 62.5 years) underwent combined aortic repair (AAA: 47 patients; occlusive disease: 86 patients; both: 12 patients) and were compared with consecutive patient groups undergoing aortic reconstruction (269 patients) or renal artery reconstruction alone (182 patients). There were 7 perioperative deaths (5.3%) after combined repair, which differed significantly from isolated aortic and renal artery repair (mortality: 0.74% and 1.65%; p ¼ 0:005). Among survivors in the combined group, a beneficial blood pressure response was observed in 63%, which differed significantly from the group receiving renal artery repair alone (90% benefited; p < 0:001). These differences in perioperative mortality and blood pressure response suggest that aortic and renal artery repair should be combined only for strong clinical indications.
Frequency of Severe Deterioration in Parameters of Renal Function During Drug Therapy, 40 Patients
Parameter Renal length Serum creatinine Glomerular filtration rate or creatinine clearance Total
Patients followed
Mean follow-up, months
Failure event
Number affected
Percent affected
38 41 30
33 25 19
$10% decrease $100% increase $ 50% decrease
14 2 1
37 5 3
17
41
41
828
Part Seven. Visceral Arterial Disease
Finally, management of patients with bilateral disease warrants special comment. When patients have severe bilateral atherosclerotic orificial stenoses, we currently proceed with simultaneous bilateral revascularization even when functional data lateralize to one side. If functional data do not lateralize, we only proceed to operation for bilateral disease when hypertension is severe and difficult to control. Similarly, in these circumstances we will correct both sides. In contrast, if severe fibromuscular dysplasia (FMD) is present bilaterally, we will only revascularize the side to which the functional data lateralize if a branch repair is required. In the absence of lateralization we will only correct the side that appears angiographically to be most severe. This apparent paradox in bias toward unilateral repair of some FMD lesions relates to the increased operative time and small branch repair frequently necessary when managing FMD and the theoretical increase in risk of technical error when managing such branch disease. In any event, if hypertension persists after unilateral repair, functional studies are repeated and contralateral repair is undertaken if the data then lateralize to the uncorrected side.
Percutaneous Transluminal Dilatation Experience with the liberal use of percutaneous transluminal angioplasty has helped to clarify its role as a therapeutic option for treatment of renovascular disease. However, accumulated data argue for its selective application. In this regard, PTA of nonorificial atherosclerotic renal artery lesions and medial fibroplasia of the main renal artery yields results generally comparable to the results of operative repair. By contrast, suboptimal lesions for PTA include congenital lesions, fibrodysplastic lesions of renal artery branches, and ostial atherosclerotic lesions. In each instance, PTA of these lesions is associated with inferior results and increased complications compared with operative repair. In an attempt to improve results of PTA for ostial atherosclerotic lesions, endoluminal stenting has been widely applied. Endoluminal stenting was first introduced in this country in 1988 as part of a multicenter trial.[19] Currently, no stent has been approved for renal use in this country, but the most common indication for their use appears to be (1) elastic recoil immediately after PTA, (2) renal artery dissection after PTA, and (3) restenosis after PTA. With 263 patients entered, results from the multicenter trial demonstrated blood pressure benefit in 61% of patients at one year. In less than 12 months mean follow-up, angiographic restenosis occurred in 32.7% of patients. Table 58-5 summarizes the published series for PTA with endoluminal stents for ostial and nonostial renal artery atherosclerosis.[20 – 32] Overall, immediate technical success is excellent. Cumulative blood pressure benefit was observed in 67% of patients, while renal function was improved in 26% of patients with preoperative renal dysfunction, even though renal function was worsened in 29% as a consequence of intervention. Table 58-6 summarizes PTA with endoluminal stent for only ostial renal artery stenosis.[20 – 32] In this patient group, renal function is improved in only 13% of patients. Although the cumulative reported experience is small, these data suggest that the renal function response after PTA with endoluminal stent is inferior
to surgical repair in patients with ischemic nephropathy and ostial atherosclerosis.
Preoperative Preparation Antihypertensive medications are reduced during the preoperative period to the minimum necessary for blood pressure control. Frequently, patients requiring large doses of multiple medications for control outside the hospital setting will have significantly reduced drug requirements while hospitalized. If continued therapy is required, then nifedipinealpha-methyldopa is the drug of choice. There is little effect on hemodynamics when this agent is combined with anesthesia. We have also commonly continued low-dose propranolol therapy as well without any adverse effects. If the patient’s diastolic blood pressure is 120 –140 mmHg, it is essential that the pressure be brought under control and that operative treatment be postponed until this is accomplished. Recently, if blood pressure has been difficult to control, we have transferred the patient to the intensive care unit where intravenous nitroprusside therapy with continuous intraarterial monitoring of blood pressure is instituted for the 24 hours prior to operation. Similarly, if the patient has a significant history of heart disease, pulmonary artery wedge pressure and cardiac output are monitored to maintain optimal cardiac hemodynamics and recognize and correct adverse changes before they become critically significant.
Operative Techniques A variety of operative techniques have been used to correct renal artery stenoses. From a practical standpoint, two basic operations have been most frequently utilized: aortorenal bypass and thromboendarterectomy. We favor aortorenal bypass for nonorificial lesions, preferably with saphenous vein, and limit endarterectomy to orificial lesions of accessory renal arteries or to the patient with severe bilateral orificial stenoses. Uncommonly, the renal artery will be redundant after it has been circumferentially mobilized. In such patients with orificial lesions, renal artery reimplantation also has been used with gratifying results (Fig. 58-1). Certain measures and maneuvers are applicable in almost all renal arterial operations. Mannitol, 12.5 g, is administered intravenously early in the operation. Just prior to renal artery cross clamping, heparin, 75 mg or 7500 units, is given intravenously. Protamine is occasionally required for reversal of the heparin at the end of the reconstruction. Exposure of the renal arteries is the most difficult yet important aspect of renal artery surgery. A midline xiphoidto-pubis incision provides excellent access to either renal artery. To expose the left renal artery, the posterior peritoneum overlying the aorta is incised longitudinally, the duodenum is mobilized to the patient’s right, and the left renal vein dissected out and mobilized (Fig. 58-2). By extending the posterior peritoneal incision to the left along the inferior border of the pancreas, an avascular plane behind the pancreas can be entered. The inferior mesenteric vein courses obliquely through the left peritoneal area. This vein is often ligated and divided to facilitate this exposure. (When this is done, one must be certain that an ascending
Palmaz Wallstent Strecker Wallstent Wallstent Wallstent Palmaz Palmaz Palmaz Palmaz Palmaz Palmaz Palmaz Total
n/r: not reported.
28 11 10 11 15 15 28 24 76 59 32 68 33 410
Stent type
96 80 80 91 100 100 100 100 100 100 100 100 100 98
Technical success (%) 14 n/r n/r 4 6 7 16 n/r 29 10 32 20 17 155
Patients with renal dysfunction 36 0 n/r 50 20 0 25 33 28 20 35 0 41 26
Improve
35 100 35 45
58 28
36 91 n/r 50 40 43
Unchanged
80
75
29 0 24 29
8 45
29 9 n/r 0 40 57
Worsened
Function response after successful angioplasty (%)
PTA with Renal Artery Stent Placement for Atherosclerotic Renal Artery Stenosis
Patients (n )
Table 58-5.
11 30 29 27 7 7 0 0 6 18 n/r 16 6 11
Cure 54 40 43 64 93 43 40 73 46 57 n/r 62 61 56
Improve
36 30 29 9 0 50 60 27 48 24 n/r 22 33 33
Failed
HTN response after successful angioplasty (%)
18 18 20 13 19 13 19 13 11 3 19 0 21 11
Major complications (%)
39 29 20 18 27 13 17 13 25 9 13 17 0 18
Restenosis (%)
20 21 22 23 24 25 26 27 28 29 30 31 32
Ref.
Chapter 58. Renovascular Disease 829
Part Seven. Visceral Arterial Disease
830 Table 58-6.
PTA with Renal Artery Stent Placement for Ostial Atherosclerotic Renal Artery Stenosis Function response (%)
HTN response (%)
Patients with ostial lesions (patients)
Patients with renal dysfunction
Improved
Unchanged
Worsened
Cured
Improved
Failed
Restenosis (%)
28 7 4 22 24 68 153
14 2 3 13 n/r 20 52
36 0 0 15 33 0 13
36 50 33
29 50 67
11 0 0 0 0 16 9
54 100 50 31 73 62 59
36 0 50 69 27 22 32
39 43 33 20 13 17 23
Total
85 58 100 73
8 0 14
Ref. 20 24 25 26 27 31
n/r: not reported.
branch of the inferior mesenteric artery is not accompanying the vein. Ligation of such an ascending arterial branch may compromise colonic perfusion if visceral artery atherosclerotic occlusions are present.) This allows excellent exposure of the entire renal hilum on the left and is of special significance when distal lesions are to be managed. The artery lies behind the left renal vein. In some cases, it is easier to retract the vein cephalad in order to expose the artery. In others, caudal retraction of the vein provides better access. Usually, the gonadal vein and adrenal vein which enter the renal vein have to be ligated and divided to facilitate exposure of the artery. Another
frequent tributary is a lumbar vein which enters the posterior wall of the left renal vein and is easily avulsed unless special care is taken in mobilizing the renal vein. The proximal right renal artery can be exposed through the same retroperitoneal exposure at the base of the mesentery by ligating two or more pairs of lumbar veins and retracting the vena cava to the patient’s right and the left renal vein cephalad. Usually, however, the right renal artery is best exposed by mobilizing the duodenum and right colon medially. The right renal vein is mobilized and usually retracted cephalad in order to expose the artery. In some patients, there is an accessory right renal artery which arises
Figure 58-1. Preoperative and postoperative arteriograms in a 5-year-old child who underwent right renal artery reimplantation.
Chapter 58.
Renovascular Disease
831
long, it may result in kinking of the vein and subsequent thrombosis. If there is any element of kinking or twisting of the graft after both anastomoses are completed, the aortic anastomosis should be taken down and redone after appropriate shortening or reorientation of the graft. In certain instances, an end-to-end anastomosis between the graft and the renal artery provides a better reconstruction. Fry et al.[33] prefer the end-to-end anastomosis. We routinely employ endto-end renal artery anastomosis when combining aortic replacement with renal revascularization and in patients with total renal artery occlusions. In combined aortic and renal reconstructions, the saphenous vein is attached to the Dacron aortic graft prior to its insertion. After the aortic graft is attached and flow is restored to the distal extremities, the renal artery can be resected and attached to the end of the saphenous vein graft without interrupting aortic flow.
Thromboendarterectomy Figure 58-2. Exposure of the retroperitoneum through the base of the mesentery.
from the anterior wall of the aorta about 1 in. above the origin of the inferior mesenteric artery. This artery is unusual in that its course is anterior to the vena cava and then over to the lower pole of the right kidney instead of the retrocaval course of the normal right renal artery. The accessory artery can easily be injured if one is unaware of its presence.
Aortorenal Bypass Three types of graft are usually available for aortorenal bypass: (1) autologous saphenous vein, (2) autologous hypogastric artery, and (3) synthetic prosthesis. The decision as to which graft should be used depends on a number of factors. We use the saphenous vein preferentially. However, if it is small—less than 4 mm in diameter—the hypogastric artery or a synthetic prosthesis may be preferable. A 6-mm polytetrafluoroethylene graft is quite satisfactory when the distal renal artery is of large caliber. When an end-to-side renal artery bypass is used, the anastomosis between the renal artery and the graft is done first. Silastic slings can be used to occlude the renal artery distally. This method of vessel occlusion is especially applicable to this procedure. In contrast to vascular clamps, these slings are essentially atraumatic to the delicate renal artery. The absence of clamps in the operative field is also advantageous. Further, when tension is applied to the slings, they lift the vessel out of the retroperitoneal soft tissue for more accurate visualization. The length of the arteriotomy should be at least three times the diameter of the renal artery to guard against late suture line stenosis. A 6-0 or 7-0 monofilament polypropylene (Prolene) suture material is employed with loop magnification. After the renal artery anastomosis is completed, the occluding clamps and slings are removed from the artery and a small bulldog clamp is placed across the vein graft adjacent to the anastomosis. The aortic anastomosis is then done. First, an ellipse of the anterolateral aortic wall is removed, and then the anastomosis is performed. If the length of the graft is too
This procedure is employed only for atherosclerotic renal artery stenosis. It is not applicable in fibromuscular disease. Transaortic endarterectomy of bilateral main renal artery lesions has been strongly advocated by Wylie et al.[34] In this procedure, the proximal aortic clamp must usually be placed above the superior mesenteric artery. If it is placed below this artery, it will seriously compromise the exposure of the orifices of the renal arteries. Visualization of the distal end of the renal artery endarterectomy, however, is often difficult or impossible with this procedure. Because of this, we currently prefer a transverse aortotomy carrying the incision across the stenoses and into each renal artery. By this method, the entire endarterectomy can be performed under direct vision (Fig. 58-3).
Nephrectomy Nephrectomy is a procedure that should be limited to a subgroup of patients with RVH in whom the kidney
Figure 58-3. Drawing of arteriotomy for bilateral renal artery thromboendarterectomies.
832
Part Seven. Visceral Arterial Disease
responsible for the hypertension has nonreconstructible vessels and has negligible or no residual excretory function. In these circumstances of unretrievable renal function, nephrectomy can provide benefit in control of hypertension while not diminishing overall excretory function. In all other circumstances in which there is significant residual excretory renal function, the price of nephrectomy (loss of functioning renal mass) is greater than the potential benefit. Exception to this rule occurs only when hypertension is uncontrollable on maximal drug therapy and residual pressures consistently are severely elevated (. 120 mmHg). This extreme conservatism for the role of nephrectomy is based on the knowledge that greater than 35% of patients with atherosclerotic lesions will develop contralateral severe lesions during follow-up. Such lesions will place such a patient at risk for clinically severe renal failure and recurrent hypertension. This is of even greater importance in children: 50% of those who initially present with a unilateral lesion subsequently will develop contralateral disease.
Postoperative Care The patient is usually kept in the surgical intensive care unit for 2 or 3 days. Body weight is measured daily. Central venous pressure is monitored, as is hourly output. These measurements are used to gauge fluid balance. Long-standing hypertension usually results in some degree of cardiac compromise. Congestive failure or pulmonary edema as the result of fluid overload is a frequent occurrence in the poorly monitored patient. Elastic stockings, leg exercise, subcutaneous miniheparin, and early ambulation are used to avoid thromboembolic complications. Postoperative hypotension is usually the result of inadequate blood replacement. Severe hypertension is commonly encountered and is treated with antihypertensive medications. Fifty percent of the patients who are eventually classified as cured require antihypertensive drugs for several weeks or months postoperatively. If there is rapid acceleration of the hypertension in the postoperative period, thrombosis of the renal artery reconstruction should be suspected and an arteriogram obtained. Even though a bypass graft may have thrombosed, the distal renal artery may remain patent and a second reconstruction may be feasible.
During the period 1987 –1997, we undertook operative management in 534 patients. Operative risk has been low, with only 18 patients (3.4%) dying as a result of renal revascularization. Technical success also has been highly predictable. Based on the results of routine postoperative renal duplex sonography, 97% of patients have had a patent reconstruction without technical errors. Blood pressure response to operation is dependent on three factors: the preoperative documentation of the causal relationship between renal artery stenosis and the hypertension, the technical success of renal revascularization, and the underlying disease. We insist that the results of RVRA or SRFS confirm the presence of RVH before intervention for unilateral renal artery disease. Having identified the functional significance of the renovascular lesion preoperatively, a benefical blood pressure response has been achieved in 90% of patients undergoing successful operation in our center. Although significant improvement in the severity of hypertension is predictably high, regardless of the underlying pathology, patients with FMD have a much higher chance of a total cure of hypertension than do patients with atherosclerosis as the source of renovascular disease (43 versus 14%). Many patients with atherosclerotic lesions have a background of previous mild essential hypertension, and most such patients have microscopic evidence of arteriolar nephrosclerosis. These factors frequently limit the likelihood of cure by renal revascularization but do not prevent improvement by reduction of severe, difficult-to-control hypertension to a mild variety easily controlled with minimal medications. Since the risk of morbid cardiovascular events secondary to hypertension is severity-related, we feel that such a reduction in the severity of hypertension in the majority of atherosclerotic patients (90%) provides protection against adverse cardiovascular events.
EFFECT OF RENAL REVASCULARIZATION ON RENAL FUNCTION Absent from most discussions of the management of RVH is the long-term adverse effect of uncorrected renal artery Table 58-7. Early Results of Operation, 1987–1997 (534
EFFECT OF OPERATION ON HYPERTENSION
patients)
Most of the controversy surrounding the role of the operative treatment of RVH relates to the risk of operation, an unacceptable frequency of technical failures, and a low rate of favorable blood pressure response to operation. Certainly the literature adequately documents the fact that poorly performed operations in poorly selected patients will result in an infrequent favorable blood pressure response. Current results of operative intervention in centers experienced with management of RVH, however, underscore the predictability of success. Although our experience spans over 20 years and includes the operative management of over 600 patients, a recent 10-year period (Table 58-7) exemplifies current expectations.
Technical success Operative mortality rate 3.4 Graft stenosis 1.6 Graft occlusion 1.6 Beneficial blood pressure response (cure or improved) Cure Atherosclerosis 14 FMD 43 Improved Atherosclerosis 76 FMD 47
Result
Percent 97
90
Chapter 58.
occlusions on renal perfusion and excretory function. The term ischemic nephropathy describes the relationship between occlusive disease of the main renal artery and excretory renal insufficiency. Since renal artery occlusions can produce both secondary hypertension and alterations in renal function, proper treatment of patients with RVH also requires understanding of the natural history of changes in renal function during nonoperative treatment and the effect of revascularization on renal function. If one considers that changes in renal function during follow-up may be independent of, or even adversely affected by, druginduced blood pressure reduction, knowledge of the probability of stability or deterioration in excretory function during nonoperative treatment is of even greater importance. In contrast to the detrimental changes in renal function that may occur during drug therapy in many patients with renovascular hypertension is the response in renal function to revascularization of the poorly functioning kidney. Through the routine use of preoperative SRFS, we have been able to compare individual kidney excretory function before and after revascularization. No change in excretory function after revascularization has been seen in kidneys with creatinine clearances greater than 30 mL/min.[35] Conversely, however, we have demonstrated a statistically significant improvement in excretory function after revascularization of kidneys with less than 20 mL/min creatinine clearances. Table 58-8 summarizes the preoperative and postoperative SRFS in 25 patients who underwent successful revascularization of kidneys with less than 30 mL/min creatinine clearance.[36] The type of renal artery lesion was atherosclerotic in 21 patients and fibromuscular dysplastie in 4 patients. Eight individuals had total renal artery occlusion. Preoperative creatinine clearances in the affected kidneys ranged from 0.27 to 30 mL/min (mean: 16 ^ 16 mL=min). Fifteen of the 16 kidneys with preoperative creatinine clearances less than 20 mL/min had improvement in renal function following revascularization ðp , 0:01Þ: Improvement (60%) or cure (36%) in hypertension followed revascularization in 24 of the 25 patients. The most dependable predictor of successful management of both hypertension and retrieval of renal function in these patients was the arteriographic demonstration of a patent distal vessel without evidence of severe intrarenal stenoses. This experience has led us to employ renal revascularization rather than nephrectomy whenever the distal artery is visualized and reasonably free of severe branch artery disease, regardless of the degree of
Table 58-8.
Renovascular Disease
833
excretory renal function impairment or the status of the contralateral renal artery. Obviously, this approach would have greatest application when contralateral renal function is reduced or contralateral renal artery disease is present. Nevertheless, since progression of apparently insignificant contralatral lesions or the development of new lesions during follow-up occurs in over 40% of patients undergoing operative management of renovascular hypertension, concern about protection of renal function should not be limited to patients with severe contralateral disease at the time of the initial evaluation. Indeed, if renal function in the poorly functioning kidney is retrievable by revascularization, then nephrectomy would be an inferior choice of operative management, regardless of the status of the contralateral kidney. Such an aggressive attitude toward the role of revascularization in managing these patients with renovascular hypertension requires that both the operative risk and the frequency of graft thrombosis be low. Nevertheless, enthusiasm for revascularization of poorly functioning kidneys in older patients must be weighed against the operative risk when severe associated cardiovascular disease is present. Currently, however, nephrectomy is employed primarily only when intrarenal disease is severe, hypertension is otherwise difficult to control, and residual excretory function in the affected kidney is negligible. Finally, the role of renal revascularization in severely azotemic patients requires special comment. Obviously, retrieval of renal function by revascularization is of greatest practical importance in this group. We have performed renal revascularization for 37 patients who were considered permanently dialysis-dependent. Thirty of 37 patients have been permanently removed from dialysis after operation. Analysis of the first 20 patients indicated that a rapid rate of decline in renal function prior to surgery and bilateral or global renovascular disease predicted retrieval of renal function.[37,38] Our experience argues that there are several variables that have value as predictors of retrieval of renal function in this group. The finding of bilateral renal artery total occlusions with visualization of normal distal renal arteries in a patient with severe hypertension and rapidly declining renal function predicts a high probability of renal function retrieval by revascularization. In contrast, unilateral renal artery occlusive disease, stenotic lesions of the renal artery branches, and a long, slow rate of decline in renal function are strong predictors that no benefit in renal function will be achieved by revascularization.
Effect of Revascularization on Excretory Function Preoperative creatinine clearance groups
Preoperative creatinine clearance Postoperative creatinine clearance Significance of difference
0 – 10 mL/min 7 Patients
11– 20 mL/min 9 Patients
21– 30 mL/min 9 Patients
3 ^ 2.4 mL/min 37 ^ 27 mL/min p , 0.02
16 ^ 2.9 mL/min 32 ^ 8.3 mL/min p , 0.01
25 ^ 1.9 mL/min 30 ^ 1.9 mL/min p . 0.5
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LATE FOLLOW-UP OF RECONSTRUCTIONS
Table 58-9. Sequential 1- to 14-Year Follow-Up Arteriography, 176 Reconstructions Status
Although our angiographic follow-up of renal reconstructions now extends beyond 23 years in some patients, our 1- to 14-year follow-up sequential angiography of 176 reconstructions remains representative (Table 58-9). Four saphenous vein grafts and two hypogastric autografts underwent aneurysmal dilatation. Only one of these, a hypogastric autograft, has required replacement (Fig. 58-4). The remaining five have stabilized, and the patients have remained cured of hypertension. Aneurysmal dilatation of autogenous grafts (vein or artery) has occurred only in children in our experience. Although the incidence of aneurysmal degeneration is low in our overall experience, all occurred in children, which suggests that the saphenous vein is particularly susceptible to this phenomenon in this age group. For this reason we prefer the normal hypogastric artery as the conduit of choice in this group. Interestingly, in the two instances of autogenous arterial graft aneurysmal degeneration, FMD of the donor hypogastric artery was identified in retrospective microscopic evaluation. Eight grafts have developed suture line or midgraft stenoses (Fig. 58-5) requiring revision from 1 to 8 years after the initial operation. Three patients have had graft occlusions during follow-up and probably represent missed graft stenoses which progressed to occlusion. One patient required correction of an aortic anastomotic false aneurysm in a Dacron graft 8 years postoperatively. The remaining 159 grafts (90%) have had no untoward changes with continued patency of the reconstruction during follow-up (Fig. 58-6). Follow-up angiography also has shown progression of mild to moderate contralateral renovascular disease in 38% of the patients. This is most important in children, where 7 of 15 with FMD had bilateral involvement.[5] Only 3 of these 7 children had the contralateral disease demonstrated at the time of the initial evaluation and
No adverse change Aneurysmal dilatation Stenosis Occlusion False aneurysm
No. of grafts
Percent
139 6 8 2 1
90 3 5 1 ,1
operation. The remaining 4 children had documentation of the development and progression of contralateral disease subsequently. This occurrence of subsequent contralateral stenosis led us to perform nephrectomy in children only if blood pressure is uncontrollable and revascularization is impossible. Since the longest followup in this group is only 10 years, the true incidence of subsequent contralateral disease requires additional longitudinal follow-up. In our last 534 patients, 20 failed repairs were equally divided between thrombosis and stenosis in 24 patients.[38] Although primary and secondary blood pressure responses were equivalent (94% versus 95% cured or improved), eventual renal function was significantly worsened ðp ¼ 0:015Þ; with 7 patients dependent on dialysis on follow-up. Considering all 534 patients, failed renal artery repair demonstrated a significant and independent association with eventual dialysis dependence and decreased dialysis-free survival. In summary, current experience with operation and PTA in respective centers devoted to their use suggests that both modalities can be performed safely and that both are initially successful methods of treating RVH. The occasional use of either modality, however, cannot be expected to produce the results reviewed in this discussion. Since control of hypertension by renal revascularization is most commonly employed for its long-term benefit in reducing associated risk
Figure 58-4. Sequential follow-up arteriogram of a 10-year-old child who underwent a hypogastric autograft to the left renal artery and an iliac vein autograft to the superior mesenteric artery. Ultimately, both grafts required replacements. (A ) Preoperative, 1970; (B ) postoperative, 1970; (C ) postoperative, 1973.
Chapter 58.
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Figure 58-5. Angiogram and corresponding renal duplex spectral analysis demonstrating significant stenosis associated with a sclerotic venous valve before (A ) and after (B ) initially successful balloon angioplasty (PTA). Hypertension and restenosis occurred 8 months after PTA and was treated by patch angioplasty.
factors, interventional therapy (operation or PTA) should provide a durable, long-term result. Although available data strongly support the role of operative management as a permanent method of renal revascularization and resolution
of renal ischemia, PTA appears to be a method that achieves only temporary benefit in many patients with atherosclerotic lesions. Certainly, such a technique may play an important role in a subgroup of high-risk patients in whom short-term
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Figure 58-6. Sequential follow-up arteriograms after autogenous vein aortorenal bypass showing its long-term durability: (A ) 1 year, (B ) 4 years, (C ) 9 years.
improvement is an acceptable goal of management. Its position among available therapeutic options, however, remains incompletely defined at this time. With this
background, the enthusiasm for PTA as a standard mode of treatment and its current widespread use appear to be premature.
REFERENCES 1.
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7.
Tucker, R.M.; Labarthe, D.R. Frequency of Surgical Treatment for Hypertension in Adults at the Mayo Clinic from 1973 Through 1975. Mayo. Clin. Proc. 1977, 52, 549. Shapiro, A.P.; Perez-Stable, E.; Scheib, E.T.; et al. Renal Artery Stenosis and Hypertension. Am. J. Med. 1969, 47, 175. Hollifield, J.W., Unpublished Data. Davis, B.A.; Crook, J.E.; Vestal, R.E.; Oates, J.A. Prevalence of Renovascular Hypertension in Patients with Grade III or IV Hypertensive Retinopathy. N. Engl. J. Med. 1979, 301, 1273. Lawson, J.D.; Boerth, R.K.; Foster, J.H.; et al. Diagnosis and Management of Renovascular Hypertension in Children. Arch. Surg. 1977, 112, 1307. Robaczewski, D.L.; Dean, R.H. Basic Science of Renovascular Hypertension. In The Basic Science of Vascular Disease; Sidawy, A.N., Sumpio, B.E., DePalma, R.B., Eds.; Futura Publishing Inc.: Armonk, New York, 1997; 691– 721. Hansen, K.J.; Starr, S.M.; Burkart, J.M.; Plonk, G.W.; Dean, R.H. Contemporary Surgical Management of Renovascular Disease. J. Vasc. Surg. 1992, 16, 319.
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Dean, R.H. Renal Artery Repair—Errors in Patient Selection and Evaluation. In Complications in Vascular Surgery; Bernhard, V.M., Towne, J.B., Eds.; Grune & Stratton: New York, 1980; 167 – 210. Hansen, K.J.; Tribble, R.W.; Reavis, S.W.; Canzanello, V.J.; Craven, T.E.; Plonk, G.W.; Dean, R.H. Renal Duplex Sonography: Evaluation of Clinical Utility. J. Vasc. Surg. 1990, 12, 227. Dean, R.H.; Burko, H.; Wilson, J.P.; Mulherin, J.H.; Foster, J.H. Deceptive Patterns of Renal Artery Stenosis. Surgery 1974, 76, 872. Vaughn, E.D.; Buhler, F.R.; Larach, J.H.; et al. Renovascular Hypertension: Renin Measurements to Indicate Hypersecretion and Contralateral Suppression, Estimate Renal Plasma Flow, and Score for Surgical Curability. Am. J. Med. 1973, 55, 402. Stanley, J.C.; Fry, W.J. Surgical Treatment of Renovascular Hypertension. Arch. Surg. 1977, 112, 1291. Davidson, J.; Lowe, B.; Dean, R.H.; Rhamy, R.K. Variability of Split Renal Function Studies in Essential and Renovascular Hypertension. Surg. Forum 1979, 30, 574.
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Hunt, J.C.; Strong, C.G. Renovascular Hypertension. Mechanisms, Natural History and Treatment. Am. J. Cardiol. 1973, 32, 562. Dean, R.H.; Kieffer, R.W.; Smith, B.M.; et al. Renovascular Hypertension. Arch. Surg. 1981, 116, 1408. Dean, R.H. Operative Management of Renovascular Hypertension. In Surgery of the Aorta and Its Body Branches; Bergan, J.J., Yao, J.S.T., Eds.; Grune & Stratton: Philadelphia, PA, 1979. Cherr, G.S., Hansen, K.J., Craven, T.E., Edwards, M.S., Ligush, J., Levy, P.J., Freedman, B.I. and Dean, R.H. Surgical management of atherosclerotic renovascular disease. J. Vasc. surg. 2002;35:236 – 245. Benjamin, M.E.; Hansen, K.J.; Craven, T.E.; Keith, D.R.; Plonk, G.W.; Geary, R.L.; Dean, R.H. Combined Aortic and Renal Artery Surgery: A Contemporary Experience. Ann. Surg. 1996, 233, 555. Rees, C.R. Renovascular Interventions. 21st Annual Meeting of the Society of Cardiovascular and Interventional Radiology, Seattle, Washington, March 1996; p 311. Rees, C.R.; Palmaz, J.C.; Becker, G.J.; et al. Palmaz Stent in Atherosclerotic Stenosis Involving the Ostia of the Renal Arteries: Preliminary Report of a Multicenter Study. Interv. Radiol. 1991, 181, 507. Wilms, G.E.; Peene, P.T.; Baert, A.L.; et al. Renal Artery Stent Placement with Use of the Wallstent Endoprosthesis. Radiology 1991, 179, 457. Kuhn, F.P.; Kutkuhn, B.; Torsello, G.; Modder, U. Renal Artery Stenosis: Preliminary Results of Treatment with the Strecker Stent. Radiology 1991, 180, 367. Joffre, F.; Rousseau, H.; Bernadet, P.; et al. Midterm Results of Renal Artery Stenting. Cardiovasc. Interv. Radiol. 1992, 15, 313. Hennequin, L.M.; Joffre, F.G.; Rousseau, H.P.; et al. Renal Artery Stent Placement: Long Term Results with the Wallstent Endoprosthesis. Radiology 1994, 191, 713. Raynaud, A.C.; Beyssen, B.M.; Turmel-Rodrigues, L.E.; et al. Renal Artery Stent Placement: Immediate and Midterm Technical and Clinical Results. J. Vasc. Interv. Radiol. 1994, 5, 849. MacLeod, M.; Taylor, A.D.; Baxter, G.; et al. Renal Artery Stenosis Managed by Palmaz Stent Insertion: Technical and Clinical Outcome. J. Hypertens. 1995, 13, 1791.
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Van de Ven, P.J.G.; Beutler, J.J.; Kaatee, R.; et al. Transluminal Vascular Stent for Ostial Atherosclerotic Renal Artery Stenosis. Lancet 1995, 346, 672. Dorros, G.; Jaff, M.; Jain, A.; Dufek, C.; Mathiak, L. Follow-Up of Primary Palmaz-Schatz Stent Placement for Atherosclerotic Renal Artery Stenosis. Am. J. Cardiol. 1995, 75, 1051. Henry, M.; Amor, M.; Henry, I.; et al. Stent Placement in the Renal Artery: Three-year Experience with the Palmaz Stent. J. Vasc. Interv. Radiol. 1996, 7, 343. Harden, P.N.; MacLoed, M.J.; Rodger, R.S.C.; et al. Effect of Renal Artery Stenting on Progression of Renovascular Renal Failure. Lancet 1997, 249, 1133. Blum, U.; Krumme, B.; Flugel, P.; et al. Treatment of Osteal Renal Artery Stenosis with Vascular Endoprostheses After Unsuccessful Balloon Angioplasty. N. Engl. J. Med. 1997, 336, 459. Boisclar, C.; Therasse, E.; Oliva, V.L.; et al. Treatment of Renal Artery Angioplasty Failure by Percutaneous Renal Artery Stenting with Palmaz Stents: Midterm Technical and Clinical Results. Am. J. Radial. 1997, 168, 245. Fry, W.J.; Brink, B.E.; Thompson, N.W. New Techniques in the Treatment of Extensive Fibromuscular Disease Involving the Renal Arteries. Surgery 1970, 68, 959. Wylie, E.J.; Perloff, D.L.; Stoney, R.J. Autogenous Tissue Revascularization Techniques in Surgery for Renovascular Hypertension. Ann. Surg. 1969, 170, 416. Dean, R.H.; Shack, R.B.; Rhamy, R.K.; Wilson, J.P.; Foster, J.H. The Effect of Renal Revascularization on Kidney Function. J. Surg. Res. 1977, 22, 443. Dean, R.H.; Lawson, J.D.; Hollifield, J.W.; et al. Revascularization of the Poorly Functioning Kidney. Surgery 1979, 85, 44. Hansen, K.J.; Thomason, R.B.; Craven, T.E.; Fuller, S.B.; Keith, D.R.; Appel, R.G.; Dean, R.H. Surgical Management of Dialysis-Dependent Ischemic Nephropathy. J. Vasc. Surg. 1995, 21, 197. Hansen, K.J.; Cherr, G.S.; Craven, T.E.; Motew, S.J.; Travis, J.A.; Wong, J.M.; Levy, P.J.; Freedman, B.I.; Ligush, J.; Dean, R.H. Management of ischemic nephropathy: dialysis-free survival after surgical repair. J. Vasc. Surg. 2000;32:472– 482. Hansen, K.J.; Deitch, J.S.; Oskin, T.C.; Ligush, J.; Craven, T.E.; Dean, R.H. Renal Artery Repair: Consequence of Operative Failures. Ann. Surg. 1998, 227, 678.
CHAPTER 59
Acute Mesenteric Vascular Disease Ronald Nathaniel Kaleya Scott J. Boley resulting from local atherosclerotic emboli or vasculitides. Acute mesenteric venous thrombosis (AMVT) and FSI caused by strangulation obstruction of the small intestine or by localized venous thrombosis comprise the venous forms of AMI.
During the past 40 years there has been increasing recognition of the importance and frequency of intestinal ischemia. In part this is because of a real increase in its incidence; more importantly, it is the result of the belated realization that many clinical manifestations have as their common etiology interference with intestinal blood flow. Abrupt interruption or dimunition of blood flow to the small intestine or the right colon leads to acute mesenteric ischemia (AMI). The term AMI actually describes a wide spectrum of bowel injury ranging from reversible alterations in bowel function to transmural necrosis of the bowel wall. Depending on the degree and duration of the ischemia as well as the length of bowel involved, a variety of clinical presentations are observed. Clinical and animal research has provided a better understanding of the clinical syndromes and pathophysiological basis of AMI and has led to the development of an effective multidisciplinary approach to the patient with suspected acute mesenteric vascular diseases. Acute intestinal ischemia is especially important to vascular surgeons not only as a primary clinical problem but also because it frequently complicates other vascular conditions and operations. Examples are the occurrence of colonic ischemia after aortic aneurysmectomy or aortoiliac reconstruction and the common association of superior mesenteric and peripheral arterial emboli. Mesenteric ischemia can be broadly classified into acute and chronic forms and into conditions of venous or arterial origin (Fig. 59-1). In the chronic forms, the viability of the bowel is not compromised, but the blood flow is inadequate to support the functional demands of the intestine, while with the acute forms, intestinal viability is threatened. Atherosclerotic narrowing or occlusion of the mesenteric arteries, producing intestinal angina, and gradually evolving mesenteric venous thrombosis are the common forms of chronic ischemia. Acute mesenteric ischemia is much more common than chronic, and ischemia of arterial origin is much more frequent than venous disease. The arterial forms of AMI include superior mesenteric arterial embolus (SMAE), nonocclusive mesenteric ischemia (NOMI), superior mesenteric artery thrombosis (SMAT), and those cases of focal segmental ischemia (FSI)
ACUTE MESENTERIC ISCHEMIA In spite of the great interest focused on acute mesenteric ischemia and the tremendous advances in roentgenologic and surgical techniques, the lethality of this intraabdominal catastrophe has with few exceptions remained as high[1,2] as in 1933, when Hibbard[3] reportedly a mortality rate of 70 percent. This lack of improvement can be attributed to three main factors: (1) failure to diagnose ischemia before intestinal gangrene occurs, (2) the progression of bowel infarction after the primary vascular or patients with nonocclusive mesenteric ischemia with its reported mortality rate of over 90%.
Historical Background The first description of mesenteric thrombosis is attributed to Antonio Beniviene of Florence in the fifteenth century, but Tiedenman’s clinical case report in 1843 first stimulated interest in this problem. The first successful bowel resection for intestinal infarction was reported by Elliott in 1895. In 1906 Delbet suggested the possibility of revascularization for superior mesenteric artery (SMA) obstruction. Although Ryvlyn in 1943 and Blinov in 1950 described patients in whom SMA embolectomy was unsuccessfully attempted,[4] Klass is generally credited with establishing the feasibility of this operation. In 1951 he described two patients who underwent successful embolectomy but died of cardiac causes postoperatively.[5] One year later Stewart performed the first SMA embolectomy with survival.[6] Successful operative approaches to acute SMA thrombosis as well as chronic mesenteric ischemia were reported in the 1950s. Ende in 1958 first described nonocclusive mesenteric ischemia
Hobson/Wilson/Veith: Vascular Surgery: Principles and Practice, Third Edition, Revised and Expanded DOI: 10.1081/0819-9-120024943 Copyright q 2004 by Marcel Dekker, Inc.
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(NOMI), and during the 1960s various attempts to treat this condition using local and regional anesthetic blocks as well as systemic and intraarterial vasodilator were reported.
Patient Population The exact incidence of AMI is difficult to determine, but in our large metropolitan medical center AMI is responsible for approximately 0.1% of all admissions. An increasing incidence has been attributed to the aging of the population, since AMI occurs predominantly, but not exclusively, in geriatric patients, especially those with significant cardiovascular and systemic disorders. Similarly, the widespread use of coronary and surgical intensive care units and other extraordinary means of cardiopulmonary support has salvaged patients who previously died rapidly of cardiovascular conditions, only to have them go on to develop AMI as a later consequence of their primary disease. Together, superior mesenteric arterial emboli and nonocclusive mesenteric ischemia are responsible for 70 – 80% of cases of acute mesenteric ischemia as reported in most recent series. A decline in the incidence of nonocclusive ischemia has been noted, possibly due to the increasing use of systemic vasodilators, such as the calcium channel blocking agents and nitrates, in coronary intensive care units. These agents may protect the mesenteric vascular beds from vasospasm and decrease the period of profound hypotension associated with acute myocardial events. In addition, the more common use of left ventricular assist devices in the treatment of cardiogenic shock has decreased the period of profound hypotension associated with left ventricular failure and, presumably, has attenuated its affect on the mesenteric circulation.
Specific Types of Acute Mesenteric Ischemia Arterial Causes Superior mesenteric artery emboli are responsible for 40–50% of episodes of acute mesenteric ischemia. The emboli usually originate from a left atrial or ventricular mural thrombus. The thrombus embolizes after being dislodged or fragmented during a period of an arrhythmia. Many patients with SMAE have a history of previous peripheral artery embolism, and approximately 20% have synchronous emboli in other arteries. Emboli to the superior mesenteric artery tend to lodge at points of normal anatomical narrowing, usually immediately distal to the origin of a major branch. In 10 – 15% of patients the emboli lodge peripherally in branches of the SMA, or in the SMA itself distal to the origin of the ileocolic artery. The embolus may completely occlude the arterial lumen, but often only partially occludes the vessel. Experimental studies suggest that initially the collateral circulation is adequate to maintain intestinal viability following most acute SMA occlusions, but after a period of partial occlusion and diminution of blood flow distal to the embolus, vasoconstriction develops in arteries both proximal and distal to the embolus. This vasoconstriction can
Figure 59-1.
Causes of mesenteric ischemia.
sufficiently impair the collateral blood flow to the SMA and its branches distal to the embolus to cause or exacerbate an ischemic injury. Nonocclusive mesenteric ischemia causes 20 –30% of episodes of AMI and is thought to result from splanchnic vasoconstriction initiated by period of decreased cardiac output associated with hypotension caused by arrhythmias, cardiogenic shock, hypovolemic shock, or vasoactive medications. The vasoconstriction may persist even after the precipitating cause has been eliminated or corrected. Predisposing factors for NOMI include acute myocardial infarction, congestive heart failure, aortic insufficiency, hepatic diseases, renal diseases, especially in patients requiring hemodialysis,[7,8] and major cardiac or intraabdominal operations. Frequently, a more immediate precipitating cause such as acute pulmonary edema, cardiac arrhythmia, or shock is present, although the consequent intestinal ischemia may not become manifest until hours or days later. Superior mesenteric artery thrombosis occurs at areas of severe atherosclerotic narrowing, most often at the origin of the SMA. The acute ischemic episode is commonly superimposed on chronic mesenteric ischemia, hence approximately 20 –50% of these patients have a history of abdominal pain with or without evidence of malabsorption and weight loss during the weeks to months preceding the acute episode. Additionally, most patients with SMAT have severe and diffuse atherosclerosis with a prior history of coronary, cerebrovascular, or peripheral arterial insufficiency.
Venous Causes Approximately 2 patients per 100,000 admissions to our institution have had operative or pathological confirmation of mesenteric venous thrombosis (MVT). This represents less than 5% of all cases of AMI. While a review of the literature suggests a male predilection of up to 1.5:1,[9,10] a review of our experience showed no such preference. In the literature, the mean age was 48 years, whereas it was 60 years at our institution. We have attributed these differences to the higher proportion of geriatric patients seen at our medical center as compared to most other institutions.
Chapter 59.
Although many conditions have been associated with MVT (Table 59-1), in older studies up to 55% of patients were thought to have no etiologic factor. However, in more recent reports contributing disorders are identified in up to 81% of patients.[11] This discrepancy can be explained by the fact that many of the cases in retrospective reviews occurred before new conditions such as antithrombin III, protein S and protein C deficiencies, and activated protein C resistance had been described.[12] It can be expected, therefore, that with increasing knowledge the number of cases of primary MVT in which no cause can be identified will decrease. Hypercoagulable states are especially important being found in 14 of 16 patients in a very recent report.[13] Oral contraceptive – related MVT accounted for about 9% of cases seen in the females in our study, but only 4% of the total series.[14] This finding is corroborated by a recent literature review, which also showed a 5% incidence in the total population; however, there was an 18% incidence in the female population. The lower incidence of oral contraceptive –related episodes in our series possibly reflects the large proportion of geriatric patients seen at our institutions. In addition, a spate of isolated case reports relating oral contraceptive use to MVT may skew the composition of cases in the literature. Recently MVT has been seen as a complication of sclerotherapy for esophageal varices.[15]
Pathophysiology of Mesenteric Vasoconstriction The intestines are protected from ischemia by their abundant collateral circulation. Communications between the celiac, superior mesenteric, and inferior mesenteric vascular beds are numerous, and it has become axiomatic over the years that at least two of these vessels must become compromised to produce symptomatic chronic intestinal ischemia. Collateral flow around occlusions of smaller arterial branches in the mesentery of the small intestine and right colon is made possible by the branching primary, secondary, and tertiary arcades. Within the bowel wall there is a network of communicating submucosal vessels that can maintain the viability of short segments of intestine where the extramural arterial supply has been compromised. Collateral pathways open immediately upon occlusion of a major vessel in response to arterial hypotension distal to the obstruction. Increased blood flow through the collateral pathways continues as long as the pressure in the vascular bed distal to the obstruction remains below systemic pressure. If, however, vasoconstriction develops in the distal arterial bed, the arterial pressure rises due to increased resistence, which ultimately impairs collateral flow to the dependent segment. Despite adequate collateral vasculature in most cases, acute interruption or dimunition of blood flow in the mesenteric circulation caused by emboli or hypotension results in intestinal ischemia secondary to persistent vasospasm. A decrease in SMA flow initially produces local mesenteric vascular responses that tend to maintain intestinal blood flow, but if the diminished flow is prolonged, active vasoconstriction develops, which may persist even after the primary cause of decreased flow is corrected. Boley and associates[16] have shown that following an acute 50%
Acute Mesenteric Vascular Disease
841
Table 59-1. Conditions Associated with Mesenteric Venous Thrombosis Hypercoagulable states Peripheral deep venous thrombosis Neoplasms Antithrombin III deficiency Protein C deficiency Protein S deficiency Oral contraceptive use Pregnancy Polycythemia vera Thrombocytosis Portal hypertension Cirrhosis Congestive splenomegaly Following sclerotherapy of esophageal varices Inflammation Pancreatitis Peritonitis (e.g., appendicitis, perforated viscus) Inflammatory bowel disease Pelvic or intraabdominal abscess Diverticular disease Postoperative state or trauma Blunt abdominal trauma Splenectomy and other postoperative states Other Decompression sickness
reduction in SMA blood flow in anesthetized dogs, the mesenteric arterial pressure (MesAP) in the peripheral mesenteric arteries fell to 49% of mean control values. When the SMA flow was maintained at 50% of normal, the MesAP returned to control values in 1 – 6 hours while the celiac flow, which had initially increased, fell to control levels. The increased vascular resistance caused by vasoconstriction ultimately resulted in decreased collateral perfusion from the celiac and inferior mesenteric systems. If the flow restrictor was removed from the SMA as soon as the MesAP rose to control values, the flow through the SMA also returned to normal. However, if the SMA occlusion was maintained for 30 –240 minutes after the MesAP had returned to control levels, the flow in the SMA never returned to normal. It remained at 30– 50% of control because of persistent arterial vasoconstriction despite the removal of the SMA flow restrictor. This decreased flow continued for up to 5 hours of observation but could be corrected by direct infusion of papaverine into the SMA. In this manner, mesenteric vasoconstriction plays a significant role in the development of ischemia both in the acute occlusive and nonocclusive arterial forms of mesenteric ischemia. When papaverine was infused during the 50% flow restriction, the MesAP remained low throughout 4 hours of observation and the SMA flow returned to normal upon release of the obstruction. Based on these observations, the use of intraarterial papaverine infusions is recommended in the management of both the occlusive and nonocclusive forms of AMI. Intraarterial papaverine is also recommended for some patients with the venous forms of mesenteric
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vascular diseases because venous thrombosis has been shown, experimentally, to cause arterial spasm.[17] In NOMI it had been presumed that the bowel injury occurs during the period of diminished cardiac output or hypotension, and that with correction of these cardiovascular problems the mesenteric blood flow returns to normal. This simplistic concept is contradicted by operative findings of persistent bowel ischemia when no arterial or venous obstruction is found and cardiac function has been optimized. It is known that in patients with NOMI the onset of abdominal signs and symptoms caused by intestinal ischemia may actually begin after the correction of the primary systemic problem. This paradox can be explained by the experimental observations that an episode of low mesenteric flow, as short as 2 hours in duration, can produce mesenteric ischemia as a result of vasoconstriction, and that the vasoconstriction and ischemia may continue after the correction of the initiating problem. The end result of an ischemic episode is dependent on many factors. Thus the extent of intestinal injury is a function of the 1) state of the systemic circulation; 2) the degree of functional or anatomical compromise; 3) the number and caliber of vessels affected; 4) the response of the vascular bed to diminished perfusion; 5) the nature and capacity of the collateral circulation to supply the needs of the dependent segment of bowel; 6) the duration of the insult; and 7) the metabolic needs of the dependent segment as dictated by its function and bacterial population. Because vasospasm may persist even after the initial cause of the ischemia is corrected, bowel injury continues unless the vasospasm is relieved. An aggressive radiological and surgical approach to these diseases targets both the cause and the persistent vasospasm.
Clinical Presentation Early identification of acute mesenteric ischemia requires a high index of suspicion by the clinician in those patients who have significant risk factors associated with this disease. AMI occurs most frequently in patients over 50 years of age who have chronic heart disease and long-standing congestive heart failure, especially those poorly controlled with diuretics or digitalis. Cardiac arrhythmias, commonly atrial fibrillation, recent myocardial infarction, or hypotension due to burns, pancreatitis, or hemorrhage all predispose the patient to acute mesenteric ischemia. Previous or synchronous arterial emboli increase the likelihood of an acute SMA embolus. Nonocclusive mesenteric ischemia has been reported following cardiac surgery and renal dialysis. Patients younger than 50 years of age and many without any of the conditions suggesting increased risk have developed AMI. Therefore, the diagnosis of AMI should be considered in any patient who develops sudden abdominal pain out of proportion to the physical findings. Acute abdominal pain varying in severity, nature, and location occurs in 75 –98% of patients with intestinal ischemia. A history of postprandial abdominal pain in the weeks to months preceding the acute onset of severe abdominal pain occurs in only the small fraction of patients with AMI caused by acute thrombosis superimposed on chronic mesenteric ischemia as in the case of SMAT. In early AMI, the pain experienced by the patient is markedly out of
proportion to the physical findings. Therefore, sudden severe abdominal pain accompanied by rapid and often forceful bowel evacuation especially with minimal or no abdominal signs strongly suggests an acute arterial occlusion in the mesenteric circulation. Unexplained abdominal distension or gastrointestinal bleeding may be the only indications of acute intestinal ischemia, especially in nonocclusive disease, since pain is absent in up to 25% of these patients. Patients surviving cardiopulmonary resuscitation who develop culture-proven bacteremia and diarrhea without abdominal pain should be suspected of having NOMI.[18] Distension, while absent early in the course of mesenteric ischemia, is often the first sign of impending intestinal infarction. The stool contains occult blood in 75% of patients, and this bleeding may precede any other symptom of ischemia. Right-sided abdominal pain associated with the passage of maroon or bright red blood in the stool, though characteristic of colonic ischemia, also suggests the diagnosis of acute mesenteric ischemia. Although there are no abdominal findings early in the course of intestinal ischemia, as infarction develops, increasing tenderness, rebound tenderness, and muscle guarding reflect the progressive loss of intestinal viability and the presence of transmural gangrene. Significant abdominal findings strongly indicate the presence of infarcted bowel. Nausea, vomiting, hematochezia, hematemesis, massive abdominal distension, back pain, and shock are other late signs often indication compromise of bowel viability.
Laboratory Findings Leukocytosis exceeding 15,000 cell/mm3 occurs in approximately 75% of patients with AMI, whereas about 50% will present with a metabolic acidemia. Elevations of serum amylase, phosphate, and other specific enzymes as well as peritoneal fluid intestinal alkaline phosphatase and inorganic phosphate have been described, but the sensitivity and specificity of these markers of intestinal ischemia have not been established. Leukocytosis out of proportion to the clinical findings, an elevated hemoglobin and hematocrit indicating hemoconcentration as a result of fluid loss into the bowel and peritoneal cavity, and blood-tinged peritoneal fluid, often with an elevated amylase content, are not specific for AMI but suggest advanced intestinal necrosis and sepsis. Serum markers are neither sensitive nor specific enough to make or exclude the diagnosis of acute mesenteric ischemia and usually become abnormal after transmural bowel infarction has occurred. Therefore, they cannot be used to establish the diagnosis of AMI early enough to prevent intestinal infarction or increase survival.
Diagnostic Studies Radiographic Signs Plain abdominal radiographs are usually normal in early mesenteric ischemia, before infarction occurs. Late in the course of the disease, formless loops of small intestine or small intestinal “thumbprinting” can suggest the diagnosis of AMI. Less commonly, isolated “thumbprinting” of the right
Chapter 59.
colon may be the only indication of AMI. The finding of colonic ischemia confined to the right colon may be the result of disease in the main SMA rather than simply interference of colonic blood flow.
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few patients, SMA occlusion. Computed tomography has also been used to identify arterial and venous thromboses as well as ischemic bowel, but only in the late stages of the disease.
Angiography Other Diagnostic Modalities Laparoscopy[19] may be useful in patients whose clinical status precludes angiography. However, laparoscopic examination of the bowel is limited to the serosal surface, making it unreliable for diagnosing early mucosal necrosis at a time when the serosa still appears relatively normal. Duplex scanning has been of some value in identifying portal and superior mesenteric venous thrombosis and, in a
Historically, angiography was limited to identifying arterial occlusions by embolus or thrombosis. Currently, selective angiography is the mainstay of diagnosis and initial treatment of both occlusive and non-occlusive forms AMI.[20] Four reliable angiographic criteria for the diagnosis of mesenteric vasoconstriction[21] (Fig. 59-2), the cause of NOMI have been identified; 1) narrowing of the origins of multiple branches of the SMA; 2) alternate dilatation and narrowing of the
Figure 59-2. Angiographic criteria of acute mesenteric ischemia: (A ) narrowing of multiple mesenteric branches, (B ) alternate spasm and dilatation of intestinal branches (string of sausage sign), (C ) spasm of arcades, (D ) impaired filling of intramural vessels. (Used with permission. Kaleya RN, et al. Mesenteric vascular diseases, in Schwartz SI, Ellis H (ed), Maingot’s Abdominal Operations, 9th ed., East Norwalk, Conn., Appleton and Lange, 1989.)
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intestinal branches (string of sausage sign); 3) spasm of the mesenteric arcades, and 4) impaired filling of intramural vessels. While mesenteric vasoconstriction occurs in hypotensive patients and in those with pancreatitis, its presence in patients with suspected intestinal ischemia who are not in shock, do not have pancreatitis, and are not receiving vasopressors is diagnostic of NOMI. Therefore, if angiography is performed sufficiently early in the disease, patients with occlusive and nonocclusive AMI can be identified before bowel infarction develops and before clinical and radiologic signs of infarction make the diagnosis of intestinal ischemia evident.
PLAN FOR DIAGNOSIS AND THERAPY Selection of Patients Patients over 50 years of age with any of the previously enumerated risk factors for AMI who develop the sudden onset of abdominal pain severe enough to call it to the attention of a
physician and which lasts for more than 2 hours should be suspected of having acute mesenteric ischemia. These patients should be managed according to an aggressive radiologic and surgical algorithm (Fig. 59-3A and B; 59-4). Less absolute indications for inclusion into this protocol include unexplained abdominal distension, colonoscopic evidence of isolated right-sided colonic ischemia or acidosis without an identifiable cause. Because the presence of diagnostic clinical or nonangiographic radiologic signs usually indicates irreversible intestinal injury, broad selection criteria are essential if early diagnosis and successful treatment are to be achieved. Some negative studies must be accepted in order to identify and salvage patients who do have AMI.
Treatment Plan General Principles of Management Initial treatment is directed towards correcting the predisposing or precipitating causes of the ischemia. Relief of acute congestive heart failure and correction of hypotension,
Figure 59-3. Algorithm for diagnosis and treatment of acute mesenteric ischemia.
Chapter 59.
hypovolemia, and cardiac arrhythmias must precede any diagnostic evaluation. Efforts to improve mesenteric blood flow will be futile if low cardiac output, hypovolemia, or hypotension persist. Frequently, these patients are septic with a very low systemic vascular resistence and sequestration of fluid into the “third space.” Optimal cardiac performance can best be achieved under these circumstances with the aid of a Swan-Ganz catheter, using serial cardiac profiles to insure maximal systemic perfusion. After resuscitation is accomplished, plain films of the abdomen are obtained. These films are taken not to establish the diagnosis of AMI, but rather to exclude other identifiable causes of abdominal pain, e.g., a perforated viscus with free intraperitoneal air. A normal plain film does not exclude AMI; indeed, ideally patients will be studied before radiologic signs are present as such findings indicate the presence of infarcted bowel. If no alternative diagnosis is made on the basis of the plain abdominal films, selective SMA angiography is performed immediately. Based on the angiographic findings and the presence or absence of peritoneal signs, the patient is treated according to the algorithms in Fig. 59-3A and B. Even when the decision to operate has been made based on clinical grounds, a preoperative angiogram must be obtained to manage the patient properly at celiotomy. Moreover, relief of mesenteric vasoconstriction is essential to treat the emboli and thromboses as well as the nonocclusive “low flow” states. Intraarterial infusion of papaverine though an angiography catheter placed percutaneously in the origin of the SMA is the best method to relieve mesenteric vasoconstriction pre- and postoperatively. It is infused at a constant rate of 30 –60 mg/h using an infusion pump. Although almost all of the papaverine infused into the mesenteric circulation is cleared during its passage through the liver, under some circumstances this dose may have systemic effects. Therefore, the systemic arterial pressure and cardiac rate and rhythm must be monitored constantly during the papaverine infusion. The clinical and angiographic
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responses of the patient to the vasodilator therapy determines the duration of the papaverine infusion.
Operative Management Laparotomy is indicated in AMI to restore intestinal arterial flow after an embolus or thrombosis and/or to resect irreparably damaged bowel. Revascularization should precede evaluation of intestinal viability because bowel that initially appears infarcted may show surprising recovery after restoring adequate blood flow. After revascularization, intestinal viability can be assessed by several methods. Traditionally, the bowel is placed in warm, saline-soaked laparotomy pads and observed over a period of 10 – 20 minutes for return of normal color, peristalsis, and the presence or absence of pulsations in the intestinal arteries. This clinical assessment is of limited accuracy, therefore, a more sensitive and specific evaluation depends on technological aids. Techniques that have been proposed include surface fluorescence,[22] perfusion fluorometry,[23] Doppler measurements of arterial flow,[24] electromyography,[25] surface temperature, serosal pH, surface oxygen consumption, and radioisotope uptake determinations. Only Doppler pulse determinations, fluorescence using an ultraviolet light after an intravenous injection of fluorescein, and perfusion fluorometry have gained wide clinical acceptance. Surface fluorescence increases the accuracy of differentiating viable from nonviable bowel, the equipment is inexpensive and the dye is safe, but the technique remains subjective. Perfusion fluorometry is more objective, allows repeated determinations, and is more accurate, in general, than surface fluorescence. The equipment is, however, expensive, and only small areas of the bowel can be evalauted at one time. Although Doppler probes are available in most operating rooms, this modality is, again, limited to examining small areas of the intestine. A practical solution is the initial use of surface fluorescence, with either perfusion fluorometry
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or Doppler examination reserved for evaluation of the equivocal areas. Short segments of bowel that are nonviable or questionably viable after revascularization are resected. If extensive portions of the bowel are involved, only the clearly necrotic bowel is resected and a planned reexploration (second look) is performed within 12– 24 hours. The decision to perform a second look operation is made during the initial celiotomy if major portions or multiple segments of intestine are of equivocal viability. The purpose of the second look celiotomy, as proposed by Shaw,[26] is “not just to allow a clear definition between dead and live bowel to take place, but also to allow time for the institution of supportive measures which may render more of the bowel viable.” Such measures may include, among others, optimizing cardiac output, SMA infusion of papaverine, antibiotic therapy, and anticoagulant therapy. The decision to perform a second look is inviolate, and it must be done irrespective of the patient’s clinical course. If a second look is planned, no anastomoses need be made until the time of the reexploration. Sachs et al.[27] found that 18% of “secondlook” procedures contributed to patient survival. If, at the initial laparotomy, there is obvious infarction of all or most of the small bowel with or without a portion of the right colon, then the surgeon is faced with a philosophical decision whether to do anything at all. Resection of all of the involved bowel will inevitably produce a patient with short bowel syndrome with its attendant problems and, almost certainly in these older patients, a commitment to lifelong parenteral nutrition. A preoperative discussion with the patient and the patient’s family concerning this problem is warranted so that an acceptable decision can be reached if this situation is encountered at surgery.
Postoperative Care The use of anticoagulants in the management of AMI remains controversial. Heparin anticoagulation may cause intestinal, submucosal, or intra-peritoneal hemorrhage, and, except in the case of mesenteric venous thrombosis, we have not used it in the immediate postoperative period. Late thrombosis following embolectomy or arterial reconstruction, however, occurs frequently enough that anticoagulation 48 hours postoperatively seems advisable. Both systemic and locally administered antibiotics have been shown to improve the survival of ischemic bowel.[28] For this reason, the high incidence of positive blood cultures in patients with AMI, and the clinical and experimental evidence that ischemic bowel permits translocation of intralumenal bacteria,[29] broad-spectrum systemic antibiotics are begun as soon as the diagnosis is entertained and continued throughout the postoperative period as dictated by the findings at celiotomy.
MANAGEMENT OF SPECIFIC TYPES OF AMI Superior Mesenteric Artery Embolus Upon identification of an SMA embolus at angiography, a papaverine infusion is begun through the catheter placed
selectively in the origin of the SMA, proximal to the occlusion. The patient is then managed according to the algorithm in Fig. 59-3, based on the site of the embolus, the presence or absence of peritoneal signs, the extent of the collateral blood flow, and the degree of vasospasm in the vascular beds both proximal and distal to the embolus as determined by an angiogram repeated following a selective intraarterial bolus injection of 25 mg of tolazoline. Minor emboli are those limited to the branches of the SMA or to the SMA distal to the origin of the ileocolic artery. Patients with minor emboli whose pain is relieved by the vasodilator therapy can be managed expectantly. However, patients with major emboli selected for nonoperative therapy must have significant contraindications to surgery, no peritoneal signs, and adequate perfusion of the vascular beds distal to the embolus following the initiation of vasodilator therapy. Direct infusion of thrombolytic agents through selectively placed catheters has been employed successfully in a small number of patients. Thrombolytic agents may require up to 36 hours to dissolve the embolus,[30] during which time there may be continued ischemia and ultimate necrosis of the bowel. These agents, which include streptokinase, urokinase, and recombinant tissue plasminogen activator, have been most successful when the embolus only partially occludes the vessel lumen, is located in a branch of the SMA, if the study is performed within 12 hours of symptom onset, and there are no peritoneal signs. The role for such therapy has yet to be determined. Embolectomy is always performed before assessing intestinal viability. The embolus is approached directly, or less optimally, through a proximal arteriotomy (Fig. 59-4). The proximal SMA is exposed by drawing the transverse colon cephalad and anteriorly, as the small intestine is retracted inferiorly. The inferior leaf of the transverse mesocolon is incised and the proximal SMA is dissected free between the pancreas and the fourth portion of the duodenum. The SMA is exposed for 2 –3 cm proximal and distal to the origin of the middle colic artery. The SMA is palpated gently to determine the most distal extent of arterial pulsation or the artery may be examined directly with a Doppler probe to identify the site of the embolus. Once the site of the embolus is found, the SMA and its branches are controlled proximally and distally with vessel loops or gentle vascular clamps. We use a longitudinal arteriotomy over the embolus or just proximal to it, and the embolus is removed and residual clots are flushed out of the artery by briefly releasing the vessel loops. A Fogarty balloon catheter is then passed proximally and distally to remove all remaining clots. The arteriotomy is closed with or without a vein patch. Following embolectomy, bowel viability is determined. If no second look is planned, the papaverine infusion is continued for an additional 12 –24 hours. An arteriogram is then obtained to exclude persistent vasospasm prior to removing the arterial catheter. If a second look is performed, the infusion is continued through the second procedure and until no vasoconstriction is present on a follow-up angiogram.
Chapter 59.
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Figure 59-4. Technique of SMA embolectomy. (A ) The artery is isolated at the base of the mesentery over the site of the embolus. (B ) Longitudinal arteriotomy is made and the vessel is cleared of debris. (C ) The arteriotomy is closed primarily or with a vein patch (shown). (Used with permission. Boley SJ, et al. In Nyhus LM (ed), Surgery Annual, New York, Appleton, Century and Crofts, 1973.)
Nonocclusive Mesenteric Ischemia NOMI is diagnosed when the angiographic signs of mesenteric vasoconstriction are seen in a patient who has the clinical picture of mesenteric ischemia and is neither in shock nor receiving vasopressors. The angiographic findings may vary from the previously described local signs to a pruned appearance of the entire mesenteric vasculature (Fig. 59-5A). A selective SMA infusion of papaverine is begun in all patients with NOMI as soon as the diagnosis is made. In patients with persistent peritoneal signs, the infusion is continued during and after exploration. At operation, manipulation of the SMA is minimized. Overtly necrotic bowel is resected, and a primary anastomosis is performed only if no second look is planned. We believe it is better to leave bowel of questionable viability than to perform a massive enterectomy because frequently the bowel will improve with supportive measures or demarcate more clearly by the time of the second look. When a papaverine infusion is used as the primary treatment for NOMI, it is continued for approximately 24 hours, after which the infusion is changed to normal saline for 30 minutes prior to a repeat angiogram. Based on the clinical course of the patient and the presence or absence of vasoconstriction on the repeat angiogram, the infusion is either discontinued or maintained for an additional 24 hours. Angiography is repeated daily until there is no radiographic evidence of vasoconstriction (Fig. 59-5B) and the patient’s clinical symptoms and signs are gone. Infusions usually are
discontinued after 24 hours but have occasionally been maintained for as long as 5 days. When papaverine is used in conjunction with surgery for nonocclusive disease, a second-look operation is frequently necessary. In such cases, the infusion is continued as previously described for second-look operations following embolectomy. The arterial catheter is removed when no angiographic signs of vasoconstriction are seen 30 minutes after cessation of vasodilator therapy.
Acute Superior Mesenteric Artery Thrombosis SMAT is most often identified on a flush aortogram showing complete occlusion of the SMA within 1 – 2 cm of its origin. Some filling of the SMA distal to the obstruction via collateral pathways is almost always present. Branches both proximal and distal to the obstruction may show local spasm or diffuse vasoconstriction. Differentiation between thrombosis and an embolus can be difficult, and in such cases the patients are treated initially for SMA embolus. A more difficult problem arises in patients with abdominal pain without abdominal signs and complete occlusion of the SMA on aortogram. In these cases it is important to differentiate between an acute and a longstanding occlusion, as the latter may be coincidental to an unrelated presenting illness. Prominent collateral vessels between the superior mesenteric and the celiac and/or inferior mesenteric circulations are
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Figure 59-5. Patient with nonocclusive mesenteric ischemia managed with papaverine infusion for three days. (A ) Initial angiogram showing spasm of the main superior mesenteric artery, origins of the branches and intestinal arcades. (B ) Angiogram repeated after 36 hours of papaverine infusion. Study was obtained 30 minutes after the papaverine infusion was replaced with saline. At this time the patient’s abdominal symptoms and sign were gone. (Used with permission. In Ravitch MM (ed), Current Problems in Surgery, Chicago, Yearbook Medical Publishers, 1978.)
characteristic of chronic SMA occlusion. If large collaterals are present and there is good filling of the SMA on the late films during the angiogram, the occlusion can be considered to be chronic and the abdominal pain is probably unrelated to mesenteric vascular disease. In the absence of peritoneal signs, such patients are treated expectantly. The absence of collateral vessels or the presence of collaterals with inadequate filling of the SMA indicates an acute occlusion. In the latter instance the middle colic artery probably occluded, interrupting the collateral circulation to an already marginal system. Prompt intervention is indicated irrespective of the abdominal findings in these cases. If possible, an angiographic catheter is placed in the proximal SMA and a papaverine infusion is begun. If the origin of the SMA cannot be identified or cannulated at angiography, a small Silastic catheter should be advanced proximally into the SMA through a jejunal artery at the time of operative revascularization to treat the associated vasospasm. This catheter is brought out through a separate
incision in the abdominal wall and is used for postoperative papaverine infusion. Revascularization procedures for SMAT are similar to those used for chronic mesenteric ischemia, in which reimplantation, thrombectomy, and endarterectomy, or some form of bypass graft to the SMA distal to the obstruction, are employed. While a short graft from the aorta to the SMA is the simplest procedure, the optimal site of origin of the graft has been disputed. Because of the mobility of the SMA, grafts originating from the infrarenal aorta may be occluded with the movement of the mesentery of the small intestine. In addition, late failure due to progressive atherosclerotic disease of the infrarenal aorta has led some surgeons to use the supraceliac aorta as the inflow for the graft. Most infrequently the common, external or internal iliac arteries are the only noncalcified vessels, and we have successfully used these as the source of inflow. Although autologous reversed saphenous vein is the preferred conduit, PTFE has been used successfully, even in the presence of peritoneal contamination.
Chapter 59.
Percutaneous balloon angioplasty, endovascular stenting, and thrombolytic therapy of the SMA also have been reported.[31] Because there is presently no good method to monitor end organ injury and because of the danger of rethrombosis with irreparable bowel loss, as was the case with one of our patients, we do not recommend these techniques for acute SMA occlusions.
Acute Superior Mesenteric Venous Thrombosis Mesenteric venous thrombosis is an infrequent, but distinct, form of intestinal ischemia. Although first described almost 100 years ago, it has only been since the development of the new imaging techniques that the varying forms of the condition have been recognized. In the past, most cases presented with a clinical picture of an acute abdomen and the diagnosis was made only at laparotomy or postmortem. However, recent discoveries have altered our concepts of the disorder, and we now recognize that thrombosis of the superior mesenteric vein can develop slowly with no symptoms, in a more subacute manner with pain, but no intestinal infarction, or acutely with the classic presentation. Other contributions have altered our understanding of the etiology, our methods of diagnosis, and our management so that much of what has been written about MVT is no longer applicable. The location of the initial thrombosis within the mesenteric venous circulation varies with the etiology. SMVT secondary to cirrhosis, neoplasm, or operative injury clearly starts at the site of obstruction and extends peripherally while thromboses caused by hypercoagulable states tend to start in smaller venous branches and propagate into the major trunks. Infarction of intestine rarely occurs unless the branches of the peripheral arcades and the vasa recta are involved, even when the junction of the portal and superior mesenteric vein is occluded. Inferior mesenteric vein thrombosis leading to infarction has been reported in fewer than 6% of cases of mesenteric venous thrombosis. When collateral circulation is inadequate and venous drainage from a segment of bowel is compromised, there is increasing congestion of the involved intestine. The bowel becomes edematous, cyanotic, and thickened with intramural hemorrhages, and ultimately similar changes involve the subjacent mesentery. Serosanguineous peritoneal fluid accompanies early hemorrhagic infarction. Arterial vasoconstriction can be marked, but pulsations persist up to the bowel wall. Late in the process transmural infarction occurs, and it may become impossible to differentiate venous from arterial occlusion. SMVT can present with a sudden acute onset, a subacute onset of weeks to months, or a chronic onset, which usually is asymptomatic until late complications occur. As many as 60% of patients have a prior history of deep vein thromboses in the extremities.[32,33] The symptoms and signs of acute SMVT (the form of the disease classically described) are both varied and nonspecific, and the disorder has long been known as the “great imitator” of other abdominal disorders. In series that predate angiography and imaging studies, a correct preoperative
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diagnosis was made infrequently. Except for abdominal pain, which was present in more than 90% of patients, no symptoms would point to the diagnosis of MVT. Moreover, even the duration, nature, severity, and location of the pain varied widely, but typically it was out of proportion to the physical findings. Although in our review the mean duration of pain before admission was 5 days, others found it to be from 2 weeks to more than one month.[34,35] Some of the latter patients would probably be considered to have the subacute form of SMVT that we are beginning to recognize today. An initially surprising finding is that survivors had a longer interval (6 days) before admission than did those patients with a fatal outcome (4.4 days). This unexpected finding can be explained by the probability that those patients with a more indolent course are those who have less extensive bowel infarction and hence a better prognosis. Other prominent symptoms include nausea and vomiting, which occur in more than half of the patients. Lower GI bleeding or bloody diarrhea, in up to 15% of patients, and hematemesis, in up to 13%, are indications of bowel infarction. The presence of hematemesis as well as bleeding per rectum should alert the physician to the possibility of a mesenteric ischemic catastrophe as several cases of MVT presenting as upper gastrointestinal bleeding have been reported. Occult blood is present in the stools of more than half of the patients. The initial physical findings in acute SMVT vary greatly, reflecting both different stages and degrees of ischemic injury. Although almost all patients present with abdominal tenderness and most have decreased bowel sounds and abdominal distention, only two thirds manifest clear signs of peritonitis. Guarding and rebound tenderness develop later in the course, however, as bowel infarction evolves. The majority have temperatures greater than 388C, but only one quarter of patients present with clinical signs of septic shock. Laboratory studies for the diagnosis of all forms of intestinal ischemia have proved to have a low specificity or a low sensitivity. In our series of 22 patients, only a white blood cell count above 12,000 mm3 and an increase in the proportion of polymorphonuclear cells were present in more than two thirds of the patients. At present, these laboratory tests can suggest – but not confirm or exclude – the diagnosis of intestinal ischemia. Patients with a personal or family history of deep venous thrombosis or other thrombotic episodes and who present with symptoms compatible with mesenteric ischemia should undergo evaluation for a hypercoagulable state. The workup should include antithrombin III, Protein S, and Protein C levels, as well as the routine coagulation profile. Antithrombin III binds to the serine protease portion of thrombin, thereby preventing the conversion of fibrinogen to fibrin. Protein S and C are vitamin K –dependant clotting factors. When activated, Protein C along with its cofactor Protein S inactivate factors V and VIII. In addition the Protein C and S complex may stimulate fibrinolysis possible via activation of plasminogen activator. In deficiency states, patients have a tendency to clot. Because protein C and S are vitamin K dependant as well as the possibility that antithrombin III deficiency states are heparin resistant, warfarin therapy is used in these patients.[36]
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We use the term subacute superior mesenteric vein thrombosis to describe patients who have abdominal pain for several weeks to months without intestinal infarction. This presentation can be attributable either to extension of the thrombotic process at a rate rapid enough to cause pain but slow enough to allow collaterals to develop before infarction occurs, or to acute thrombosis of only enough venous drainage to produce reversible ischemic injury. Most often the diagnosis has been made serendipitously on imaging studies done for other suspected diagnoses, and the pain has subsided spontaneously or after initiation of anticoagulant therapy. Typically the pain is the only symptom, although some patients have had nausea or diarrhea. Physical examination and laboratory tests are normal. The pain has been related to meals in a few patients, but mostly it has been nonspecific in site and nature. Some patients who start off with this type of presentation do ultimately develop intestinal infarction; hence the distinction between the acute and subacute forms of SMVT may become blurred. The late occurrence of infarction may be the result of recurrent SMVT. Histologically new and old thromboses have been found at the time of autopsy in nearly half of cases with major vein thromboses.[37] Moreover, some patients with the subacute onset, in which the symptoms subside, may later develop the problems seen with asymptomatic chronic SMVT. The term chronic mesenteric venous thrombosis has been applied to patients who have no symptoms during the period when the thrombosis occurs. These patients may never develop problems related to the SMVT, but those who do have gastrointestinal bleeding from esophageal or intestinal varices.[38] Most have bleeding esophageal varices, and all of these have associated thrombosis of the portal or splenic vein. The physical findings of chronic MVT are those of portal hypertension if the portal veins are involved, but when only the superior mesenteric veins are involved there may be no abnormal findings. Laboratory studies with portal or splenic vein involvement may also show secondary hypersplenism with pancytopenia or primarily thrombocytopenia. The absence of any reliable specific symptoms, signs, or laboratory studies makes a preoperative diagnosis of acute mesenteric venous thrombosis very difficult. Moreover, the variability in the course of the disease—with some patients having an indolent course of days to weeks and others having a relatively acute onset and progressive course—further obscures the diagnosis. The continuing difficulty in diagnosing mesenteric venous thrombosis was graphically described by Anane-Sehaf and Blair in the statement, “perhaps the best overall finding was an uneasy feeling on the part of the examining physician that his patient looks sick but that he could not say why or from what.” Hence in the past in 90–95% of patients the correct diagnosis has only been made at laparotomy. In more recent series in which the newer diagnostic modalities have been used, the majority of patients have been diagnosed without, or prior to, operation. Roentgenographic and other imaging studies can establish the definitive diagnosis of MVT before intestinal infarction occurs. Plain films of the abdomen, if abnormal, almost always reflect the presence of infarcted bowel, and when present the changes rarely permit differentiation of venous and arterial forms of ischemia. In our series 75% of patients had abnormal plain films, but 50% showed only a nonspecific
ileus pattern and in only 25% did the study suggest the presence of some form of acute mesenteric ischemia. Gas in the wall of the bowel or in the portal vein and free air in the peritoneal cavity, all late signs of intestinal infarction, may be seen on plain films. Barium enemas are of little value since MVT rarely involves the colon. Some authors report small bowel studies to be both specific and sensitive when these have been done.[40] Characteristic findings include 1) marked thickening of the bowel wall and valvulae conniventes due to congestion and edema, 2) separation of loops due to mesenteric thickening, 3) a long transition zone between involved and uninvolved bowel with progressive narrowing of the lumen by the thickened wall, and 4) “thumbprints” or pseudotumors. Selective mesenteric arteriography can establish a definitive diagnosis before bowel infarction, can differentiate venous thrombosis from arterial forms of ischemia, and provides access for the administration of intraarterial vasodilators if relief of the associated arterial vasoconstriction is deemed important in a specific patient. The angiographic findings of MVT have been determined experimentally and clinically and include 1) demonstration of a thrombus in the superior mesenteric vein (SMV) with partial or complete occlusion, 2) failure to visualize the SMV or portal vein, 3) slow or absent filling of the mesenteric veins, 4) arterial spasm, 5) failure of arterial arcades to empty, and 6) a prolonged blush in the involved segment. In addition the angiogram may show reconstitution of venous blood flow above the thrombus, which can be an important in factor in deciding therapy. Ultrasonography,[41,42] computerized tomography,[43] and magnetic resonance imaging[44] have all been used to demonstrate thrombi in the superior mesenteric and portal veins before bowel infarction. Ultrasonography is of less value in pure SMV thrombosis because overlying gas may prevent good visualization of the vein, but the study can be used as a quick screening test in problem cases. Thickening of the bowel wall and free peritoneal fluid are sonographic findings suggesting intestinal ischemia. Gastrointestinal CT scanning can establish the diagnosis in more than 90% of patients with MVT by demonstrating the thrombus, venous collateral circulation, and involved intestine. Specific findings include thickening and persistent enhancement of the bowel wall, enlargement of the SMV, a central lucency in the lumen of the vein representing a thrombus, a sharply defined vein wall with a rim of increased density, and dilated collateral vessels in a thickened mesentery. These findings may be more indicative of the chronic form of MVT because most of the patients underwent CT for another indication and the mesenteric thrombosis was found serendipitously. Some authors believe that when a diagnosis of MVT is made on CT, little is gained by a subsequent selective mesenteric angiogram. However, the better delineation of thrombosed veins, and the access for administration of intraarterial vasodilators that this study provides, may make it of value in selected patients. Thus, there is no firm information on the desirability of performing angiography and CT in the patient with acute MVT. A small number of patients diagnosed just by imaging techniques, and without abdominal findings, have been treated successfully without angiography or operation.
Chapter 59.
Magnetic resonance imaging has also been used to diagnose MVT in a few patients, but its only apparent advantage is that it avoids the use of ionizing radiation. There have been isolated reports of MVT being diagnosed by various endoscopic methods. Routine gastroduodenoscopy and colonoscopy will rarely be of value as the duodenum and colon are infrequently involved, but examination of the proximal jejunum with a long endoscopic can suggest the diagnosis if that portion of the bowel is involved. Laparoscopy may be useful in circumstances where the diagnosis is uncertain. Scintiangiography has been diagnostic of MVT, but it has not been proven clinically reliable.[45] As previously stated the correct diagnosis of mesenteric venous thrombosis is usually made at laparotomy. The hallmarks of MVT are serosanguineous peritoneal fluid, dark red to blue-black edematous bowel, striking thickening of the mesentery, good arterial pulsations in the involved segment, and thrombus in cut mesenteric veins; at this stage some degree of intestinal infarction has invariably occurred. Thus, as with the other forms of acute mesenteric ischemia improved survival will only come from earlier diagnosis. For this reason, during the past 15 years we have employed the same diagnostic protocol for patients with suspected MVT as for those suspected of having arterial forms of AMI. However, the recent successful nonoperative pharmacologic treatment of several patients diagnosed by imaging techniques as having MVT suggests that in some patients use of the aggressive protocol is not necessary. Today, if patients with suspected AMI have factors suggesting MVT, we first obtain a contrast-enhanced CT. A past history of deep vein thrombosis or a family history of an inherited coagulation defect are examples of factors that would prompt us to order a CT as the first imaging study. Patients with no factors suggesting venous thrombosis are promptly resuscitated and undergo selective mesenteric angiography. Until the past few years a diagnosis of MVT mandated prompt laparotomy. However, with the advent of newer methods of diagnosis, MVT is being identified in patients who have not yet infarcted their bowel and in whom nonoperative therapy is proving successful. In the small select group of patients who have no physical findings suggesting intestinal infarction and who have a diagnosis of MVT made by ultrasonography, CT, MRI or angiography, a trial of anticoagulant or thrombolytic therapy may prove worthwhile. Heparin and streptokinase have been used successfully in the few case reports of this type of therapy.[46] Should signs of intestinal infarction develop, immediate operation is indicated. The extent of bowel resection has also been a subject of disagreement. In older articles the authors have recommended wide resection beyond the apparently infarcted bowel because the thrombosis often extended beyond the resected mesentery. More recent experience suggests that it is not necessary to sacrifice viable bowel when heparin and second-look operations are used. We believe that only the apparently nonviable bowel should be excised as determined by clinical evaluation and, if necessary, by administration of fluorescein with examination under a Wood’s lamp. Although routine second-look operations have been recommended,[47] most surgeons use this procedure only in selected patients.
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Therapeutic options are mesenteric venous thrombectomy[48] and intraarterial papaverine infusions through the SMA angiographic catheter,[49] both of which have been used in only a few patients. The limited experience with these two modalities makes it impossible to define their respective roles in the treatment of MVT. However, their inclusion in our algorithm of management is based upon a rational application of the available information. If at operation a short ischemic segment of bowel is found, then local resection with prompt heparinization should be done. The more difficult problems come when one finds extensively involved bowel that is not all frankly nonviable. The angiographic findings may then be essential to make a reasoned decision. If the angiogram demonstrates that the major vein is open or reconstituted, indicating that blood is flowing through the vein or around the obstruction, then a second-look operation should be performed 12–18 hours later, using the intervening time to improve circulation with papaverine infused into the SMA. In one instance, where this situation was noted on opening the abdomen, the surgeon found almost all of the small bowel to be blue, but at a second look 18 hours later, after infusing papaverine and starting heparin therapy, the entire small bowel was pink and viable. The basis for this therapy is that the MVT has been shown experimentally to have an associated arterial spasm, which contributes to the ischemia. Relief of the arterial vasoconstriction may improve the blood supply adequately to preserve viability. If at laparotomy a long segment of questionable bowel is found and the angiogram or operative findings indicate complete thrombosis of the SMV at its junction with the portal vein, with or without extension into the portal vein, then venous thrombectomy is indicated. A second-look operation should be performed after thrombectomy if the bowel is not clearly viable. Again, heparin therapy is promptly instituted. Intraarterial papaverine may be beneficial if there appears to be arterial vasoconstriction after the thrombectomy. This approach to the various surgical findings one might encounter is predicated on salvaging the maximum length of bowel. Thrombectomy, when short segments of bowel are involved, is not indicated, nor is there any evidence that it is advantageous when venous flow is reconstituted around a thrombus.
Prognosis and Complications Although mortalities of 70–90% have been reported through 1980 using traditional methods of diagnosis and therapy, the aggressive approach described above can reduce these catastrophic figures.[50 – 53] Of our first 50 patients managed by this approach, 35 (70%) proved to have AMI. Of these, 33 had angiographic signs of ischemia. The remaining 2 patients had normal angiograms. Of 65 patients from two institutions using this protocol, 36 (55%) survived, including 14 of 26 with NOMI, 14 of 23 with SMAE, 4 of 6 with SMAT, and 4 of 6 with superior mesenteric venous thrombosis. Most of the survivors lost no bowel or less than 3 feet of small intestine. In a separate review of 47 patients with intestinal ischemia resulting from SMA emboli, a survival rate of 55% was achieved in patients managed according to our aggressive
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Table 59-2. Review of Literature: Mortality of AMI With and Without Intraarterial Papaverine Author
Year
N
Levy[54] Batellier[55] Finucane[56] Georgiev[57] Paes[58] Clavien[59] Koveker[53] Clark[60] Sachs[61] Rogers[62] Kraucz[63] Boley[64]
1990 1990 1989 1989 1988 1986 1985 1984 1984 1982 1978 1978
62 65 32 175 38 81 39 27 49 12 40 35
Vasodilator No No No No No No No Yes/no No No No Yes
Mortality (%) 40 50 66 93 53 71 85 52 65 67 78 45
protocol, whereas only 20% of those patients treated by traditional methods survived. Intraarterial papaverine as the primary treatment was successful in four patients; two of these were not operated upon, and the other two had normal intestine at the time of delayed laparotomy. Of special interest in this study was the observation that of those patients with SMA emboli who were placed in the protocol within 12 hours of reporting their pain to their physician and who were managed strictly according to this protocol, two thirds survived. Using the aggressive approach outlined above, this catastrophic mortality has been substantially reduced. Overall, 50% or more of the patients presenting with AMI and treated according to the present algorithm survive, and approximately 70 –90% lose less than a meter of intestine.[32,34] Ninety percent of patients with AMI who had angiography but no signs of peritonitis have survived, demonstrating the potential value of early diagnosis. Ideally all patients with AMI should be studied at a time when the plain films of the abdomen are normal and prior to the development of an acute surgical abdomen. Our approach to the diagnosis and management of AMI is based upon several observations: 1) if the diagnosis is not made before intestinal infarction occurs, the mortality rate is 70–90%; 2) the diagnosis of both the occlusive and nonocclusive forms of AMI can be made in most patients by angiography; 3) vasoconstriction, which persists even after the etiology of the ischemia is corrected, is the cause of NOMI and a contributing factor in the other forms of AMI; and 4) the vasoconstriction can be relieved by vasodilators infused into the SMA. The cornerstones of our approach, therefore, are prompt diagnosis by the earlier and more liberal use of angiography and the incorporation of intraarterial papaverine in the treatment of both occlusive and nonocclusive mesenteric ischemia (Table 59-2). The widespread adoption of this protocol for the treatment of patients at risk could potentially improve the overall results of treatment of AMI. The mortality rate for MVT is lower than that encountered in the other forms of acute mesenteric ischemia,
varying from 32% in our series to approximately 50% in the literature. Overall recurrence rates have been about 20 –25%, but this is reduced to 13% if the patient is anticoagulated with heparin in the immediate postoperative period. Almost all patients with MVT have had some infarcted bowel, but the amount of resected bowel has been less than in patients with the arterial forms of AMI.
COLONIC ISCHEMIA Over the last three decades, colonic ischemia (CI) has come to be recognized as one of the most common colonic disorders in the elderly population. Though described more than a century ago, colonic ischemia continues to be a difficult clinical problem because of the diverse outcomes associated with ischemic injury to the colon. Inadequate blood flow to all or part of the colon can produce a heterogeneous spectrum of clinical syndromes and pathological findings ranging from completely reversible intramural and submucosal hemorrhage to transmural colonic gangrene. Although some patients develop the severe complications of gangrene, perforation, ischemic stricture, and persistent colitis, most episodes of CI are noncatastrophic with transient symptoms and pathological changes.
Historical Background Before 1950 colonic ischemia was considered synonymous with colonic infarction. During the 1950s, however, there were many reports of different forms of iatrogenic ischemic injury of the colon resulting from high ligation of the inferior mesenteric artery in the course of aneurysmectomy or colectomy for colon carcinoma.[65,66] In 1963, Bernstein and Bernstein[67] termed the persistent colitis following iatrogenic ischemic injuries “ischemic ulcerative colitis.” Also in 1963, based on retrospective and experimental studies, Boley et al.[68,69] described the clinical, roentgenological and pathological features of the previously unrecognized noniatrogenic, noncatastrophic reversible forms of ischemic colonic injury. Their later animal research,[70] reported in 1965, confirmed that spontaneous colonic ischemia could also result in irreversible pathological colonic injury, specifically stricture, gangrene, and chronic colitis. Subsequently, in 1966, Marston et al.[71] applied the term “ischemic colitis” to a group of 16 patients, of whom one had colonic gangrene, 12 ischemic strictures, and 3 reversible colitis. Today colonic ischemia is used to describe a general pathophysiological process that can lead to a variety of clinical conditions. The specific conditions resulting from ischemic injury to the colon are classified as reversible and nonreversible and can then be further categorized as (1) reversible ischemic colopathy (submucosal or intramural hemorrhage); (2) reversible or transient ischemic colitis; (3) chronic ulcerative ischemic colitis; (4) ischemic colonic stricture; or (5) colonic gangrene (Fig. 59-6).
Chapter 59.
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Pathophysiology of Colonic Ischemia Reduction in blood flow to the colon may reflect several pathological conditions. Inadequate systemic perfusion may occur during cardiogenic shock, or it may result from either local morphological or functional changes in the mesenteric vasculature. Atherosclerotic or thrombotic occlusion of the inferior mesenteric artery (IMA), focal cholesterol or blood clot emboli, vasculitides or spontaneous or drug-induced vasoconstriction can lead to insufficient blood flow and cellular ischemia. Whatever the cause of the ischemic insult, the end results are the same—a spectrum of bowel damage ranging from completely reversible functional alterations to total hemorrhagic necrosis of portions or all of the colon. The colon is normally protected from ischemia by collateral circulation between the celiac, superior mesenteric, inferior mesenteric, and iliac arterial beds. Collateral flow around small arterial branches is made possible by the multiple arcades within the colonic mesentery, and inferior mesenteric artery occlusions are bypassed via the arc of Riolan, the central anastomotic artery, and the marginal artery of Drummond. However, the colon has an inherently lower blood flow than the small intestine and is therefore more sensitive to injury during acute reductions in blood flow. More importantly, experimental studies have shown that functional motor activity of the colon is accompanied by a dimunition of blood flow. The pronounced effect of “straining” on systemic arterial and venous pressure in constipated, as compared with normal, patients provides indirect evidence that constipation may accentuate the adverse circulatory effects of defecation. Geber[72] has postulated that “the combination of normally low blood flow and decreased blood flow during functional activity would seem to make the colon (1) rather unique among all areas of the body where increased motor activity is usually accompanied by an increased blood flow and (2) more susceptible to pathology.”
Clinical Presentation Although most patients have no identifiable cause for their colonic ischemic episodes, features of the clinical history that suggest colonic ischemia include previous episodes of either small bowel or colonic ischemia or a precipitating cardiovascular event leading to a transient low flow state. Up to 20% of the patients have an associated lesion such as a potentially obstructing colonic stricture, carcinoma, or diverticulitis, which not only may make the diagnosis more obscure but may complicate treatment. Colonic ischemia usually presents with the sudden onset of mild abdominal pain, usually localized to the left lower quadrant and crampy in character. Less commonly the pain is severe, or conversely, in other patients, the description of pain can only be elicited retrospectively, if at all. An urgent desire to defecate frequently accompanies the pain and is followed, within 24 hours, by the passage of either bright red or maroon blood in the stool. The bleeding is not vigorous and blood loss requiring transfusion is so rare that it should suggest an alternative diagnosis.
Figure 59-6.
End results of colonic ischemia.
Physical examination may reveal mild to severe abdominal tenderness elicited in the location of the involved segment of bowel. Any part of the bowel may be affected, but the splenic flexure and descending and sigmoid colon are the most common sites. Although specific etiologies, when identified, tend to affect defined areas of the colon, no prognostic implications can be derived from the distribution of the disease. Nonocclusive ischemic injuries usually involve the “watershed” areas of the colon—the splenic flexure and the junction of the sigmoid and rectum—whereas ligation of the inferior mesenteric artery produces changes in the sigmoid. Similarly, the length of bowel affected varies with the cause. For example, atheromatous emboli result in short segment changes and nonocclusive injuries usually involve much longer portions of the colon. Depending on the severity and duration of the ischemic insult, the patient may develop fever or leukocytosis. There is usually no acidemia, hypotension, or septic shock. In more severe ischemia, signs of peritonitis may develop. The diagnosis of CI is usually made after the period of ischemia has passed and blood flow to the affected segment of colon has returned to normal. Many cases of transient or reversible ischemia are probably missed because a barium enema or colonoscopy is not performed early in the course of the disease. To date, no study has provided an accurate determination of the incidence of colonic ischemia. In addition, several retrospective reviews of older clinical material have revealed many cases of CI that were either undiagnosed or misdiagnosed because the various clinical manifestations of this disorder were not recognized. Using the modern clinical, roentgenologic and pathologic criteria for the diagnosis of colonic ischemia, two retrospective reviews of 154 patients in whom colitis was identified after the age of 50 revealed that 72 –74% of the patients, in fact, had colonic ischemia.[73,74] Half of these patients had been previously diagnosed as having inflammatory bowel disease. In our experience with more than 250 cases of colonic ischemia, there is no significant sex predilection. Approximately 90% of patients with this disease are above the age of 60 and have other evidence of systemic atherosclerotic disease. Oral contraceptive[75] and cocaine use,[76] however,
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are responsible for an increasing number of cases in the younger population. Other reported associated causes are listed in Table 59-3. What finally triggers an ischemic episode remains conjectural in most instances; whether increased demand by colonic tissues is superimposed on an already marginal flow or whether flow itself is acutely diminished has yet to be ascertained.
Plan for Diagnosis and Management Despite similarities in the initial presentation of most episodes of CI, the outcome cannot be predicted at its onset unless the initial physical findings indicate an unequivocal intraabdominal catastrophe. The ultimate course of an ischemic insult depends on many factors, including (1) the cause, i.e., occlusive or nonocclusive; (2) the caliber of an occluded vessel; (3) the duration and degree of ischemia; (4) the rapidity of onset of the ischemia; (5) the condition of the collateral circulation; (6) the metabolic requirements of the affected bowel; (7) the presence and virulence of the bowel flora; and (8) the presence of associated conditions such as colonic distension. Most commonly, symptoms subside within 24 –48 hours and clinical, roentgenographic, and endoscopic evidence of healing is seen within 2 weeks. More severe but still reversible ischemic damage may take 1 –6 months to resolve. In about 50% of patients with CI, the ischemic damage is too severe to heal, and the patient ultimately develops irreversible disease. In approximately two thirds of these patients, CI follows a more protracted course, developing into either chronic segmental ischemic colitis or ischemic stricture. In the remaining one third, signs and symptoms of an intraabdominal catastrophe, such as gangrene with or without perforation, become obvious within hours of the initial presentation. Because the outcome of an episode of colonic ischemia usually cannot be predicted, patients must be examined serially for evidence of peritonitis, rising temperature, elevation of the white blood count, or worsening symptoms. Patients with diarrhea or bleeding persisting beyond the first 10–14 days usually go on to perforation or, less frequently, a protein wasting enteropathy. Strictures may develop over weeks to months and may be asymptomatic or produce progressive bowel obstruction. Some of the asymptomatic strictures resolve spontaneously over many months.
DIAGNOSIS Early and appropriate diagnosis of CI depends upon serial radiographic and/or colonoscopic evaluation of the colon as well as repeated clinical evaluations of the patient. The more severe cases of CI may be difficult to distinguish from acute mesenteric ischemia (AMI), whereas the less severe cases may present similarly to acute or chronic idiopathic ulcerative colitis, Crohn’s colitis, infectious colitis, or diverticulitis. A combination of radiographic, colonoscopic, and clinical findings may be necessary to establish the diagnosis of colonic ischemia.
Table 59-3. Causes of Colonic Ischemia Hemodynamic causes Cardiogenic shock Hemorrhagic shock Arrhythmia Occlusive causes Inferior or superior mesenteric artery emboli Cholesterol emboli syndrome especially following angiography or angioplasty Inferior mesenteric artery thrombosis Traumatic causes Blunt or penetrating trauma Ruptured ectopic pregnancy Aneurysmectomy Aortoiliac reconstruction Gynecologic operations Colonic bypass procedures Lumbar aortography Colectomy with high ligation of the IMA Strangulated hernia Drug-induced causes Digitalis Oral contraceptives Cocaine Systemic causes Periarteritis nodosa Systemic lupus erythematosis Rheumatoid arthritis Necrotizing arteritis Thromboangiitis obliterans Polycythemia vera Parasitic infestation
In the patient with suspected CI, if abdominal x-rays are nonspecific, sigmoidoscopy is unrevealing and there are no signs of peritonitis, a gentle barium enema or colonoscopy should be performed in the unprepared bowel within 48 hours of the onset of symptoms. The most characteristic finding on the barium enema is “thumbprinting” or “pseudotumors” or hemorrhagic nodules or bullae during colonoscopy. Segmental distribution of these findings, with or without ulceration, is very suggestive of CI, but the diagnosis of colonic ischemia cannot be made conclusively on a single study. In fact, persistence of the thumbprints suggests a diagnosis other than colonic ischemia, e.g., lymphoma or amyloidosis. Repeated radiographic or endoscopic examinations of the colon together with observation of the clinical course are necessary to confirm the diagnosis. Segmental colitis associated with a tumor or other potentially or partially obstructing lesions is also characteristic of ischemic disease. The radiographic findings of universal colonic involvement, loss of haustrations or pseudopolyposis are more typical of chronic idiopathic ulcerative colitis, whereas the presence of skip lesions, linear ulcerations, or fistula suggest Crohn’s colitis.
Chapter 59.
It is imperative to obtain the diagnostic study early in the course of the disease because the thumbprinting will disappear, within days, as the submucosal hemorrhages are either resorbed or evacuated into the colon when the overlying mucosa ulcerates and sloughs. Barium enema or colonoscopy performed one week after the initial study should reflect the evolution of the disease, either by the return to normal or by the replacement of the thumbprints with a segmental ulcerative colitis pattern. If colonoscopy is chosen as the initial study, caution is indicated. Distension of the bowel with air to pressures greater than 30 mmHg diminishes colonic blood flow, shunts blood from the mucosa to the serosa, and causes a progressive decrease in the arteriovenous oxygen difference. Since Kozarek and colleagues[77] showed that intraluminal pressures exceed 30 mmHg during routine colonoscopy, there is a potential risk for induced or exacerbated CI following colonoscopy. This can be minimized by insufflation with carbon dioxide, which increases colonic blood flow at similar pressures.[78] Biopsies of nodules or bullae identified endoscopically early in the course of CI reveal submucosal hemorrhage, while biopsies of the surrounding mucosa usually show nonspecific inflammatory changes.[79] Histologic evidence of mucosal infarction, though rare, is pathognomonic for ischemia. Angiography seldom shows significant occlusions or other abnormalities and is not indicated in patients suspected of having CI. When the clinical presentation does not allow a clear distinction between CI and AMI, and plain films of the abdomen do not show the characteristic “thumbprinting” pattern of colonic ischemia, an “air enema” performed by gently insufflating air into the colon under fluoroscopic observation is obtained. The submucosal edema and hemorrhages that produce the “thumbprinting” pattern of colonic ischemia can be accentuated and identified in this manner. Once the provisional diagnosis of CI is made, a gentle barium enema is performed to determine the site and distribution of the disease as well as to determine any associated lesion that predisposed to the episode of ischemia, i.e., carcinoma, stricture, or diverticulitis. If, however, thumbprinting is not observed and the air enema does not suggest the diagnosis of CI, a selective mesenteric angiogram is immediately performed to exclude the diagnosis of AMI. In addition, colonic ischemia localized to the right colon may be a manifestation of AMI and should be treated accordingly. Because AMI progresses rapidly to an irreversible outcome and optimal diagnosis and treatment of this condition requires angiography, the diagnosis of AMI must be established or excluded prior to a barium study. Residual barium from a contrast study of the colon may obscure the mesenteric vessels and therefore preclude an adequate angiographic examination and intervention.
General Principles of Management Once the diagnosis of colonic ischemia has been established, and the physical examination does not suggest intestinal gangrene or perforation, the patient is treated expectantly. Parenteral fluids are administered and the bowel is placed at rest.
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Broad-spectrum antibiotics including an aminoglycoside and coverage for enterococcus and anaerobic organisms is begun, because antibiotic therapy has been shown to reduce the length of bowel damaged by ischemia, although it will not prevent colonic infarction. Cardiac function is optimized to ensure adequate systemic perfusion. Medications that cause mesenteric vasoconstriction, e.g., digitalis and vasopressors, should be withdrawn if possible. The urine output is monitored and maintained with parenteral isotonic fluids. If the colon appears distended, either clinically or radiographically, it is decompressed with a rectal tube, with or without gentle saline irrigations. Contrary to their efficacy in ulcerative colitis, parenteral corticosteroids are contraindicated because they increase the possibility of perforation and secondary infection. Appropriate management of patients seen during or soon after the ischemic episode requires serial radiographic or endoscopic evaluations of the colon and continued monitoring of the patient. The WBC, hemoglobin, and hematocrit should be repeated frequently during the acute episode. Though rarely needed, blood products should be administered according to the patient’s requirements. Serum potassium and magnesium must be monitored as the levels of these electrolytes may be disturbed by the associated diarrhea and tissue necrosis. Systemic levels of LDH, CPK, SGOT, and SGPT may reflect the degree of bowel necrosis but are nonspecific. Patients having significant diarrhea are begun on parenteral nutrition early. Narcotics should be withheld until it is clear that an intraabdominal catastrophe is not present and that the patient is clinically improving. Cathartics are contraindicated. No attempt should be made to prepare the bowel for surgery in the acute phase because this may precipitate a perforation. Increasing abdominal tenderness, guarding, rebound tenderness, rising temperature, and paralytic ileus during the period of observation are indicative of colonic infarction. These signs, though not specific for colonic ischemia, dictate the need for expedient laparotomy for resection of the affected segment of colon. The serosal appearance of infarcted colon ranges from wet tissue paper to mottled, thickened, aperistaltic bowel. The resected specimen should be opened in the operating suite and examined for mucosal injury, and if the margins are involved, additional colon should be removed until the margins appear grossly normal.
Management of Reversible Lesions In the mildest cases of colonic ischemia, in which signs and symptoms of illness disappear within 24 – 48 hours, submucosal and intramural hemorrhages are resorbed, and there is complete clinical and radiographic resolution within 1–2 weeks, no further therapy is indicated. More severe ischemic insults result in necrosis of the overlying mucosa with ulceration and inflammation and the subsequent development of a segmental ulcerative colitis. Varying amounts of mucosa may slough, which may ultimately heal over several months. Patients with such protracted healing may be clinically asymptomatic even in the presence of persistent radiographic or endoscopic evidence of disease. These asymptomatic patients are placed on a high-residue diet, and frequent follow-up evaluations are performed to confirm complete healing or the development of a stricture or
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persistent colitis. Recurrent episodes of sepsis in asymptomatic patients with unhealed areas of segmental colitis are usually caused by the diseased segment of bowel and are an indication for elective resection.
Management of Irreversible Lesions Patients with persistent diarrhea, rectal bleeding, proteinlosing enteropathy, or recurrent sepsis for more than 10 –14 days usually go on to perforation. Hence, early resection is indicated to prevent this complication. A GoLytelyw bowel preparation is administered along with an oral and intravenous antibiotics prior to surgery. At no time, however, should enemas be used to prepare the bowel. Despite a normal serosal appearance, there may be extensive mucosal injury, and the extent of resection should be guided by the distribution of disease as seen on the preoperative studies rather than the appearance of the serosal surface of the colon at the time of operation. As in all resections for colonic ischemia, the specimen must be opened at the time of operation to insure normal mucosa at the margins. If at the time of surgery the segmental ulcerative colitis involves the rectum, a mucous fistula or Hartmann’s procedure with an end colostomy should be performed. The mucous fistula can be fashioned through diseased bowel, and, in some cases, this segment will heal sufficiently to allow subsequent restoration of bowel continuity. Local steroid enema may be helpful in this setting; however, parenteral steroids are, again, contraindicated. A simultaneous proctocolectomy is rarely indicated. In those instances in which the patient has had a concurrent or recent myocardial infarction, or if the patient has major medical contraindications to surgery, a trial of prolonged parenteral nutrition with concomitant intravenous antibiotic therapy may be considered as an alternative, albeit, less optimal method of management.
Management of the Late Manifestations of Colonic Ischemia Colonic ischemia may not manifest clinical symptoms during the acute insult but still produce chronic segmental ulcerative colitis. Patients with this form of colonic ischemia may be frequently misdiagnosed if not seen during the acute episode. Barium enema studies may show a segmental colitis pattern, a stricture simulating a carcinoma or even an area of pseudopolyposis. The clinical course at this stage of disease is often indistinguishable from other kinds of colitis or stenosis unless the patient has been followed from the time of the acute episode. Crypt abscesses and pseudopolyposis usually considered histologically diagnostic of chronic idiopathic ulcerative colitis can be found with ischemic colitis. Regardless, the de novo occurrence of a segmental area of colitis or stricture in an elderly patient should be considered most likely ischemic and treated accordingly. The natural history of segmental colitis in the elderly is that of ischemic colitis; the involvement remains localized, resection is not followed by recurrence and the response to steroid therapy is usually poor. Patients with chronic
segmental ischemic colitis are initially managed symptomatically. Local steroid enemas may be helpful, but parenteral steroids should be avoided. In patients whose symptoms cannot be controlled by medication, segmental resection of the diseased bowel should be performed.
Management of Ischemic Strictures Patients with asymptomatic segmental ulcerative colitis may go on to develop a stenosis or stricture of the colon. Strictures that produce no symptoms should be observed, and some of these will return to normal over 12 –24 months with no further therapy. If, however, symptoms of obstruction develop, a segmental resection is required.
Management of Special Clinical Problems Colonic Ischemia Complicating Abdominal Aortic Surgery Mesenteric vascular reconstruction is not indicated in most cases of colonic ischemia, but it may be required to prevent CI during and after aortic reconstruction. One to two percent of patients develop clinically symptomatic colonic ischemia but a higher incidence, up to 10%, is noted when routine colonoscopy is performed.[80] Although clinical evidence of this complication occurs in only 1 –2% of patients, when it does occur it is responsible for approximately 10% of the deaths following aortic replacement.[81] Factors that contribute to the occurrence of postoperative colonic ischemia include rupture of the aneurysm, hypotension, operative trauma to the colon, hypoxemia, arrhythmias, prolonged cross-clamp time, and improper management of the IMA during aneurysmectomy. The most important aspect of management of colonic ischemia following aortic surgery is its prevention. Collateral blood flow to the left colon after occlusion of the IMA comes from the SMA via the arc of Riolan (“the meandering artery”), the central anastomotic artery, or the marginal artery of Drummond, and from the internal iliac arteries via the middle and inferior hemorrhoidal arteries. If these collateral pathways are intact, postoperative colonic ischemia can be minimized. Therefore, aortography as well as a full mechanical and antibiotic bowel preparation are essential prior to aortic reconstruction. Aortography is advised to determine the patency of the celiac axis, SMA, IMA, and internal iliac artery. The presence of a “meandering artery” does not, in and of itself, allow safe ligation of the IMA as the blood flow in the “meandering artery” frequently originates from the IMA and reconstitutes an obstructed SMA. Ligation of the IMA in the latter circumstance can be catastrophic with infarction of the small and large bowel. Ligation of the IMA is safe only when it has been confirmed angiographically that the blood flows in the “meandering artery” from the SMA to the IMA. Reimplantation of the IMA and revascularization of the SMA is required, therefore, in those instances when the SMA is occluded or tightly stenosed and the IMA provides inflow to the “meandering artery.” Occlusion of both hypogastric arteries on the preoperative arteriogram indicates that the rectal blood flow is dependent
Chapter 59.
upon collateral flow from the IMA or from the SMA via the meandering artery. In this circumstance, reconstitution of flow to one or both hypogastric arteries is desirable at the time of aneursymectomy. At operation, cross-clamp time should be minimized and hypotension must be avoided. If a meandering artery is identified, it should be carefully preserved. Because the serosal appearance of the colon is not a reliable indicator of collateral blood flow, several methods have been suggested to determine the need for IMA reimplantation. Stump pressure in the transected IMA greater than 40 mmHg or a mean IMA stump pressure to mean systemic blood pressure ratio greater than 0.40 indicates adequate collateral circulation and can be reliably used to avoid IMA reimplantation. Doppler ultrasound flow signals at the base of the mesentery and at the serosal surface of the colon with temporary IMA inflow occlusion also suggests that the IMA can be ligated safely without reimplantation. Tonometric determination of intramural pH of the sigmoid colon has been used to identify inadequate colonic blood flow during aneurysmectomy.[82 – 84] A tonometric balloon passed into the sigmoid colon through the anus prior to crossclamping the aorta enables one to evaluate the effect that occlusion and restoration of aortic flow has on the colonic intramural pH. The intramural pH is a metabolic marker of tissue acidosis and will reflect any clinically significant ischemia, thus indicating the need for revascularization while the abdomen is open. When IMA reimplantation is deemed necessary, the IMA should be excised with a patch of aortic wall (Carrell patch), and this patch should be sutured into the side of the aortic prosthesis. When the SMA is occluded as well, a jump graft from the aortic graft to the side of the SMA should be performed. The difficulty in accurately assessing colonic ischemia postoperatively and the significant mortality associated with its occurrence mandates that postoperative colonoscopy be performed in high-risk patients. Patients at high risk for the development of postoperative colonic ischemia following aortic reconstruction are those with ruptured abdominal aortic aneurysms, prolonged cross-clamping time, a patent IMA on preoperative aortography, nonpulsatile flow in the hypogastric arteries at operation, and postoperative diarrhea. In these cases colonoscopy is routinely performed within 2 –3 days of the operation, and if colonic ischemia is identified, therapy is begun before major complications develop.
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Fulminating Universal Colitis A rare fulminating form of colonic ischemia involving all or most of the colon and rectum has been recently identified in a few patients. They have the sudden onset of a toxic universal colitis picture. Bleeding, fever, severe diarrhea, abdominal pain and tenderness, often with signs of peritonitis, have been present. The clinical course is rapidly progressive. The management of this condition is similar to that of other forms of fulminating colitis. Total abdominal colectomy with an ileostomy is usually required. A second-stage proctectomy has been necessary in some patients within one month of the original surgery. The histologic appearance is a combination of ischemic changes and severe colitis.
Lesions Mimicking Colon Carcinoma Ischemic colitis can present with lesions that appear, on barium enema and colonoscopy, to be colon carcinoma. Colonoscopy may be able to distinguish the malignant lesions from those resulting from ischemic cicatrization and is advisable when an annular lesion is identified on barium enema. The treatment is local resection with immediate restoration of bowel continuity.
Colitis Associated with Colon Carcinoma Acute colitis in patients with carcinoma of the colon has been recognized for many years.[84] The colitis is usually, but not always, proximal to the tumor and occurs with and without clinical obstruction. It is of ischemic origin and has the radiologic and endoscopic appearance of ischemic colitis. Clinically, patients may present with symptoms of colonic ischemia or with symptoms related to the primary cancer, i.e., crampy pain of a chronic nature, bleeding, or acute colonic obstruction. In most cases, however, the predominant complaints are related to the ischemic episode –sudden onset of mild to moderate abdominal pain, fever, bloody diarrhea, and abdominal tenderness. It is imperative for both the radiologist and surgeon to be aware of the frequent association of colonic ischemia and colon cancer. The radiologist must be careful to exclude cancer in every case of colonic ischemia, and for the surgeon it is vital to examine any colon resected for cancer to exclude the presence of an ischemic process in the area of the anastomosis, because involvement may lead to stricture or a leak.
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28. Cohn, I.; Floyd, C.E.; Dresden, C.F.; Bornside, G.H. Strangulation Obstruction in Germ-Free Animals. Ann. Surg. 1962, 156, 692. 29. Wells, C.L. Relationship Between Intestinal Microecology and the Translocation of Intestinal Bacteria. Antonie Leeuwenhoek 1990, 58, 87– 93. 30. Vujic, I.; Stanley, J.; Gobien, R.P. Treatment of Acute Embolus of the Superior Mesenteric Artery by Topical Infusion of Streptokinase. Cardiovasc. Interv. Radiol. 1984, 7, 94– 96. 31. Becker, G.J.; Katzen, B.T.; Dake, M.D. Noncoronary Angioplasty. Radiology 1989, 170, 921. 32. Clavien, P.A.; Durig, M.; Harder, F. Venous Mesenteric Thrombosis: A Particular Entity. Br. J. Surg. 1988, 75, 252– 255. 33. Clavien, P.A.; Huber, O.; Mirescu; et al. Contrast Enhanced CT Scan as a Diagnostic Procedure in Mesenteric Ischemia Due to Mesenteric Venous Thrombosis. Br. J. Surg. 1989, 76, 93– 94. 34. Sack, J.; Aldrete, J.S. Primary Mesenteric Venous Thrombosis. Surg. Gynecol. Obstet. 1982, 154, 205–208. 35. Matthews, J.; White, R.R. Primary Mesenteric Venous Occlusive Disease. Am. J. Surg. 1971, 122, 579– 583. 36. Bertina, R.M. Hereditary Protein S Deficiency. Haemostasis 15, 241– 245, 185. 37. Johnson, C.C.; Baggenstoss, A.H. Mesenteric Venous Occlusion: Study of 99 Cases of Occlusion of Veins. Mayo Clin. Proc. 1949, 24, 628– 636. 38. Warshaw, A.L.; Gongliang, J.; Ottinger, L.W. Recognition and Clinical Implications of Mesenteric and Portal Vein Obstruction in Chronic Pancreatitis. Arch. Surg. 1987, 122, 410– 415. 39. Anane-Sehaf, J.C.; Blair, E. Primary Mesenteric Venous Occlusive Disease. Surg. Gynecol. Obstet. 1975, 141, 740– 742. 40. Clemett, A.R.; Chang, J. The Radiological Diagnosis of Spontaneous Mesenteric Venous Thrombosis. Am. J. Gastroenterol. 1975, 63, 209– 215. 41. Kidambi, H.; Herbert, R.; Kidami, A.V. Ultrasonic Demonstration of Superior Mesenteric and Splenopertal Venous Thrombosis. J. Clin. Ultrasound 1986, 14, 199–201. 42. Matos, C.; Van Gansbeke, D.; Zalcman, M.; et al. Mesenteric Venous Thrombosis: Early CT and Ultrasound Diagnosis and Conservative Management. Gastrointest. Radiol. 1986, 11, 322– 325. 43. Rosen, A.; Korobkin, M.; Silverman, P.M.; et al. Mesenteric Vein Thrombosis: CT Identification. Am. J. Roentgenol. 1984, 143, 83– 86. 44. Al Karawi, M.A.; Quaiz, M.; Clark, D.; et al. Mesenteric Vein Thrombosis: Non-invasive Diagnosis and Followup (US + CT) and Non-invasive Therapy by Streptokinase and Anticoagulants. Hepatogastroenterology 1990, 37, 507– 509. 45. Smith, R.W.; Selby, J.B. Scintiangiographic Diagnosis of Acute Mesenteric Ischemia. Am. J. Roentgenol. 1979, 132, 67– 69. 46. Verbanck, J.J.; Rutgeerts, L.J.; Haerens, M.H.; et al. Partial Splenoportal and Superior Mesenteric Venous Thrombosis: Early Sonographic Diagnosis and Successful Conservative Management. Gastroenterology 1984, 86, 949– 952.
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CHAPTER 60
Chronic Visceral Ischemia: A Surgical Condition Darren B. Schneider Louis M. Messina Ronald J. Stoney anastomose with similar branches of the inferior pancreaticoduodenal artery to provide the collateral pathway between the CA and SMA. Similarly, the superior mesenteric – inferior mesenteric collateral flow is carried by terminal branch connections of the middle and left colic arteries, respectively. Finally, the IMA collateral flow from the iliac system (via the hypogastric arteries) is provided by the sigmoid-hemorrhoidal anastomoses. The CA and SMA arise from the ventral surface of the upper abdominal aorta and may be compromised by atherosclerotic disease of the ventral aspect of the aortic wall extending into the vessel origins. Typically these orifice lesions do not extend more than 1 –2 cm into the visceral branches. This proximal distribution of disease spares the primary branches of the visceral trunks and allows the development of extensive collateral blood flow, using the previously described normal anastomotic pathways. Infrarenal aortic atherosclerotic disease is very common; it frequently occludes the IMA origin and also compromises iliac flow. The multiple vessels supplying the gastrointestinal tract and the many collateral pathways imply that visceral branch occlusive disease is predictably extensive before symptoms result.
The critical reduction of visceral blood flow by any one of several pathologic processes may produce the clinical syndrome of chronic intestinal ischemia. Although the pathologic lesion was described over a century ago,[1] a clinical correlation was first established by Dunphy[2] in 1936. Twenty years later, Mikkelson[3] coined the term intestinal angina and suggested that a surgical approach to the chronically occluded vessels was feasible. Within a year, the first successful operation for visceral occlusive disease was performed.[4] Today, chronic mesenteric ischemia is a recognized and challenging clinical problem. However, methods of diagnosis and treatment are still in evolution. The most common causative lesion is atherosclerosis of the aorta, causing stenosis or occlusion of the visceral branch origins. Other rare etiologies include extrinsic compression and congenital anomalies as well as inflammatory and dysplastic arterial lesions. This chapter reviews the topic of chronic visceral ischemia caused by atherosclerosis and describes the evolution of definitive surgical revascularization options over the past three decades.
ANATOMIC CONSIDERATIONS Normally the blood supply to the gastrointestinal tract is provided by three aortic branches, the celiac axis (CA), the superior mesenteric artery (SMA), and the inferior mesenteric artery (IMA) and also by the paired internal iliac arteries. In the physiologic state, 90% of the splanchnic blood flow is provided by the CA and the SMA. There is potential for extensive collateralization of these vessels, involving any or all of these systems (Fig. 60-1). Terminal branches of the gastroduodenal and superior pancreaticoduodenal arteries
CLINICAL PRESENTATION Abdominal pain caused by chronic mesenteric ischemia is rarely recognized and infrequently considered. This is surprising, because the clinical presentation and physical findings are classic. The affected patient is usually a female in the sixth decade of life with a history of postprandial, crampy midabdominal or epigastric pain. Abdominal pain is universally present in visceral ischemia, and less than 10% of symptomatic patients will describe an atypical pain pattern.[5,6] As the pain episodes increase in frequency and severity, the patient develops a food aversion resulting in
Supported in part by the Pacific Vascular Research Foundation.
Hobson/Wilson/Veith: Vascular Surgery: Principles and Practice, Third Edition, Revised and Expanded DOI: 10.1081/0819-9-120024944 Copyright q 2004 by Marcel Dekker, Inc.
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erals developing between anastomotic beds or occasionally may be remarkable for the absence of any significant aortic visceral branches (Fig. 60-3). The IMA orifice is usually seen best on an oblique projection (Fig. 60-4).
PATHOPHYSIOLOGY The pathophysiology of the postprandial pain of mesenteric vascular origin is poorly understood. Experimental evidence does suggest that mesenteric blood flow increases following food ingestion. However, intestinal motor activity probably has a greater influence on mesenteric blood flow. During
Figure 60-1. pathways.
Intestinal vascular supply with collateral
weight loss, the most common physical finding. Although a substantial number of patients will complain of gastrointestinal motility disturbances (episodic diarrhea or constipation), nausea, vomiting, and documented malabsorption are rare. On physical exam, three quarters of these patients have an abdominal bruit and approximately one third have additional findings of peripheral vascular disease. Laboratory studies are nonspecific, though occasionally there is occult blood in the stool. These symptoms—vague at onset and insidious in progression—often mimic visceral malignancy or are mistaken for functional bowel disease. In a thorough evaluation of weight loss and postprandial abdominal pain, intestinal ischemia should be seriously considered. Endoscopy and gastrointestinal contrast studies are useful only to exclude other processes. Conventional biplanar aortography remains the gold standard to confirm the diagnosis of visceral ischemia. Mesenteric duplex scanning[7] and contrast-enhanced magnetic resonance angiography[8] may also be clinically useful to screen for CA and SMA stenosis. However, when surgery is planned, arteriography is essential. The single most important view of the aortogram is the lateral projection. The origins and proximal portions of both the CA and the SMA are well visualized in profile on this view (Fig. 60-2). The anterior-posterior projection may demonstrate large collat-
Figure 60-2. Lateral aortogram showing occlusion of the celiac axis and stenosis of the superior mesenteric artery.
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Figure 60-3. (A ) Anteroposterior aortogram showing absence of significant abdominal aortic branches (“pruned” aorta) and large wandering collateral. (B ) Selective inferior mesenteric artery injection demonstrates extensive collateralization with reconstitution of the celiac branches (open arrows ) via the gastroduodenal (solid arrows ).
peristalsis, resistance changes in the intramural vessel segments lead to decreased arterial inflow and increased venous outflow. In a patient with impaired splanchnic circulation, this balance of increased flow and increased resistance after a meal may be disturbed, leading to tissue hypoxia, intestinal luminal acidosis, and true visceral pain. Because the development of the intestinal collateral circulation and its capacity are difficult to predict, the exact percentage of patients with atherosclerosis involving the visceral arteries who will ultimately become symptomatic is unknown. Usually at least two of the three aortic branches must be significantly diseased for symptoms to develop. Eighty-nine percent of symptomatic patients undergoing operation at our hospital (97 of 109) had angiographically demonstrated critical stenosis or occlusion of both the CA and the SMA. Although it is rare for single-vessel disease to produce symptoms, 5 of 8 patients were symptomatic with only CA disease and 2 patients had only critical SMA disease to explain their symptoms.
REVASCULARIZATION OPTIONS Although many techniques for visceral revascularization have been described, there are three basic procedures: reimplantation, bypass, and endarterectomy. To alleviate ischemic symptoms and prevent bowel infarction, revascularization of both the CA and the SMA is preferred, since these two
branches supply most of the splanchnic flow under normal conditions. In addition, long-term symptom relief has been correlated with the completeness of the revascularization.[5] If the operative repair must be limited, we prefer to revascularize the CA. The rationale for this choice is provided by two observations. First, isolated celiac disease is a more common cause of symptoms than isolated SMA disease. Second, when a major visceral branch reconstruction (CA or SMA) failed postoperatively, only those patients with celiac reocclusion experienced recurrent symptoms.
Reimplantation Revascularization of the major visceral branches can be performed by transecting the artery distal to the orifice lesion and reimplanting the normal vessel into an adjacent segment of aorta or graft. There are two inherent difficulties with this approach. First, the location and short length of the celiac trunk and its proximity to the SMA make its reimplantation technically difficult. Second, the presence of atheroma on the ventral surface of the aorta makes anastomosis of either the CA or SMA difficult and allows for later restenosis or occlusion secondary to disease progression in the aortic wall. Therefore, reimplantation as the definitive procedure for visceral occlusive disease is rarely performed now. Occasionally, following prosthetic aortic replacement, reimplantation of the inferior mesenteric artery as Carrel patch on the aortic graft will ensure perfusion of the sigmoid colon.
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Figure 60-4. Oblique projection demonstrating celiac occlusion and stenosis of the SMA and IMA.
Bypass The bypass concept, so successful in peripheral vascular beds, was adopted for visceral branch repairs soon after thromboendarterectomy was attempted. Occlusive visceral lesions may be bypassed using autogenous tissue or a prosthetic graft, and the bypass may be oriented to provide antegrade or retrograde flow.
Retrograde Bypass The original aortomesenteric bypass, as described, originates from the ventral surface of the infrarenal aorta and courses cephalad and anteriorly to terminate on the inferior surface of the uninvolved mid-SMA. Because the SMA is mobile, it is difficult to ensure that a graft in this position will not be redundant or kink as a result of movement of the mesentery. Additionally, the site of origin on the infrarenal aorta may be involved or predictably will develop atherosclerosis, contributing to late graft failure. Finally, retrograde flow is associated with turbulence, an additional factor which may play a role in late graft occlusion. Several large series have reported a significant incidence of symptom recurrence and late graft occlusion,[9 – 13] which may have
resulted in part from these technical disadvantages of the retrograde bypass. For these reasons we prefer to install all grafts to provide antegrade flow to the visceral branches.
Autogenous Antegrade Bypass The antegrade aortovisceral bypass originates from the ventral surface of the subdiaphragmatic or supraceliac aorta. It courses caudad and its distal end is anastomosed to the divided CA proximal to its bifurcation or to the SMA behind the pancreas. The operative approach to the supraceliac aorta and CA is through the gastrohepatic ligament. The left lobe of the liver is retracted to the right and the esophagus mobilized to the left to expose the crura of the diaphragm. Separation of these muscular fibers provides exposure of the distal thoracic aorta (Fig. 60-5). Dissection continues caudally, with division of the median arcuate ligament and the celiac ganglia to expose the CA out to and including the trifurcation. Further dissection of the anterior surface of the aorta below the CA, with elevation and caudad reflection of the body of the pancreas, allows access to the proximal SMA (Fig. 60-6).
Chapter 60.
Chronic Visceral Ischemia: A Surgical Condition
865
Figure 60-5. Transabdominal anterior approach to the supraceliac aorta showing line of division of crural fibers. Inset: Typical celiac orifice lesion. (From Wylie E.J.; Stoney, R.J.; Ehrenfeld, W.K.: Manual of Vascular Surgery, Vol. I. New York, Springer-Verlag, 1980, p. 210. Reproduced by permission.)
Venous Conduits. Six antegrade autogenous reversed saphenous vein grafts have been used to revascularize the CA or SMA, and five have failed within 2 years (Table 60-1). Three were successfully converted to prosthetic antegrade grafts with sustained relief of symptoms. Fibrosis and stricture, not progressive or recurrent atherosclerosis, was the cause of occlusion and recurrent symptoms in these patients. Because of this experience and other reports of aneurysmal degeneration and late occlusion of aortorenal saphenous vein bypass grafts, we have abandoned the use of vein conduits for visceral reconstruction. Arterial Conduits. Arterial autografts are reliable conduits in aortic branch repairs and other settings, but their use for visceral reconstruction poses two problems. First, the hypogastric artery, the most frequently harvested donor vessel, is an important visceral collateral pathway, as
previously described; therefore, it may not be wise to sacrifice it. Second, multiple visceral artery bypasses (CA and SMA) usually are required and an adequate length of arterial autograft for these reconstructions cannot be obtained. These concerns make the arterial autograft a less desirable conduit for antegrade aortovisceral bypass.
Prosthetic Antegrade Bypass The antegrade prosthetic aorta visceral bypass employs straight knitted Dacron tubes (5 –6 mm in diameter) for single-vessel bypass and small bifurcation grafts (10 £ 5 mm or 12 £ 6 mm) when both the CA and the SMA are revascularized. Initial concern about possible visceral erosion by these grafts has been resolved, since no such complication has occurred in the 34 patients (57 vessels) treated with this procedure and followed from 1 to 14 years.
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Figure 60-6. Mobilization and caudad retraction of body of the pancreas. (From Wylie, E.J.; Stoney, R.J.; Ehrenfeld, W.K.: Manual of Vascular Surgery, Vol. I. New York, Springer-Verlag, 1980, p. 213. Reproduced by permission.)
The supraceliac aorta is temporarily occluded below the diaphragm and above the celiac origin. If a single bypass is planned, an elliptical segment is excised from the midventral aortic wall (Fig. 60-7). If a bypass to both vessels is planned, the aortonomy is placed at an oblique angle on the right anterolateral aspect of the aorta to allow proper alignment of the graft limbs (Fig. 60-8). A
Table 60-1.
preclotted, knitted, flanged tubular graft (single bypass) or bifurcation graft (double bypass) is anastomosed to the aorta using a 4-0 suture. The graft is then clamped and aortic flow is restored. The mean aortic occlusion time is 24 min (range, 16–45 min). The vessel to be bypassed is then clamped and transected and the proximal end is oversewn. An end-to-end anastomosis is fashioned between
Operations for Visceral Atherosclerosis, 1959–1997
Procedure Transaortic endarterectomy Antegrade bypass (prosthetic) Antegrade bypass (vein) Antegrade bypass (artery) Transarterial endarterectomy Reimplantation Total
Patients
Visceral arteries repaired
Known late occlusions
Known early occlusions
60 34 5 2 5 3 109
126 57 6 2 7 5 203
4 2 4 1 1 1 13
2 2 1 0 1 0 6
Late occlusions are those occurring after 1 year; early occlusions are those occurring before 1 year.
Chapter 60.
Chronic Visceral Ischemia: A Surgical Condition
867
Figure 60-7. Position of elliptical aortotomy for antegrade aortoceliac bypass. (From Wylie, E.J.; Stoney, R.J.; Ehrenfeld, W.K.: Manual of Vascular Surgery, Vol. I. New York, Springer-Verlag, 1980, p. 211. Reproduced by permission.)
the graft limb and the distal, nondiseased visceral vessel using 5-0 suture. The right (SMA) limb of the bifurcated graft travels along the right anterolateral aspect of the aorta, behind the pancreas, to parallel the course of the SMA and allow proper orientation (Figs. 60-9 and 60-10). The antegrade prosthetic visceral bypass is advantageous because of the absence of disease in the aorta at the graft origin, the short length of the graft segments used, and the antegrade flow. A transabdominal approach is used, and this is well tolerated by patients with significant operative risk even though temporary supraceliac aortic occlusion is required. Among 34 patients who underwent this procedure, there were 3 perioperative deaths (Table 60-2). Careful intraoperative monitoring of cardiac function, recently using a transesophageal two-dimensional ultrasound probe, and manipulation of preload and afterload have contributed greatly to this improved outcome (see Chap. 20). Symptom relief was obtained in 29 of 31 patients who survived. Only 2 of 57 vessels bypassed demonstrated a late occlusion (Table 60-1).
Endarterectomy Shaw and Maynard[4] first used endarterectomy in 1958 to disobliterate the SMA and thus effect the first surgical cure of intestinal angina. Although this approach is theoretically attractive, there are certain limitations. The difficulties of surgical access to the upper aorta initially prompted endarterectomy via the diseased visceral vessel itself (transarterial endarterectomy). However, attempts to adequately remove the diseased aortic intima surrounding the visceral vessel orifice by this route are generally unsuccessful. The frequent failure of these reconstructions suggests that progression of aortic wall disease is inevitable. Additionally, distal embolization from loose, incompletely removed, atheromatous fragments is possible. Transaortic endarterectomy, originally introduced for the treatment of renal atherosclerosis, has therefore been adopted for visceral atherosclerosis. Transabdominal aortovisceral endarterectomy requires unrestricted exposure of the upper abdominal aorta, from which the visceral branches arise. Initially, these
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Part Seven. Visceral Arterial Disease
Figure 60-8. Position of aortotomy for antegrade bifurcated graft to the CA and SMA. (From Wylie, E.J.; Stoney, R.J.; Ehrenfeld, W.K.: Manual of Vascular Surgery, Vol. I. New York, Springer-Verlag, 1980, p. 213. Reproduced by permission.)
operations were performed using a thoracoretroperitoneal (two-cavity) approach. A left transthoracic extraperitoneal approach with paracostal division of the diaphragm (to avoid phrenic nerve injury) was used to achieve adequate exposure. The disadvantages of this approach include increased pulmonary morbidity and increased operating time. These prompted our decision to reexamine aortic exposure. Our objective was a transabdominal exposure that would allow total access to the entire abdominal aorta. We then adopted and refined transabdominal medial visceral rotation to achieve unrestricted access and exposure of the lower thoracic and entire abdominal aorta and its branches.[14] With the patient in the supine position and a nasogastric tube in place, a full midline abdominal incision is made. A multiarmed self-retaining retractor system (OmniTract) is placed to facilitate exposure after a thorough exploration of the abdominal contents. The small intestine is placed in a plastic “bowel bag” and retracted to the right. The descending colon, spleen, and pancreas are mobilized. This maneuver is begun by incising the left lateral peritoneum and splenoreal ligament. The viscera are mobilized in a plane such that the spleen, pancreas, and left colon are reflected anteriorly and to the right, while the left kidney, adrenal gland, ureter, and gonadal vein remain in their native positions. The visceral
mobilization is a precise surgical maneuver. To stray out of the plane may lead to pancreatic injury or troublesome adrenal bleeding in the cephalic aspect of this dissection. Similarly, the correct plane between the descending colon mesentery and ureter must be maintained caudally to avoid colon devascularization or ureteral injury. The spleen and pancreatic tail are handled gently and protected with a moistened pad. Self-retaining retractor blades are then positioned to maintain the exposure. The aorta is now clearly in view, with the left renal vein as the only structure crossing the aorta. The renal vein is fully mobilized to facilitate cephalad or caudal retraction, or, if necessary, it may be divided. The celiac and superior mesenteric arteries are exposed by incising the dense autonomic ganglia on the anterior surface of the aorta. As this neural tissue is mobilized to the right, the supraceliac aorta becomes visible. Division of the median arcuate ligament and separation of the muscle of the left crus exposes the distal thoracic aorta as well. Direct transaortic exposure of the CA and SMA orifices is obtained using a left longitudinal aortotomy in the anterolateral aortic wall, following control of the aorta and its branch vessels (Fig. 60-11). If the atheroma is localized to the ventral aortic wall, a trapdoor endarterectomy is performed. If the disease is circumferential, as is often seen
Chapter 60.
Chronic Visceral Ischemia: A Surgical Condition
869
Figure 60-9. Final alignment of bifurcated graft (pancreas cutaway to show course of graft limbs). (From Wylie, E.J.; Stoney, R.J.; Ehrenfeld, W.K.: Manual of Vascular Surgery, Vol. I. New York, Springer-Verlag, 1980, p. 214. Reproduced by permission.)
with coexistent renal disease, sleeve aortic endarterectomy is performed (Fig. 60-12). The distal aortic endpoint is obtained by sharp beveled transection. The endarterectomy is extended into the visceral trunks and the atheromatous core gently extracted. All the visceral branches as well as the renal vessels can be disobliterated in this manner. Following this, the aortotomy is closed using 4-0 suture and flow is restored to the viscera, kidneys, and lower extremities. If distal aortic disease is present, aortoiliac or aortofemoral reconstruction by endarterectomy or bypass may be performed at this point without further renal or intestinal ischemia. The mean supraceliac aortic occlusion time is 29 min. When SMA occlusion rather than stenosis is present, thrombus usually propagates to the first branch orifice. In order to remove this completely and secure a clean endpoint, a separate longitudinal SMA arteriotomy may be required. Following completion of the transaortic thromboendarterectomy, this incision is closed and aortic flow is restored. Clamp exclusion of the SMA orifice allows closure with a saphenous vein patch to prevent narrowing of the SMA trunk (Fig. 60-13). As with antegrade bypass, intraoperative assessment is performed using duplex ultrasonic imaging,[15] and a postoperative duplex scan or aortogram (Fig. 60-14) is always obtained prior to hospital discharge. Transaortic endarterectomy has provided consistent symptom relief and long-term patency. There have been 7 deaths
among 60 patients secondary to myocardial infarction, hemorrhage, and cerebral hypoxia (Table 60-2). Fifty-one of 53 patients surviving the perioperative period have been cured of their symptoms. There were four late visceral artery occlusions, three of which were symptomatic (Table 60-1). Reoperation and antegrade aortovisceral bypass was successful in relieving symptoms again in all three cases. Morbidity consisted of myocardial infarction, transient renal failure, hemorrhage, pneumothorax, severe chronic incisional pain following a thoracoperitoneal repair, and mild, transient spinal cord ischemia. The spinal cord ischemia, manifested by bilateral lower extremity weakness, occurred during a transaortic CA, SMA, and renal endarterectomy involving a 30-min crossclamp time; it resolved during the first postoperative week, with the patient ambulating independently by the time of discharge. The technique is attractive because it is entirely autogenous and anatomic. When it is employed, transabdominal medial visceral rotation avoids bicavitary morbidity.
NONOPERATIVE THERAPY Medical treatment of visceral ischemic symptoms is quite limited. Some patients have experienced symptomatic improvement using long-acting nitrates with meals. The mechanism of action is unclear but may be related to
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Part Seven. Visceral Arterial Disease
Figure 60-10. (A ) Preoperative study showing CA occlusion and SMA stenosis. (B ) Postoperative angiogram of antegrade aortoceliacSMA bypass. (From Wylie, E.J.; Stoney, R.J.; Ehrenfeld, W.K.: Manual of Vascular Surgery, Vol. I. New York, Springer-Verlag, 1980, p. 216. Reproduced by permission.)
alterations in mesenteric vascular resistance. It is unknown whether patients so treated have an improved long-term outcome, since this treatment obviously does not alter the underlying disease process. Similarly, dietary manipulation may reduce symptoms but should be regarded only as a method of maintaining nutrition while evaluation and preparation for definitive treatment continue. Percutaneous transluminal mesenteric angioplasty may relieve symptoms of chronic visceral ischemia,[16] but the long-term durability of this approach appears to be inferior to operative revascularization.[17] The addition of stenting may improve long-term patency following angioplasty by preventing restenosis, but this remains unproven. At present, mesenteric angioplasty should be reserved for patients who have prohibitive surgical risks or be used as a temporizing measure prior to surgical correction.
Table 60-2.
RECURRENT VISCERAL ISCHEMIA Although operative visceral revascularization can effectively correct chronic visceral ischemia, late failures do occur (Table 60-3). Recurrent visceral ischemia following failed primary visceral revascularization occurred in 17% of patients (19 of 109). Seven of these 19 patients presented with acute visceral ischemia, and 6 died due to bowel infarction. Although recurrent acute visceral ischemia is associated with a high mortality rate, the 12 patients with recurrent chronic visceral ischemia had better outcomes. Ten patients underwent reoperation, and the 9 survivors were rendered free of symptoms. We have performed a total 30 visceral reoperations in 24 patients, including patients referred for treatment of recurrent visceral ischemia after
Results of Visceral Revascularization (Current Procedures)
Procedure Transaortic endarterectomy Antegrade bypass (prosthetic) Total
Patients
Morbidity
Mortality
Known occlusions
Symptom relief
60 34 94
15 11 26
7 3 10
6 4 10
51 29 80
Chapter 60.
Chronic Visceral Ischemia: A Surgical Condition
871
Figure 60-11. Development of endarterectomy plane through anterolateral trapdoor aortotomy. (From Wylie, E.J.; Stoney, R.J.; Ehrenfeld, W.K.: Manual of Vascular Surgery, Vol. I. New York, Springer-Verlag, 1980, p. 217. Reproduced by permission.)
primary visceral revascularization at other institutions. The established techniques of transaortic visceral endarterectomy and antegrade aortovisceral prosthetic bypass have both been used in the reoperative setting and achieved durable relief of
symptoms.[18] We now routinely monitor patients who undergo visceral revascularization with mesenteric duplex scanning in order to identify patients with failing visceral repairs before they develop symptoms of recurrent visceral
Figure 60-12. Combined visceral and renal endarterectomy with sleeve aortic endarterectomy. (From Wylie, E.J.; Stoney, R.J.; Ehrenfeld, W.K.: Manual of Vascular Surgery, Vol. I. New York, Springer-Verlag, 1980, p. 217. Reproduced by permission.)
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Part Seven. Visceral Arterial Disease
Figure 60-13.
An SMA endarterectomy completed through a separate arteriotomy and closed with a vein patch.
Figure 60-14. Postoperative arteriogram showing patent SMA and CA after endarterectomy: (A ) postoperative; (B ) preoperative.
Chapter 60. Table 60-3.
Chronic Visceral Ischemia: A Surgical Condition
873
Literature Review: Surgical Management of Chronic Visceral Ischemia
Year
Patients
Operative mortality, total (%)
1988 1989 1991 1992 1992 1994 1995 1995 1997
41 20 74 20 58 26 25 21 24
2 (5) 2 (10) 9 (12) 0 (0) 6 (10) 3 (11) 3 (12) 0 (0) 1 (4)
No. vessels revascularized
Bypass, No. vessels
Endarterectomy, No. vessels
Late recurrence, total (%)
Mean follow-up (months)
60 NA 140 36 119 29b 38 37 38
39 15 patients 39 27 92 29 38 37 38
10 5 patients 101 2 9 0 0 0 0
6 (16) 4 (20) 9 (12) 0 (0)a 5 (10) 3 (18) 4 (11)c 3 (14) 3 (13)
42 49 71 36 40 40 35 NA 29
Ref. 26 27 24 28 29 30 31 32 33
a
Two patients had early graft thrombosis and required intestinal resection. All patients had isolated bypass to the SMA. Three patients required repeat bypass. c Based objective follow-up with either duplex scanning or arteriography. b
ischemia. If recurrence is detected by duplex scanning or recurrent symptoms develop, biplanar aortography is obtained prior to reoperation.
DISCUSSION Since the natural history of asymptomatic visceral atherosclerosis is unknown, revascularization in these patients is a consideration only when an indicated aortic operation would further jeopardize intestinal blood flow. In such patients, preservation of collateral flow or reconstruction of the involved visceral branch may be indicated. Incidentally discovered visceral disease may be safely followed, since the presence of disease does not imply clinical significance and the disease does not invariably progress to intestinal infarction. For the symptomatic patient, the decision for surgical revascularization is influenced by the extent of disease, the severity of symptoms, and the general condition of the patient. Classic, severe symptomatology in the presence of significant and appropriate lesions on angiography demands aggressive operative treatment to avoid intestinal infarction with fatal consequences.[19] Considerable judgment is required in deciding for or against surgery in a patient who has atypical symptoms and mild atherosclerotic visceral disease on aortography. Single-vessel disease (or mild twovessel disease) takes on a different significance if one suspects that collateralization may be impaired secondary to previous gastrointestinal surgery or associated severe aortoiliac disease.[20,21] Unfortunately, no simple method exists for determining if the demonstrated lesions are sufficient to produce the symptoms experienced. The nutritionally impaired patient requires preoperative preparation with either intravenous hyperalimentation or dietary manipulation until an anabolic state is restored. The technique and operative approach selected are dictated by the patient’s operative risk and the distribution of the disease to be corrected.[22] In preoperatively optimized symptomatic patients, we prefer transaortic endarterectomy via transabdominal medial visceral rotation. We now reserve the
extended exposure of the thoracoretroperitoneal approach for aneurysms that involve the thoracoabdominal aorta. The wide exposure provides safe access to and control of the entire aneurismal aorta and its branches. Definitive treatment of these aneurysms involves inclusion grafting and direct vessel reattachment. The transabdominal approach for an antegrade prosthetic bypass is an appropriate choice for higher-risk patients, in whom the limited dissection is better tolerated.[23] It may also be an appropriate choice for patients with prior left colon, renal, or pancreatic surgery, where the dissection planes for visceral rotation are obliterated. Although this technique has been used in a smaller number of patients, early results suggest that it provides symptomatic relief and protection against visceral infarction comparable to those obtained by transaortic visceral endarterectomy;[24] the two methods may be equivalent for visceral revascularization. The fact that either can be employed using the same approach to the aorta makes visceral revascularization possible with two equivalent options.[25]
SUMMARY In summary, chronic intestinal ischemia is most often caused by atherosclerotic involvement of the visceral arteries, with multiple vessel involvement in at least 89% of cases. Aortography is required to make the diagnosis, which is frequently delayed because of nonspecific symptoms and minimal physical findings that do not suggest chronic visceral ischemia. Since the preponderance of splanchnic flow is carried by the CA and SMA, revascularization of both these vessels is performed whenever possible. However, sustained symptom relief and intestinal protection can be achieved with CA revascularization alone. The technique and operative approach chosen for a given case is determined by the extent of disease involvement and the patient’s operative risk. The best results—in terms of low operative mortality and morbidity, sustained symptom relief, and long-term patency—have been obtained with a
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Part Seven. Visceral Arterial Disease
transabdominal approach and medial visceral rotation, which allows transaortic endarterectomy or antegrade aortovisceral prosthetic bypass. Both procedures require temporary supraceliac aortic occlusion. This calls for careful intraoperative management but was tolerated by our patients without significant cardiac, renal, or spinal cord ischemia and no intestinal or lower extremity ischemic complications.
Transaortic endarterectomy provides the opportunity for one-step correction of complex, multivessel atherosclerotic disease. It is also an autogenous repair. The transabdominal antegrade prosthetic bypass is appropriate for poorer-risk patients; early results suggest excellent long-term results, comparable to those of the visceral transaortic endarterectomy.
REFERENCES 1. Chiene, J. Complete Obliteration of Celiac and Mesenteric Arteries: Viscera Receiving Their Blood Supply Through Extraperitoneal System Vessels. J. Anat. Physiol. 1869, 3, 65. 2. Dunphy, J.E. Abdominal Pain of Vascular Origin. Am. J. Med. Sci. 1936, 192, 102. 3. Mikkelson, W.P. Intestinal Angina: Its Surgical Significance. Am. J. Surg. 1957, 94, 262. 4. Shaw, R.S.; Maynard, E.P. III. Acute and Chronic Thrombosis of Mesenteric Arteries Associated with Malabsorption: Report of Two Cases Successfully Treated by Thromboendarterectomy. N. Engl. J. Med. 1958, 258, 874. 5. Hollier, L.H.; Bernatz, P.E.; Pairolero, P.C.; et al. Surgical Management of Chronic Intestinal Ischemia: A Reappraisal. Surgery 1981, 90, 940. 6. Reul, G.J., Jr.; Wukasch, D.C.; Sandiford, E.M.; et al. Surgical Treatment of Abdominal Angina: Review of 25 Patients. Surgery 1974, 75, 682. 7. Moneta, G.L.; Lec, R.W.; Yeager, R.A.; Taylor, L.M., Jr.; Porter, J.M. Mesenteric Duplex Scanning: A Blinded Prospective Study. J. Vasc. Surg. 1993, 17, 79. 8. Meaney, J.F.; Prince, M.R.; Nostrant, T.T.; Stanley, J.C. Gadolinium-Enhanced MR Angiography of Visceral Arteries in Patients with Suspected Chronic Mesenteric Ischemia. J. Magn. Reson. Imaging. 1997, 7, 171. 9. Hertzer, N.R.; Beven, E.G.; Humphries, A.W. Chronic Intestinal Ischemia. Surg. Gynecol. Obstet. 1977, 145, 321. 10. Zelenock, G.B.; Graham, L.M.; Whitehouse, W.M., Jr.; et al. Splanchnic Arteriosclerotic Disease and Intestinal Angina. Arch. Surg. 1980, 115, 497. 11. McCollum, C.H.; Graham, J.M.; DeBakey, M.E. Chronic Mesenteric Arterial Insufficiency: Results of Revascularization in 33 Cases. South. Med. J. 1976, 69, 1266. 12. Stoney, R.J.; Ehrenfeld, W.K.; Wylie, E.J. Revascularization Methods in Chronic Visceral Ischemia Caused by Atherosclerosis. Ann. Surg. 1977, 186, 468. 13. Stoney, R.J.; Wylie, E.J. Recognition and Surgical Management of Visceral Ischemia Syndromes. Ann. Surg. 1996, 164, 174. 14. Reilly, L.M.; Ramos, T.K.; Murray, S.P.; Cheng, S.W.; Stoney, R.J. Optimal Exposure of the Proximal Abdominal Aorta: A Critical Appraisal of Transabdominal Medial Visceral Rotation. J. Vasc. Surg. 1994, 19, 375. 15. Okuhn, S.P.; Reilly, L.M.; Bennett, J.B.; Hughes, L.D.; Goldstone, J.; Ehrenfeld, W.K.; Stoney, R.J. Intraoperative Assessment of Renal and Visceral Artery Reconstruction: The Role of Duplex Scanning and Spectral Analysis. J. Vasc. Surg. 1987, 5, 137.
16.
17.
18.
19. 20.
21. 22. 23.
24.
25.
26.
27.
28.
29.
Allen, R.C.; Martin, G.H.; Rees, C.R.; Rivera, F.J.; Talkington, C.M.; Garrett, W.V.; Smith, B.L.; Pearl, G.J.; Diamond, N.G.; Lee, S.P.; Thompson, J.E. Mesenteric Angioplasty in the Treatment of Chronic Intestinal Ischemia. J. Vasc. Surg. 1996, 24, 415. Rose, S.C.; Quigley, T.M.; Raker, E.J. Revascularization for Chronic Mesenteric Ischemia: Comparison of Operative Arterial Bypass Grafting and Percutaneous Transluminal Angioplasty. J. Vasc. Interv. Radiol. 1995, 6, 339. Schneider, D.B.; Schneider, P.A.; Reilly, L.M.; Ehrenfeld, W.K.; Messina, L.M.; Stoney, R.J. Reoperation for Recurrent Chronic Visceral Ischemia. J. Vasc. Surg. 1998, 27, 276. Bergan, J.J.; Dry, L.; Conn, J.J.; Trippel, O.H. Intestinal Ischemic Syndrome. Ann. Surg. 1969, 169, 120. Stoney, R.J.; Wylie, E.J. Surgery of Celiac and Mesenteric Arteries. In Vascular Surgery Principles and Techniques, 2nd Ed.; Haimovici, H., Ed.; McGraw-Hill: New York, 1976; 668– 679. Fry, W.J.; Kraft, R.D. Visceral Angina. Surg. Gynecol. Obstet. 1963, 117, 417. Perdue, G.D.; Smith, R.B. Intestinal Ischemia Due to Mesenteric Arterial Disease. Am. Surg. 1970, 36, 152. Stoney, R.J.; Olcott, C., IV. Visceral Artery Syndromes and Reconstruction. Surg. Clin. North. Am. 1979, 59, 637. Cunningham, C.G.; Reilly, L.M.; Rapp, J.H.; Schneider, P.A.; Stoney, R.J. Chronic Visceral Ischemia. Three Decades of Progress. Ann. Surg. 1991, 214, 276. Wylie, E.J.; Stoney, R.J.; Ehrenfeld, W.K. Manual of Vascular Surgery; Egdahl, R.H., Ed.; Springer-Verlag: New York, 1986; Vol. I. Rheudasil, J.M.; Stewart, M.T.; Schellack, J.V.; Smith, R.B.d.; Salam, A.A.; Perdue, G.D. Surgical Treatment of Chronic Mesenteric Arterial Insufficiency. J. Vasc. Surg. 1988, 8, 495. MacFarlane, S.D.; Bcebe, H.G. Progress in Chronic Mesenteric Arterial Ischemia. J. Cardiovasc. Surg. 1989, 30, 178. Calderon, M.; Reul, G.J.; Gregoric, I.D.; Jacobs, M.J.; Duncan, J.M.; Ott, D.A.; Livesay, J.J.; Cooley, D.A. LongTerm Results of the Surgical Management of Symptomatic Chronic Intestinal Ischemia. J. Cardiovasc. Surg. 1992, 33, 723. McAfee, M.K.; Cherry, K.J., Jr.; Naessens, J.M.; Pairolero, P.C.; Hallett, J.W., Jr.; Gloviczki, P.; Bower, T.C. Influence of Complete Revascularization on Chronic Mesenteric Ischemia. Am. J. Surg. 1992, 164, 220.
Chapter 60. 30.
Gentile, A.T.; Moneta, G.L.; Taylor, L.M., Jr.; Park, T.C.; McConnell, D.B.; Porter, J.M. Isolated Bypass to the Superior Mesenteric Artery for Intestinal Ischemia. Arch. Surg. 1994, 129, 926. 31. McMillan, W.D.; McCarthy, W.J.; Bresticker, M.R.; Pearce, W.H.; Schneider, J.R.; Golan, J.F.; Yao, J.S. Mesenteric Artery Bypass: Objective Patency Determination. J. Vasc. Surg. 1995, 21, 729.
Chronic Visceral Ischemia: A Surgical Condition 32.
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Johnston, K.W.; Lindsay, T.F.; Walker, P.M.; Kalman, P.G. Mesenteric Arterial Bypass Grafts: Early and Late Results and Suggested Surgical Approach for Chronic and Acute Mesenteric Ischemia. Surgery 1995, 118, 1. Moawad, J.; McKinsey, J.F.; Wyble, C.W.; Bassiouny, H.S.; Schwartz, L.B.; Gewertz, B.L. Current Results of Surgical Therapy for Chronic Mesenteric Ischemia. Arch. Surg. 1997, 132, 613.
CHAPTER 61
Sexual Function and Vascular Surgery Ralph G. DePalma sal closure of venous outflow; during erection, intracavernous pressure increases to levels ranging from 80 to 90 mmHg. Higher intracavernous pressures contributing to penile rigidity are generated by contraction of the pelvic floor muscles. The physiology and anatomy of penile erection have recently been reviewed.[11,12] Recent findings indicate that endothelially derived relaxant factor is involved in nonadrenergic, noncholinergic neural transmission, which leads to cavernosal smooth-muscle relaxation required for normal erection.[14] Histochemically, nerve fibers positive for the reduced form of nicotinamide – adenine dinucleotide phosphate and diaphorase are found in human penile tissue, indicating nitric oxide synthase activity.[15] Other neurotransmitters such as vasoactive intestinal polypeptide and fibers positive for acetylcholinesterase are also present.[16] When the penis is flaccid, the corporal smooth muscle is contracted; contraction is due to a normally present overriding adrenergic tone. With erection, smooth-muscle relaxation occurs. Various other receptors are present in penile smooth muscle, including those responsive to vasoactive intestinal polypeptide, dopamine, histamine, prostaglandin (PG), and probably several other substances. The initiating event of penile erection is vasodilation. With increased intracavernosal flow, an increased amount of oxygen is thought to stimulate nitric oxide synthesis by cavernosal nerves and endothelium.[17] Cavernosal oxygenation promotes penile erection, whereas hypoxemia is inhibitory. Testosterone, in addition to its central effects, has been shown experimentally to stimulate nitric oxide synthase activity in corporal tissues,[18] enhancing sensitivity to cavernosal nerve stimulation in animals. Nitric oxide, in turn, activates conversion of guanosine triphosphate to cyclic guanosine monophosphate (cGMP), providing a message leading to relaxation of the smooth muscle within the corpora cavernosa.[19] Agents that inhibit hydrolysis of cGMP may increase levels of messenger cGMP enhancing smooth-vessel relaxation, thus promoting penile erection.[20] Cyclic nucleotide phophodiesterase (PDE) isoenzymes increase hydrolysis of cGMP; among these PDE5 and PDE6 are specific for the substrate in human cavernosal tissue.[21] Inhibitors of PDE comprise a new class of oral agents for treatment of impotence.
Since arterial blood flow into the corpora cavernosa initiates and maintains penile erection, important relationships exist between sexual function and vascular surgery. Leriche’s 1923 paper[1] listed impotence as the first symptom in men with aortoiliac occlusion. Highly successful operations were developed to correct aortoiliac occlusive and aneurysmal disease; however, these procedures themselves often provoked postoperative impotence and other sexual disabilities.[2,3] Sexual dysfunction after aortoiliac reconstruction is caused by failure to perfuse the internal iliac arteries or by injury to the genital autonomic nerves. In the last decade, techniques of aortic reconstruction have evolved to minimize these complications.[4 – 8] In some men, these reconstructive methods also offer the prospect of restored erectile function. As methods to prevent or treat impotence due to aortoiliac disease evolved, it was recognized that small vessel occlusion also causes vasculogenic impotence.[9,10] Within the last decade, interest in the entity of vasculogenic impotence has increased, and advances in its diagnosis and treatment have been made. Arterial disease of the pudendal arteries themselves as well as pudendal interruption caused by embolism or trauma were documented by selective internal iliac angiography. Cavernosal leakage and intrinsic dysfunctions of the corpora also cause vasculogenic impotence.[11] Table 61-1 provides a general overview of the causes of vasculogenic impotence. From the standpoint of the general vascular surgeon, interest in and knowledge of the techniques of aortic reconstruction to prevent sexual dysfunction postoperatively are paramount. This chapter also reviews current concepts of the physiology of normal erection as well as current medical and surgical approaches to the diagnosis and treatment of impotence.
PHYSIOLOGY OF ERECTION Penile erection requires adequate arterial inflow and closure of venous outflow. Both are mediated by intact neural mechanisms and relaxation of the smooth muscle of the corpora cavernosa. Increased arterial inflow causes caverno-
Hobson/Wilson/Veith: Vascular Surgery: Principles and Practice, Third Edition, Revised and Expanded DOI: 10.1081/0819-9-120024945 Copyright q 2004 by Marcel Dekker, Inc.
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Table 61-1.
Classification of Vasculogenic Impotence
Arterial Large vessel Aorta and branches to internal iliac division Small vessel Proper pudendal and penile arteries Combined Embolic to cavernosal arteries from aortic aneurysm or ulcerated plaques Cavernosal Fibrosis Idiopathic or postpriapic Peyronie’s disease Deformity and /or venous leakage Refractory states Diabetes, antihypertensive drugs, hormonal Venous Congenital Cavernous-spongious leak Acquired Cavernosal leak syndrome
plaques. Finally, an estimation of testicular size completes the physical examination. Atrophy or absence of testicular mass suggests the diagnosis of primary hypogonadism. However, in men with vasculogenic impotence, physical examination alone is often unrevealing.
NONINVASIVE LABORATORY TESTING FOR IMPOTENCE In patients presenting with the primary complaint of impotence, the author recommends noninvasive neurovascular tests prior to the office visit. These tests help select patients for further studies or procedures. The following sequence of testing has been reviewed[22,23] and is further described.
VASCULAR TESTING Penile Brachial Pressure Indices
HISTORY AND PHYSICAL EXAMINATION Both history and physical examination contribute clues to the possible etiology of impotence. Gradual erectile failure occurring in the absence of traumatic life events and associated with vascular disease of the lower extremity suggests large vessel arteriogenic impotence. In these men the intensity and duration of atherosclerotic risk factors—mainly smoking, hypertension, diabetes, and hypercholesterolemia— contribute to atherosclerosis and arteriogenic impotence. The disease pattern involves the aortoiliac segments and often the first segment of the internal iliac artery. Abdominal aortic aneurysms and ulcerative atheromatous disease of the abdominal aorta also cause embolic occlusion of the pudendal arteries. Traumatic arterial occlusions are caused by perineal or pelvic injuries; this trauma history is important. Urologic, vascular, or rectal operations also cause impotence. Thus, the history of the immediate onset of erectile failure following an operation is critical. Postoperative erectile dysfunction can be due to either vascular or neural interruption or both. Alcohol and drug abuse contribute to erectile failure. Drugs used to treat hypertension commonly cause erectile failure. Diabetes leads to erectile failure in several ways because of its vascular, neuropathic, and metabolic effects. On physical examination, absence of distal pulses suggests large vessel disease. Femoral bruits in the presence of normal femoral pulses suggest pelvic or internal iliac disease. While sensory testing of the extremities, perineum, or glans occasionally reveals neuropathies associated with impotence in diabetics, noninvasive testing must be routinely employed to detect subtle neuropathic changes. To complete the physical examination, the prostate should be examined, along with palpation of the corpora cavernosa for Peyronie’s
The Penile brachial pressure index (PBPI) is a ratio between systolic pressure detected by a Doppler probe placed distal to a penile cuff and systemic or brachial arm pressure. On an average-size penis, a cuff of at least 2.5 cm is used. The cuff is inflated and then deflated. Reappearance of Doppler signals in the dorsal artery branches just proximal to the corona of the glans signals reflow. Normally, this pressure is systemic. A PBPI above 0.75 suggests that no major occlusion exists between the aorta and the distal measurement point. A PBPI of less than 0.6 suggests major vascular obstruction in the aortoiliac beds. A PBPI between 0.75 and 0.6 is abnormal and may be associated with lesions involving the internal pudendal and penile arteries.
Penile Plethysmographic Pulse Volume Recordings With the penis in the flaccid state, the plethysmographic pulse volume recording (PPVR) is performed using a pneumoplethysmographic cuff with a contained transducer. The variables recorded are crest, time, waveform, and presence or absence of a dicrotic notch. The PPVR measures total pulsation of all penile arteries as the cuff compresses the penile tissue. The cuff is applied and inflated to mean arterial pressure calculated as diastolic plus one-third of systemic pressure. Waveforms are recorded on a polygraph with a chart speed of 25 mm/s and a sensitivity setting of 1. Normally, the upstroke of the waveform is completed by 0.2 s (5 mm); normal wave form amplitudes vary from 5–6 to 30 mm in height. Figure 61-1 shows data obtained from potent and impotent men using both these tests. Recently we have correlated the sensitivity and specificity of these tests with arteriography. Noninvasive screening was 85% sensitive and 70% specific.
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oral medications, intraurethral or intracavernous instillation of vasoactive agents fail or vacuum constrictor devices prove ineffective, workup would include more elaborate and invasive delineation of erectile physiology. We continue to use prescreening with penile brachial indices and penile pulse volume recordings prior to an office visit as this is simple and cost-effective and also helps determine doses of intracavernous or intraurethral agents.[28]
INTRACAVERNOUS INJECTION
Figure 61-1. (A ) Correlation of pulse-volume recordings with penile brachial indices. (B,C ) Characteristic pulse-volume recordings and penile brachial indices in potent and impotent men. [From Depalma R: Prevention of sexual dysfunction in aorta-iliac surgery. In Jamieson C (ed): Current Operative Surgery. London, Bailliere Tindall, 1985. Reproduced by permission.]
Neurologic Testing Subtle neurologic disorders may contribute to erectile failure. Among 290 impotent men evaluated, 84, or 28%, exhibited at least one neurologic abnormality. The reader is referred to these publications[22 – 24] for methods and normal reference latencies for pudendal, lumbar, and cortical somatosensory evoked potentials. Since many impotent patients are diabetics, pudendal responses can usefully be compared with spinal and cortical evoked potential responses elicited from posterior tibial nerve stimulation. Mean bulbocavernosus reflex time in our laboratory is 28.3 –37.5 ms. Abnormal neurologic findings on noninvasive testing contraindicate vascular operations for impotence and provide an important indication for prosthetic insertion. Neurologic testing is valuable in evaluating the complaint of impotence following injury or operations on the rectum, genitourinary tract, or aorta. These are now used selectively by the author. Various noninvasive or invasive alternatives can be used to investigate the chief complaint of impotence. The current approach is a limited patient goal–directed approach depending on clinical presentation and responsiveness to initial therapy.[25 – 27] Should simple measures such as
In 1982 it was found that erection could be stimulated by intracavernous injection (ICI) of the vasoactive agents papervine[29] and phentolamine.[30] This discovery helped to illuminate the process of cavernosal smooth muscle function as well as providing important tools for diagnosis and treatment. The use of prostaglandin E1 10 –20 mg has been found to be effective and safe.[11] Observation of a normal erection after ICI suggests that the arterial system is capable of delivering adequate inflow and that corporal smoothmuscle relaxation and venous closure are relatively functional. Failure to erect implies a possible need for further testing, although on occasion anxiety in the clinical situation can produce enhanced androgenic tone, which will override ICI. Interestingly, heavy cigarette smoking just before injection of 80 mg of papervine in normal young volunteers inhibited erection in a significant number.[31]
DUPLEX DOPPLER SCANNING Dorsal and deep cavernosal arteries can be examined by duplex Doppler scanning at intervals before and after intracorporeal injection of vasoactive agents. There has been increasing interest in this noninvasive method of evaluating both arterial inflow and venous leakage.[32 – 34] It has been suggested that Doppler measurement of maximal systolic velocity in the cavernosal arteries after vasoactive injection is an accurate indicator of arterial inflow. Asymmetric flow in the cavernosal arteries also suggests arterial insufficiency. The increase in diameter of the cavernosal arteries after injection is not predictive of proximal arterial patency. However, for definitive diagnosis of pudendal arterial insufficiency and venous leakage, further invasive studies must be undertaken, especially when surgery is to be considered for the primary complaint of impotence. My approach is to observe the quality of erection after increasing doses of ICI and use duplex scanning when failure occurs or a Peyronie’s plaque is found. Ultrasonography can also be used at the same time to scan for an abdominal aneurysm. A recent study demonstrates pitfalls of ultrasonography in evalution of the veno-occlusive mechanism.[35] Duplex scanning with evaluation of end diastolic flow showed 22% false-positive results based on subsequent nocturnal penile tumescence monitoring, which proved normal in 8 of 37 men. These findings suggest anxiety in the clinical setting where duplex scanning was done.
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NOCTURNAL PENILE TUMESCENCE MONITORING Nocturnal penile tumescence (NPT) monitoring is not used routinely but selected when psychogenic impotence is likely or in cases of injury with continuing medico-legal issues. Optimal NPT study is performed in a sleep laboratory with 3 nights of monitoring and measurement of penile rigidity when erection occurs.[36] Normal penile rigidity or pressure is taken at 400– 500 g of axial buckling pressure. This test is both time-consuming and expensive, but it is important because a normal sleep erection virtually rules out organic erectile dysfunction. For screening purposes, RigiScan home NPT monitor is also employed. This might help by minimizing both expense and anxiety in the clinical situation.
CAVERNOSOMETRY AND CAVERNOSAL ARTERY OCCLUSION PRESSURE These tests provide estimates of both venous leakage and arterial perfusion. These are invasive tests generally done in collaboration with our colleagues in urology and radiology. During maximal erection, sinusoidal pressure at some point equilibrates with arterial inflow pressure and flow ceases: this value is cavernosal artery occlusion pressure (CAOP). During studies using fine needles inserted into the cavernous bodies, it is possible to measure CAOP with a Doppler probe. When arterial pressure is reduced by proximal occlusion, penile rigidity cannot occur. Cavernosal pressure also cannot rise when venous leakage is excessive. Such leakage can be due either to congenital problems or to the more commonly acquired leaks through the tunica albuginea. The techniques previously reported by the author[23] have been modified from those described by Bookstein et al.,[37] Goldstein,[38] and Lue et al.[39] To perform cavernosometry and cavernosography, two 21-gauge butterfly needles are placed into each corpora cavernosa for the influsion of pharmacologic agents, saline, and pressure monitoring. Constant cavernosal pressure monitoring and an automatic infusion pump are used; 60 mg of papaverine and 1 mg of phentolamine are diluted to a total volume of 5 mL and injected. After 15 min heparinized saline is infused at a rate of 20 mL/min. The infusion rate is gradually increased until a rigid erection occurs. Cavernosal artery pressure than usually exceeds 100 mmHg; the infusion rate is lowered to achieve a steady-state cavernosal pressure at this level. This allows recording of the rate of flow to induce erection (FIE) and flow to maintain erection (FME). Infusion rate is then further increased to produce a suprasystolic cavernosal pressure of 150 mmHg, and the infusion is stopped. The rate of fall of cavernosal pressure over the succeeding 30 s is recorded. We consider FME to be the most important measurement. To visualize venous leaks, diluted nonionic contrast is injected and spot filming at various angles is performed to identify specific abnormal opacified veins. An FME that is considered to be normal has been estimated at various levels.
Figure 61-2. Technique of aortoiliac endarterectomy. (A ) Exposure and (B ) arteriotomy preserve inferior mesenteric artery and sympathetic nerves. [From Depalma R: Prevention of sexual dysfunction in aorto-iliac surgery. In Jamieson C (ed): Current Operative Surgery. London, Bailliere Tindall, 1985. Reproduced by permission.]
An FME above 45 mL/min exceeds the ability of even a normal arterial system to compensate for increased venous leakage. Goldstein,[40] for example, posits that a decline in pressure exceeding 1 mmHg/s from a cavernosal pressure of 150 mmHg suggests cavernosal leakage. Following these measurements, CAOP is measured using a Doppler probe. The CAOP is thought to be normal when it is greater than 90 mmHg. However, the cavernosal-brachial gradient must be considered. In some cases, a gradient greater than 30 mmHg suggests arterial flow reduction even if the CAOP is greater than 90 mmHg. When CAOP is abnormal and if reconstruction is considered, highly selective pudendal arteriography following intracavernosal injection of vasoactive agents is also required as a separate procedure. This procedure can be performed at the same time as cavernosometry.
VASCULAR OPERATIONS AND PREVENTION OF SEXUAL DISTURBANCES Operations for Aortoiliac Occlusive Disease The operative principles used to prevent sexual disabilities employ dissection methods which preserve both vascular and neural elements of the erectile processes. These procedures restore or maintain internal iliac flow, avoid atheroembolism, and minimize nerve injuries caused by dissection. In selected cases, endarterectomy using a nerve-sparing technique is a useful procedure (Fig. 61-2). The use of common iliac stents has been found to be useful, while external iliac stenting may reduce steal from the internal pudendal axis via the superior gluteal artery.[35]
Chapter 61.
While erectile failure is the most common postoperative sexual disability related to aortoiliac surgery, interruption of autonomic nerve fibers in the periaortic area can also cause ejaculatory dysfunction. This phenomenon may be distressing for certain men and their partners. In couples desiring pregnancy, anejaculation can be a serious complication. Anorgasmia in the presence of normal penile erection is a rare and distressing neural complication of aortoiliac dissections. To avoid these complications, the use of nerve-sparing dissection techniques is worthwhile. Figures 61-2 through 61-5 illustrate techniques for large vessel reconstruction for obstructive disease.
Aortoiliac Aneurysm Repair In planning aortic aneurysm repair, it is important to have information about the anatomy of the internal iliac arteries prior to operation. In these cases, the author recommends
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aortography prior to aneurysm repair. This step is also important in detecting other abnormalities such as accessory renal arteries or suprarenal aneurysmal involvement. Oblique views will ensure adequate visualization of the internal iliac and its branches. An inlay technique for abdominal aortic aneurysmectomy is used. This method minimizes interference with the neural fibers and preserves collaterals of the inferior mesenteric artery. Incision into the aorta is made to the right, avoiding the neural plexuses on the left side. The orifice of the inferior mesenteric artery is sutured from within. Techniques of aneurysm reconstruction are illustrated in Fig. 61-6. Overall, the results of aortoiliac surgery for large vessel disease and associated impotence have been satisfying.[8] Among 125 patients operated on by the author who were preoperatively impotent, 38 regained potency; 30 patients who were potent preoperatively remained potent. The average age of postoperatively potent patients in each group was 57.9 and 57.3 years, respectively. Of 125 patients, 4 sustained the
Figure 61-3. Acceptable technique for aortoiliac and aortofemoral bypasses. (A and A1) End-to-end aortic anastomosis with suprainguinal end-to-side bypasses when the external iliac arteries are relatively uninvolved. (B and B1) Acceptable method of reconstruction when the external iliac arteries are occluded or stenotic. End-to-end aortic anastomosis is employed proximally. Distally end-to-side or side-to-side anastomoses may be used as shown. [From Depalma R: Prevention of sexual dysfunction in aorto-iliac surgery. In Jamieson C (ed): Current Operative Surgery. London, Bailliere Tindall, 1985. Reproduced by permission.]
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Figure 61-4. (A, B ) Transluminal angioplasty combined with femorofemoral bypass for totally occluded right common iliac artery and stenotic left common iliac artery. (C ) Bilateral internal iliac artery flow is improved. [From DePalma R: Prevention of sexual dysfunction in aorto-iliac surgery. In Jamieson C (ed): Current Operative Surgery. London, Bailliere Tindall, 1985. Reproduced by permission.]
complication of postoperative impotence. These patients, rendered impotent by aortoiliac surgery, were those who required emergency procedures; 1 had internal iliac artery aneurysms requiring ligation. It is important to note that the average age of 53 impotent men pre- and postoperatively was 65.1 years; the postoperatively potent patients, by contrast,
approximated 57 –58 years of age. The effects of aging on penile erection require consideration. In a report[41] on the effects of age on sexual function and on nocturnal penile tumescence, a significant negative relationship was noted between age and sexual desire, arousal, and nocturnal activity. The prevalence of sexual dysfunction increases with age. Of significant importance are age-related decreases in frequency, duration, and degree of nocturnal penile tumescence, which clearly correlate with these changes. It is not known whether the aging effect relates to vascular disease or to some component of the normal aging process affecting the cavernosal tissues. In assessing results of aortoiliac surgery, age is clearly a critical factor affecting prospects for return of sexual function.
OPERATIONS SPECIFICALLY FOR IMPOTENCE Internal Iliac Endarterectomy
Figure 61-5. Technique of axillobifemoral graft with hood of the graft being extended over the stenotic origin of the deep femoral artery. [From DePalma R: Prevention of sexual dysfunction in aorto-iliac surgery. In Jamieson C (ed): Current Operative Surgery. London, Bailliere Tindall, 1985. Reproduced by permission.]
When the segmental distribution of atherosclerosis involves the internal iliac arteries, endarterectomy can be accomplished. Selective angiography detects isolated lesions of the main iliac internal artery or its divisions, including the pudendal artery supplying the penis. Selective angiography is done using intracorporeal injection of vasoactive agents to induce artificial erection to better expose penile runoff. The anatomy of the internal pudendal artery is illustrated in
Chapter 61.
Figure 61-6. (A ) Technique of aortic and aortoiliac aneurysm repair by the inlay method. Note incision in the right side of the aneurysm. The iliac arteries are clamped after minimal mobilization. (B ) Straight graft sutured in place with minimal dissection of aneurysm wall. (C ) Bifurcation graft placed to preserve nerves crossing left iliac artery. [From DePalma R: Prevention of sexual dysfunction in aorto-iliac surgery. In Jamieson C (ed): Current Operative Surgery. London, Bailliere Tindall, 1985. Reproduced by permission.]
Fig. 61-7. Exposure of the internal iliac artery lends itself well to an extraperitoneal approach. This exposure is illustrated in Fig. 61-8. Occasionally, endarterectomy of the distal reaches of the internal iliac artery can excise plaque at the origin of the pudendal artery at the level of the greater sciatic notch. After
Figure 61-7. Illustration of right internal pudendal artery and its branches as seen on highly selective angiography.
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Figure 61-8. Exposure and techniques from endarterectomy of or bypass to the right internal iliac artery. (From DePalma et al.[42] Reproduced by permission.)
renal transplantation, bypasses are also used to restore flow to a patent pudendal outflow tract.
PENILE MICROVASCULAR SURGERY Microvascular bypass procedures for the treatment of erectile dysfunction were introduced in 1973 using direct implantation of the inferior epigastric artery into the corpora.[43] These procedures failed due to fibrosis at the level of the graft-tunica junction and poor runoff.[5] At present, these operations employ mainly revascularization of the dorsal penile artery using microvascular techniques.[42] In this author’s experience, the inferior epigastric artery has been uniformly useful as a neoarterial source (Fig. 61-9). Rates of success in penile microvascular surgery have been reported to vary from 31 to 80%, depending in part on patient selection.[11] The best candidates are young men with discrete lesions of the pudendal artery, common penile artery, or both. An alternative approach is arterialization of the deep dorsal vein using the inferior epigastric artery. This procedure, shown in Fig. 61-10, was initially described by Virag et al.[44] It has also been reported to have variable results. Success rates range from 20 to 75%.[11] Important
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Figure 61-9. Technique of dorsal penile artery microvascular bypass. (From DePalma et al.[42] reproduced by permission.)
complications include priapism and hyperemia of the glans penis.
VENOUS INTERRUPTION PROCEDURES When impotence is due to corporal veno-occlusive dysfunction, surgery aims to decrease the excessive venous outflow. The following criteria to select patients are suggested: (1) a flow to maintain erection of greater than 40 mL/min; (2) normal cavernosal artery occlusion pressure (i.e., greater than 90 and less than 20 mmHg between the brachial and cavernosal artery pressures); (3) absence of diabetes and treatment for hypertension or endocrine abnormalities; and (4) normal selective pudendal arteriography. Experience in the diagnosis and treatment of venous ligation surgery has been summarized by Lewis.[45] Correction of radiographically proven deep penile dorsal vein leakage into the obturator pudendal and internal iliac veins has been useful in the author’s experience when this is the sole source of leakage.[46] A variety of surgical approaches have been used to treat other sites of leakage, including spongiolysis where leaks are occurring between the corpus
Figure 61-10. Deep dorsal vein arterialization. Variations: (A ) Completed inferior epigastric artery to deep dorsal vein arterialization ligatures proximally and distally. (B ) Completed anastomosis without distal ligature: glans hypervascularization has complicated this type of procedure. (C ) Dorsal artery to deep dorsal vein arteriovenous fistula with overlying graft (Hauri’s variation.) (From DePalma et al.[42] Reproduced by permission.)
cavernosum and spongiosum. Recently, to evaluate the efficacy of venous ligation, postoperative dynamic cavernosography and cavernosometry at 3 months has been recommended. The addition of embolic radiographic techniques can improve results to correct residual or recurrent venous leakage detected postoperatively.[47] Venous interruption operations are still evolutionary. Reports in the literature concerning their effectiveness also range widely, from 28 to 76%.[11] Long-term follow-up for significant numbers of patients is now about 3 years. The increased use of postoperative cavernosography and cavernosometry will be important in assessing the efficacy of these procedures as well as in ruling out sham effects.[48]
Chapter 61.
In considering vascular intervention for treatment of impotence, it is important to define subsets of anatomic patterns of vascular involvement.[49] Hatzichristou and Goldstein[50] have described angiographic patterns in procedure selection focusing on planning of microvascular procedures for penile revascularization based on localized disease. The following broader subsets of anatomic patterns can be considered: 1. 2. 3. 4.
Aortoiliac macrovascular disease Pudendal and penile artery segments obstruction Diffuse obliterative penile artery disease Cavernosal leakage: congenital or acquired
Based on data obtained by meta-analysis, a recent report in the urologic literature[51] concluded that the results of venous and arterial surgery, predominantly microvascular, did not appear to justify routine use for treatment of erectile failure. The controversies surrounding vascular and microvascular interventions for impotence were reviewed recently.[49] It is clear that no life table data on potency have been published in the urologic literature as usually shown in reports of patency and limb salvage in the vascular literature. While most men increasingly respond to medical therapy, a subset of men— approximately 6–7% of those complaining of impotence— fail to respond to medical treatment, intracavernous injection, or vacuum devices.[52] Those men become candidates for either revascularization or prosthetic implantation. Since prosthetic implantation precludes a physiologic erection, some might choose revascularization as a first step. The future applicability of microvascular procedures such as dorsal penile artery bypass, deep dorsal vein arterialization, and venous interruption require scrutiny and long-term follow-up based on selected cohorts with comparable anatomic and physiologic bases or vasculogenic impotence. Younger patients with pelvic trauma are probably the best candidates for these procedure, but they are not the only candidates. An important exception resides in that challenging group of men with aortoiliac disease, particularly those with aneurysms and localized pelvic arterial occlusive disease. In a recent report of 10 years of experience with vascular interventions for impotence, men with the sole complaint of impotence underwent interventions for aortoiliac aneurysms or occlusive disease.[52] In these men, 58% resumed spontaneous function over follow-up periods ranging from 33 to 48 months; an additional 15% functioned with intracavernosally administered agents or vacuum constrictor devices. These men with aortoiliac disease averaged 61 years of age. In contrast, during the same period, men selected for microvascular procedures for penile artery bypass, deep dorsal vein arterialization, and venous ligation had an average age of 42–47.3 years. This age difference was statistically significantly at a p-value of 0.001 by analysis of variance. A significant difference between observed and expected frequencies of spontaneous erection was shown between those undergoing aortoiliac intervention and men having penile arterial or venous procedures. At 33–48 months after these operations, only 27–33% of these men reported spontaneous erections. When intracavernosal administration of PGE or vacuum constrictor devices were added, however, 72– 77% reported functional erections that could not be previously obtained.
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MEDICAL TREATMENT As noted, many men respond to medical treatment, and as seen from a consideration of physiology, erectile failure is a vascular dysfunction. However, impotence can also be caused by endocrine, metabolic, neurogenic, and psychological factors. Some form of arterial inflow abnormality is associated with this complaint about half of patients screened noninvasively.[13] However, this finding, as will be seen, is not always caused by macrovascular inflow compromise. Arteriogenic impotence can also be related to intrinsic penile artery or smooth muscle abnormalities. Endocrine causes of impotence are uncommon;[12,53] only 3–4% of patients screened show lowered testosterone, and prolactinomas are also rare—about 0.2. Similarly restoration of a euthyroid state has not notably improved erectile function in hypothyroidism. The most common association with arteriogenic impotence is a variety of antihypertensive drugs; angiotensin-converting enzyme inhibitors are thought to spare erectile function. Antidepressants such as selective serotonin uptake inhibitors reduce sexual behavior and thus affect potency. Bupropion, another class of antidepressant, exhibits prosexual behavior including effects on libido, arousal, and duration and intensity of orgasm.[54] Oral medications for erectile dysfunction include phentolamine, yohimbine, trazodone, pentoxifylline, apomorphine, and sildenafil.[55] Isoxsuprine, an alpha1-blocker, has also been useful.[56] Sildenafil, a Type V phosphodiesterase inhibitor, the main isoenzyme innvolved in the metabolism of cyclic guanosine monophosphate in the corpus cavernosum,[57] has been approved for use in the United States. The reader will appreciate that diagnosis and treatment are intertwined. Figure 61-11 offers a branched-chain logical approach to diagnosis and treatment. Note that initial treatment is medical and that the various noninvasive or invasive alternatives are employed selectively. Treatment begins with a limited patient goal–directed approach, depending on responsiveness or unresponsiveness to initial therapy.[27] If simple measures such as oral medications fail, more elaborate investigations are advised. Should the intracavernosal or intraurethral administration of vasoactive agents fail or vacuum constrictor devices prove ineffective, workup would then progress to invasive delineation of abnormal physiology. This approach assumes that significant macrovascular disease such as aneurysm is ruled out.
CONCLUSIONS There has been remarkable progress in the last two decades in the diagnosis and treatment of impotence. This has resulted in a specialized journal, the International Journal of Impotence Research, with contributions from many specialties including urology, vascular surgery, radiology, internal medicine, and the basic scientific disciplines. The availability of drugs administered by injection, intraurethral instillation, or orally that act directly upon the smooth muscle of the corpora cavernosum has been a revolutionary advance. For the vascular surgeon, the need for understanding and avoiding iatrogenic impotence is critical. Prior to aortoiliac surgery,
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Figure 61-11. Branched-chain logic illustrating sequences of testing and treatment for impotence. Broken lines indicate optional steps. Note that surgical treatment, bottom right, will comprise a minority unresponsive to conservative treatment.
Chapter 61.
careful inquiries should be made as to the importance and frequency of sexual function. Although modern techniques offer greatly improved function, some patients become dysfunctional postoperatively and should be warned of this possibility. Such patients in particular are those experiencing
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atheroembolization, emergency procedures, and internal iliac aneurysms. These individuals require careful attention, investigation, and treatment, which might require prosthetic insertion. A sensitive approach to problems related to sexual dysfunction in vascular patients will be rewarding.
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Leriche, R. Des Obliterations Arterielle Hautes (Obliteration de la Terminasion de l’Aorte) Comme Causes des Insuffisances Circulatoires des Membres Inferieurs. Bull. Mem. Soc. Chir. 1923, 49, 1404. May, A.G.; DeWeese, J.A.; Rolo, C.G. Changes in Sexual Function Following Operation on the Abdominal Aorta. Surgery 1969, 65, 41. Sabri, S.; Cotton, L.T. Sexual Function Following AortoIliac Reconstruction. Lancet 1971, 2, 121. DePalma, R.G. Aorto-Iliac Dissection Principles. In Vasculogenic Impotence; Zorgniotti, A., Rossi, G., Eds.; Springfield, IL: Thomas, 1980; 299– 308. DePalma, R.G.; Kedia, K.; Persky, L. Vascular Operations for Preservation of Sexual Function. In Surgery of the Aorta and Its Body Branches; Bergan, J.J., Yao, J.S.T., Eds.; Grune & Stratton: New York, 1979; 277– 296. Weinstein, M.H.; Machleder, H.I. Sexual Function After Aorto-Iliac Surgery. Ann. Surg. 1974, 181, 787. DePalma, R.G. Etiology and Management of Sexual Problems Related to Aorto-Iliac Disease and Surgery. In Current Critical Problems in Vascular Surgery; Veith, F.J., Ed.; Appleton-Century-Crofts: New York, 1982; 429– 443. DePalma, R.G.; Edwards, C.M.; Schwab, F.J.; Steinberg, D.L. Modern Management of Impotence Associated with Aortic Surgery. In Arterial Surgery: New Diagnostic and Operative Techniques; Bergan, J.J., Yao, J.S.T., Eds.; Grune and Stratton: Orlando, FL, 1988; 337– 348. Ginestie, J.F.; Romieu, A. Radiologic Exploration of Impotence; The Hague: Martinus Nijhoff, 1978. Ware, J.C.; Kryger, M.H.; Roth, T.; Dement, W.C., (Eds.) Vasculogenic Impotence; Thomas: Springfield, IL, 1980. Krane, R.J.; Goldstein, I.; DeTejada, I.N. Medical Progress. Impotence. N. Engl. J. Med. 1989, 321, 1648. DePalma, R.G. New Developments in the Diagnosis and Treatment of Impotence. West. J. Med. 1996, 164, 54. DePalma, R.G. Anatomy and Physiology of Normal Erection. In The Basic Science of Vascular Disease; Sidawy, A.D., Sumpio, B.E., DePalma, R.G., Eds.; Futura: Armonk, NY, 1997; 701– 773. Rajfer, J.; Aronson, W.J.; Bush, P.A.; Dorey, F.J.; Ignarro, L.J. Nitric Oxide as a Mediator of Relaxation of the Corpus Cavernosum in Response to Nonadrenergic Neurotransmission. N. Engl. J. Med. 1992, 326, 90. Gopalakrishnakone, P.; Adaikan, P.G.; Ponraj, G.; Ratnamm, S.S. NADPH-Diaphorase and VIP Positive Nerve Fibres in Human Penile Erectile Tissue (abstr.). Int. J. Impot. Res. 1994, 6 (Suppl. I), A26. Adaikan, P.G. Physiopharmacological Basis of Treatment for Erectile Dysfunction (abstr). Int. J. Impot. Res. 1994, 6 (Suppl. 1), PL1.
17.
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Azsadzoi, K.M.; Nehra, A.; Siroky, M.B. Effects of Cavernosal Hypoxia and Oxygenation on Penile Erection (abstr). Int. J. Impot. Res. 1994, (Suppl. I), D4. Brock, G.B.; Zvara, P.; Sioufi, R.; et al. Nitric Oxide Synthase Is Testosterone Dependent (abstr). Int. J. Impot. Res. 1994, 6 (Suppl. I), D42. Burnett, A.L. Role of Nitric Oxide in the Physiology of Erection. Biol. Reprod. 1995, 52, 485. Beavo, J.A. Cyclic Nucleotide Phosphodiesterases: Functional Implication of Multiple Isoforms. Physiol. Rev. 1995, 75, 725. Gingell, C.; Ballard, S.A.; Tang, K.; et al. Cyclic Nucleotide Phosphodiesterase and Erectile Function. Int. J. Impot. Res. 1997, 9 (Suppl. I), 510. DePalma, R.G.; Emsellem, H.A.; Edwards, C.M.; et al. A Screening Sequence for Vasculogenic Impotence. J. Vasc. Surg. 1987, 5, 228. DePalma, R.G.; Schwab, F.J.; Emsellem, H.A.; et al. Noninvasive Assessment of Impotence. In NonInvasive Diagnosis of Vascular Diseases; Pearce, W.H., Yao, J.S.T., Eds.; Saunders: Philadelphia, PA, 1990; 119–132. Emsellem, H.A.; Bergsrud, D.W.; Depalma, R.G. Pudendal Evoked Potentials in the Evaluation of Impotence (ABS). J. Clin. Neurophysiol. 1988, 359, 5. DePalma, R.G.; Emsellem, H.A.; Edwards, C.M.; et al. A Screening Sequence for Vasculogenic Impotence. J. Vasc. Surg. 1997, 5, 228. DePalma, R.G. What Constitutes an Adequate Impotence Workup? World J. Urol. 1992, 10, 157. Lue, T.F. Impotence: A. Patient’s Goal-Directed Approach to Treatment. World J. Urol. 1990, 8, 67. DePalma, R.G.; Ball, E.M. Cost Effective Approach to the Diagnosis and Treatment of Impotence. Int. J. Impot. Res. 1996, 8, 171. Virag, R. Intracavernous Injection of Papaverine for Erectile Failure (letter). Lancet 1982, 2, 938. Brindley, G.S. Pilot Experiments on the Actions of Drugs Injected into the Human Corpus Cavernosum Penis. Br. J. Pharmacol. 1986, 87, 495. Glina, S.; Reichelt, A.S.; Leao, P.P.; Dos Reis, J.M. Impact of Cigarette Smoking on Papaverine-Induced Erection. J. Urol. 1988, 140, 523. Lue, T.F.; Hricak, H.; Marick, K.W. Evaluation of Vasculogenic Impotence with High Resolution Ultrasonography. Radiology 1985, 155, 777. Quam, J.P.; King, B.F.; James, E.M.; et al. Duplex and Color Doppler Sonographic Evaluation of Vasculogenic Impotence. Am. J. Roentgenol. 1989, 153, 1141.
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34. Schwartz, A.U.; Wang, K.Y.; Mack, L.A.; et al. Evaluation of Normal Erectile Function with Color Flow Doppler Sonography. Am. J. Roentgenol. 1989, 153, 1155. 35. Mansour, M.O.A. Anxiety Mediated Impotence Misdiagnosis as Venogenic Impotence by Color Duplex Scanning: A Comparison with Nocturnal Tumescence Monitoring. Int. J. Impot. Res. 1994, 6 (Suppl. I), A30. 36. Ware, J.C.; Kryger, M.H.; Roth, T.; Dement, W.C., (Eds.) Principles and Practice of Sleep Medicine; W.B. Saunders: Philadelphia, 1989; 689–695. 37. Bookstein, J.J.; Fellmeth, B.; Moreland, S. Pharmacoangiographic Assessment of the Corpora Cavernosa. Cardiovasc Interv. Radiol. 1988, 11, 218. 38. Goldstein, I. Overview of Types and Results of Vascular Surgical Procedures for Impotence. Cardiovasc. Interv. Radiol. 1988, 11, 240. 39. Lue, T.F.; Hricak, H.; Schmidt, R.; Tanagho, E.A. Functional Evaluation of Penile Veins by Cavernosography in Papaverine-Induced Erection. J. Urol. 1986, 135, 476. 40. Goldstein, I. Vasculogenic Impotence: Its Diagnosis and Treatment. In Sexual Dysfunction Problems in Urology; Devere-White, R., Ed.; Lippincott: Philadelphia, PA, 1987; 547– 563. 41. Schiavi, R.C.; Schreiner-Engel, P.; Mandeli, F.; et al. Healthy Aging and Male Sexual Function. Am. J. Psychiatry 1990, 146, 6. 42. DePalma, R.G.; Olding, M.; Schwab, F.J. Vascular Surgery for Impotence. In Techniques in Arterial Surgery; Bergan, J.J., Yao, J.S.T., Eds.; Saunders: Philadelphia, PA, 1990; 294– 301. 43. Michal, V.; Kramar, R.; Pospichal, J.; Heihal, L. Direct Arterial Anastomosis on Corpora Cavemosa Penis in the Therapy of Erective Impotence. Rozhl. Chir. 1973, 52, 587. 44. Virag, R.; Frydmann, D.; Legman, H.; Bouily, P. Possibilities Chirurgicales dans l’Impuissance Vasculaire. Gaz. Med. Fr. 1983, 90, 2031.
45. Lewis, R.W. Venous Ligation Surgery for Venous Leakage. Int. J. Imp. Res. 1990, 2, 1. 46. DePalma, R.G.; Schwab, F.; Druy, E.M.; et al. Experience in Diagnosis and Treatment of Impotence Caused by Cavernosal Leak Syndrome. J. Vasc. Surg. 1989, 10, 117. 47. Yu, G.W.; Schwab, F.J.; Melograno, F.S.; et al. Preoperative and Postoperative Dynamic Cavernosography and Cavernosometry: Objective Assessment of Venous Ligation for Impotence. J. Urol. 1992, 147, 618. 48. DePalma, R.G. Editorial Comment (Letter). Int. J. Impot. Res. 1989, 1, 150. 49. DePalma, R.G. Vascular Surgery for Impotence: A Review. Int. J. Impot. Res. 1997, 9, 61. 50. Hatzichristou, D.; Goldstein, I. Penile Microvascular Arterial Bypass. Surg. Annu. 1993, 2, 208. 51. Montague, D.K.; Barada, F.H.; Belker, A.M.; et al. Clinical Guidelines Panel on Erectile Dysfunction; Summary Report on the Treatment of Organic Erectile Dysfunction. J. Urol. 1996, 156, 2007. 52. DePalma, R.G.; Olding, M.; Yu, G.E.; et al. Vascular Interventions for Impotence; Lessons Learned. J. Vasc. Surg. 1995, 21, 76. 53. Keogh, E.T.; Earle, C.M.; Chew, K.K.; et al. Medical Management of Impotence (abstr.). Int. J. Impot. Res. 1994, 6 (Suppl. I), S13. 54. Modell, J.G.; Katholi, C.R.; Modell, J.D.; DePalma, R.L. Comparative Side Effects of Bupropion, Fluoxetine, Paroxetine and Sertralinestraline. Clin. Pharmacol. Ther. 1997, 61, 476. 55. Lue, T.F. Oral Medication for Erectile Dysfunction. Int. J. Impot Res. 1997, 9, 511. 56. DePalma, R.G. Impotence in Vascular Disease: Relationship to Vascular Surgery. Br J. Surg. 1982, 69, 514. 57. Boolell, M.; Allen, M.S.; Ballard, S.A.; et al. Sildenafil: An Orally Active Type 5 Cyclic GMP Specific Phosphodiesterase Inhibitor for the Treatment of Penile Erectile Dysfunction. Int. J. Impot. Res. 1996, 8, 47.
CHAPTER 62
Thoracic Outlet Disorders: Thoracic Outlet Compression Syndrome and Axillary Vein Thrombosis Herbert I. Machleder
The term thoracic outlet compression syndrome first appeared in the medical literature as used by Rob and Standeven[1] in 1958. The significance of this change in nomenclature was the impetus it gave at a critical point to categorization of a group of painful disorders involving the shoulder and upper extremity. The idea of unifying a group of diverse neurovascular compression syndromes arising at the shoulder girdle was ready for acceptance, and in subsequent literature there was an attempt to define the underlying anatomical variations which resulted in the symptom complex in the majority of these patients. Although there was now a clear tendency to focus attention on some common basic structural relationship, long-standing biases which crossed interdisciplinary lines continued to confuse the diagnosis and therapy of thoracic outlet compression syndrome. For about a century prior to this pivotal period, neurovascular compression phenomena around the shoulder girdle were classified relative to either the suspected specific compressive component or the suspected etiologic abnormality. A diffuse literature, therefore, exists describing the costoclavicular syndrome, cervical rib syndrome, scalenus anticus syndrome, subclavius tendon syndrome, pectoralis minor muscle syndrome, and effort thrombosis or Paget-Schroetter syndrome. The syndrome is characterized by symptoms of neurovascular compression at the thoracic outlet and occurs widely within the population in a spectrum ranging from mild numbness and tingling of the fingers when the arms are placed in certain stress positions to severe functional disability and incapacitation, venous hypertension, and arterial insufficiency to a degree where digital gangrene and ischemic tissue loss become manifest. In a recent epidemiologic study, thoracic outlet compression was considered “an important often neglected cause of cervical brachial pain, weakness and sensory disturbance.”[2]
CERVICAL RIB Historically, the evolution in recognition of thoracic outlet compression has moved synchronously with changing concepts of etiology and therapy. The earliest wellrecognized description in the English literature was the neurovascular compressive effects of a cervical rib. The opportunity to identify a distinct anatomic characteristic in this particular group of individuals focused attention on the cervical rib as the dominant structural abnormality for many years. In 1861, Holmes Coote resected a cervical rib in a patient hospitalized at St. Bartholomew’s in London and demonstrated its clear-cut relationship with a large subclavian aneurysm.[3,4] With the perfection of radiographic techniques the identification of the cervical rib became more common, and reports in the medical literature subsequent to this initial description were authored by John B. Murphy and William S. Halsted. By the early 1920s, thoracic outlet neurovascular compression by cervical rib was a well-accepted concept.[5,6] With increasing interest and attention focused on the problem, it became evident that a large group of patients presented with fairly typical symptoms of neurovascular compression at the thoracic outlet without evidence of an accompanying cervical rib or any other demonstrable musculoskeletal structural abnormality. It was also clear that although some patients presented with signs and symptoms predominantly of arterial insufficiency, a small group of patients presented with evidence of intermittent venous obstruction, and still the largest group of patients presented predominantly with symptoms of nerve compression of the brachial plexus. Despite these vagaries it was evident that the compressive phenomenon was located at the thoracic outlet where the neurovascular bundle passes between the clavicle and first rib.
Hobson/Wilson/Veith: Vascular Surgery: Principles and Practice, Third Edition, Revised and Expanded DOI: 10.1081/0819-9-120024946 Copyright q 2004 by Marcel Dekker, Inc.
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SCALENE MUSCLE In 1938 Naffziger introduced the concept of the scalenus anticus syndrome as one of the group of anomalies encompassed by the broader category of thoracic outlet compression. It was thought that the scalenus anticus muscle compressed the brachial plexus and vascular structures by tension and eventual fibrosis and adhesions.[7] Acceptance of this concept by the medical and surgical community was widespread, and division of the scalenus anticus muscle in the neck gained favor as a therapeutic maneuver for a large group of patients suffering from thoracic outlet compression with or without an accompanying cervical rib.[8] Treatment, however, continued to be plagued by a high rate of symptomatic recidivism, and the quest continued for more effective means of decompression or enlargement of the thoracic outlet.
FIRST THORACIC RIB Telford and Stopford[9] reported that the compression syndrome could be relieved by resection of the normal first rib, postulating that this structure formed the underlying unyielding base of the thoracic outlet tunnel. Concomitant with this new concept, there were reattempts to identify specific manifestations of compression with more specific abnormalities of thoracic outlet configuration. Notable in this regard were the studies of McCleery et al.,[10] who felt that intermittent compression and obstruction of the subclavian vein was most likely caused by impingement on the vein by the subclavius muscle and tendon at the most medial aspect of the thoracic outlet channel. They recommended resection of the subclavian tendon as an effective method of decompression of the proximal thoracic outlet. The surgical approach to the thoracic outlet was brought around full circle, anatomically, when Rosati and Lord[11] recommended claviculectomy as a method of removing the roof of the thoracic tunnel, thereby providing adequate and effective long-term decompression. The operation, however, was rather disfiguring from a cosmetic standpoint and was not popular, particularly in young individuals who seemed to have a much higher incidence of thoracic outlet compression requiring surgical correction. As follow-up of patients improved and long-term results were analyzed, the pivotal role of the first thoracic rib began to take on much greater significance as a structure common to all of the manifestations of thoracic outlet compression. Whether the compressive phenomena were medially, centrally, or laterally located, resulting in either venous arterial or brachial plexus compression, the first rib seemed to be a common underlying structure with the accessory component being the subclavius tendon, scalenus anticus muscle, a rudimentary or well-developed cervical rib, or an exostosis of the first rib. Resection of the first rib gained increasing acceptance then as the procedure that would most likely provide long-term and adequate decompression along the whole lower dimension of the thoracic outlet. Resection of the first rib by the posterior approach was reintroduced and described by Clagett[12] in 1962. Based on
this work and the excellent results afforded by first thoracic rib resection, Roos[13] popularized the transaxillary approach, which is retained today as the most common surgical method of first thoracic rib resection. The relative ease of operation coupled with low morbidity and excellent cosmetic result has served to establish this procedure as the standard for first rib resection.
ANATOMY AND PATHOPHYSIOLOGY Normal Anatomy The historical evolution of therapeutic and diagnostic concepts in thoracic outlet compression is best understood by reviewing the anatomic structures that form the boundaries of the thoracic outlet (Fig. 62-1). The thoracic outlet can be visualized in a triangular configuration with the apex directed toward the manubrium of the sternum. The base of the triangle is made up of the first thoracic rib, and the hypotenuse or superior limb is made up of the clavicle and underlying subclavius muscle and tendon. The medially disposed apex of the triangle can also be thought of as the fulcrum of a pair of scissor blades such that they form a more or less acute apical angle, depending on arm position. It is this scissor movement that accounts for the symptoms and signs that occur in the various stress position maneuvers. At the most medial aspect of the thoracic outlet, the subclavian vein exits the thorax and demarcates the entrance to the thoracic outlet tunnel. At this point the first rib and clavicular head join the manubrium of the sternum in a fibrocartilaginous joint. The subclavius tendon, which lies just beneath the clavicle, inserts at the junction of the first rib and clavicle, and with enlargement and hypertrophy can serve to indent the subclavian vein at that acute apical angle. The structure of the thoracic outlet continues laterally, as the clavicle and subclavius muscle form the roof, and the generally flat, smooth superior surface of the first rib forms the floor. A more or less prominent tubercle occurs at the superior posterior surface of the first rib at the site of insertion of the scalenus anticus muscle, which is the second structure to enter the thoracic outlet just lateral to the subclavian vein. The scalenus anticus muscle has a fairly consistent insertion on the posterior margin of the thoracic rib. This insertion may vary in its extent along the rib margin and probably accounts for some elements of neurovascular compression when the muscle is particularly hypertrophic or is accompanied by posttraumatic or congenital fibrotic bands. The section of first rib which lies laterally and adjacent to the scalenus anticus insertion is a common site of fusion for either a welldeveloped cervical rib or the rudimentary fibrocartilaginous bands, which have been implicated in many instances of thoracic outlet compression. The subclavian artery is the third structure entering the normal thoracic outlet, just lateral to the insertion of the scalenus anticus muscle. The artery enters the thoracic outlet from a somewhat more cephalad location, as the innominate artery branches to form the arch of the subclavian and right common carotid arteries. An apparently high arching subclavian artery is a fairly distinctive characteristic of thoracic outlet compression. This relatively
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Figure 62-1. Anatomic configuration of thoracic outlet as seen from an anterior perspective. The clavicle has been reflected laterally from the manubrium, hinged on its acromial attachment. The first rib can be seen underlying the thoracic outlet structures and attaching to the manubrium of the sternum, and the pectoralis minor tendon inserting on the coracoid process. (From Machleder, H.I.: Vascular Disorders of the Upper Extremity, 2d ed. Mt. Kisco, New York, Futura Press, 1989. With permission.)
high arch may be related to descent of the clavicle toward the first rib position and may well be significant to the development of thoracic compression in those patients with this propensity. Insertions of cervical ribs and fibrocartilaginous bands are also observed just lateral to the subclavian artery, and occasionally a synostosis or exostosis will be found in this portion of the first thoracic rib. Lateral to the subclavian artery, the brachial plexus enters the thoracic outlet with the C7 and T1 roots disposed inferiorly and the C4, C5, and C6 roots oriented superiorly. Lateral to the brachial plexus, the scalenus medius muscle has a rather broad and variable attachment to the first rib and may be traversed by the long thoracic nerve innervating the serratus anterior muscle.
Scalene Muscle Abnormalities Early descriptions[7,8] of scalene muscle abnormalities have led recent investigators[14,15] to reexamine the characteristics of this muscle, using contemporary techniques of histochemical and morphometric analysis.
Human skeletal muscle usually comprises predominantly type 2, quick-reacting fibers that have low oxidative enzyme capacity and increased reactivity with phosphorylase and myosin ATPase. A smaller percentage of slow, tonic, contracting type 1 fibers, characterized by greater oxidative capacity, complete the complement. The enzyme systems within muscle fibers are largely determined by the pattern of contractile activity, with tonic stimulation increasing oxidative activity and decreasing glycolytic activity. These changes are manifest histochemically by reduced staining reactivity with phosphorylase and myosin ATPase and greater reactivity with nicotinamide adenine dinucleotide –tetrazolium reductase, a mitochondrial oxidative enzyme. Studies of normal anterior scalene muscle have demonstrated a predominance of type 1 fibers to a degree unparalleled in human skeletal muscle. This characteristic provides scalene muscle with a unique structure for maintaining sustained contraction (Fig. 62-2).[14] The increasing dominance, and hypertrophy, of type 1 fibers in thoracic outlet compression syndrome was described in 1986 by the group working at UCLA[14] and was subsequently confirmed by Sanders and Pearce[16] as well
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Figure 62-2. (A ) Anterior scalene muscle from a patient with thoracic outlet compression syndrome. There is hypertrophy and predominance of type 1 (pale-staining) fibers. Type 2 (dark-staining) fibers are sparse (110£). (B ) Residual anterior scalene muscle 6 months after scalenotomy, illustrating atrophy and decreased representation of the type 1 fiber system (myosin adenosine triphosphatase, pH 9.3, 110£). (From Ref. 14.)
as by Stoney[17] at the University of California in San Francisco. Using a computerized planometric technique, Sanders and coworkers demonstrated increased connective tissue in anterior and middle scalene muscles of patients with posttraumatic thoracic outlet compression symptoms (TOS). It is their impression that fibrosis, as originally described by Ochsner et al.,[8] is an important element in the pathophysiology of this disorder. These particular myopathic changes in the scalene muscles have not as yet been corroborated by other investigators. The results of current studies strongly suggest that in patients with thoracic outlet compression syndrome there exists a striking adaptive transformation and recruitment response in the type 1 fiber system, reflecting chronic increased tone or motor neuron stimulation. In posttraumatic thoracic outlet compression syndrome, it seems particularly likely that stretch injury to the muscle initiates a response characterized by muscle contraction and brachial plexus stimulation that, if uninterrupted, serves to accentuate and perpetuate the neurovascular compressive phenomenon. This area clearly represents a useful field for further investigation. Recently the role of the scalene muscle has been further demonstrated by Jordan and Machleder.[18]
Although multiple abnormalities can account for reduction of the available space in the thoracic outlet, the rigid boundaries are formed by the clavicle superiorly and the first rib inferiorly. It has remained evident that the most effective decompression, irrespective of the specific site of impingement, will be a surgical procedure directed at one of the rigid structures.
CLINICAL PRESENTATION Despite advances in the therapy of thoracic outlet compression syndrome and careful attention to anatomic details, the basic underlying pathophysiology remains enigmatic. Even the readily demonstrable cervical rib has an unclear relationship to the basic disease process. Cervical ribs occur with considerable frequency in the asymptomatic population and make up only as many as 25% of patients who have well-established thoracic outlet compression symptoms. The symptoms, which begin in the second, third, and fourth decades of life, may arise spontaneously. More commonly, relatively minor shoulder or cervical trauma can precipitate the entire symptom complex in a previously asymptomatic individual. It has been noted at the time of surgery that
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congenital fibrocartilaginous bands traverse the brachial plexus and enter various portions of the thoracic outlet. Clavicular fracture and hyperextension neck injuries also seem to result in rather typical symptoms of thoracic outlet compression. There are developmental changes in the clavicular sternal angle over the passage of time, particularly after adolescence, that bear some relationship to changes in anatomic configuration of the thoracic outlet and probably account for the peculiar age distribution of this syndrome. It would seem likely that in some individuals the close tolerance of clearance space existing in the thoracic outlet is easily upset by cervical brachial trauma, with the resultant muscle spasm generating a cycle of pain, spasm, and increasing disability, which often cannot be interrupted without surgical intervention. The spectrum of thoracic outlet compression symptoms ranges from mild to disabling, as previously described. The specific symptom complex of the compressive phenomena can be attributed to the region of the neurovascular bundle affected. Arterial compression is perhaps the least common, comprising only 1% of all cases seen. These patients may present with typical Raynaud-type symptoms or indeed may have intermittent ischemia and rubor of their hands and digits. Occasionally peripheral embolization and frank gangrene of the fingertips will arise from arterial compression at the thoracic outlet. Venous compression occurs slightly more commonly and often may present rather suddenly. Although deep venous thrombosis in the upper extremity is uncommon (approximately 2% of all cases of deep venous thrombosis) and occasionally is associated with congestive heart failure and metastatic or mediastinal tumors, it is most commonly associated with effort thrombosis. Spontaneous thrombosis of the subclavian vein was described by Sir James Paget in 1875 and again by Von Schroetter in 1884. This event has often been referred to as the Paget-Schroetter syndrome.[19,20] The syndrome, however, is most likely secondary to thoracic outlet compression and occurs generally after extreme effort involving the upper extremity, as in weight lifting, tugging, and stressful activities with the arms in the abducted, externally rotated position. Clinically the patient may have a painful injury in the shoulder region followed in several days by swelling of the fingers, forearm, or entire upper extremity, with great difficulty using the arms in abduction or external rotation. The clinical course is rather protracted, with continued disability being the rule rather than the exception. Collateral venous channels do develop over time, but normal activity is rarely feasible in the presence of chronic subclavian vein occlusion. Patients who develop acute thrombosis of the subclavian vein should be hospitalized immediately for an attempt at thrombolytic therapy. Two approaches have been utilized: first, the use of systemic fibrinolytic drugs such as streptokinase, or, second, heparinization as a temporizing measure, which will rarely result in lysis of the thrombus or significant improvement in the patient’s symptoms. The objectives of heparinization are to prevent propagation of thrombus during the early period of stabilization and to avoid the loss of important collateral veins in the supraclavicular
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and thoracic outlet area. More recently, direct intravenous local fibrinolytic therapy has been utilized with varying success. The catheter is placed via the antecubital veins directly into the axillosubclavian vein thrombus, and streptokinase therapy is begun with lower doses than are required for general systemic therapy. The streptokinase activates plasminogen to plasmin, and clot lysis should take place over a period of 12–24 h. This should be followed by heparin and then dicumarol anticoagulation for maintenance of patency and prevention of rethrombosis. Arm elevation should be avoided in these instances because it generally exacerbates the symptoms and may also complicate the compressive phenomena at the thoracic outlet. These patients, whose thrombosis is based on thoracic outlet compression, should then be considered for early decompression by first rib resection or scalenectomy. Venography is very helpful in demonstrating compression after the vein has regained patency. Perhaps the most frequent manifestation of thoracic outlet compression involves the brachial plexus. Two patterns of brachial plexus compression have emerged: first is that affecting the upper cords and generally presenting with pain in the side of the neck, head, and suprascapular area of the trapezius muscle as well as the lateral shoulder and radial nerve distribution of the arm. The second type of brachial plexus compression involves predominantly lower plexus involvement and is likewise characterized by pain in the suprascapular area of the trapezius muscle, the neck and shoulder, and the ulnar aspect of the arm from axilla down to the ulnar nerve distribution in the fingers.[21] In all of the various manifestations of thoracic outlet compression, patients typically complain of specific physical or occupational disability. The syndrome is particularly stressful in waitresses, who are unable to maintain their arms in abduction and external rotation in carrying trays of food and dishes; plumbers, carpenters, and mechanics, who work with their arms above their heads, also find particular disability relative to their occupational requirements. Driving poses considerable difficulty related to numbness and tingling of the fingers. Women will often complain of pain and weakness when reaching for objects above their heads, fixing or washing their hair, and other activities of a similar nature. The syndrome is seen with particular severity in certain athletes, especially baseball pitchers and swimmers. Even sedentary activities can be significantly affected by thoracic outlet compression and can lead to occupational disability in typists and keyboard operators, who develop rapid tiring and reduction of speed and accuracy in addition to pain and weakness. In these sedentary workers particularly, thoracic outlet compression symptoms must be differentiated from other peripheral nerve entrapment such as carpal tunnel syndrome, which entraps the median nerve at the wrist and may give rise to very similar hand, wrist, and forearm symptoms. Ulnar nerve entrapment at the olecranon groove may also present in a similar manner. Generally these conditions are easily differentiated by clinical evaluation and physical examination. Epidemiologically there appears to be a bimodal distribution of individuals with thoracic outlet compression. One group is composed of individuals with extensive muscle development around the shoulder and upper arm, whose
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compression is very likely related to muscle hypertrophy and the stress of their activities. Another group are individuals of very asthenic habitus, this latter group being more responsive to physical therapy and attempts to restore the normal postural relationships of the upper thorax.
NONINVASIVE LABORATORY EVALUATION Vascular Tests Although the majority of patients present with neurologic rather than vascular impairment, various stages of vascular compressive phenomena can be demonstrated in most patients with documented thoracic outlet compression syndrome. This hemodynamically significant compressive phenomenon can be documented using appropriate thoracic outlet maneuvers, and the pulse volume and pressure changes can be verified by simple tests available in the peripheral vascular laboratory, the simplest test being measurement of bilateral brachial artery pressure using the Doppler flowmeter. The Doppler flow signal can be assessed at either the brachial, radial, or ulnar arteries. A reduction of 20 mmHg or more from the neutral to the stress position, or when comparing one side to the other, is considered indicative of a positive test. Digital plethysmography can be utilized as an alternative to direct pressure measurement, and the damping factor of the systolic waveform shape can be noted with various thoracic outlet maneuvers. As a consequence of extensive potential collateralization around the subclavian artery, there will often be a palpable or Doppler-detectable radial or ulnar pulse despite complete obstruction of the subclavian artery at the level of the thoracic outlet. A pressure discrepancy or abnormality detected in the neutral position should indicate to the clinician the desirability of angiographic investigation to better evaluate the presence of a significant stenosis, poststenotic dilatation, or atherosclerotic degeneration of the vessel at the point of trauma. Significant venous obstruction in the upper extremity can be detected using the Doppler flowmeter, although clinically this approach is not applied very frequently. Changes in venous flow pattern with the arm placed in various thoracic outlet maneuvers has enabled some investigators to diagnose venous obstructive phenomena accurately and consistently.[22]
neurologic dysfunction of the upper extremity. These studies are of particular usefulness in separating thoracic outlet compression symptoms from carpal tunnel median nerve compression, which occasionally presents with a similar pattern and overlapping disability. Carpal tunnel compression syndrome of the median nerve occurs in about 10% of patients with well-documented thoracic outlet obstruction. Early experience using somatosensory evoked potentials suggests that this method of evaluating peripheral nerve function may prove more helpful in documenting the neurologic abnormalities seen with thoracic outlet compression syndrome.
Somatosensory Evoked Response In 1979, Siivola et al.[23] described the use of multiple recording positions between wrist and scalp to delineate more accurately the site of a peripheral nerve lesion at the brachial plexus. They established latencies and amplitudes from median and ulnar nerve stimulation in normal persons and described the case of a 47-year-old woman with TOS and a brachial plexus lesion. This first reported use of somatosensory evoked response (SEP) in the evaluation of TOS compared median and ulnar amplitudes between the right and left arms. The accuracy of sensory evoked responses in the diagnosis of TOS was further explored by Glover et al.[24] and Siivola et al.[25,26] In 1987, Machleder and associates[27] studied a large number of patients pre- and postoperatively and described a specific protocol for interpretation of the somatosensory evoked responses in thoracic outlet compression. The receiver operator curves were constructed to favor specificity over sensitivity such that a false-positive test would be very unusual. The evoked responses were abnormal in 74% of patients having an established clinical diagnosis of thoracic outlet compression syndrome, with a substantial number of the remaining patients having evidence of vascular compression (26%). In an analysis of the pre- and postoperative studies, 92% of the patients demonstrated an excellent correlation between test results and clinical course. Relief of symptoms was reflected in improved test outcome, while patients with continued symptoms had test results indicating persistent or residual nerve dysfunction (Fig. 62-3).[27]
Electrophysiologic Blocks Electrophysiologic Tests A number of electrophysiologic tests have been used in an attempt to further delineate the thoracic outlet syndrome, but results have been quite variable. It is generally conceded that nerve conduction times and electromyography have relatively little value in establishing a definitive diagnosis of thoracic outlet compression. Nerve conduction across Erb’s point, the olecranon groove, and the carpal tunnel is useful in establishing other causes for apparent
Anesthetic block of the anterior scalene muscle has been used in the past as a diagnostic test by investigators and clinicians. A recent report described the use of electrophysiologic guidance for the accurate performance of specific muscle blockade. This technique has proven valuable as an adjunctive measure to diagnosis of neurovascular compression at the level of the brachial plexus. It helps to differentiate radicular-type pain and dysesthesias, which may be coming from the nerve root, brachial plexus, or peripheral nerve.[18]
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Figure 62-3. Right ulnar (A ) and left ulnar (B ) preoperative and left ulnar postoperative (C ) sensory evoked response tracings from a patient with thoracic outlet compression syndrome. Sensory and motor deficits were present in the distribution of the lower cord of the brachial plexus. Note the improved amplitude at Erb’s point (peripheral peak, recorded over the brachial plexus, P). This change, after first rib resection, coincided with relief of symptoms. (From Ref. 27.)
PHYSICAL EXAMINATION Physical examination of the patient with complaints suggestive of thoracic outlet compression should include a complete examination of the head and neck to detect signs of cervical spine disease and discogenic disease with radiculopathy, as well as cervical osteoarthritis with neuroforaminal compression. Although neck pain is quite common with thoracic outlet compression syndrome, restriction of normal neck movement and flexibility or tenderness over the cervical spine is not usually seen. Compression of the disk spaces by downward pressure on the head rarely elicits symptoms in patients with thoracic outlet compression syndrome but may be quite useful in demonstrating cervical discogenic disease. Muscle spasm and tenderness can often be encountered in patients with thoracic outlet compression, particularly at the lateral border of the trapezius muscle and along the lateral border of the sternocleidomastoid muscle, over the course of the scalenus anticus muscle and brachial plexus. Tenderness
to pressure over the brachial plexus is also characteristically found in patients with thoracic outlet neurovascular compression. Clavicular percussion on the symptomatic side will often provoke symptoms, whereas it is generally easily tolerated on the noninvolved side. Palpation of the radial pulse, with the arm in the neutral position, then using the various thoracic outlet maneuvers—Adson’s maneuver, the costoclavicular maneuver, and the scalenus anticus maneuver—and the abduction external rotation position is useful to detect changes in pulse volume. Very often the positional change will evoke the symptom complex, particularly with abduction and external rotation. With the arm in the abducted and externally rotated position (as with a hand raised in a greeting), rapid clenching and unclenching of the hand will lead to fatigue, tiring, and inability to maintain the position for more than 60 –90 s. Normally this type of activity is well tolerated for 3 –5 min. A bruit is very commonly heard at the lateral third of the infraclavicular area as the arm is brought from neutral into the abducted, externally rotated position. Occasionally the bruit is
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better heard at the lateral portion of the supraclavicular fossa. The bruit typically extends through only a short range of movement, and unless auscultation takes place continually, as the arm is moved from neutral to abduction and external rotation, the bruit may well be missed as the pulse is obliterated and the volume flow reduced. Although one or another of these signs may be elicited in normally asymptomatic individuals, which has prompted some investigators to denigrate the value of positional evaluation, it is the constellation of signs and the presence of concomitant symptoms, together with a fairly typical history, that establishes the diagnosis of thoracic outlet compression. The isolated finding of one abnormality on physical examination is generally insufficient to diagnose thoracic outlet compression reliably. It has been demonstrated in the past that a number of asymptomatic individuals obliterate their pulse with extreme abduction or hyperabduction. Additionally the finding of a cervical rib on routine chest x-ray does not establish the diagnosis of thoracic outlet compression. Adson’s test, for example, long the hallmark of thoracic outlet compression, has been reported to be positive in less than 3% of patients diagnosed, treated, and cured of the syndrome.[28] The hyperabduction maneuver, for years an important diagnostic feature of this syndrome, was demonstrated by Wright to be positive in more than 80% of normal individuals.[29] Supernumerary ribs occur in 0.5 –1% of the asymptomatic population.[30] The clinical significance of this lack of specificity of the diagnostic tests is diminished when placed in the context of the complete clinical evaluation.
ANGIOGRAPHY Although the vast majority of patients suffering from thoracic outlet compression present with symptoms of brachial plexus nerve compression, vascular presentations, such as acute axillosubclavian vein thrombosis, or acute ischemic events associated with intermittent subclavian artery obstruction or distal embolization are indications for angiography. Patients who have unequivocal signs of arterial insufficiency, such as evidence of peripheral embolization, Raynaud’s syndrome, asymmetry of resting brachial artery pressures in the neutral position, or evidence of a subclavian bruit in the neutral position, should undergo arteriography to delineate significant arterial damage, particularly atherosclerotic stenosis at the point of compression or poststenotic dilatation and aneurysm formation. Typically, angiography is performed via the transfemoral arterial route with the patient in the supine position, although it is occasionally difficult to demonstrate any areas of compression using this technique even when the patient has unequivocal clinical signs of arterial compression. This problem has been clarified with the advent of digital intravenous angiography, and we have found that patients having normal arteriographic findings in the abducted, externally rotated position while supine will demonstrate unequivocal compression in the sitting position. The difficulty of doing standard angiography in the sitting position has limited its usefulness in this regard, and the greater mobility of the patient during digital
angiography has helped us recognize this limitation. The patient should be studied arteriographically with arms in the neutral position and also in positions of thoracic outlet stress such as abduction and external rotation (Fig. 62-4). Although evidence of axillosubclavian artery compression can be demonstrated in asymptomatic individuals, this generally requires that the arm be placed in a relatively extreme degree of hyperabduction. Nevertheless, the angiogram must be interpreted cautiously where there is no clear-cut evidence of arterial damage or evidence of poststenotic dilatation. It is important to reiterate that the angiogram is best interpreted in light of the clinical evaluation, history, and physical assessment. As an isolated finding, it has unfortunately relatively little specificity. This underscores the lack of a single objective test that will help diagnose thoracic outlet compression syndrome. Gelabert and Machleder[31] recently outlined the proper interpretation of arteriographic studies at the thoracic outlet in a review of the treatment of arterial compressive abnormalities.
Venography Venography should be undertaken in patients with thoracic outlet compression whose symptoms suggest intermittent compression of the subclavian vein or actual axillosubclavian vien thrombosis. As with arteriography, the study should be performed with the arm in the neutral and then in the abducted, externally rotated position. Injection can be done in one of the hand veins using 30–40 mL of meglumine diatrizoate or by direct injection into the brachial vein. Evidence of collateralization is very important in interpreting these venographic studies.
MEDICAL THERAPY In general, once the diagnosis of thoracic outlet compression is established, a course of conservative therapy should be instituted prior to consideration of surgical intervention. It has been our experience that patients who develop the syndrome in the setting of occupational strain or muscular hypertrophy derive little benefit from a program of exercise and physical therapy. Patients in certain occupational categories—such as plumbers, carpenters, mechanics, and athletes with extensive shoulder girdle development—are generally relieved of their symptoms during a period of suspension of occupation or muscular stress. This is particularly true when the syndrome has been precipitated by some acute soft tissue trauma in the head and neck region. If the period of rest is followed by progressive rehabilitation using multimodal therapy such as diathermy, massage, and muscle relaxants, the program can often be quite beneficial. Those individuals who have posture deformities and an asthenic habitus will generally respond to a series of thoracic outlet exercises designed for postural rebalance and strengthening of the shoulder girdle.[32] In general, the response is quite prompt, and the symptoms are either severely exacerbated or the patient notes rather early beneficial signs. In those who have severe exacerbation of their symptoms, we have found it unproductive to persist with physical therapy. A number of exercises are designed for
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Thoracic Outlet Disorders: Thoracic Outlet Compression Syndrome and Axillary Vein Thrombosis
Figure 62-4. (A ) Right subclavian angiogram of a workman having rapid onset of fatigue and aching in the arm when used in the outstretched or overhead position. (B ) The characteristic area of thoracic outlet compression is seen when the arm is placed in the abducted position.
reestablishment of muscular balance of the thoracic outlet, particularly overcoming scalenus or sternocleidomastoid muscle spasm. Certain therapeutic modalities have a particular propensity for exacerbating symptoms, and in general these should be avoided. Cervical collars and cervical traction will very often cause considerable discomfort.
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One subgroup of patients becomes quite symptomatic at night. Generally, these patients sleep on their abdomens with their arms placed above the head or beneath the face. They often awaken with dysesthesias during the night, and occasionally severe vascular symptoms lead to digital ischemia. Retraining these patients to sleep with their arms at their sides and even passing a loose band around the waist, through which the arms are inserted at night, has been found to alleviate symptoms successfully. Episodes severe enough to cause digital gangrene have, in fact, been controlled using these conservative measures alone.[29] Significant changes in occupation or sports activities are an obvious means to avoid symptomatic exacerbation. We have often found that patients do make these modifications and adjustments after unsuccessfully seeking medical relief for their symptoms. Many patients, in fact, develop protective maneuvers and activities which significantly modify symptoms and may obviate the requirement for any additional therapy. At the more modest end of the symptom spectrum, patients can be reassured and quite tolerant of their mild symptoms when educated as to the nonsystemic nature of this process. Often patients are concerned that a progressive degenerative neurologic disease is developing, and that anxiety coupled with the lack of objective confirmatory evidence of disease becomes very unsettling. As a consequence, the physician is often faced with a neurotic and distraught individual. Surprisingly, a significant improvement in these individuals can be expected with patient and careful explanation on the part of the physician. As is so often the case, patients with even modest chronic pain suffer an indolent but progressive psychological disability, which acts as an impediment to their medical care and very often exacerbates interfamily and professional stresses. The fact that many of these patients have been quite successful and well adjusted prior to the onset of their symptoms should suggest considerable caution on the part of the physician in labeling any of these symptoms psychosomatic. In our experience, neurotic patterns are more commonly a result of the chronic debilitating nature of unremitting pain rather than the achievement of significant secondary gain from development of the painful disabling syndrome. Despite the effectiveness of conservative therapy in most patients, it has been reported in the literature that between 10 and 30% of patients presenting to the physician with thoracic outlet compression syndrome eventually require surgical therapy for control of their symptoms.[33] The presence of progressive arterial symptoms should particularly indicate the necessity for surgical therapy. Evidence of intermittent venous obstruction which continues despite conservative measures should also lead to the consideration of surgical therapy. Spontaneous obstruction of the subclavian vein is quite difficult to reverse, and the progression of symptoms after subclavian vein thrombosis is particularly disabling and unresponsive to therapy. In this group of patients early intervention is probably well indicated.
SURGICAL THERAPY Current surgical practice in the treatment of thoracic outlet syndrome remains controversial. Specifically there are three
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major approaches. The first is resection of the first rib, the second is scalenectomy alone, and the third is a combination of first rib resection and scalenectomy done during the same operative procedure. Kashyap et al.[34] recently reviewed some of the advantages and disadvantages of different surgical approaches.
First Rib Resection The most effective single surgical procedure is probably resection of the first thoracic rib. Two anatomic approaches have been utilized in recent years: the posterior approach as popularized by Clagett[12] and the transaxillary approach described by Roos.[13] In the transaxillary approach, the patient is positioned in the lateral decubitus position and an incision is made between the lateral border of the pectoralis major and the medial border of the latissimus dorsi muscle at the lower portion of the axilla. The rib and accompanying superior periosteum are removed after dividing the insertions of the scalenus anticus muscle and subclavius muscle tendon. The adequacy of the operation depends on removing the rib far posteriorly so that residual compression of the brachial plexus is obviated. Recuperation is generally fairly prompt, and patients usually leave the hospital by the third postoperative day (Fig. 62-5). Occasionally entrance into the pleural cavity during the operative procedure does result in pneumothorax, which is resolved by tube drainage through the incision. The tube is removed at the completion of the procedure. Residual pneumothorax may require aspiration at the time of the upright chest film in the recovery room. Two major complications have been reported with this procedure, although the exact incidence is not known. The long thoracic nerve can be injured in its position traversing the scalenus medius muscle, resulting in winging of the scapula. The other major neurologic deficit has been reported as partial, partialtemporary, or occasionally protracted paresis of the extremity from injury to the brachial plexus. Several other approaches to the first rib have been utilized, specifically the posterior and the anterior supraclavicular approaches. Insufficient numbers of these cases have been reported to assess the effectiveness when compared with the transaxillary approach. It is generally reported that between 85 and 95% of patients have good or excellent results, and approximately 5 – 10% of patients represent failures in therapy. Major complications have rarely been reported, but in a survey done by Dale there is the implication that after first rib resection, a significant number of major or minor neurologic deficits which are not reflected in the medical literature may occur.[33]
Scalenectomy The second major surgical approach to thoracic outlet compression syndrome is division of the scalenus anticus muscle or, in fact, resection of the lower portion of the muscle. This approach has been described by Sanders et al.[35] The procedure of scalenectomy involves division of the scalenus anticus muscle in the supraclavicular area and removal of the entire lower portion to the attachment of the
first rib. The scalene muscle overlies the brachial plexus, and very often fibrotic cords or tense bands can be seen compressing the brachial plexus from above. There seem to be numerous small attachments of the scalenus anticus muscle to the perineurium of the brachial plexus, and these generally must be divided with great care as the muscle is dissected back toward the insertions on the transverse processes of the cervical vertebrae. Reported complications of this procedure have been uncommon, although phrenic nerve injury has been observed. Early reports of success with this procedure are in the neighborhood of 85% excellent results, with 15% of the patients either unrelieved of their symptoms or experiencing only modest relief of pain.
Combined Operations It seems clear that if the precise cause of compression could be identified preoperatively or by objective testing, one or more of the various operative procedures might be more suitably tailored to the patient’s particular pathologic anatomy and symptom complex. Nevertheless, identification of the exact site of compression has remained elusive, and it seems evident that scalenectomy and first rib resection benefit two different groups of patients: those whose primary symptoms are upper plexus compression benefited by scalenectomy, and those whose primary symptoms are lower plexus compression benefited primarily by first rib resection. This observation has encouraged a number of surgeons to apply a combined approach, with first rib resection followed by scalenectomy at the same operative sitting. Long-term results of these combined procedures are not yet available for analysis.[36] In recent years there has been increasing interest in correcting neurovascular compression at the thoracic outlet by a supraclavicular approach. Reilly and Stoney[37] reported improvement over their previously reported results using the supraclavicular route for anterior scalene, first rib, and middle scalene excision. Most recent reports indicate that although excellent results can be anticipated initially, by the end of 2 years the recurrence rate exceeds 15% for either scalenectomy or first rib resection. Further recurrences after that period of time are not well documented, and it is unclear whether patients are lost to follow-up or whether there is no further attrition of those who have achieved excellent or satisfactory results. Sanders and Pearce,[16] in a comprehensive long-term study of their patients treated for TOS, compared the results after transaxillary first rib resection, scalenectomy alone, and supraclavicular first rib resection with scalenectomy. There were no statistically significant differences between these groups. They reported sustained improvement of symptoms in 79% of patients at 1 year, 73% at 3 years, and 69% at 10 years regardless of the initial operation performed.
Paget-Schroetter Syndrome The Paget-Schroetter syndrome—or effort thrombosis of the axillosubclavian vein, as it is commonly termed—has unique characteristics, which have a major impact on the therapeutic protocol. A comprehensive approach was described by Kunkel and Machleder[38] based on an improved under-
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Figure 62-5. (A ) The thoracic outlet as seen from the transaxillary approach to first rib resection. (B ) Resection of muscle attachments. (C ) After removal of first rib. (From Machleder, H.I.: Vascular Disorders of the Upper Extremity, 2d ed. Mt. Kisco, New York, Futura Press, 1989. With permission.)
standing of the pathophysiology as well as newer therapeutic options. This algorithm emphasized an interdisciplinary approach using recently perfected endovascular and thrombolytic techniques.
The thrombotic episode, manifest by sudden edema of the hand and arm, was routinely investigated with venography. A regimen of locally instilled, high-dose urokinase was initiated and continued until clot lysis was achieved (usually within
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24–48 h). The patient was then treated by anticoagulation with heparin until dicumeral effect had reached a therapeutic level. Excellent results were obtained when definitive therapy was delayed and anticoagulation continued until the thrombophlebitic process in the axillosubclavian vein had entirely resolved (usually 3 months).
Definitive therapy was directed at correcting the underlying venous compression at the thoracic outlet by transaxillary first rib resection and resection of the subclavius muscle tendon. When the process has been of long duration, stricture and thickening of the vein may leave a residual stenosis even after external compression has been removed. In
Figure 62-6. (A ) Following an episode of “effort thrombosis,” the characteristic area of venous compression at the thoracic outlet is seen after clot lysis. (B ) At a later interval, the first rib is removed and a residual area of vein fibrosis is corrected by balloon angioplasty. (From Refs. 38, 39.)
Chapter 62.
Thoracic Outlet Disorders: Thoracic Outlet Compression Syndrome and Axillary Vein Thrombosis
these cases, postoperative balloon angioplasty restored the luminal configuration without reocclusion or the need for venous bypass or reconstruction (Fig. 62-6).[39] There have been clear indications in the literature regarding the appropriate use of transluminal balloon angioplasty in this condition. There have likewise been a number of reports highlighting the risk of stent placement in the retroclavicular portion of the axillosubclavian vein.[40,41] Machleder has outlined an effective multidisciplinary approach that has proven effective in a large number of patients followed prospectively.[42,43] The foundation of successful treatment of patients with thoracic outlet compression syndrome rests on careful diagnostic evaluation, the basis of which is a meticulous history and physical examination, particularly in the absence of reliable, specific, objective tests. Other nerve entrapment processes must be carefully ruled out in the evaluation of these patients, particularly cervical radiculitis, discogenic disease, and nerve compression at the neuroforamina. Ulnar
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nerve entrapment and median nerve entrapment at the carpal tunnel are occasionally confusing diagnostic entities with similar presentations. It should be obvious that careful and meticulous operative technique is necessary, particularly when working around the delicate neurovascular structures and brachial plexus, to minimize postoperative fibrosis and scarring. After diagnosis, a careful program of physical therapy is generally advisable prior to the recommendation for operative intervention. This will enable the surgeon to observe the patient over a somewhat longer period of time than that afforded by an initial consultation. In general, at the time these patients reach the surgeon for therapy, they have undergone numerous consultations, diagnostic tests, and a wide spectrum of therapies of varying effectiveness and legitimacy. Very often, the patients are psychologically disabled by this course of events, and the surgeon should be prepared to deal with this difficult and challenging aspect of management.
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Rob, C.G.; Standeven, A. Arterial Occlusion Complicating Thoracic Outlet Compression Syndrome. Br. Med. J. 1958, 2, 709. Waris, T. Epidemiologic Screening of Occupational Neck and Upper Limb Disorders; Methods and Criteria. Scand. J. Work. Environ. Health 1979, 5, 25. Coote, H. Exostosis of the 7th Cervical Vertebrae Surrounded by Blood Vessels and Nerves. Lancet 1861, 1, 360. Hutchinson, J.; Jackson, J.H.; Coote, H. Pressure on the Axillary Vessels and Nerve by an Exostosis from the Cervical Rib: Interference with the Circulation of the Arm, Removal of the Rib and Exostosis, Recovery. Med. Times Gaz. 1861, 2, 108. Murphy, J.B. Case of Cervical Rib with Symptoms Resembling Subclavian Aneurysm. Ann. Surg. 1905, 41, 399. Halsted, W.S. An Experimental Study of Circumscribed Dilation of an Artery Immediately Distal to a Partially Occluding Band, and Its Bearing on a Dilation of the Subclavian Artery Observed in Certain Cases of Cervical Rib. J. Exp. Med. 1916, 24, 271. Naffziger, H.C.; Grant, W.T. Neuritis of the Brachial Plexus, Mechanical in Origin: The Scalenus Anticus Syndrome. Surg. Gynecol. Obstet. 1938, 67, 722. Ochsner, A.; Gage, M.; DeBakey, N. Scalenus Anticus [Naffziger] Syndrome. Am. J. Surg. 1935, 28, 669. Telford, E.D.; Stopford, J.S.P. The Vascular Complications of the Cervical Rib. Br. J. Surg. 1937, 18, 559. McCleery, R.S.; Kesterson, J.E.; Kirtley, J.A.; Love, R.B. Subclavius and Anterior Scalenus Muscle Compression as the Cause of Intermittent Obstruction of the Subclavian Vein. Ann. Surg. 1951, 133, 588. Rosati, L.M.; Lord, J.W. Neurovascular Compression Syndromes of the Shoulder Girdle. Modern Surgical Monographs; Grune & Stratton: New York, 1968.
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Clagett, O.T. Presidential Address: Research and Prosearch. J. Thorac. Cardiovasc. Surg. 1962, 44, 153. Roos, D.B. Transaxillary Approach for 1st Rib Resection to Relieve Thoracic Outlet Syndrome. Ann. Surg. 1966, 163, 354. Machleder, H.I.; Moll, F.; Verity, A. The Anterior Scalene Muscle in Thoracic Outlet Compression Syndrome. Arch. Surg. 1986, 121, 1141. Sanders, R.J.; Ratzin Jackson, C.G.; Banchero, N.; Pearce, W.H. Scalene Muscle Abnormalities in Traumatic Thoracic Outlet Syndrome. Am. J. Surg. 1990, 159, 231. Sanders, R.J.; Pearce, W.H. The Treatment of Thoracic Outlet Syndrome: A Comparison of Different Operations. J. Vasc. Surg. 1989, 10, 626. Stoney, R.J. Personal Communication. Jordan, S.E.; Machleder, H.I. Diagnosis of Thoracic Outlet Compression Using Electrophysiologically Guided Anterior Scalene Blocks. Ann. Vasc. Surg. 1998, 12, 260. Hughes, E.S. Venous Obstruction in the Upper Extremity. Int. Abstr. Surg. 1949, 88, 89. Adams, J.T.; Deweese, J.A. “Effort” Thrombosis of the Axillary and Subclavian Veins. J. Trauma 1971, 11, 923. Roos, D.B. The Place for Scalenectomy and 1st-Rib Resection in Thoracic Outlet Syndrome. Surgery 1982, 92, 1077. Sumner, D.S. Vascular Laboratory Diagnosis and Assessment of Upper Extremity Vascular Disorders. In Vascular Disorders of the Upper Extremity; Machleder, H.I., Ed.; Futura Press: Mt. Kisco, New York, 1989. Siivola, J.; Myllyla, V.V.; Sulg, I.; Hokkanen, E. Brachial Plexus and Radicular Neurography in Relation to Cortical Evoked Responses. J. Neurol. Neurosurg. Psychiatry 1979, 42, 1151. Glover, J.L.; Worth, R.M.; Bendick, P.J.; et al. Evoked Responses in the Diagnosis of Thoracic Outlet Syndrome. Surgery 1981, 89, 86.
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25. Siivola, J.; Sulg, I.; Pokela, R. Somatosensory Evoked Responses as a Diagnostic Aid in Thoracic Outlet Syndrome (A Preoperative Study). Acta Chir. Scand. 1982, 148, 647. 26. Siivola, J.; Pokela, R.; Sulg, I. Somatosensory Evoked Responses as a Diagnostic Aid in Thoracic Outlet Syndrome (A Postoperative Study). Acta Chir. Scand. 1983, 149, 147. 27. Machleder, H.I.; Moll, F.; Nuwer, M.; Jordan, S. Somatosensory Evoked Potentials in the Assessment of Thoracic Outlet Compression Syndrome. J. Vasc. Surg. 1987, 6, 177. 28. Ross, D.B. Pathophysiology of Congenital Anomalies and Thoracic Outlet Syndrome. Acta Clin. Belg. 1980, 79, 353. 29. Wright, I.S. The Neurovascular Syndrome Produced by Hyperabduction of the Arms. Am. Heart J. 1945, 29, 1. 30. Pollak, E.W. Surgical Anatomy of the Thoracic Outlet Syndrome. Surg. Gynecol. Obstet. 1980, 150, 97. 31. Gelabert, H.A.; Machleder, H.I. Diagnosis and Management of Arterial Compression at the Thoracic Outlet. Ann. Vasc. Surg. 1997, 11, 359. 32. Rosati, L.M.; Lord, J.W. Neurovascular Compression Syndrome of the Shoulder Girdle; Grune & Stratton: New York, 1961. 33. Dale, W.A. Thoracic Outlet Compression Syndrome: Critique in 1982. Arch. Surg. 1982, 117, 1437. 34. Kashyap, V.S.; Ahn, S.S.; Machleder, H.I. Thoracic Outlet Neurovascular Compression: Approaches to Anatomic Decompression and Their Limitations. Semin. Vasc. Surg. 1998, 11, 116.
35. Sanders, R.J.; Monsur, J.W.; Gerber, W.F.; et al. Scalenotomy vs. 1st Rib Resection for Treatment of Thoracic Outlet Syndrome. Surgery 1979, 85, 109. 36. Wylie, E.J. Discussion in Roos: The Place for Scalenectomy and 1st Rib Resection of Thoracic Outlet Syndrome. Surgery 1982, 92, 1084. 37. Reilly, L.M.; Stoney, R.J. Supraclavicular Approach for Thoracic Outlet Decompression. J. Vasc. Surg. 1988, 8, 329. 38. Kunkel, J.M.; Machleder, H.I. Treatment of PagetSchroetter Syndrome: A Staged, Multidisciplinary Approach. Arch. Surg. 1989, 124, 1153. 39. Machleder, H.I. Upper Extremity Venous Thrombosis. Semin. Vasc. Surg. 1990, 3, 1. 40. Lee, M.C.; Grassi, C.J.; Belkin, M.; Mannick, J.A.; Whittemore, A.D.; Donaldson, M.C.: Early Operative Intervention After Thrombolytic Therapy for Primary Subclavian Vein Thrombosis: An Effective Treatment Approach. J. Vasc. Surg. 1998, 27(6), 1101– 1107. 41. Azakie, A.; McElhinney, D.B.; Thompson, R.W.; Raven, A.B.; Messina, L.M.; Stoney, R.J. Surgical Management of Subclavian Vein Effort Thrombosis as a Result of Thoracic Outlet Compression. J. Vasc. Surg. 1998, 28, 777. 42. Machleder, H.I. Evaluation of a New Treatment Strategy for Paget-Schroetter’s Syndrome. J. Vasc. Surg. 1993, 17, 305. 43. Machleder, H.I. Thrombolytic Therapy and Surgery for Primary Axillo-Subclavian Vein Thrombosis: Current Approach. Semin. Vasc. Surg. 1996, 9, 46.
CHAPTER 63
Raynaud’s Syndrome and Upper Extremity Small Artery Occlusive Disease James M. Edwards Lloyd M. Taylor, Jr. John M. Porter† All physicians who treat vascular disease encounter occasional patients with fixed or intermittent upper extremity ischemia, a group estimated to comprise about 5% of patients with limb ischemia. A large majority of patients with upper extremity ischemia complaints have only intermittent vasospasm of the hands and fingers, a condition termed Raynaud’s syndrome (RS). An estimated 5 –10% of patients with upper extremity ischemia symptoms have severe hand and finger ischemia or digital ischemia ulceration associated with fixed arterial occlusive disease of the palmar and digital arteries. Only a small percentage of these patients develop distal arterial occlusion as a result of potentially correctable arterial obstruction at or proximal to the wrist, including proximal subclavian and innominate atherosclerosis, subclavian aneurysms with or without a coexistent cervical rib, subclavian and upper extremity giant cell arteritis, radiation arteritis, and associated disorders.[1 – 3] In our practice, an estimated 90 –95% percent of patients with fixed arterial occlusive disease of the palmar and digital circulation develop the condition as a complication of arteritis accompanying one or more of a variety of systemic disease processes and not as a complication of a proximal arterial occlusive disease with distal embolization. The disease distribution in our practice is clearly influenced by the nature of our referral base: during the last three decades, we in the Division of Vascular Surgery at the Oregon Health Sciences University have prospectively evaluated over 1100 patients with vasospastic and/or obstructive upper extremity small artery disease, including over 200 patients with upper extremity gangrene caused by occlusive disease of the palmar and digital arteries.[4 – 7] The disease distribution encountered in our practice may or may not accurately mirror distribution in the general population.
The discussion which follows will focus on both upper extremity vasospasm and fixed arterial occlusive disease of both the large and small arteries of the upper extremities.
RAYNAUD’S SYNDROME Raynaud’s syndrome defines a clinical condition characterized by episodic digital ischemia occurring in response to cold or emotional stimuli. All patients with RS have palmar and digital episodic vasospasm which may be primary (vasospastic RS) associated with normal arteries between attacks or may be secondary (obstructive RS) and associated with fixed palmar and digital arterial obstruction. Uncomplicated primary vasospastic RS never produces digital ischemic ulceration. All patients with digital ischemic ulceration have one or more of a variety of systemic disease processes, which have as one of their manifestations obstruction of the palmar and digital arteries. These diseases are listed in Table 63-1. Interestingly, the actual clinical vasospastic attacks of the two groups may be indistinguishable. This section is concerned with the diagnosis, classification, and treatment of vasospastic as well as obstructive diseases of the palmar and digital arteries. The division of patients with upper extremity small artery disease into these two subgroups (vasospastic and obstructive) is somewhat arbitrary, and we recognize that there clearly is a continuum of disease between these two categories.[8,9] However, the subgrouping emphasizes the unique and important diagnostic and therapeutic implications of each of these disorders.
Pathophysiology †
Raynaud’s syndrome may be classified as obstructive or vasospastic. The episodic attacks of both types of RS
Deceased.
Hobson/Wilson/Veith: Vascular Surgery: Principles and Practice, Third Edition, Revised and Expanded DOI: 10.1081/0819-9-120024947 Copyright q 2004 by Marcel Dekker, Inc.
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Part Eight. Vascular Disorders of the Upper Extremity and Vasculitis Table 63-1. Diseases Associated with Raynaud’s
Syndrome Immunologic and connective tissue disorders Scleroderma Mixed connective tissue disease Systemic lupus erythematosus Rheumatoid arthritis Dermatomyositis Polymyositis Vasculitis induced by hepatitis B antigen Drug-induced vasculitis Sjo¨gren’s syndrome Undifferentiated connective tissue disease Obstructive arterial diseases Atherosclerosis Thromboangiitis obliterans Thoracic outlet syndrome Environmental conditions Vibration injury Direct arterial trauma Cold injury Drug-induced Raynaud’s syndrome without vasculitis Ergot Cytotoxic drugs Birth control pills Miscellaneous Vinyl chloride disease Chronic renal failure Cold agglutinins Cryoglobulinemia Neoplasm Neurologic disorders Central Peripheral Endocrinology disorders
classically consist of pallor of the affected part upon cold exposure or emotional stimulation followed by cyanosis and rubor upon rewarming, with full recovery in 15 –45 min. The hands and fingers are most affected in a large majority of patients, although the toes, cheeks, and ears are occasionally involved. About 5% of affected patients have primary symptoms in the feet and toes. The initial pallor of an attack is caused by spasm of the digital arteries and arterioles. After a variable period of time, the capillaries and probably the venules dilate in response to both hypoxia and the accumulation of products of anaerobic metabolism. As the arterial spasm relaxes, the initial blood flow into the dilated capillaries rapidly desaturates, causing cyanosis. Finally, rubor results from increasing amounts of blood entering the dilated capillary bed, and the digits return to normal as the capillaries constrict. Many patients do not demonstrate the classic tricolor changes during a Raynaud’s attack and experience cold hands with only pallor or cyanosis. A number of patients experience no visible color change at all, suffering only episodic attacks of hand and finger coldness. Since these patients may have the same arteriographic and hemodynamic abnormalities encoun-
tered in patients with the classic tricolor changes, we no longer consider color changes essential for diagnosis. The underlying pathophysiology of RS has been the object of investigation for over a century. Episodic digital ischemia was first described by Maurice Raynaud in 1862.[10] He hypothesized that the condition was due to vasospasm as a majority of his patients had normal radial pulses associated with distal hand ischemia. Hutchinson, in the latter part of the nineteenth century, accurately observed that episodic hand ischemia occurred in association with a variety of disease processes and clearly did not represent the single disease entity suggested by Raynaud.[11] In 1932, Allen and Brown, recognizing the frequency with which other diseases were associated with RS, proposed dividing the syndrome into Raynaud’s phenomenon, which occurred in association with a systemic disease process, and Raynaud’s disease, which represented a benign, idiopathic form of vasospasm without any associated disease.[12] Eventually, a number of investigators, including our group, observed that classification of patient by the pathophysiologic cause (obstruction versus vasospasm) made more sense than classification by the presence or absence of an associated disease.[13 – 16] This is particularly important since autoimmune disease may be missed at the initial evaluation or present years after the onset of digital vasospastic symptoms. Additionally, evaluation, treatment, and response to treatment of patients is better directed by the pathophysiologic classification. At present, we feel there is little justification in attempting to separate RS into “disease” and “phenomenon.” We have chosen to refer to the condition as Raynaud’s syndrome to avoid the semantic confusion implicit in use of the terms disease and phenomenon. Indirect measurements of blood flow and pressure in the hands and fingers of patients with obstructive RS have demonstrated considerably decreased flow at room temperature, with striking additional decrease with cooling. In these patients, we hypothesize that a normal arterial vasoconstrictive response to cold overcomes the diminished intraluminal distending pressure and causes complete arterial closure. Abnormally forceful cold-stimulated arterial constriction is not required to cause digital arterial closure in patients with obstruction RS. Our theory suggests that all patients with palmar and digital arterial obstruction severe enough to produce a significant decrease in digital artery pressure at rest will have at least some degree of cold-induced RS. Patients with vasospastic RS do not have significant hand or digital artery obstruction and have normal digital blood pressures and near normal blood flow at room temperature. Arterial closure in these patients is caused by a markedly increased force of cold-induced vasospasm. Sir Thomas Lewis in the 1920s observed that conduction anesthetic block of the digital nerves did not prevent vasospasm and concluded that sympathetic nerves were not the source of the vasospastic stimulus.[17] He hypothesized a “local vascular fault” as the cause of the hyperreactivity to cold observed in the digital arteries in patients with vasospastic RS. Recent studies suggest that vasospastic RS may be a manifestation of altered adrenergic receptor activity. Coffman and Cohen found decreased digital nutritive blood flow in patients with RS, which was increased after chemical denervation with reserpine.[18] We have shown a marked
Chapter 63.
Raynaud’s Syndrome and Upper Extremity Small Artery Occlusive Disease
decrease in cold-induced spasm of the digital arteries in patients with vasospastic RS after intraarterial reserpine treatment.[19] Jamieson and associates suggested that patients with RS may possess adrenergic receptors that are abnormally hypersensitive to cold exposure.[20] The subcategorization of the alpha adrenoceptors into alpha1 and alpha2 sybtypes has increased our understanding of the pathogenesis of vasospasm. Alpha2 adrenoceptors are present in a pure population on human platelets and are the predominant adrenoceptors of the distal extremity. They are felt to be the primary receptor type responsible for peripheral resistance and vasospasm. We found that platelet alpha2 receptors are elevated in patients with vasospastic RS (Fig. 63-1), and serum of RS patients causes a decrease of measurable alpha2 adrenoceptor levels on normal platelets (Fig. 63-2).[21,22] There is no direct evidence linking elevated platelets to elevated arterial wall alpha2 adrenocaptor levels, but there is evidence in other systems (beta lymphocytes and atrial wall) that such a relationship exists. To explain the decrease in measurable alpha2 adrenoceptor levels observed in the incubation studies, we have hypothesized a circulating factor (possibly an antibody) in patients with RS. We suspect that an antireceptor antibody may constitute the primary pathophysiologic abnormality in these patients. The role of endothelial cell –derived contracting factors (EDCF) such as the 21-amino-acid peptide endothelin in the pathogenesis of vasospastic RS remains uncertain at this time.[23] We have demonstrated marked augmentation of the potent contractile effect of endothelin with cooling of human vascular segments in organ chamber studies.[24] Interestingly, immersion of one arm into ice water has produced marked elevations of the venous effluent endothelin level in normal controls.
Figure 63-1. Alpha2 adrenergic receptor levels in patients with spastic Raynaud’s syndrome. (From Edwards et al.[22] Reproduced by permission.)
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A relative decrease in the level of naturally occurring vasodilating agents has also been hypothesized as the cause of Raynaud’s syndrome. The best studied of these is calcitonin gene –related peptide (CGRP). Patients with scleroderma appear to have a decrease in cutaneous CGRP and respond favorably to CGRP infusion.[25,26]
Epidemiology Increasingly more data are available about the prevalence of RS in the general population. Many people who are troubled by cold sensitivity do not seek medical attention. Whether or not these mildly affected individuals will exhibit immunologic abnormalities with the same frequency as the more severely affected patients studied in referral centers is unknown. Some 22% of randomly selected, healthy women aged 21 –50 years in Copenhagen described symptoms of Raynaud’s syndrome, while a survey in Oregon revealed that nearly 30% of persons interviewed described some coldinduced digital color changes.[27,28] These areas both have cool, damp climates, an observation which may be of considerable importance in the clinical expression of symptoms. Whether or not cool, damp climates increase the incidence of RS or merely increase the number of people who develop symptoms is not known.[29] We suspect the latter. Women comprise 70–90% of most reported patient groups with RS. Typically, younger women will have vasospastic RS without evidence of associated disease. Some patients will develop an associated disease at a later date. Older males with RS usually have digital artery occlusion, often from arteriosclerosis or autoimmune disease.
Figure 63-2. Effect of serum from normal subjects and from patients with spastic Raynaud’s syndrome on normal platelets. Open triangles = incubation with buffer; closed circles = incubation with normal serum; open circles = incubation with serum from patients with spastic Raynaud’s syndrome. (From Edwards et al.[22] Reproduced by permission.)
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Select occupational groups have a high prevalence of RS, especially those associated with the use of vibrating tools.[8,30] This association has obvious implications regarding occupational hazards and resulting liability. Symptomatic vasospasm occurs in 40 –90% of chain saw operators and miners who use vibrating tools. The likelihood of developing symptoms is directly related to the chronicity of exposure. A number of individuals with chronic exposure to vibration develop ongoing arterial damage, leading to digital artery obstruction. Several reports have described an increased incidence of RS among food workers who work in cold areas.[31,32]
Associated Diseases The general classification of disorders associated with RS is presented in Table 63-1. All or nearly all of these conditions may be associated with diffuse obstructive palmar and digital arterial disease, which in some patients is sufficiently severe to produce ischemic ulceration. The possibility that digital gangrene or ulceration may result from intrinsic small artery occlusive disease with normal proximal arteries is often considered only after an extensive evaluation of a patient with hand and finger ischemia fails to reveal proximal arterial obstruction or a cardiac embolic source. Seventy-one percent of all of our RS patients have secondary RS in association with one of the diseases or conditions listed in Table 63-1. That percentage undoubtedly does not apply to minimally symptomatic patients who have never sought medical care; the incidence in this group is unknown. However, available evidence indicates that the likelihood of coexisting disease in all patients with RS is sufficiently high to warrant a thorough evaluation of each patient, as described later in this chapter. Large artery occlusive disease proximal to the wrist may result in ischemic finger ulceration, usually in association with digital artery embolization. The usual causes of large
artery obstructive disease in the upper extremity are described in another chapter. Giant cell arteritis, a cause of proximal artery obstruction, is being diagnosed with sufficient frequency in our clinical practice to warrant description.[33] Although the most frequent symptoms of giant cell arteritis are related to temporal arteritis and polymyalgia rheumatica, the appearance of isolated arm ischemia in older women is sufficiently characteristic of this condition to warrant consideration of this diagnosis even in the absence of other manifestations of the disease. This is especially true in elderly females with bilateral upper extremity ischemic symptoms in the absence of recognized atherosclerotic risk factors. The symptoms may range from cold intolerance to exertional pain to pulselessness and severe ischemia, although tissue loss is uncommon. The erythrocyte sedimentation rate is nearly always elevated ( . 30 mm/h in elderly persons) and provides a useful screening test. The angiographic features most suggestive of arteritis are (1) long segments of smooth stenosis interspersed among normal areas, (2) smoothly tapered occlusion, (3) absence of irregular plaques and ulceration, and (4) distribution of these abnormalities among the subclavian, axillary, and brachial arteries (Fig. 63-3).[34] Without question, however, the most frequent cause of upper extremity ischemia in our practice has been intrinsic small artery occlusive disease of the palmar and digital arteries. Ischemia in these circumstances may progress to fingertip ulceration or gangrene. A partial listing of systemic conditions which may be associated with digital gangrene is shown in Table 63-2. The most frequently associated disease states encountered in patients with ischemic digital ulceration are the autoimmune or connective tissue diseases. All connective tissue diseases have an associated arteritis, or, in the case of scleroderma, an obliterative arteriography, which may cause progressive obstruction of the small- and medium-sized arteries of the hands and fingers. In our patients, scleroderma, particularly with the CREST variant, is the autoimmune disease most frequently associated with
Figure 63-3. Arch aortography demonstrating smooth, diffuse left axillary artery stenosis characteristic of giant cell arteritis.
Chapter 63.
Raynaud’s Syndrome and Upper Extremity Small Artery Occlusive Disease
Table 63-2. Systemic Diseases That May Cause Localized Digital Gangrene Connective tissue disease and other arteridities Scleroderma-CRSTa,b Rheumatoid arthritisa Sjo¨gren’s syndromea Systemic lupus erythematosusa Polyarteritis nodosa Mixed connective tissue diseasea Wegener’s granulomatosis Allergic granulomatosis Henoch-Scho¨nlein purpura Hypersensitivity angiitisa Myeloproliferative disorders Polycythemia rubra vera Thrombocytosis Leukemia Myeloid metaplasia Immunoglobulin abnormalities Mixed cryoglobulinemia Myeloma or benign monoclonal gammopathy Cold agglutinin disease Tumor-produced globulins Miscellaneous Systemic malignancy Disseminated intravascular coagulopathy Chronic renal failure (calciphylaxis) Atherosclerosisa Buerger’s disease (thromboangiitis obliterans)a a
Most frequently associated with digital gangrene. CREST or CRST is a subset of scleroderma with a better prognosis. C = Calcinosis; R = Raynaud’s; E = Esophageal involvement (not required by some, hence CRST vs. CREST); S = Sclerodactyly; T = Telangectasias. b
digital artery obstruction. While virtually all patients with scleroderma develop Raynaud’s syndrome,[35] it is important to note that this symptom may precede recognition of the underlying connective tissue disease by years. Those diseases in Table 63-2 which, in our experience, have been most frequently associated with the development of digital gangrene are pointed out. Patients who have clinical and serologic evidence of connective tissue disease but do not fulfill the criteria for a specific disease diagnosis are classified as having undifferentiated connective tissue disease.[36] We apply the term hypersensitivity angiitis to a subset of patients with digital gangrene resulting from intrinsic small artery occlusive disease.[37] These patients are characterized by the precipitous onset of severe ischemia at the tips of multiple fingers without any premonitory signs or symptoms. Patients can typically recall the day of onset of their symptoms. Immunologic evaluation in this patient group has consistently failed to reveal any diagnostic serologic abnormalities, while arteriography has consistently demonstrated diffuse palmar and digital arterial occlusion. The acute ischemic event has completely resolved with conservative therapy in each patient. Long-term follow-up of these patients (up to 22 years) has not demonstrated the development of
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connective tissue disease or recurrent ischemic events in the large majority. Remote arteriography has revealed the anticipated persistent occlusive disease with the development of collateral digital circulation. Although in the absence of tissue confirmation our designation of this condition as hypersensitivity angiitis remains speculative, its clinical similarity to hypersensitivity angiitis appears to us sufficiently close to warrant use of this classification. Buerger’s disease is another cause of widespread digital artery occlusions and finger gangrene.[38] It appears to represent a thrombotic arteriopathy occurring mainly in young male smokers and is characterized by the occurrence of segmental thrombotic occlusions in both the upper and lower extremities. This particular disease entity, its diagnosis, and its treatment are thoroughly reviewed in another chapter. A small number of patients with digital gangrene will be found to have a malignancy. Digital artery obstruction associated with malignancy has been previously described by us and others.[39,40] In certain patients, the malignancyassociated ischemia is due to arterial thrombosis, while in others the mechanism appears to be that of an inflammatory arteritis.
PATIENT PRESENTATION Raynaud’s Syndrome The usual patient with vasospastic RS is a young woman who describes symptoms that began during childhood. Both hands are affected equally, although the thumbs may be spared. On questioning, some increased sensitivity of the feet and toes may be elicited, and between 5 and 10% of patients describe primary symptomatic involvement of the feet and toes. Conversely, obstructive RS has a 1:1 male-to-female ratio, and most patients are over 40 years of age. The lower extremities are infrequently involved, and there may be only a few involved digits. In fact, the asymmetry of digital involvement is an important difference between vasospastic and obstructive RS. Most Raynaud’s syndrome attacks are produced by cold exposure, although about half of these patients describe occasional attacks in response to fear or anger. The stimulus for an attack may be as mild as walking into an air-conditioned room, getting one’s hands wet, or picking up a cold glass. In addition to color changes, attacks are usually associated with numbness. Severe pain is rare. Most spontaneous indoor attacks resolve in 5– 10 min. Many if not most attacks precipitated by outdoor cold exposure terminate only when the patient enters a warm area or applies heat to the part.
Digital Gangrene The term digital gangrene as used in this chapter refers to tissue necrosis with full-thickness skin loss occurring usually at the fingertip and varying from black-blue cutaneous gangrene to necrotic ulceration, as seen in Fig. 63-4A. Two thirds of our patients with digital gangrene were women, with a median age at presentation of 46 years.[5] The patients were easily divisible in two groups based on their presentation with
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an acute or chronic history of finger gangrene. Approximately 40% presented within several weeks to a few months of the acute onset of digital ischemia. Most of these patients experienced the precipitous onset of cyanosis and pain involving the distal portions of multiple fingers, followed in days to several weeks by the development of skin necrosis with a variable amount of tissue loss. Systemic signs and symptoms of connective tissue disease were usually absent in these patients. About 60% of patients presented with a chronic history of digital gangrene.[5] Patients frequently describe multiple exacerbations and remissions extending over years. Patients in this group were, on average, 5 –10 years older than those in the acute group. The acutely symptomatic patients as a group were younger, less likely to have preexisting RS, and less likely to be tobacco users than members of the chronic group.
CLINICAL EVALUATION All patients presenting for evaluation of RS or digital gangrene should be carefully questioned and examined for symptoms and signs of connective tissue disease, including arthritis, arthralgia, myalgia, skin rash, alopecia, sclerodactyly, dysphagia, xerostomia, xerophthalmia, telangiectasia, hand swelling, digital skin binding, and oropharyngeal ulceration. A specific search should be made for evidence of healed infarcts at the digital tips and calcinosis cutis. A history of angina pectoris, myocardial infarction, or transient ischemic attacks or findings of diminished peripheral pulses and/or bruits should be carefully sought as an indication of generalized atherosclerosis. Symptoms of carpal tunnel syndrome should be sought, as it is present in up to 15% of patients with RS. Other causes of digital artery occlusion should be considered, including a clear history of frostbite, repetitive trauma (“hypothenar hammer syndrome”), vibrating tool use, accidental intraarterial drug injection, proximal embolic source, drug ingestion (ergot intoxication), and exposure to environmental toxins, including heavy metals and vinyl chloride. Physical exam should include palpation for cervical rib and clavicular anomalies as well as careful pulse palpation and blood pressure determinations. We have found that initial and sequential color photographs of the hands and fingers may be helpful in objectively documenting the patient’s clinical course.
Noninvasive Vascular Laboratory Evaluation Digital photoplethysmography and finger pneumatic cuffs are used to obtain digital waveforms from all fingers and pressures from the index, long, and ring fingers, which permits both the detection and quantitation of obstructive digital artery disease.[41] Patients with clinical evidence of vasospasm are further tested with the digital hypothermic challenge test described by Nielsen and associates, which quantitates the decrease in finger pressure with digital
Figure 63-4. (A) Painful digital ulcer in patient with obstructive Raynaud’s syndrome with widespread palmar and digital arterial obstruction. (B) Same patient 3 months later showing complete healing following conservative treatment with soap-and-water scrubs and antibiotics.
cooling.[42] In our experience, this has been the most accurate (92%) test for RS. Several other tests are used for the objective diagnosis of RS, including thermal entrainment, which may be as accurate as the digital hypothermic challenge test.[43] However, neither test is widely available. The simple measurement of digital temperature recovery after exposure to cold water is very sensitive (100%) but not specific (50%). The objective documentation of digital vasospasm, while often unnecessary in clinical practice, is of great value in industrial compensation cases and epidemiological screening. Digital photoplethysmography with digital blood pressure determination is almost as accurate as angiography in the detection of significant palmar and digital arterial obstruction. The finding of a digital blood pressure 20– 30 torr or more below the brachial blood pressure establishes the diagnosis of distal arterial obstruction.[6] However, the noninvasive vascular lab does not eliminate the need for upper extremity angiography in certain patients.
Chapter 63.
Raynaud’s Syndrome and Upper Extremity Small Artery Occlusive Disease
Angiography The purpose of angiography is not to confirm distal arterial obstruction, which is presumed present in patients with digital gangrene, but to rule out a proximal disease process such as subclavian artery stenosis, subclavian aneurysm, and so on, which may be serving as a source of emboli and may be amenable to surgical repair. Particularly if the patient’s signs and symptoms are unilateral, the diagnosis of isolated distal small artery occlusive disease can be established with certainty only after proximal arterial disease has been angiographically eliminated. Complete angiography has traditionally constituted an integral portion of the evaluation of patients with digital gangrene and has included visualization of the arterial circulation from the aortic arch to the fingertips of both hands. These angiograms are best performed by the transfemoral approach, using magnification technique for the filming of the hand circulation. An example of the detail obtainable is shown in Fig. 63-5. The angiograms may be obtained before and after cold exposure (cryodynamic angiography) and before and after intraarterial tolazoline if significant vasospasm is present on the initial films. The accurate assessment of digital and palmar arterial spasm requires the meticulous placement of a small angiographic catheter into the axillary artery, being careful to ensure minimal contact of the catheter with the arterial wall so as to reduce the incidence of induced artefactual vasospasm. It is essential that the digital temperature be raised to at least 328C prior to injection to minimize coldinduced vasospasm. An external heating pad used in conjunction with digital temperature probes has been useful in this regard. A detailed description of our angiographic technique has been published by Rosch and associates.[19] In recent years we have been increasingly willing to forgo arteriography in patients with bilateral finger ischemia and a normal upper extremity arterial exam to the wrist. The likelihood of finding bilateral proximal arterial disease in such patients does not appear sufficient to warrant the small risk of arteriography.
Laboratory Evaluation The hematologic and serologic evaluation of patients with upper extremity ischemia is outlined in Tables 63-3 and 63-4. The details and methodology of these tests have been described. The use of the additional tests noted in Table 63-4 is based on the history, physical examination, and initial laboratory results. As previously noted, these tests are performed in a search for a disease process which, in our experience, has been present in about 70% of patients with RS. It is important to note that all patients with digital ulceration have a disease process in addition to episodic digital vasospasm. The clinical and laboratory information gained through the investigations described above should allow each patient to be accurately assigned to one of the disease categories listed in Table 63-2.
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TREATMENT Vasospasm Few agents currently used have ever been subjected to rigorous double-blind, placebo-controlled trials; even in these trials, the primary assay of efficacy has invariably been the patients’ subjective assessment of improvement—a method with obvious limitations. Vasodilators, usually alphaadrenergic blocking drugs, have traditionally been the cornerstone of drug treatment of RS. In recent years, the focus of drug therapy has shifted to the calcium channel blockers. At present, our first-line therapy is nifedipine, 30 mg extended release, once a day.[44] Unfortunately, about 10– 25% percent of patients discontinue nifedipine because of side effects, including weakness, headaches, light-headedness, or lassitude. Patients who do not respond or who have side effects with nifedipine are started on captopril (12.5–25 mg per day) or losartan (12.5 – 50 mg one to three times a day).[45,46] Other vasodilators we occasionally use include dibenzyline and prazosin. Other treatments that have been proposed include prostaglandin E1, plasmapheresis, and biofeedback. To date, no randomized, controlled trials of these treatments have demonstrated efficacy. Our limited experience with a prostaglandin I2 analog, iloprost, an investigational agent, has been insufficient to draw any conclusions regarding its efficacy. Oral iloprost may be available in the future, but a double-blind study demonstrated symptomatic but not objective improvement in patients.[47]
Digital Gangrene Treatment of digital ischemic ulceration resulting from palmar and digital artery occlusive disease should be directed at four main points. First, surgically treatable lesions, although rare, must be detected and treated or their presence eliminated by testing, as outlined below. Second, elimination or reduction of any associated vasospasm should be attempted by cold avoidance and the elimination of tobacco use. The same vasodilators which are used for vasospastic RS may be helpful. We also use pentoxifylline empirically as long as the patient has ulcers present. Recently, we have documented a significant relaxing effect of pentoxifylline and its analogs on human vascular tissue in vitro, and this effect may play some role in its benefit. Although selected patients occasionally improve dramatically, the response to drugs has been neither predictable nor reliable. We currently regard no vasoactive or hemorrheologic drugs of proven efficacy in the treatment of patients with digital ischemia or gangrene. Of historic interest only is the intravenous Bier block of intraarterial reserpine to achieve a regional sympathetic block, which usually resulted in both angiographic and symptomatic benefit over the short term. Parenteral reserpine has been withdrawn from the market. Third, basic wound care is stressed. Gangrenous ulcers should be scrubbed with soap and water twice daily and dressed with dry gauze. Antibiotics appropriate to culture results are used for lesions with surrounding cellulitis. Conservative surgical debridement of necrotic tissue is
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Figure 63-5.
Magnification view of a normal hand arteriogram.
performed as needed, including removal of protruding phalangeal tips. Formal phalangeal amputation is performed only when an entire digital segment (i.e., total phalanx) is necrotic. Most patients require amputation of a portion or all of the distal phalanx, although occasionally amputation at the midphalangeal level is required. Partial phalangeal
amputation has been very effective in controlling ulcer pain in our experience. Fourth, medical therapy as appropriate is initiated for the treatment of associated systemic disease(s), in consultation with and under the supervision of one of our immunology or rheumatology colleagues.
Chapter 63. Table 63-3.
Raynaud’s Syndrome and Upper Extremity Small Artery Occlusive Disease
Diagnostic Evaluation of Upper Extremity Ischemia
Laboratory
Radiographic
Vascular laboratory
Routine
In selected patients
Complete blood count Urinalysis Sedimentation rate Chemistry panel Immunology screen (see Table 63-4) Hand films
Hypercoagulable screen Thyroid panel
Finger plethysmography Digital hypothermic challenge test
Other
Surgical Therapy A small percentage of patients with digital ischemia will have palmar and digital arterial occlusion due to proximal arterial lesions which result in distal embolization. In these patients, surgery may correct the lesion and prevent further ischemia, but it will obviously not improve the obstruction already present. Upper extremity sympathectomy has frequently been suggested as a treatment for both obstructive and episodic vasospastic ischemia of the upper extremity. When used for vasospastic RS, the usual history of the procedure is that the patient experiences a few months of good results followed by a gradual recurrence of symptoms. It is not known whether the recurrence represents an incomplete initial sympathectomy due to anatomic variation, development of receptor hypersensitivity to circulating catecholamine, or possible sympathetic regeneration. In patients upon whom we and others have performed thoracic sympathectomy for hyperhidrosis who also happened to have RS, the RS
Table 63-4. Essential Complete
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Immunologic Tests Antinuclear antibody Rheumatoid factor Serum protein electrophoresis Cold agglutinins VDRL Hep-2 ANA Anti-double-stranded DNA antibody Extractable nuclear antigen SSA SSB Complement C3, C4 Cryoglobulins Hepatitis panel
Chest films Arm/hand arteriography Barium swallow Toe plethysmography Segmental arm pressures Segmental leg pressures Schirmer’s test Skin/mucosal biopsy Nerve conduction Electromyography
recurred within 6 months without recurrence of hyperhidrosis. Lumbar sympathectomy done for severe lower extremity vasospastic disease, in contrast to the upper extremities, has a high likelihood of long-term success.[48] We have no explanation for the observed differential effects of upper and lower limb sympathectomy. Thoracic sympathectomy for vasospasm occasionally results in anecdotal long-term success, but this usually occurs in the patient with mild vasospasm who is most likely to respond to drug therapy. At present, we feel that sympathectomy is contraindicated in patients who meet the vascular lab criteria of obstructive RS. This includes all patients with autoimmune disease. We consider thoracic sympathectomy only in patients with proven primary vasospastic RS who are sufficiently symptomatic that their livelihood is threatened, and these patients are all warned that the beneficial effects of surgery may be shortlived. A number of authorities consider thoracic sympathectomy of definite benefit in the healing of ischemic lesions of the fingers. A rate of healing in the range of 80% has been reported with this treatment. Interestingly, we have achieved the same healing rate without sympathectomy with the conservative treatment program described above.[5] At present, the moderate surgical risk, the expense, and the lack of improved long-term results following thoracic sympathectomy for either vasospasm or digital artery obstruction constitute, in our opinion, persuasive arguments against its use. Digital periarterial sympathectomy has been advocated as an improved method of sympathectomy.[49] Direct microvascular bypass of occluded segments of palmar and digital arteries and arteriovenous reversal at the wrist have also been reported to improve healing.[50,51] None of these procedures has been tested in a controlled prospective fashion. While each may eventually be found to benefit a select few patients, there is no indication these techniques will be of benefit to a large number of patients with generalized small vessel disease.
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RESULTS OF TREATMENT Raynaud’s Syndrome About 90% of patients with RS will respond to the simple measures of cold and tobacco avoidance. Just over half of the patients with disease sufficiently severe to warrant pharmacologic therapy will respond to the calcium channel blockers. Unfortunately, approximately 30% of the responders will experience unacceptable side effects, reducing the actual response rate to only about 30 –40% of those who begin medication. The once-daily extended-release formulation of nifedipine taken in the evening has a lower incidence of side effects and may be worth trying in patients who did not tolerate standard-release nifedipine. As mentioned previously, occasional patients who have to discontinue nifedipine because of side effects will respond to other vasodilators, such as captopril and losartan, which rarely have significant side effects. Dibenzyline and prazosin are occasionally beneficial but have a high incidence of orthostatic hypotension.
Digital Ischemia Complete healing of ischemic finger ulcers without recurrence has been achieved in 90% of 100 patients with ischemic finger ulceration treated with the conservative program outlined above (Fig. 63-4B). About one fourth of patients with ischemic finger ulceration require surgical debridement or a conservative amputation before healing. Half of the patients who heal will have residual RS symptoms of the obstructive type, as would be predicted. The healing process occurs over several weeks to several months and is associated with the development of collateral arterial circulation, not with the recanalization of the major arterial channels. In the remaining 10% of patients, recurrent tissue loss of ulceration will persist despite optimal conservative care. In our experience, these patients have all had connective tissue disease, most commonly scleroderma. We are not able to predict reliably which patients will experience recurrent or persistent ischemic finger ulceration. Obviously, the patient
who presents with chronic disease is at higher risk for recurrent problems. It is extremely important to note that ischemic finger ulceration resulting from intrinsic small artery occlusive disease does not herald an inexorable progression to major tissue loss. Rather, it appears that the natural history of the disorder, regardless of etiology, is one of short periods of exacerbation followed by long periods of remission with healing and stable, mild symptoms. Appreciation of this basically benign prognosis has major therapeutic implications. It is unclear to what degree out treatment with simple wound care and low-dose oral vasodilators has been responsible for the overall good results achieved by 90% of our patients. We suspect that this outcome reflects the natural history of the condition. Beneficial results claimed for any mode of therapy in past or future studies must be carefully evaluated against this standard. This is particularly true of cervicothoracic sympathectomy, which has been recommended for finger gangrene resulting from small artery disease and for which the outcome—healing without recurrence—is no better than with conservative therapy. The same caveat is true when evaluating new pharmacologic therapies. The influence of vasospasm in patients with digital artery occlusions is difficult to define, but it appears minimal. Most of our patients have not displayed significant vasospasm on cryodynamic hand angiography, although some have a moderate amount of vasospasm, and an objective response to vasodilating agents can be demonstrated angiographically. The major underlying lesions, however, are fixed organic arterial occlusions. In our experience, improvement of finger perfusion has occurred gradually, accompanied by the development of collateral circulation. Elimination of moderate accompanying vasospasm may offer at least modest benefit. We have persisted in administering vasodilators to these patients despite the absence of controlled studies supporting this position. While many of these patients are cigarette smokers, the cessation of tobacco use has had curiously little impact on critical outcome. Half of our patients with chronic, recurrent digital gangrene never smoked. A number of patients with prompt healing without recurrence have continued to smoke.
REFERENCES 1. McNamara, M.F.; Takli, H.S.; Yao, J.S.T.; Bergan, J.J. A Systematic Approach to Severe Hand Ischemia. Surgery 1978, 83, 1 – 21. 2. Dale, W.A.; Lewis, M.R. Management of Ischemia of the Hand and Fingers. Surgery 1970, 67, 62– 79. 3. Hardy, J.D.; Conn, J.H.; Fain, W.R. Nonatherosclerotic Occlusive Lesions of Small Arteries. Surgery 1965, 57, 1 – 12. 4. Porter, J.M.; Snider, R.L.; Bardana, E.J.; Rosch, J.; Eidemiller, L.R. The Diagnosis and Treatment of Raynaud’s Phenomenon. Surgery 1975, 77, 11– 23.
5. Mills, J.L.; Friedman, E.I.; Taylor, L.M., Jr.; Porter, J.M. Upper Extremity Ischemia Caused by Small Artery Disease. Ann. Surg. 1987, 206, 521– 528. 6. Mclafferty, R.B.; Edwards, J.M.; Taylor, L.M., Jr.; Porter, J.M. Diagnosis and Long-Term Clinical Outcome in Patients Presenting with Hand Ischemia. J. Vasc. Surg. 1995, 22, 361– 369. 7. Landry, G.J.; Edwards, J.M.; McLafferty, R.B.; Taylor, L.M.J.; Porter, J.M. Long-Term Outcome of Raynaud’s Syndrome in a Prospectively Analyzed Patient Cohort. J. Vasc. Surg. 1996, 23, 76– 85.
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Raynaud’s Syndrome and Upper Extremity Small Artery Occlusive Disease
Taylor, W.; Pelmear, P.L. Raynaud’s Phenomenon of Occupational Origin. An Epidemiological Survey. Acta Chir. Scand. 1976, 465 (Suppl.), 27 – 32. Porter, J.M.; Rivers, S.P.; Anderson, C.J.; Baur, G.M. Evaluation and Management of Patients with Raynaud’s Syndrome. Am. J. Surg. 1981, 142, 183– 189. Raynaud, M. On Local Asphyxsia and Symmetrical Gangrene of the Extremities: Selected Monographs; New Sydenham Society: London, 1888. Hutchinson, J. Raynaud’s Phenomena. Med. Press Circular 1901, 128, 403– 405. Allen, E.; Brown, G. Raynaud’s Disease: A Critical Review of Minimal Requisites for Diagnosis. Am. J. Med. Sci. 1932, 83, 187– 200. Porter, J.M.; Bardana, E.J.J.; Baur, G.M.; Wesche, D.H.; Andrasch, R.H.; Rosch, J. The Clinical Significance of Raynaud’s Syndrome. Surgery 1976, 80, 756– 764. Gifford, R.W.J.; Hines, E.A., Jr. Raynaud’s Disease Among Women and Girls. Circulation 1957, 16, 1012– 1021. de Takats, G.; Fowler, E.F. Raynauds Phenomenon. J. Am. Med. Assoc. 1962, 179, 99– 106. Velayos, E.E.; Robinson, H.; Porciuncula, F.U.; Masi, A.T. Clinical Correlation Analysis of 137 Patients with Raynaud’s Phenomenon. Am. J. Med. Sci. 1971, 262, 347– 356. Lewis, T.; Pickering, G. Observations upon Maladies in Which the Blood Supply to the Digits Ceases Intermittently or Permanently and upon Bilateral Gangrene of the Digits: Observations Relevant to So-Called “Raynaud’s Disease.” Clin. Sci. 1934, 1, 327– 366. Coffman, J.D.; Cohen, A.S. Total and Capillary Fingertip Blood Flow in Raynaud’s Phenomenon. N. Engl. J. Med. 1971, 285, 259– 263. Rosch, J.; Porter, J.M.; Gralion, B.J. Cryodynamic Hand Angiography in the Diagnosis and Management of Raynaud’s Syndrome. Circulation 1977, 55, 807– 814. Jamieson, G.G.; Ludbrook, J.; Wilson, A. Cold Hypersensitivity in Raynaud’s Phenomenon. Circulation 1971, 44, 254– 264. Keenan, E.J.; Porter, J.M. Alpha-Adrenergic Receptors in Platelets from Patients with Raynaud’s Syndrome. Surgery 1983, 94, 204– 209. Edwards, J.M.; Phinney, E.S.; Taylor, L.M.J.; Keenan, E.J.; Porter, J.M. Alpha 2-Adrenergic Receptor Levels in Obstructive and Spastic Raynaud’s Syndrome. J. Vasc. Surg. 1987, 5, 38– 45. Zamora, M.R.; O’Brien, R.F.; Rutherford, R.B.; Weil, J.V. Serum Endothelin-1 Concentrations and Cold Provocation in Primary Raynaud’s Phenomenon. Lancet 1990, 336, 1144– 1147. Dalman, R.L.; Harker, C.T.; Taylor, L.M., Jr.; Porter, J.M. Contactile Response of Human Vascular Tissue to Endothelin. Surg. Forum 1990, 41, 332. Bunker, C.B.; Terenghi, G.; Springall, D.R.; Polak, J.M.; Dowd, P.M. Deficiency of Calcitonin Gene-Related Peptide in Raynaud’s Phenomenon. Lancet 1990, 336, 1530– 1533. Shawket, S.; Dickerson, C.; Hazleman, B.; Brown, M.J. Prolonged Effect of CGRP in Raynaud’s Patients: A Double-Blind Randomised Comparison with Prostacyclin. Br. J. Clin. Pharmacol. 1991, 32, 209– 213.
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Olsen, N.; Nielsen, S.L. Prevalence of Primary Raynaud Phenomena in Young Females. Scand. J. Clin. Lab. Investig. 1978, 38, 761 –764. Edwards, J.M. Raynaud’s Syndrome. Ann. Vasc. Surg. 1994, 8, 509– 513. Maricq, H.R.; Carpentier, P.H.; Weinrich, M.C.; Keil, J.E.; Palesch, Y.; Biro, C.; Vionnet-Fuasset, M.; Jiguet, M.; Valter, I. Geographic Variation in the Prevalence of Raynaud’s Phenomenon: A 5 Region Comparison. J. Rheumatol. 1997, 24, 879–889. Taylor, W. The Hand-Arm Vibration Syndrome – Diagnosis, Assessment and Objective Tests: A Review. J. R. Soc. Med. 1993, 86, 101– 103. Mackiewicz, Z.; Piskorz, A. Raynaud’s Phenomenon Following Long-Term Repeated Action of Great Differences of Temperature. J. Cardiovasc. Surg. 1977, 18, 151– 154. Kaminski, M.; Bourgine, M.; Zins, M.; Touranchet, A.; Verger, C. Risk Factors for Raynaud’s Phenomenon Among Workers in Poultry Slaughterhouses and Canning Factories. Int. J. Epidemiol. 1997, 26, 371 – 380. Rivers, S.P.; Baur, G.M.; Inahara, T.; Porter, J.M. Arm Ischemia Secondary to Giant Cell Arteritis. Am. J. Surg. 1982, 143, 554– 561. Klein, R.G.; Hunder, G.G.; Stanson, A.W.; Sheps, S.G. Large Artery Involvement in Giant Cell Temporal Arteritis. Ann. Int. Med. 1975, 83, 806– 821. Dabich, L.; Bookstein, J.J.; Zweifler, A.; Zarafonetis, C.J. Digital Arteries in Patients with Scleroderma. Arteriographic and Plethysmographic Study. Arch. Intern. Med. 1972, 130, 708– 714. Rich, A.M.; Reade, P.C. Undifferentiated Connective Tissue Disease. Oral Surg. Oral Med. Oral Pathol. 1984, 58, 408– 412. Baur, G.M.; Porter, J.M.; Bardana, E.J.J.; Wesche, D.H.; Rosch, J. Rapid Onset of Hand Ischemia of Unknown Etiology. Ann. Surg. 1977, 184 –189. Mills, J.L.; Taylor, L.M., Jr.; Porter, J.M. Buerger’s Disease in the Modern Era. Am. J. Surg. 1987, 154, 123–132. Taylor, L.M., Jr.; Hauty, M.G.; Edwards, J.M.; Porter, J.M. Digital Ischemia as a Manifestation of Malignancy. Ann. Surg. 1987, 206, 62– 71. Paw, P.; Dharan, S.M.; Sackier, J.M. Digital Ischemia and Occult Malignancy. Int. J. Colorectal Dis. 1996, 11, 196–197. Holmgren, K.; Baur, G.M.; Porter, J.M. The Role of Digital Photoplethysmography in the Evaluation of Raynaud’s Syndrome. Bruit 1981, 5, 19– 26. Nielsen, S.L.; Lassen, N.A. Measurement of Digital Blood Pressure After Local Cooling. J. Appl. Physiol. Respir. Environ. Exer. Physiol. 1977, 43, 907– 910. Lafferty, K.; de Trafford, J.C.; Roberts, V.C.; Cotton, L.T. Raynaud’s Phenomenon and Thermal Entrainment: An Objective Test. Br. Med. J. 1983, 286, 90– 92. Corbin, D.O.; Wood, D.A.; Macintyre, C.C.; Housley, E. A Randomized Double Blind Cross-Over Trial of Nifedipine in the Treatment of Primary Raynaud’s Phenomenon. Eur. Heart J. 1986, 7, 165– 170.
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45. Madsen, J.L.; Hvidt, S. Raynaud’s Disease Treated with Captopril (Capoten). A Randomized Double-Blind CrossOver Study. Ugeskr. Laeger 1984, 146, 2695– 2697. 46. Pancera, P.; Sansone, S.; Secchi, S.; Covi, G.; Lechi, A. The Effects of Thromboxane A2 Inhibition (Picotamide) and Angiotensin II Receptor Blockade (Losartan) in Primary Raynaud’s Phenomenon. J. Intern. Med. 1997, 242, 373– 376. 47. Belch, J.J.; Capell, H.A.; Cooke, E.D.; Kirby, J.D.; Lau, C.S.; Madhok, R.; Murphy, E.; Steinberg, M. Oral Iloprost as a Treatment for Raynaud’s Syndrome: A Double Blind Multicentre Placebo Controlled Study. Ann. Rheum. Dis. 1995, 54, 197– 200.
48.
Janoff, K.A.; Phinney, E.S.; Porter, J.M. Lumbar Sympathectomy for Lower Extremity Vasospasm. Am. J. Surg. 1985, 150, 147–152. 49. el-Gammal, T.A.; Blair, W.F. Digital Periarterial Sympathectomy for Ischaemic Digital Pain and Ulcers. J. Hand Surg. 1991, 16, 382– 385. 50. Jones, N.F.; Raynor, S.C.; Medsger, T.A. Microsurgical Revascularisation of the Hand in Scleroderma. Br. J. Plast. Surg. 1987, 40, 264– 269. 51. King, T.A.; Marks, J.; Berrettoni, B.A.; Seitz, W.H. Arteriovenous Reversal for Limb Salvage in Unreconstructible Upper Extremity Arterial Occlusive Disease. J. Vasc. Surg. 1993, 17, 924– 932.
CHAPTER 64
Vasculitis and Dysplastic Arterial Lesions Hisham S. Bassiouny Bruce L. Gewertz The vascular surgeon may occasionally encounter organ or limb ischemia resulting from vasculitic or dysplastic lesions distinct from the much more common atherosclerotic process. This chapter will discuss these unusual disorders and review diagnostic and therapeutic options in the most common lesions. To aid in clinical differentiation, arteritis may be classified by the size of the involved vessel. One such classification is presented in Table 64-1 and Fig. 64-1.[1] There is, however, substantial overlap among different vasculitides, and the type of vessel involved is merely one of many features that must be determined before a diagnosis can be rendered. The most prominent arteritis involving the aorta and its primary branches is Takayasu’s arteritis. Other inflammatory disorders involve medium-sized and small muscular arteries or the arterioles and capillaries and rarely require operative consideration.[2,3] Fibrodysplastic lesions will be discussed separately, as there is minimal, if any, inflammatory component to these lesions.
contributed large numbers of patients from Mexico and India. In the United States, there seems to be an increased recognition of this disorder in Caucasians.[5] A majority of patients (70%) are first affected between 10 and 30 years of age. The precise etiology remains unknown, although infections and autoimmune phenomena have been suggested. The association of this disorder with rheumatoid arthritis, ankylosing spondylitis, and ulcerative colitis appears to reinforce the latter mechanism. Currently, there is no experimental model for this form of aortitis. Clinical Presentation. The disease process can be broadly divided into two stages: an early phase (“prepulseless”) and late phase (“pulseless”). Initial symptoms include generalized malaise and other nonspecific indicators such as a skin rash, anorexia, myalgia, weight loss, fatigue, and fever. Laboratory examinations at this time may reflect the general inflammatory process. The erythrocyte sedimentation rate (ESR) is nearly always increased and mild hypochromic anemia is evident. Elevated alpha2 and/or gamma fractions are frequently noted.[6] A high prevalence of antiendothelial cell antibodies (AECAs) has been identified in the sera of patients with documented Takayasu’s arteritis. Although long-term observations are as yet unavailable, AECAs may present an objective measure of the activity of Takayasu’s arteritis.[7] After a variable period of time from the onset of vague constitutional symptoms, arterial lesions become evident. A vast majority of patients present during the pulseless stage and predictably demonstrate an absence of one or more peripheral pulses. Symptoms at this time reflect the extremity or organ that is rendered ischemic. Light-headedness or vertigo are frequent complaints if the aortic arch or extracranial carotid vessels are involved. Emotional instability, “drop attacks,” and headache may also be present, along with more lateralizing signs such as hemiparesis. Ocular symptoms include blurring, diplopia, and progressive blindness. A rare but reported symptom is decreasing vision on physical exertion (“visual claudication”). Such ocular complaints can be associated with retinal atrophy or
VASCULITIS AND VASCULITIC DISORDERS Large-Vessel Lesions Takayasu’s Arteritis Takayasu’s arteritis is a dramatic and unusual disorder involving the aorta and its primary branches. Because of its chronic obliterative nature, it is also called pulseless disease and occlusive thromboarteriopathy. Women are much more frequently affected than men (8:1), although the true incidence and distribution of these lesions remain ill defined. The disease was originally named for the Japanese ophthalmologist who described associated ocular abnormalities in 1908.[4] Perhaps as a consequence of his early observation, the highest incidence appears to be in the Orient, especially Japan, although more recent reports have
Hobson/Wilson/Veith: Vascular Surgery: Principles and Practice, Third Edition, Revised and Expanded DOI: 10.1081/0819-9-120024948 Copyright q 2004 by Marcel Dekker, Inc.
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Names and Definitions of Vasculitis Adopted by the Chapel Hill Consensus Conference on the Nomenclature of Systemic Vasculitis
Table 64-1.
Giant-cell (temporal) arteritis
Takayasu’s arteritis Polyarteritis nodosa Kawasaki’s disease
Large-Vessel Vasculitis Granulomatous arteritis of the aorta and its major branches, with a predilection for the extracranial branches of the carotid artery. Often involves the temporal artery. Usually occurs in patients more than 50 years old and is often associated with polymyalgia rheumatica. Granulomatous inflammation of the aorta and its major branches. Usually occurs in patients younger than 50. Necrotizing inflammation of medium-sized or small arteries without glomerulonephritis or vasculitis in arterioles, capillaries, or venules. Arteritis involving large, medium-sized, and small arteries and associated with mucocutaneous lymph node syndrome. Coronary arteries are often involved. Aorta and veins may be involved. Usually occurs in children. Small-Vessel Vasculitis
Wegener’s granulomatosisa
Churg-Strauss syndromea
Microscopic polyangiitisa
Henoch-Scho¨nlein purpura
Essential cryoglobulinemic vasculitis
Cutaneous leukocytoelastic angiitis
Granulomatous inflammation involving the respiratory tract and necrotizing vasculitis affecting small to medium-sized vessels (e.g., capillaries, venules, arterioles, and arteries). Necrotizing glomerulonephritis is common. Eosinophil-rich and granulomatous inflammation involving the respiratory tract and necrotizing vasculitis affecting small to medium-sized vessels and associated with asthma and eosinophilia. Necrotizing vasculitis with few or no immune deposits affecting small vessels (capillaries, venules, or arterioles). Necrosizing arteritis involving small and medium-sized arteries may be present. Necrotizing glomerulonephritis is very common. Pulmonary capillaritis often occurs. Vasculitis with IgA-dominant Immune deposits affecting small vessels (capillaries, venules, or arterioles). Typically involves skin, gut, and glomeruli and is associated with arthralgias or arthritis. Vasculitis with cryoglobulin immune deposits affecting small vessels (capillaries, venules, or arterioles) and associated with cryoglobulins in serum. Skin and glomeruli are often involved. Isolated cutaneous leukocytoelastic angiitis without systemic vasculitis or glomerulonephritis.
“Large vessel” refers to the aorta and the largest arterial branches directed toward major body regions (e.g., to the extremities and the head and neck). “Medium-sized vessel” refers to the main visceral arteries and their branches. “Small vessel” refers to arterioles, venules, and capillaries, although arteries, especially small arteries, may be included in this category of vasculitis. Note that all three categories affect arteries, but only small-vessel vasculitis has a predilection for vessels smaller than arteries. a There vasculitides are associated with antineutrophil cytoplasmic autoantibodies (ANCA). Source: Adapted from Jennette and Falk.[1]
hemorrhage. Ophthalmoscopic examination may also demonstrate optic atrophy and retinal vein or artery thrombosis. It has been observed that many of these patients assume a characteristic “face-down” posture to prevent neck extension, which further compromises carotid or vertebral flow. Extremities with arterial stenoses may manifest exerciserelated symptoms; with worsening of occlusive lesions, rest pain or tissue loss may occur. Compromise of the external carotid circulation can cause atrophy of the facial muscles as well as ulcerations of the palate, nose, or ear. Chronic intestinal or renal ischemia is associated with abdominal aortic involvement.[8] Noninvasive vascular tests suggest Takayasu’s arteritis if bilateral upper extremity and extracranial occlusive disease are documented in a patient of appropriate age. Arteriography is most useful in confirming the diagnosis and is essential for planning operative therapy.[9,10] Arteriography allows classification of Takayasu’s arteritis into four main types based on the distribution of lesions: type I is limited to the aortic arch
and its primary branches (Figs. 64-2 and 64-3); type II includes lesions of the descending thoracic and abdominal aorta; type III extends from the aortic valve to the abdominal aorta (essentially combining types I and II); and type IV comprises lesions with pulmonary artery involvement but has also been taken to include all cases presenting with aneurysms.[11,12] Pathology. The classic gross appearance of Takayasu’s arteritis is a “tree-bark” surface not dissimilar to that seen in luetic arteritis. Patchy involvement with numerous skip areas is the most common pattern, although some patients present with continuous involvement. Although inflammation is most severe in the adventitia and outer media, Takayasu’s arteritis is truly a pan-arteritis. The media are infiltrated by lymphocytes, plasma cells, and histocytes. Polymorphonuclear and multinucleated giant cells are consistently observed, especially around the vasa vasorum. Elastic and smooth muscular components of the media are gradually
Chapter 64.
Figure 64-1. Conference).
Vasculitis and Dysplastic Arterial Lesions
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Schematic and detailed characterization of classification proposed by Jennette and Falk.[1] (Chapel Hill Consensus
eroded by this process and extensive transmural fibrosis is evident. Additional intimal proliferation may contribute to the occlusive lesions.[6,8] Therapy. Unfortunately, corticosteroids are not of proven efficacy in this disorder, although there is still some enthusiasm for medical treatment if the disease can be recognized in the prepulseless stage.[13] Other medical therapies have included cytotoxic agents; unfortunately, these drugs are also of questionable benefit. In patients with symptomatic lesions, operative therapy is directed toward bypass of involved and occluded vessels.[14] It is not uncommon for patients to require bilateral carotid revascularization with grafts originating from the ascending aorta. If possible, it is prudent to delay operation until active signs of the disease have resolved. In patients presenting with cerebrovascular insufficiency, this may be impossible. Indications of quiescence include normalization of markedly elevated ESR and white blood cell counts. Operative dissection should be confined to the nondiseased portions of the aorta and distal vessels, as the inflammatory nature of the arteritis may predispose to injury of adjacent structures. In general, the disease is limited to the more proximal brachycephalic vessels; carotid bifurcation disease and axillary involvement are minimal. A most versatile procedure is anastomosis of a bifurcated aortic graft to the ascending aorta with limbs to carotid or brachycephalic vessels. The proximal anastomosis must be tailored obliquely to lie parallel to the ascending aorta so as to avoid kinking or compression when the sternum is closed (Fig. 64-4). Although endarterectomy has been performed on these lesions, clinical experience strongly favors bypass using prosthetic grafts because of the uncertain strength of the inflamed arterial wall after endarterectomy. Even without
endarterectomy, the development of pseudoaneurysms at anastomoses remains a problem. Some surgeons routinely buttress suture lines with pledgets or place interrupted sutures at regular intervals along a continuous suture line.[15] Miyata et al.[16] reviewed their experience in 91 patients with Takayasu’s arteritis treated surgically over 40 years. A total of 259 anastomoses had a remarkably high follow-up of 93% at 30 years. The cumulative incidence of anastomotic aneurysms at 20 years was 12.0%. Continued systemic inflammation or steroid administration had little influence on formation of anastomotic aneurysm. Instead, anastomotic aneurysms tended to occur after operations for aneurysmal lesions.
Temporal Arteritis Temporal arteritis may be distinguished from Takayasu’s arteritis on clinical grounds. It is a far more prevalent disorder and nearly always occurs in patients over the age of 50. While women are affected more commonly than men, the proportion is 2:1, rather than the 8:1 ratio recognized for Takayasu’s arteritis. The incidence of temporal arteritis is surprisingly high, especially in the north central regions of the United States. One series documented a prevalence of 133 cases per 100,000 people aged 50 and over.[17] As with vascular inflammatory lesions, autoimmune mechanisms are implicated. This is particularly true in temporal arteritis, which is frequently associated with polymyalgia rheumatica.[18,19] Clinical Presentation. In most series, the mean age of onset is as high as 70 years. While the onset of ocular symptoms is classically described as abrupt, careful histories will often elicit symptoms present for several months before the diagnosis is established. Fatigue, weight loss, and fever are
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Figure 64-2. Typical distribution of lesions in Takayasu’s arteritis (type I), with severe uniform stenoses of the brachiocephalic and left common carotid arteries. Patient presented with syncope and dizziness.
Figure 64-3. Selective injection of left subclavian, demonstrating poststenotic dilation of patent vertebral artery. Note restriction of disease to intrathoracic subclavian with normal caliber of left axillary artery.
characteristic of the disorder. Typical presentations also include headache associated with scalp tenderness over the distribution of the temporal artery. The character of the headache is variable, although this manifestation is often severe and may be misdiagnosed as “migraine” headache. The most worrisome presenting symptoms are blindness and diplopia. Fifty percent of patients experience some visual disturbances. While visual loss may be partial or complete, it is generally accepted that once established, the deficit is permanent. The mechanism of these visual changes is thought to be ischemia of the retina or optic nerve associated with arteritis of branches of the ophthalmic or posterior ciliary arteries.[20,21] Ophthalmoscopic examination may occasionally demonstrate central retinal artery occlusion, although this is less common. Before the emphasis on early diagnosis and aggressive treatment with steroids, the incidence of permanent visual loss was as high as 60%. More recent series have documented a much lower incidence, approximating 10–20%. Other specific complaints include difficulty in mastication or swallowing consistent with ischemia of the facial muscles, tongue, and pharynx. Neuropsychiatric symptoms are
prevalent and include memory loss, depression, and anxiety.[22] While many patients with temporal arteritis have concomitant atherosclerosis, approximately 10 –15% demonstrate nonatherosclerotic large artery occlusive lesions similar to those seen in Takayasu’s arteritis.[23] Laboratory examinations reflect the nonspecific inflammatory process. Most common abnormalities include normochromic normocytic anemia associated with decreased albumin and increased fibrinogen, alpha2, and gamma globulins. The erythrocyte sedimentation rate usually remains quite high (100 mm/h) until successful treatment is initiated. In roughly a third of patients, liver function tests are abnormal.[17,24] It has been recently demonstrated that Takayasu’s arteritis is often associated with a hypercoagulable state and thrombus formation,[25] which may also contribute to thrombotic complications allowing arterial reconstructions. The diagnosis should be strongly suspected in any patient over the age of 50 who presents with a new onset of headache, visual symptoms, or hip and shoulder pain compatible with polymyalgia rheumatica. Physical examination may demonstrate scalp tenderness, although this feature can be quite short-lived.
Chapter 64.
Vasculitis and Dysplastic Arterial Lesions
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artery biopsy even if no other symptoms of temporal arteritis are evident. Such “blind” biopsies yield a 10– 20% incidence of pathologically proven but clinically silent temporal arteritis.[29] In view of this relatively low yield, it may be more appropriate to follow patients with polymyalgia rheumatica closely and to initiate steroid therapy immediately if scalp tenderness or visual changes are noted. Pathology. The pathologic lesion is best described as a granulomatous inflammation of the media, with varying degrees of fibrocellular intimal proliferation. Mononuclear and polymorphonuclear leukocytes are identified within the media, but lymphocytes and histiocytes predominate. The internal elastic lamina is characteristically necrotic and disrupted. Late in the disease, fibrosis with recanalization of the lumen is often seen. The classic multinucleated or Langhans giant cells are demonstrated in the majority of cases.[30] Treatment. Once the diagnosis is made by biopsy, temporal arteritis is best treated nonsurgically. Patients are usually started on 45 to 60 mg of prednisone per day. An equivalent dose of another steroid preparation can also be administered. In patients with active visual symptoms, intravenous steroids are appropriate. Most patients respond to treatment quite rapidly; visual changes and scalp tenderness subside within 12–24 h. Although some authors have suggested that steroid therapy should be reduced after 1 month, the incidence of early relapse is relatively high (approximately 20%), leading many physicians to continue therapy for 1 –2 years.[31,32] Despite its lack of specificity, the ESR is the most reliable test to assess activity of the disease during the gradual tapering of the steroid dose. Figure 64-4. Bifurcated graft originates at ascending aorta, with distal anastomoses at carotid bifurcations.
The most definitive diagnosis procedure is biopsy of the temporal artery; adjacent branches of the external carotid can be sampled if other areas of tenderness are elicited. It is important that an adequate length of temporal artery be exposed (at least 2–3 cm) and that atraumatic technique be used in removing the specimen. In the few patients with suspected large artery involvement, arteriography may be indicated. However, such studies are less useful in this disorder in comparison to their central diagnostic role in Takayasu’s arteritis.[26,27] The usefulness of color duplex ultrasonography in patients suspected of having temporal arteritis was examined by Schmidt et al.[28] In 73% of patients with biopsy confirmed temporal arteritis, ultrasonography showed a dark halo around the lumen of the temporal arteries (Fig. 64-5) (see also color plate). The halos disappeared after a mean of 16 days of treatment with corticosteroids. The authors concluded that in patients with typical clinical signs and demonstration of such an appearance on ultrasonography, it may be possible to make a diagnosis of temporal arteritis and begin treatment without performing a temporal artery biopsy. Reproducibility of these findings in other hands is still forthcoming. It remains controversial whether all patients with polymyalgia rheumatica should be subjected to temporal
Thromboangiitis Obliterans Thromboangiitis obliterans, also known as Buerger’s disease, classically involves the medium- and small-sized arteries of the distal lower extremity and, less commonly, those of the upper extremity.[33] Although it is controversial, we believe that it is a unique clinicopathologic entity distinct from premature atherosclerotic arterial occlusive disease as evidenced by the characteristic anatomic, histopathologic, and angiographic features.[34] The prevalence of this disease varies according to the strictness with which the diagnostic criteria are applied. Classic criteria for the disease include (1) most severe involvement in the digital circulation, (2) highest incidence in young males, (3) close association with tobacco dependency, and (4) recurrent episodes of superficial thrombophlebitis. Patients with all four of these components represent a most challenging, if extremely small, subgroup of those evaluated for finger or toe ischemia. Results of therapy are notoriously poor because of the difficulty in moderating the strong tobacco addiction. Although this disease was originally thought to be limited to Jews, additional investigation has revealed a broad incidence across all ethnic groups, with a particularly high prevalence in some Asian countries. Although men are predominantly affected, a larger number of cases have recently been reported in women. This may reflect both improved diagnosis and increased tobacco use by women.[35]
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Figure 64-5. Characteristic ultrasound appearance of acute temporal arteritis with “halo” (lower panel) and turbulent blood flow (upper panel) (see also color plate). (From Schmidt et al.[28])
The differential diagnosis includes collagen vascular disease, ergot abuse, autoimmune vasculitis, embolic disease, thoracic outlet syndrome, or hypothenar “hammer” syndrome.
Clinical Presentation. Patients present with manifestations of recurrent migratory thrombophlebitis and varying degrees of distal limb ischemia. More that 90% are males with a long history of cigarette smoking. It has been suggested that tobacco use in Buerger’s disease patients may not be excessive but, rather, that the disease may reflect a specific hypersensitivity to even small or moderate doses of tobacco.[34] When questioned carefully, patients may describe less specific symptoms such as hand or foot claudication, cold sensitivity, dysesthesia, rubor, or cyanosis, which predate the development of ischemic lesions of the fingers and toes. True claudication of the major muscle mass of the leg is relatively uncommon (10% of patients). When present, these symptoms occur late in the course of the disease due to progression of proximal disease. Severe digital ischemia is accompanied by severe pain, which often leads to an addictive pattern of analgesic abuse. Migratory superficial thrombophlebitis is observed in one-third to one-half of patients with Buerger’s disease and may precede arterial involvement.[36,37] On examination, radial, ulnar, and tibial pulses may be reduced or absent, but popliteal and brachial pulses are generally palpable. Secondary infection of the digital ischemic ulcerations is common, with involvement of the underlying soft tissue and bone (Fig. 64-6). Trophic changes of toe- and fingernails may be accompanied by digital clubbing in as many of 50% of patients. The proximal aspects of the limbs and uninvolved digits are, in general, well preserved. Cold sensitivity in the hands can be demonstrated in the majority of patients and is due to multiple occlusive lesions involving the palmar and plantar arches. The noninvasive vascular laboratory may be quite helpful in diagnosis. Assessment of the patency of the palmar arch and the digital flow patterns can be easily achieved using the continuous-wave Doppler probe. The photophlethysmograph allows documentation of digital pressures.
The most confusing differential diagnosis is that of peripheral arterial embolization presenting with “blue toe” or “blue finger” syndromes. Vegetative cardiac lesions and aneurysmal or ulcerative arterial lesions in the axillary, femoral, or popliteal arteries should be investigated. In the absence of echocardiographic documentation of intracavitary cardiac thrombi, arteriography may be useful for diagnostic purposes. In classic Buerger’s disease, multiple segmental occlusions are demonstrated in the medium and small arteries of the forearm and hand, leg, and foot. Proximal or intervening arterial segments often appear normal. Importantly, these occlusions and tapered stenoses are not reversible with the intraarterial administration of vasodilators. In angiographic studies by Shionoya et al.[38] and Suzuki et al.,[39] bilateral involvement of the infrapopliteal arteries
Figure 64-6. Distinctive presentation of Buerger’s disease, with erythema and ulceration of the most distal fingertip. Ulcers are typically unresponsive to local care and severely painful. General appearance of fingers is described as “pruned,” with a tapered contour due to wasting of subcutaneous tissue.
Chapter 64.
was observed in all patients presenting with the stigmata of Buerger’s disease. The anterior and posterior tibial arteries were most commonly involved, with relative sparing of the peroneal artery. Superficial femoral artery involvement was noted in 40% of cases. Distal upper extremity arterial involvement occurs in 10 –15% of cases and is commonly seen in the later stages of the disease. Many arteriographers have described a corkscrew appearance, which is believed to represent both recanalization of previously occluded arteries and enlargement of periadventitial vessels along thrombosed arterial segments. In a few patients, a proximal atherosclerotic lesion may contribute to the distal ischemia.
Pathology. Study of arterial specimens recovered in the acute phase reveals a classic panangiitis with lymphocytes and fibroblasts abundant within a relatively well-preserved arterial wall.[34,37,40] In later stages of the disease, the vessels are occluded by chronic thrombus, which is highly cellular and composed primarily of fibroblasts. Recanalization of thrombosed arteries and veins is frequently observed. Remarkably, such diseased segments are in direct continuity with normal proximal and distal vessels. Features of atherosclerotic plaque formation are notably absent.
Therapy. Steroid therapy has no place in thromboangiitis obliterans, unlike the other forms of arteritis discussed previously in this chapter. The most specific and useful therapy is complete abstinence from tobacco. Unfortunately, results of even the most rigorous behavioral modification programs have been discouraging in this group of patients. Their abuse of cigarettes is a true physiologic addiction. The most crucial surgical therapy is appropriate care of ischemic and gangrenous digits. Cautious applications of tepid soaks and other local therapies are appropriate. Treatment with intravenous antibiotics followed by longterm oral antibiotics is recommended in patients with active ischemic lesions. Although surgical debridement may be complicated by poor wound healing, drainage and removal of infarcted tissue is frequently necessary. Additional modalities of therapy that have been useful include sympathectomy, which is often combined with primary amputation of a single involved digit. The temporary increase in skin blood flow following sympathectomy (2 –4 weeks) seems to improve the chances of healing such amputations. Recent clinical trials in Great Britain and Japan have centered on continuous infusions of prostaglandin, including PGE1, and PGI2. In these studies, intraarterial therapy appears more efficacious than the intravenous route; healing or improvement was noted in 79% of patients in one small series of 29 patients.[41] The benefits of these vasoactive agents, while controversial,[42] are presumably due to dilation of collateral pathways and an anticoagulant effect on the microcirculation. Other vasodilating agents have not been shown to clearly benefit these lesions. Epidural anesthesia to reduce rest pain, foot dependency, and edema may be offered as a temporary measure in periods of acute exacerbation. Hyperbaric oxygen therapy has also been used to minimize pain and promote healing but remains of unproven value.[43] The efficacy of fibrinolytic agents and heparin in limiting
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the thrombotic process in the acute stage of the disease also remains unclear. If a proximal atherosclerotic occlusion lesion is demonstrated, bypass or percutaneous angioplasty may be appropriate; unfortunately, such lesions are present in only a small percentage of patients. Amputation is indicated in instances of secondary infection of gangrenous digits or intractable pain. Even if patients do not permanently restrict their tobacco use, abstinence during the first 7 –10 days following amputation and other debridement procedures appears to be of some benefit. Prognosis. In one large series of 193 patients with Buerger’s disease, 75% eventually developed digital ischemia, tissue loss, or gangrene. Arterial reconstructive surgery was deemed possible in only 17% with suboptimal patency rates of less than 50% during a 1- to 9-year follow-up period.[44,45] Although digital ischemic lesions are common, the amputation rate for major limbs remains less than 5%. Foot salvage can be achieved in the majority of cases with abstinence from smoking, meticulous care of ischemic lesions, selective prostaglandin therapy, and sympathectomy.
Kawasaki’s Disease Kawasaki’s disease is a systemic vasculitis of the smalland medium-sized arteries with a unique predilection of the coronary arteries. This acute febrile illness was first described in 1967 by Kawasaki in a group of Japanese schoolchildren who presented with a unique constellation of signs and symptoms including high fever, cervical lymph node enlargement, conjunctivitis, and truncal, solar, and palmar erythema.[46] Although this was initially thought to be a benign and self-limiting disease, it was soon recognized that sudden unexpected death occurring in about 2% of patients in the subacute phase due to cardiac complications. Approximately 15–20% of patients develop coronary artery aneurysms.[47] This complication is most common in the first month of the illness but may appear up to 4 years after initial symptoms. An intense vasculitis that historically resembles infantile polyarteritis nodosa underlies the degeneration of the arterial wall and aneurysm formation. Although rare, abdominal aortic, brachial, axillary, iliac, renal, and mesenteric aneurysms have also been reported. The syndrome is more common in Japan but has been diagnosed worldwide. In the United States the incidence is rising; 3000 children are diagnosed annually; 80 –90% of these are below 5 years of age.[48] Asians are affected six times more frequently than Caucasians. Outbreaks have seasonal variations, and definable case clusters occur at 2- to 3-year intervals. The etiology is unknown but has been attributed to innumerable viral and bacterial pathogens. More recently, an inherited defect in T-lymphocyte immunoregulation has been demonstrated in some patients with Kawasaki’s disease.[49] Clinical Presentation. The diagnostic criteria for Kawasaki’s disease include six principal signs: (1) high-grade fever (408C or more) persisting for at least 5 days; (2) polymorphic rash; (3) conjunctival congestion; (4) oropharyngeal changes, erythema, and fissuring of the lips, mucosal injection, and
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strawberry tongue; (5) acute nonpurulent cervical lymphadenopathy; and (6) erythema of the palms and soles, edema of the hands and feet, and desquamation of the fingertips. Associated findings also include sterile pyuria with urethritis, transient elevation of the liver enzymes, and asymptomatic gallstones; these occur in 7 – 30% of patients. Classic laboratory findings include leukocytosis, thrombocytosis, and elevation of acute-phase reactants. Complement levels are normal; viral and bacterial cultures as well as antinuclear and rheumatoid factors are usually negative.[50] Cardiovascular manifestations remain the most disturbing feature of this disease. Based on echocardiographic and angiographic data, the majority of aneurysms involve the coronary arteries and develop during the convalescent phase of the disease, 10 –14 days after the onset of fever. Peripheral aneurysms are nearly always associated with coronary involvement. Other cardiac abnormalities include myocarditis, valvulitis, and dysrhythmias. The natural history of coronary artery aneurysms has been determined using serial angiography and echocardiography.[47,51,52] It is generally accepted that aneurysms smaller than 8 mm in size eventually regress, while those greater than 8 mm are associated with high morbidity and mortality secondary to aneurysm rupture and thrombosis. Male children over 2 years of age who present with fever lasting more than 3 weeks and with persistent elevation of the ESR appear to be more vulnerable to persistent coronary artery aneurysms.[53] The observation that saccular aneurysms are less likely to regress than fusiform aneurysms suggests a more severe medial disruption in the saccular configuration. In a 13-year follow-up study of 594 patients with Kawasaki’s disease,[54] 25% developed coronary aneurysms in the acute phase of the disease. It is noteworthy that 55% of these aneurysms apparently regressed, based on arteriographic follow-up. Whether this change in appearance was related to intraluminal thrombosis or true remodeling remains unknown. Pathogenesis. The predilection of the coronary arteries to aneurysmal degeneration may be related to the additional stresses imposed by the bimodal systolic pressure wave characteristic of the coronary circulation in the presence of a necrotizing inflammation of the media. The fact that both the incidence of aneurysm formation and the morbid consequences have been reduced by the early administration of anti-inflammatory and immunoglobulin therapy would suggest that rapid control of the necrotizing process limits the injury and protects newly proliferating smooth muscle cells. In a study by Barron et al.,[49] an elevated serum level of interleukin-2 receptor was found to be a reliable predictor of the development of aneurysms in 82 children with clinical evidence of Kawasaki’s disease. Diagnosis. Echocardiography is recommended in any patient who satisfies the classic criteria of the disease, and it is useful in detecting coronary arterial involvement. Coronary catherization is performed only in those children in whom aneurysms are suggested by ultrasound. Management. Prompt initiation of anti-inflammatory agents such as aspirin and ticlopidine has reduced mortality from 2%
to about 0.5%. Intravenous gamma globulin combined with aspirin has been found to dramatically reduce the incidence of coronary artery aneurysms if started within 10 days of the onset of illness.[55] Such therapy may prevent deposition of circulating immune complexes, thereby limiting the vasculitic process. Currently there is no evidence to suggest that this therapy is effective in regressing chronic coronary aneurysms. Operative treatment with saphenous interposition grafting is limited to patients with symptomatic or expanding coronary and peripheral arterial aneurysms.[56]
Behc¸et’s Disease Behc¸et’s disease[57] is a rare vasculitis with protean manifestations in the systemic arteries and veins as well as the pulmonary circulation. Venous complications include recurrent episodes of deep venous thrombosis, which occasionally result in vena cava thrombosis. While arterial symptoms are elicited in only 10 – 20% of patients, sudden arterial occlusions and aneurysmal ruptures represent a frequent cause of death in this otherwise benign disease. Clinical Presentation. First manifestations of Behc¸et’s disease include relapsing iridocyclitis associated with oral and genital ulcerations. Patients may also present with poorly characterized polyarthritis and neurologic deficits compatible with both central lesions and peripheral neuropathies. Involvement of the gastrointestinal tract is unusual but may result in spontaneous ileal and cecal perforations associated with ulcerative enteritis.[58 – 60] Abdominal aortic and peripheral aneurysms have been reported, although the frequency of these lesions remains ill defined.[61 – 63] Diagnosis is based on the history of mucosal ulcerations associated with arterial and venous disease in a young patient. Generally, the disease has a predilection for males. This helps distinguish it from Takayasu’s arteritis, which has a distinct female predominance. Physical examination may demonstrate central or peripheral aneurysms and, rarely, absence of peripheral pulses. Ultrasound or computerized tomography (CT) can confirm the impression of aneurysmal dilation. Arteriography is occasionally needed to better delineate the pattern of thoracic aortic involvement; however, such studies should generally be reserved for preoperative evaluation (Fig. 64-7). Pathology. The histologic picture is consistent with focal arteriolitis. Lymphocytes and polymorphonuclear leukocytes are widely infiltrated, resulting in fibrinoid necrosis with complete or partial vascular occlusion. This inflammatory process is noted in both the arteries and veins of involved areas. Aneurysms may appear grossly infected in some patients. While it is impossible to definitively rule out such an etiology, intraoperative cultures are typically negative and graft infections have not been reported following in situ reconstruction. On occasion, however, it may be impossible to grossly differentiate Behcet’s disease aneurysms from true infected aneurysms, and extraanatomic reconstruction may be appropriate.[64]
Chapter 64.
Figure 64-7. Preoperative angiogram in patient with Behc¸et’s disease and abdominal pain demonstrates large infrarenal aneurysm with intraluminal thrombus.
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analysis and elevated serum creatinine levels are found in patients with renal involvement.[70] Antinuclear antibody and rheumatoid factor are positive in 10 and 20% of patients, respectively. The precise etiology of this group of disorders is dependent on the associated collagen disease and, in general, reflects continuing immune complex damage of the small vessels, especially the postcapillary venules and muscular arterioles. The inciting antigen may be a drug, a virus such as hepatitis B, or tumor antigen. Vascular injury also may be accentuated by external factors such as trauma or hypothermia. Treatment depends on associated vital organ involvement and whether vasospasm is an important contributing factor to digital ischemia. Cases of necrotizing vasculitis strictly limited to the skin may be treated with local sulfones. Steroids and/or immunosuppressant drugs are indicated if there is evidence of progressive skin involvement, nephropathy, or internal organ damage. If cryoglobulins or other circulating proteins are identified, plasmapheresis may be of benefit. Digital vasospasm can be managed with vasodilators such as nifedepine and nicotinamide. In some instances, acute digital ischemia can be temporarily ameliorated by tourniquetcontrolled intravenous reserpine injection or a Bier block.[71] At the current time, antithrombotic agents are of unproven value.
Fibromuscular Dysplasia
Therapy. Patients frequently are first seen for complications of venous thrombosis. Most authors recommend that patients be maintained indefinitely on both support stockings and anticoagulation with warfarin. The need for long-term anticoagulation makes it essential that any complaints of abdominal or back pain be aggressively evaluated, as they may herald expansion or rupture of a previously undiagnosed aortic aneurysm.
Small-Vessel Disease A large number of disorders are incorporated in this classification, including hypersensitivity angiitis, mixed cryoglobulinemia, and collagen disease vasculitis.[65] The common underlying pathology in necrotizing vasculitis is fibrinoid necrosis of the arterial or venous wall characteristically involving the cutaneous vessels. More than 50% of patients with necrotizing vasculitis will present with palpable purpuric nodules, most frequently on the lower extremities. These cutaneous lesions are usually associated with fever and multiple-system organ involvement. Digital ischemic ulceration may be the first manifestation of a systemic autoimmune disease.[66,67] The diagnosis is confirmed by skin biopsy. Histologic examination reveals neutrophilic infiltration of the vessel wall, fibrinoid necrosis, and dermal hemorrhage.[68] Direct immunofluorescence studies of the lesion demonstrate IgM or IgA, which is commonly associated with Henoch-Scho¨nlein purpura.[69] In two thirds of patients, the ESR is elevated. Abnormal urine
Since the first report of arterial fibrodysplasia in 1938, these lesions have received much attention[72,73] as a cause of renovascular hypertension.* Additional reports have focused on the neurologic manifestations of extracranial dysplastic lesions and the occasional case of mesenteric vascular involvement.[74 – 78] Clinically significant fibromuscular dysplasia is most common in women between the ages of 20 and 40 years and can be distinguished from the other lesions discussed previously in this chapter by the lack of a true inflammatory component. The etiology of these lesions remains unknown, although hormonal influences, mechanical stress, and disorders of vascular wall nutrition have been suggested.[79] Clinical Presentation. The clinical presentation is dependent on the location of the dysplastic lesion. By far the most common site of involvement is the main renal artery and its secondary branches (Fig. 64-8). Hemodynamically significant stenoses predictably decrease renal perfusion pressure, resulting in hyper-reninemia and activation of the angiotensin-aldosterone axis. Dysplastic renal artery lesions must be investigated in any young patient presenting with diastolic hypertension greater than 100 mmHg. The incidence of renovascular hypertension is bimodal, with a first peak at 2 –4 years of age and a second large peak at 20–40 years. Females predominate 8:1 in the second group, but this sex predilection is less obvious in prediatric patients.
*For a full discussion of renovascular hypertension, see Chap. 60.
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Figure 64-9. Duplex ultrasound of the juxtarenal aorta (AO), right renal artery (RA), and right renal vein (RV). An irregular stenosis is noted in the proximal renal artery. Figure 64-8. Tapered fibrodysplastic lesion of right renal artery extends to bifurcation.
Physical findings other than hypertension are not very specific. Although flank bruits are classically associated with renal artery stenosis, the specificity and sensitivity of this sign are both low in most clinical series. Intravenous pyelograms (IVPs) may suggest the diagnosis, especially if disparity in renal size, hyper-concentration of dye, or ureteral notching from collateral vessels are demonstrated. However, the principal function of an IVP is the exclusion of primary renal parenchymal disease. Currently, noninvasive examination of renal arterial flow patterns by duplex ultrasonography is evolving as the most suitable screening method for significant renal arterial stenoses. Although B-mode real-time imaging of the renal arteries is possible (Fig. 64-9), resolution is often suboptimal. Quantitation of the degree of stenosis currently relies on serial velocity measurements along the renal artery from the aorta to the hilum of the kidney. Barnes[80] and others have demonstrated that a renal:aortic peak systolic velocity ratio of 3.5 or more is indicative of hemodynamically significant renal stenosis greater than 60%. Using these criteria, duplex Doppler ultrasonography carries a specificity rate of 93–97% and a sensitivity rate of 83– 90% as compared to angiography.[81,82] The examination requires considerable technical expertise and proper patient
preparation. Color-flow imaging appears to facilitate identification of the juxtarenal aorta, the left renal vein, and the origin of the renal arteries. Its value in detecting significant renal arterial stenoses, however, remains to be determined. Specific diagnosis requires arteriography. Intravenous digital angiography can suffice, although it is usually necessary to perform arterial catheterization with Seldinger technique, which allows selective injections and oblique views. Fibrodysplastic lesions generally spare the proximal portion of the renal artery but extend distally to the major branches of the vessel (Fig. 64-10). While renal vein renin ratios and renal systemic renin values are commonly obtained, the diagnostic reliability of these determinations is compromised by bilateral disease and the multiple medications which are usually required to control hypertension. Nonetheless, renal systemic renin values can predict the degree of improvement following successful revascularization.[79,83] Patients with carotid involvement* present with intermittent neurologic deficits often corresponding to the middle cerebral artery distribution. Mechanisms for cerebral
*See Chap. 60 for a full discussion of this topic, including the role of percutaneous balloon angioplasty.
Chapter 64.
Figure 64-10. Severe stenosis of right renal artery associated with an extensive network of capsular collaterals from adrenal (top ) and ureteral (bottom ) arteries. The presence of these collateral vessels confirms the hemodynamic significance of the main renal artery lesion.
ischemia include platelet or thrombotic emboli as well as “low flow” distal to an obstructing lesion. Noninvasive studies such as oculoplethysmography and duplex scanning may detect these lesions; however, arteriography is usually required for a full definition of the extent of disease. Fibromuscular disease may vary from a localized web at the carotid bifurcation to diffuse involvement of the entire extracranial and intracranial internal carotid artery. These lesions are occasionally associated with subintimal internal carotid artery dissections, distinguished angiographically by an irregular narrowed arterial lumen. Pathology. Dysplastic lesions are most conveniently classified into four general types:[76] (1) intimal fibroplasia, (2) medial hyperplasia, (3) medial fibroplasia, and (4) perimedial dysplasia. Of these, medial fibroplasia accounts for more than 85% of all lesions (Fig. 64-11). Gross examination of excised vessels demonstrates a wide range of morphology from focal stenoses to series of stenoses with intervening aneurysmal dilations (producing a “chain of lakes” appearance (Fig. 64-12). Histologic examination of medial fibroplasia reveals few intact smooth muscle cells in the media and a marked
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Figure 64-11. A spontaneous dissection (upper right ) compromises the lumen in this renal artery with severe medial fibroplasia. Urgent aortorenal bypass was required.
increase in collagen and ground substance. Disease may be limited to the outer media or extend throughout the entire media, although the intima may be fractured and some degree of intimal fibrosis can be seen. In the medial and intimal lesions, the adventitia is usually spared completely. Treatment.* Indications for operation in patients with renovascular hypertension include the documentation of an appropriate renal artery lesion in an adult with severe hypertension, requiring multiple adrenergic blocking agents for control. Other candidates for surgery in fibrodysplasia include children with severe hypertension and any patient with a documented decrease in renal function. These renal artery lesions can usually be treated quite successfully with aortorenal bypass using autologous vein or artery.[83] In rare instances of distal segmental involvement, ex vivo repair with autotransplantation may be appropriate.[84] Overall, perioperative kidney loss is less than 2% and cure or
*Discussed more fully in Chap. 56.
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Part Eight. Vascular Disorders of the Upper Extremity and Vasculitis
Figure 64-12. Classic “chain of lakes” appearance, with saccular dilations and segmental stenoses.
improvement of hypertension can be expected in 90% of patients. In a retrospective review from the University of Michigan, Stanley et al.[85] reviewed a 30-year experience (1963 – 1993) with operative correction of renovascular hypertension in 57 pediatric patients. The most common renal artery pathology was atypical medial-perimedial dysplasia, usually associated with secondary intimal fibroplasia. Aortorenal bypass with autogenous vein was the most prevalent
procedure (60%) early in the experience but was infrequently utilized in the last decade of the study. In fact, direct reimplantations of distal vessels into the aorta as well as reimplantation of segmental arteries into adjacent renal arteries accounted for the majority of reconstructions in the modern era. Percutaneous transluminal angioplasty has demonstrated encouraging early results in some cases.[86] However, longterm results have yet to be clearly documented. Cerebrovascular manifestations of carotid artery disease such as transient ischemic attacks or stroke strongly indicate surgical therapy.* Operations have included intraoperative dilation, vein graft bypass, and extracranial-intracranial (ECIC) bypass. Surgery is generally not indicated for carotid artery dissections secondary to fibromuscular dysplasia; the majority of these lesions will resolve with anticoagulation alone, despite their frightful appearance on angiography. It may be helpful to repeat angiography in 3 –6 months if the lesion cannot be followed by duplex ultrasound. If cerebral ischemia persists, extraanatomic reconstruction with an ECIC bypass may be a more prudent option, as distal extension of these lesions into the petrous portion of the carotid artery makes a cervical approach difficult or impossible. Fibromuscular dysplasia of the mesenteric vessels is quite rare. If acute or chronic intestinal ischemia does result, the operative approach is similar to the treatment of atherosclerotic occlusive lesions. It must be remembered, however, that fibromuscular dysplasia may extend more distally in the mesenteric vessels.
*Fully discussed in Chap. 56.
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Szilagyi, E.D.; DeRusseo, F.J.; Elliot, J.P., Jr. Thromboangiitis Obliterans: Clinico-angiographic Correlations. Arch. Surg. 1964, 88, 824. Shionoya, S.; Hiari, M.; Kawai, S. Pattern of Arterial Occlusion in Buerger’s Disease. Angiology 1982, 33, 375. Suzuki, S.; Mine, H.; Umehara, I.; et al. Buerger’s Disease (Thromboangiitis Obliterans): An Analysis of the Arteriograms of 119 Cases. Clin. Radiol. 1982, 33, 235. Lie, J.T. Thromboangiitis Obliterans (Buerger’s Disease) Revisited. Pathol. Annu. 1988, 23 ((part 2)), 257. Shionoya, S. Clinical Experience with Prostaglandin E1 in Occlusive Arterial Disease. Inter. Angio. 1984, 3, 99. Schuler, J.J.; Flanigan, D.P.; Holcroft, J.W.; et al. Efficacy of Prostaglandin E1 in the Treatment of Lower Extremity Ischemic Ulcers Secondary to Peripheral Vascular Occlusive Disease: Results of a Prospective Randomized DoubleBlind, Multicenter Clinical Trial. J. Vasc. Surg. 1984, 1, 160. Sakakibara, K.; Takahaski, H.; Kobayashi, S. Clinical Experience of Hyperbaric Oxygen Therapy (OHP) for Chronic Peripheral Vascular Disorders. In Hyperbaric Medicine and Underwater Physiology; Shiraki, D., Matsuoka, S., Eds.; Undersea Medical Society: Bethesda, Maryland, 1983; 337. Shionoya, S.; Ban, I.; Nakata, Y.; et al. Vascular Reconstruction in Buerger’s Disease. Br. J. Surg. 1976, 63, 841. Shionoya, S. Buerger’s Disease (Thromboangiitis Obliterans). Rutherford Vasc. Surg. 1989, 3, 207. Kawasaki, T. Acute Febrile Mucocutaneous Syndrome with Lymphoid Involvement with Specific Desquamation of the Fingers and Toes. Arerugi 1967, 16, 178. Kato, H.; Koike, S.; Yamamoto, M.; et al. Coronary Aneurysms in Infants and Young Children with Acute Febrile Mucocutaneous Lymph Node Syndrome. J. Pediatr. 1975, 86, 892. Rauch, A.M. Kawasaki Syndrome: Critical Review of U.S. Epidemiology. Prog. Clin. Biol. Res. 1987, 20, 33. Barron, K.; et al. Abnormalities of Immunoregulation in Kawasaki Syndrome. J. Rheumatol. 1988, 15, 1243. Leung, D.Y. Immunologic Abnormalities in Kawasaki Syndrome. Prog. Clin. Biol. Res. 1987, 20, 159. Capannari, T.E.; Daniels, S.R.; Meyer, R.A.; et al. Sensitivity, Specificity and Predictive Value of TwoDimensional Echocardiographic in Detecting Coronary Artery Aneurysms in Patients with Kawasaki Disease. J. Am. Coll. Cardiol. 1986, 7, 355. Yoshikawa, J.; Tanagihara, K.; Owaki, T.; et al. CrossSectional Echo-cardiographic Diagnosis of Coronary Artery Aneurysms in Patients with the Mucocutaneous Lymph Node Syndrome. Circulation 1979, 59, 133. Kato, H.; Inoue, O.; Akagi, T. Kawasaki Disease: Cardiac Problems and Management. Pediatr. Rev. 1988, 9, 209. Kato, H.; Sugimura, T.; Akagi, T.; Sayo, N.; Hashino, K.; Maeno, Y.; Kazue, T.; Eto, G.; Yamakawa, R. LongTerm Consequences of Kawasaki Disease: a 10 – 21-Year Follow-up Study of 594 Patients. Circulation 1996, 94, 1379. Newburger, J.W.; et al. The Treatment of Kawasaki Syndrome with Intravenous Gammaglobulin. N. Engl. J. Med. 1986, 315, 341.
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56. Kitamura, S. Surgery for Coronary Heart Disease Due to Mucocutaneous Lymph Node Syndrome (Kawasaki Disease). In Kawasaki Disease: Proceedings of the Second International Kawasaki Disease Symposium; Shulman, S.T., Ed.; Liss: New York, 1987. ¨ ber Rezidivierende Aphthose Durch ein Virus 57. Behcet, H. U Verursachte Geschwure am Mund, am Auge und an den Genitalien. Dermatol. Wochnschr. 1937, 105, 1152. 58. Chajet, T.; Fainaru, M. Behcet’s Disease: Report of 41 Cases and a Review of the Literature. Medicine 1975, 54 (3), 179. 59. James, D.G. Behcet’s Syndrome. N. Engl. J. Med. 1979, 301, 431. 60. Lebwohl, O.; Forde, K.A.; Berdon, W.E.; et al. Ulcerative Esophagitis and Colitis in a Pediatric Patient with Behcet’s Syndrome. Am. J. Gastroenterol. 1977, 68, 550. 61. Enoch, B.A.; Castillo-Olivares, J.L.; et al. Major Vascular Complications in Behcet’s Syndrome. Postgrad. Med. J. 1968, 44, 453. 62. Haim, R.S.; Reshef, R.; Peleg, E.; Riss, E. Cardiac Involvement and Superior Vena Cava Obstruction in Behcet’s Disease. N. Engl. J. Med. 1979, 301, 431. 63. Little, A.G.; Zarins, C.K. Abdominal Aortic Aneurysm and Behcet’s Disease. Surgery 1982, 91, 359. 64. Ketch, L.L.; Buerk, C.A.; Liechty, R.D. Surgical Implications of Behcet’s Disease. Arch. Surg. 1980, 115, 759. 65. Montgomery, H. Montgomery’s Textbook of Dermatopathology; Harper & Row: New York, 1967; 685. 66. Baur, G.M.; Porter, J.M.; Bardana, E.J.; et al. Rapid Onset of Hand Ischemia of Unknown Etiology. Ann. Surg. 1977, 186, 184. 67. Porter, J.M.; Taylor, L.M. Small Artery Disease of the Upper Extremity. World J. Surg. 1983, 7, 326. 68. Sanchez, N.P.; Van Hale, H.M.; Su, W.P.D. Clinical and Histophathologic Spectrum of Necrotizing Vasculitis: Report of Findings in 101 Cases. Arch. Dermatol. 1985, 121, 220. 69. Wall Bake, A.W.L.; Lobatto, S.S.; et al. IgA Antibodies Directed Against Cytoplasmic Antigens of Polymorphonuclear Leukocytes in Patients with Henoch-Scho¨nlein Purpura. Adv. Exp. Med. Biol. 1987, 216B, 1593. 70. Heng, M.C.Y. Henoch-Scho¨nlein Purpura. Br. J. Dermatol. 1985, 112, 235. 71. Taylor, L.M.; Rivers, S.P.; Porter, J.M. Treatment of Finger Ischemia with Bier Block Reserpine. Surg. Gynecol. Obstet. 1982, 154, 39.
72. Fry, W.J.; Ernest, C.B.; Stanely, J.C.; et al. Renovascular Hypertension in the Pediatric Patient. Arch. Surg. 1973, 107, 692. 73. Harrison, E.G.; McCormack, L.J. Pathologic Classification of Renal Artery Disease in Renovascular Hypertension. Mayo Clin. Proc. 1971, 46, 161. 74. Ehrenfeld, W.K.; Wylie, E.J. Fibromuscular Dysplasia of the Internal Carotid Artery: Surgical Management. Arch. Surg. 1974, 109, 676. 75. Morris, G.C., Jr.; Lechter, A.; DeBakey, M.E. Surgical Treatment of Fibromuscular Disease of the Carotid Arteries. Arch. Surg. 1968, 96, 636. 76. Sandok, B.A.; Houser, O.W.; Baker, I.I.I.; et al. Fibromuscular Dysplasia: Neurologic Disorders Associated with Disease Involving the Great Vessels in the Neck. Arch. Neurol. 1971, 24, 462. 77. Stanley, J.C.; Fry, W.J.; Seeger, J.F.; et al. Extracranial Internal Carotid and Vertebral Artery Fibrodysplasia. Arch. Surg. 1974, 109, 215. 78. Wylie, E.J.; Binkley, F.M.; Palubinskas, A.J. Extrarenal Fibromuscular Hyperplasia. Am. J. Surg. 1966, 112, 149. 79. Stanley, J.C.; Gewertz, B.L.; Bove, E.L.; Fry, W.J. Arterial Fibrodysplasia: Histophathologic Character and Current Etiologic Concepts. Arch. Surg. 1975, 110, 561. 80. Barnes, R.W. Utility of Duplex Scanning of the Renal Artery. In Arterial Surgery: New Diagnostic and Operative Techniques; Bergan, J.J., Yao, J.S.T., Eds.; Grune and Stratton: Orlando, Florida, 1988; 351 –366. 81. Hansen, K.J.; Tribble, R.; Reavis, S.W.; et al. Renal Duplex Sonography: Evaluation of Clinical Utility. J. Vasc. Surg. 1990, 12, 227. 82. Kohler, T.R.; Zierler, R.E.; Martin, R.I.; et al. Noninvasive Diagnosis of Renal Artery Stenosis by Ultrasonic Duplex Scanning. J. Vasc. Surg. 1986, 4, 450. 83. Ernst, C.B.; Stanley, J.C.; Marshall, F.F.; et al. Autogenous Saphenous Vein Aortorenal Grafts: A Ten-Year Experience. Arch. Surg. 1972, 105, 855. 84. Gewertz, B.L.; Stanley, J.C.; Fry, W.J. Renal Artery Dissections. Arch. Surg. 1977, 112, 409. 85. Stanley, J.C.; Zelenock, G.B.; Messina, L.M.; Wakefield, T.W. Pediatric Renovascular Hypertension: A Thirty-Year Experience of Operative Treatment. J. Vasc. Surg. 1995, 21 (2), 212. 86. Tyagi, S.; Kaul, U.A.; Satsangi, D.K. Percutaneous Transluminal Angioplasty for Renovascular Hypertension in Children: Initial and Long-Term Results. Pediatrics 1997, 99 (1), 44.
CHAPTER 65
Natural History of Deep Venous Thrombosis and Its Implications for Sequelae in the Involved Limb Matthew Waltham Alberto Smith Kevin G. Burnand
and he was also the first person to recognize the importance of the calf-perforating veins and lipodermatosclerosis.[5] Oschner and DeBakey reported that deep vein thrombosis was common after surgical operations and advocated its avoidance and treatment by vein ligation or anticoagulants to prevent pulmonary embolism.[6] Homans had previously advocated vein ligation to prevent pulmonary embolism as a consequence of deep vein thrombosis. He also recognized that the postthrombotic leg was an important cause of venous ulceration.[7] Homans, Bauer, and Linton advocated ligation of the deep veins in patients with post-thrombotic limbs to prevent venous reflux and reduce the risk of recurrent venous ulceration.[8 – 10] The advent of the coumarin anticoagulants, heparin, and recently the low molecular weight heparins has focused attention away from the avoidance of postthrombotic sequelae; protection against the lethal complications of pulmonary embolism has now taken center stage. The development of vena caval filters by Mobin-Uddin[11,12] and Greenfield[13] has added a further therapeutic option to pulmonary embolism prevention. There is little evidence that any of the present treatments including thrombolysis and thrombectomy reduce the incidence of postthrombotic limb.
The precise mechanism by which thrombi develop in the deep veins of the leg is not known, and even less is known about their subsequent natural history. Although thrombi are said to “lyse,” it is debatable if this is ever really complete without pharmacologic assistance. It is not even known how long a thrombus has to be in contact with a venous valve before it is irretrievably damaged. In the face of these uncertainties this chapter summarizes past theories on causation and resolution of venous thrombi and then reviews more recent clinical and experimental work that has been undertaken to try and unravel the natural history of deep venous thrombi.
HISTORY It was Baillie who perhaps first noted the importance of “stasis” or reduced blood flow as a cause of thrombosis,[1] and Rokitansky subsequently reported that thrombosis occurred in a vein at the site of an injury or adjacent to inflammation.[2] Hunter also stressed the role of inflammation and infection as causes of thrombi, although this association is now considered unimportant as it is rarely seen today.[3] In 1856 Virchow’s detailed pathological studies led him to postulate that thrombosis may be caused by a slowing or cessation of blood flow (stasis), increased thrombotic potential of the blood (hypercoagulability) and abnormalities in the vessel wall (endothelial lining).[4] These etiological factors, known as Virchow’s triad, are still accepted. In 1866 John Gay recognized clot and thrombi in the deep veins of many of the limbs he dissected with venous ulcers,
THE INITIATION OF VENOUS THROMBOSIS (PATHOGENESIS) The initiation of venous thrombosis depends upon a complex interaction between the blood constituents and the endo-
Hobson/Wilson/Veith: Vascular Surgery: Principles and Practice, Third Edition, Revised and Expanded DOI: 10.1081/0819-9-120024949 Copyright q 2004 by Marcel Dekker, Inc.
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thelium. The relative importance of these factors is still poorly understood.
Stasis Most venous thromboses occur in the deep veins of leg, suggesting that the erect stance of humans produces gravitational slowing of the blood flow in the veins. The seminal work of Sevitt and Gallagher showed that many thrombi developed in the valve cusps in patients who died of pulmonary embolism after fracture of the femur.[14] Sevitt suggested that packets of fibrin surrounded by platelets built up in the valve cusps where blood flow was relatively static. These gradually spread across the vessel lumen by a process of encrustation until flow was reduced or cut off, at which point thrombus extended up the vessel wall as loose propagated fibrin thrombus as far as the next collateral veins. Good flow through the proximal tributaries had the potential to maintain patency above the loose thrombus preventing further propagation, while poor flow through these veins or compromise of their orifices might lead to further propagation to the next collateral inflow and so on up the vein. The initial “white” thrombus has a coralline (coral-like) structure consisting of layers of platelets and white cells (lines of Zahn) broken up by red cells entrapped in a fibrin mesh (Fig. 65-1) (see also color plate). The propagated “red” thrombus is much more amorphous and consists predominantly of red cells bound by fibrin providing a much less adherent “loose” thrombus, which is more easily detachable. Propagated thrombi are usually the source of pulmonary emboli, especially when they lie free in the vein with blood flow passing on either side preventing attachment. Even if embolism occurs, the fixed head of the thrombus is usually retained and may act as a source for further propagation. Although some authors have suggested that thrombus can form in the valve cusp without endothelial attachment, this is probably rare, and the thrombus origin is usually the result of white cell and platelet attachment to some point on the endothelium. Occlusion of an isolated vein in an animal model fails to cause thrombosis,[15] and it may be that slowing of blood flow is merely a facilitator rather than an initiator of thrombus formation.
Changes in the Vessel Wall Functional changes in the endothelial lining of the vessel wall are now being examined in greater detail. Abnormal platelet, leukocyte, and endothelial activation by cells may be an important factor in the genesis of a thrombus, but endothelial damage alone only produces cellular adhesion, not thrombus in an animal model.[16] Eddy currents within valve pockets may cause localized endothelial disturbance or activation, which promotes leukocyte and platelet adhesion. In animal studies leukocytemediated disturbance of endothelium occurs before platelet and red cell deposition are observed, and this has been proposed as an initiating mechanism.[17 – 19] Thrombus formation is reduced by substances that inhibit leukocyte adhesion and migration in animal models and in patients having hip replacements.[20 – 22] No significant increase in the
Figure 65-1. Staining for CD41 (red) in early human venous thrombus (see color plate).
expression of adhesion receptors has, however, been found during thrombin-induced experimental thrombogenesis in man.[23] Prolonged stasis does upregulate endothelial adhesive receptors in the rabbit external jugular vein, causing increased adhesion of leukocytes to the vessel wall, although this does not progress to endothelial damage and thrombus generation.[15]
Hypercoagulability of the Blood The discovery of a number of prothrombotic conditions (known generally as thrombophilias) has led to the hypothesis that blood hypercoagulability is the major factor in thrombogenesis. In reality most patients with these conditions are at increased risk when a second thrombogenic factor is operating, e.g., injury, operation, pregnancy, or the contraceptive pill. The conditions that are now known to cause thrombophilia include antithrombin deficiency, protein C deficiency, protein S deficiency, activated protein C resistance (Factor V Leiden mutation), and antiphospholipid syndrome. Activated protein C resistance, for example, is present in 5% of the total population, but is found in 20% of those with deep vein thrombosis.[24] The process of thrombus initiation may be continually occurring on a daily basis as low levels of fibrin degradation products can be measured within all subjects’ blood throughout life. This process is probably overcome by the body’s own natural thrombolytic defenses.
THROMBUS RESOLUTION Organization and Natural Lysis Natural thrombolysis was originally thought to be dependent on a fibrinolytic response by the local endothelium. Studies using a rat model of thrombosis without endothelial damage[25] did not demonstrate an increase in local plasminogen activator activity in the adjacent vessel wall,[26] but there was a reduction of tissue plasminogen
Chapter 65.
activator activity within 48 hours, which corresponded to the disappearance of the endothelium beneath the thrombus. Plasminogen activator activity was also found in the thrombus, which increased as organization proceeded. The intensity of immunohistochemical staining for plasminogen activator increased as the thrombus became organized and was predominantly located within a developing monocyte infiltrate.[27] There was a corresponding rise in tissue plasminogen activator mRNA within the monocytic cell infiltrate, suggesting that these cells were the source of tissue plasminogen activator within the thrombus. In vitro studies have shown that peripheral blood monocytes have the ability to synthesize tissue plasminogen activator, urokinase, and the urokinase receptor, all of which may be influenced by thrombin, cytokines, and lipopolysaccharide. These stimuli can also induce the production of inhibitors of fibrinolytic activation at the same time.[28 – 33] Monocytes have also been recently shown to actively degrade fibrin in the absence of plasmin.[34] The mechanism of subsequent organization and recanalization of thrombi has been described by Cox[35] and Sevitt.[36] Initially the thrombus is loosely anchored to the vein wall by fibrinous attachments, which become progressively more secure. There is a local inflammatory response in the adjacent wall, and the thrombus is invaded by leukocytes and fibroblasts in a process comparable to normal wound healing. The attached thrombus gradually contracts on the vein wall. There is disruption of the periphery of the thrombus with formation of small fragments, which may break free and embolize to the lungs. This fragmentation leads to the formation of pockets and clefts in the thrombus, which are rapidly lined with flat endothelial cells. The surface of the thrombus is also covered with endothelial cells, which may activate plasminogen and therefore contribute to the formation of these clefts by local fibrinolysis. The clefts can extend deeply into the thrombus, sometimes passing from one side to another, and may be potential canals. Progressive peripheral fragmentation may be important in reducing the bulk of the thrombus and is particularly effective in small thrombosed veins. Communications may develop between the pockets, helping to recanalize the venous lumen. The center of the thrombus is filled with invading cells. Lytic spaces appear around these cells, and there is a gradual reduction in red cells and platelets, with hemosiderin appearing within macrophages.
Recanalization Analyses of organizing thrombi show that most undergo recanalization with the formation of new vascular channels (Fig. 65-2) (see also color plate). These channels begin as spaces in the thrombus around invading cells. Virchow showed that these spaces do not initially communicate directly with the patent functioning parts of the vessel lumen either side of the occluded segment. As the thrombus is progressively organized, the spaces coalesce to form channels. Leriche thought these channels were of no functional significance,[37] but it is now clear that they eventually join to restore blood flow within the vessel.
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Figure 65-2. Cells lining microvessels stained for VCAM-1 in recanalizing human thrombus (see color plate).
Sevitt also demonstrated that the vasa venorum send capillary buds into organizing thrombus, which go on to anastomose, and therefore this process may be affected by the degree of peripheral attachment of the thrombus.[38] It is still not known, however, whether there is de novo formation of vessels within the thrombus and, if so, where the endothelialtype cells originate that go on to line these vessels.
The Role of the Monocyte in Thrombus Resolution In 1860 Virchow recorded that many leukocytes were incorporated into venous thrombi. These cells may play an important role in orchestrating thrombus organization and resolution by the excretion of proteases, growth, and angiogenic factors. The origin and nature of the mononucleated cells that invade from adherent zones has also given rise to controversy. Ultrastructural studies have identified them as macrophages that migrate through the vein wall,[39] and Kwaan showed that radioactively labeled leukocytes injected intravenously subsequently migrated into experimental thrombi.[40] Monocytes are normally found in large numbers in wounds and play a central role in wound healing.[41,42] These cells, which can be activated by a variety of sources, are potently angiogenic through the production and secretion of factors, such as vascular endothelial growth factor (VEGF).[43,44] The formation of microvessels within the fibrin-rich matrix is a prominent feature during natural thrombus resolution, and these are usually located in areas that have a high macrophage density (Fig. 65-3) (see also color plate). It is possible, therefore, that monocytes produce and secrete angiogenic factors. The vessels express both constitutive endothelial markers such as CD31 and markers of endothelial cell activation such as tissue factor and vascular cell adhesion molecule (VCAM-1). This adhesion molecule is known to be involved in leukocyte trafficking in inflamed tissues[45] and may be performing the same function in thrombosis. Raised levels of the soluble form of VCAM-1, which is produced as the result of shedding from the cell membrane, have also been found in the blood of patients with confirmed deep vein thrombosis.
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Figure 65-3. Staining for CD68 (monocyte/macrophage marker) in organizing human venous thrombus (see color plate).
THE CLINICAL RESOLUTION OF THROMBOSIS The thrombus is replaced with a vascular granulation tissue, which becomes progressively more fibrous and contracts. Humoral activation of fibrinolysis may play a part in the early resolution of nonocclusive thrombi (except at areas of adherence) but is not likely to occur within occlusive thrombi except at the ends where they are exposed to luminal blood. Once the thrombus has become organized, the fibrin is replaced with collagen-based connective tissue and fibrinolysis is probably no longer effective. The end product of organization may be fibrous intimal thickenings, projecting fibrous stalks, nodules, and strings. At any stage part of the thrombus may break free as a thromboembolism. This most commonly occurs after about 10 days. Emboli usually impact in the pulmonary vasculature or very rarely may pass through a cardiac septal defect or patent ductus arteriosus into the systemic arterial circulation and impact in the brain or periphery (paradoxical embolism). Phlebography was first used by Bauer to define the state of the deep veins in patients with deep vein thrombosis.[46] Clinical regression of human thrombi can be monitored using phlebography[47] or duplex ultrasonagraphy[48] with color duplex scanning producing results comparable to phlebography.[49] Resolution occurs in 70% of limbs with occlusive thrombi and is related to the initial thrombus load. Recanalization predominantly takes place in the first 6 weeks, with calf vein thrombi resolving faster than more proximal thrombi.
THE POSTTHROMBOTIC LIMB Many patients with proximal vein thromboses subsequently develop symptoms of chronic venous insufficiency in their lower limbs.[50,51] In one series 67% had pain and/or swelling of the leg, 23% developed ankle skin pigmentation, and 3% developed leg ulceration.[52] The process of thrombus
formation, organization, and resolution causes valve destruction and incompetence,[53] which may progressively worsen with time.[54,55] The thrombus leads to a variable degree of persistent venous obstruction, which together with valvular incompetence causes ambulatory venous hypertension and eventually produces the postthrombotic limb. Valve damage and subsequent incompetence is not an inevitable consequence of thrombosis. In a duplex ultrasound study 12 years after acute thrombosis, the majority of vein segments that had recanalized, either partially or completely, were found to contain competent valves.[56] Valvular incompetence, particularly in combination with residual venous obstruction, was the single most important cause of a postthrombotic leg. Thrombi that resolve more rapidly cause less valvular incompetence,[57] and therefore treatments that enhance thrombus resolution may result in fewer long-term complications.[58]
THE EFFECT OF TREATMENT ON THE NATURAL HISTORY OF VENOUS THROMBOSIS The aims of treating venous thrombosis are to prevent propagation and embolism, to prevent vein and valve damage, to reduce the long-term complications of the postphlebitic leg, and to prevent recurrence. Current treatment only partly achieves these objectives. Established deep vein thrombosis requires urgent treatment, and current opinion is that this should be in the form of anticoagulation.[59] The early use of anticoagulation prevents the progression of deep vein thrombosis,[60] and in a rabbit study anticoagulation increased the rate of recanalization of thrombus.[61] In humans it is highly effective in preventing thrombus extension and reducing morbidity and death from pulmonary embolism.[62,63] Anticoagulation does not appear to have any significant fibrinolytic activity, but the prevention of thrombus propagation may minimize further valve damage and thus lessen the incidence of long-term complications. Traditionally unfractionated heparin is given as an intravenous infusion, but more recently low molecular weight heparin given as a subcutaneous injection has been shown to be as effective as unfractionated heparin for the initial treatment of proximal thromboses.[64 – 66] It has yet to be determined whether there is a difference in the incidence of the postphlebitic syndrome compared with conventional treatment. Johnson and McCarty first showed that thrombolytic agents can lyse venous thrombi in man.[67] Thrombus is effectively removed[68] and valve function can be preserved compared with treatment by anticoagulation alone.[69,70] This should theoretically reduce the severity of the postthrombotic syndrome. Long-term postthrombotic sequelae are reduced if lytic therapy is successful in severe thrombosis, but such results are not consistent and there are many failures of therapy.[71] Unfortunately, many of the trials to date have found that thrombolytic therapy results in more intracerebral hemorrhagic complications than anticoagulation,[72] and most patients have contraindications to the currently available
Chapter 65.
thrombolytic agents.[73] On balance most believe there is insufficient evidence of benefit to use thrombolysis. The role of thrombectomy is unclear. Basy first described venous thrombectomy in a patient with axillary vein thrombosis,[74] and Lawen described removal of a thrombus from a leg vein.[75] Early results were poor, and thus thrombectomy has remained unpopular.[76,77] A prospective trial of thrombectomy combined with a temporary arteriovenous fistula compared to a control group treated with anticoagulants showed less leg swelling, fewer symptoms of venous claudication, and less ulceration at both 6 months[78] and 10 years.[79] In another study long-term follow-up in a small group of young patients showed good venous function after thrombectomy.[80] Thrombectomy may thus be indicated for severe iliofemoral thrombosis and in patients with contraindications to anticoagulation.[81]
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FUTURE THERAPEUTIC POSSIBILITIES The aim of future treatments of acute deep vein thrombosis will be to reduce valve damage and hemodynamic disturbance and hence reduce the incidence of the post-phlebitic syndrome. Novel thrombolytic agents that have a more specific action on the thrombus together with catheterdirected administration systems and lower systemic doses may achieve rapid and complete reperfusion with fewer haemorrhagic complications[82] although good prospective trials are awaited. Enhancement of thrombus recanalization and resolution with growth factors may reduce residual venous obstruction and reflux and improve long-term symptoms.
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Thrombosis: An Experimental Study. Br. J. Haematol. 1985, 449– 457. Schaub, R.G.; Simmons, C.A.; Koets, M.H.; Romano, P.J.; Stewart, G.J. Early Events in the Formation of a Venous Thrombus Following Local Trauma and Stasis. Lab Investig. 1984, 51, 218 –224. Stewart, G.J.; Ritchie, W.G.M.; Lynch, P.R. Venous Endothelial Damage Produced by Massive Sticking and Emigration of Leucocytes. Am. J. Path. 1974, 74, 507. Schaub, R.G.; Yamashita, A. Leukocyte-Mediated Vein Injury and Thrombosis Is Reduced by a Lipoxygenase Inhibitor. Exp. Mol. Path. 1986, 45, 343– 353. Stewart, G.J. Neutrophils and Deep Vein Thrombosis. Haemostasis 1993, 23, 127– 140. Cooke, E.D.; Bowcock, S.A.; Lloyd, M.J.; Pilcher, M.F. Intravenous Lignocaine in Prevention of Deep Vein Thrombosis After Elective Hip Surgery. Lancet 1977, 2, 797–799. Downing, L.J.; Wakefield, M.D.; Strieter, R.M.; Prince, M.R.; Londy, F.J.; Fowlkes, J.B.; Hulin, M.S.; Kadell, A.M.; Wilke, C.A.; Brown, S.L.; Wrobleski, S.K.; Burdick, M.D.; Anderson, D.C.; Greenfield, I.J. Anti-P-Selectin Antibody Decreases Inflammation and Thrombus Formation in Venous Thrombosis. J. Vasc. Surg. 1997, 25, 816–828. Quarmby, J.W.; Smith, A.; Humphries, J.; Burnand, K.G.; Collins, M.; McGuinness, C.L. Increased Expression of Soluble VCAM-1 in Venous Thrombosis. SVS & ISCVS Joint Annual Meeting, Boston, MA, June 1997. Koster, T.; Rosendaal, F.R.; de Ronde, H.; Briet, E.; Vandenbroucke, J.P.; Bertina, R.M. Venous Thrombosis Due to Poor Anticoagulant Response to Activated Protein C: Leiden Thrombophilia Study. Lancet 1993, 342, 1503– 1506. Northeast, A.D.R.; Creighton, L.J.; Gaffney, P.J.; Burnand, K.G. Vein Wall Fibrinolysis: The Response to Thrombosis. Ann. N.Y. Acad. Sci. 1992, 667, 127– 140. Northeast, A.D.R.; Soo, K.S.; Bobrow, L.G.; Gaffney, P.J.; Burnand, K.G. The Tissue Plasminogen Activator and
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Urokinase Response In Vivo During Natural Resolution of Venous Thrombus. J. Vasc. Surg. 1995, 22, 573– 579. Soo, K.S.; Northeast, A.D.R.; Happerfield, L.C.; Burnand, K.G.; Bobrow, L.G. Tissue Plasminogen Activator Production by Monocytes in Venous Thrombolysis. J. Pathol. 1996, 178, 190– 194. Hamilton, J.A.; Hart, P.H.; Leizer, T.; Vitti, G.F.; Campbell, I.K. Regulation of Plasminogen Activator Activity in Arthritic Joints. J. Rheumatol. 1991, S27, 106– 109. Nykjaer, A.; Petersen, C.M.; Christensen, E.I.; Davidsen, O.; Gliemann, J. Urokinase Receptors in Human Monocytes. Biochim. Biophys. Acta 1990, 1052, 399– 407. Lundgren, C.H.; Sawa H.; Soble, B.E.; Fujii, S. Modulation of Expression of Monocyte/Macrophage Plasminogen Activator Activity and Its Implications for Attenuation of Vasculopathy. Circulation 1994, 90, 1927 –1934. Kung, S.K.P.; Lau, H.K.F. Modulation of the Plasminogen Activation System in Murine Macrophages. Biochim. Biophys. Acta 1993, 1176, 113– 122. Kuraoka, S.; Campeau, J.D.; Rodgers, K.E.; Nakamura, R.M.; DiZerega, G. Effects of IL-1 on Postsurgical Macrophage Secretion of Protease and Protease Inhibitor Activities. J. Surg. Res. 1992, 52, 71–78. Hart, P.H.; Burgess, D.R.; Vitti, G.F.; Hamilton, J.A. Interleukin-4 Stimulates Human Monocytes to Produce Tissue-Type Plasminogen Activator. Blood 1989, 74, 1222 –1225. Simon, D.I.; Ezratty, A.M.; Francis, S.A.; Rennke, H.; Lascalzo, J. Fibrinogen Is Internalized and Degraded by Activated Human Monocytoid Cells Via Mac-1 (CD11b/CD18): A Non-Plasmin Fibrinolytic Pathway. Blood 1993, 82, 2414– 2422. Cox, J.S.T. The Maturation and Canalization of Thrombi. Surg. Gynecol. Obstet. 1963, 116, 593– 599. Sevitt, S. The Mechanisms of Canalisation in Deep Vein Thrombosis. J. Pathol. 1973, 110, 153– 165. Leriche R. Thromboses Arte´rielles. Paris, 1946; 64. Sevitt, S. Organic Canalisation and Vascularisation of Deep Vein Thrombi Studied with Dyed Micropaque Injected at Necropsy. J. Pathol. 1970, 100, Pi. Scott, G.B.D. A Quantitative Study of the Fate of Occlusive Red Venous Thrombi. Br. J. Exp. Pathol. 1968, 49, 544. Kwaan, H.C., Communication to the Workshop on Venography for Deep Vein Thrombosis, Washington, D.C., 1971. Leibovich, S.J.; Ross, R. The Role of the Macrophage in Wound Repair. In Angiogenesis in Health and Disease; Maragoudakis, M.E., Gullino, P., Lelkes, P.I., Eds.; Plenum Press: New York, 1992. Rohovsky, S.; D’Amore, P.A. Growth Factors and Angiogenesis in Wound Healing. In Growth Factors and Wound Healing; Zeigler, T.R., Pierce, G.F., Herndon, D.N., Eds.; Springer: New York, 1997. Frank, S.; Hubner, G.; Breier, G.; Longaker, M.T.; Greenhalgh, D.G.; Werner, S. Regulation of Vascular Endothelial Growth Factor Expression in Cultured Keratinocytes. Implications for Normal and Impaired Wound Healing. J. Biol. Chem. 1995, 270, 12607– 12613. Ferrera, N. The Biology of Vascular Endothelial Growth Factor, a Specific Regulator of Angiogenesis. In Growth
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Factors and Wound Healing; Zeigler, T.R., Pierce, G.F., Herndon, D.N., Eds.; Springer: New York, 1997. Adams, D.H.; Shaw, S. Leukocyte Endothelial Cell Interactions and Regulation of Leukocyte Migration. Lancet 1994, 343, 831– 836. Bauer, G. A Venographic Study of Thromboembolic Patients. Acta Chir. Scand. 1940, 84 (Suppl. 61). Lea Thomas, M.; McAllister, V. The Radiological Progression of Deep Vein Thrombus. Radiology 1971, 99, 37– 40. Van Ramshorst, B.; Legemate, D.A.; Verzijlbergen, J.F.; Hoeneveld, H.; Eikelboom, B.C.; de Valois, J.C.; Meuwissen, O.J.A.T. Duplex Scanning in the Diagnosis of Acute Deep Vein Thrombosis of the Lower Extremity. Eur. J. Vasc. Surg. 1991, 5, 255– 260. Rosfors, S.; Eriksson, M.; Leijd, B.; Nordstro¨m, E. A Prospective Follow-Up Study of Acute Deep Vein Thrombosis Using Colour Duplex Ultrasound, Phlebography and Venous Occlusion Plethysmography. Int. Angiol. 1997, 16, 39–44. Bauer, G. A Roentgenological and Clinical Study of the Sequels of Thrombosis. Acta Chir. Scand. 1942, 86 (Suppl. 74). Negus, D. The Post-Thrombotic Syndrome. Ann. R. Coll. Surg. Engl. 1970, 47, 92– 105. Strandness, D.E.; Langlois, Y.; Cramer, M.; Randlett, A.; Thiele, B.L. Long-Term Sequelae of Acute Venous Thrombosis. J. Am. Med. Assoc. 1983, 250, 1289– 1292. Edwards, E.A.; Edwards, J.E. The Effect of Thrombophlebitis on the Venous Valve. Surg. Gynecol. Obstet. 1937, 65, 310– 320. van Haarst, E.P.; Liasis, N.; van Ramshorst, B.; Moll, F.L. The Development of Valvular Incompetence After Deep Vein Thrombosis: A 7 Year Follow-Up Study with Duplex Scanning. Eur. J. Vasc. Endovasc. Surg. 1996, 12, 295– 299. Caps, M.T.; Manzo, R.A.; Bergelin, R.O.; Meissner, M.H.; Strandness, D.E., Jr. Venous Valvular Reflux in Veins Not Involved at the Time of Acute Deep Vein Thrombosis. J. Vasc. Surg. 1995, 22, 524– 531. Franzeek, U.K.; Schalch, I.; Bollinger, A. On the Relationship Between Changes in the Deep Veins Evaluated by Duplex Sonography and the Post-Thrombotic Syndrome 12 Years After Deep Vein Thrombosis. Thromb. Haemostasis 1997, 77, 1109–1112. O’Shaughnessy, A.M.; Fitzgerald, D.E. Natural History of Proximal Deep Vein Thrombosis Assessed by Duplex Ultrasound. Int. Angiol. 1997, 16, 45– 49. Breddin, H.K. Treatment of Deep Vein Thrombosis: Is Thrombus Regression a Desirable Endpoint? Semin. Thromb. Haemostasis 1997, 23, 179– 183. Comerota, A.J. Modern Day Treatment of Acute Deep Vein Thrombosis. Aust. N.Z. J. Surg. 1995, 65, 773– 779. Bauer, G. Venous Thrombosis. Early Diagnosis with the Aid of Phlebography and Abortive Treatment with Heparin. Arch. Surg. 1941, 43, 463. Wright, H.P.; Kibik, M.M.; Hayden, M. Influence of Anticoagulant Administration on the Rate of Recanalisation of Experimentally Thrombosed Veins. Br. J. Surg. 1952, 40, 163– 166. Sevitt, S.; Gallagher, N.G. Prevention of Venous Thrombosis and Pulmonary Embolism in Injured Patients. A Trial
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of Anticoagulant Prophylaxis with Phenindione in Middle Aged and Elderly Patients with Fractured Necks of Femur. Lancet 1959, 2, 981. Hirsh, J. Heparin. N. Engl. J. Med. 1991, 324, 1565– 1574. Hull, R.D.; Raskob, G.E.; Pineo, G.F.; Green, D.; Trowbridge, A.A.; Elliott, C.G.; Lerner, R.G.; Hall, J.; Sparling, T.; Brettell, H.R.; Norton, J.; Carter, C.J.; George, R.; Merli, G.; Ward, J.; Mayo, W.; Rosenbloom, D.; Brant, R. Subcutaneous Low-Molecular-Weight Heparin Compared with Continuous Intravenous Heparin in the Treatment of Proximal-Vein Thrombosis. N. Engl. J. Med. 1992, 326, 975– 982. Levine, M.; Gent, M.; Hirsh, J.; Leclerc, J.; Anderson, D.; Weitz, J.; Ginsberg, J.; Turpie, A.G.; Demers, C.; Kovacs, M.; Geerts, W.; Kassis, J.; Desjardins, L.; Cusson, J.; Cruickshank, M.; Powers, P.; Brien, W.; Haley, S.; Willan, A. A Comparision of Low-Molecular-Weight Heparin Administered Primarily at Home with Unfractionated Heparin Administered in the Hospital for Proximal DeepVein Thrombosis. N. Eng. J. Med. 1996, 334, 677– 681. Koopman, M.M.W.; Prandoni, P.; Piovella, F.; Ockelford, P.A.; Brandjes, D.P.M.; van der Meer, J.; Gallus, A.S.; Simmonneau, G.; Chestermen, C.H.; Prins, M.H.; Bossuyt, P.M.M.; de Haes, H.; ven den Belt, A.G.M.; Sagnard, L.; D’Azemar, P.; Buller, H.R. Treatment of Venous Thrombosis with Intravenous Unfractionated Heparin Administered in the Hospital as Compared with Subcutaneous Low-Molecular-Weight Heparin Administered at Home. N. Engl. J. Med. 1996, 334, 682– 687. Johnson, A.J.; McCarty, W.R. The Lysis of Artificially Induced Intravascular Clots in Man by Intravenous Infusion of Streptokinase. J. Clin. Investig. 1959, 38, 1627. Turpie, A.G.G.; Levine, M.N.; Hirsh, J.; Ginsberg, J.S.; Cruickshank, M.; Jay, R.; Gent, M. Tissue Plasminogen Activator (rt-PA) vs. Heparin in Deep Vein Thrombosis. Chest 1990, 97 (Suppl. 4), 172S– 175S. Watz, R.; Savidge, G.F. Rapid Thrombolysis and Preservation of Valvular Venous Function in High Deep Vein Thrombosis. Acta Med. Scand. 1979, 205, 293– 298. Meissner, M.H.; Manzo, R.A.; Bergelin, R.O.; Markel, A.; Strandness, D.E. Deep Venous Insufficiency: The Relationship Between Lysis and Subsequent Reflux. J. Vasc. Surg. 1993, 18, 596– 605.
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Kakkar, V.V.; Lawrence, D. Hemodynamic and Clinical Assessment After Therapy for Acute Deep Vein Thrombosis, a Prospective Study. Am. J. Surg. 1985, 150 (Suppl. 4A), 54– 63. Goldhaber, S.Z.; Buring, J.E.; Lipnick, R.J.; Hennekens, C.H. Pooled Analyses of Randomized Trials of Streptokinase and Heparin in Phlebographically Documented Acute Deep Vein Thrombosis. Am. J. Med. 1984, 76, 393 – 397. Markel, A.; Manzo, R.A.; Strandness, D.E., Jr. The Potential Role of Thrombolytic Therapy in Venous Thrombosis. Arch. Intern. Med. 1992, 152, 1265 –1267. Basy, L. Thrombose de la Veine Axillaire Droite (Thrombo-phlebite par Effort). Phlebotomie, Ablation de Caillots, Suture de la Veine. Meme. Acad. Chir. 1926, 52, 529. ¨ ber Operative ThrombanLawen, A. Weitere Erfahrungen U entfernung bei Venethrombose. Arch. Klin. Chir. 1938, 193, 723. Karp, R.B.; Wylie, E.J. Recurrent Thrombosis After Iliofemoral Venous Thrombectomy. Surg. Forum. 1966, 17, 147. Lansing, A.M.; Davis, W.M. Five-Year Follow-up Study of Iliofemoral Venous Thrombectomy. Ann. Surg. 1968, 168, 620–628. Plate, G.; Einarsson, E.; Ohlin, P.; Jensen, R.; Qvarfordt, P.; Eknlof, B. Thrombectomy with Temporary Arteriovenous Fistula: The Treatment of Choice in Acute Iliofemoral Venous Thrombosis. J. Vasc. Surg. 1984, 1, 867 – 876. Plate, G.; Eklof, B.; Norgren, L.; Ohlin, P.; Dahlstrom, J.A. Venous Thrombectomy for Iliofemoral Vein Thrombosis— 10-Year Results of a Prospective Randomised Study. Eur. J. Vasc. Endovasc. Surg. 1997, 14, 367– 374. Swedenborg; Ha¨gglo¨f, R.; Jacobsson, H.; Johansson, J.; Johnsson, H.; Larsson, S.; Nilsson, E.; Zetterquist, S. Results of Surgical Treatment for Iliofemoral Venous Thrombosis. Br. J. Surg. 1986, 73, 871– 874. Meissner, A.J.; Huszeza, S. Surgical Strategy for Management of Deep Venous Thrombosis of the Lower Extremities. World. J. Surg. 1996, 20, 1149– 1155. Armon, M.P.; Hopkinsin, B.R. Thrombolysis for Acute Deep Vein Thrombosis. Br. J. Surg. 1996, 83, 580– 581.
CHAPTER 66
Pathophysiology of Chronic Venous Insufficiency Peter J. Pappas Walter N. Dura´n Robert W. Hobson II destruction of the valves upon which the mechanism principally depends bring about a degree of surface stasis which obviously interferes with the nutrition of the skin and subcutaneous tissues.... It is to be expected, therefore that skin which is bathed under pressure in stagnant venous blood will readily form permanent, open sores or ulcers.”[2] This statement resulted in a generation of investigators trying to seek a causal relationship between hypoxia, stagnant blood flow, and the development of CVI. The first investigator to address the question of hypoxia and CVI scientifically was Alfred Blalock.[3] He obtained venous samples from the femoral, greater saphenous, and varicose veins in 10 patients with CVI isolated to one limb and compared their oxygen content to samples taken from corresponding veins in the opposite limb. Seven of the patients had active ulcers at the time. All samples were collected in the recumbent and standing positions. He reported that in patients with unilateral CVI the oxygen content was higher in the femoral vein of the affected limb. He speculated that this observation may be reflective of increased venous flow rather than stagnation.
INTRODUCTION Injury to infrainguinal vein walls and venous valves results in valvular reflux and a dysfunctional venous system. The effect of persistent valvular reflux is a chronic increase in ambulatory venous pressure. Prolonged venous hypertension initiates a cascade of pathologic events that manifest themselves clinically as lower extremity edema, pain, itching, skin discoloration, varicose veins, venous ulceration, and, in its severest form, limb loss. These clinical symptoms collectively refer to the disorder known as chronic venous insufficiency (CVI).[1] The clinical diagnosis, evaluation, and management of patients with CVI will be reviewed elsewhere. The purpose of this chapter is to review the pathologic alterations that occur at the tissue level as a result of CVI.
HISTORICAL THEORIES In the twentieth century numerous theories have been postulated regarding the etiology of CVI and the cause of venous ulceration. These theories have been disproven over time and are discussed here for historical interest only.
ARTERIOVENOUS FISTULA THEORY The concept of increased venous flow in the dermal venous plexus was expanded upon by Pratt, who reported that increased venous flow in patients with CVI could be clinically observed.[4] He attributed the development of venous ulceration to the presence of arteriovenous connections and coined the term “arterial varices.” He reported that in a series of 272 patients with varicose veins who underwent vein ligation, 24% had arteriovenous connections. Of the 61 patients who developed recurrences, 50% occurred in patients with arteriovenous communications identified clinically by the presence of arterial pulsations in venous conduits. Pratt hypothesized that increased venous flow shunted nutrient- and
VENOUS STASIS THEORY In 1917, John Homans published a manuscript entitled “The Etiology and Treatment of Varicose Ulcer of the Leg” in Surgery, Gynecology and Obstetrics.[2] This manuscript was a clinical treatise on the diagnosis and management of patients with CVI. In this manuscript Dr. Homans coined the term postphlebitic syndrome and speculated on the cause of venous ulceration. He stated that “overstretching of the vein walls and
Hobson/Wilson/Veith: Vascular Surgery: Principles and Practice, Third Edition, Revised and Expanded DOI: 10.1081/0819-9-120024950 Copyright q 2004 by Marcel Dekker, Inc.
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oxygen-rich blood away from the dermal plexus leading to areas of ischemia and hypoxia and resulting in venous ulceration. Pratt’s clinical observations, however, have never been confirmed with objective scientific evidence. Experiments with radioactively labeled microspheres have never demonstrated shunting and have therefore cast serious doubt on the validity of this theory.
DIFFUSION BLOCK THEORY Hypoxia and alterations in nutrient blood flow were again proposed as the underlying etiology of CVI in 1982 by Burnand et al.[5] These authors performed a study in which skin biopsies were obtained from 109 limbs of patients with CVI and 30 limbs from patients without CVI. Foot vein pressures were measured in the CVI patients at rest and after 5, 10, 15, and 20 heel raises as well. Vein pressure measurements were then correlated with the number of capillaries observed on histologic section. The authors reported that venous hypertension was associated with increased numbers of capillaries in the dermis of patients with CVI. Whether the histologic sections represented true increases in capillary quantity or an elongation and distension of existing capillaries was not answered by this study. However, in a canine hind limb model, the authors were able to induce enlargement in the number of capillaries with experimentally induced hypertension.[6] This important study was one of the first studies to demonstrate a direct effect of venous hypertension on the venous microcirculation. In a later study, Browse and Burnand[7] noted that the enlarged capillaries observed on histologic examination exhibited pericapillary fibrin deposition and coined the term “fibrin cuff.” They speculated that venous hypertension led to widening of endothelial gap junctions with subsequent extravasation of fibrinogen leading to the development of fibrin cuffs. These authors speculated that the cuffs acted as a barrier to oxygen diffusion and nutrient blood flow and caused epidermal cell death. Although pericapillary cuffs do exist, it has not been proven they act as a barrier to nutrient flow or oxygen diffusion.
LEUKOCYTE ACTIVATION Dissatisfaction with the fibrin cuff theory and subsequent observations of decreased circulating leukocytes in blood samples obtained from the greater saphenous veins in patients with CVI led Phillip D. Colleridge Smith et al. to propose the leukocyte trapping theory.[8] This theory states that circulating neutrophils are trapped in the venous microcirculation secondary to venous hypertension. The subsequent sluggish capillary blood flow leads to hypoxia and neutrophil activation. Neutrophil activation leads to degranulation of toxic metabolites with subsequent endothelial cell damage. The subsequent heterogeneous capillary perfusion causes alterations in skin blood flow and eventual skin damage. The problem with the leukocyte trapping theory is that neutrophils have never been directly observed obstructing capillary flow,
therefore casting doubt on its validity. However, there is significant evidence that leukocyte activation plays a major role in the pathophysiology of CVI.
ROLE OF LEUKOCYTE ACTIVATION AND FUNCTIONAL STATUS IN CVI In 1988, Thomas et al.[9] reported that 24% fewer white cells left the venous circulation after a period of recumbency in patients with CVI as compared to normal patients. They studied three groups of 10 patients each. Group 1 consisted of patients with no signs of venous disease. Group 2 were patients with uncomplicated primary varicose veins, and group 3 were patients with longstanding CVI as determined by Doppler ultrasonography, strain gauge plethysmography, and foot volumetry. Patients had the greater saphenous vein cannulated just above the medial malleolus. Venous samples were obtained at various time points with patients in the sitting and supine position. Samples were then placed in an automated cell counter and the number of leukocytes and erythrocytes determined. The ratio of white cells to red cells at the various time points was then compared using the Wilcoxon signed rank and Wilcoxon rank sum tests. The authors reported that with leg dependency, packed cell volume significantly increased in patients with CVI as compared to normal controls, whereas patients with primary varicose veins showed no difference from controls. They also noted that the relative number of white cells were significantly decreased compared to controls and primary varicose vein patients (28% vs. 5%; p , 0.01). The authors concluded that the decrease in white cell number was due to leukocyte trapping in the venous microcirculation secondary to venous hypertension. They further speculated that while trapped, the leukocytes may be activated and release toxic metabolites, causing damage to the microcirculation and the overlying skin. These important observations were the first to implicate abnormal leukocyte activity in the pathophysiology of CVI. The importance of leukocytes in the development of dermal skin alterations was emphasized by Scott et al.[10] These authors obtained punch biopsies from patients with primary varicose veins, lipodermatosclerosis, and lipodermatosclerosis and healed ulcers and determined median number of white blood cells (WBCs) per high power field (40£ magnification) in each group. No patients with active ulcers were included, and no attempt to identify the type of leukocyte was made. The authors reported that in patients with primary varicose veins, lipodermatosclerosis, and healed ulceration there was a median of 6, 45, and 217 WBCs per mm2, respectively. This study demonstrated that with clinical progression and increasing severity of CVI, there was a progressive increase in the number of leukocytes in the dermis of CVI patients. The types of leukocyte involved in dermal venous stasis skin changes is controversial. In a study performed by Wilkerson et al., skin biopsies were obtained from 23 patients who required surgical ligation, stripping, and/or avulsion for their varicose veins.[11] The condition of the skin was recorded
Chapter 66. Pathophysiology of Chronic Venous Insufficiency
as liposclerotic, eczematous, or normal. Lipodermatosclerosis was defined clinically as palpable induration of the skin and subcutaneous tissues and eczema as visible erythema with scaling of the skin. Using immunohistochemical techniques, the authors stained for leukocyte-specific cell surface markers and reported that macrophages and lymphocytes were the predominant leukocytes observed in this patient population. Neutrophils and B lymphocytes were rarely observed. T lymphocytes and macrophages were predominantly observed perivascularly and in the epidermis. However, Pappas et al. performed a quantitative morphometric assessment of the dermal microcirculation using electron microscopy and reported that macrophages and mast cells were the predominant cells observed in patients with CVI dermal skin changes.[12] Furthermore, lymphocytes were never observed. This discrepancy may reflect the types of patients that were studied. Wilkerson et al.[11] biopsied patients with erythematous and eczematous skin changes whereas Pappas et al.[12] predominantly evaluated older patients with dermal fibrosis. Patients with eczematous skin changes may have an autoimmune component to their CVI whereas patients with dermal fibrosis may reflect changes consistent with chronic inflammation and altered tissue remodeling. Given the predominant role of leukocytes in CVI pathology, there has been great interest in the activation state and functional status of leukocytes in CVI patients. Pappas et al.[13,14] explored the hypothesis that circulating leukocytes in CVI patients were in an altered state of activation and therefore may be involved in leukocytemediated injury. They measured the expression of cell surface activation markers of circulating leukocytes using fluorescence flow cytometry. Relative to normal individuals, patients with chronic venous stasis ulcers had a decreased expression of the CD3+/DR+ and CD3+/CD38+ markers on T lymphocytes and an increased expression of CD14+/CD38+ markers on monocytes. Circulating neutrophils demonstrated no evidence of activation. Although Pappas et al.[13] identified a population of circulating cells demonstrating altered activation markers, their results did not test the functional status of these cells. In a follow-up study, Pappas et al.[14] tested the hypothesis that circulating mononuclear cells in CVI patients were dysfunctional by challenging monocytes with test mitogens.[14] Lymphocyte and monocyte cell function was measured as the degree of proliferation in response to a mitogenic challenge. Fifty patients were separated into four groups: Group 1, 14 patients with normal limbs; Group 2, 10 patients with class II CVI (stasis dermatitis only); Group 3, 15 patients with active venous ulcers; Group 4, 11 patients with healed venous ulcers and current evidence of lipodermatosclerosis. Systemically circulating lymphocytes and monocytes were obtained by antecubital venipuncture from Groups 1 –4. Cells were cultured in the presence of staphylococcal enterotoxins (SEs) A, B, C1, D, and E (mitogens) and phytohemagglutinin (PHA), a control mitogen. Proliferative responses to PHA indicated that lymphocytes and monocytes from CVI patients were not globally depressed. However, patients in Group 2 did not exhibit the same degree of proliferation to PHA as did Groups 1, 3, and 4. Differences in proliferative responses between Groups 2 and 1 ð44:38 ^ 43:9 vs. 118:87 ^ 27:1; p # 0:05Þ and Groups 2 and 3 ð44:38 ^ 43:9 vs. 105:95 ^
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60:99; p # 0:05Þ were significant. Challenges with SEs A and B revealed significant diminution of proliferative responses in groups 2 ð42:73 ^ 11:55; p # 0:05Þ and 3 ð45:57 ^ 9:1; p # 0:05Þ and Groups 3 ð36:81 ^ 6:9; p # 0:05Þ and 4 ð35:04 ^ 7:5; p # 0:05Þ; compared to SEA controls ð68:68 ^ 9:9Þ and SEB controls ð66:25 ^ 13:56Þ, respectively. A trend towards diminished cellular function with progression of CVI was observed with staphylococcal enterotoxins B, C1, D, and E, strongly suggesting biologic significance. Furthermore, patients with LDS and a history of healed ulcers uniformly exhibited the poorest proliferative responses (Fig. 66-1). This study indicated that deterioration of mononuclear cell function was associated with CVI and suggested that lymphocyte and monocyte function diminished with clinical disease progression. The authors speculated that the decreased capacity for mononuclear cell proliferation in response to various challenges may manifest itself clinically as poor and prolonged wound healing.
THE VENOUS MICROCIRCULATION Numerous investigations have attempted to evaluate the microcirculation of patients with CVI.[12,15 – 18]. The majority of these investigations were qualitative descriptions of vascular abnormalities, which lacked uniformity of biopsy sites and patient stratification. Prior to 1997 it was widely accepted that endothelial cells from the dermal microcirculation appeared abnormal, contained Weibel-Palade bodies, were edematous, and demonstrated widened interendothelial gap junctions.[17] Based on these descriptive observations, it has been assumed that the dermal microcirculation of CVI patients has functional derangements related to permeability and ulcer formation. It was not until 1997 that a quantitative morphometric analysis of the dermal microcirculation was reported.[12] The objectives of this investigation were to quantify differences in endothelial cell structure and local cell type with emphasis on leukocyte cell type and their relationship to arterioles, capillaries, and postcapillary
Figure 66-1. Histogram of leukocyte proliferative responses upon exposure to phytohemagglutinin (PHA) and staphylococcal enterotoxins A, B, C1, D, and E (*p # 0:05 compared to controls. ** p # 0:05 PHA group 2 compared to PHA group 3).
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venules (PCVs). Variables assessed were number and types of leukocytes, endothelial cell thickness, endothelial vesicle density, interendothelial junctional width, cuff thickness, and ribosome density. Thirty-five patients had two 4 mm punch biopsies obtained from the lower calf (gaiter region) and lower thigh. Patients were separated into one of four groups according to the 1995 ISCVS/SVS (International Society for Cardiovascular Surgery/Society for Vascular Surgery) CEAP classification.[1] Group 1 consisted of five patients with no evidence of venous disease. Skin biopsies from these patients served as normal controls. Groups 2 –4 consisted of patients with CEAP class 4 ðn ¼ 11Þ; class 5 ðn ¼ 9Þ; and class 6 ðn ¼ 10Þ CVI.
Endothelial Cell Characteristics No significant differences were observed in endothelial cell thickness of arterioles, capillaries, and PCVs from either gaiter or thigh biopsies. Qualitatively, endothelial cells appeared metabolically active. Many nuclei exhibited a euchromatic appearance, implying active mRNA transcription. In most instances ribosome numbers were so abundant that they exceeded the resolution capacity of the image analysis system and were unable to be quantified. The prominence in ribosome content and the euchromatic appearance of the endothelial cell nucleus strongly suggested active protein production. No significant differences in vesicle density were observed in gaiter biopsies between groups. Class 6 patients exhibited an increased number of vesicles in arterioles and PCV endothelia from thigh biopsies but did not differ compared to gaiter biopsies. Mean interendothelial junctional width varied within a normal range of 20–50 nm. Significantly widened interendothelial gap junctions were not observed and thus conflicted with the reports of Wenner et al.[17] Mean basal lamina thickness differed significantly at the capillary level in both gaiter and thigh biopsies. Differences were most pronounced in patients with class 4 disease. These data indicated that endothelial cells from the dermal microcirculation of CVI patients were far from abnormal. They demonstrated increased metabolic activity suggestive of active cellular transcription and protein production. Most surprising was the observation of uniformly tight gap junctions. Previously these gap junctions were reported to be as wide as 180 nm, and it was assumed that these widened junctions were responsible for macromolecule extravasation and edema formation.[5] Pappas et al.[27] suggested that alternate methods for tissue edema like increased transendothelial vesicle transport, formation of transendothelial channels, and alterations in the glycocalyx lining the junctional cleft may be involved in CVI edema and macromolecule transport.[12]
Types and Distribution of Leukocytes The most striking differences in cell type and distribution were observed with mast cells and macrophages (Figs. 66-2 through 66-4). In both gaiter and thigh biopsies, mast cell numbers were two to four times greater than control in class 4 and 5 patients around arterioles and PCVs ð p , 0:05Þ: Class 6 patients demonstrated no difference in mast cell number
Figure 66-2. Histogram demonstrating mast cell and macrophage density surrounding postcapillary venules according to disease classification. Increased mast cell content was observed in class 4 and 5 patients compared to controls and class 6 patients ð p # 0:05Þ: Increased macrophage content was observed in class 6 patients compared to control and class 4 and 5 patients ð p # 0:05Þ:
compared to controls. Mast cell numbers around capillaries did not differ across groups in either gaiter or thigh biopsies. Macrophages demonstrated increased numbers in class 5 and 6 patients around arterioles and PCVs, respectively ð p , 0:05Þ: Differences in macrophage numbers around capillaries were observed primarily in class 4 patients in both gaiter and thigh biopsies. Surprisingly, lymphocytes, plasma cells, and neutrophils were not present in the immediate perivascular space. Fibroblasts were the most common cells observed in both gaiter and thigh biopsies. Pappas et al. speculated that mast cells and macrophages may function to regulate tissue remodeling resulting in dermal fibrosis.[12] The mast cell enzyme chymase is a potent activator of matrix metalloproteinase-1 and 3 (collagenase and stromelysin).[19 – 21] In an in vitro model using the human mast cell line HMC-1, these cells were reported to spontaneously adhere to fibronectin, laminin, and collagen type I and III, all components of
Chapter 66. Pathophysiology of Chronic Venous Insufficiency
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Figure 66-4. Photomicrograph demonstrating a well-developed perivascular cuff, a cytoplasmic tail from a migrating macrophage, a macrophage entering a lymphatic, a fibroblast, and interstitial collagen deposition (4300£ ).
Figure 66-3. Photomicrograph of a mast cell, fibroblast, and macrophage surrounding a capillary (4300£ ).
the perivascular cuff (see below).[21] Chymase also causes release of latent transforming growth factor-b1 (TGF-b1), secreted by activated endothelial cells, fibroblasts, and platelets from extracellular matrices.[22] Release and activation of TGF-b1 initiates a cascade of events in which macrophages and fibroblasts are recruited to wound-healing sites and stimulated to produce fibroblast mitogens and connective tissue proteins, respectively.[23] Mast cell degranulation leading to TGF-b1 activation and macrophage recruitment may explain why decreased mast cell and increased macrophage numbers were observed in class 6 patients. Macrophage migration, as evidenced by the frequent appearance of cytoplasmic tails in perivascular macrophages, further substantiates the concept of inflammatory cytokine recruitment (Fig. 66-4).
Extracellular Matrix Alterations Once leukocytes have migrated to the extracellular space, they localize around capillaries and postcapillary venules. The perivascular space is surrounded by extracellular matrix (ECM) proteins and forms a perivascular “cuff.” Adjacent to these perivascular cuffs and throughout the dermal interstitium is an intense and disorganized collagen deposition.[5,12] Perivascular cuffs and the accompanying collagen deposition are the sine qua non of the dermal microcirculation in CVI patients (Fig. 66-4). The perivascular cuff was originally thought to be the result of fibrinogen extravasation and erroneously referred to as a “fibrin cuff.”[5] It is now known that the cuff is a ring of ECM proteins
consisting of collagens type I and III, fibronectin, vitronectin, laminin, tenascin, and fibrin.[24] The role of the cuff and its cell of origin is not completely understood. The investigation by Pappas et al.[29] suggested that the endothelial cells of the dermal microcirculation were responsible for cuff formation. The cuff was once thought to be a barrier to oxygen and nutrient diffusion, but[29] recent evidence suggests that cuff formation is an attempt to maintain vascular architecture in response to increased mechanical load.[25] Although perivascular cuffs may function to preserve microcirculatory architecture, several pathologic processes may be related to cuff formation. Immunohistochemical analyses have demonstrated TGF-b1 and a2-macroglobulin in the interstices of perivascular cuffs.[26] It has been suggested that these “trapped” molecules are abnormally distributed in the dermis, leading to altered tissue remodeling and fibrosis. Cuffs may also serve as a lattice for capillary angiogenesis, explaining the capillary tortuosity and increased capillary density observed in the dermis of CVI patients.
PATHOPHYSIOLOGY OF STASIS DERMATITIS AND DERMAL FIBROSIS The mechanisms modulating leukocyte activation, fibroblast function, and dermal extracellular matrix alterations were the focus of investigation in the 1990s. CVI is a disease of chronic inflammation due to a persistent and sustained injury secondary to venous hypertension. It is hypothesized that the primary injury is extravasation of macromolecules (i.e., fibrinogen and a2-macroglobulin) and red blood cells (RBCs) into the dermal interstitium.[5,6,15,17,26] RBC degradation products and interstitial protein extravasation are potent chemoattractants and presumably represent the initial underlying chronic inflammatory signal responsible for leukocyte recruitment. It has been assumed that these
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cytochemical events are responsible for the increased expression of intercellular adhesion molecule-1 (ICAM-1) on endothelial cells of microcirculatory exchange vessels observed in CVI dermal biopsies.[11] ICAM-1 is the activationdependent adhesion molecule utilized by macrophages, lymphocytes, and mast cells for diapedesis. As stated above, all these cells have been observed by immunohistochemistry and electron microscopy in the interstitium of dermal biopsies.[11,12]
Cytokine Regulation and Tissue Fibrosis Our laboratory has been interested in the mechanisms regulating dermal tissue remodeling in CVI patients. Leukocyte recruitment, ECM alterations, and tissue fibrosis are characteristic of chronic inflammatory diseases caused by alterations in TGF-b1 gene expression and protein production. To determine the role of TGF-b1 in CVI, dermal biopsies from normal patients and CEAP class 4, 5, and 6 CVI patients were analyzed for TGF-b 1 gene expression, protein production, and cellular location.[27] Quantitative RT-PCR for TGF-b1 gene expression was performed on 24 skin biopsies obtained from 24 patients. Patients were separated into four groups according to the ISCVS/SVS classification for CVI: normal skin ðn ¼ 6Þ; CEAP class 4 ðn ¼ 6Þ, CEAP class 5 ðn ¼ 5Þ, and CEAP class 6 ðn ¼ 7Þ: TGF-b1 gene transcripts for controls, class 4, 5, and 6 patients were 7:02 ^ 7:33; 43:33 ^ 9:0; 16:13 ^ 7:67, and 7:22 ^ 0:56 £ 10214 mol=mg total RNA, respectively. The difference in TGF-b1 gene expression in class 4 patients was significantly elevated compared to control and class 5 and 6 patients ( p , 0:05) (Fig. 66-5).[27] An additional 38 patients had 54 biopsies from the lower calf (LC) and lower thigh (LT) analyzed for TGF-b1 protein concentration. The amounts of active TGF-b1 in pg/g of tissue from LC and LT biopsies compared to normal skin biopsies were as follows: normal skin (, 1.0 pg/g), class 4 (LC, 5061 ^ 1827; LT 317:3 ^ 277), class 5 (LC, 8327 ^ 3690; LT 193 ^ 164),
Figure 66-5. Bar graph demonstrating increased TGF-b1 gene transcript levels from skin biopsies in class 4 patients compared to controls and class 5 and 6 patients ð p # 0:05Þ:
and class 6 (LC, 5392 ^ 1800; LT, 117 ^ 61) (Fig. 66-6). Differences between normal skin and class 4 and 6 patients were significant ( p # 0:05 and p # 0:01, respectively). No differences between class 4, 5, and 6 patients were observed. Differences between LC and LT within each CVI group were significant (class 4, p # 0:003; class 5, p # 0:008; class 6, p # 0:02). These data demonstrate that in areas of clinically active CVI, increased amounts of active TGF-b1 are present compared to normal skin. Furthermore, active TGF-b1 protein concentrations of biopsies from the LT did not differ from normal skin, demonstrating a regionalized response to injury.[27] Immunohistochemistry and immunogold labeling experiments were performed to identify the sourses of active TGFb1 protein production. Immunohistochemistry of normal skin and ipsilateral thigh biopsies of CVI patients demonstrated mild TGF-b1 in the basal layer of the epidermis. The dermis demonstrated few capillaries, ordered collagen architecture, and no interstitial leukocytes. CVI dermal biopsies from areas of clinically active disease demonstrated staining of the basal layer of the epidermis, interstitial leukocytes, and fibroblasts. Many perivascular leukocytes demonstrated positive staining of intracellular granules and appeared morphologically similar to previously reported mast cells (Fig. 66-7).[27] Numerous capillaries with perivascular cuffs were observed, but cuffs did not stain positively for TGF-b1.[27] This study conflicts with the observations reported by Higley et al., in which they reported positive TGF-b1 staining in perivascular cuffs and an absence of TGF-b1 in the provisional matrix of the venous ulcer compared to healing donor skin graft sites.[26] They concluded that TGF-b1 was therefore abnormally “trapped” in the perivascular cuff and therefore unavailable for normal granulation tissue development. Differences between the two studies may relate to biopsy site selection. Higley et al.[27] biopsied chronic, non-healing venous ulcer edges and ulcer bases, while patients with active ulcers in the study by Pappas et al.[27] were biopsied 5–10 cm away from an active ulcer. Therefore, the former study
Figure 66-6. Bar graph demonstrating differences in active TGF-b1 protein concentration between and within CVI groups compared to controls. Increased active TGF-b1 protein was observed in class 4 and 6 patients compared to control and class 5 patients ð p # 0:05Þ: Differences between calf and thigh biopsies were significant within CVI groups ð p # 0:05Þ:
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Figure 66-7. Immunohistochemistry for TGF-b1 demonstrating positive in granules of perivascular leukocytes which appear morphologically to mast cells (magnification 575£).
reflects the biology of chronic wound healing, while our data suggest active tissue remodeling in response to a chronic injury stimulus. Immunogold labeling confirmed the presence of TGF-b1 in dermal leukocytes. Positive labeling of gold particles was similarly observed in collagen fibrils of the ECM. This observation may explain why the molecular regulation of TGF-b1 in CVI patients demonstrates differential gene and protein production according to disease classification. As stated above, the gene expression of TGF-b1 was increased in class 4 patients only, while the protein production was essentially increased in class 4, 5, and 6 patients. These differences may be related to disease severity and the pluripotential responses of TGF-b1. TGF-b1 can have inhibitory and stimulatory effects that are primarily dependent on local concentration, cell source, and surrounding ECM. In the study by Pappas et al.,[27] class 4 patients were younger than the other study groups, never experienced an episode of venous stasis ulceration, and clinically demonstrated less dermal tissue fibrosis. TGF-b1 in these patients may therefore be involved in limiting the response to injury. Indeed, one could speculate that early on in the disease process, a low-grade production of TGF-b1 is a normal woundhealing response and may serve to prevent the onset and development of tissue fibrosis. With continued and prolonged exposure, an imbalance in tissue remodeling in patients with class 5 and 6 disease clinically manifests itself as dermatofibrosis. A pathologic effect of increased ECM deposition is an alteration in the storage and release of growth factors.[22] The latent form of TGF-b1 is secreted from cells bound to one of three latent TGF-b1 –binding proteins (LTBP). Once secreted, LTBPs mediate binding of latent TGF-b1 to matrix proteins. Matrix release of TGF-b1 is mediated by multiple serine proteinases, including plasmin, mast cell chymase and leukocyte elastase.[22,28 – 30] An increase in the number of mast cells and circulating leukocyte elastase has been reported in CVI patients.[12,31] The increase in active TGF-b1 observed in class 5 and 6 patients may therefore result from ECM release of latent TGF-b1, resulting in tissue fibrosis. This hypothesis is consistent with the demonstration of immunogold labeling to collagen fibrils in the ECM of CVI patients. The modulation of TGF-b1
release from the ECM may therefore provide a faster means of signal transduction than simple control of gene expression and therefore explain the sustained increase of TGF-b1 in class 5 and 6 patients in the absence of increased gene expression. This study did not demonstrate increased TGFb1 staining in the ECM by ICC because the primary antibody used was specific only for active TGF-b1 and therefore may have missed LAP- and LTBP-associated TGF-b1. In summary, the study by Pappas et al.[27] demonstrated increased gene expression of TGF-b1 in patients with class 4 CVI and increased protein production in patients with class 4, 5, and 6 CVI. Active TGF-b1 protein appeared to originate from leukocytes, many of which were morphologically similar to mast cells. Similarly, fibroblasts stained positively for TGF-b1, suggesting that they are the target cells for activated leukocytes. The authors hypothesized that increased active TGF-b1 protein observed in class 5 and 6 patients, in the absence of a corresponding increase of gene expression, is the result of ECM storage of TGF-b1. Immunogold labeling of collagen fibrils containing active TGF-b1 gold-labeled particles supports this position. These data, therefore, suggest that activated leukocytes traverse perivascular cuffs and release TGF-b1, which binds to interstitial dermal fibroblasts. Once bound, collagen production is stimulated, and if the process proceeds unabated, tissue fibrosis and end organ dysfunction ensues.
Dermal Fibroblast Function Several studies have reported aberrant phenotypic behavior of fibroblasts isolated from venous ulcer edges when compared to fibroblasts obtained from ipsilateral thigh biopsies of normal skin in the same patients. Hasan et al. compared the ability of venous ulcer fibroblasts of produce aI procollagen mRNA and collagen after stimulation with TGF-b1.[32] These authors were not able to demonstrate differences in aI procollagen mRNA levels after stimulation with TGF-b1 between venous ulcer fibroblasts and normal fibroblasts (control) from ipsilateral thigh biopsies. However, collagen production was increased by 60% in a dose-dependent
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Figure 66-8. Electron photomicrograph at 11,830£ of a normal and varicosed vein. Note organized structure of alternating smoothmuscle cells interspersed by longitudinally arranged collagen bundles in normal vein. Smooth-muscle cells appear spindle shaped with a prominent nucleus (large arrow = smooth muscle cell; small arrows = collagen). Electron photomicrograph at 4240£ of a varicose vein. Smooth-muscle cells exhibit prominent vacuoles and are elliptical instead of spindle shaped. The smooth-muscle cells are separated by diffusely deposited collagen bundles, which impart a disorganized architectural appearance to the vein wall (arrows = vacuoles within smooth muscle cells).
manner in controls, whereas venous ulcer fibroblasts were unresponsive. This unresponsiveness was associated with a fourfold decrease in TGF-b1 type II receptors. A similar investigation reported a decrease in collagen production from venous ulcer fibroblasts and similar amounts of fibronectin production when compared to normal controls.[33] Fibroblast responsiveness to growth factors was further delineated by Stanley et al.[34] These investigators characterized the proliferative responses of venous ulcer fibroblasts when stimulated with basic fibroblast growth factor (bFGF), epidermal growth factor (EGF), and interleukin 1-b (IL-1b). In their initial study, they reported that venous ulcer fibroblast growth rates were markedly suppressed when stimulated with bFGF, EGF, and IL-1b. They noted that normal fibroblasts appeared compact and tapered with well-defined nuclear morphologic features, whereas venous ulcer fibroblasts appeared larger, polygonal, and with varied nuclear mopphologic features. Venous ulcer fibroblasts appeared morphologically similar to fibroblasts undergoing cellular senescence. The authors therefore concluded that the blunted growth response of their cells was associated with cellular senescence.[34] Other characteristics of senescent cells are an overexpression of matrix proteins such as fibronectin (cFN) and enhanced activity of b-galactosidase (SA-b-Gal). In an evaluation of seven patients with venous stasis ulcers, the same group of investigators noted a higher percentage of SAb-Gal positive cells in venous ulcers compared to normal controls (6.3% vs. 0.21%; p # 0:06).[35] They also reported that venous ulcer fibroblasts produced one to four times more cFN by Western blot analysis compared to controls. In a follow-up investigation they noted an increase in FN mRNA and protein production but reported that the previously observed growth inhibition could be reversed with bFGF.[36] These data support the hypothesis that venous ulcer fibroblasts phenotypically behave like senescent cells. However, these responses may not be reflective of events
occurring in the lower extremity dermis of CVI patients. The biology of a stasis ulcer is similar to that of chronic nonhealing wounds and may not be reflective of active ongoing tissue remodeling observed in CVI patients without venous ulcers. Furthermore, what role senescence has on disease progression has yet to be determined.
ROLE OF MATRIX METALLOPROTEINASES AND THEIR INHIBITORS IN VENOUS ULCER HEALING The signaling event responsible for the development of a venous ulcer and the mechanisms responsible for prolonged wound healing are poorly understood. Wound healing is an orderly process that involves inflammation, reepithelialization, matrix deposition, and tissue remodeling. Tissue remodeling and matrix deposition are processes controlled by matrix metalloproteinases (MMPs) and tissue inhibitors of matrix metalloproteinases (TIMPs). In general, MMPs and TIMPs are not constitutively expressed. They are induced temporarily in response to exogenous signals such as various cytokines or growth factors, cell-matrix interactions, and altered cell-cell contacts. TGF-b1 is a potent inducer of TIMP-1 and inhibitor of MMP-1. Several studies have demonstrated that prolonged and continuous TGF-b 1 production causes tissue fibrosis by stimulating ECM production and inhibiting degradation by affecting MMP and TIMP production. Alterations in MMP and TIMP production may similarly modulate the tissue fibrosis of the lower extremity in CVI patients. In patients with active ulcers, increases in MMP activity from ulcer exudates and decreased expression of TIMP-1 in keratinocytes from venous ulcers have been reported.[37,38] These observations suggest that
Chapter 66. Pathophysiology of Chronic Venous Insufficiency
excessive proteolysis may be responsible for the decreased healing rates seen with venous stasis ulcers.
MACROSCOPIC ALTERATIONS The sine qua non of CVI is venous hypertension secondary to valvular incompetence and reflux. Up to 30% of patients develop valvular reflux after an episode of deep venous thrombosis.[1] The remaining 70% have no identifiable cause and are designated as having primary reflux. Patients with primary reflux are hypothesized to have intrinsic or genetic vein wall abnormalities that predispose to varix formation.[39 – 43] Clinical reports of reflux and varicose vein development at distant sites in the lower extremity prior to proximal development support this hypothesis and challenge the concept that proximal venous hypertension is the initial event leading to distal disease.[44] Whatever the initiating event, several unique anatomic and biochemical abnormalities have been observed. Normal and varicose greater saphenous veins (GSVs) are characterized by three distinct muscle layers within their walls. The media contains an inner longitudinal and an outer circular layer, while the adventitia contains a loosely organized outer longitudinal layer.[12,39] In normal GSVs, these muscle layers are composed of smooth-muscle cells (SMCs), which appear spindle shaped (contractile phenotype) when examined with electron microscopy (Fig. 66-8). The cells lie in close proximity to each other, are in parallel arrays, and are surrounded by bundles of regularly arranged collagen fibers. In varicosed veins, the orderly appearance of the muscle layers of the media is replaced by an intense and disorganized deposition of collagen.[12,39] Collagen deposits separate the normally closely opposed SMCs and are particularly striking in the media. SMCs appear elliptical, rather than spindle shaped, and demonstrate numerous collagen-containing vacuoles, imparting a secretory phenotype (Fig. 66-8).[12,40] What causes SMCs to dedifferentiate from a contractile to a secretory phenotype is not known. Increased phosphorylation of the retinoblastoma protein, an intracellular regulator of
945
cellular proliferation and differentiation, has been observed in varicose veins and may contribute to this process.[45] Similarly, in vitro coculture studies of SMCs and endothelial cells demonstrate SMCs with a contractile phenotype. The addition of an endothelin-1 antagonist to this SMC-EC coculture system caused the SMCs to change from a contractile to a secretory phenotype. These two observations suggest that endothelin-1 and the retinoblastoma protein may modulate SMC differentiation and contribute to the formation of varicose veins. Biochemical and functional analyses of varicose veins demonstrate alterations in collagen, elastin, and endothelin content as well as contractility abnormalities. Ghandi et al. quantitatively demonstrated an increase in collagen content and a decrease in elastin content compared to normal GSVs.[41] The net increase in collagen:elastin ratio suggested an imbalance in connective tissue matrix regulation. These observations were further substantiated by Parra et al.[46] These authors measured the proteolytic activity and enzyme content of MMP-2, MMP-3, MMP-9, TIMP-1, and TIMP-2 in 13 varicose vein segments obtained from the saphenofemoral junction. They reported an increase in TIMP-1 and a decrease in MMP-2 protein content and no differences in proteolytic activity.[46] These observations are consistent with those reported by Ghandi et al.[41] Lowell et al. evaluated the contractile responses of varicose and normal GSV rings to noradrenaline, potassium chloride, endothelin, calcium ionophore A23187 and nitric oxide.[42] This study demonstrated decreased contractility of varicose veins when stimulated by noradrenaline, endothelin, and potassium chloride. Similarly, endothelium-dependent and -independent relaxations after A23187 or nitric oxide administration were diminished compared to normal GSVs, respectively. The mechanisms responsible for decreased varicose vein contractility appear to be receptor mediated. Decreased endothelin B receptors have been observed in varicose veins compared to normal GSVs. Feedback inhibition of receptor production secondary to increased endothelin-1 is postulated to mediate the decreased receptor content in varicose vein walls.[43] The exact in vivo mechanisms are unknown and require further investigation.
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Bishop, J.E. Regulation of Cardiovascular Collagen Deposition by Mechanical Forces. Mol. Med. Today 1998, 4, 69– 75. Higley, H.R.; Kasander, G.A.; Gerhardt, C.O.; Falanga, V. Extravasation of Macromolecules and Possible Trapping of Transforming Growth Factor-bl in Venous Ulceration. Br. J. Dermatol. 1995, 79– 85. Pappas, P.J., You, R., Rameshwar, P., Gorti, R., DeFouw, D.O., Phillips, C.A., et al. Dermal Tissue Fibrosis in Patients with Chronic Venous Insufficiency (CVI) Is Associated with Increased Transforming Growth Factor-b1 (TGF-b1) Gene Expression and Protein Production. In Press. J. Vasc. Surg. 1999; 30(6): 1129– 1145. O’Kane, S.; Ferguson, W.J. Transforming Growth Factor bs and Wound Healing. Int. J. Biochem. Cell. Biol. 1997, 29, 63– 78. Border, W.A.; Noble, N.A. Transforming Growth Factor b in Tissue Fibrosis. N. Engl. J. Med. 1994, 331, 1286– 1292. Grande, J.P. Role of Transforming Growth Factor-b in Tissue Injury and Repair. PSEBM 1997, 214, 27– 40. Shields, D.A.; Sarin, A.S.; Scurr, J.H.; Smith, P.D.C. Plasma Elastase in Venous Disease. Br. J. Surg. 1994, 81, 1496– 1499. Hasan, A.; Murata, H.; Falabella, A.; Ochoa, S.; Zhou, L.; Badiavas, E.; et al. Dermal Fibroblasts from Venous Ulcers Are Unresponsive to the Action of Transforming Growth Factor-b1. J. Dermatol. Sci. 1997, 16, 59– 66. Herrick, S.E.; Ireland, G.W.; Simon, D.; McCollum, C.N.; Ferguson, M.W. Venous Ulcer Fibroblasts Compared with Normal Fibroblasts Show Differences in Collagen but Not in Fibronectin Production Under Both Normal and Hypoxic Conditions. J. Investig. Dermatol. 1996, 106, 187– 193. Stanley, A.C.; Park, H.; Phillips, T.J.; Russakovsky, V.; Menzoian, J.O. Reduced Growth of Dermal Fibroblasts from Chronic Venous Ulcers Can Be Stimulated with Growth Factors. J. Vasc. Surg. 1997, 26, 994– 1001. Mendez, M.V.; Stanley, A.; Park, H.; Shon, K.; Phillips, T.J.; Menzoian, J.O. Fibroblasts Cultured from Venous Ulcers Display Cellular Characteristics of Senescence. J. Vasc. Surg. 1998, 28, 876– 883. Mendez, M.V.; Stanley, A.; Phillips, T.J.; Murphy, M.; Menzoian, J.O.; Park, H. Fibroblasts Cultured from Distal Lower Extremities in Patients with Venous Reflux Display Cellular Characteristics of Senescence. J. Vasc. Surg. 1998, 28, 1040– 1050. Vaalamo, M.; Weckroth, M.; Puolakkainen, P.; Kere, J.; Saarinen, P.; Lauharanta, J.; et al. Patterns of Matrix Metalloproteinase and TIMP-1 Expression in Chronic and Normally Healing Human Cutaneous Wounds. Br. J. Dermatol. 1996, 135, 52– 59. Saarialho-Kere, U.K.; Kovacs, S.O.; Pentland, A.P.; Olerud, J.E.; Welgus, H.G.; Parks, W.C. Cell – Matrix Interactions Modulate Interstitial Collagenase Expression by Human Keratinocytes Actively Involved in Wound Healing. J. Clin. Investig. 1993, 92, 2858– 2866. Rose, A. Some New Thoughts on the Etiology of Varicose Veins. J. Cardiovasc. Surg. 1986, 27, 534– 543. Travers, J.P.; Brookes, C.E.; Evans, J.; Baker, D.M.; Kent, C.; Makins, G.S.; et al. Assessment of Was Structure and Composition of Varicose Veins with Reference to
Chapter 66. Pathophysiology of Chronic Venous Insufficiency Collagen, Elastin and Smooth Muscle Content. Eur. J. Vasc. Enodvasc. Surg. 1996, 11, 230– 237. 41. Ghandi, R.H.; Irizarry, E.; Nackman, G.B.; Galpern, V.J.; Mulcare, R.J.; Tilson, M.D. Analysis of the Connective Tissue Matrix and Proteolytic Activity of Primary Varicose Veins. J. Vasc. Surg. 1993, 18, 814– 820. 42. Lowell, R.C.; Gloviczki, P.; Miller, V.M. In Vitro Evaluation of Endothelial and Smooth Muscle Function of Primary Varicose Veins. J. Vasc. Surg. 1992, 16, 679– 686. 43. Barber, D.A.; Wang, X.; Gloviczki, P.; Miller, V.M. Characterization of Endothelin Receptors in Human Varicose Veins. J. Vasc. Surg. 1997, 26, 61– 69.
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Labropoulos, N.; Giannoukas, A.D.; Delis, K.; Mansour, M.A.; Kang, S.S.; Nicolaides, A.N.; et al. Where Does the Venous Reflux Start? J. Vasc. Surg. 1997, 26, 736– 742. 45. Pappas, P.J.; Gwertzman, G.A.; DeFouw, D.O.; Padberg, F.T., Jr.; Silva, M.B., Jr.; Duran, W.N.; et al. Retinoblastoma Protein: A Molecular Regulator of Chronic Venous Insufficiency. J. Surg. Res. 1998, 76, 149 – 153. 46. Parra, J.R.; Cambria, R.A.; Hower, C.D.; Dassow, M.S.; Freischlag, J.A.; Seabrook, G.R.; et al. Tissue Inhibitor of Metalloproteinase-1 Is Increased in the Saphenofemoral Junction of Patients with Varices in the Leg. J. Vasc. Surg. 1998, 28, 669– 675.
CHAPTER 67
Etiology and Surgical Management of Varicose Veins John J. Bergan
venous insufficiency and then suggest proper intervention based upon this etiology.
INTRODUCTION It is generally agreed that varicose veins afflict from 40 to 60% of women and 15 to 30% of men. Therefore, it is surprising that the etiology and development of this common problem remain obscure. Actually, in Western populations the incidence of varicose veins varies with the definition applied. Most investigators favor the definition of Arnoldi,[1] who said that varicosities are “any dilated, elongated, or tortuous veins, irrespective of size.” Thus, some epidemiologic studies would include telangiectasias and reticular veins, while others would exclude these entities. The definition of Arnoldi is particularly useful because it presents a unifying concept for reticular varicosities, telangiectasias, and major varicose veins. Since all three are elongated, dilated, and have incompetent valves, they probably have a common origin and respond to the same physical forces and acquired influences. The dilation and elongation implies that these abnormal veins have been responsive to effects of pressure. The causes and results of venous valve dysfunction are more subtle. They might be explained simply by the dilation of a vein and valve annulus, which stretches beyond the capability of its leaflets to close together. However, such a simplistic view does not explain the disappearance, perforation, and splitting of valves noted by several authorities or the stunted valves observed angioscopically in refluxing vein segments. Dodd and Cockett[2] defined varicose veins, saying “a varicose vein is one which has permanently lost its valvular efficiency.” They further explained varicosities by suggesting that it was pressure over a course of time that causes a varix to become elongated, tortuous, pouched, and thickened. Venous pressure appears inextricably linked to development of venous insufficiency. In assessing the etiology and pathogenesis of varicose veins, it would be best to accept the definition of Arnoldi and search for the factor or factors that best fit research observations and clinical experience.[3] It is the purpose of this presentation to offer evidence for a common factor of causation and development of the three forms of primary
RISK FACTORS: THE PATHOLOGIC SUBSTRATE Table 67-1 lists the factors that provide the substrate for development of varicose veins. In the mind of the lay public, heredity is the single most important factor in causation of varicose veins. Yet evidence for the role of genetic predisposition in development of varicose veins is limited. There are many methodologic difficulties in interpreting available data. However, CornuThe´nard and colleagues performed a very carefully planned study, which presents useful conclusions.[4] Their investigations were based on prospective evaluation of 67 patients with varicose veins compared to 67 controls. The patients, controls, and parents of each study group were all examined for varicose stigmata. This provided a total of 402 subjects. This study demonstrated a prominent role for hereditary in development of varicose veins ð p , 0:001Þ: If both parents had varicose veins, the children had a 90% chance for developing varicosities. When one parent was affected, the risk was 25% for males and 62% for females. This contrasted with a risk of only 20% when neither parent was afflicted with varicose veins. Interestingly, in this study both the total number of pregnancies and the presence of constipation were found to influence development and aggravation of varicosities. Although a third generation of individuals was not examined, an autosomal recessive type of inheritance with variable penetrance would be compatible with the results observed. A dominant mode of transmission has been discussed by many authors, as has crossed transmission, but there is little evidence for either of these. It is generally agreed that varicose veins may appear for the first time during pregnancy and may be exacerbated by pregnancies. The widely held view is that varicose veins are caused by pressure of the gravid uterus, which obstructs venous return. That concept has been refuted by the
Hobson/Wilson/Veith: Vascular Surgery: Principles and Practice, Third Edition, Revised and Expanded DOI: 10.1081/0819-9-120024951 Copyright q 2004 by Marcel Dekker, Inc.
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Commonly Ascribed Causes of Varicose Veins
Hereditary Pregnancy Obesity Standing occupation Chair sitting Low-fiber diet/constipation
Tight underclothes Raised toilet seats Lack of exercise Smoking Oral contraceptives
Source: Ref. [3].
observation that a majority of varices appear during the first 3 months of pregnancy when the uterus is not large enough to cause mechanical obstruction. Multiparous women frequently note that the first sign of another pregnancy is the sudden appearance of a new cluster of varicosities or a major telangiectatic blemish. This could be explained by an hormonal effect due to the profound elaboration of progesterone by the corpus luteum. Progesterone inhibits smooth-muscle contraction in the uterus and vein wall. While that is logical, the physiologic venous function study performed by Struckmann’s group[5] failed to find a statistical correlation between venous muscle pump function and changes in hormone concentrations of estradiol, estriol, or progesterone. These authors felt that venous insufficiency developing during pregnancy was caused primarily by mechanical obstruction or other causes not related to the hormone studied. Also, the immunocytochemical investigations of Sadick and Niedt failed to find estrogen or progesterone receptors in lower extremity telangiectasias.[6] Despite that negative evidence, intuitively one would implicate progesterone as an etiologic factor in the development of varicose veins. As progesterone does inhibit smooth-muscle contraction, it could have a profound downregulating effect on function of the smooth muscle of the venous wall. Miller et al. speculated on hormonal effects on venous function, saying that the excitatory effects of some agents might be more prominent when estrogen and progesterone are elevated, as would be found during some phases of the menstrual cycle.[7] Vin and coworkers established that functional venous symptomatology is aggravated upon the appearance of new varicose veins or blue telangiectatic veins during the course of progestogen or estroprogestogen treatment with oral contraceptives. [8] Therefore, heredity and female hormones, principally progesterone, can be thought of as the substrate for action by physical factors that elongate and dilate superficial veins.
INTRINSIC FACTORS Among the theories that have been proposed to explain the cause of varicose veins is the hypothesis invoking a weakness in the vein wall. A significantly reduced vein wall elasticity has suggested that the role of venous valves in development of varicose veins is secondary to changes in the elastic properties of the vein wall.[9] Such abnormality of vein wall function
could very well be the result of progesterone effectively inhibiting smooth-muscle contraction. In vitro evaluation of varicose veins has shown that maximal contractions in response to stimulation by potassium chloride, norepinephrine, and endothelin are reduced compared to normal control veins. Endothelium-dependent relaxations were also attenuated, which suggests that endothelial and smoothmuscle function is impaired in vein segments removed from patients with primary varicose veins.[10] Thulesius et al. showed a functional disturbance of smooth-muscle function in varicose veins.[11] Therefore, the combination of venous wall abnormalities and hormonal effect could be acting interdependently. Scanning electron microscopy has shown varying degrees of thinning of the media of the varicose venous wall. These areas of thinning coincide with areas of varicose dilation.[12] Replacement of smooth muscle by collagen is also a characteristic of varicose veins. Interestingly, the collagen content and wall area is greater proximally compared to distally in varicose saphenous veins compared to controls. There is a higher content of smooth muscle and elastin in varicose veins proximally as compared to distally. This suggested to Travers and his group that varicose veins were a dynamic response to venous hypertension rather than a passive thinning of venous wall components, as has been postulated by others.[13] Our own work in this area has been based on the hypothesis that both the venous valve and the venous wall are affected by the elements that cause varicose veins. We and others[14] have observed absence of the subterminal valve in saphenous veins in patients with venous varicosities requiring surgical intervention. As mentioned earlier, perforation, splitting, and atrophy of venous valves has been seen during intraoperative saphenous angioscopy,[15] and angioscopy has revealed that approximately 50% of varicose saphenous veins have no functional valves between the groin and the knee. Other direct observations have shown that a widening of the space between valve leaflets is the first and most common cause of reflux in venous varicosities.[16,17] These observations led us to explore the possible role of leukocyte infiltration of venous valves and the venous wall in genesis of varicosities. Our investigations identified the presence of leukocytes in the venous valves, in the venous wall, and in the base of the valve leaflet. CD-64 monoclonal antibody staining revealed their precise identification as monocytes that become macrophages on penetration into the wall. These were found in greater numbers on the proximal side of the valve cusp and in the proximal venous wall than on the distal surface of the valve and distal venous wall and were associated with increased ICAM-1 expression.[18] But the greatest number of tissue macrophages were seen in the base of the valve. Liberation of toxic products by the monocyte could very well explain both venous wall weakness and venous valvular destruction.[19] If true, this would suggest that vein wall weakening and valve destruction are occurring simultaneously. Why obesity would be associated with varicose veins is unclear. Nevertheless, in case-controlled studies, obesity defined as greater than 20% over ideal weight was much more common in patients with truncal varicosities and telangiectasias than in controls. Even population-based studies have
Chapter 67.
Etiology and Surgical Management of Varicose Veins
shown a positive relationship between body mass and varicose veins. Multivariant analyses, including weight and height, have revealed weight to be significantly related to occurrence of varicose veins in women but not in men.[2] Central obesity, often referred to as android obesity, is more dangerous than peripheral or gynoid obesity. This is believed to be secondary to increased fat metabolism which leads to hyperglycemia, diabetes, insulin-induced sodium reabsorption, and hypertension. These factors together are known as syndrome X, and it has been found that this type of obesity is associated with a marked increase in intraabdominal pressure. Urinary bladder pressure can be used as an estimate of intraabdominal pressure, and such pressures plotted against abdominal diameter display a straight-line relationship with an r value of +0.67.[20] For decades, a standing occupation has been implicated in causation of varicose veins, yet it is only with development of duplex scanning that this has been proven to be true. In a study of 387 male workers with a standing occupation, venous insufficiency was present in 29% of the individuals and correlated with age, weight, and duration of standing work.[21] Of some interest to surgeons was examination of the distribution and extent of venous reflux in the lower extremities of vascular surgeons as compared to volunteers. Vascular surgeons were chosen because they are typically thought to lead a life of prolonged standing. In symptom-free vascular surgeons, there was greater superficial venous reflux than in controls. Even deep venous reflux and perforator incompetence was greater in the vascular surgeons.[22] Fortunately, in other studies, such changes in reflux have been reversed by physical conditioning. This has been shown to improve venous hemodynamics.[23] In contrast to that improvement in venous function during physical therapy has been the observation that deterioration of venous function is seen while patients await corrective surgery.[24] Other risk factors for varicosities include the wearing of tight undergarments, which presumably produce proximal limb venous hypertension, a low-fiber diet, which supposedly predisposes to constipation and increased abdominal straining, and raised toilet seats, which prevent squatting during defecation. Similarly, the Western habit of chair sitting rather than squatting during resting has been thought by some to increase hydrostatic pressure and blood pooling in the legs. All of these theoretical and unproven theories are related to venous hypertension, which itself is linked to development of venous insufficiency.
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in endothelial cells and circulating leukocytes.[25 – 28] A shift of fluid shear stresses from normal physiological levels as well as mechanical stretching of the venous wall or the leaflet tissue may serve to promote inflammatory gene products. Alterations of venous or valve leaflet tissue stresses may serve as mechanisms that promote the inflammatory state and the high propensity for venous valve failure. The process may be further enhanced in the presence of humoral inflammatory mediators which serve to suppress the anti-inflammatory reaction of normal physiological fluid shear stresses. If such venous hypertension were to be the stimulus for activation of leukocytes, such activation would introduce a cascade of events. Leukocytes would roll rather than flow through the venous stream and would adhere to venous endothelium. Such activation and adherence producing leukocyte-endothelial interaction could explain the presence of monocytes on the endothelium in the valves and in the venous wall in specimens removed at varicose vein surgery. It is but a short step in thought to ascribe valve destruction and vein wall thinning and weakening to such monocyte infiltration. Thus, hydrostatic forces are easily linked to development of varicosities. But more subtle is the effect of hydrodynamic forces (Fig. 67-1). These derive from muscular contraction and can be transmitted through failed perforator vein valves to unsupported subcutaneous and intradermal venulectasias. According to Faria and Moraes, telangiectasias were first thought to be associated with elevated venous pressure by Meischer in 1919.[29] Faria showed that telangiectasias are
PHYSICAL FORCES It is acknowledged that the hydrostatic weight of the column of blood transmitted from the level of the right atrium through valveless vena cava and iliac veins is exerted directly on the femoral vein and the saphenofemoral junction. This hydrostatic pressure can easily be increased by intraabdominal pressure as implied in theories which link constipation, low-fiber diet, and raised toilet seats to development of varicosities. An increasing body of evidence suggests that fluid shear stress serves as a mechanism to control inflammatory reactions
Figure 67-1. Diagram of the development of varicose veins and telangiectasias derived from duplex studies performed by George Somjen. LSV ¼ long saphenous vein. It can be seen how perforating veins relate to the saphenous vein and to reticular veins in the subcutaneous tissue. Ultimately, pressure is transmitted to all of the subcutaneous veins and even epidermal veins, which become dilated to form telangiectasias. Thus, hydrostatic and hydrodynamic pressures are the forces that cause elongation and dilation of unsupported veins, venules, and telangiectasias.
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linked to varicose veins. His observations support the view that telangiectasias, like varicose veins, are related to high venous pressure. Using injection of radiographic contrast media into telangiectasias, Moraes et al. showed direct connections of the telangiectasias with named veins such as the greater saphenous and other superficial veins.[30] Communicating veins directly connecting the telangiectasias to the saphenofemoral junction were also demonstrated, but the most important observations were that telangiectasias were directly connected to perforating veins. Thus, even telangiectasias and venulectasias were shown to be connected to the two most important sources of venous hypertension. The contrast studies allowed visualization of the deep venous system in 61 of 74 limbs. The greatest number of perforating veins were found between 15 and 35 cm below the greater trochanter, where 102 of the total of 142 perforating veins were identified. It should be emphasized that contraction of muscles within their muscular compartments causes tremendous elevation of intracompartmental pressure and that these elevations are transmitted through failed check valves in the perforating veins. These direct demonstrations of interconnections of intradermal venous abnormalities with venous hypertension support the theory that telangiectasias and varicose veins are pathologically identical and only differ in size. Muscular compartmental forces during exercise are enormous. These range between 100 and 300 mmHg. The effects of these pressures on weakened vein walls would be to further dilate and elongate the affected conduits. Further, the dilation of the venous wall could easily render the contained valve incompetent.
SUMMARY OF ETIOLOGY A unifying concept that links telangiectasias, reticular varicosities, and varicose veins to hereditary and hormonal factors is intriguing. On a hereditary-hormonal substrate, the factors of hydrostatic and hydrodynamic forces interact to affect vein valves and vein walls weakened by unknown factors, which remain to be discovered. The etiology of primary varicose veins may be diverse, but it can be simplified. First, elongated, dilated, and tortuous veins with incompetent valves, regardless of size, are varicose, and this definition includes telangiectasias, reticular varicosities, and varicose veins. Next, a hereditary predisposition acted upon by female hormones and venous hypertension may produce the pathologic changes. Venous hypertension is the sum of hydrostatic pressure caused by gravity and hydrodynamic forces from muscular compartment pressure and intra-abdominal straining.
Table 67-2. Varicose Veins: Indications for Intervention General appearance Aching pain Leg heaviness Easy leg fatigue Superficial thrombophlebitis
External bleeding Ankle hyperpigmentation Lipodermatosclerosis Atrophie blanche Venous ulcer
stimulates consultation. Ultimately, this may be the only indication for intervention. Unfortunately, negative physician perception regarding availability and efficacy of treatment of varices may deny the patient the precise care which is sought.[31] Furthermore, symptoms of primary venous insufficiency may be present but not recognized by the patient until asked for during thorough history taking.[32] The characteristic symptoms include aching pain, easy leg fatigue, and leg heaviness, all worsening as the day progresses so that the patient sits down in the afternoon and elevates the legs for some relief. These symptoms will be maximal on the first day of a menstrual period. The symptoms may not be recognized by the patient as being due to the varicose veins or telangiectasias. They must be asked for by the examining physician. Neither the patient nor the physician may understand that these symptoms arise from telangiectatic blemishes just as from venous varicosities. However, this is true. Some 50% of patients with telangiectasias will have such symptoms, and 85% will be relieved of them by appropriate therapy.[33] Other indications for intervention for venous varicosities include superficial thrombophlebitis in varicose clusters, external bleeding from high-pressure venous blebs,[34] or advanced changes of chronic venous insufficiency. These include the severe ankle hyperpigmentation, subcutaneous lipodermatosclerosis, atrophie blanche, or frank ulceration of chronic venous insufficiency (CVI). Specific findings on physical examination which lead toward groin-to-knee stripping rather than phlebectomy include the finding of axial reflux in the greater saphenous or lesser saphenous vein. Experience teaches that any therapy of varicosities in the persistent presence of saphenous reflux will fail.[35] Large varices of the medial thigh lend themselves to phlebectomy rather than to sclerotherapy for two reasons.[36] First, large varices, in general, respond better to removal if only to avoid superficial thrombophlebitis after injection. Second, large varices in this location are usually markers for large incompetent mid-thigh (Hunterian) or distal thigh (Dodd) perforating veins which are detached by phlebectomy. These are difficult to compress after sclerotherapy.
TESTING BEFORE INTERVENTION INDICATIONS FOR INTERVENTION Indications for intervention in primary venous insufficiency are listed in Table 67-2. Often it is the appearance of telangiectatic blemishes or protuberant varicosities that
Within a few years after venous imaging was revolutionized by the introduction of B-mode ultrasound,[37] it could be said that “varicose vein surgery appears best guided by color-flow duplex scanning.”[38]
Chapter 67.
Etiology and Surgical Management of Varicose Veins
Clinical examination is perfectly adequate to make an overall diagnosis of varicose veins. Clinical examination may not identify those varicosities that lie deep or are not prominent. In direct tests of venous function such as plethysmography, venous pressure measurements give information, but not specific information, about abnormally functioning venous segments. Only imaging can do that. Venous imaging was revolutionized by the introduction of Bmode ultrasound. This has virtually replaced phlebography because it is a noninvasive, repeatable, low-cost technique which is easily learned. The anatomical information which is provided is useful not only in selection of treatment but also as a guide to that treatment in surgery. Therefore, there are two types of examination—one that can be performed by a technologist and provides general information prior to surgery and one in which the surgeon participates in the diagnostic maneuvers and derives significant information which guides his operation. For the general examination, the patient stands or is in a 60- to 80-degree near-upright position. Weightbearing is on the opposite extremity, and maneuvers to initiate venous flow may be by pneumatic cuff deflation or by calf squeeze and release. Examination is performed with a 5- or 7-MHz lineararray transducer. Use of the pneumatic cuff technique allows standardization of the operation across all patients being studied. However, the technique is cumbersome, and calf squeeze and release, if carefully performed, gives all the information that is necessary. The examination searches for prolonged retrograde flow during the relaxation phase, and incompetence is confirmed if the duration of retrograde flow exceeds 0.5 seconds. Examination begins at the groin, and the saphenofemoral junction is identified at the longitudinal plane. The common femoral vein, 2 –3 cm superior to the saphenofemoral junction, is interrogated, the patient instructed to perform a Valsalva maneuver, and flow is augmented using thigh or calf squeeze or pneumatic cuff. Color duplex images and Doppler spectrum in the compression and relaxation phases are recorded. Reflux at the common femoral vein may be present normally. The sample volume is then placed in the greater saphenous vein 2–3 cm distal to the saphenofemoral junction. Competence of this junction is evaluated as above. The greater saphenous vein is identified by its relationship to the deep and superficial fascia which ensheathe it, anchoring it to the deep fascia and forming the saphenous compartment. This was first described by Thomson in 1979.[39] High-resolution Bmode ultrasound imaging of the superficial fascia in the transverse plane has shown this to be strongly ultrasound reflective, giving a characteristic image of the saphenous vein called the “saphenous eye.”[40] The saphenous eye is a constant marker, clearly demonstrable in transverse sections of the medial aspect of the thigh. This differentiates the saphenous vein from varicose tributaries and other superficial veins. Casual examination of the thigh will often reveal an elongated, dilated vein, which is considered to be the long saphenous vein. This opinion is refuted by ultrasound scanning using the anatomical markers of the saphenous eye.[41,42] The vein is traced distally and reflux evaluation is done above and below the knee. This is because at mid-thigh the Hunterian, and in the distal thigh the Dodd, perforating veins may be the source of reflux even if saphenofemoral junction
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competence is present. Attention is then turned to the posterior aspect of the knee, and interrogation is done on the popliteal vein, the saphenopopliteal junction, and distally along the course of the lesser saphenous vein. When the examination is done not for varicose veins alone but for severe chronic venous insufficiency, then imaging of the calf perforating veins must be done very carefully. The more extensive examination performed with the surgeon in attendance is different only in detail. For example, the saphenous vein is scanned by moving the probe up and down along its course. Double segments, sites of branching of collaterals, and large perforating veins are identified. As the course of the vein is marked on the skin, longitudinal scans are obtained in addition to transverse scans for greater detail. On the medial aspect of the thigh, the varicosities are often arranged in multiple parallel channels. It is in this area that more than 50% of the saphenous veins are seen to be as double or even triple segments.[43] Although the saphenous vein may appear to be doubled, in fact a parallel channel which is actually the anterolateral tributary vein or the medial posterior tributary vein may be the actual source of reflux. Failure to recognize multiple varicose channels is a frequent cause of incomplete surgery. Ruckley’s group has identified that more than 70% of the recurrent varicose veins are in the territory of the greater saphenous vein[44] and over 60% of patients with recurrence in this area after saphenous ligation have a persistent refluxing saphenous vein. In assessing the refluxing veins in relation to the saphenous vein, it is well to remember that for the most part the saphenous vein lies deep to the superficial fascia and varicose tributaries are superficial to the tela aponeurotica (Fig. 67-2). Either the superficial or the deep channel may be competent and the other incompetent. Frequently, many tiny incompetent varicose veins fill by retrograde flow while the adjacent saphenous vein under the superficial fascia remains competent. Furthermore, the saphenofemoral junction may itself be competent and the varicosities of the upper thigh be fed with high pressure from pudendal veins through pelvic escape points. It is in the popliteal fossa with assessment of the short saphenous vein that the duplex scan is of particular value. Reflux can be identified from other structures in the popliteal vein, gastrocnemius veins, or in the superficial veins tributary to the short saphenous vein. Furthermore, as the saphenopopliteal junction is not constant, duplex scanning may allow proper marking of the exact entry of the short saphenous vein into the popliteal. In about half of the short saphenous veins scanned, a rather long segment extends proximally along the knee joint crease and becomes subfascial at various levels in the thigh. This vein may terminate proximally into the long saphenous vein, even into the saphenofemoral junction, or it may disappear into tributaries of the muscular branches of the thigh or gluteal area. In the posterior aspect of the lower extremity in the lateral aspect of the popliteal fossa, a perforating vein directly connecting the superficial veins to the popliteal vein can regularly be found. This is obvious clinically as a posterolateral leg vein.[45] When this vein is large enough to be removed surgically, it should be marked. More often, it is the source of band-like distributions of telangiectasias across the anterolateral aspect of the middle third of the thigh.
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obliteration of their target vessels. Since a variety of surgical approaches have been used, discussion of these is appropriate. Retrospective reviews of surgical experience are looked upon with disfavor today. Yet a thread of wisdom can be found in some such studies. Lofgren et al. examined limbs of patients up to 5 years following high saphenous ligation or complete ankle-to-groin stripping and found 94% excellent or good results after stripping compared to 40% after high tie.[46] This and other studies[47] were dismissed by Dormandy as he presented his prospective, randomized study.[48] He compared saphenous vein stripping and stab avulsion to saphenous high tie and mid-thigh perforator interruption, finding no differences in either patient or physician evaluation at 3 years.[49] Results of this study were criticized because evaluation was entirely subjective rather than objective.[50]
PROSPECTIVE STUDIES
Figure 67-2. The relationships of the important structures in the leg. Note the proximity of the saphenous nerve to the saphenous vein and note the separation of tributaries to the saphenous vein by the membranous fascia. Note the subfascial location of the short saphenous vein and its proximity to the sural nerve.
Finally, it is important to remember that reflux is not just gravitational, although that source of reverse flow is important. It is said that a source of deep to superficial reflux “may be difficult to detect and may even challenge our concept of gravitational reflux.”[45] Now, of course, we understand that such a source of reflux is simply a failure of perforating vein valve function with outward flow during muscular contraction.
OPTIONS IN INTERVENTION: LIGATION VERSUS STRIPPING Objectives of treatment should be ablation of the hydrostatic forces of axial reflux and removal of the hydrodynamic forces of perforator vein reflux. In surgery these should be combined with phlebectomy of vein clusters in as cosmetic a fashion as possible. Sclerotherapy should be used to ablate highpressure, feeding reticular vessels in combination with injection of their targets, the epidermal veins, telangiectasias. The objectives of sclerotherapy and surgery are identical. These are ablation of high-pressure conduits and excision or
In addition to Dormandy’s work, there have been six prospective studies comparing stripping of the saphenous vein with high ligation.[50,56] The Middlesex group,[50] in their prospective, randomized study, used duplex scanning for postoperative examination of valvular incompetence and PPG as a measure of overall determination of venous function. “Both objective tests of venous function and subjective assessment suggest that the results 21 months after surgery . . . are improved by . . . long saphenous vein stripping from groin to calf.” At Maastricht,[51] stripping and ligation were prospectively randomized. Physician and patient assessment of results at 3 years was supplemented by Doppler ultrasound examination with the conclusion that “the results remained significantly better for the stripping group.” In Copenhagen, Jakobsen’s prospective evaluation (confirmed by Carl Arnoldi) concluded that saphenous varices are best treated by radical operation (stripping as compared to high tie) in spite of the fact that the period of disability is significantly longer.”[52] In the New Zealand trial, each patient served as his own control, and evaluation was by a single observer at intervals up to 3 –5 years after operation.[53] Results, judged only by incidence of recurrent varicosities “were significantly better in limbs from which the long saphenous vein had been stripped.” However, saphenous nerve paresthesias biased patient evaluation against ankle-togroin stripping.” At Lund, conventional subjective and objective evaluation was supplemented by foot volumetry before and after treatment.[54] The authors concluded that “this study clearly supports the conclusion that CST (compression sclerotherapy) alone or in combination with high tie cannot replace radical surgery (saphenous stripping, perforator interruption, and stab avulsion) for varicose vein disease with saphenous incompetence.” Only Hammarsten et al.’s study concluded that “the removal of the long saphenous vein per se is of no therapeutic value if all perforators have been ligated.”[55] However, as emphasized in a later letter, only “by means of a thorough (ascending and descending) phlebographic mapping of the insufficient perforators . . . was precise perforator ligation possible.”[56] Commenting on this, Darke suggested that, with regard to elimination of perforator-induced saphenous
Chapter 67.
Etiology and Surgical Management of Varicose Veins
recurrences, “the simplest and least costly and uncomplicated way of eradicating the problem is to remove the saphenous trunk along with the existing and potentially incompetent perforators.”[57]
FATE OF SAPHENOUS LIGATION Fate of the long saphenous vein after proximal ligation has been defined by duplex scanning. Rutherford’s evaluation showed that only 8–10 cm of proximal saphenous vein was obliterated after high ligation. He found postligation that all saphenous veins were patent.[58] Friedell et al. studied patients in Florida at a mean follow-up of 10 months and found 78% of saphenous veins completely patent, 15% with less than 10 cm obliterated, and only 7% with a greater length obliterated.[59] In Cardiff, 75 limbs were assessed at a mean follow-up of one year by duplex scans. In 49 limbs (65%) the entire saphenous vein was patent from ankle to groin, and in two additional limbs less than 5 cm was lost proximally.[60] In a physiological evaluation of high saphenous ligation using duplex scans and PPG, the Middlesex group found persistent reflux in 24 of 52 limbs with successful proximal ligation:[61] “A satisfactory outcome was associated with absence of reflux down the long saphenous vein after operation” concluded the authors, who added that proximal ligation “fails to control functionally significant reflux within the long saphenous vein in a high proportion of cases.”
RECURRENT VARICOSITIES Some lessons can be learned from studies of recurrent varicose veins. These have been termed “a national problem” by Thomson of Gloucester.[62] Using duplex venous imaging and a careful search for sources of reflux, Thibault and Lewis studied 122 limbs with recurrent varicose veins.[63] Of these, 71.3% had recurrent, incompetent superficial thigh veins in the long saphenous distribution. Redwood and Lambert[64] studied 127 limbs with recurrent varicose veins and found that when a single site of reflux was found, it was at the saphenofemoral junction in 58% of limbs. They concluded that “the high recurrence rate from the groin emphasizes the need for meticulous dissection around the saphenofemoral junction at the time of the initial surgery.” Patterns of incompetence in 100 limbs with recurrent varicose veins were studied by duplex ultrasonography in Adelaide, Australia.[65] Saphenofemoral or recurrent groin tributary incompetence was present in 44 limbs and an incompetent long saphenous remnant in 20, with the authors saying, “the high incidence of long saphenous remnant incompetence in which no other site of incompetence was detected . . . supports the argument for stripping.” Ruckley’s group studied 128 limbs with recurrent varicose vein by varicograms and provided a useful classification of recurrent varices. That is, a Type 1 recurrence required reexploration of the groin, while a Type 2 recurrence allowed operation to be performed without reexploration of the groin.[44] In 75 of 128 limbs, the long saphenous vein was
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present in the thigh, and in 37 it was present to groin level. Clearly, in all but 24 instances of the 128 limbs, the site of recurrence could have been prevented by more complete primary procedure. Another important observation deriving from this paper is that saphenofemoral tributaries must be removed beyond their primary or even secondary tributaries in order to avoid leaving behind a network of collaterals that can defeat the primary operation. Ruckley concludes, “it is clear from this and previous work that a large number of patients are undergoing inadequate first-time varicose vein surgery. The importance of accurately identifying and ligating the saphenofemoral venous complex, of obliterating all tributaries back to the secondary tributary points, and of stripping the long saphenous vein in the thigh and preventing recurrent varices must be emphasized yet again.”[66] Ligation of the saphenous vein at the saphenofemoral junction has been practiced widely in the belief that this would control gravitational reflux while preserving the vein for subsequent arterial bypass. It is true that the saphenous vein is largely preserved after proximal ligation.[67] However, reflux continues and hydrodynamic forces are not controlled.[68] Recurrent varicose veins are more frequent after saphenous ligation than after stripping of the saphenous vein in the thigh.[44] Also, recurrent varicose veins are more frequent after saphenous ligation and sclerotherapy than after stripping and sclerotherapy.[51] Prospective, randomized trials comparing proximal saphenous ligation and stab avulsion of varices to stripping of the thigh portion of the saphenous vein and stab avulsion of varices have shown superior results for the latter procedure.[69] Careful duplex evaluation of proximal saphenous vein ligation 2 years following intervention showed that, “a large group of patients (33%) had developed significant collateral veins at the level of the operative site.” Ninety-five percent of the saphenous veins were patent to within 10 cm of ligation, and 88% were incompetent.[70] In studying recurrent varicose veins, preservation of patency of the saphenous vein and continued reflux in the saphenous vein have been found to be the most frequent elements in such recurrence.[44] In patients presenting for surgical relief of recurrent varicosities, it has been found that two thirds required removal of the saphenous vein as part of the repeat procedure.
ANKLE-TO-GROIN STRIPPING Before accurate delineation of site of origin of varicosities by duplex scan, ankle-to-groin stripping of the saphenous vein was considered to be the standard operation that should be done in every operated case. Turn-of-the-century publications had conveyed the belief that reflux was uniformly distributed over the entire length of the saphenous vein. The object of excision of the saphenous vein is to remove its gravitational reflux and detach its perforator vein tributaries. It has been found unnecessary to remove the below-knee portion. Removing the thigh portion detaches perforating veins and communicating veins which enter the saphenous vein.[71] In the leg below the knee, perforating veins enter the posterior arch vein circulation for the most part. There are many venous variations on this general theme
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Venous and Lymphatic Disorders
of perforator attachments, and the variations may be the cause of postoperative recurrent varicosities. A further argument against routine removal of the saphenous vein below the knee has been the discovery of saphenous nerve injury associated with this operation. This has occurred in the upper third of the leg as well as adjacent to the ankle incision.
EXCISION OF VARICOSE CLUSTERS Table 67-3 shows the common patterns of clusters of varicosities and indicates which perforating veins will be detached from the superficial venous circulation by local phlebectomy. In one-third of patients, the saphenofemoral junction will be found to be competent and therefore can be left intact. When this is true, thigh varicosities often arise from a refluxing anterolateral tributary to the saphenofemoral junction. Judgment will determine whether the saphenous vein should be removed, left in place intact, or ligated. Stab avulsion of clusters of varicosities derived from reflux from Hunterian or Dodd perforating veins may also remove segments of the greater saphenous vein (Fig. 67-3). Approximately 15% of patients will be found to have lesser saphenous venous incompetence, and the operation will need to include careful removal of some or all of that structure.
Because the objective of saphenous vein removal is to detach perforating veins which carry superficial venous blood from the saphenous system to the deep system, stripping of the saphenous vein need only be done from groin to knee. Introduction of the stripper can be done from above as incompetence of saphenous valves has been proven by preoperative duplex scanning. Sometimes, when subcutaneous fat is excessive, it is difficult to identify the stripper within the saphenous vein at knee level. The saphenous vein can be identified preoperatively and marked at the medial aspect of the popliteal space where the saphenous vein is relatively constant. This allows placement of a cosmetically satisfactory incision on the medial aspect of the knee. However, with preoperative duplex testing confirming saphenous vein reflux, the stripper can be placed from
VARICOSE VEIN SURGERY Following the principle that surgical removal of large varicose veins is superior to sclerotherapy, operation is offered to patients if the symptoms are attributable directly to varicose veins and after evaluation that indicates that the patient will be likely to benefit from removal of the varicose veins. Formerly, as indicated previously, the operation of saphenous vein removal was performed as a stripping procedure from ankle to groin, often placing the intraluminal stripper through the ankle incision. Several problems were encountered using that technique. The most common was saphenous nerve injury due to avulsion of saphenous nerve 7–13 cm below the knee joint crease. Less frequently, the stripper entered the femoral vein through angulated perforating veins, and cases have been reported of stripping of the superficial femoral vein because of this.
Table 67-3.
Targets of Phlebectomy of Varicose Clusters
Location of varices
Perforator
Medial thigh, mid-third Medial thigh, distal third Medial leg, upper third Ankle, posteromedial Ankle, anteromedial Posterolateral knee crease
Hunterian Dodd Boyd Cockett Sherman Unnamed
Figure 67-3. The relationships of important perforating veins to the saphenous vein and to the posterior arch circulation. Perforating veins that are part of the greater saphenous vein circulation in the thigh are detached by groin-to-knee removal of the saphenous vein. Note the very important anterior and posterior tributaries to the saphenous vein near the saphenofemoral junction.
Chapter 67.
Etiology and Surgical Management of Varicose Veins
above downward to exit at a cosmetically placed incision on the medial aspect of the knee. Exposure of the saphenous vein at its termination is done through a proximal incision, either in the upper thigh skin fold or 1 cm above it where the saphenous vein regularly enters the femoral vein. The more proximal incision can be made much shorter because it is directly over the termination of the saphenous vein. Exposure must allow exposing the femoral vein 1 cm above and 1 cm below the saphenous vein. This is to verify that no other tributaries are entering the femoral vein rather than the saphenous vein. Regularly, the epigastric and circumflex iliac tributaries can be seen to enter the saphenous vein and are markers for its location. Less important are the pudendal veins, but of greatest importance are the medial posterior and lateral anterior tributaries. Ruckley advocates dissecting all tributaries to the saphenous junction beyond their primary tributaries in order to avoid leaving a network of veins behind.[66] Our own practice is to bring each tributary into the incision, avulsing the tributaries as this is done, and applying pressure wherever tributary bleeding is troublesome. While many surgeons advocate clipping or ligating tributaries to the saphenous vein, we find that electrocoagulation is perfectly satisfactory. A good rule is to cannulate with the internal stripper each major vein entering the groin incision. In this way, very large lateral anterior tributary veins can be stripped to knee level and even the posteromedial tributary can be stripped to mid-thigh or below. Leaving these large tributaries behind contributes to recurrent varicosities.
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Increasingly, the technique of inversion stripping is being taken up (Fig. 67-4). Our own technique adds the hemostatic pack, which has been described elsewhere.[72] If saphenopopliteal incompetence is found, attention must be paid to the short saphenous vein. Because of the specter of sural nerve injury, many surgeons turn to proximal short saphenous ligation rather than stripping, but the inversion technique described by Oesch[73] has simplified short saphenous stripping and has corrected the problem of sural nerve injury. That injury was found to be associated with an ankle incision and exposure of the short saphenous vein posterior to the lateral malleolus. In any event, imaging of the saphenopopliteal junction must be carried out, and, increasingly, duplex scans are favored rather than the intraoperative films advocated by Hobbs.[74] When varicose veins are simply huge or if operations are done for varicose veins of the Klippel-Trenaunay syndrome, an Esmarch tourniquet is used to exsanguinate the limb and an orthopedic tourniquet inflated to 250 mmHg is utilized. Interestingly, the orthopedic tourniquet will not only allow the passage of the saphenous vein intraluminal stripper, but also the stripping can be done while the tourniquet is inflated. The use of the Esmarch exsanguination and proximal tourniquet markedly reduces blood loss and tidies up the performance of the operation. Distal phlebectomies can be done under direct vision without troublesome bleeding. In the United States, it is not routine to give deep venous thrombosis prophylaxis nor is any attention paid to the taking of oral contraceptive pills or hormone replacement therapy. How-
Figure 67-4. General principles of inversion stripping of the saphenous vein. Note the ligature that affixes the proximal end of the saphenous vein to the intraluminal stripper and the method of inversion of the saphenous vein. Artist’s license has made the incisions larger than they would be made in the patient. However, the principle of stripping is illustrated by the removal of communicating veins as well as perforating veins by groin-to-knee stripping. Note the relationships of the perforating veins to the posterior arch circulation.
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ever, in England and on the European continent, very often prophylaxis for deep venous thrombosis is employed, using either subcutaneous unfractionated heparin 5000 units twice a day or the equivalent fractionated heparin dose. Our practice is to avoid hospitalization of the patients. Many surgeons have taken up the techniques developed by dermatologists as these colleagues have provided surgeons with satisfactory instrumentation, which minimizes the size of the incisions. In particular, the Muller hooks are of value, as are the Varaday dissectors.[75] Targets of surgical phlebectomy are major varices fed by refluxing perforating veins as well as reticular veins which nourish telangiectasias. The extraction of these veins is performed through minimal skin incisions, 1–3 mm, or even puncture with a No. 18 needle. Definitive removal of the veins is far more successful than sclerotherapy, and dermatologic ambulatory phlebectomy has proven itself to be complementary to stripping of the greater saphenous vein and its tributary varices.
MODERN SAPHENOUS ABLATION Prolonged exposure to high-frequency alternating current [radiofrequency (RF)] energy results in total loss of vessel wall architecture, disintegration, and carbonization. [76] Application of this knowledge has allowed treatment of the greater saphenous vein by intraluminal techniques.[77] The preliminary results obtained in 389 patients treated with RF energy were clouded by third-degree burns of the skin, saphenous nerve injury, periphlebitis, peroneal nerve injury, and wound infection.[78] Elimination of saphenous vein reflux is done using RF heating.[79] The VNUS vein treatment system utilizing the Closurew catheter (VNUS Medical Technologies, Sunnyvale, California) is the most used system in this country and in Western Europe. This system uses electrodes specifically designed for treatment of the saphenous vein and includes monitoring of electrical and thermal effects of the catheter. Clinically, the device produces precise tissue destruction with minimal formation of thrombus. Bipolar electrodes are used to heat the vein wall. The net effect is venous spasm and collagen shrinkage, which produces maximal physical contraction. In practice, elimination of venous flow is accomplished by Esmarch bandaging and proximal saphenofemoral junction compression. Saphenous vein ablation has been performed using intravenous sedation and tumescent anesthesia alone[80] and with general anesthesia[81] with and without proximal saphenofemoral ligation.[82] Acute closure has been achieved in 93% of 141 saphenous veins in the first large series to be reported[83] and 1-year continued closure exceeds 90% with only a small fraction of the original anatomic failures requiring retreatment.[84] Surgical series have shown that undesirable outcomes after saphenous stripping are evident quite early.[85] It is acknowledged that surgical stripping results in recurrent truncal vein reflux in 20% of limbs[86] and that 73% of limbs destined for recurrent varicosities at 5 years have already done so at 1 year.[87] Thus, the 1-year results of VNUS Closure seem destined to be comparable to stripping in the long term.
Goldman, who has taken the lead in endovenous closure in our office, uses large amounts of tumescent anesthesia containing 0.1% lidocaine with epinephrine.[88] Intraoperative ultrasound monitoring ensures that the greater saphenous vein is separated from the skin by the tumescent anesthesia, thus avoiding skin burns. Performing endovenous obliteration of the saphenous vein without dissection of the saphenofemoral junction violates a cardinal rule in saphenous vein surgery. This holds that each of the tributaries must be individually divided. It is advocated by some that each of the tributaries should be dissected back beyond their primary and even secondary tributaries.[89] Careful duplex evaluation of saphenous obliteration by Pichot has revealed marked shrinking and obliteration of the saphenous vein itself but with preservation of tributaries to the saphenofemoral junction.[90] A discussion of this point occurred at the annual meeting of the American Venous Forum in February 2000.[91] Sixty limbs treated with saphenofemoral junction ligation and division of tributaries were compared to 120 limbs treated without high ligation. Of the 49 high ligation limbs followed a sufficient length of time, 2% developed recurrent reflux by 6 months and in the 97 non –high ligation limbs followed for that length of time, 8% developed recurrent reflux 9 ð p ¼ n:s:Þ: In limbs followed to 12 months, no new instances of reflux developed. Actuarial recurrence curves were not different with or without saphenofemoral ligation, and the experience predicted a greater than 90% freedom from recurrent reflux and varicosities at 1 year for both groups. The issue is not settled, but it is acknowledged that should a tributary develop reflux and prove to be a source of recurrent varicosities, the problem can be managed without further surgery by using sclerotherapy. Many surgeons would prefer ambulatory phlebectomy at this point, but in either event the problem is not a major deterrent to use of endovascular saphenous vein obliteration by radiofrequency energy without saphenofemoral ligation.
SCLEROTHERAPY Sclerotherapy is an integral part of treatment of venous insufficiency and should not be regarded as a substitute for surgery but instead as supplemental. Virtually any vein can be sclerosed, but recanalization is the rule in large veins that may be the target of venous hypertension. Before sclerotherapy is initiated, all sites of reflux from the deep venous system into the superficial varicosities should be divided. This implies that the major named perforating veins referred to elsewhere should not be the source of reflux, nor should the saphenofemoral or saphenopopliteal junctions be refluxing. Sclerosing agents themselves have the ability to denature biologic molecules within the vein wall. Their full categorization, chemical structure, and biologic activity is described elsewhere.[92] It is commonly and erroneously thought that the result or objective of satisfactory sclerotherapy is formation of an intravascular thrombus. In fact, the opposite is true. Such thrombosis increases the likelihood of superficial thrombophlebitis and recanalization of the treated vein.
Chapter 67.
Etiology and Surgical Management of Varicose Veins
General principles guiding successful sclerotherapy include the fact that it is essential that the vein be empty of blood as the sclerosant is injected. Usually the extremity in a horizontal position achieves nearly complete emptying of superficial veins. If the needle is inserted while the limb is dependent, the vein is more distended and easier to cannulate. However, before injection the limb should once again be horizontal or perhaps elevated 5 – 30 degrees. The second general principle is that no more than 0.5 –1 mL of sclerosant per injection site should be used.[93,94] For sodium tetradecyl sulfate and sodium morrhuate, the concentration of such solution should range from 0.25 –0.5%. Admittedly, higher concentrations and larger volumes are required for varicosities greater than 3 mm in diameter. However, moderate sclerotherapy limits this technique to vessels of smaller diameter. The maximum quantity to be used in any one treatment session should be equivalent to 10 –15 mL of 1% solution, depending on the patient’s body weight. The third general principle in the practice of successful sclerotherapy is compression. The importance of such compression was recognized as early as the 1930s by some.[95,96] External compression attempts to prevent the return of blood into the vein lumen. The duration and degree of compression depends on the size of the varicosity, with compression of telangiectasias and reticular varicosities requiring only a few hours and, conversely, up to 6 – 8 weeks for very large varicosities. Clearly, large varicosities with great intramural pressures require longer durations of compression, but it is exactly these veins which can best be removed by ambulatory phlebectomy. Compression is easily achieved by application of gradient compression, 30 –40 mmHg, at the ankle. If sclerotherapy is considered an adjunct to surgery, success is to be expected.
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Sources of gravitational reflux should be attended to by surgery. Sources of hydrodynamic pressure from muscular compartments should be dealt with surgically and large varicosities removed. This will leave telangiectasias and reticular varicosities smaller than 3 mm for subsequent sclerotherapy. It is exactly these targets that are most susceptible to sclerotherapy.
DUPLEX-GUIDED SCLEROTHERAPY Duplex-guided sclerotherapy continues to be practiced even into the present century[97 – 99], but long-term studies have failed to prove that it is advantageous as compared to either high ligation alone, high ligation with sclerotherapy, or sclerotherapy alone. More recent attempts to place the sclerosant solution through an intravenous catheter have been reported.[100] This maneuver adds interventional radiologists to the list of people who care for venous disorders. This technique mirrors experience obtained in the 1950s when surgical placement of the catheter and injection of sclerosant was practiced with disastrous results.[101] A 10-year report comparing endovascular saphenous sclerotherapy with surgical ligation of the saphenofemoral junction and surgical ligation of the saphenofemoral junction plus sclerotherapy has revealed the superior results of surgery and the inferior results of sclerotherapy.[102] Even though sclerotherapy produced 18.8% failure of control of saphenofemoral junction incompetence and 43.8% failure of obliteration of distal saphenous reflux, the conclusion of this paper was that endovascular sclerotherapy is an effective, cheaper treatment option.[103]
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Content. Eur. J. Vasc. Endovasc. Surg. 1996, 11, 230–237. Gradman, W.S.; Segalowitz, J.; Grundfest, W. Venoscopy in Varicose Vein Surgery: Initial Experience. Phlebology 1993, 8, 145– 150. Van Cleef, J.F.; Desvaux, P.; Hugentobler, J.P.; et al. Endoscopic Veincuse. J. Mal. Vasc. (Paris) 1991, 16, 184–187. Van Cleef, J.F.; Desvaux, P.; Hugentobler, J.P.; et al. E´tude Endoscopique des Reflux Valvulaires Saphe´niens. J. Mal. Vasc. (Paris) 1992, 17, 113– 116. Van Cleef, J.F. A Vein Has a Preferential Axis of Flattening. J. Dermatol. Surg. Oncol. 1993, 19, 468 – 470. Takase, S.; Schmid-Scho¨nbein, G.W.; Bergan, J.J. Expression of Adhesion Molecules and Cytokines on Saphenous Veins in Chronic Venous Insufficiency. Ann. Vasc. Surg. 2000, 14, 427– 435. Ono, T.; Bergan, J.J.; Schmid-Scho¨nbein, G.W.; Takase, S. Monocyte Infiltration into Venous Valves. J. Vasc. Surg. 1998, 27, 158– 166. Sugarman, H.J.; Windsor, A.; Bessos, M.; Wolfe, L. Intraabdominal Pressure, Sagittal Abdominal Diameter and Obesity Comorbidity. J. Intern. Med. 1997, 241, 71– 79. Krijnen, R.M.A.; de Boer, E.M.; Ader, H.J.; Bruynzeel, D.P. Venous Insufficiency in Male Workers with a Standing Profession: Epidemiology. Dermatology 1997, 194, 111– 120. Labropoulos, N.; Delis, K.T.; Nicolaides, A.N. Venous Reflux in Symptom-Free Vascular Surgeons. J. Vasc. Surg. 1995, 22, 150– 154. Hartmann, B.R.; Drews, B.; Kayser, T. Physical Therapy Improves Venous Hemodynamics in Cases of Primary Varicosity: Results of a Controlled Study. Vasc. Surg. 1997, 48, 157– 162. Sarin, S.; Shields, D.A.; Farrah, J.; Scurr, J.H.; Coleridge Smith, P.D. Does Venous Function Deteriorate in Patients Waiting for Varicose Vein Surgery? J. Roy. Soc. Med. 1993, 86 (1), 21 – 23. Topper, J.N.; Cai, J.; Falb, D.; Gimbrone, M.A., Jr. Identification of Vascular Endothelial Genes Differentially Responsive to Fluid Mechanical Stimuli: Cyclooxygenase-2, Manganese Superoxide Dismutase, and Endothelial Cell Nitric Oxide Synthase Are Selectively Upregulated by Steady Laminar Shear Stress. Proc. Natl. Acad. Sci. U.S.A. 1996, 93, 10417 –10422. Bao, X.; Lu, C.; Frangos, J.A. Temporal Gradient in Shear But Not Steady Shear Stress Induces PDFG-A and MCP-1 Expression in Endothelial Cells: Role of NO, NF Kappa B and erg-1. Arterioscler. Thromb. Vasc. Biol. 1999, 19, 996–1003. Davies, P. Flow-Mediated Endothelial Mechanotransduction. Physiol. Rev. 1995, 75, 519–560. Moazzam, F.; DeLano, F.A.; Zweifach, B.W.; SchmidScho¨nbein, G.W. The Leukocyte Response to Fluid Stress. Proc. Natl. Acad. Sci. U.S.A. 1997, 94, 5338– 5343, For commentary see pp. 4825 – 4827. Faria, J.L.; Moraes, I.N. Histopathology of the Telangiectasia Associated with Varicose Veins. Dermatologica 1963, 127, 321– 329.
30. Moraes, I.N.; Puech-Leao, L.E.; Simoes, J.C.; Martins de Toledo, O.; Correa Netto, A. Microangiographic Study of Telangiectasias. J. Cardiovasc. Surg. 1962, 3, 415– 419. 31. Weiss, R.A.; Weiss, M.A.; Goldman, M.P. Physicians’ Negative Perception of Sclerotherapy for Venous Disorders: Review of a 7-Year Experience with Modern Sclerotherapy. South. Med. J. 1992, 85, 1101 – 1106. 32. Marshall, M. Besenreiser—Nicht nur ein Kosmetisches Problem. Duplexsonographische Befunde bei Besenreiservarikose. Perfusion 1996, 9, 285– 287. 33. Weiss, R.A.; Weiss, M.A. Resolution of Pain Associated with Varicose and Telangiectatic Leg Veins After Compression Sclerotherapy. Dermatol. Surg. 1990, 16, 333– 336. 34. Bergan, J.J. Management of External Hemorrhage from Varicose Veins. Vasc. Surg. 1997, 31, 413– 418. 35. Bishop, C.C.R.; Fronek, H.S.; Fronek, A.; Dilley, B.; Bernstein, E.F. Real-Time Duplex Scanning After Sclerotherapy of the Greater Saphenous Vein. J. Vasc. Surg. 1991, 14, 505– 510. 36. Ramelet, A.-A. La Phle´bectomie Ambulatoire Selon Muller: Technique, Avantages, De´savantages. J. Mal. Vasc. 1991, 16, 119– 122. 37. Sandager, G.; Williams, L.R.; McCarthy, W.R.; Flinn, W.R.; Yao, J.S.T. Assessment of Venous Valve Function by Duplex Scan. Bruit 1986, 10, 238– 241. 38. DePalma, R.G.; Hart, M.T.; Zanin, L.; Massarin, E.H. Physical Examination, Doppler Ultrasound and ColorFlow Duplex Scanning: Guides to Therapy for Primary Varicose Veins. Phlebology. 1993, 8, 7 – 11. 39. Thomson, H. The Surgical Anatomy of the Superficial and Perforating Veins of the Lower Limb. Ann. R. Coll. Surg. Engl. 1979, 61, 198– 203. 40. Zamboni, P. La Chirurgia Conservativa del Sistema Venoso Superficiale; Gruppo Editoriale Faenza Editrice: Faenza, 1996; 3 – 9. 41. Caggiati, A. Fascial Relationship of the Long Saphenous Vein. Circulation 1999, 100, 2547– 2549. 42. Caggiati, A. The Saphenous Compartments. Surg. Radiol. Anat. 1999, 21, 29– 34. 43. Shah, D.M.; Chang, B.B.; Leopold, P.W.; et al. The Anatomy of the Greater Saphenous Venous System. J. Vasc. Surg. 1986, 3, 273. 44. Stonebridge, P.A.; Chalmers, N.; Beggs, I.; Bradbury, A.W.; Ruckley, C.V. Recurrent Varicose Veins: A Varicographic Analysis Leading to a New Practical Classification. Br. J. Surg. 1995, 82, 60– 62. 45. Georgiev, M. The Preoperative Duplex Examination. Dermatol. Surg. 1998, 24, 433– 440. 46. Lofgren, K.A.; Ribisi, A.P.; Myers, T.T. An Evaluation of Stripping Versus Ligation for Varicose Veins. Arch. Surg. 1958, 76, 310– 316. 47. Larson, R.H.; Lofgren, E.D.; Myers, T.T.; Lofgren, K.A. Long-Term Results After Vein Surgery. Study of 1,000 Cases After Ten Years. Mayo. Clin. Proc. 1974, 49, 114– 117. 48. Woodyer, A.B.; Reddy, P.J.; Dormandy, J.A. Should We Strip the Long Saphenous Vein? John Libbey & Co.: London, 1986; 151 – 154.
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Etiology and Surgical Management of Varicose Veins
Woodyer, A.B.; Reddy, P.J.; Dormandy, J.A. Should We Strip the Long Saphenous Vein? Phlebology 1986, 1, 221– 224. Sarin, S.; Scurr, J.H.; Coleridge-Smith, P.D. Stripping of the Long Saphenous Vein in the Treatment of Primary Varicose Veins. Br. J. Surg. 1994, 81, 1455– 1458. Rutgers, P.H.; Kistlaar, P.J.E.H.M. Randomized Trial of Stripping Versus High Ligation Combined with Sclerotherapy in the Treatment of the Incompetent Greater Saphenous Vein. Am. J. Surg. 1994, 168, 311– 315. Jakobsen, B.H. The Value of Different Forms of Treatment for Varicose Veins. Br. J. Surg. 1979, 66, 182– 184. Neglen, P.; Einarsson, E.; Eklof, B. The Functional LongTerm Value of Different Types of Treatment for Saphenous Vein Incompetence. J. Cardiovasc. Surg. (Torino) 1993, 34, 295–301. Munn, S.R.; Morton, J.B.; MacBeth, W.A.A.G.; MeLeish, A.R. To Strip or Not to Strip the Long Saphenous Vein? A Varicose Veins Trial. Br. J. Surg. 1981, 68, 426– 428. Hammarsten, J.; Pedersen, P.; Cederlund, C-G.; Campanello, M. Long Saphenous Saving Surgery for Varicose Veins: A Long-Term Followup. Eur. J. Vasc. Surg. 1990, 4, 361– 364. Hammersten, J.; Campanello, M.; Pederson, P. Long Saphenous Vein-Saving Surgery for Varicose Veins [Letter/Comment]. Eur. J. Vasc. Surg. 1993, 7, 763– 764. Darke, S.G. Fewer Recurrences with Stripping. (Letter). Eur. J. Vasc. Surg. 1993, 7, 764. Rutherford, R.B.; Sawyer, J.D.; Jones, D.N. The Fate of Residual Saphenous Vein After Partial Removal or Ligation. J. Vasc. Surg. 1990, 12, 422– 428. Friedell, M.L.; Samson, R.H.; Cohen, M.J.; et al. High Ligation of the Greater Saphenous Vein for Treatment of Lower Extremity Varicosities: The Fate of the Vein and Therapeutic Results. Ann. Vasc. Surg. 1992, 6, 5 – 8. Fligelstone, L.; Carolan, G.; Pugh, N.; Shandall, A.; Lane, I. An Assessment of the Long Saphenous Vein for Potential Use as a Vascular Conduit After Varicose Vein Surgery. J. Vasc. Surg. 1993, 18, 836– 840. McMullin, G.M.; Coleridge Smith, P.D.; Scurr, J.H. Objective Assessment of High Ligation Without Stripping the Long Saphenous Vein. Br. J. Surg. 1991, 78, 1139– 1142. Thomson, W.H.F. Recurrent Varicose Veins: A National Problem. Br. J. Surg. 1994, 81, 150. Thibault, P.K.; Lewis, W.A. Recurrent Varicose Veins: Evaluation Utilizing Duplex Venous Imaging. J. Dermatol. Surg. Oncol. 1992, 18, 618– 624. Redwood, N.F.W.; Lambert, D. Patterns of Reflux in Recurrent Varicose Veins Assessed by Duplex Scanning. Br. J. Surg. 1994, 81, 1450– 1451. Quigley, F.G.; Raptis, S.; Cashman, M. Duplex Ultrasonography of Recurrent Varicose Veins. Cardiovasc. Surg. 1994, 2, 775– 777. Bradbury, A.W.; Stonebridge, P.A.; Callam, M.J.; Walter, A.J.; Beggs, A.I.; Ruckley, C.V. Recurrent Varicose Veins: Assessment of the Saphenofemoral Junction. Br. J. Surg. 1994, 81, 373– 375. Fligelston, L.; Carolan, G.; Pugh, N.; Minst, P.; Shandall, A.; Lane, I. An Assessment of the Long Saphenous Vein
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for Potential Use as a Vascular Conduit After Varicose Vein Surgery. J. Vasc. Surg. 1993, 18, 836– 840. McMullin, G.M.; Coleridge Smith, P.D.; Scurr, J.H. Objective Assessment of High Ligation Without Stripping the Long Saphenous Vein. Br. J. Surg. 1991, 78, 1139– 1142. Munn, S.R.; Morton, J.B.; MacBeth, W.A.A.G.; McLeish, A.R. To Strip or Not to Strip the Long Saphenous Vein? A Varicose Veins Trial. Br. J. Surg. 1981, 68, 426– 428. Fitridge, R.A.; Fronck, H.S.; Dilley, R.B.; Bernstein, E.F.; Benveniste, G.L. Assessment of Reflux in the Greater Saphenous Vein (GSV) Two Years Following High Ligation. Cardiovasc. Surg. 1995, 3, 71. Papadakis, K.; Christodoulou, C.; Christopoulos, D.; et al. Number and Anatomical Distribution of Incompetent Thigh Perforating Veins. Br. J. Surg. 1989, 76, 581 – 584. Bergan, J.J. Common Anatomic Patterns of Varicose Veins. In Varicose Veins and Telangiectasias: Diagnosis and Management; Bergan, J.J., Goldman, M.P., Eds.; Quality Medical Publishing: St. Louis, 1993. Oesch, A. Pin Stripping: A Novel Method of Atraumatic Stripping. Phlebology 1993, 8, 171– 173. Hobbs, J.T. Perioperative Venography to Ensure Accurate Saphenopopliteal Ligation. Br. Med. J. 1980, 2, 1578. DeRoos, K.P.; Neumann, H.A.M. Muller’s Ambulatory Phlebectomy for Varicose Veins of the Foot. Dermatol. Surg. 1998, 465– 470. Sigel, B.; Dunn, M.R. The Mechanism of Blood Vessel Closure by High-Frequency Electrocoagulation. Surg. Gynecol. Obstet. 1965, 823– 831. Politowski, M.; Szpak, E.; Marszalek, Z. Varices of the Lower Extremities Treated by Electrocoagulation. Surgery 1964, 355– 360. Politowski, M.; Zelazny, T. Complications and Difficulties in Electrocoagulation of Varices of the Lower Extremities. Surgery 1966, 59, 932– 934. Weiss, R.A.; Goldman, M.P. Controlled RF-Mediated Endovenous Shrinkage and Occlusion. In Varicose Veins & Telangiectasias: Diagnosis and Management, 2nd Ed.; Goldman, M.P., Weiss, R.A., Bergan, J.J., Eds.; Quality Medical Publishing, Inc.: St. Louis, Missouri, 1999. Goldman, M.P. Closure of the Greater Saphenous Vein with Endoluminal Radiofrequency Thermal Heating of the Vein Wall in Combination with Ambulatory Phlebectomy: Preliminary 6-Month Followup. Dermatol. Surg. 2000, 26, 105. Chandler, J.G.; Pichot, O.; Sessa, C.; Schuller-Petrovic, S.; Kabnick, L.S.; Bergan, J.J. Treatment of Primary Venous Insufficiency by Endovenous Saphenous Vein Obliteration. Vasc. Surg. 2000, 34, 201– 214. Whiteley, M.S.; Pichot, O.; Sessa, C.; Kabnick, L.S.; Schuler-Petrovic, S.; Chandler, J.G. Endovenous Obliteration: An Effective, Minimally Invasive Surrogate for Saphenous Vein Stripping. J. Endovasc. Surg. 2000, 7, 11–17. Manfrini, S.; Gasbarro, V.; Danielsson, G.; et al. Endovenous Management of Saphenous Vein Reflux. J. Vasc. Surg. 2000, 32, 330– 342. Chandler, J.G., Personal Communication.
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Sarin, S.; Scurr, J.H.; Coleridge Smith, P.D. Assessment of Stripping the Long Saphenous Vein in the Treatment of Primary Varicose Veins. Br. J. Surg. 1992, 79, 889– 893. Dwerryhouse, S.; Davies, B.; Harradine, K.; Earnshaw, J.J. Stripping the Long Saphenous Vein Reduces the Rate of Reoperation for Recurrent Varicose Veins: Five-Year Results of a Randomized Trial. J. Vasc. Surg. 1999, 29, 589–592. Jones, L.; Braithwaite, B.D.; Selwyn, D.; Cooke, S.; Earnshaw, J.J. Neovascularization Is the Principal Cause of Varicose Vein Recurrence: Results of a Randomized Trial of Stripping the Long Saphenous Vein. Eur. J. Vasc. Endovasc. Surg. 1996, 12, 442– 445. Goldman, M.P. Closure of the Greater Saphenous Vein with Endoluminal Radiofrequency Thermal Heating of the Vein Wall in Combination with Ambulatory Phlebectomy: Preliminary 6-Month Followup. Dermatol. Surg. 1998 2000, 26, 452–456. Bergan, J.J. Saphenous Vein Stripping by Inversion: Current Technique. Surg. Rounds 2000, 118– 124. Pichot, O.; Sessa, C.; Chandler, J.G.; Nuta, M.; Perrin, M. Role of Duplex Imaging in Endovenous Obliteration for Primary Venous Insufficiency. J. Endovasc. Ther. 2000, 7, 451–459. Chandler, J.G.; Pichot, O.; Sessa, C.; Schuller-Petrovic, S.; Osse, F.J.; Bergan, J.J. Defining the Role of Extended Saphenofemoral Junction Ligation: A Prospective Comparative Study. J. Vasc. Surg. 2000, 32, 941– 953. Goldman, M.P. Sclerotherapy: Treatment of Varicose and Telangiectatic Leg Veins. Mosby Year Book: St. Louis, 1991; 183. Fegan, W.G. Continuous Compression Technique of Injecting Varicose Veins. Lancet 1963, 2, 109–112. Sigg, K. Treatment of Varicosities and Accompanying Complications (Ambulatory Treatment of Phlebitis
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with Compression Bandage). Angiology 1952, 3, 355 – 379. deTakats, G. The Injection Treatment of Varicose Veins. Surg. Gynecol Obstet. 1930, 50, 545– 561. deTakats, G. Causes of Failure in the Treatment of Varicose Veins. J. Am. Med. Assoc. 1931, 96, 1111– 1114. Cornu-Thenard, A.; de Cottreau, H.; Weiss, R.A. Sclerotherapy. Continuous-Wave Doppler-Guided Injections. Dermatol. Surg. 1995, 21, 867– 870. Kanter, A. Clinical Determinants of Ultrasound-Guided Sclerotherapy Outcome. Part I: The Effects of Age, Gender, and Vein Size. Dermatol. Surg. 1998, 24, 131–135. Kanter, A. Clinical Determinants of UltrasoundGuided Sclerotherapy Outcome. Part II: The Search of the Ideal Injectate Volume. Dermatol. Surg. 1998, 24, 136 – 140. Min, R.J.; Navarro, L. Transcatheter Duplex UltrasoundGuided Sclerotherapy for Treatment of Greater Saphenous Vein Reflux: A Preliminary Report. Dermatol Surg. 2000, 26, 410– 414. DePalma, R.G.; Rose, S.S.; Bergan, J.J. Treatment of Varicosities of Saphenous Origin: A Dialogue. In Varicose Veins & Telangiectasias: Diagnosis and Management, 2nd Ed.; Goldman, M.P., Weiss, R.A., Bergan, J.J., Eds.; Quality Medical Publishing: St. Louis, 1999; 193–225. McPheeters, H.O. Saphenofemoral Ligation with the Immediate Retrograde Injection. Surg. Gynecol. Obstet. 1945, 81, 355– 364. Belcaro, G.; Nicolaides, A.N.; Ricci, A.; Dugall, M.; Errichi, B.M.; Vasdekis, S.; Christopoulos, D. Endovascular Sclerotherapy, Surgery, and Surgery Plus Sclerotherapy for Superficial Venous Incompetence: A Randomized 10-Year Followup Trial: Final Results. Angiology. 2000, 5, 529–534.
CHAPTER 68
Deep Vein Thrombosis: Prevention and Management Lazar J. Greenfield Mary C. Proctor with venous thrombosis have not been successful. [5] However, in 1962, Seeger and Marciniak[6] identified a naturally occurring inhibitor of activated factor X which was subsequently named antithrombin III. The subsequent finding of a congenital deficiency of this substance in a small group of patients was correlated with a strong predisposition to the development of venous thrombosis.[7] More recent work has demonstrated an association between an inherited mutation of factor V (factor V Leiden) and activated protein C resistance leading to increased risk of initial and recurrent DVT.[8,9] In addition to these inherited risk factors, several diseasespecific conditions have been associated with increased evidence of DVT, including malignancy, certain types of trauma, and sepsis.[10 – 12] Besides these factors, which possess strong biological validity, several other risk factors were suggested from the early epidemiologic work by Coon.[13,14] However, much is unknown regarding these factors, and prospective studies are urgently needed.
Deep vein thrombosis (DVT) is a serious and potentially lifethreatening disorder. The magnitude of the problem is suggested by the fact that an estimated 180,000 –250,000 patients per year are diagnosed clinically as having deep vein thrombosis, while twice this number may suffer from venous stasis ulcers and as many as 7 million may have lower extremity stasis changes and edema on a chronic basis. In addition to the disability associated with the postthrombotic syndrome, the mortality from the most serious complication of deep vein thrombosis, pulmonary thromboembolism, has been estimated to be in the range of 200,000 deaths per year in which it is either the sole cause or a major contributing factor.[1,2] The frequency of deep vein thrombosis itself is difficult to determine since it may remain clinically silent or may be misdiagnosed when nonspecific lower extremity signs and symptoms are present. Using the very sensitive 125I-labeled fibrinogen scanning test in a series of unselected general surgical patients, Kakkar et al.[3] found that 30% of them developed positive scans in the calf in the postoperative period. The diagnosis was confirmed by venography, and in 35% of them the abnormality disappeared within 72 h. In 23% there was propagation of the thrombus into more proximal veins, and in half of these patients pulmonary thromboembolism occurred. The consequences of untreated deep vein thrombosis, then, are sufficiently serious to warrant aggressive diagnosis and management.
ETIOLOGY AND PATHOPHYSIOLOGY In surgical patients, stasis is probably the most important predisposing factor, since there is a significant reduction in lower extremity venous flow following induction of general anesthesia, which persists throughout the procedure. There is also a relationship between the duration of bed rest and the incidence of venous thrombosis, which provides the stimulus for early ambulation. Vessel wall injury also can occur in collapsed vessels when the intimal walls are in contact, and some intimal injury can be demonstrated after hypoxemia. Current work by Wakefield et al. has characterized the role of inflammation in the development and resolution of thromboembolism, demonstrating a beneficial effect from neutralizing antibodies to local cytokines and adhesion molecules.[15] Ultrastructural study shows leukocytic attachment between endothelial intercellular junctions in areas of venous stasis alter trauma at a remote site. These changes can become the nidus for the formation of a propagating
HISTORICAL PERSPECTIVE Our present knowledge of the causes of deep vein thrombosis and its relationship to pulmonary thromboembolism can be traced to the early work of Virchow,[4] who in 1856 introduced the term thrombosis and suggested three possible mechanisms which remain the foundation of our approach to the etiology of the disorder: stasis, hypercoagulability, and endothelial damage. Despite years of investigation, efforts to identify a common coagulation factor abnormality in patients
Hobson/Wilson/Veith: Vascular Surgery: Principles and Practice, Third Edition, Revised and Expanded DOI: 10.1081/0819-9-120024952 Copyright q 2004 by Marcel Dekker, Inc.
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thrombus. Once a nidus of thrombus begins in the presence of stasis, the substances that promote platelet aggregation, including activated factor X, thrombin, fibrin, and catecholamines, remain at high concentration in that area. Opposing this process is the fibrinolytic system of the blood and vein walls. The endothelium of the vein wall contains an activator that converts plasminogen into plasmin, which lyses fibrin. As might be expected, however, the fibrinolytic system is inhibited after surgery and trauma, and there is also less activity in the veins of the lower extremity than in the upper extremity. When contrast medium is injected in supine, immobilized patients, it may remain in venous valve sinuses for as long as 1 h, confirming the stasis that exists in the soleal veins. This is the favored location for the formation of a nidus of thrombus as described. Successive layering of platelets, fibrin, red cells, and leukocytes produces an organized white thrombus, which is more adherent to the vein wall than the propagating red thrombus, which extends into the venous stream (Fig. 68-1). The latter free-floating thrombus is more likely to cause symptoms and more likely to result in embolism. If the original thrombus becomes attached circumferentially, it causes interruption of flow, retrograde thrombosis, and signs of venous stasis in the extremity. Subsequent edema
formation within the confines of the deep fascia produces pain and a characteristic Homans’ sign elicited by forcible dorsiflexion of the foot, although the latter is a nonspecific and unreliable indicator of the disorder. The site of venous obstruction determines the level at which swelling is observed clinically. Swelling at the thigh level always implies obstruction at the level of the iliofemoral system, while swelling of the calf or foot suggests obstruction at the level of the iliofemoral system, while swelling of the calf or foot suggests obstruction at the femoropopliteal level. Autopsies suggest that it is more common for thrombi to originate in the soleus veins and then propagate proximally, but there is also evidence of primary thrombosis of femoral and iliac venous tributaries. Resolution of deep vein thrombosis with recanalization will affect the competence of the valves within the veins and can result in the postthrombotic syndrome, as discussed in Chap. 69. Complete spontaneous lysis of large thrombi is relatively uncommon, and even when patients are treated adequately with heparin to prevent further thrombosis, complete lysis occurs in less than 20% of cases. It seems likely that complete dissolution of small asymptomatic calfvein thrombi is a more common occurrence, but the actual frequency is unknown.
Figure 68-1. Venous thrombosis begins when stagnant flow permits platelets to sit in a valvular sinus, forming a nidus of thrombus. The cycle of fibrin retraction and thrombin release aggregates more platelets as the thrombus either propagates upstream without occulsion or occludes the vein with retrograde thrombosis. [By permission of Hardy J (ed): Hardy’s Textbook of Surgery, Philadelphia, Lippincott, 1983, p. 971.]
Chapter 68.
Deep Vein Thrombosis: Prevention and Management
DIAGNOSIS Major venous thrombosis involving the deep venous system of the thigh and pelvis produces a characteristic clinical picture of pain, extensive pitting edema, and blanching that has been termed phlegmasia alba dolens, or “milk leg.” Association with pregnancy may relate to hormonal effects on blood, relaxation of vessel walls, or mechanical compression of the left iliac vein at the pelvic brim, resulting in the term “milk leg of pregnancy.” It was originally believed that the blanching was caused by spasm and compromise of arterial flow, but arteriograms fail to confirm this, and efforts to achieve sympatholysis to overcome “vasospasm” are illadvised, since it is usually the subcutaneous edema that is responsible for the blanching. In addition to pregnancy, other mechanical factors that can affect the left iliac vein include compression from the iliac artery or an overdistended bladder and congenital webs within the vein. These factors are responsible for the observed 4:1 preponderance of left versus right iliac vein involvement. With further progression of venous thrombosis to impede most of the venous return from the extremity, there is a danger of limb loss from cessation of arterial flow. The clinical picture is characteristic, with sufficient congestion to produce phlegmasia cerulea dolens, or a painful blue leg. With the loss of sensory or motor function, the diagnosis can be made on clinical grounds and treatment started. Venous gangrene is likely unless an aggressive approach is utilized to remove the thrombus by open thrombectomy and to restore blood flow. A variant of this disorder associated with malignant disease occurs peripherally in the leg and has a high mortality rate. As indicated earlier, these major complications represent less than 10% of the patients with venous thrombosis. In fact, only 40% of patients with venous thrombosis have any clinical signs of the disorder. In addition, false-positive clinical signs occur in up to 50% of patients studied.[16] Because of this there has been a great deal of interest in the development of screening tests that could reveal thrombi before they became evident clinically. Of course, contrast venography provides direct evidence of both occlusive and nonocclusive thrombi, but it is invasive and requires the patient to move to a radiography suite. Venography is also impossible to perform in up to 10% of patients, and the results are subject to a high degree of interobserver disagreement. Ideally, the screening test would be accurate, noninvasive, and performed at the bedside. Although the ideal has not been achieved, a number of tests have proved useful, as documented more completely in Chap. 9.
Ultrasound In the majority of U.S. medical centers, ultrasound has replaced venography as the method of choice for diagnosing deep venous thrombosis. While it is known to be sensitive and specific in diagnosing symptomatic DVT, evidence is now accumulating to suggest that with the addition of color flow Doppler, it can identify asymptomatic proximal deep vein thrombosis. Gruen et al. showed that the negative predictive value of duplex is greater than venography.[17] Cronan and
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Dorfman found a sensitivity of 93% and specificity of 99% in a venographically controlled study.[18] Color flow technology provides a two-dimensional image that improves visualization of augmentation, distinguishes artery from vein, and aids in identification of nonocclusive thrombus.[19] Baxter et al. reported the sensitivity and specificity to be 90% even in asymptomatic patients.[20] Table 68-1 demonstrates the sensitivities and specificities as reported in the literature. The criteria for determining a positive scan are lack of vein compressibility and presence of visible thrombus. If either of these conditions is present, the scan is positive. An abnormal Doppler signal, absence of flow phasicity, or evidence of echogenic thrombus provides supporting data but is not sufficient to consider the scan positive. They are considered equivocal and require a repeat of the scan in 3 days. Absence of all criteria is considered a negative scan. By applying these criteria, well-trained technologists doing frequent studies should be able to obtain high levels of sensitivity and specificity. The ability to repeat the testing at the bedside is one of its major advantages.
Impedance Plethysmography The impedance plethysmography (IPG) method measures the volume response of the extremity to temporary occlusion of the venous system. The diagnosis of venous thrombosis depends on the changes in venous capacitance and rate of emptying after release of the occlusion. A proximal thigh cuff is inflated to 40 –50 mmHg pressure for 50–120 s or until maximum filling has occurred by plateau of the electrical signal. The inflation cuff is then rapidly deflated, allowing rapid outflow and reduction of volume in a normal limb. Prolongation of the outflow wave suggests major venous thrombosis with 95% accuracy and is much more reliable than any voluntary technique of venous occlusion. The deficiency with this technique, as with all noninvasive methods, is in the detection of calf vein thrombosis or the definition of new pathology in patients with old thrombotic sequelae. The strain-gauge plethysmograph can be used in a similar fashion. A positive IPG test can be used to make therapeutic decisions in the absence of clinical conditions that can produce falsepositive tests such as cardiac failure, constrictive pericarditis, hypotension, arterial insufficiency, or external compression of Literature Review of Colorflow Duplex Asymptomatic Patients, 1992 –1995
Table 68-1.
Year
Site
Sensitivity (%)
Specificity (%)
1994 1994 1993 1992 1992 1995 1995
Distal Proximal Distal Limb Limb Limb Proximal Distal Distal
79 100 80 79 38 100 100 87.5 67
97 100 97 97 92 100 98.8 98.7 93
1995
Ref. 21 21 22 23 24 17 25 26
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veins. This test has largely been replaced by the duplex examination described above.
Radioactive-Labeled Fibrinogen Radioactive-labeled fibrinogen testing was frequently used as a screening method for DVT, especially in clinical studies, but was subject to a high false-positive rate. Recent concern regarding transmission of bloodborne diseases has resulted in the prohibition of this method in the United States.
Venography The injection of contrast material for direct visualization of the venous system of the extremity is the most accurate method of confirming the diagnosis of venous thrombosis and the extent of the involvement. Injection is usually made into the foot while the superficial veins are occluded by tourniquet. A supplementary injection into the femoral veins may be required to visualize the iliofemoral system. Both filling defects and nonvisualization can be found and provide an assessment of the threat of a thrombus such as one seen to be floating free and extending into the iliofemoral system (Fig. 68-2). Potential false-positive examinations may result from external compression of a vein or washout of the contrast material from collateral veins. The procedure can also be performed with isotope injection using a gamma scintillation counter to record flow of the isotope. Delayed imaging of persistent “hot spots” may also reflect isotope retention at the sites of thrombus formation. A perfusion lung scan can also be obtained for baseline comparison and to detect silent embolism. There is less definition of deep vein thrombi with this technique than with contrast venography, but it is a valuable technique for sequential study of patients and avoids the potential thrombogenesis of the injection of contrast medium.
Assay of Fibrin or Fibrinogen Products The degradation of intravascular fibrin can be detected by measuring the plasma products of the lysis of fibrin or fibrinogen. Both fibrinopeptide A and fibrin fragment 1 þ 2 can be detected by radioimmunoassay but are not specific for acute venous thrombosis. A negative test could conceivably have some value in excluding the diagnosis, but the tests are difficult and will require more investigation and simplification. The use of an ELISA test for d-dimer has shown some promise in ruling out thromboembolic states.[27 – 29] The evidence is that a negative d-dimer can safely exclude the diagnosis of thromboembolism, but a positive test requires further diagnostic studies.
PROPHYLAXIS The importance of thromboembolism prophylaxis cannot be overstated. As the length of hospitalizations is being reduced, any event that delays discharge assumes significance. The first step is to assess the patient’s risk. Broad guidelines have been
Figure 68-2. Contrast venogram shows a thrombus originating in a femoral vein tributary (screws ) and extending to the level of the groin (arrow ). Such a thrombus might well be asymptomatic. [By permission of Hardy J (ed): Hardy’s Textbook of Surgery, Philadelphia, Lippincott, 1983, p 972.]
defined by Consensus Conferences[30] and the American College of Chest Physicians (ACCP).[31] They provide categories of risk based upon medical condition, surgical intervention, length of operative time, and age. In addition to these factors, the patient’s individual characteristics need to be factored in, such as coexisting disease, mobility, inherited defects of coagulation, and prior history of DVT. Levels of intervention range from early ambulation and elastic stockings among those at low risk to combination therapy at the high end. Interventions include both mechanical and pharmacologic methods. Intermittent compression devices are effective in preventing DVT in patients undergoing major surgery or with neurologic injuries.[32 – 36] However, their effectiveness against pulmonary embolism (PE) has not been demonstrated. The foot pump has been studied in patients undergoing orthopedic procedures and has been shown to decrease DVT.[37] The major advantage of these devices is their ability to be used in patients at high risk of bleeding. Heparin has been a mainstay in prophylaxis of both DVT and PE. Standard unfractionated heparin given pre- and postoperatively or to medical patients significantly reduces the risk of thromboembolism. The newer low molecular weight heparins (LMWH) have also proved efficacious in prevention of DVT and PE. They are approved for use in both abdominal
Chapter 68.
Deep Vein Thrombosis: Prevention and Management
and orthopedic cases.[38 – 41] The use of warfarin as prophylaxis has been controversial. The potential for bleeding complications and the availability of other effective agents has[42 – 44] limited its use; however, new evidence based on clinical trial data has led the ACCP to reevaluate its position.
TREATMENT The approach to management of the patient with DVT is based on minimizing the risk of pulmonary embolism, limiting further thrombosis, and facilitating resolution of existing thrombi to avoid the postthrombotic syndrome. Routinely, the patient is placed at bed rest with the foot of the bed elevated 8–10 in. Generally, pain, swelling, and tenderness resolve over a 5- to 7-day period, at which time ambulation can be permitted with continued elastic stocking support. Standing still and sitting should be prohibited in order to avoid the increased venous pressure and stasis. Currently, some patients are being treated on an ambulatory basis. Compression stockings are worn while out of bed. These patients are treated with LMWH.[45 – 48]
Anticoagulation The foundation of therapy for DVT is adequate anticoagulation, initially with heparin and then with warfarin derivatives for prolonged protection against recurrent thrombosis. Unless there are specific contraindications, heparin should be administered in an initial dose of 100 – 150 units per kilogram intravenously. Heparin is an mucopolysaccharide that neutralizes thrombin, inhibits thromboplastin, and reduces the platelet release reaction. It should be administered by continuous intravenous infusion regulated by whole blood or partial thromboplastin clotting time. Bleeding complications can be minimized by doses of heparin that prolong the laboratory clotting determinations in the range of twice normal with no loss of effectiveness. Continuous intravenous infusion regulated by an infusion pump seems to minimize the total dose required for control and is associated with a lower incidence of complications. The use of LMWH provides the advantage of subcutaneous injection versus continuous intravenous infusion and offers predictable pharmacokinetic dosing, which eliminates the need for continuous laboratory monitoring. The side effects associated with heparin treatment include bleeding, thrombocytopenia, hypersensitivity, arterial thromboembolism, and osteoporosis. Bleeding is more likely to occur in elderly females, in patients treated with aspirin, or in patients who have had recent surgery or trauma. It has been well demonstrated that bleeding can occur when the results of laboratory monitoring tests are within the therapeutic range, which may be because of its effect on platelets. The adverse event profile of LMWH is similar to that of UFH. In some cases the risk of bleeding has been less with LMWH, but these reports have not been supported by strong clinical trials. Evidence is still being gathered regarding the association between LMWH and osteoporosis. For the most part, patients who have developed thrombocytopenia on unfractionated
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Heparin will cross-react with LMWH. For these patients, a new class of anticoagulants, heparinoids, have proved useful.[49,50] Arterial thromboembolism can complicate heparin administration by any route and is more common in the elderly. It tends to occur after 7–10 days of therapy and is associated with thrombocytopenia. This complication carries a high morbidity and mortality rate and requires immediate cessation of heparin treatment. Thrombocytopenia as a complication is caused by an immune reaction but is rapidly reversed when heparin is stopped, usually within 2 days. Hypersensitivity to heparin may take the form of a skin rash or, rarely, may produce anaphylaxis. Subcutaneous injections which show urticaria may become necrotic as an unusual form of sensitivity. Osteoporosis has been seen in patients on longterm heparin therapy in excess of 6 months. This is probably caused by a direct effect on bone resorption and can be avoided by shorter periods of treatment and dosage less than 15,000 units per day. Oral administration of anticoagulants is begun shortly after initiation of heparin therapy, since several days usually are required to bring the international normalized rates (INR) within the therapeutic range of 2.0–3.0 times the control value and to provide the maximal antithrombotic effect. The warfarin derivatives block the synthesis of several clotting factors, and prolongation of the prothrombin time beyond the range suggested is associated with an increased incidence of bleeding complications. The nonhemorrhagic side effects are uncommon but include skin necrosis, dermatitis, and a syndrome of painful blue toes. Skin necrosis is heralded by painful erythema in areas of large amounts of subcutaneous fat and is reversible if the drug is stopped. Fortunately, the administration of plasma usually can restore the prothrombin time rapidly. After an episode of acute DVT, anticoagulation should be maintained for a minimum of 3 months; some investigators favor 6 months for thrombi in the larger veins. There are many drugs, such as barbiturates, that interact with the warfarin derivatives, and therefore a routine for regular monitoring of prothrombin time is essential after the patient leaves the hospital. Oral anticoagulants are teratogenic and should not be used during established or planned pregnancy. In the pregnant patient, heparin is the drug of choice, and for longterm management, subcutaneous self-administration should be taught. This regimen allows a normal delivery and can be continued postpartum.
Fibrinolysis In spite of great interest in the use of fibrinolytic agents to activate the intrinsic plasmin system, the results of randomized studies have been disappointing. Both streptokinase and urokinase have been used and found to be effective, although they are associated with an incidence of 25 –30% of hemorrhagic complications and fever.[51] In 10% of patients, streptokinase is also associated with allergic reactions, which vary from urticaria to anaphylaxis and can produce an adult respiratory distress syndrome.[52] In addition, fibrinolytic agents have no advantage over heparin in the treatment of recurrent venous thrombosis or when thrombosis has existed
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for over 72 h, and the lytic agents are contraindicated in the postoperative or posttraumatic patient. Catheter-directed thrombolysis has been used to deliver urokinase directly to the thrombus and lower the risk of systemic bleeding. Outcomes for patients treated in this manner are being collected into a venous registry. The findings should shed light on the cost-effectiveness of this intervention.
Surgical Approaches Operative Thrombectomy A direct surgical approach to remove thrombi from the deep veins of the leg via the common femoral vein has been employed and facilitated by the use of Fogarty venous balloon catheters and an elastic wrap for milking the distal extremity. Although the operative results are impressive, venograms obtained prior to discharge from the hospital show rethrombosis in the majority of patients, and there does not seem to be any lesser incidence of the postthrombotic syndrome. The procedure is usually reserved for limb salvage in the presence of phlegmasia cerulea dolens and impending venous gangrene. A modification of this technique involving the addition of an arteriovenous fistula has increased the long-term patency of the proximal vein.[53] Einarsson et al. reported good results with 61% of segments patent on venograms and normal venous pressure in 82% of cases despite some proximal stenosis.[54] Combination therapy involving thrombolysis and thrombectomy has been attempted in a limited number of patients.[55]
Vena Cava Interruption
Early surgical efforts to prevent recurrence of pulmonary embolism were directed to the common femoral vein, which was ligated bilaterally. This resulted in a high incidence of sequelae due to stasis in the lower extremity and an unacceptable rate of recurrent pulmonary embolism. The next approach was ligation of the inferior vena cava below the renal veins, which added the adverse effect of a sudden reduction in cardiac output. This effect, coupled with stasis sequelae and recurrent embolism through dilated collateral veins, led to efforts to compartmentalize the vena cava by means of sutures, staples, and external clips in order to provide filtration without occlusion. Since these procedures required general anesthesia and laparotomy, the next logical step was to devise a transvenous approach that could be performed under local anesthesia. The Mobin-Uddin “umbrella” unit was the first to be inserted from the jugular vein and positioned under fluoroscopy below the renal veins, where it usually produced thrombosis of the vena cava (70% of cases[56]) and is no longer used. The Greenfield cone-shaped filter was developed to maintain patency after trapping emboli and to permit continued flow to avoid stasis and facilitate lysis of the embolus (Fig. 68-3). It can be inserted from either the jugular vein or the femoral vein, the latter reserved for instances where there is an inadequate size of the jugular vein or an open wound of the neck.[57] The recurrent embolism rate with this device has been 2–4%, and its long-term patency rate of 98% allows it to be placed above the renal veins when necessary for embolism control such as when there is thrombus within the renal veins or vena cava (Fig. 68-4).[58] Advances in percutaneous radiographic techniques have led to many new filter devices designed to be inserted through smaller carrier systems. Among these devices are the Simon Nitinol filter, the VenaTech filter, and the Bird’s Nest filter. Each of these devices has been associated with
Adequate anticoagulation usually is effective in managing DVT, but if recurrent pulmonary embolism occurs during anticoagulant therapy or if there is a contraindication to anticoagulation, then a mechanical approach is necessary. Mechanical protection is also indicated as prophylaxis against recurrence of embolism for the patient who has required pulmonary embolectomy and in some high-risk patients who could not tolerate recurrence (Table 68-2). Table 68-2.
Indications for Insertion of a Vena Cava Filter
1. Recurrent thromboembolism despite adequate anticoagulation 2. Thromboembolism in a patient who has a contraindication to anticoagulation 3. Complication of anticoagulation forcing therapy to be discontinued 4. Chronic pulmonary embolism with associated pulmonary hypertension and cor pulmonale (class V patient) 5. Immediately following pulmonary embolectomy 6. Relative indications: Patient with more than 50% of the pulmonary vascular bed occluded (class III) who would not tolerate addditional embolism; patient with a large iliofemoral thrombus despite anticoagulation; septic embolism despite control of focus and antibiotics
Figure 68-3. The Greenfield filter is made of stainless steel and is cone-shaped to preserve flow after an embolus is trapped. Flow preservation provides continued filtration, minimizes stasis sequelae, and facilitates lysis of the trapped thrombus.
Chapter 68.
Deep Vein Thrombosis: Prevention and Management
Figure 68-4. Contrast study of the vena cava showing a large thrombus in the inferior vena cava. Control of this “widowmaker” thrombus requires placement of the Greenfield filter above the level of the first lumbar vertebrae.
device-specific problems. All appear to function well as a filter. The Nitinol design has a high rate of trapping, which results in more frequent caval occlusion relative to the other devices. It has also been associated with some limb fractures.[59] The VenaTech device has been associated with caval stenosis or obstruction. The cause of this occurrence remains under study.[60] The Bird’s Nest filter is the only device approved for use in vena cavas larger than 28 mm. However, there are problems with wire prolapse, it is difficult to place relative to the other devices, and it requires a longer segment of the cava for adequate deployment.[61] The complications of filter insertion range in severity from minor wound hematomas caused by early resumption of anticoagulation to potentially lethal migration of the device into the pulmonary artery as documented with the Mobin-
969
Uddin umbrella. The most common complication with the Greenfield filter has been misplacement in 7% of cases.[58] When misplacement occurs below the diaphragm, the patient has inadequate protection, but the location in the renal or iliac vein poses no circulatory problem. A second filter can be placed in the appropriate location or the misplaced filter can be retrieved using a guide wire.[62] This is always advocated for misplacement into the tricuspid valve or if a rhythm disturbance occurs. Air embolism can occur during jugular insertion, but the risk is minimized by having the patient hold his or her breath while the vein is open. In some patients the veins may be too small or fragile to permit insertion of the carrier catheter, and rarely the patient may be too obese to permit fluoroscopy. Recurrent embolism after filter placement has been seen in 2 –4% of cases and may be caused by a source of thrombus outside the filtered flow region such as the upper extremities or the right atrium. Secondary infection of captured thrombus within a Greenfield filter has been produced experimentally, but it was possible to sterilize the filter and thrombus with antibiotic therapy.[6] The capture of a very large embolus within a filter has the potential to suddenly occlude the vena cava with a precipitous fall in blood pressure. In a patient with known prior pulmonary embolism, this event can be mistaken for recurrent pulmonary embolism, with disastrous results from vasopressor therapy. The basic distinction between functional hypovolemia and right ventricular overload can be made by the measurement of central venous pressure and PaO2. The response to volume resuscitation for the patient with sudden vena caval occlusion should be dramatic. There is one circumstance where migration of a Greenfield filter is possible after discharge. This occurs when there is failure to flush heparinized saline through the cylindrical carrier and a thrombus forms within it during the period of positioning under fluoroscopy. The thrombus can then tether the limbs of the filter, preventing their expansion and fixation to the wall of the vena cava. Only one such episode has been reported to the author, and it remains a totally preventable complication, much less likely to occur with the use of a guidewire to facilitate insertion and minimize the time that the carrier is used.[57] For optimal protection, a continuous drip of heparinized saline can be attached by intravenous tubing directly to the insertion catheter.
OTHER THROMBOTIC DISORDERS The term thrombophlebitis should be restricted to the disorder of the superficial veins characterized by a local inflammatory process, which is usually aseptic. The cause in the upper limb is usually acidic fluid infusion or prolonged cannulation. In the lower extremities it is usually associated with varicose veins and may coexist with DVT. The association with the injection of contrast material can be minimized by washout of the contrast material with heparinized saline.
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Thrombophlebitis Migrans This condition of recurrent episodes of superficial thrombophlebitis has been associated with visceral malignancy, systemic collagen vascular disease, and blood dyscrasias. Involvement of the deep veins and the visceral veins has also been described.
intraluminal abscess, which can occur after the traditional approach of ligation of the vena cava.[63]
PULMONARY THROMBOEMBOLISM Overview
Subclavian Vein Thrombosis This disorder is most likely to be secondary to an indwelling catheter and can occur in the pediatric age group. It may also occur as a primary event in a young, athletic person (“effort thrombosis”), as a result of injury or congenital constriction at the thoracic inlet. When the diagnosis is made early, thrombolytic agents and a venogram should be obtained to determine whether operative decompression of the vein is indicated. First rib resection by anterior or axillary approach has been successful in preventing rethrombosis. When the diagnosis is made 3 or more days after the event, there is usually a good response to elevation and anticoagulation, although some venous insufficiency and discomfort with exercise may persist. In some cases, stents have been placed, but the outcomes have been variable. The stents can be crushed if not placed in conjunction with rib resection.
Abdominal Vein Thrombosis Thrombosis of the inferior vena cava can result from tumor invasion or propagating thrombus from the iliac veins. Most commonly, however, it results from ligation, plication, or insertion of occluding caval devices. Thrombosis of the renal vein is most likely to occur in association with the nephrotic syndrome. It can be a source of thromboembolism and has been treated successfully by suprarenal placement of the Greenfield filter.[64] Portal vein thrombosis can occur in the neonate, usually secondary to propagating septic thrombophlebitis of the umbilical vein. Collateral development leads to the occurrence of esophageal varices. Thrombosis of the portal, hepatic, splenic, or superior mesenteric vein in the adult can occur spontaneously but usually is associated with hepatic cirrhosis. Thrombosis of mesenteric or omental veins can simulate an acute abdomen but usually results in prolonged ileus rather than intestinal infarction. Hepatic vein thrombosis (Budd-Chiari syndrome) usually produces massive hepatomegaly, ascites, and liver failure. It can occur in association with a congenital web, endophlebitis, or polycythemia vera. Although some success has been reported using a direct approach to the congenital webs, the usual treatment is a side-to-side portacaval shunt to allow decompression of the liver. The development of pelvic sepsis after abortion, tubal infection, or puerperal sepsis can lead to septic thrombophlebitis of the pelvic veins and septic thromboembolism. Ovarian vein and caval ligation has been used traditionally, but the emphasis should be on drainage or excision of the abscesses and appropriate antibiotic therapy. We have also used the Greenfield filter in this situation, since it is inert stainless steel and avoids the development of an
The clinical significance of major pulmonary embolism can be appreciated by reference to the annual mortality attributed to it, which has been estimated to be 90,000 deaths in the United States alone. It is estimated that 5 of every 1000 adults undergoing major surgery will die from massive pulmonary embolism. Since it represents the most important complication of DVT, it is of particular concern to surgeons whose patients are prone to develop deep vein thrombosis in the immediate postoperative period. The full spectrum of the disorder ranges from asymptomatic minor embolism to sudden death from massive embolism.
Diagnosis The signs and symptoms of an embolic episode obviously depend primarily on the quantity of embolus involved and to a lesser extent on the cardiopulmonary status of the patient. In the classic presentation, the patient suddenly develops chest pain, cough, dyspnea, tachypnea, and marked anxiety. Although hemoptysis has traditionally been associated with pulmonary embolism, it is actually an uncommon sign; when present, it usually occurs late in the course and probably represents pulmonary infarction. Objectively, the patient with major embolism usually shows tachycardia, an increased pulmonary second sound, cyanosis, prominent jugular veins, and varying degrees of hypotension. Less commonly, there may be wheezing, a pleural friction rub, splinting of the chest wall, rales, low-grade fever, ventricular gallop, and wide splitting of the pulmonic second sound. The incidence of these findings is shown in Table 68-3. The differential diagnosis includes esophageal perforation, pneumonia, septic shock, and myocardial infarction. Since all of these entities are life-threatening, it is mandatory that an orderly approach be formulated to confirm or reject the working diagnosis. Laboratory studies in general are not very helpful in the differential diagnosis, although a white blood Table 68-3.
Clinical Manifestations of Major Pulmonary
Embolism Symptoms Dyspnea Apprehension Pleural pain Cough Hemoptysis Syncope
Incidence (%)
Signs
Incidence (%)
80 60 60 50 27 22
Tachypnea Tachycardia Accentuated P2 Rales S3 or S4 Pleural rub
88 63 60 51 47 17
Source: Adapted from the Urokinase Pulmonary Embolism Trial.[65]
Chapter 68.
Deep Vein Thrombosis: Prevention and Management
cell count of less than 15,000/mL may be suggestive when a pulmonary infiltrate is present to help rule out pneumonitis. The following determinations are particularly useful in the evaluation of suspected major embolism.
Electrocardiography The most common electrocardiographic change associated with pulmonary embolism is nonspecific ST and T wave changes (66% of patients). More specific signs of right ventricular overload such as the often quoted S1, Q3, T3 pattern are seldom seen. Consequently, the primary value of the electrocardiogram is to exclude the presence of a myocardial infarction. Unfortunately, the finding of a myocardial infarction does not exclude the diagnosis of pulmonary embolism, and in some cases a lung scan or pulmonary angiogram may be required to clarify the problem.
Chest Radiography Although the chest radiograph may suggest the diagnosis of pulmonary embolism because of central vascular enlargement, asymmetry of the vascular markings with segmental or lobar ischemia (Westermark’s sign), or pleural effusion, these signs are nonspecific. The chest radiograph then serves to exclude other diagnostic possibilities such as pneumonia, pneumothorax, esophageal perforation, or congestive heart failure. It also is essential in the interpretation of a lung scan, since any radiographic density or evidence of chronic lung disease makes a perfusion defect in that area less likely to represent pulmonary embolism. Chronic lung disease also reduces the applicability of lung scanning to the diagnosis.
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Lung Scan Availability and widespread usage of lung photoscanning has led to overemphasis of this test and a tendency to overdiagnosis of pulmonary embolism. In the presence of a normal chest radiograph in a nonhypotensive patient, the lung scan is a valuable screening test that has increasing validity as the size of the perfusion defect approaches lobar distribution. Smaller peripheral perfusion defects are much more difficult to interpret, since pneumonitis, atelectasis, or other ventilation abnormalities alter pulmonary perfusion. A normal lung scan, on the other hand, essentially excludes the diagnosis of pulmonary embolism. Adding a ventilation scan for combined ventilation-perfusion imaging increases the accuracy of the diagnosis of thromboembolism, provided that there is a large area of ventilation-perfusion mismatch, but matched defects do not rule out embolism.[67] The assumption that the underperfused regions of the lung after embolism will remain normally ventilated producing the mismatch in the scans is clouded by the known physiological effect of bronchoconstriction produced by embolism. Adding the additional variable of wide variance in scan interpretation among observers makes the diagnosis much more reliable when based on arteriography (Fig. 68-5).[2] An alternative approach to the patient with suspected embolism and an abnormal perfusion scan is to perform venography and initiate anticoagulation if it is positive.[67] If negative, pulmonary angiography would be required to exclude the diagnosis of embolism (Fig. 68-6). Transesophageal echocardiography is a useful noninvasive technique for diagnosing pulmonary embolism.[68,69] During
Arterial Blood Gases Blood gas and pH determinations can provide support for the diagnosis of pulmonary embolism. Hypoxemia with PaO2 less than 60 mmHg is found in the majority of patients and felt to be due to shunting by overperfusion of nonembolized lung and a widened alveolar-arterial oxygen gradient due to reduced cardiac output. The reduction in arterial PCO2 that follows major embolism is the most discriminating finding since hypoxemia can be seen in several disorders likely to be misdiagnosed as massive embolism, e.g., septic shock.[66] In the absence of hypoxemia and hypocarbia, the diagnosis of major embolism in the severely ill patient can be excluded with moderate confidence, and an alternative diagnosis should be sought.
Central Venous Pressure In the patient with systemic hypotension, the central venous pressure can provide valuable information as well as access for the administration of drugs and fluids. Low central venous pressure virtually excludes pulmonary embolism as the primary cause of the hypotension, since massive embolism almost always is accompanied by right ventricular overload and elevated right atrial pressures. Elevated right ventricular filling pressures may be transient, however, as hemodynamic accommodation occurs, and in subacute or chronic embolism the central venous pressure may be normal.
Figure 68-5. Selective pulmonary arteriogram with injection of contrast medium into the right main pulmonary artery. A coiled thrombus can be seen obstructing flow to the upper and lower lobes.
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Figure 68-6. Schematic approach to the expeditious diagnosis of pulmonary thromboembolism based on clinical status. As an alternative to pulmonary arteriography in the patient with a positive lung scan, noninvasive venous studies can be obtained to demonstrate DVT and justify anticoagulation.
the acute symptomatic phase, findings of a dilated pulmonary artery, small left ventricle, and paradoxical motion of the interventricular septum are signs of major embolism.[70]
Pulmonary Arteriography Selective pulmonary arteriography is the most accurate method of confirming the presence, size, and distribution of pulmonary emboli. The procedure is invasive, requiring passage of a catheter into the main pulmonary artery for injection of a bolus of contrast medium. A rapid film changer produces a series of radiographs that outline areas of decreased perfusion and usually show filling defects or the rounded trailing edge of impacted emboli (Fig. 68-5). Straight cutoffs of the smaller pulmonary arteries are more difficult to interpret, particularly if there is associated chronic lung disease that tends to obliterate pulmonary vessels. The procedure can be performed at low risk, although this the most hazardous group of patients for this type of study, which usually carries a 0.5% mortality rate.[71] Avoidance of main pulmonary artery injection of contrast medium minimizes the complication rate. Additional useful information is obtained prior to contrast medium injection by measurement of pulmonary arterial (PA) pressures. A normal pulmonary angiogram excludes the diagnosis of pulmonary embolism in acutely ill patients. Although the resolution rate for pulmonary emboli is unpredictable, it is unrealistic to assume that a negative arteriogram within a week of the clinical event might miss the diagnosis because of rapid fibrinolysis. In the Urokinase Pulmonary Embolism Trial report, the earliest complete resolution was not seen before 14 days.[65]
Pathophysiology Although DVT precedes pulmonary embolism, less than 33% of patients with documented pulmonary embolism show
clinical signs of venous thrombosis. Despite this, it is estimated that 85– 90% of all pulmonary emboli originate from the veins of the lower extremity, while the remainder arise from the right side of the heart or other veins. In fact, the lower incidence of DVT after embolism may reflect the evacuation of the thrombus from the lower extremity. In addition, the emboli tend to be multiple, fragmenting either in the right side of the heart or during impaction into the pulmonary vascular bed. Older thombi, however, contain laminated fibrin layers that make them more solid and more difficult to lyse. Once the embolus has lodged and interrupted pulmonary blood flow, the ratio of regional ventilation to perfusion increases, and the lung responds by bronchoconstriction to reduce wasted ventilation. This response is mediated by local reduction in CO2 output, since it can be prevented by ventilation with increased concentration of CO2. Some experimental studies also suggest a generalized neural reflex vasoconstriction, but even if this occurs in humans, it is not likely to be as significant a factor in survival as the mechanical effect of major vascular occlusion. Similarly, the effects of vasoactive humoral agents can be demonstrated in animals, and there is good documentation that serotonin is elaborated from platelets adherent to the embolus, which also contributes to the bronchoconstriction observed. The ability of heparin to inhibit the release of serotonin adds further justification to the early use of this drug. Other vasoactive agents such as histamine and prostaglandins may play a role in humans, but the net effect is a reduction in size of peripheral airways, reduced lung volume, and reduced static pulmonary compliance. The hypoxemia that characterizes major embolism is thought to be caused by diminished cardiac output reducing venous oxygenation, although the findings in some patients resemble true arteriovenous shunting. The latter becomes anatomically possible if there is an unobliterated foramen ovale that opens in the presence of elevated right atrial pressures. Such an opening can also allow passage of a venous embolus into the systemic circulation, which then is termed paradoxical embolism. Although there may be some improvement in PaO2 after supplemental oxygen is administered, the effects usually are minimal. The return of pulmonary blood flow effected by embolectomy restores respiratory gas exchange, but the ischemia appears to result in some loss of capillary integrity, causing interstitial pulmonary edema or overt pulmonary hemorrhage. Pulmonary infarction as a consequence of embolism is relatively rare and associated clinically with problems of poor systemic perfusion such as shock or congestive heart failure. In these patients the symptoms include pleuritic chest pain, dyspnea, cough, and hemoptysis. The signs include fever, tachycardia, splinting, and occasionally friction rub. There is usually prominent leukocytosis, an elevated lactic dehydrogenase level, and bilirubinemia. A wedge-shaped density usually is seen on the chest film. The pulmonary vascular and cardiac effects of embolism are a direct consequence of the degree of obstruction of the pulmonary vascular bed. Occlusion of more than 30% of the vascular tree is required to begin to elevate mean PA pressure, and usually more than 50% occlusion is required to reduce systemic pressure. The degree of pulmonary hypertension
Chapter 68.
Deep Vein Thrombosis: Prevention and Management
produced is proportional to the extent of angiographic vascular occlusion, but in a previously normal patient, the limit of mean pressure generated by the right ventricle is approximately 40 mmHg. The fate of pulmonary emboli in patients is not easy to predict, although a great deal of experimental work in animals has been reported. Injection of autologous thrombi into the pulmonary circulation of dogs is followed by relatively rapid recovery of pulmonary function and objective evidence of lysis over a period of weeks. Activation of plasminogen to plasmin, which is found in high concentration in the pulmonary circulation, promotes this fibrinolytic effect. Unfortunately, the resolution of aged thrombi proceeds more slowly and is hampered further by impaction of the embolus and isolation from pulmonary blood flow. Consequently, resolution after massive embolism in patients is unpredictable and often incomplete. It is not unusual to find residual fibrin strands or webs in the pulmonary arteries at autopsy as remnants of prior embolism.
Classification and Management The hemodynamic variables mentioned above provide a means of classification of patients that employs four grades of severity and is a useful guide to therapy and prognosis (Table 68-4). The minor degrees of embolism usually can be managed by anticoagulants alone with a satisfactory outcome. Heparin is selected for initial treatment in a dose range designed to prolong the partial thromboplastin time to at least twice normal. At this dosage of approximately 150 units per kilogram there is adequate protection against further attachment of thrombi and platelets to the embolus. Many clinicians also begin oral anticoagulation therapy with warfarin at the same time as heparin administration in order to allow several days’ overlap of the drugs as INR is extended into the therapeutic range. In some patients, however, anticoagulants cannot be used because of associated problems (e.g., peptic ulcer disease), and management must be directed to a mechanical means of protection against recurrent embolism as outlined previously. Other patients, in whom anticoagulation appears to be adequate, sustain recurrent embolism and become candidates for mechanical protection. The third indication for mechanical protection is to protect against recurrent embolism in a patient who has sustained massive pulmonary embolism
Table 68-4. Category Minor Major Massive Chronic
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requiring open or catheter embolectomy. In these patients, even though a satisfactory embolectomy of the pulmonary circulation has been performed, the original focus of venous thrombosis remains untreated and is very likely to promote recurrent embolism, usually of major size. There are additional relative indications for vena caval devices to prevent embolism. One is in the high-risk patient over 40 years of age who is obese, has a serious associated medical illness (e.g., heart disease) or malignant disease, has a history of recent DVT, and is about to undergo a major surgical procedure or requires cessation of anticoagulation. Another relative indication exists in the patient with a long, free-floating thrombus at the groin level. More recently, prophylactic filter placement has been suggested for patients who sustain major multiple trauma with an ISS $ 9 and who are at high risk of PE.[72,73] The final relative indication is in the patient in whom 40–50% of the vascular bed has been occluded by embolism and who would most likely not be able to tolerate an additional embolus, particularly if there is associated cardiac or pulmonary disease. Pulmonary emboli may accumulate gradually over a prolonged period if they are small enough to produce microembolism rather than macroembolism. The clinical picture in this case is then one of chronic cor pulmonale because significant pulmonary hypertension results from obliteration of the pulmonary vascular bed. The presentation may be subtle with only dyspnea or syncope one exertion, but there is a loud P2 and right ventricular strain on the ECG. The sequence may also not be accompanied by significant respiratory symptoms and may explain the etiology in some of the patients considered to have primary pulmonary hypertension. When the diagnosis is made, there is a very limited life expectancy, and the patient may benefit from a vena caval filter to prevent further embolism even if the disorder is primary pulmonary hypertension.[74] The rationale is that these patients develop right heart failure predisposing to DVT and pulmonary embolism, which is lethal even if small. When acute cardiopulmonary decompensation occurs in these patients after embolism, they are not good candidates for embolectomy because of fixation of the older thrombi to the pulmonary arterial wall. They should be classified separately and managed by long-term anticoagulation and filter placement (Fig. 68-7). In cases in which the emboli originate from a septic focus, usually the pelvis in a female, the classic treatment has been vena caval ligation with ligation of the ovarian or spermatic
Stratification of Pulmonary Thyromboembolism Signs and symptoms
Gases
Anxiety Hyperventilation Dyspnea Collapse Dyspnea Shock Dyspnea Syncope
PaO2 , 80 mmHg PaCO2 , 35 mmHg PaO2 , 65 mmHg PaCO2 , 30 mmHg PaO2 , 50 mmHg PaCO2 , 30 mmHg PaO2 , 70 mmHg PaCO2 ¼ 30 – 40 mmHg
PA occlusion(%)
Hemodynamics
20 – 30
Tachycardia
30 – 50
CVP elevated, PA . 20 mmHg Responds to resuscitation CVP elevated, PA . 25 mmHg Requires pressors, inotropes CVP elevated, PA . 40 mmHg Fixed low cardiac output
. 50 . 50
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Figure 68-8. Following massive pulmonary embolism with shock, the patient who fails to respond to resuscitation must be supported by partial venoarterial bypass using the femoral vessels, which can be cannulated under local anesthesia. Then, after general anesthesia and sternotomy, a second cannula in the superior vena cava allows total bypass for open embolectomy through the main pulmonary artery. [By permission of Hardy J (ed): Hardy’s Textbook of Surgery, Philadelphia, Lippincott, 1983, p 981.]
Figure 68-7. Vena cava study showing free flow of contrast medium through the Greenfield filter (arrow ) placed in an infrarenal location at L3.
veins. It must be recognized, however, that large collateral veins develop as a consequence of vena caval occlusion and may then become the avenues of recurrent embolism. For this reason, we have used the Greenfield filter at either suprarenal or infrarenal level in conjunction with antibiotic therapy.
Pulmonary Embolectomy For those patients who sustain massive embolism, management must be a coordinated and rapidly responsive effort, since survival may be only a matter of minutes. As indicated
earlier, it is critical to document the presence of massive pulmonary embolism by pulmonary arteriography since the clinical diagnosis, regardless of “classic” appearance, often is in error. The initial approach to patients who have either transient collapse or persistent systemic hypotension should include full heparinization and administration of inotropic drugs if necessary to support the circulation while the diagnosis is confirmed. Isoproterenol (4 mg in 1000 mL 5% dextrose in water) is useful initially because of its bronchodilator and vasodilator effects as well as its positive inotropic cardiac effect. It may provoke arrhythmias, however, and necessitate the use of dopamine. For the patient with minor PE who responds to heparin and does not require vasopressors for systemic pressure or urine output, careful monitoring is essential to determine whether anticoagulation alone will control the disorder. The very high mortality rate associated with the Trendelenburg procedure[75] prompted the use of extracorporeal circulation to bypass the impacted pulmonary
Chapter 68.
Deep Vein Thrombosis: Prevention and Management
circulation. Embolectomy during cardiopulmonary bypass was reported first by Sharp in 1962.[76] Since then partial bypass support has also been utilized (Fig. 68-8). Local anesthesia is used, and the femoral artery and vein are cannulated for venoarterial bypass. Once the sternotomy is performed, the partial bypass can be converted to total bypass by insertion of a superior vena caval catheter; the pulmonary emboli are then removed through a pulmonary arteriotomy. Open pulmonary embolectomy still carries a high mortality rate, however, and the most serious complication is uncontrollable pulmonary hemorrhage, which may follow restoration of pulmonary perfusion.[77] Consequently, an alternative approach utilizing local anesthesia has been suggested by Greenfield et al.[78] for transvenous removal of pulmonary emboli. A cup device attached to a steerable catheter (Boston Scientific Corp, Natick, MA 02172) is inserted in the femoral or jugular vein, and the cup is positioned adjacent to the embolus seen on arteriography (Fig. 68-9). The position is verified by injection of contrast medium through the catheter. Then syringe suction is applied to aspirate the embolus into the cup, where it is held by suction as the catheter and captured embolus are withdrawn. Clinical experience with the technique in 46 patients showed that emboli could be extracted in 35 (76%), with an overall survival of 70%. In cases of acute PE, the success rate was 84%. Long-term survival was statistically significantly improved for those in whom the embolectomy was successful.[79] Emboli could not be removed when they had been impacted for more than 72 h or if the patient arrested at the time of angiography, in which case open embolectomy was required. Placement of a Greenfield vena caval filter after removal of sufficient emboli to produce near normal hemodynamics protected the patients from recurrent embolism.
Chronic Pulmonary Embolism and Pulmonary Hypertension Recurrent thromboembolism may lead to progressive obliteration of the pulmonary vascular bed if the thrombi fail to undergo lysis. The resultant pulmonary hypertension produces exertional dyspnea and signs of right heart strain with cor pulmonale. With further progression of right heart overload, tricuspid insufficiency may develop. This disorder may be difficult to distinguish from primary pulmonary hypertension, although the latter is more likely to be found in women under 20 years of age without a history of deep venous thrombosis. Open thrombectomy for chronic occlusion was first performed by Allison et al.[80] in 1958 and remains a possibility for improving pulmonary blood flow. Unfortunately, to be eligible for this procedure the occlusion must involve the proximal portion of the pulmonary arterial tree and the distal bed must be patent. The physiological basis for continued distal patency after proximal occlusion is via bronchial arterial collateral flow. The procedure also
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Figure 68-9. For the patient with massive PE who responds to resuscitation but remains hypotensive, catheter embolectomy can be performed under local anesthesia through the jugular or femoral vein. The steerable cup catheter is positioned under fluoroscopy adjacent to the embolus and syringe suction applied to capture the thrombus in the cup, where it is held by sustained suction as the catheter is withdrawn. Repeat passage and control medium injection are used to clear all unattached emboli from branches of the pulmonary arteries.
has a significant mortality rate, reported at 17% by Moser et al.[81] in a series of 42 patients. The complications of the procedure reported by these authors include hemorrhagic pneumonitis, cardiac failure, persistent pulmonary hypertension, pulmonary edema, hemothorax, empyema, and pulmonary infarction. The long-term results in surviving patients have been favorable with improved respiratory function and relief of pulmonary hypertension. For the majority of patients with severe pulmonary hypertension, however, the outlook is poor unless they receive maximum protection from recurrent embolism, which in our experience has required both anticoagulation and vena caval filter placement.[74]
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20. Baxter, G.M.; McKochnie, S.; Duffy, P. Colour Doppler Ultrasound in Deep Venous Thrombosis: A Comparison with Venography. Clin. Radiol. 1990,. 21. Leutz, D.W.; Stauffer, E.S. Color Duplex Doppler Ultrasound Scanning for Detection of Deep Venous Thrombosis in Total Knee and Hip Arthroplasty Patients: Incidence, Location, and Diagnostic Accuracy Compared with Ascending Venography. J. Arthroplasty. 1994, 9, 543. 22. Rose, S.; Zwiebel, W.; Nelson, B.; et al. Symptomatic Lower Extremity Deep Venous Thrombosis: Accuracy, Limitations, and Role of Color Duplex Flow Imaging in Diagnosis [published erratum appears in Radiology 176(3):879, 1990]. Radiology 1990, 175, 639. 23. Mattos, M.; Londrey, G.; Leutz, D.W.; et al. Color-Flow Duplex Scanning for the Surveillance and Diagnosis of Acute Deep Venous Thrombosis. J. Vasc. Surg. 1992, 15, 366. 24. Davidson, B.L.; Elliott, G.; Lensing, A.W. Low Accuracy of Color Doppler Ultrasound in the Detection of Proximal Leg Vein Thrombosis in Asymptomatic High-Risk Patients. Ann. Intern. Med. 1992, 117, 735. 25. Labropoulos, N.; Giannoukas, A.D.; Nicolaides, A.N.; et al. New Insights into the Pathophysiologic Condition of Venous Ulceration with Color-flow Duplex Imaging: Implications for Treatment? J. Vasc. Surg. 1995, 22 (1), 45. 26. Robertson, P.L.; Goergen, S.K.; Waugh, J.R.; et al. ColourAssisted Compression Ultrasound in the Diagnosis of Calf Deep Venous Thrombosis. Med. J. Aust. 1995, 163, 515. 27. Engel, S.; Evans, S.P.; Mikk, M.; et al. D-Dimer in the Early Diagnosis of Thromboembolic Disease in Acute Spinal Injuries. Med. J. Aust. 1993, 158, 705. 28. Grau, E.; Linares, M.; Estany, A.; et al. Utility of D Dimer in the Diagnosis of Deep Venous Thrombosis in Outpatients. Thromb. Haemostasis 1991, 66 (4), 510. 29. Glassman, A.B.; Jones, E. Thrombosis and Coagulation Abnormalities Associated with Cancer. Ann Clin Lab Sci 1994, 24, 1 –5. 30. Anonymous; Prevention of Venous Thromboembolism: European Concensus Statement. Int Angiol. 1992, 11 (3), 151. 31. Clagett, G.P., Jr.; Andersson, F.A.; Heit, J.A.; et al. Prevention of Venous Thromboembolism. Chest 1995, 108 (4), 312S. 32. Blackshear, W.; Prescott, C.; LePain, F.; et al. Influence of Sequential Pneumatic Compression on Postoperative Venous Function. J. Vasc. Surg. 1987, 5 (3), 432. 33. Davidson, J.E.; Willms, D.C.; Hoffman, M.S. Effect of Intermittent Pneumatic Leg Compression on Intracranial Pressure in Brain-Injured Patients. Crit. Care Med. 1993, 2 (2), 224. 34. Millard, J.; Hill, B.; Cook, P.; et al. Intermittent Sequential Pneumatic Compression in Prevention of Venous Stasis Associated with Pneumoperitoneum During Laparoscopic Cholecystectomy. Arch. Surg. 1993, 128, 914. 35. Knudson, M.M.; Lewis, F.R.; Clinton, A.; et al. Prevention of Venous Thromboembolism in Trauma Patients. J Trauma 1994, 36 (1), 158. 36. Gersin, K.; Grindlinger, G.A.; Lee, V.; et al. The Efficacy of Sequential Compression Devices in Multiple Trauma
Chapter 68.
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42.
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44.
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47.
48.
49.
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Patients with Severe Head Injury. J. Trauma 1994, 37 (2), 205. Bradley, J.G.; Krugener, G.H.; Jager, H.J. The Effectiveness of Intermittent Plantar Venous Compression in Prevention of Deep Venous Thrombosis After Total Hip Arthroplasty. J. Arthroplasty 1993, 8, 57. Yano, Y.; Kambayashi, J.I.; Murata, K.; et al. Bedside Monitoring of Warfarin Therapy by a Whole Blood Capillary Coagulation Monitor. Thromb. Res. 1992, 66, 583. Geerts, W.H.; Jay, R.M.; Code, K.I.; et al. A Comparison of Low-Dose Heparin with Low-Molecular-Weight Heparin as Prophylaxis Against Venous Thromboembolism After Major Trauma. N. Engl. J. Med. 1996, 335 (10), 701. Bergqvist, D.; Benoni, G.; Bjorgell, O.; et al. LowMolecular-Weight Heparin (Enoxaparin) as Prophylaxis Against Venous Thromboembolism After Total Hip Replacement. N. Engl. J. Med. 1996, 335 (10), 696. Harenberg, J.; Roebruck, P.; Stehle, G.; et al. Heparin Study in Internal Medicine (HESIM): Design and Preliminary Results. Thromb. Res. 1992, 68, 33. Gerhart, T.N.; Robertson, L.; Yett, H.; et al. LowMolecular-Weight Heparinoid Compared with Warfarin for Prophylaxis of Deep-Vein Thrombosis in Patients Who Are Operated on for Fracture of the Hip. J. Bone Joint Surg. 1991, 73-a, 494. Palmer, A.J.; Koppenhagen, K.; Kirchhof, B.; et al. Efficacy and Safety of Low Molecular Weight Heparin, Unfractionated Heparin and Warfarin for Thrombembolism Prophylaxis in Orthopaedic Surgery: A Meta-Analysis of Randomised Clinical Trials. Haemostasis 1997, 27, 75. Hull, R.D.; Raskob, G.E.; Pineo, G.F.; et al. Subcutaneous Low-Molecular-Weight Heparin vs Warfarin for Prophylaxis of Deep Vein Thrombosis After Hip or Knee Implantation. An Economic Perspective. Arch. Intern. Med. 1997, 157, 298. Hirsch, J.; Siragusa, S.; Cosmi, B.; et al. Low Molecular Weight Heparins (LMWH) in the Treatment of Patients with Acute Venous Thromboembolism. Thromb. Haemostasis 1995, 74 (1), 360. Hull, R.D.; Pineo, G.F. Low Molecular Weight Heparin Treatment of Venous Thromboembolism. Prog. Cardiovasc. Dis. 1994, 37, 71. Schafer, A.I. Low-Molecular-Weight Heparin—An Opportunity for Home Treatment of Venous Thrombosis. N. Engl. J. Med. 1996, 334, 724. Hirsh, J.; Crowther, M. Low Molecular Weight Heparin for the Out-of Hospital Treatment of Venous Thrombosis: Rationale and Clinical Results. Thromb. Haemostasis 1997, 78, 689. Parent, F.; Bridey, F.; Dreyfus, M.; et al. Treatment of Severe Venous Thrombo-embolism with Intravenous Hirudin (HBW 023): An Open Pilot Study. Thromb. Haemostasis 1993, 70, 386. Schiele, F.; Lindgaerde, F.; Eriksson, H.; et al. Subcutaneous Recombinant Hirudin (HBW 023) Versus Intravenous Sodium Heparin in Treatment of Established Acute Deep Vein Thrombosis of the Legs: A Multicentre Prospective Dose-Ranging Randomized Trial. Thromb. Haemostasis 1997, 77, 834.
51. 52.
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62. 63.
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65. 66.
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Bell, W.R.; Meek, A.G. Guidelines for the Use of Thrombolytic Agents. N. Engl. J. Med. 1979, 301, 1266. Martin, T.R.; Sandblom, R.I.; Johnson, R.J. Adult Respiratory Distress Syndrome Following Thrombolytic Therapy for Pulmonary Embolism. Chest 1983, 83, 151. Comerota, A.J. Venous Thrombectomy and Arteriovenous Fistula Versus Anticoagulation in the Treatment of Iliofemoral Venous Thrombosis. J. Vasc. Surg. 1992, 15 (5), 887. Einarsson, E.; Albrechtsson, U.; Eklof, B.; et al. Follow-up Evaluation of Venous Morphologic Factors and Function After Thrombectomy and Temporary Arteriovenous Fistula in Thrombosis of Iliofemoral Vein. Surg. Gynecol. Obstet. 1986, 163, 111. Comerota, A.J.; Aldridge, S.C.; Cohen, G.; et al. A Strategy of Aggressive Regional Therapy for Acute Iliofemoral Venous Thrombosis with Contemporary Venous Thrombectomy or Catheter-Directed Thrombolysis. J. Vasc. Surg. 1994, 20, 244. Cimochowski, G.E.; Evans, R.H.; Zarius, C.K.; et al. Greenfield Filter Versus Mobin-uddin Umbrella, the Continuing Quest for the Ideal Method of Vena Caval Interruption. J. Thorac. Cardiovasc. Surg. 1980, 79, 358. Greenfield, L.J.; Stewart, J.R.; Crute, S. Improved Technique for Greenfield Vena Caval Filter Insertion. Surg. Gynecol. Obstet. 1983, 156, 217– 219. Greenfield, L.J.; Michna, B.A. Twelve Year Clinical Experience with the Greenfield Filter. Surgery 1988, 104, 706. McCowan, T.; Ferris, E.; Carver, D.K.; et al. Complications of the Nitinol Vena Caval Filter. J. Vasc. Intervent. Radiol. 1992, 3, 401. Crochet, D.P.; Stora, O.; Ferry, D.; et al. Vena Tech-LGM Filter: Long-Term Results of a Prospective Study. Radiology 1993, 188, 857. Vesely, T. Technical Problems Adn Complications Associated with Inferior Vena Cava Filters. Seemin. Intervent. Radiol. 1994, 11 (2), 121. Greenfield, L.J.; Crute, S.L. Retrieval of the KimrayGreenfield Vena Caval Filter. Surgery 1980, 88, 719. Peyton, J.W.R.; Hylemon, M.B.; Greenfield, L.J.; et al. Comparison of Greenfield Filter and Vena Caval Ligation for Experimental Septic Thromboembolism. Surgery 1983, 93, 533. Stewart, J.R.; Peyton, J.W.R.; Crute, S.I.; Greenfield, L.J. Clinical Results of Suprarenal Placement of the Greenfield Vena Cava Filter. Surgery 1982, 92. Urokinase Pulmonary Embolism Trial; A National Cooperative Study. Circulation 1973, 47 (Suppl. II), 47. Goodall, R.J.R.; Greenfield, L.J. Clinical Correlations in the Diagnosis of Pulmonary Embolism. Ann. Surg. 1980, 191, 219. Hull, R.D.; Hirsh, J.; Carter, C.J.; et al. Pulmonary Angiography, Ventilation Lung Scanning, and Venography for Clinically Suspected Pulmonary Embolism with Abnormal Perfusion Scan. Ann. Intern. Med. 1983, 98, 891. Hunter, J.; Johnson, K.R.; Karagianes, T.G.; et al. Detection of Massive Pulmonary Embolus-in-Transit by Transesophageal Echocardiography. Chest 1991, 100, 1210.
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69. Cerel, A.; Burger, A. The Diagnosis of Pulmonary Artery Thrombus by Transesophageal Echocardiography. Chest 1993, 103, 944. 70. Vuille, C.; Urban, P.; Jolliet, P.; et al. Right Atrial Thrombus in Pulmonary Embolism: Contribution of Echocardiography and Indication for Thrombolytic Therapy. Schweiz. Med. Wochenschr. 1993, 123, 1945. 71. Bell, W.R.; Simon, T.L. A Comparative Analysis of Pulmonary Perfusion Scans with Pulmonary Angiograms— from a National Cooperative Study. Am. Heart. J. 1976, 92, 700. 72. Rogers, F.B.; Shackford, S.R.; Wilson, J.; et al. Prophylactic Vena Cava Filter Insertion in Severely Injured Trauma Patients: Indications and Preliminary Results. J. Trauma 1993, 35 (4), 637. 73. Rodriguez, J.L.; Lopez, J.M.; Proctor, M.C.; et al. Early Placement of Prophylactic Vena Caval Filters in Injured Patients at High Risk for a Pulmonary Embolism. J. Trauma 1996, 40 (5), 797. 74. Greenfield, L.J.; Scher, L.A.; Elkins, R.C. KMA-Greenfieldw Filter Placement for Chronic Pulmonary Hypertension. Ann. Surg. 1979, 189, 560.
¨ ber die operative Behandlung der 75. Trendelenburg, I. U Embolie der Lungenarterie. Arch. Klin. Chir. 1908, 86, 686. 76. Sharp, E.H. Pulmonary Embolectomy: Successful Removal of a Massive Pulmonary Embolus with the Support of Cardiopulmonary Bypass: A Case Report. Ann. Surg. 1962, 156, 1. 77. Brown, S.; Muller, D.; Buckberg, G. Massive Pulmonary Hemorrhagic Infarction Following Revascularization of Ischemic Lungs. Arch. Surg. 1974, 108, 795. 78. Greenfield, C.J.; Peyton, M.D.; Brown, P.P.; Elkins, R.C. Transvenous Management of Pulmonary Embolic Disease. Ann. Surg. 1974, 189, 461. 79. Greenfield, L.J.; Proctor, M.C.; Williams, D.; et al. LongTerm Experience with Transvenous Catheter Pulmonary Embolectomy. J. Vasc. Surg. 1993, 18, 450. 80. Allison, P.R.; Dunhill, M.S.; Marshall, R. Pulmonary Embolism. Thorax 1980, 15, 273. 81. Moser, K.M.; Daily, P.O.; Peterson, K.; et al. Thromboendarterectomy for Chronic Major-Vessel Thromboembolic Pulmonary Hypertension. Ann. Int. Med. 1987, 107, 560– 565.
CHAPTER 69
Chronic Venous Insufficiency: Natural History and Classification Robert L. Kistner Bo Eklof Elna M. Masuda cause. In addition, the venous system of the lower extremity has an enormous capacity to compensate for its abnormalities, a capacity that is highly variable from person to person, leading to great confusion about the progression to severe late sequelae in certain cases and not in others. Add to this the multiple levels and combinations of segmental involvement, the different responses to obstruction and to reflux, the response of the veins to various treatment regimens, and a picture emerges of a protean maze of routes in which clinical CVD states develop. This wide variety of clinical presentations of CVD will only become clear as venous disease is routinely diagnosed accurately and completely by objective testing, placed into definite categories by a universal classification scheme, and studied over time.
Reliable studies place the occurrence of chronic venous disease (CVD) in about 20% of the adult population.[1] It occurs in a wide diversity of forms ranging from a minor, perhaps negligible, finding to a lifestyle-limiting condition that is essentially incurable. The onset of symptoms varies from birth in the congenital syndromes to an insidious onset during early, middle, or later life, or a more or less rapid development after an episode of thrombophlebitis. For a condition that is so ubiquitous, there has been a dearth of critical scientific study, rendering CVD a fertile field for investigation. This investigation has been begun with the advent of the accurate duplex scan, which provides a noninvasive, objective, safe, and affordable method to study the progress of the venous disease over time. The beginning of literature in CVD dates back to early Greece, when ulcers of the legs were pictured in the art of the times. The management of ulcers was addressed by Hippocrates 400 years before Christ. The anatomy of the venous system was illustrated by Leonardo da Vinci circa 1450, the valves described by Fabricius by 1600, and the presence of venous valves was the cornerstone upon which William Harvey, a student of Fabricius, based the modern concept of the circulation.[2] The real developments in understanding of the physiology and natural history of venous insufficiency occurred in the 20th century with contributions by Homans,[3] Linton,[4] Bauer,[5] and many others. But even today there is a relatively meager amount of true scientific study in CVD. The purpose of this chapter is to examine the development of chronic venous insufficiency from the early stages of venous disease to the fullblown clinical syndromes of late venous insufficiency typified by the venous ulcer and the brawny scarred leg of neglected venous disease. To imagine that a single identifiable natural history of CVD exists is unrealistic. The fact is that CVD has many causes, and the basis for its development is reliant upon the underlying
GENERAL COMMENTS ABOUT DEVELOPMENT OF CVD There are certain properties of lower extremity CVD that are common to all causes of CVD and underlie its response to pathologic states. As outlined in Table 69-1, these are: 1.
The venous system requires patency of enough channels to return the volume of blood from the extremity to the heart. Collaterals develop over time when the normal main channels become obstructed or are congenitally absent. The early response to acute obstruction is swelling and pain, but this is progressively relieved over time if further thrombosis is prevented and swelling is controlled. This tendency for spontaneous collateralization varies from case to case and cannot be accurately predicted for the individual.
Hobson/Wilson/Veith: Vascular Surgery: Principles and Practice, Third Edition, Revised and Expanded DOI: 10.1081/0819-9-120024953 Copyright q 2004 by Marcel Dekker, Inc.
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Part Nine. Table 69-1. 1. 2. 3. 4. 5. 6. 7. 8.
2.
3.
4.
5.
Venous and Lymphatic Disorders
Constant Factors in Natural History of Lower Extremity CVD
Obstruction is compensated by collaterals. Reflux is poorly compensated and leads to late sequelae. Competence is not important above the common femoral vein; competence is critical below the common femoral vein. Deep vein valves prevent pooling and pain. Superficial and perforator valves protect the lower leg skin. Obstruction is the only important chronic complication of iliac vein disease. Reflux is the more important complication below the common femoral vein. Obstruction of iliac veins combined with peripheral reflux is the worst combination.
The venous system requires valves in the periphery to ensure the uni-directional flow within the system. Without uni-directional flow the venous system becomes inefficient, blood pools in the leg veins, the capacitance of the veins accommodates larger amounts of blood, and stasis ensues. Sustained hypertension in the veins leads to further dilation of venous walls, valvular incompetence, and late severe sequelae of aching, swelling, and ultimate skin scarring and ulceration. These changes occur slowly over many years, and their rate of progression varies widely. Valves are critical in all of the branches below the common femoral vein but are of no proven importance in the iliac veins and do not exist in the inferior vena cava. Valves become increasingly numerous as the venous system is traced through the thigh and calf. The popliteal and calf valves and the perforator valves protect the skin of the lower leg from hypertension in the deep veins, due either to obstruction or reflux. When the deep system alone is diseased, the symptoms are pain and swelling, but skin changes often do not occur. The saphenous valves and the perforator valves protect the skin of the lower leg from hypertension in the superficial veins and drain both longitudinally via the saphenous and its tributaries and horizontally via the perforator veins. Ultimately, even the saphenous veins function as perforator veins when they traverse the deep fascia and enter the deep veins in the common femoral or the popliteal veins. When this drainage system is interrupted, unnamed collaterals develop to compensate. But when this drainage system becomes incompetent and the obstructive stimulus for collateralization is not present, pooling
6.
7.
8.
and stasis occur. Distal skin complications develop as a late complication. The critical function of the iliac vein is patency to provide adequate drainage for the extremity. Valvular function is not an issue and need not be a consideration for treatment in this site. The critical function of the valves in the extremity is to provide competence to the existing outflow channels, and thereby ensure uni-directional flow. While large amounts of obstruction can be readily tolerated in the leg veins, reflux due to valve loss leads to late sequelae and is the key element in the great majority of cases of lower extremity CVD.[6 – 8] The worst combination of pathology in the lower extremity veins is that of proximal obstruction in the iliac veins and contiguous axial reflux in the thigh and calf. These extremities become severely disabled by postthrombotic disease with recurrent ulceration and represent the worst combination of physiologic derangement to the lower extremity veins.
In contrast to the constant factors in CVD, there is a list of variable factors (Table 69-2) in CVD that profoundly impact the understanding of its natural history. The dominant aspect of these variables is the etiology of the CVD in a given instance because this determines the pathologic changes that will develop in the affected segments, and it is these changes distributed over certain segments in the extremity that give rise to the natural history in that case.
CEAP CLASSIFICATION OF CVD In order to discuss the natural history of CVD, the disease processes that occur in CVD have to be separated into an
Table 69-2. Variable Factors in Natural History of Lower Extremity CVD 1. 2. 3. 4. 5. 6. 7.
Etiology, i.e., congenital, primary, secondary Anatomic distribution in segments of the lower extremity veins Pathogenetic mechanism, i.e., reflux, obstruction, both Age, sex, and activity level of the patient Method of treatment of acute stages of the disease, as in thrombophlebitis treated by anticoagulation vs. no treatment, elastic support vs. no support, etc. Compliance of the patient with the recommended treatment regimen Recurrent episodes of DVT
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organized classification. The dominant classification is the CEAP (clinical class, etiology, anatomy, pathophysiology) classification, which was developed in 1994 by a subcommittee of the American Venous Forum[9,10] and will be followed in this chapter. This has been officially accepted by venous and vascular societies in the United States and around the world and has been published in many languages on at least five continents. The major advantage of this classification is that it addresses more than just the clinical entity by requiring information about the etiology of the problem, its distribution in the venous tree, and its mechanism of development through reflux or obstruction.
DEMOGRAPHICS IN CVD CVD is very widespread, affecting approximately 20% of the adult population and up to 50% of women over 50 years of age according to accepted estimates of its prevalence.[1] Serious forms of venous insufficiency are found in an unidentified number of cases and include those who suffer from lifestyle-limiting pain and swelling, those with severe indurative changes to the calf with and without inflammatory changes of lipodermatosclerosis, and to the 2% who ultimately develop ulceration. A reliable demographic study of CVD in the United States still does not exist and will probably never be performed, but the widespread prevalence of its occurrence is undeniable. The importance of CVD lies in the disability it causes in loss of time from work rather than its threat to life or limb. The impact of CVD upon industry has been profound in the past because deep venous thrombosis (DVT) was less effectively treated before heparin/Coumadin anticoagulation was understood and widely practiced. There was a time when CVD was such an important loss of time from work that it was estimated to rival back problems as the major cause of lost work time. Perhaps due to the introduction of effective therapy of acute DVT by anticoagulation with heparin/Coumadin and the presentday insistence upon accurate diagnosis of acute DVT by an imaging study, the frequency of severe postthrombotic disease with ulceration is decreased, and the older statistics of severe postthrombotic disability developing in up to 80% of the iliofemoral vein thromboses[11,12] are no longer correct. The likelihood of developing ulceration following an iliofemoral DVT at the present time is closer to 15% than to 50%. With the adoption of more precise diagnoses and the availability of more effective treatment to preserve both patency and valvular competence in the acute stages of thrombophlebitis, the frequency and severity of longterm sequelae are likely to continue to decrease.
CONTRIBUTION OF THE ULTRASOUND SCAN A seminal contribution to the understanding of the natural history of CVD is the recent availability and widespread use of the duplex scan. This combination of ultrasound
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imaging with Doppler-derived flow analysis provides a noninvasive imaging technique that renders it practical to identify which segments are involved with disease and whether the problem is one of reflux or obstruction segment by segment. While these scans can diagnose the presence of both reflux and obstruction and are useful in estimating the quantity of reflux, they are not predictable indicators of the physiologic severity of obstruction. Since the duplex scan is safe, affordable, and widely available, it has become the source of an entire new appreciation of the events that occur over time in the chronically diseased venous system. With this modality it is apparent that the vast majority of CVD is due to primary (nonpostthrombotic) venous reflux rather than secondary (postthrombotic) obstructive disease, a finding that provides new opportunities for treatment. The medical profession now has accurate testing to study the consequences of CVD of different etiologies and distributions and to truly discern the natural history of sequelae in each clinical situation as a guide to appropriate therapy at the time of presentation.
ETIOLOGIES OF CVD Appreciation of the natural history of CVD of the lower extremity requires an understanding of the several etiologies of chronic venous insufficiency because the clinical behavior of congenital, primary, and secondary causes of venous insufficiency follow separate paths. It is from the etiology that the type of pathogenetic mechanism flows, i.e., reflux, obstruction, or a combination of these, and it is the anatomic distribution of these abnormalities in the venous tree that gives rise to the clinical sequelae. For those who would diagnose and treat chronic venous insufficiency it is essential to study these variations and to appreciate their effect upon the results of day-to-day management of the problem. CVD is categorized into congenital, primary, and secondary etiologies by the CEAP classification. Of these, the primary form represents the vast majority of cases (over 80%) of CVD cases, congenital is unusual (1 –2%), and the remainder are postthrombotic.[8,13]
CONGENITAL The congenital forms of CVD are those that are present at birth and represent developmental abnormalities in the structure or the anatomy of the extremity veins. The classical example is the Klippel-Trenaunay syndrome, which consists of varicose veins, venous hemangioma, and increased leg size and is well described in the literature.[14 – 16] Another is the Parkes-Weber syndrome,[17] which is a collection of varicose veins secondary to microscopic A-V fistulae. Other venous abnormalities include aplasia of the venous valves,[18] venous contributions to hemangiomata and A-V fistulae, and compression syndromes such as the common iliac vein obstructions due to the crossing of the iliac artery[9] or popliteal vein entrapment syndromes.
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ACQUIRED VENOUS DISEASE Primary Primary venous disease is the most frequent cause of CVD. It could be considered developmental rather than the result of a noxious event in life such as thrombophlebitis or traumatic occlusion. Its clinical expressions include varicose veins and telangiectases, as well as more severe clinical syndromes that occur with prolonged reflux of the deep and perforator veins, such as stasis dermatitis, lipodermatosclerosis, stasis pigmentation, and ulceration. This category excludes the secondary, or postthrombotic, causes of CVD. There are two paths within this broad category of primary venous insufficiency (PVI), one of which is the cosmetically disturbing but generally benign condition of large, tortuous veins in the extremity, and the other is the serious venous insufficiency with skin and subcutaneous thickening, discoloration, brawny edema, and ultimately ulceration.
Secondary The secondary causes of venous insufficiency are mainly the postthrombotic cases, but also those external problems that cause venous obstruction such as tumors and trauma. The entrapment syndromes could be classified here if there is no obvious congenital basis. Varicose veins, typically the result of primary venous disease, can develop as a compensatory mechanism after deep vein occlusion, and in this case should be classified as secondary varicose veins. This fact was originally described and classified by Homans in 1916.[20] In much of the literature, all varicose veins in patients with prior DVT are considered secondary, but this ignores the fact that varicose veins are often present in patients before the DVT occurred and are truly primary in their etiology.
NATURAL HISTORY OF DEVELOPMENT OF CVD Congenital Disease The distinguishing feature of congenital venous disease is that there is a deformity of the normal venous structure, which occurs during fetal development. This may take the form of abnormal structure of the venous wall, absence of valves, or abnormal anatomic location of the veins. All of these may be seen in the Klippel-Trenaunay syndrome.[14 – 16] In this syndrome the child is born with a nevus ipsilateral to the side, which later becomes grossly abnormal as it develops varicose veins and subsequent increased growth of the affected limb. The diagnosis, recognizable in infancy, becomes more dramatic as the child grows because the discrepancy in limb size and appearance becomes increasingly obvious. In adult life there may be severe degrees of pain associated with gross deformity and swelling in the abnormal extremity. The abnormal veins may be localized to any area of the venous tree, may be generalized, and may even replace normal
subeutaneous and muscular tissue with tissue that can only be described as venous spaces. With the passage of time the involvement of the limb may progress as massive venous abnormalities appear. This can become crippling. The pathophysiology is mainly reflux through abnormal venous channels, but relative obstruction may co-exist when entire segments of the venous tree are completely absent or become thrombosed. Treatment is supportive. Surgical procedures to achieve debulking and on some occasions valve repair or segment transfer can be of use. For the most part the syndrome is not reversible and the individual will have to endure it throughout life. On occasion amputation may be warranted to improve the overall clinical state of the patient.
Primary Disease The development of PVI is a progressive process throughout life. The pathophysiology of the disease begins with the development of dilated venous walls and valvular incompetence, which ultimately leads to different clinical syndromes. Its most frequent clinically obvious form is that of varicose veins, where the pathologic changes consist of hyperplasia of the endothelium, increased collagen and decreased elastin in the media and endothelial layers,[21,22] progressing to interruption of the syncytial muscular layers of the media as muscle fibers become entrapped in collagen wraps (Fig. 69-1). The valve structures demonstrate progressive atrophy in the saphenous vein, and this sometimes progresses to an avalvular condition. The walls of the vein show alternate areas of thinning and thickening, venous aneurysm formation, and whitish streaking of the intima. The identical pathological changes that are seen in the saphenous vein are also found in the perforator veins and in the superficial varices. The deep veins show similar changes of elastin and collagen, but the valvular change is often elongation and stretching of the valve cusp rather than atrophy (Fig. 69-2). These changes in the deep veins are not worked out at this time due to a lack of study material. The distribution of the venous changes appears to begin in the superficial veins, where they have been identified early in life in the saphenous veins. In a remarkable study of the development of primary vein disease, Schultz-Ehrenburg followed the course of a large group of 740 original students, which fell to 459 final students over three successive time frames at ages 10 –12, 14 –16, and 18– 20. This is known as the Bochum study.[23] He found progression in the venous changes with the appearance of 2% saphenous reflux at age 11 years up to 20% at age 19 years. This was accompanied by the clinical appearance of large varices from 0% at age 11 to 6% at age 19, and the increase of small varices excluding telangiectases from 10% at 11 years to 40% at age 19. This same phenomenon of increased prevalence of varicose vein disease has been seen in adults as they age. The influence of pregnancy on development of varicose veins has long been recognized, even if the actual mechanism of their development is not clear. When the history of varicose veins is carefully extracted from middle-aged adults, the story is often gotten that the varicosities first appeared in adolescence and were slowly progressive over time.
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Figure 69-2. Descending venogram showing reflux through floppy valves in a superficial femoral vein with primary deep vein incompetence. Figure 69-1. Endothelial surface of a saphenous vein with primary disease showing atrophy of the valve cusp and saccule formation on the back wall.
Varicose veins are often deemed to be a benign condition that is well tolerated over time and need not be treated except for cosmetic reasons. This point of view ignores the nowestablished fact that 30 –50% of venous ulcers are caused by superficial reflux[24,25] in the saphenous or in the saphenous plus perforator veins with no involvement of the deep system and no evidence of postthrombotic disease. While these cases represent the minority of individuals with varicose veins, it is not known which cases will go on to severe venous insufficiency out of the large population with varices. The natural history of primary venous disease follows two main courses. In the first instance, varices appear at some point in life, which may vary from adolescence to older age, and progress to a certain point where they seem to remain more or less static over long periods of time. Symptoms may be entirely absent or vary from mild to severe aching or swelling. Occasionally the symptoms are severe enough to interfere with work. Varices may become worse with pregnancy or perhaps with certain occupations and warrant treatment because of symptoms. They may also render the patient more susceptible to thrombosis, which can occur in the varices as a localized superficial
phlebitis or may be multifocal and involve the deep system in more than 20% of the cases.[26] The second course is one of severe venous insufficiency marked by skin changes of pigmentation, thickening, lipodermatosclerosis, and ultimate ulceration. It is not clear why some have extensive superficial vein changes with very mild symptoms and others have similar changes but a very severe clinical syndrome. One finding that has emerged from studies with the CEAP classification is that those who develop ulceration of the ankle from strictly superficial primary reflux have reflux all the way from the groin to the ankle.[27] The importance of axial reflux from groin to ankle is clear in all studies on the pathologic findings in venous ulcer disease, whether superficial or deep. In studying the distribution of primary disease, it has become clear that primary disease is seldom found in the deep veins unless it also affects the saphenous vein. It appears to involve the superficial veins first and may be isolated to the saphenous veins, or it may progress to involve the perforator and deep veins. In contrast, secondary (postthrombotic) disease usually presents in the deep veins, and often the superficial and perforator veins remain normal. The pathophysiology of primary disease is always limited to reflux alone. This contrasts sharply with postthrombotic disease where the pathogenetic change begins with obstruction and progresses over time to obstruction with reflux. This is an
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important difference between primary and secondary disease because it translates directly into the types of restorative surgical procedures that are available. Since reflux disease can be treated quite effectively in the superficial, perforator, and deep veins, surgery is an important option for nearly all cases of primary reflux disease, especially when it causes severe clinical complications. The surgical options are more limited in secondary disease, where obstruction plays an important role.
Secondary Disease In contrast to primary disease, which has an insidious onset, secondary (postthrombotic) disease has a definite time of onset when the thrombosis occurs. The pathologic process starts with occlusion that involves a certain distribution of segments within the extremity. From this beginning, a dynamic process ensues in which the thrombus matures and in doing so undergoes retraction and shrinkage from the venous wall, is invaded by neovascularization, and over time the obstructing thrombus is often replaced by a patent channel. The late result is a mixture of obstruction and reflux because the recanalized vein typically does not have functional valves, and the recanalization leaves scars, synechiae, and masses in the restored lumen (Fig. 69-3). The ultimate result is highly variable, from permanent total obstruction to total patency, with or without severe reflux. In addition to this course of the thrombotic process, other areas of the extremity’s veins may be affected by primary reflux disease, independent of the thrombotic process. The events that follow acute thrombophlebitis were beautifully described in a classic paper by Gunnar Bauer in 1948.[11] In this paper he describes the very early findings in symptomatic venous patients achieved with descending phlebography with the patient at a 458 angle with the foot down and correlated these findings with resected vein segments obtained at the time of popliteal vein ligation. In postthrombotic veins he found patterns of recanalization varying from nearly complete obstruction with large collaterals to widely patent, thickened veins, but most typically there were webs created by partitions in the vein secondary to retained portions of the old clot that had shrunken and become endothelialized. It would be difficult to know if those veins were more disadvantaged by reflux occurring in a valveless vein or by relative obstruction due to a distorted lumen. In 1952, Linton[4] described the fact that the natural history of postthrombotic disease begins with a symptom-free interval after the acute episode when the superficial femoral vein (SFV) is thrombosed, followed by development of late sequelae after recanalization occurs and the now-valveless vein allows free reflux when the patient is in the erect position. The key to understanding the course of postthrombotic clinical events is the process that has been termed recanalization because this results in conversion of an obstructive lesion into a more or less patent channel, but one in which valvular competence is likely to be destroyed. The clinical course of DVT begins with an abrupt onset of the thrombosis, which can be silent but typically is heralded by swelling, tenseness of the leg, and pain. When the leg is elevated and after 24–72 hours, the swelling usually reverts to near normal. This relief is especially dramatic when intravenous heparin is given in therapeutic
Figure 69-3. Postthrombotic greater saphenous vein with synechiae, distorted luminal masses, and destroyed valve.
dosage. The process of opening effective collateral occurs during this time, aided by the antithrombotic and antiinflammatory effects of heparin. Heparin is an extremely effective agent to stop the extending thrombosis and to prevent further embolization from the clot. Once the acute thrombosis is controlled and the collaterals are opened, there ensues an interval phase of mild symptoms. During this time the patient returns to an active lifestyle and should be encouraged to use external support on the extremity. The thrombus remains occlusive for a time, but a dynamic process of healing of the thrombus follows. Neovascularization begins in the thrombus, where microscopic new vessels can be found invading the clot. Simultaneously, the thrombus appears to shrink and retract from the vein wall. A new intimal lining of the vessel covers the thrombus and the scars within the vein. The patient often feels very well, although a variable amount of swelling and tightness, or pain, may persist. This interval phase may last 3 months to several years, but over time some patients become increasingly symptomatic with swelling, heaviness, and, in certain instances, skin changes. Follow-up by duplex scan shows progressive recanalization of the obstructed segment, a process that may be seen to begin in 6–12 weeks[28] and may progress over months to years.
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Figure 69-4. Postthrombotic femoral vein with multiple septae, seen from above.
The end product of this long healing process after DVT is highly variable and is presently under study. In some cases the obstruction never goes away, but these are the minority. In most cases of thrombosis below the inguinal ligament the thrombus becomes recanalized and a new lumen appears. The quality of the new lumen is highly variable from a totally patent wide open lumen to one that contains synechiae, partitions, and intraluminal masses (Fig. 69-4). About half of these cases show detectable reflux after one year[28] by duplex scan, but it is not yet known what will happen after several or many years. Some individuals will stabilize and accommodate to the new vein, others will slowly develop increasing swelling, pain, and pigmentation, and a minority will proceed to late ulceration, which may require 10 –20 years to develop. During this long course of development of late sequelae, intercurrent episodes of minor or even major deep vein thromboses may occur and are difficult to diagnose (Fig. 69-5). In addition to the changes that occur at the site of the thrombosis, the longitudinal study of post-DVT changes at the University of Washington[28] has identified frequent valve incompetence at a distance from the site of the thrombus and have interpreted this as a possible remote effect of the thrombosis. Since the veins were not studied prior to the thrombosis, it is not known whether these same valve sites were competent or incompetent before the thrombosis. In the history of valve reconstruction, the first valve repair ever done[29] was performed in a refluxing valve proximal to a recent distal thrombosis, and this repair discovered a normal valve structure with elongated cusps, which became competent after repair and remained competent with an asymptomatic leg for a follow-up of 12 years. In a series of valve repairs, nearly one third were performed in cases with distal thrombosis and proximal primary valve cusp elongation, with results comparable to those cases where the entire disease process was one of primary valve incompetence and better than the results in pure postthrombotic
Figure 69-5. Venogram showing gross distortion of veins and replacement by random collaterals around superficial femoral vein occlusion.
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valve replacement surgery.[30] These cases have been attributed to a combination of proximal primary valve incompetence that was asymptomatic prior to the DVT in the more distal veins. When the new DVT became recanalized, it has been reasoned that the total axial reflux was produced by a combination of proximal primary and distal postthrombotic disease and resulted in a severe clinical syndrome. The ability to prospectively follow a large series of DVT patients for 5 years and beyond is only now developing, and it will not be for a number of years that the natural history of DVT will be learned. Of course, all patients diagnosed with DVT at the popliteal level or above will be treated with anticoagulants, so the true natural history of the untreated patient will probably never be known in any more detail than has already been outlined.
EFFECT OF SEGMENTAL DISTRIBUTION OF THROMBUS UPON CVD In the future, the course of the anticoagulated patient can be studied and used as the modified natural history of acute DVT and secondary CVD. When prospective studies are carried out, it will be possible to observe the effect of thrombus in various segments of the extremity. For instance, it is now known by prospective study that isolated calf vein thrombi seldom extend into the popliteal vein or above and rarely embolize in otherwise healthy individuals even if they are not treated with anticoagulants.[31] Over time, the isolated calf thrombus usually disappears and the vein becomes patent, often without gross reflux. The natural history of thrombotic obstruction seems to vary with the segments involved in the process. Isolated thrombi in the calf cause few if any long-term symptoms. Isolated iliac vein thrombi associated with a patent and competent femoral system may be symptomatic but are often adequately collateralized and become asymptomatic over time. Conversely, obstruction in the ilio-femoral vein coupled with reflux in the common/SFV and below is the worst combination for the erect active patient. Long-term occlusion in the SFV is often silent, especially when the saphenous and profunda femoris veins are patent and competent. Reflux in the SFVpopliteal-tibial channel is poorly tolerated and over long periods of time may lead to very severe sequelae that limit work capacity. When the process involves the greater saphenous vein (GSV), or the GSV and the profunda femoris vein (PFV), in addition to the SFV, symptoms are increasingly severe.
INFLUENCE OF ANATOMIC DISTRIBUTION OF CHRONIC VENOUS DISEASE The anatomic distribution of reflux and of obstruction is a major determining factor in the ultimate clinical manifestation of the disease. The CEAP classification divides the
venous system below the diaphragm into three divisions and 18 segments, as presented in Table 69-3. The divisions are superficial, perforator, and deep veins in the extremity, and all pelvic veins are deep veins.
Superficial Veins The saphenous veins, especially the greater saphenous, give rise to the largest single important source of CVD (Fig. 69-6).[13] Reflux rather than obstruction is the important physiologic problem in the saphenous vein. The vast majority of saphenous vein disease is primary degenerative disease rather than postthrombotic secondary disease, although both occur. Saphenous incompetence is accompanied by varicose veins, which usually result in a mild clinical problem of heaviness, aching, or mild swelling and are a frequent source of cosmetic discomfort. In some cases saphenous incompetence is the sole cause of advanced skin changes, even ulceration. The reason for ulceration occuring in some cases of saphenous reflux and not in others is not known, but it is a fact that some patients experience a long history of apparently benign varicose veins that is ultimately followed by appearance of skin changes and ulceration. Perhaps it is related to an increase in the volume of reflux until a critical burden of reflux is reached,[32] or perhaps the saphenous reflux becomes complicated by perforator reflux that transmits high pressure to the gaiter skin and leads to severe changes,[7] or perhaps there are molecular changes due to stasis and venous hypertension that reach a critical stage and become a cause of ulceration.[33 – 35] Over the course of time, or perhaps even in the beginning, incompetent saphenous veins may communicate directly or indirectly with incompetent perforator veins. Once the combination of perforator and deep vein reflux begins, the stage is set for transmission of deep subfascial pressure to the surface, where skin and subcutaneous tissue changes may ensue. Lipodermatosclerosis or thick brawny skin may follow, and ultimately ulceration may occur. The finding in our unpublished studies of a typical histologic appearance of primary disease that produces identical histologic changes in the collagen, elastin, and muscularis of the endothelium and media of the varices, saphenous veins, and perforator veins indicates the disease in all of these vessels is related. The involvement is progressive over time. The valvular changes of primary disease in the saphenous vein are related to atrophy of the cusps that may progress to the point of virtual disappearance of the valve cusps along the course of the vein. These changes are distinctly different than found in postthrombotic disease of the saphenous vein, where there is an identifiable luminal thrombus with lymphocytes and hemosiderin and neovascularization in the thrombus, and the valves are literally scarred and destroyed. There are many cases where the thrombosis occurs in a vein that was originally affected by primary disease and the histologic changes of both primary and secondary disease are found.
Perforator Disease Certain patterns of superficial insufficiency, mostly due to primary disease, are associated with advanced skin changes, including ulceration. In the GSV these changes usually occur
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Table 69-3. 18 Anatomic Segments Superficial veins (AS) 1 Telangiectases/reticular veins Greater (long) saphenous (GSV) 2 Above knee 3 Below knee 4 Lesser (short) saphenous (LSV) 5 Nonsaphenous Deep veins (AD) Inferior vena cava Iliac 7 Common 8 Internal 9 External 10 Pelvic – gonadal, broad ligament, other Femoral 11 Common 12 Deep 13 Superficial 14 Popliteal 15 Crural – anterior tibial, posterior tibial, peroneal (all paired) 16 Muscular – gastrocnemial, soleal, other Perforating veins (AP) 17 Thigh 18 Calf Source: Classification and grading of chronic venous disease in the lower limbs: A consensus statement. Phlebology 10:42–45, 1995.
with reflux throughout the length of the saphenous vein in the thigh and calf, and often with perforator reflux in the medial calf.[7,36] These perforators usually connect the posterior tibial vein with the posterior arch vein and may be direct or indirect connections via several branches. Some of the connections are between the posterior tibial or a muscular
vein and the GSV itself. In the lesser saphenous vein there may be connections between the peroneal vein and the lesser saphenous via incompetent perforators that cause posteriorlateral ulcers. Distal infra-malleolar ulcers may be associated with perforators that connect with the distal arch vein that curves around the inferior margin of the lateral malleolus.
Figure 69-6. Distribution of clinical, etiologic, pathophysiologic, and anatomic findings in 102 consecutive cases encountered in the Straub Clinic Vascular Surgery Department. (From Kistner, R.L., Eklof, B., Masuda, E.M.: Diagnosis of chronic venous disease of the lower extremities: The “CEAP” Classification. Mayo Clin. Proc. 71:338– 345, 1996.)
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Deep Veins Disease of the deep veins can be due to primary disease that produces pure reflux or to postthrombotic disease that results in mixtures of reflux and obstruction. The clinical picture and response to treatment is largely related to the distribution of the disease. Left untreated, CVD is prone to progress over long periods of time. It is not unusual in cases of venous ulceration to trace the original history back 10 or 15 years in the case of postthrombotic disease, and longer in the case of pure primary reflux. In cases of mixed primary and secondary disease, there may have been a very long history of primary reflux which was minimally symptomatic, or not symptomatic at all, only to become severely symptomatic a few months or one or 2 years after the thrombotic episode. The chronicity of venous disease is one of its salient features, which make it appear that the venous hypertension produces subtle changes that progress imperceptibly until a threshold is reached where symptoms and signs appear. The theories of fibrin cuffing around the vessels and of white blood cell margination at the site of ulceration address local factors that may explain the actual site and even the time of ulceration, but the underlying mechanism that provides the basis for these events is the long, slow response of the tissues to chronically sustained venous hypertension.
Patterns of Segmental Disease Some patterns of deep vein involvement by reflux and obstruction tend to be associated with ulceration, while others appear more benign (Table 69-4). In pure reflux disease, longitudinal reflux from the groin to the lower leg is the usual setting in which ulceration occurs. When the popliteal, or the superficial femoral and profunda, valves are intact, ulceration due to deep vein disease is very unlikely. Isolated popliteal and calf reflux is a possible but statistically unlikely cause of venous ulcer, and isolated calf reflux almost never is the cause of ulceration. Although isolated calf and perforator reflux may be the cause of lipodermatosclerosis, there is usually proximal reflux in either the deep or superficial veins when this occurs. Thrombosis of the iliac vein is often a benign problem if the femoral vein is patent and the thigh veins are competent. Excellent collateral can substitute effectively for the iliac occlusion, and treatment may not be needed over the long term. Occlusion of the SFV in the presence of a patent and competent PFV, and especially with an additional patent and competent GSV, is usually tolerated without symptoms.
Table 69-4.
Patterns in Chronic Venous
Disease Isolated calf vein thrombosis Isolated iliac vein thrombosis Isolated superficial femoral occlusion Femoral-popliteal-tibial reflux Iliac obstruction, femoral-popliteal reflux
The important thing is to avoid recanalization and reflux through the SFV. Reflux in the superficial femoral-popliteal and into the tibial veins can be the source of advanced symptoms of pain and swelling and is the setting in which ulceration occurs most frequently when the perforator and superficial veins also reflux. This can be due to either primary or secondary disease. Occlusion of the iliac vein connected with reflux in the femoral-popliteal-tibial veins is the worst combination. It is always postthrombotic because primary disease does not cause occlusion in the iliac vein. In the postthrombotic limb where both reflux and obstruction exist, the combination of disease above and below the popliteal level is associated with severe skin changes and ulcers. In this instance the recanalized veins are severely deformed and may have masses of shrunken, endothelialized tissue in the lumen, which are the remnants of the old occlusive DVT. These masses with their associated synechiae and septae cause a variable degree of obstruction to return flow in the veins; unfortunately, the physiologic tests that are available (venous pressures and plethysmography) do not provide reliable correlations between the presence of obstruction and the clinical importance of the obstruction, and both duplex scan and venography are prone to underestimate it. Added to this obstruction is the reflux that is due to valvular scarring and destruction. Physiologically, reflux seems to dominate as a cause of dysfunction in the majority of cases. The pattern that is particularly associated with advanced complications, the worst combination, is the case with occlusion of the iliac veins coupled with peripheral reflux throughout the extremity. This always is a postthrombotic state because primary disease does not cause iliac occlusion. This patient is often severely incapacitated by recurrent ulceration and brawny skin changes.
APPLICATION OF NATURAL HISTORY TO TREATMENT OF CVD Certain principles that might be evoked in CVD are: 1. 2.
3. 4.
The dominant factor in CVD in over 80% of the cases is reflux. Postthrombotic disease is considerably less frequent, but is statistically more severe in its clinical manifestation than PVI. PVI produces pure reflux. Postthrombotic disease produces mixtures of obstruction and reflux; initially obstruction is dominant, but reflux is more important in the later phases.
Treatment in CVD has been rooted in the application of external support to the erect extremity for all ages, and there is no reason now to alter this because the principle is correct. The challenge to the veins in the lower extremity is to return the blood to the active circulation in a sufficiently effective manner to prevent sequelae of pooling in the leg. The two impediments to this return are obstruction and valvular reflux,
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and the body is able to compensate more or less for obstruction but has no innate compensation for reflux in the erect state. The treatment of reflux by external support is acceptable to most patients, but the addition of bedrest to elevate the legs and alteration of an individual’s way of life is a major price to pay. With the introduction of the CEAP classification it has become obvious that the majority of venous disease is due to primary reflux,[8,13] and nearly all combinations of primary reflux can be treated surgically with good results. Since primary disease has no obstructive element, and since the operations of stripping for the saphenous vein, perifascial interruption for the large refluxing perforator vein, and valvuloplasty for the incompetent but structurally intact venous valve are all successful and readily available, surgery offers excellent therapy for the primary cases of venous insufficiency.[37 – 45]
Ulceration In the case of ulceration, 30% or more have been found to be due to saphenous or saphenous plus perforator disease, and these can all be treated surgically on an outpatient basis with excellent early results.[25,46] Long-term studies remain to be done, but seem likely to be favorable. Of the ulcers that are due to deep vein disease, almost always associated with either perforator or saphenous disease, about half appear to be due to postthrombotic disease, which usually begins in the deep veins, and the other half to primary deep venous reflux disease. Those that are due to deep primary disease can be reconstructed with a 75% chance of long-term control (.10 years).[30] Reflux in the saphenous and perforator veins and perhaps in the proximal thigh veins may be due to concurrent primary disease that was silent prior
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to the distal DVT. With the advent of newer endovascular techniques of balloon angioplasty and stenting in the iliac vein, it has become increasingly feasible to restore patency in the obstructed iliac veins. Reflux below the common femoral vein can be repaired successfully in most patients with primary reflux by valvuloplasty techniques. In patients with postthrombotic secondary reflux, valve repair is usually not feasible and some form of valve substitution is needed to restore competence. This is most often done by transplantation of an axillary or brachial vein segment that contains a valve into the superficial femoral or the popliteal vein. Decisions about surgery in these cases requires full venous evaluation that identifies disease in every segment of the extremity and differentiates between reflux and obstruction and between primary and secondary disease, because it is only in this way the surgeon can learn what is available to work with in the various segments of the venous tree. The evaluation of surgical treatment in these cases will require a much more intense investigation of the natural history of specific disease patterns coupled with exploratory surgical efforts by those who will diagnose accurately and are capable of specific surgical techniques with acceptable results. Ultimately, some form of randomized treatment trials will be necessary to compare surgical measures to nonsurgical management. When this is done, it will require the utmost care to evaluate the patients thoroughly and accurately. It can be considered a reasonable ambition to look forward to the time when lower extremity venous disease will be as thoroughly diagnosed as arterial desease and when a high proportion of cases will be effectively treated by both surgical and yet-to-be-developed medical measures. At that time it will no longer be necessary to adjust the patient to the venous disease; it will be possible to adapt the treatment to the patient’s activity requirements.
REFERENCES 1.
2.
3. 4.
5.
6.
Abenhaim, L., Kurz, X., Norgren, L., Clement, D., and the VEINES Task Force. The Management of Chronic Venous Disorder of the Leg. An Evidence-Based Report of an International Task Force. McGill University, Sir Mortimer B. Davis—Jewish General Hospital, 1997; 27– 40. Browse, N.L.; Burnand, K.G.; Lea Thomas, M. Diseases of the Veins: Pathology, Diagnosis and Treatment; Edward Arnold: London, 1988; 1 – 27. Homans, J. The Aetiology and Treatment of Varicose Ulcers of the Leg. Surg. Gynecol. Obstet. 1917, 24, 300. Linton, R.R. Modern Concepts in the Treatment of the Postphlebitic Syndrome with Ulcerations of the Lower Extremity. Angiology 1952, 3, 431– 439. Bauer, G. A Roentgenological and Clinical Study of the Sequels of Thrombosis. Acta Chir. Scand. 1942, 86 (Suppl. 74), 1– 116. Labropoulos, N.; Giannoukas, A.D.; Nicolaides, A.N.; Ramaswami, G.; Leon, M.; Burke, P. New Insights into the Pathophysiologic Condition of Venous Ulceration with
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Color-Flow Duplex Imaging: Implications for Treatment? J. Vasc. Surg. 1995, 22 (1), 45– 50. Hanrahan, L.M.; Araki, C.T.; Rodrigues, A.A.; Kechejian, G.J.; LaMorte, W.W.; Menzoian, J.O. Distribution of Valvular Incompetence in Patients with Venous Stasis Ulceration. J. Vasc. Surg. 1991, 13 (6), 805– 811. Kistner, R.L.; Eklof, B.; Masuda, E.M. Diagnosis of Chronic Venous Disease of the Lower Extremities: The “CEAP” Classification. Mayo Clin. Proc. 1996, 71 (4), 338–345. Porter, J.M.; Moneta, G.L. Reporting Standards in Venous Disease: An Update. International Consensus Committee on Chronic Venous Disease. J. Vasc. Surg. 1995, 21 (4), 635–645. Classification and Grading of Chronic Venous Disease. A Consensus Statement. J. Vasc. Surg. 1995, 21, 635 – 645. Bauer, G. The Etiology of Leg Ulcers and Their Treatment by Resection of the Popliteal Vein. J. Int. Chir. 1948, 8, 937–961.
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12. Gjores, J.E. The Incidence of Venous Thrombosis and Its Sequelae in Certain Districts of Sweden. Acta Chir. Scand. Suppl. 1956, 206, 1 – 88. 13. Labropoulos, N. CEAP in Clinical Practice. Vasc. Surg. 1997, 31, 224– 225. 14. Jacob, A.G.; Driscoll, D.J.; Shaughnessy, W.J.; Stanson, A.W.; Clay, R.P.; Gloviczki, P. Klippel-Trenaunay Syndrome: Spectrum and Management. Mayo Clin. Proc. 1998, 73, 28– 36. 15. Servelle, M. Klippel and Trenaunay’s Syndrome. Ann. Surg. 1985, 201 (3), 365– 373. 16. Browse, N.L.; Burnand, K.G.; Lea Thomas, M. Diseases of the Veins: Pathology, Diagnosis and Treatment; Edward Arnold: London, 1988; 603 – 625. 17. Parkes-Weber, F. Angioma Formation in Connection with Hypertrophy of Limbs and Hemi-Hypertrophy. Br. J. Dermatol. 1907, 19, 231– 235. 18. Plate, G.; Brudin, L.; Eklof, B.; Jensen, R.; Ohlin, P. Congenital Vein Valve Aplasia. World J. Surg. 1986, 10 (6), 929– 934. 19. May, R.; Thurner, J. The Cause of the Predominantly Sinistral Occurrence of Thrombosis of the Pelvic Veins. Angiology 1957, 8, 419– 427. 20. Homans, J. Operative Treatment of Varicose Veins and Ulcers Based upon a Classification of These Lesions. Surg. Gynecol. Obstet. 1916, 22, 143– 158. 21. Rose, S.S.; Ahmed, A. Some Thoughts on the Aetiology of Varicose Veins. J. Cardiovasc. Surg. 1986, 27 (5), 534– 543. 22. Travers, J.P.; Brookes, C.E.; Evans, J.; Baker, D.M.; Kent, C.; Makin, G.S.; Mayhew, T.M. Assessment of Wall Structure and Composition of Varicose Veins with Reference to Collagen Elastin and Smooth Muscle Content. Eur. J. Vasc. Endovasc. Surg. 1996, 11 (2), 230– 237. 23. Schultz-Ehrenburg, U.; Weindorf, N.; Von Uslar, D.; Hirche, H. Prospective Epidemiological Investigations on Early and Preclinical Stages of Varicosis. In Phlebologie ’89; Davy, A., Stemmer, R., Eds.; John Libbey Ltd.: Paris, 1989; 163 – 165. 24. Labropoulos, N. Clinical Correlation to Various Patterns of Reflux. Vasc. Surg. 1997, 31, 242– 246. 25. Sethia, K.K.; Darke, S.G. Long Saphenous Incompetence as a Cause of Venous Ulceration. Br. J. Surg. 1984, 71 (10), 754– 755. 26. Bergqvist, D.; Jaroszewski, H. Deep Vein Thrombosis in Patients with Superficial Thrombophlebitis of the Leg. Br. Med. J. 1986, 292 (6521), 658– 659. 27. Lees, T.A.; Lambert, D. Patterns of Venous Reflux in Limbs with Skin Changes Associated with Chronic Venous Insufficiency. Br. J. Surg. 1993, 80 (6), 725– 728. 28. Meissner, M.H.; Manzo, R.A.; Bergelin, M.S.; Markel, A.; Strandness, D.E.J. Deep Venous Insufficiency: The Relationship Between Lysis and Subsequent Reflux. J. Vasc. Surg. 1993, 18 (4), 596– 605.
29. Kistner, R.L. Surgical Repair of a Venous Valve. Straub Clin. Proc. 1968, 34, 41– 43. 30. Masuda, E.M.; Kistner, R.L. Long-Term Results of Venous Valve Reconstruction: A 4- to 21-Year Follow-Up. J. Vasc. Surg. 1994, 19 (3), 391– 403. 31. Masuda, E.M.; Kessler, D.M.; Kistner, R.L.; Eklof, B.; Sato, D.T. The Natural History of Calf Vein Thrombosis: Lysis of Thrombi and Development of Reflux. J. Vasc. Surg. 1998, 28, 67– 74. 32. Christopoulos, D.; Nicolaides, A.N.; Szendro, G. Venous Reflux: Quantification and Correlation with the Clinical Severity of Chronic Venous Disease. Br. J. Surg. 1988, 75 (4), 352– 356. 33. Burnand, K.G.; Whimster, I.; Naidoo, A.; Thomas, M.L.; Browse, N.L. Pericapillary Fibrin in the Ulcer-Bearing Skin of the Leg: The Cause of Lipodermatosclerosis and Venous Ulceration. Br. Med. J. 1982, 285 (6348), 1071– 1072. 34. Scott, H.J.; Smith, P.D.C.; Scurr, J.H. Histologic Study of White Blood Cells and Their Association with Lipodermatosclerosis and Venous Ulceration. Br. J. Surg. 1991, 78 (2), 210– 211. 35. Pappas, P.J.; Duran, W.N.; Hobson, R.W.I. Pathology and Cellular Physiology of Chronic Venous Insufficiency. In Handbook of Venous Disorders: Guidelines of the American Venous Forum; Yao Ga, Ed.; Chapman and Hall: London, 1996; 44 – 59. 36. Labropoulos, N.; Leon, M.; Nicolaides, A.N.; Sowade, O.; Volteas, N.; Ortega, F.; Chan, P. Venous Reflux in Patients with Previous Deep Venous Thrombosis: Correlation with Ulceration and Other Symptoms. J. Vasc. Surg. 1994, 20 (1), 20 – 26. 37. Kistner, R.L. Methods for Reconstruction of Deep Venous Reflux: Long-Term Results. Vasc. Surg. 1997, 31, 268– 271. 38. Moneta, G.L. The Case Against Aggressive Treatment. Vasc. Surg. 1997, 31, 271– 273. 39. Perrin, M.R. Results of Deep-Vein Reconstruction. Vasc. Surg. 1997, 31, 273– 275. 40. Lurie, F. Results of Deep-Vein Reconstruction. Vasc. Surg. 1997, 31, 275– 276. 41. Hoshino, S. Endoscopic Valvuloplasty. Vasc. Surg. 1997, 31, 276. 42. Sottiurai, V.S. Results of Deep-Vein Reconstruction. Vasc. Surg. 1997, 31, 276– 278. 43. Taheri, S.A. Vein Valve Transplantation. Vasc. Surg. 1997, 31, 278– 281. 44. Raju, S. Results of Deep Vein Reconstruction. Vasc. Surg. 1997, 31, 281– 286. 45. Bergan, J.J. Venous Reflux: Guidelines for Management. Vasc. Surg. 1997, 31, 286– 296. 46. Burnand, K.; O’Donnell, T.; Lea, M.T.; Browse, N.L. Relationship Between Post-Phlebitic Changes in Deep Veins and Results of Surgical Treatment of Venous Ulcers. Lancet 1976, I, 936– 938, 1976.
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Surgical Management of Lower Extremity Chronic Venous Insufficiency Jae-Sung Cho Peter Gloviczki
or postthrombotic valvular incompetence is the most frequent etiology, most operations treat valvular reflux by excision, stripping, or ligation of the incompetent superficial and/or perforator veins. Deep vein valvular incompetence is restored by various surgical techniques, including direct or indirect valve repairs, valve transplantation, and vein transposition. Finally, venous bypasses are considered in patients with deep venous obstruction. In surgical candidates the operation is usually performed on the superficial and perforator veins first, and in most centers deep vein valve reconstruction is considered in patients who have recurrent problems after failure of ablation of superficial and perforator reflux. Surgical treatment for obstruction should be carefully planned, and recent advances in endovascular techniques, such as venous stenting (see Chapter 71), may soon restrict some of the indications for surgical repair.
INTRODUCTION The main goal of surgical treatment of chronic venous insufficiency (CVI) is to achieve healing of venous ulcers and to prevent new or recurrent ulcerations. Additional objectives in patients with less severe disease include improvement of edema, stasis skin changes (induration, eczema), and treatment of primary or secondary varicosity. Relief of symptoms like heaviness of the leg, aching, or venous claudication is equally important. CVI is a spectrum of venous disease ranging from asymptomatic spider veins or telangiectasia to chronic nonhealing venous ulcerations (see Chapter 69). Valvular incompetence with venous reflux accounts for most cases of advanced CVI, whereas deep venous obstruction is the underlying cause in 5– 10% of all patients. In many patients a combination of venous obstruction and valvular incompetence plays a role in the development of venous stasis changes. In this chapter we will focus on the strategy, techniques, and results of surgical treatment of patients with advanced CVI. We discuss the latest advances in minimally invasive endoscopic venous surgery and present current techniques and results of deep vein valve reconstructions and venous bypasses. The management of milder forms of chronic venous disease, such as telangiectasia or primary varicosity, is discussed in detail in Chapter 67.
PREOPERATIVE EVALUATION Careful patient evaluation before surgery should establish the presence and severity of chronic venous disease, reveal its etiology (congenital, primary, or secondary), determine the anatomic segments involved (superficial, perforator, or deep), and establish the primary pathophysiology, such as reflux, obstruction, or a combination of both. Details of the updated CEAP (clinical class, etiology, anatomy, pathophysiology) classification and patient evaluation are discussed in detail by Kistner et al. in Chapter 69. Noninvasive evaluation using phlethysmographic techniques and duplex scanning is detailed in Chapter 9. Specific preoperative tests needed for certain procedures will be mentioned in this chapter before discussion of each operation.
THE STRATEGY OF SURGICAL TREATMENT Surgical treatment is designed to decrease ambulatory venous hypertension, the most important cause of CVI. Since primary
Hobson/Wilson/Veith: Vascular Surgery: Principles and Practice, Third Edition, Revised and Expanded DOI: 10.1081/0819-9-120024954 Copyright q 2004 by Marcel Dekker, Inc.
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ABLATION OF SUPERFICIAL REFLUX It is important to recognize that patients with isolated superficial incompetence, with varicose veins, and incompetent greater or lesser saphenous system can develop advanced CVI and venous ulcerations. Preoperative duplex scanning will identify valvular incompetence of the greater saphenous vein. Ablation of the saphenous reflux is accomplished by high ligation and saphenous stripping, using the inversion technique to remove the incompetent portion of the greater saphenous vein, usually from the groin to below the knee. Avulsion of varicose veins is performed through small stab wounds using venous hooks. Evaluation, different techniques, and results of ablation of the superficial venous system are discussed in detail in Chapter 67.
INTERRUPTION OF INCOMPETENT PERFORATING VEINS The prevalence of incompetent perforators in limbs with venous ulceration is estimated to be between 56 and 63% of the limbs studied by duplex scanning.[1 – 3] Recent investigations using duplex scanning and AVP measurements have also demonstrated the functional and hemodynamic significance of perforator incompetence. In one study, 70% of incompetent perforators were of moderate or major hemodynamic significance, and the presence of significant perforator incompetence correlated with the severity of CVI.[4] Using duplex scanning, Labropoulos et al. reported a good correlation between the number and size of incompetent perforating veins and the severity of CVI.[5] Controversy over the importance of perforators still continues, since some studies failed to observe any benefit from perforator interruption.[6,7] The classic Linton procedure[8] that included ligation of incompetent perforators through a long incision along the medial aspect of the leg has been largely abandoned because of frequent wound complications and need for prolonged hospitalization. Subsequent variations of this procedure lacked visual control and resulted in incomplete interruption of perforating veins.[9 – 11] Recent progress in minimally invasive endoscopic surgery has resulted in renewed interest in surgical treatment of perforator vein incompetence. Subfascial endoscopic perforator surgery (SEPS) is used now with increasing frequency to treat patients with venous ulcers.[12 – 20]
Figure 70-1. Anatomy of medial superficial and perforating veins of the leg. (Mayo q1996.)
perforator interruption or those with extensive skin changes or large legs may not be suitable for SEPS.
Preoperative Tests Preoperative duplex scanning is the single most important test to diagnose perforator incompetence and map the sites of the perforators (Fig. 70-2). Patency and incompetence of the deep and superficial veins is also determined, and in patients with incompetent superficial system, concomitant ablation of the superficial reflux is performed. Strain gauge or air plethysmography will confirm global valvular incompetence and document postoperative improvement in venous function. Contrast phlebography is preserved for patients with deep venous obstruction.
Patient Selection In good-risk patients with clinical class 4, 5, or 6 disease (lipodermatosclerosis, healed or active ulcerations), the presence of incompetent perforators (Fig. 70-1) is an indication for surgical treatment. Contraindications include nonambulatory or high-risk patients, associated extensive deep venous occlusion, chronic arterial occlusive disease, infected ulcer, or morbid obesity. Diabetes, rheumatoid arthritis, or scleroderma are relative contraindications. Patients with previous
Endoscopic Techniques SEPS was described in the mid-1980s in Germany,[12] but the original technique has been modified by various investigators.[13 – 15] The authors use laparoscopic instrumentation introduced through two endoscopic port sites made proximal to the site of the ulceration.[15 – 17] Using a bloodless surgical field provided by orthopedic tourniquet, the endoscopic camera and the instruments are introduced into the subfascial
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Figure 70-2. Duplex scanning shows incompetent calf perforating vein. Arrow indicates bidirectional flow in the vein. (With permission from Gloviczki P.; Bergan J.J. (eds.). Atlas of Endoscopic Perforator Vein Surgery. London, Springer-Verlag, 1998.)
space through the ports to dissect and interrupt medial calf perforators (Fig. 70-3). Carbon dioxide is insufflated into the subfascial space to a pressure of 30 mmHg.[18] Under videoscopic guidance, the perforating veins are divided between the clips (Fig. 70-4), or coagulated and divided using the ultrasonic harmonic scalpel. The dissection is extended distally a couple of centimeters proximal to the medial malleolus, and all important medial calf perforators (Cockett
II, Cockett III, and proximal paratibial perforators) are divided (Fig. 70-1). The Cockett veins are frequently located in a duplication of the deep fascia, which has to be incised to dissect the veins. The fascia of the deep compartment is also opened (paratibial fasciotomy) to expose all perforator veins that join the posterior tibial veins in this region. SEPS allows interruption of all incompetent medial calf perforators above the ankle (Fig. 70-5). However, the retromalleolar Cockett I
Figure 70-3. Setup of subfascial endoscopic perforator vein surgery (SEPS) using two endoscopic ports. (With permission from Gloviczki P.; Cambria R.A.; Rhee R.Y.; Canton L.G.; McKusick M.A. Surgical Technique and Preliminary Results with Endoscopic Subfascial Division of Perforating Veins. J. Vasc. Surg. 1996; 23:517– 523.)
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Figure 70-4. Endoscopic clipping and division of a calf perforator vein. (With permission from Gloviczki P.; Cambria R.A.; Rhee R.Y.; Canton L.G.; McKusick M.A. Surgical Technique and Preliminary Results with Endoscopic Subfascial Division of Perforating Veins. J. Vasc. Surg. 1996; 23:517 – 523.)
perforator, if incompetent, will usually have to be divided using an open technique.
Results Accumulated data with SEPS indicate its advantages over open procedures.[12,16,19] In a prospective, randomized study
Figure 70-5.
consisting of 39 patients, wound complications were noted in 53% of patients in the open ligation group as compared to none in the endoscopic ligation group.[19] Ulcer recurrence did not differ between the two groups at a mean follow-up of 21 months. The Mayo Clinic experience was reported by Rhodes et al.20 It included 57 consecutive SEPS procedures,
View of the subfascial space after clipping of the perforating veins.
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Figure 70-6. Ulcer recurrence on the basis of cause of chronic venous insufficiency. Dashed line represents standard error of greater than 10%. (With permission from Gloviczki P.; Bergan J.J.; Rhodes J.M.; et al. Mid-Term Results of Endoscopic Perforator Vein Interruption for Chronic Venous Insufficiency: Lessons Learned from the North American Subfascial Endoscopic Perforatory Surgery Registry. J. Vasc. Surg. 1999; 29, 489– 502.)
performed in 48 patients, with concomitant ablation of saphenous reflux in 41.[20] At a mean follow-up of 17 months, minor wound complications occurred in 5% of the limbs, while all ulcers healed at a median of 36 days after surgery. Recurrence or new ulcer development occurred in 9% of all patients. Cumulative ulcer recurrence at 2 years for the entire group was 18%. These results were similar to those reported by others using a variety of SEPS techniques.[13,19,21 – 25] The safety and efficacy of SEPS was also confirmed in the North American (NASEPS) Registry.[22,26] In this series, 146 patients, of whom 122 had active (C6) or healed ulcers (C5), were followed for a mean of 24 months. Wound complication rates were 6%. Cumulative ulcer healing rates at one year were 88% with a median time to healing of 54 days. Ulcer recurrence at 2-years was 28%. Of note, limbs with primary valvular incompetence were shown to have a better outcome than did those with postthrombotic syndrome: 2-year cumulative recurrence rates were 20% and 46%, respectively (Fig. 70-6). Overall recurrence rate was 23% at last follow-up. Although this recurrence rate is high, it still compares favorably to results of nonoperative management.
this technique starts with complete dissection of the adventitia and identification of valve commissures. The marking suture is then placed in the commissure and used as a guide to the placement of the venotomy incision, which should be on a direct line distal to the commissure. The incision is then extended to and through the marking suture, extending proximally in the vein for 2 –3 cm. The vein is laid open, and retention sutures are placed in four corners for traction during the repair. The valve is exposed and the stretched floppy leaflets are repaired to restore a cup-like configuration to both cusps. Valve competence after repair is confirmed by the strip test.[31] The original operation demands technical skill and precise surgical judgment. The floppy, delicate valve cusps are easily
OPERATIONS FOR INCOMPETENCE OF DEEP VEINS Valvuloplasty When ablation of superficial system and interruption of incompetent perforators are not effective to prevent ulcer recurrence and control the patient’s symptoms, repair of deep venous valves can be considered. The valve that is most amenable to direct repair is the most proximal valve in the superficial femoral vein. Direct surgical repair of incompetent deep vein valves was pioneered by Kistner (Fig. 70-7).[27 – 30] The critical portion of
Figure 70-7. Internal valvuloplasty by Kistner method. (A ) Vertical incision through commissure. (B ) View of floppy valve after venotomy. (With permission from Bergan J.J.; Yao J.S.T. (eds.). Venous Disorders. Philadelphia, W.B. Saunders, 1991; 265.)
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injured in the hands of inexperienced surgeon. Two modifications of the original technique have been made. Raju[32,33] in 1983 modified the transvalvular approach of Kistner to a supravalvular incision. A transverse venotomy (60% of circumference) is made in the common femoral vein at the level of origin of profunda femoris (Fig. 70-8). The redundant valve leaflets are visualized, and using a continuous 7-0 Prolene suture the leaflets are shortened. Sottiurai in 1986[33,34] combined transverse and vertical venotomy to provide an adequate exposure of the valve cusps (Fig. 70-9). A transverse venotomy is made 4 –6 mm superior to the commissure of the valve cusps. A vertical venotomy originating from the midpoint of the transverse is made extending into the valvular sinus, without injuring the valve cusps. The floppy edges are plicated against the wall at the commissure using a double armed 7-0 Prolene sutures. Valve competence can also be restored by placing an external row of sutures along the diverging cusp margins on the vein wall.[33,35] Sutures are placed at each commissure and carried inferiorly until the valve becomes competent. Anticoagulation of heparin or warfarin sodium is not necessary using this technique since venotomy was not made. Closed technique using angioscopic control has been described at the Mayo Clinic (Figs. 70-10, 70-11).[36] The major advantage of this technique is avoidance of venotomy and precise anatomic repair.
Results Long-term follow-up of valvuloplasty for primary valvular incompetence showed good clinical results in 63–90% of patients.[34,37 – 41] Kistner in an analysis of 4–21-year follow-up of 48 patients reported clinical improvement in 73% of patients at 10 years.[41] Of importance was that 60% of the extremities remained symptom-free, and half of these did not wear compression stockings postoperatively. Two or more recurrences were observed in 17% of cases. Postoperative imaging studies correlated well with the clinical outcome. However, physiologic improvement as determined by late venous pressure
Figure 70-9. Internal valvuloplasty by Sottiurai method. (A ) Tshaped incision above valve. (B ) View of valve during repair. (With permission from Bergan J.J.; Yao J.S.T. (eds.). Venous Disorders. Philadelphia, W.B. Saunders, 1991; 266.)
studies did not correlate well with clinical improvement; a number of patients experienced clinical benefit without reduction in venous pressure. This may indicate that there are residual abnormalities that may not be manifested clinically but produce abnormal venous pressure. Repair of multiple valves may achieve better results.[38,42] Raju[43] reported improved hemodynamic results when simultaneous repair of the superficial and deep femoral veins and posterior tibial veins was performed as compared to single valve repair.
Venous Transposition and Valve Transplantation In valvular incompetence secondary to postthrombotic syndrome the valves are deformed from cicatrization and contracture to such an extent that repair is rarely possible. Two surgical options are available. First, the valves can be treated by transposition of the incompetent vein to the adjacent greater saphenous or profunda femoris vein containing a competent valve.[44] The other option is transplantation of valvecontaining segment of the axillary or brachial vein into the superficial femoral vein or popliteal vein segment.[45]
Results
Figure 70-8. Internal valvuloplasty by Raju method. (A ) Horizontal incision above valve. (B ) View of valve from above and suture placement after venotomy. (With permission from Bergan J.J.; Yao J.S.T. (eds.) Venous Disorders. Philadelphia, W.B. Saunders, 1991; 265.)
Long-term outcome following valve transposition[38,41,46 – 50] reports good outcome from 40–70% of patients, whereas the numbers following transplantation[38,47,49,51 – 54] are 30–90%. Raju[50] in a report of axial transformation of profunda femoris vein noted actuarial 66% 5-year recurrence-free survival rate. This is inferior to that achieved in patients with primary venous incompetence and represents greater severity of injury to the deep veins. The long-term results of external repair or angioscopic repair are not yet available.
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Figure 70-10. Angioscopic repair of the first incompetent valve of the superficial femoral vein. (With permission from Gloviczki, Merrell S.W.; Bower T.C. Femoral Vein Valve Repair Under Direct Vision Without Venotomy: A Modified Technique with Use of Angioscopy. J. Vasc. Surg. 1991; 14:645– 648.)
OPERATION FOR VENOUS OBSTRUCTION
prudent to wait 6 months to a year before deep vein reconstruction is performed.[55,56]
Direct venous bypass surgery should only be considered in those patients in whom lifestyle-limiting symptoms are elicited on a daily basis. Indications for surgical intervention are swelling and venous claudication. Since recanalization of deep veins following acute thrombosis is frequent, it is
Bypass for Femoropopliteal Venous Occlusion First described by Warren and Thayer in 1954[57] and popularized by Husni[56] and May,[58] saphenopopliteal
Figure 70-11. (A ) Angioscopic view of needle passage through the valve leaflets. (B ) Valve leaflet redundancy may be reassessed after each suture is tied. (C ) Sutures are usually required in both commissures to achieve complete valvular competence. (D ) Final angioscopic appearance of a competent valve after repair. (With permission from Gloviczki, Merrell S.W.; Bower T.C. Femoral Vein Valve Repair Under Direct Vision Without Venotomy: A Modified Technique with Use of Angioscopy. J. Vasc. Surg. 1991; 14:645 –648.)
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bypass (May-Husni procedure) can provide effective relief of femoropopliteal venous occlusion in the presence of patent tibial veins and pelvic outflow tract. The ipsilateral saphenous vein must be free of disease. Ambulatory venous pressure after exercise should not drop by more than one third of the resting pressure of the contralateral limb.[59] The vein is exposed through a 10 –20 cm long incision posterior to the medial border of the tibia. Popliteal vein is dissected and the site of anastomosis determined. The distal saphenous vein is transected and anastomosed to the side of popliteal vein caudal to the site of obstruction. This allows venous drainage of the superficial stasis at the ankle and provides outflow of intramuscular calf muscle blood. Temporary arteriovenous fistula can be constructed as advocated by Gruss.[59,60]
Results With the relative paucity of these operations, definitive conclusions cannot be drawn; however, the available data are promising with reported functional improvement in approximately 75% of patients. In nine series that included 218 operated patients, functional improvement was reported in 77%.[37,59 – 66] In an earlier review of 59 operations, Smith and Trimble[67] reported clinical success in 76% of the patients. Crude patency rates at variable follow-up ranged from 5 to 100%, but only four of nine studies reported on late imaging of the grafts to ascertain patency.
anastomosis is affected with a 6-0 prolene using standard vascular surgical technique. If the graft is kinked at the saphenofemoral junction of the donor limb, the vein may be divided and reanastomosed to avoid torsion.[63] If a prosthetic graft is used, because of either lack of or inadequate size of saphenous vein, the graft should be at least 8 mm in diameter. Endovenectomy of the recanalized vein is often required to assure adequate inflow into the prosthesis. Temporary arteriovenous fistula is constructed by anastomosing a tributary to the saphenous vein to the common femoral or superficial femoral vein. At the completion of procedure, venous pressure is measured. The patients are maintained on anticoagulation with an international normalized ratio between two to three as long as the graft is patent. An arteriovenous fistula can be ligated after 6 months. A postoperative phlebogram is obtained and the graft imaged by duplex scanning every 3 months for the first year and then every 6 months thereafter for the lifetime of the graft. Graft thrombosis, when suspected, should be confirmed by phlebography.
Results Analysis of multiple series showed a clinical improvement rate of 63–89%.[55,60,61,63,65,66,72,73] Reported patency rates range from 70 –85%, although the follow-up period varies widely and objective documentation of graft patency is rarely done. In the largest series reported by Husni of 85 bypasses,[61] graft patency was observed in 47 of 67 grafts
For Common Femoral or Iliac Vein Obstruction Initially described by Palma[68,69] and popularized by Dale,[62,70,71] cross-pubic bypass (Palma-Dale procedure) is the most common procedure performed to treat unilateral iliac vein obstruction (Fig. 70-12). Only about 3% of patients with CVI are candidates for this operation.[72] Patients with leftsided iliac vein thrombosis frequently have chronic occlusion of the origin of the left common iliac vein, usually caused by compression of the vein by the overriding right common iliac artery (May-Thurner syndrome). The authors prefer the Palma-Dale procedure as the surgical treatment of choice over iliac vein patch or repositioning of iliac artery behind the iliac vein. If possible, iliac vein stenting in these patients appears to be a good alternative. The Palma-Dale procedure can be performed using either contralateral saphenous vein (as originally described) or externally supported ePTFE graft. Disease-free contralateral saphenous vein should be assured. The contralateral saphenous vein is exposed through a vertical incision in the groin from the saphenofemoral junction down to distal third of the thigh. On the affected limb, exposure of common femoral, superficial femoral, and profunda femoris veins is obtained. Dissection of these veins is limited to the anterior surface, and the tributaries are left intact to avoid angulation and to maintain collateral outflow. The vein is then tunneled subcutaneously to the recipient side in the suprapubic region. It is vital to avoid twisting of the graft and to maintain gentle curvature of the graft. An anteromedial vertical venotomy that is two to three times the diameter of the bypass conduit is made and intraluminal webs, if present, excised. The
Figure 70-12. Illustration of left-to-right femorofemoral venous bypass (Palma-Dale procedure). (With permission from Rhee R.Y.; Gloviczki P.; Luthra H.S.; et al. Iliocaval Complications of Retroperitoneal Fibrosis. Am. J. Surg. 1994; 168:179– 183.)
Chapter 70.
Surgical Management of Lower Extremity Chronic Venous Insufficiency
at the last follow-up that ranged from 6 months to 15 years. Clinical improvement was achieved in 74% of the patients. Better long-term results were noted when a temporary distal arteriovenous fistula was used and when the grafts were implanted for extrinsic compression as compared to PTS.
Prosthetic Femorocaval, Iliocaval, or Inferior Vena Cava Bypass Anatomic in-line iliac or iliocaval bypass (Fig. 70-13) can be performed for unilateral disease, when autologous conduit for suprapubic graft is not available, or for bilateral iliac, iliocaval, or IVC occlusion. Extensive venous thrombosis, tumors, and retroperitoneal fibrosis resistant to nonoperative therapy[74 – 77] are potential indications. Failure of previous endovascular attempts, including stent placement, are other indications. The femoral vessels for the arteriovenous fistula or for the site of the distal anastomosis are exposed. The iliac vein or the distal segment of the IVC is exposed through a right oblique flank incision using the retroperitoneal approach. The vena cava at the level of the renal vein is best exposed through a midline or a right subcostal incision. The ascending colon is mobilized medially and the cava exposed retroperitoneally. The infrarenal IVC is reconstructed with a 16– 20 mm graft, the iliocaval segment usually with a 14 mm and the femorocaval segment with a 10 or 12 mm PTFE graft
Figure 70-13. Illustration of a right iliocaval bypass with a 14mm ringed expanded polytetrafluoroethylene (ePTFE) graft. Note the right saphenous vein to femoral artery fistula with an ePTFE sleeve. (With permission from Rhee R.Y.; Gloviczki P.; Luthra H.S.; et al. Iliocaval Complications of Retroperitoneal Fibrosis. Am. J. Surg. 1994; 168:179 – 183.)
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(Fig. 70-14). The arteriovenous fistula is constructed first in patients who undergo a long iliocaval bypass. Short iliocaval bypass with significant pressure gradient can be performed without an arteriovenous fistula. Reconstruction of the vena cava with a straight PTFE graft, if the inflow is good, can also be performed without an additional arteriovenous fistula. In patients who undergo femorocaval bypass, the proximal and distal anastomoses of the bypass are performed first, followed by construction of the arteriovenous fistula before restoration of flow through the graft. A tributary of the greater saphenous vein is most frequently used for the arteriovenous fistula. While Dale did not favor the use of an arteriovenous fistula with PTFE grafts,[78] the authors, in agreement with Sottiurai, advocate use of distal arteriovenous fistula in all femorocaval or longer iliocaval grafts to help maintain patency. We prefer to keep the fistula patent as long as possible.
Figure 70-14. Venogram 1.6 years after implantation of left common femoral IVC 10 mm ePTFE graft for isolated left iliac vein occlusion. Patient is symptom-free at 6 years. Arrow indicates site of end-to-end distal anastomosis. (With permission from Gloviczki P.; Pairolero P.C.; Toomey B.J.; et al. Reconstruction of Large Veins for Nonmalignant Venous Occlusive Disease. J. Vasc. Surg. 1992; 16:750 – 761.)
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Results Experience with femorocaval or iliocaval bypass is limited, and only a few series are available. A Mayo Clinic series reported on 12 such bypasses with a follow-up that extended up to 5 years.[79] Seven grafts were patent at last follow-up, six of which remained asymptomatic. Improvement in the seventh patient was also documented. Alimi et al.[80] reported results of eight iliac vein reconstructions with femorocaval or iliocaval bypasses for both acute and chronic obstructions. Of four patients who had chronic obstruction, three grafts were patent at last follow-up.
Husfeldt[81] performed four femorocaval bypasses, all of which were patent at a follow-up of 4 –30 months. The largest experience with PTFE reconstruction of large veins was presented by Sottiurai et al.[82] In that series, 52 of 56 grafts (93%) used for a variety of central vein reconstructions were patent at one year with employment of arteriovenous fistula using the saphenous vein between the adjacent artery and the graft. The site of the fistula was at 2 cm proximal to the heel of the graft, where an ovoid 410 mm defect was cut in the graft wall to standardize flow through the fistula.
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14. Bergan, J.J.; Ballard, D.J.; Sparks, S. Subfascial Endoscopic Perforator Surgery: The Open Technique. In Atlas of Endoscopic Perforator Vein Surgery; Gloviczki, P., Bergan, J.J., Eds.; Springer-Verlag: London, 1998; 141– 149. 15. O’Donnell, T.F., Jr. Surgical Treatment of Incompetent Communicating Veins. In Atlas of Venous Surgery; Bergan, J.J., Kistner, R.L., Eds.; W.B.Saunders: Philadelphia, 1992; 111– 124. 16. Gloviczki, P.; Cambria, R.A.; Rhee, R.Y.; Canton, L.G.; McKusick, M.A. Surgical Technique and Preliminary Results of Endoscopic Subfascial Division of Perforating Veins. J. Vasc. Surg. 1996, 23, 517– 523. 17. Atlas of Endoscopic Perforator Vein Surgery. SpringerVerlag: London, 1998. 18. Gloviczki, P.; Canton, L.G.; Cambria, R.A.; Rhee, R.Y. Subfascial Endoscopic Perforator Vein Surgery with Gas Insufflation. In Atlas of Endoscopic Perforator Vein Surgery; Gloviczki, P., Bergan, J.J., Eds.; Springer-Verlag: London, 1998; 125 – 138. 19. Pierik, E.G.J.M.; van Urk, H.; Hop, W.C.J.; Wittens, C.H.A. Endoscopic Versus Open Subfascial Division of Incompetent Perforating Veins in the Treatment of Venous Leg Ulceration: A Randomized Trial. J. Vasc. Surg. 1997, 26, 1049– 1054. 20. Rhodes, J.M.; Gloviczki, P.; Canton, L.G.; Rooke, T.; Lewis, B.D.; Lindsey, J.R. Factors Affecting Clinical Outcome Following Endoscopic Perforator Vein Ablation. Am. J. Surg. 1998, 176, 162– 167. 21. Negus, D.; Friedgood, A. The Effective Management of Venous Ulceration. Br. J. Surg. 1983, 70, 623– 627. 22. Gloviczki, P.; Bergan, J.J.; Canton, L.G.; et al. Mid-Term Results of Endoscopic Perforator Vein Interruption for Chronic Venous Insufficiency: Lessons Learned from the North American Subfascial Endoscopic Perforator Surgery Registry. J. Vasc. Surg. 1999, 29, 498– 50. 23. Jugenheimer, M.; Junginger, T. Endoscopic Subfascial Sectioning of Incompetent Perforating Veins in Treatment of Primary Varicosis. World J. Surg. 1992, 16, 971–975. 24. Wolters, U.; Schmitz-Rixen, T.; Erasmi, H.; Lynch, J. Endoscopic Dissection of Incompetent Perforating Veins in the Treatment of Chronic Venous Leg Ulcers. Vasc. Surg. 1996, 30, 481– 487.
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CHAPTER 71
Lytic Therapy and Venous Stenting: Indications and Results Anthony J. Comerota
Thrombolytic therapy and venous stents are used to restore patency to occluded or stenosed segments of the venous system. Thrombolytic therapy is used for acute thrombotic complications of the venous system, whereas venous stents are used to correct chronic stenotic or occlusive lesions. Confusion abounds as to the proper form of therapy for patients with acute and chronic venous diseases. In large part, the confusion exists because of lack of consensus on proper patient selection. Patients with both acute and chronic venous disease limited to the infrainguinal venous system caudal to the profunda femoris vein often have controllable symptoms and acceptable long-term sequelae following routine anticoagulation. Although some patients will have a severe post-thrombotic venous insufficiency syndrome, most in that morbid subset are difficult to identify during their initial presentation. Since patients with infrainguinal deep vein thrombosis (DVT) represent the largest subgroup who have acute proximal DVT, they likewise represent a large percentage of patients with chronic venous disease. It is known that sacrifice of the femoral vein in the thigh extending from the junction of the profunda femoris vein to the adductor canal results in minimal long-term venous morbidity.[1] Likewise, ligation of the femoral vein caudad to the profunda femoris vein results in minimal venous morbidity.[2] While there are selected indications for lytic therapy in patients with isolated infrainguinal venous thrombosis, such as those with popliteal and complete “trifurcation” calf vein thrombosis, the focus of this chapter’s section on thrombolytic therapy for DVT will be directed toward iliofemoral venous thrombosis, since these patients often present with the most severe manifestations of acute DVT and suffer the most debilitating postthrombotic symptoms. The discussion on stents in the venous system will address the specific indication for the stent and the expected results. Thrombolytic therapy and venous stenting are in evolution, but currently available data offer reasonable guidance to the clinician for appropriate use in properly selected patients.
THROMBOLYTIC THERAPY The early complication of acute deep venous thrombosis is pulmonary embolism, while the long-term morbidity is the postthrombotic syndrome. It appears that both thrombolytic therapy and standard anticoagulation are essentially equivalent in reducing the pulmonary embolic complication of acute DVT.[3] The important question remaining is whether pharmacologic removal of clot reduces the postthrombotic sequelae compared to standard anticoagulation. Although randomized trials of systemic lytic therapy compared to anticoagulation for acute DVT have been performed, they have failed to capture the attention of many physicians interested in this problem. In the absence of generally accepted prospectively derived data, the answer to this important question might be obtained by examining the underlying pathophysiology of the postthrombotic syndrome and reviewing the available data on the treatment of extensive venous thrombosis. Early reports of thrombolytic therapy for acute DVT used systemically infused plasminogen activators. This technique delivers only a fraction of the infused plasminogen activator to the thrombus, therefore a poorer lytic response is anticipated compared to catheter-directed techniques. Thirteen studies have been reported in the literature that compare anticoagulant therapy with thrombolytic therapy for acute DVT.[4 – 18] The diagnosis was established with ascending phlebography, and phlebography was repeated to assess the results of systemic thrombolysis. Unfortunately, data regarding the extent of DVT are not available, therefore iliofemoral DVT was not categorized separately from femoral-popliteal DVT. After pooling the data, it was found that only 4% of patients treated with anticoagulation had significant or complete lysis and an additional 14% had partial lysis. The majority, 82%, had either no objective phlebographic clearing or they extended their thrombi. In patients treated with thrombolytic therapy, 45% had significant or complete clearing of the clot, 18% had partial clearing, and the remaining 33% failed to improve or worsened.
Hobson/Wilson/Veith: Vascular Surgery: Principles and Practice, Third Edition, Revised and Expanded DOI: 10.1081/0819-9-120024955 Copyright q 2004 by Marcel Dekker, Inc.
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Two studies, using identical protocols for patient selection and treatment, followed their patients for 1.6–6.5 years for the development of symptoms of the postthrombotic syndromc.[14,19] The long-term evaluation demonstrated that the majority of patients who were free of postthrombotic symptoms were treated with streptokinase (the plasminogen activator used in both of these studies), whereas the majority of patients who had severe symptoms of postthrombotic syndrome were treated with anticoagulation alone. The important basic issue is whether lysis of deep venous thrombi preserves valvular function. In a long-term follow-up of a prospective, randomized study, Jeffrey and colleagues showed significant functional benefit 5–10 years after therapy for acute DVT in patients who initially enjoyed successful lysis.[16] Using photoplethysmography and foot volumetry to assess overall leg venous function and direct Doppler examination of the popliteal valve, they found that patients who had initially successful lysis had significantly better venous hemodynamics compared to patients who did not lyse. These observations become important when making recommendations for treatment of patients with acute (extensive) DVT and are consistent with our understanding of the progressive pathophysiology of the postthrombotic syndrome and studies on the natural history of acute DVT. The underlying pathophysiology of the postthrombotic syndrome is ambulatory venous hypertension.[20] The pathologic features leading to increased ambulatory pressures are obstruction of the venous system and valvular dysfunction. Reducing or eliminating either or both of these features should reduce the virulence of the postthrombotic syndrome. Consistent with our understanding of the pathophysiology of the postthrombotic syndrome are the observations of the natural history of acute DVT (treated with anticoagulation). Valvular reflux is progressive over time, affecting most patients by one year after their acute episode.[21] However, some patients had normal valvular function despite their DVT, and they were found to have spontaneously lysed their clots, much more rapidly than patients who developed valvular dysfunction.[22,23] Persistent venous obstruction associated with valvular insufficiency causes the most severe postthrombotic syndrome.[24,25] It is not surprising, then, that Akesson et al.[26] observed that resolution of iliac vein obstruction with restoration of patency improved valvular function and reduced ambulatory venous pressure.
Figure 71-1. Algorithm for treatment of iliofemoral DVT.
iliocaval system is involved. In patients with unilateral iliofemoral venous thrombosis, our preferred approach is catheter-directed thrombolysis using an ultrasound-guided popliteal vein or posterior tibial vein puncture with advancement of a coaxial infusion catheter system (Fig. 71-2). This is
Patient Selection and Evaluation Patients presenting with a swollen, painful lower extremity, especially when the swelling extends to the inguinal ligament, should be suspected of having iliofemoral venous thrombosis with or without involvement of the infrainguinal venous system. These patients should be considered for treatment that restores patency to the deep venous system, especially the iliofemoral venous segment. Our suggested algorithim is illustrated in Fig. 71-1. The diagnosis is established with venous duplex imaging. The proximal extent of thrombus is evaluated with an iliocavagram. This is important to assess whether thrombus extends into the vena cava and whether the contralateral
Figure 71-2. Algorithm for catheter directed thrombolysis for iliofemoral DVT.
Chapter 71.
recommended to patients who do not have the traditional contraindications to thromobolytic therapy, which include acute bleeding, severe uncontrolled hypertension, intracranial disease, and recent eye operation. Other relative contraindications should be weighed and factored into the overall risk-benefit equation. The risk of intracranial bleeding is discussed with each patient. Available data suggest that the real risk of intracranial bleeding in these patients is less than 0.5%. Urokinase has been the most commonly used plasminogen activator, and a dose of 500,000–750,000 units is usually used to “lace” the thrombus. A dose of 250,000 units per hour is then split between the proximal and distal infusion catheter. Repeat phlebograms are obtained at approximately 4–6 hours and every 12 hours thereafter to assess clot lysis. Repositioning of the catheters is performed as appropriate. During the past several years recombinant tissue plasminogen activator (rtPA) and reteplase have been used since UK was removed from the market. rtPA is given as a 4–6 mg bolus and a 1–4 mg/h continuous infusion depending on location, extent of thrombus, and physician preference. Reteplase has also been used with equal success at a dose of a 2–4 mg bolus and a 1–2 mg/h continuous infusion. The most notable modification to evolve recently is the expanded volume of the plasminogen activator infused. It is common to dilate the solution so that a volume of 100 cc or more is infused per hour. I believe the larger-volume infusion permeates the thrombus with more efficient distribution of the plasminogen activator, resulting in more rapid lysis. If nonocclusive thrombus extends into the vena cava, a vena caval filter is recommended to reduce the risk of pulmonary embolism during infusion. However, if the vena cava is obliterated with thrombus, we have not routinely placed a filter, since catheters imbedded into the caval occlusion generally achieve lysis in a concentric manner. In general, our preference is to avoid placement of a vena caval filter in case venous thrombectomy is required. Following successful lysis, complete phlebographic visualization of the venous system is performed. In our experience, at least 50% of the patients have an underlying iliac vein stenosis requiring angioplasty and/or stenting. Initially, angioplasty of an underlying venous stenosis is performed. If successful, no further intervention is recommended. Frequently, however, the iliac stenosis does not completely respond to angioplasty (Fig. 71-3), and a stent is required to achieve a good anatomic result. During thrombolysis, heparin is infused through the sheath at a dose of approximately 500 units per hour. The puncture site is carefully monitored, and if bleeding becomes troublesome, heparin is discontinued until lytic therapy is completed. Full heparin anticoagulation follows thrombolysis and the patients are quickly converted to oral anticoagulation with coumadin. Intermittent pneumatic compression garments are applied during hospitalization and a minimum of a 30 – 40 mmHg ankle gradient compression stocking is prescribed upon discharge. The patient’s INR is maintained at approximately 2.5 – 3.0, and oral anticoagulation is recommended for a period of at least one year. Updating our previously reported experience,[27] we have treated 58 patients in this fashion. Two patients had failure of appropriate catheter positioning and are considered treatment failures. Fifty-five patients had appropriate catheter positioning, and successful lysis was achieved in 48 (defined by
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Figure 71-3. (A) Phlebogram demonstrating extensive DVT of left iliofemoral segment (B) Superficial femoral vein of a young woman. The clot extended from the popliteal vein to the common iliac vein. Catheter was placed via ultrasound-guided popliteal vein puncture to deliver intrathrombus urokinase. (C) Following successful lysis of the thrombus, patency is restored, revealing a stenotic (occlusive) lesion of left common iliac vein. (D) Balloon angioplasty opens the left common iliac vein, but partial recoil of this fibrous lesion required stenting to maintain adequate luminal diameter. (E) Following placement of an intraluminal stent, iliac vein has normal diameter restored.
quantifiable clot dissolution and restoration of patency to the deep venous system at discharge). Clinical outcome was directly related to the degree of clot lysis. Notable is the observation that no patient with successful lysis suffers with venous claudication or a severe postthrombotic syndrome. Most have had a good to excellent short- and long-term outcome. One patient who had symptoms for 3 months prior to treatment has moderate swelling and discomfort, but continues to pursue full-time employment and all activities of daily life. Two patients suffered major complications during therapy. One patient developed a large hematoma of a femoral puncture site, which required operative evacuation and repair of an inadvertent tangential femoral artery puncture wound. A second patient was found to have an iliac vein stenosis following lysis, and balloon angioplasty and stenting was performed. During subsequent anticoagulation with heparin, she developed a large retroperitoneal hematoma requiring discontinuation of her anticoagulation. Rethrombosis of the iliofemoral venous system ensued. The patient had operative evacuation of the retroperitoneal hematoma and venous thrombectomy with construction of an arteriovenous fistula. Unfortunately, she suffered major pulmonary complications and died. This patient represents the only mortality from this
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approach in our experience. None of our patients have experienced an intracranial bleed, and none have had a symptomatic pulmonary embolus.
Review of Pertinent Literature Semba and Dake[28] have popularized catheter-directed lysis and venous stenting for both acute and chronic venous occlusions. Their initial experience reviewed 27 limbs in 21 patients. Twenty of the 27 limbs had acute deep venous thrombosis, with 7 suffering chronic venous occlusion. Catheter directed urokinase was used, and the average dose was 4.9 million units infused over an average of 30 hours. They achieved complete lysis in 72%, partial lysis in 20%, none in two patients, and in 2 chronically occluded iliac veins the lesion could not be crossed with a guidewire. Following lysis, 16 limbs had an underlying venous stenosis, 14 of which were treated with angioplasty and stent; and only 2 were treated with angioplasty alone. The authors reported no serious complication, nor were there any clinically apparent pulmonary emboli. Their overall technical and clinical success rate was 85%. Molina and colleagues[29] treated 11 patients with acute iliofemoral venous thrombosis with good success, using much smaller doses of urokinase via the catheter-directed approach. They used 60,000 units per hour, suggesting that smaller doses can be used successfully.
A more recent clinical review was reported by Bjarnason et al.[30] They reported a consecutive series of 87 limbs treated with iliofemoral venous thrombosis during a 5-year period extending from 1990 to 1995. Urokinase was delivered via a multiside hole infusion catheter system, and angioplasty, stent placement, mechanical thrombectomy, and other adjunctive procedures were included in this approach. Their overall technical success rate was better in patients with iliac vein occlusion (86%) compared to patients with femoral vein occlusion (63%) (Table 71-1). The one-year patency rate was 78% for iliac veins and 51% for femoral veins. Patients with an underlying malignancy had a poorer outcome compared to those with benign diseases. Success rates were lower in patients who had symptoms for more than 4 weeks prior to therapy compared to those who had a more recent onset of symptoms. Major bleeding complications occurred in 7% of patients, and minor bleeding occurred in another 14%. Mewissen et al. recently reported the results of the North American Venous Registry, which is the largest single database of patients with acute deep venous thrombosis treated with thrombolytic therapy.[31] Catheter-directed lysis appeared better in recanalizing acutely thrombosed veins than systemic thrombolytic therapy. The venous registry confirmed Bjarnason’s prior observation that iliofemoral venous thrombosis enjoyed a significantly better 12-month patency following successful lysis than did femoral popliteal venous thrombosis (Table 71-1). An important observation, consistent with current therapy, is that correction of an underlying
Table 71-1. Treatment Outcomes of Two Trials Outcome
Bjarnason et al.[30] ðn ¼ 77Þ
Mewissen et al.[31] ðn ¼ 287Þ
Initial success Iliac Femoral Patency at 1 year Iliac Femoral Success (thrombus age) Acute Chronic Success (prior DVT) þ Prior DVT þ Prior DVT Success: malignancy Yes No Iliac stent: patent at 1 year þ Stent 2 Stent Duration of Rx (mean) Dose of urokinase Complication Major bleed Intracranial (spontaneous) Pulmonary embolus Fatal PE Death 20 lysis
79% 86% 63%
83% 83% 79%
63% 40%
64% 47%
85% (1– 21 days) 42% (.21 days)
85% (1 – 10 days) 68% (.10 days)
85% 87%
20% (complete lysis) 36% (complete lysis)
79% 98%
NA NA
54% 75% 75 hours 1 £ 107 IU
74% 53% 48 hours 6:77 £ 106 IU
5% 0% 1% (1 patient) 0% 0%
11% ,1% (1 patient) 1% (6 patients) 0.2% (1 patient) 1.4% (2 patients)
Chapter 71.
iliac stenosis with angioplasty and stenting preserved 12-month patencies significantly better than in those patients in whom angioplasty and stenting was not performed. In this large clinical experience, the associated treatment mortality was very low (,0.5%) considering the severity of the thrombotic event and the comorbidities of these patients. There was only one intracranial bleed (, 0.3%) and one fatal PE (, 0.3%) among these three studies. The National Venous Registry offered an opportunity to pursue a study assessing health-related quality of life in patients treated with catheter-directed thrombolysis compared to a similar cohort of patients who were treated with anticoagulation alone. An 80-item health-related quality-oflife questionnaire was developed and validated.[32] A validated questionnaire was then administered to 98 patients, who were treated with iliofemoral DVT at least 6 months earlier. Sixty-eight patients were treated with catheterdirected thrombolysis and were identified through The National Venous Registry. Thirty-patients were treated with anticoagulation alone and were identified through their physician or a medical record review.[33] All patients treated with anticoagulation alone were candidates for thrombolysis but were treated with anticoagulation because of physician preference. Patients who received catheter-directed thrombolysis reported better overall physical functioning ð p ¼ 0:046Þ; less stigma ð p ¼ 0:033Þ; less health distress ð p ¼ 0:022Þ and fewer postthrombotic symptoms ð p ¼ 0:006Þ compared with patients treated with anticoagulation alone. Within the lytic group, phlebographically successful lysis correlated with an improved health-related quality of life ð p ¼ 0:038Þ: Interestingly, lytic failures and heparin-treatment outcomes were similar. Failure of catheter-directed thrombolysis did not adversely affect outcome compared with standard anticoagulation alone, but it did not appear to improve quality of life either. These data serve as an important foundation for the design of a randomized trial evaluating the treatment of patients with acute iliofemoral DVT. Such a trial should be multicenter and incorporate a strategy of thrombus removal versus anticoagulation alone.
2.
3.
1.
2.
STENTS IN THE VENOUS SYSTEM
4.
Background
5.
1.
Balloon-Expandable Stents—These stents require the use of a balloon catheter for its insertion and deployment within the wall of a diseased blood
1007
vessel. Examples of this type of stent include the Palmez and Strecker stents. Self-Expanding Stents—These stents are compressed into a small-diameter introducer sheath and then released in the diseased vessel by withdrawing the sheath while keeping the stent in place. Examples of this type of stent include the Wallstent and Gianturco wire stent. Thermal Expanding Stents—These stents are made of Nitinol, a nickel-titanium alloy characterized by its unique property of thermal recovery.[35] When cooled to 08C, the coil spring transforms into a straight wire, which can be used for introduction into a Teflon catheter. Once the introducer enters the warm blood stream, it returns to its original shape. Although the concept is unique, these types of stents are not widely used.
Although intravascular stenting is most commonly used in the arterial system, this chapter focuses on the currently accepted indications for endovascular stenting in the venous system. Whether there is a difference in thrombogenicity of stents in the arterial system compared to the venous system is not known, but there is experimental information regarding platelet deposition. Parsson et al.[36] placed endovascular expanding metallic stents in the iliac arteries and iliac veins of pigs 4 weeks after creating a stenosis of the target vessel. Arterial and venous stents were deployed and platelet deposition quantified with Indium-111L–labeled platelets. There was a marked increase of deposited platelets in the arterial segments, which were stented with a decrease in platelet deposition on venous stents. The authors suggested that these experimental findings supported the use of metallic stents in the venous system. The disease entities that have been treated with venous stents are:
3.
Stenotic and occlusive venous lesions have been treated by the use of thrombolytic therapy, open surgical management, or percutaneous transluminal angioplasty and endoluminal stent placement. The use of endoluminal stents in various areas of cardiovascular medicine has been in practice since 1985. Stents are designed to provide a scaffold to maintain intraluminal structure and patency of the artery and vein.[34] Intravascular stents may be categorized into one of three basic types:
Lytic Therapy and Venous Stenting
Venous stenosis of the iliofemoral system following lysis of acute iliofemoral deep venous thrombosis or due to the postthrombotic syndrome Dilation of axillary and subclavian vein stenosis following thrombosis of the axillosubclavian vein in Paget-Schroetter syndrome Use of stents for venous stenosis and occlusion associated with hemodialysis access Superior vena cava syndrome, usually due to neoplastic encroachment of the vena cava Budd-Chiari syndrome
Iliac Vein Stents The use of stenting in the iliac venous system was suggested in the prior section on iliofemoral venous thrombosis with thrombolysis. If following the course of thrombolytic therapy there is evidence of venous stenosis, or there is evidence of chronic occlusion of the iliac vein, balloon angioplasty and endoluminal stenting is the currently preferred procedure. Semba and Dake[28] and Bjarnason et al.[30] demonstrated that thrombus resistant to thrombolysis, especially when adjacent
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vein segments were patent, could be successfully treated with angioplasty and stent placement. The hemodynamic significance of a venous stenosis or occlusion is demonstrated by: 1. 2.
The presence of collateral venous flow around the stenotic area A pressure gradient of 3 mmHg or more
The availability of endovascular stents for iliac vein occlusion offers new opportunities of percutaneous treatment of venous strictures. We prefer to treat strictures primarily with angioplasty and use stents when the vein lesion recoils and demonstrates that angioplasty alone will not be successful. Antonucci et al.[37] concur with that approach. As mentioned earlier, balloon angioplasty and stenting can be used for chronic venous disease. Our experience has been favorable in those patients requiring a single stent, but those patients requiring stents to be “stacked” have a significant risk of reocclusion.
Axillo-Subclavian Venous Stenosis (Paget-Schroetter Syndrome) Venous thrombosis of the upper extremity is relatively uncommon, accounting for approximately 2% of all DVT.[38] There are three primary etiologies of upper extremity venous thrombosis: 1. 2.
3.
Catheter-related thrombosis (e.g., central venous pressure lines, pacemakers, chemotherapy catheters) Malignancy or systemic disease (tumor masses compressing the axillary or subclavian veins or the presence of systemic disease such as congestive heart failure, malignancy, or uremia) Effort or spontaneous venous thrombosis (no specific underlying etiology)[39]
Historically, many terms have been used to describe the syndrome of idiopathic axillary-subclavian venous thrombosis, including Paget-Schroetter syndrome, primary thrombosis, effort thrombosis, and spontaneous axillo-subclavian vein thrombosis.[38 – 48] Patients are usually healthy young individuals living active lives. Often these individuals are involved in exercise programs or sports activities such as swimming, weight lifting, football, or body building, or they may be laborers.[43,45 – 47] The pathophysiology of Paget-Schroetter syndrome has been thought to be multifactoral. There is compression of the subclavian vein between the first rib and the clavicle, often by an exostosis of the first rib.[48] This external compression is thought to contribute to stasis of venous return and damage to the vein wall. Other factors causing external compression include anomalous subclavius or anterior scalene muscle, congenital fibromuscular bands, or narrowing of the costoclavicular space from depression of the shoulder. Also, it has been suggested that the stress of exercise may temporarily cause hypercoagulability. [39] Additionally, repetitive shoulder arm motion may cause microscopic intimal tears in the vessel wall.[39]
The natural history of the disease reflects the development of venous hypertension due to chronic axillosubclavian vein compression, with the acute symptoms resulting from sudden thrombosis and occlusion of collateral venous drainage.[47] Following resolution of the acute thrombotic manifestations, patients may be relatively free of symptoms at rest and edema may resolve within 1 – 3 weeks. When normal activity is resumed after a period of recuperation, this frequently leads to symptoms of upper extremity hypertension, which may be exacerbated by using arms in the overhead position. Hyperextension may occlude the subclavian vein as well as the first rib collaterals.[49] Patients typically present with sudden onset of discomfort, feeling of heaviness, swelling, and occasionally cyanosis of the affected extremity.[50] The management of PagetSchroetter syndrome has undergone significant evolution since its original description. A multidisciplinary approach which offers thrombolytic therapy to dissolve the clot, surgical decompression of the vein via first rib resection, and occasionally percutaneous transluminal angioplasty with stenting, if required, to dilate intrinsic vein lesions has been proposed and appears promising.[47 – 53] (Fig. 71-4) The appropriate sequencing of the various interventional procedures continues to be defined. Experience with preoperative percutaneous angioplasty has yielded less than favorable results. In Machleder’s experience, 7 of 12 preoperative angioplasties resulted in occlusion immediately after the procedure, whereas 5 had no effect on the stenosis.[48] Furthermore, failure of preoperative angioplasty was associated with poor or no long-term patency. It was concluded that percutaneous transluminal angioplasty may have a role in correcting the residual subclavian vein stenosis following first rib resection. In that group, 7 of the 9 postoperative angioplastics were successful and demonstrated long-term patency. Angioplasty with stenting prior to first rib resection is frequently associated with stent compression (Fig. 71-4) and stent fracture.[49] Most would agree that decompression of the thoracic outlet by first rib resection should precede stenting of the subclavian vein. If, however, a stent is placed prior to first rib resection, a self-expanding Wallstent is the device of choice.
Venous Stenosis in Hemodialysis Patients Stenoses or occlusions complicating arteriovenous fistulas used for hemodialysis usually occur at the site of venous anastomosis or in the native venous system immediately proximal to the fistula.[54] Proximal stenosis may be caused by strictures or hypertrophied valves. These are thought to be related to turbulence at venous junctions and valves. In patients with arteriovenous fistula and central vein stenosis, the clinical presentation of venous obstruction is magnified by the high flow and pressure through the fistula.[51] This problem complicates hemodialysis since the high venous outflow resistance is associated with increased recirculation and inadequate dialysis, which leads to thrombosis of the access site. Clinically, the swelling can be troublesome and on rare occasion lead to tissue breakdown.
Chapter 71.
Lytic Therapy and Venous Stenting
1009
Figure 71-4. Young woman with catheter-induced DVT of right subclavian vein. (A) Catheter in place across occlusion. (B) Following lysis, a Wallstent was placed to maintain patency. (C) Compression of Wallstent between clavicle and first rib is evident with abduction of arm associated with recurrence of symptoms. (D) Following right first rib resection and redilation of stent, normal luminal diameter is restored and right arm symptoms relieved. (E) Patency is maintained and compression does not occur with abduction following first rib resection.
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Thrombosis of the access site is frequently the final common event.[54 – 58] Traditional methods of management of venous stenosis include vein patch angioplasty, graft extension, abandonment of the access site, or balloon angioplasty. The frequency with which an arteriovenous fistula can be surgically modified is limited, and numerous options may be used in a relatively short period of time. The technical success of percutaneous intervention has been reported to be high, but patency at follow-up is low secondary to the high rate of restenosis.[59,60] The recurrence rate is especially high in central veins,[61,62] in which a 6-month patency has been reported as low as 25%.[58] Endovascular stenting has been successful in treating patients in which balloon dilation alone has failed. Vorwerk et al. reported a cumulative patency rate of 88% at 6 months, 86% after one year, and 77% after 2 years in a group of 65 hemodialysis patients.[60] These excellent results include multiple interventions for recurrent stenosis and require diligent surveillance.
Superior Vena Cava Syndrome Obstructions of the superior vena cava (SVC) (or inferior vena cava) caused by malignant neoplasms can produce severe venous congestive symptoms.[63 – 66] Malignant SVC syndrome is most often due to bronchogenic carcinoma. It may also be due to lymphoma, metastatic disease, or rarely to direct extension of neoplasm from the right atrium into the superior vena cava or from the pericardium to the superior vena cava (i.e., angiosarcoma).[67] SVC obstruction produces the superior vena cava syndrome, which is characterized by: 1. 2. 3. 4. 5.
Facial and upper extremity swelling Appearance of superficial thoracic venous collaterals Neck swelling Headache Conjunctival injection
Malignant caval obstruction has been treated with nonsurgical methods such as radiation and chemotherapy, with the goal of shrinking the tumor and subsequently recanalizing the obstructed vessels.[63 – 65,68] Shrinking the tumor requires time, however, and relief from the obstruction is not always obtained. Percutaneous balloon angioplasty has been used effectively for correcting benign obstructions of the vena cava.[69 – 72] Good results have not been observed in many malignant cases because of difficulty in dilating the lesion or because of recoil after balloon deflation.[73,74] Obstructions of the vena cava have been treated predominantly with Gianturco stents in tandem[73 – 78] because these stents can be made with large diameters suitable for the lumen of the vena cava and the open structure of the stents does not cause occlusion of the various venous side branches. Studies report successful relief of congestive symptoms in 74–100% of patients.[73 – 81] In a study by Furui et al.,[76] symptoms were relieved in 90% of patients. The computed tomography (CT) scan appearance of malignant caval obstruction was divided into three types: malignant lesions tangential to the cava, tumors
that partially encircle the cava, and those that completely surround the cava. In that study, obstructions that were tangential to lesions were most amenable to stent placement. Sixteen such lesions were treated, and 69% were completely opened. In contrast, occluded cavas that were completely enveloped by lesions were resistant to stent placement. Only two of five were successfully treated, and neither was completely opened. The authors speculate that failures might have been treated with Gianturco stents with thicker wire, Wallstents or Palmaz stents. Wallstents, and Palmaz stents are thought to have a greater tendency to maintain form against extrinsic compression than standard Gianturco stents.[68,82] Nicholson et al.[83] prospectively evaluated 76 patients with malignant superior vena cava obstruction treated with percutaneous stent insertion and compared their outcome with 25 patients who were previously treated by radiation therapy. Stent insertion provided more rapid relief of symptoms, and significantly fewer patients developed recurrent symptoms ð p ¼ 0:001Þ:
Budd-Chiari Syndrome The classic triad of abdominal pain, ascites, and tender hepatomegaly describes the Budd-Chiari syndrome and is attributable to increased intrahepatic pressure and portal hypertension secondary to hepatic venous outflow obstruction.[84] Many predisposing conditions are recognized, including inferior vena caval webs,[85] myeloproliferative disorders,[86] and oral contraceptive use.[87] It has been estimated, however, that 30 – 66% of these cases are idiopathic.[88 – 90] When hepatic veins become occluded, the centrilobular regions of the liver become intensely congested, resulting in cell atrophy and impaired regeneration.[91] The natural history of hepatic vein thrombosis is variable, ranging from long-term asymptomatic survival to acute illness with a rapidly fatal course.[88,92] The clinical picture depends on the severity of the hepatic vein thrombosis and the rapidity with which it develops. Generally, there are two or three major hepatic veins. Occlusion of only one vein is well tolerated. Typically, there is an enlargement of the caudate lobe of the liver, which is relatively spared from the changes seen elsewhere in the liver.[93] The venous drainage of the caudate lobe into the retrohepatic inferior vena cava is separate from the remainder of the liver. It is the enlarged caudate lobe that may compress the retrohepatic inferior vena cava.[94] As the obstruction progresses to near or complete occlusion, hepatomegaly, ascites, variceal hemorrhage, and progressive liver dysfunction due to necrosis and fibrosis may occur.[94] The result of this progressive liver disease is hepatic failure and death. The medical management of Budd-Chiari syndrome consists of controlling the ascites by the use of diuretics, correction of an underlying coagulopathy, and improvement of the patient’s nutritional status.[84] The success of medical management is determined by the severity and progression of the underlying disease. The surgical management goals consist of relief of the portal hypertension and relief of the intrahepatic venous congestion. Portosystemic shunt operations have been effective in managing patients with Budd-Chiari syndrome
Chapter 71.
by converting the portal vein into an outflow tract, thus decompressing the massive hepatic congestion.[90] Side-toside portacaval shunts,[95] splenorenal shunts,[96] and mesocaval shunts[97] have all been used successfully for that purpose. Cameron also describes the use of a mesoatrial shunt for decompression when the inferior vena cava is thrombosed or severely compressed.[98] Percutaneous transluminal venous angioplasty has been used in selected patients with Budd-Chiari syndrome with favorable results. Eguchi et al. first described the use of balloon membranotomy to open an obstructed inferior vena cava.[99] Meier et al. described a successful percutaneous transluminal angioplasty for treatment of hepatic venous webs.[100] In a review of the literature by Sporano, there were 14 cases of Budd-Chiari syndrome due to membranous obstruction of the IVC and right hepatic vein which had been treated successfully by percutaneous transluminal angioplasty without complications.[101] In those 14 patients, restenosis requiring repeat dilation was needed in 5, and 3 required three or more dilations. To assist in the maintenance of patency and prevent restenosis following successful balloon angioplasty, the use of expandable vascular stents is becoming more popular. Lopez et al.[84] presented a successful case of placement of a left
Lytic Therapy and Venous Stenting
1011
hepatic stent after dilation with resolution of symptoms and elimination of a significant pressure gradient. In follow-up at one year, the patient was doing well without complications. Significant stenoses of the suprahepatic inferior vena caval anastomosis following orthotopic liver transplantation have been successfully treated with percutaneous transluminal angioplasty.[102]
SUMMARY The use of percutaneous transluminal angioplasty with endoluminal stent in the central venous system appears to serve as an important adjunctive therapy in selected difficult patients with significant venous stenosis or stricture. Due to the complex management requirements of these patients, it is important that a multidisciplinary approach be used in these challenging clinical situations. The concept of multidisciplinary treatment derives from improved understanding of the role of operative treatment as well as the development of endovascular techniques for angioplasty and stenting, frequently combined with the delivery of thrombolytic agents.
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Rosch, J.J.; Dotter, C.T.; Seaman, A.J.; et al. Healing of Deep Vein Thrombosis: Venographic Findings in a Randomized Study Comparing Streptokinase and Heparin. Am. J. Roentgenol. 1976, 127, 533. Marder, V.J.; Soulen, R.L.; Atichartakarn, V. Quantitative Venographic Assessment of Deep Vein Thrombosis in the Evaluation of Streptokinase and Heparin Therapy. J. Lab. Clin. Med. 1977, 89, 1018. Arnesen, H.; Heilo, A.; Jakobsen, E.; et al. A Prospective Study of Streptokinase and Heparin in the Treatment of Deep Vein Thrombosis. Acta Med. Scand. 1978, 203, 457. Elliot, M.S.; Immelman, E.J.; Jeffrey, P.; et al. A Comparative Randomized Trial of Heparin Versus Streptokinase in the Treatment of Acute Proximal Venous Thrombosis: An Interim Report of a Prospective Trial. Br. J. Surg. 1979, 66, 838. Watz, R.; Savidge, G.F. Rapid Thrombolysis and Preservation of Venous Valvular Function in High Deep Vein Thrombosis. Acta Med. Scand. 1979, 205, 293. Jeffrey, P.; Immelman, E.; Amoore, J. Treatment of Deep Vein Thrombosis with Heparin or Streptokinase: LongTerm Venous Function Assessment. In: Proceedings of the Second International Vascular Symposium, London, 1986; Abstract No. S20.3. Turpie, A.G.G.; Levine, M.N.; Hirsh, J.; et al. Tissue Plasminogen Activator vs Heparin in Deep Vein Thrombosis. Chest 1990, 97, 172s. Goldhaber, S.Z.; Meyerovitz, M.F.; Green, D.; et al. Randomized Controlled Trial of Tissue Plasminogen Activator in Proximal Deep Venous Thrombosis. Am. J. Med. 1990, 88, 235.
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Arnesen, H.; Hoiseth, A.; Ly, B. Streptokinase or Heparin in the Treatment of Deep Vein Thrombosis: Follow-Up Results of a Prospective Study. Acta Med. Scand. 1982, 211, 65. Comerota, A.J. Venous Thromboembolism. In Vascular Surgery; Rutherford, R.B., Ed.; J.B. Lippincott: Philadelphia, 1995; 1785– 1814. Markel, A.; Manzo, R.; Bergelin, R.; Strandness, E. Valvular Reflux After Deep Vein Thrombosis: Incidence and Time of Occurrence. J. Vasc. Surg. 1992, 15, 377. Killewich, L.A.; Bedford, G.R.; Beach, K.W.; et al. Spontaneous Lysis of Deep Vein Thrombi: Rate and Outcome. J. Vasc. Surg. 1989, 10, 89. Meissner, M.H.; Manzo, R.A.; Bergelin, R.O.; et al. Deep Venous Insufficiency: The Relationship Between Lysis and Subsequent Reflux. J. Vasc. Surg. 1993, 18, 596. Shull, K.C.; Nicolaides, A.N.; Fernandez, J.F.; et al. Significance of Popliteal Reflux in Relation to Ambulatory Venous Pressure and Ulceration. Arch. Surg. 1979, 114, 1304. Johnson, B.; Manzo, R.A.; Bergelin, R.O.; Strandness, D.E. Relationship Between Changes in the Deep Venous System and the Development of the Post-Thrombotic Syndrome After an Acute Episode of Lower Limb Deep Vein Thrombosis: A One to Six Year Follow-Up. J. Vasc. Surg. 1995, 21, 307– 313. Akesson, H.; Lindh, M.; Ivancev, K.; Rosberg, B. Venous Stents in Chronic Iliac Vein Occlusions. Eur. J. Vasc. Endovasc. Surg. 1997, 13, 334– 336. Comerota, A.J.; Kagan, S.A. Catheter-Directed Thrombolysis for the Treatment of Acute Iliofemoral Deep Venous Thrombosis. Phlebology 2001, 15 (3-4), 149–155. Semba, C.P.; Dake, M.D. Iliofemoral Deep Vein Thrombosis: Aggressive Therapy with Catheter Directed Thrombolysis. Radiology 1994, 191, 487– 494. Molina, J.E.; Hunter, D.W.; Yedlieka, J.W. Thrombolytic Therapy for Iliofemoral Venous Thrombosis. Vasc. Surg. 1992, 26, 630– 637. Bjarnason, H.; Kruse, J.R.; Asinger, D.A.; et al. Iliofemoral Deep Venous Thrombosis: Safety and Efficacy Outcome During 5 Years of Catheter-Directed Thrombolytic Therapy. J. Vasc. Intern. Radiol. 1997, 8, 405–418. Mewissen, M.; Seabrook, G.R.; Meissner, M.H.; et al. Catheter-Directed Thrombolysis for Lower Extremity Deep Vein Thrombosis: Report of a National Multi-Center Registry. Radiology 1999, 8, 405– 418. Mathias, S.D.; Prebil, L.A.; Putterman, C.; Chmiel, J.; Throm, R.; Comerota, A.J. A Health-Related Quality of Life Measure in Patients with Deep Venous Thrombosis. A Validation Study. Drug Inf. J. 1999, 33 (4), 1173– 1187. Comerota, A.J.; Throm, R.; Mathias, S.; et al. CatheterDirected Thrombolysis Improves Health Related Quality of Life. J. Vasc. Surg. 2000, 32, 130–137. Ahn, S.S.; Concepcion, B. Endovascular Surgery, in Vascular Surgery: A Comprehensive Review; Moore, W.S., Ed.; W.B. Saunders: Philadelphia, 1998; 305 – 329. Dotter, C.T.; Buschmann, R.W.; McKinney, M.K.; et al. Transluminal Expandable Nitinol Coil Stent Grafting: Preliminary Report. Radiology 1983, 147, 259– 300. Parsson, H.; Norgren, L.; Ivaheev, K.; Thorne, J.; Jonsson, B.A. Thrombogenicity of Metallic Vascular Stents in
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Ingram, T.L.; Reid, S.H.; Pisnado, J. Percutaneous Transluminal Angioplasty of Brachiocephalic Vein Stenoses in Patients with Dialysis Shunts. Radiology 1988, 166, 45– 47. Palder, S.B.; Kirkman, R.L.; Whittemore, A.D.; et al. Vascular Access for Hemodialysis. Ann. Surg. 1985, 202, 235– 239. Munda, R.; First, M.R.; Alexander, J.W.; et al. Polytetrafluoroethylene Graft Survival in Hemodialysis. J. Am. Med. Assoc. 1983, 249, 219– 222. Elson, J.D.; Becker, G.J.; Wholey, M.H.; et al. Vena Caval and Central Venous Stenoses: Management with Palmaz Balloon Expandable Intraluminal Stents. J. Vasc. Interv. Radiol. 1991, 2, 215– 223. Quinn, S.F.; Schumann, E.S.; Hall, L.; et al. Venous Stenosis in Patients Who Undergo Hemodialysis: Treatment with Self Expandable Endovascular Stents. Radiology 1992, 183, 499– 504. Beathard, G. Percutaneous Transvenous Angioplasty in the Treatment of Vascular Access Stenosis. Kidney Int. 1992, 42, 1390– 1397. Vorwerk, D.; Guenther, R.W.; Mann, H. Venous Stenosis and Occlusion in Hemodialysis Shunts: Follow-Up Results of Stent Placement in 65 Patients. Radiology 1995, 195, 140– 146. Glanz, S.; Gordan, D.; Lipkowitz, G.; et al. Axillary and Subclavian Vein Stenoses: Percutaneous Angioplasty. Radiology 1988, 168, 371– 373. Schwab, S.; Quarles, L.; Middleton, J.; et al. Hemodialysis Associated Subclavian Vein Stenosis. Kidney Int. 1988, 33, 1156– 1159. Boruchow, I.B.; Johnson, J. Obstruction of the Vena Cava. Surg. Gynecol. Obstet. 1972, 134, 115– 121. Lokich, J.J.; Goldmann, R. Superior Vena Cava Syndrome: Clinical Management. J. Am. Med. Assoc. 1975, 231, 58– 61. Perez, C.A.; Present, C.A.; Van Amburg, A.L. Management of SVC Syndrome. Semin. Oncol. 1978, 5, 123– 134. Stanford, W.; Doty, D.B. The Role of Venography and Surgery in the Management of SVC Obstruction. Ann. Thorac. Surg. 1986, 41, 158– 163. Becker, G.J.; Kumpe, D.A. Percutaneous Transluminal Angioplasty and Other Endovascular Technologies. In Vascular Surgery; Rutherford, R.B., Ed.; WB Saunders: Philadelphia, 1995; 352 – 394. Furui, S.; Sawada, S.; Kuramoto, K.; et al. Gianturco Stent Placement in Malignant Caval Obstruction: Analysis of Factors for Predicting Outcome. Radiology 1995, 195, 147– 152. Yamada, R.; Sato, M.; Kawabata, Y.; et al. Segmental Obstruction of the Hepatic IVC Treated by Transluminal Angioplasty. Radiology 1983, 149, 91– 96. Martin, L.G.; Henderson, J.M.; Millikan, W.J.; et al. Angioplasty for Long Term Treatment of Patients with Budd-Chiari Syndrome. Am. J. Roentgenol. 1990, 154, 1007– 1010. Sherry, C.S.; Diamond, N.G.; Myers, T.P.; et al. Successful Treatment of SVC Syndrome by Venous Angioplasty. Am. J. Roentgenol. 1986, 147, 834– 835. Capek, P.; Cope, C. Percutaneous Treatment of SVC Syndrome. Am. J. Roentgenol. 1989, 152, 183– 184.
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Putnam, J.S.; Vehida, B.; Antonovic, R.; et al. SVC Syndrome Associated with Massive Thrombosis: Treatment with Expandable Wire Stents. Radiology 1988, 167, 722– 728. Rosch, J.; Bedell, J.E.; Putnam, J.; et al. Gianturco Expandable Wire Stents in Treatment of SVC Syndrome Recurring After Maximal Tolerance Radiation. Cancer 1987, 60, 1243– 1246. Charnsangavej, C.; Carrasco, C.H.; Wallace, S.; et al. Stenosis of the Vena Cava: Preliminary Assessment of Treatment with Expanding Metallic Stents. Radiology 1986, 161, 295– 298. Furui, S.; Sawada, S.; Iric, T.; et al. Hepatic Inferior Vena Cava Obstruction: Treatment with Gianturco Expandable Metallic Stents. Radiology 1990, 176, 665– 670. Carrasco, C.H.; Charnsangavej, C.; Wright, K.; et al. Gianturco Stents in Vena Caval Stenosis. Radiology 1990, 177, 202. Dondelinger, R.F.; Goffette, P.; Kurdziel, J.C.; et al. Expandable Metal Stents for Stenoses of Vena Cava and Larger Veins. Semin. Interv. Radiol. 1991, 8, 252– 263. Sawada, S.; Fujiwara, T.; Kobayasahi, M.; et al. Application of Expanded Metallic Stents to the Venous System. Acta. Radiol. 1992, 33, 156– 159. Rosch, J.; Uchida, B.T.; Hall, L.D.; et al. Gianturco-Rosch Expandable Z-Stents in the Treatment of Superior Vena Cava Syndrome. Cardiovasc. Interv. Radiol. 1992, 15, 319– 327. Irving, J.D.; Dondelinger, R.F.; Reidy, J.F.; et al. Gianturco Self-Expanding Stents: Clinical Experience in the Vena Cava and Large Veins. Cardiovasc. Interv. Radiol. 1992, 15, 328– 329. Falconc, B.G.; Wallace, S.; Gianturco, C. Elastic Characteristics of the Self Expandable Metallic Stents. Investing. Radiol. 1988, 23, 370– 376. Nicholson, A.A.; Ettles, D.F.; Arnold, A.; et al. Treatment of Malignant Superior Vena Cava Obstruction: Metal Stents or Radiation Therapy. J. Vasc. Interv. Radiol. 1997, 8, 781– 788. Lopez, R.R.; Benner, K.G.; Hall, L.; et al. Expandable Venous Stents for the Treatment of the Budd Chiari Syndrome. Gastroenterology 1968, 54, 1070– 1084. Yamamoto, S.; Yokoyama, Y.; Takeshige, K.; et al. Budd Chiari Syndrome with Obstruction of the Inferior Vena Cava. Gastroenterology 1968, 54, 1070– 1084. Powell-Jackson, P.R.; Melia, W.; Canalese, J.; et al. Budd Chiari Syndrome: Clinical Patterns and Therapy. Q. J. Med. 1982, 201, 79– 88. Greyson, M.J.; Reilly, M.C. Budd Chiari Syndrome After Oral Contraceptives. Br. Med. J. 1968, 1, 512– 513. Clain, D.; Freston, J.; Kreel, L.; et al. Clinical Diagnosis of Budd-Chiari Syndrome. Am. J. Med. 1967, 43, 544. Raby, N.; Karani, H.; Meire, M.; et al. Budd-Chiari Syndrome: Shunt Selection and Post-Operative Assessment. Clin. Radial. 1989, 40, 456– 460. Mitchell, M.C.; Boitnott, J.K.; Kaufman, S.; et al. BuddChiari Syndrome: Etiology, Diagnosis and Management. Medicine 1982, 61, 199– 218. Cameron, J.L.; Herlong, H.F.; Sanfey, H.; et al. The BuddChiari Syndrome; Treatment by Mesenteric-Systemic Venous Shunts. Ann. Surg. 1983, 198, 335– 344.
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Parker, R.G. Occlusion of the Hepatic Veins in Man. Medicine 1959, 38, 369. Powell-Jackson, P.R.; Karani, H.; Ede, R.J.; et al. Ultrasound Scanning and 99 mm Tc Sulfur Colloid Scanning in the Diagnosis of Budd-Chiari Syndrome. Gut 1986, 27, 1502– 1506. Shaked, A.; Goldstein, R.M.; Klintmalm, G.B.; et al. Portosystemic Shunt Versus Orthotopic Liver Transplantation for the Budd-Chiari Syndrome. Surg. Gynecol. Obstet. 1992, 174, 453– 459. Orloff, M.J.; Johansen, K.H. Treatment of Budd-Chiari Syndrome by Side to Side Portocaval Shunt: Experimental and Clinical Results. Ann. Surg. 1978, 188, 494– 512. Langer, B.; Stone, R.M.; Colapinto, R.F.; et al. Clinical Spectrum of the Budd-Chiari Syndrome and Its Surgical Management. Am. J. Surg. 1973, 129, 137– 145. Huguet, C.; Ligeois, A.; Levy, V.G.; et al. Interposition Mesocaval Shunt for Chronic Primary Occlusion of the
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Hepatic Veins. Surg. Gynecol. Obstet. 1979, 148, 691– 698. Cameron, J.L.; Maddrey, W.C. Mesoatrial Shunt. A New Treatment for Budd-Chiari Syndrome. Ann. Surg. 1978, 187, 402–406. Eguchi, S.; Takeuchi, Y.; Asano, Y. Successful Balloon Membranotomy for Obstruction of the Hepatic Portion of the Inferior Vena Cava. Surgery 1974, 76, 837– 840. Meier, W.L.; Waller, R.M.; Sones, P.J. Budd-Chiari Syndrome. Treated by Percutaneous Transluminal Angioplasty. Am. J. Roentgenol 1981, 137, 1257 –1258. Sporano, J.; Chang, J.; Trasi, S.; et al. Treatment of BuddChiari Syndrome with Percutaneous Transluminal Angioplasty: Case Report and Review of the Literature. Am. J. Med. 1987, 82, 821 –828. Bismuth, H.; Sherlock, D.J. Portasystemic Shunting Versus Liver Transplantation for the Budd-Chiari Syndrome. Ann. Surg. 1991, 214, 581– 589.
CHAPTER 72
Management of Portal Hypertension Atef A. Salam Tarek A. Salam Portal hypertension is defined as the elevation of portal venous pressure above 12 mmHg. The portal pressure is more accurately measured in relation to the inferior vena caval pressure, and portal hypertension is considered present if the difference between portal pressure and caval pressure (known as the corrected portal pressure) exceeds 11 mmHg (150 mm saline).[1] In clinical practice, however, portal hypertension is usually recognized by the pathologic disturbances it produces, including esophageal varices and splenomegaly, and in the presence of underlying liver disease, portal hypertension usually contributes to the development of ascites and liver cell failure.
of portal hypertension in certain countries in the Mediterranean area, South America, as well as the Far East.[2] The schistosoma ova are deposited in the wall of the intrahepatic portal vein terminal branches, resulting in periportal fibrosis with constriction and obstruction of these branches before they join the hepatic sinusoids. Much less commonly, presinusoidal portal hypertension results from the deposition of cellular infiltrate due to myeloproliferative diseases such as myelosclerosis and meyloid leukemia. Congenital hepatic fibrosis is associated with the formation of dense fibrous tissue bands surrounding and compressing the portal zones, resulting in another form of presinusoidal portal hypertension. Other rare forms of presinusoidal portal hypertension include Wilson’s disease and primary biliary cirrhosis.
ETIOLOGY AND PATHOGENESIS Portal hypertension is generally the result of obstruction of the portal blood flow. Very rarely, portal hypertension occurs due to increased portal flow as a result of a splanchnic arteriovenous fistula. Portal hypertension is classically divided into two major categories, depending on whether the obstruction to flow occurs before the level of the hepatic sinusoids (presinusoidal portal hypertension) or at or beyond the sinusoids (sinusoidal or postsinusoidal portal hypertension). The clinical implication of this distinction is related to the fact that, unlike sinusoidal or postsinusoidal causes of portal hypertension, the liver function in presinusoidal portal hypertension is usually well preserved until the very late stages of the disease. These patients thus tolerate the complications of the disease as well as the interventions needed quite well. Both presinusoidal and postsinusoidal forms of portal hypertension can occur due to intrahepatic or extrahepatic causes (Table 72-1).
EXTRAHEPATIC PRESINUSOIDAL PORTAL HYPERTENSION Extrahepatic obstruction of the portal vein accounts for less than 5% of causes of portal hypertension. Portal vein thrombosis in children frequently complicates periumbilical sepsis and neonatal omphalitis. Necrotizing enterocolitis and unrecognized visceral perforation (usually appendiceal) are also commonly associated with portal vein thrombosis. Congenital atresia of the portal vein is a rare cause of portal obstruction. Cavernomatous transformation is believed to be the end result of thrombosis and obstruction of the portal vein leading to the neoformation of hepatopetal collaterals to bypass the obstructed portal vein. Different patterns of collateral formation have been identified radiologically depending on the site and extent of the portal vein occlusion. In adults, portal vein thrombosis can complicate pancreatitis, pancreatic cancer, low flow states, intraabdominal sepsis, and occasional cases of polycythemia. More commonly, however, portal vein thrombosis occurs with no apparent cause. Portal vein thrombosis can also occur by
INTRAHEPATIC PRESINUSOIDAL PORTAL HYPERTENSION Hepatic schistosomiasis is the most famous example of presinusoidal portal hypertension. It is still the leading cause
Hobson/Wilson/Veith: Vascular Surgery: Principles and Practice, Third Edition, Revised and Expanded DOI: 10.1081/0819-9-120024956 Copyright q 2004 by Marcel Dekker, Inc.
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Causes of Portal Hypertension
Presinusoidal Extrahepatic: portal vein thrombosis Intrahepatic: schistosomiasis, congenital hepatic fibrosis, myeloproliferative disorders, primary biliary cirrhosis Sinusoidal Cirrhosis: alcoholic, posthepatitic, hemochromatosis, postsinusoidal Intrahepatic: cirrhosis Extrahepatic: Budd-Chiari syndrome
extension of the thrombotic process in cases of splenic or superior mesenteric vein thrombosis.
SINUSOIDAL PORTAL HYPERTENSION
the obstructive process involves the hepatic venous outflow outside the liver. The etiology of the obstruction is obscure. Inflammatory or neoplastic thrombosis or fibrosis of the hepatic veins and sometimes the adjacent vena cava represent the underlying cause of obstruction. Membranous webs obstructing the hepatic veins and/or the inferior vena cava have also been described.
PATHOPHYSIOLOGY OF PORTAL HYPERTENSION With obstruction of the portal circulation, collateral channels develop between the high-pressure portal system and the lowpressure systemic venous system, resulting in hepatofugal flow. This typically occurs at the sites of anatomical connection between the two systems. The most famous of these sites are: 1.
Sinusoidal obstruction accounts for over 90% of cases of portal hypertension. Liver cirrhosis resulting from chronic alcoholism is by far the most common cause of portal hypertension in the western world. It is considered the tenth leading cause of death in the United States. Cirrhosis complicating viral hepatitis is also a fairly common cause of portal hypertension. Other types of cirrhosis such as biliary cirrhosis secondary to extrahepatic bile duct obstruction are quite rate. The mechanism by which liver cirrhosis causes portal hypertension is quite complex. Widespread destruction of the liver parenchyma results in the formation of regenerative nodules with overgrowth of fibrous tissue. Such regeneration nodules result in compression of the thin-walled sinusoids as well as the hepatic vein radicals, causing elevation of the portal pressure. So both sinusoidal and postsinusoidal obstruction actually coexist in liver cirrhosis. In addition to obstruction of the portal flow, destruction of the hepatic architecture and the formation of new vessels within the fibrous tissue septa result in direct communication between the portal vein terminal branches and the tributaries of the hepatic vein, thus bypassing the hepatocytes. Up to one third of the portal flow may be shunted through these channels directly into the hepatic veins.[3] Similarly, arteriovenous shunts develop between the intrahepatic branches of the hepatic artery and portal vein. Both types of shunts lead to increased splanchnic flow and thus contribute to the portal hypertension.
2.
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The gastroesophageal junction, where the coronary vein (portal) connects with the azygous vein (systemic) leading to the development of gastroesophageal varices. The anorectal region, where submucosal communication develops between the superior rectal vein (portal) and the inferior and middle rectal vein tributaries (systemic). Hemorrhoids may develop as a result of dilatation of such collaterals. The anterior abdominal wall, where the umbilical and periumbilical veins (portal) join the superior and inferior epigastric veins (systemic), occasionally resulting in the formation of the classic caput medusae. The retroperitoneum, where collaterals develop between the vein of Retzius and the inferior vena cava.
Angiographic studies have shown that the range of reduction of portal perfusion of the cirrhotic liver as a result of spontaneous portosystemic shunting varies widely from patient to patient. At one end of the spectrum, antegrade portal blood flow to the liver is only minimally affected. At the other end, there is total diversion of portal blood away from the liver, in which case there is reversal of the direction of blood flow in the portal vein. Hepatic wedge venography shows minimal change in patients with antegrade portal perfusion, but with reversal of portal blood flow the contrast injected in the wedge position opacifies the portal vein in a retrograde fashion. (Figs. 72-1 through 72-3.) Spontaneous reversal of portal blood flow occurs in less than 5% of cirrhotic patients.
POSTSINUSOIDAL PORTAL HYPERTENSION
ESOPHAGEAL VARICES
Intrahepatic postsinusoidal portal hypertension is usually seen in association with sinusoidal portal hypertension in cases of cirrhosis due to obstruction of the hepatic vein radicals. Extrahepatic postsinusoidal portal hypertension is classically demonstrated in cases of Budd-Chiari syndrome where
Of the various sites of portosystemic collaterals, gastroesophageal varices are by far the most clinically significant. They occur in about 30% of all cirrhotic patients. The mere presence of esophageal varices, however, does not implicate them as the source of upper gastrointestinal bleeding. Only
Chapter 72. Management of Portal Hypertension
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Figure 72-1. (A ) Splenoportogram showing good liver portal perfusion. (B ) Corresponding hepatic wedge venogram showing no filling of intrahepatic branches of the PV.
about one third to one half of patients with esophageal varices will bleed from them. Mechanical irritation by food bolus, gastroesophageal reflux (common in cirrhotics, especially with ascites due to increased intraabdominal pressure), as well as hypoprothrombinemia due to liver cell failure are all contributing factors to bleeding from esophageal varices. The degree of portal hypertension, however, has not been shown to be a predictor for the risk of bleeding from esophageal varices.[4] More important predictors for variceal bleeding include variceal size and the presence of cherry red spots.[5,6]
ENCEPHALOPATHY As a result of shunting of portal blood away from the liver into the systemic circulation, several potential “cerebral toxins” are released. Examples include ammonia, nitrogenous amines, false neurotransmitters, aromatic amino acids, short-chain fatty acids, and metacarpans.
ASCITES Over 80% of patients with portal hypertension develop ascites of varying extent during the course of their disease. Ascites in
Figure 72-2. (A ) Splenoportogram showing moderately reduced liver portal perfusion. (B ) Corresponding hepatic wedge venogram showing partial filling of intrahepatic branches of the PV.
cirrhotic patients is multifactorial as a result of portal hypertension, reduced intravascular oncotic pressure due to hypoalbuminemia, an increase in lymph leakage from the distended splanchnic lymphatics, and increased salt and water retention by the kidneys. The initial reduction of the effective intravascular volume leads to reduced renal perfusion and renal glomerular filtration rate, which ultimately leads to increased proximal tubular sodium reabsorption. A decrease in a natriuretic hormone (third factor) also contributes to sodium retention. Normally this factor blocks sodium reabsorption at the proximal tubule, preventing salt overload. Reduced renal cortical perfusion and glomerular filtration rate also stimulates renin production from the juxtaglomerular apparatus, which ultimately causes an elevated aldosterone level, increasing sodium and water retention at the distal tubular level. Water retention occurs mostly as a result of sodium retention. The increase in ADH (antidiuretic hormone) production as a result of the hyperreninemic state, however, also impairs free water clearance.
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The size of the spleen, however, correlates poorly with the degree of portal hypertension.[7] The liver may be enlarged or shrunken, firm in consistency, and macronodular in patients with cirrhosis. Bleeding from esophageal varices may be the initial presentation. Stigmata of liver disease including palmar erythema, spider nevi, gynecomastia, jaundice, as well as ascites and encephalopathy may or may not be present. These manifestations are more commonly seen in cirrhotics and only very late in the course of the disease in patients with presinusoidal portal hypertension.
LABORATORY TESTING Serum albumin, bilirubin, and prothrombin have been shown to be good indicators of the degree of liver disease. The Child’s classification based on these three parameters together with the presence of ascites and encephalopathy have been shown to be a good predictor of operative survival in cirrhotic patients[8] (Table 72-2). Liver enzymes (SGOT, SGPT, LDH) are indicators of hepatocellular destruction. Hemogram may reveal evidence of hypersplenism in the form of reduction of platelets and white cell count. Anemia is commonly present and is multifactorial, related to additional factors such as gastrointestinal bleeding and malnutrition. Patients with encephalopathy commonly have elevated serum ammonia levels, which do not correlate with the grade of encephalopathy.[9]
ENDOSCOPY
Figure 72-3. (A ) Splenoportogram showing total loss of liver portal perfusion. (B ) Corresponding hepatic wedge venogram showing retrograde falling of the main portal vein (reversal of flow).
Upper gastrointestinal endoscopy is a key step in the workup of patients with portal hypertension. It has become a relatively simple, well-tolerated procedure that can be performed promptly in the emergency room if necessary. The presence of esophageal varices and their grade is noted. Several endoscopic signs have been shown to be good predictors for the risk of bleeding.[5,6] It is important to note that even in the presence of esophageal varices, other sources of bleeding are quite common. Forty to 60% of patients with portal hypertension will have associated gastritis or peptic ulcer disease. Less common sources of bleeding include Mallory-Weiss tears.
DIAGNOSTIC WORKUP
RADIOGRAPHIC STUDIES
Clinical manifestations of portal hypertension depend on the associated complications. Splenomegaly is invariably present.
With the widespread availability and high diagnostic accuracy of endoscopy, the use of barium studies for
Table 72-2.
Child’s Classification of Cirrhotic Patients Bilirubin (mg/100 mL)
Class A Class B Class C
, 2.0 2.0– 3.0 . 3.0
Albumin (g/100 mL) 3.5 3.0– 3.5 ,3.0
Ascites
Encephalopathy
Nutrition
Absent Easily controlled Difficult to control
Absent Minimal Advanced
Excellent Good Poor
Chapter 72. Management of Portal Hypertension
establishing the presence of esophageal varices has become uncommon. Ultrasonography provides a non-invasive tool for measurement of the size of the liver and spleen and the detection of ascites. Furthermore, duplex Doppler scanning of the portal vein has become increasingly accurate in determining the portal vein size and patency as well as the flow direction and velocity. The presence of large periportal collaterals can also be demonstrated. Angiographic studies for demonstrating the splanchnic circulation can be performed by several techniques.[10] In addition to outlining the venous anatomy and direction of blood flow, portal pressure can be measured simultaneously. 1.
2.
3.
4.
Splenoportography performed via a percutaneous transsplenic puncture is becoming unpopular because of its bleeding complications, especially in patients with coagulopathy. The transhepatic approach is less likely to be complicated by bleeding and is preferred by some radiologists. This approach also allows for sclerosis of the coronary vein.[11] Transumbilical catheterization of the portal vein is quite a safe approach but requires a cut-down on the umbilical vein. Furthermore, dilatation of the umbilical vein for catheterization is often tedious. This approach has thus failed to gain wide popularity among radiologists. Currently, the most widely used imaging technique is celiac and superior mesenteric angiography with venous phase studies. This outlines the celiac, superior mesenteric, and portal veins, showing their size and patency and demonstrating the grade of liver perfusion. For a complete evaluation, the hepatic veins are entered via a femoral vein puncture. Contrast study of the hepatic veins and the inferior vena cava is obtained. The catheter tip is then advanced into the right hepatic vein and wedged into a distal branch and a pressure reading is obtained. Wedged hepatic pressure has been shown to correlate well with sinusoidal pressure. It is thus elevated in patients with cirrhosis and remains normal in presinusoidal or extrahepatic portal hypertension.
While mostly an investigative tool, portal pressure measurement can be helpful in decision making in patients with Budd-Chiari syndrome regarding the choice of the operative approach. Patients with a high pressure gradient between the portal vein and the inferior vena cava are good candidates for portocaval shunting. Patients with elevated caval pressure that minimizes or eliminates this gradient may require a mesoatrial shunt for adequate decompression of the portal system.
LIVER BIOPSY Percutaneous needle liver biopsy provides histopathological diagnosis of the underlying liver pathology. The type of liver disease not only affects the prognosis but may also influence the choice of treatment.[12]
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MANAGEMENT OF BLEEDING ESOPHAGEAL VARICES In the emergency setting, diagnosis is usually based on clinical examination and confirmed by endoscopy. Liver functions help determine the Child’s class and the overall prognosis.
RESUSCITATION AND PATIENT MONITORING Regardless of the underlying source of bleeding, initial resuscitative measures include the placement of multiple large-bore intravenous catheters and preferably a central line. Prompt administration of fresh whole blood or packed red cells with fresh frozen plasma to correct the coagulation defects secondary to the underlying liver disease. Thrombocytopenia secondary to hypersplenism is also commonly present and is corrected by the administration of platelet packs if platelet count is less than 40,000/mm3. A Foley catheter should be inserted for monitoring urine output. Radial arterial catheter allows for blood gases and pH measurement as well as continuous blood pressure monitoring. A Swan-Ganz (pulmonary artery) catheter is useful for serial determination of cardiac output but is not routinely required. Frequent monitoring throughout the process of resuscitation includes measurement of vital signs, urine output, central venous pressure, and serial hematocrit value. Measures to support the liver and prevent encephalopathy include the administration of hypertonic glucose solution and vitamin K and correction of electrolyte and acid-base abnormalities, especially hypokalemia and metabolic alkalosis. Measures to remove and minimize synthesis of ammonia by colonic bacteria include removal of blood from the stomach by lavage with ice-cold saline via a nasogastric tube and the use of cathartics (magnesium sulfate) to clear the bowel of blood and nitrogenous amines. The administration of lactulose, which is converted by bowel bacteria into lactic acid and acetic acid, results in lowering of the colonic pH. The lower pH traps ammonia in its ionized form (NH4+), which is less diffusable through the colonic mucosa. Neomycin, a nonabsorbable antibiotic (usually given as an enema), destroys the urease-producing bacteria, thus decreasing ammonia production in the gut.
SPECIFIC MEDICAL TREATMENT The infusion of vasopressin in cases of acute gastrointestinal hemorrhage is a very useful adjunct to the initial resuscitative management of these patients. Although the major clinical experience has been with its use in portal hypertension and bleeding, esophageal varices, the drug has also been shown effective in other causes of gastrointestinal bleeding, including gastritis, gastric erosions, peptic ulcer disease, arteriovenous malformations, and Mallory-Weiss tears. Vasopressin is also called antidiuretic hormone (ADH). In addition to its action
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on the distal tubules, reducing free water clearance, it has a general vasopressor effect on the smooth muscles of the vascular system. Its effect is most marked on the splanchnic vascular bed, thereby reducing portal flow. Vasopressin also reduces cardiac output and heart rate. As a result, hepatic blood flow is reduced by about 40% with reduction of the wedged hepatic venous pressure (WHVP). Vasopressin injection has been shown effective in control of variceal bleeding in about 80% of cases [13,14] and should thus be used as a first-line therapy before resorting to more invasive techniques such as balloon tamponade or injection sclerotherapy. The initial dosage is 0.2–0.4 unit/mL to be administered by continuous drip over 48 –72 hours and then tapered off. If the initial dosage fails to control bleeding, it may be increased at 0.1 unit/mL/min increments up to a maximum dose of 1.0 unit/mL/min. Because of its general vasopressor effect, vasopressin can cause coronary vasoconstriction, which together with reduction of cardiac output can result in myocardial ischemia. Careful EKG monitoring of heart rhythm and rate is done during vasopressin infusion. Should any ST-segment changes occur, the infusion rate is reduced or its administration is abandoned altogether. Administration of sublingual nitroglycerin in conjunction with vasopressin has been shown to reduce some of its cardiac side effects while maintaining the beneficial reduction of portal pressure.[15] In an attempt to minimize the systemic side effects of vasopressin and to increase its efficacy, selective catheterization of the superior mesenteric artery with direct intraarterial infusion was recommended.[16] Subsequent studies, however, failed to show any advantage for the intraarterial technique over the simpler and less invasive systemic intravenous administration of vasopressin.[17,18]
OTHER AGENTS FOR CONTROL OF BLEEDING Vasopressin Analogue Triglyceryl lysine vasopressin was shown by Freeman et al. in 1982 to provide effective bleeding control in about 70% of cases. Given in an initial bolus dose of 250 g followed by continuous intravenous infusion at a rate of 250 g/h, somatostatin has been shown in several studies to effectively reduce portal pressure and thus control variceal bleeding.[19 – 21] Somatostatin analogue SMS 201 has been shown to reduce the intravariceal pressure as well as portal pressure, suggesting that it may be of value in control of variceal bleeding.[22]
Beta-Adrenergic Blockers Propranolol in doses that reduce the resting heart rate by about 25% has been shown in a number of French studies by Lebrec and associates to decrease portal perfusion and to reduce the rate of bleeding from esophageal varices both in patients who have never bled from varices before and in patients who have had one or more prior bleeding episodes.[22 – 27] Some of these studies have also shown a trend towards improved survival. It has also been shown by some authors to reduce the frequency of bleeding from congestive gastropathy.[22,28] Subsequently,
several other studies failed to show a difference compared to placebo.[29,30] Meta-analysis of these studies showed a 20% reduction of recurrent variceal bleeding compared to the placebo group (45% vs. 66%) with no significant difference in mortality rates (22% vs. 28%).[31] The use of beta blockers in the management of acute bleeding episodes is undesirable because of its cardiac effect. Following stabilization, however, beta blockers may prove useful in preventing rebleeding.
Organic Nitrates Nitrates such as isosorbide dinitrate reduce portal pressure by decreasing resistance to portal and collateral blood flow and by promoting reflex splanchnic vasoconstriction. Chronic administration of organic nitrates may have a prophylactic benefit for variceal bleeding.[32,33]
ENDOSCOPIC VARICEAL SCLEROSIS Injection sclerotherapy aims at systematic eradication of varices by thrombosis and organization. Endoscopic sclerotherapy was first introduced by Crafoord and Frenckner in 1939[34] using the rigid esophagoscope. The procedure was temporarily abandoned in favor of the surgical shunting procedures in the 1950s and 1960s. In the early 1970s the procedure was revived, and with the introduction of the flexible fiberoptic endoscopy, the use of the procedure has rapidly expanded both in the emergency control of variceal bleeding and in the long-term prevention of rebleeding.[35 – 38] At the present time endoscopic sclerotherapy represents the mainstay of therapy for most patients with liver cirrhosis and bleeding varices.
TECHNICAL ASPECTS Intravariceal injection aims at eradication of the varices by a process of thrombosis and organization. A different technique is perivariceal injection, which aims at induction of sclerosis and fibrosis in the submucosa surrounding the esophageal varices, thus surrounding the variceal channels with thickened walls that are less likely to rupture without actual obliteration of the varices themselves. Several studies have compared the two techniques and the general concept is that direct obliteration of the varices by intravariceal injection is more appropriate. It is important to remember, however, that 25–40% of intravariceal injection extravasates into the surrounding submucosa (paravariceal tissues) and that paravariceal injection sometimes enters the variceal lumen.[39,40] A variety of sclerosing agents have been used, the most popular of which have been ethanolamine, sodium morruate, and sodium tetradecylsulfate. Other agents have been used in various combinations with the standard agents, including thrombin, alcohol, and hypertonic saline. Depending on the size of the varix, an average of 2 mL/varix is usually sufficient for each injection. More recently the use of histoacryl has been popularized as an effective sclerosant for esophageal varices. Proponents of
Chapter 72. Management of Portal Hypertension
histoacryl advocate its use to sclerose gastric varices as well. In an alert and cooperative patient, injection sclerotherapy can usually be performed under light sedation. On the other hand, actively bleeding patients with altered level of consciousness may require endotracheal intubation under general anesthesia to avoid the risk of aspiration.
VARICEAL BANDING First introduced by Steigmann,[41] this technique aims at placement of an elastic O-ring around the base of the varix in a manner similar to that used for hemorrhoids. The technique has been shown to be as effective as standard sclerotherapy in controlling variceal bleeding with a lower rate of local and systemic complications.[42]
COMPLICATIONS OF VARICEAL INJECTION SCLEROTHERAPY AND BANDING Several complications are seen following sclerotherapy with varying degrees of severity, including: 1.
2. 3. 4.
Stricture formation occurs in about 6-12% in most series. Most are membraneous in nature and are thus easily dilatable. Perforation rate varies between 1 and 5% in different series. Bleeding from injection ulcers is reported in about 5% of cases. Systemic side effects including fever, tachycardia, retrosternal chest pain, and occasionally pleural effusion and atelectasis are reported with variable frequency.[43 – 45]
RESULTS For acute bleeding, varices endoscopy should be performed as soon as the initial resuscitative measures are taken and the vasopressin infusion started. Endoscopy is essential to confirm the presence of varices as the source of bleeding and to rule out other causes of upper gastrointestinal bleeding. If bleeding is still active at the time of endoscopy, despite the initial supportive measures and vasopressin infusion, then endoscopic variceal injection (or banding) should be performed. This is presently considered the treatment of choice in the acute setting providing more than 90% effective control of bleeding.[46 – 49] The superiority of endoscopic sclerotherapy over medical treatment alone with or without the use of balloon tamponade in controlling bleeding in the acute setting has been shown by several randomized trials.[50 – 52] Furthermore, improved overall survival was noted in some of these studies.[52]
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INJECTION SCHEDULE FOR LONGTERM PREVENTION OF REBLEEDING Following successful bleeding control with sclerotherapy a long-term injection schedule is followed to prevent recurrent bleeding aiming at complete eradication of the varices. While different injection schedules are being followed in different centers, the general consensus is that the first two to three sessions should be carried out 5 –10 days apart to prevent early rebleeding. Subsequently, sclerotherapy sessions are carried out every 3 –6 weeks until all varices are obliterated. Following complete eradication of the varices (usually achieved after a 6- to 12-month period), endoscopic followup and reinjection of any recurrent varices if present should be carried out at 6-monthly to yearly intervals.
RESULTS OF LONG-TERM INJECTION SCLEROTHERAPY Generally about 30 –50% of patients will suffer rebleeding episodes of varying degrees of severity while undergoing sclerotherapy.[53] Following complete eradication of the varices, however, rebleeding is quite rare. Banding is also associated with a similarly high rebleeding rate from persistent varices, which drops significantly after complete eradication.[54] Compared to conventional medical therapy, long-term sclerotherapy has provided a significant reduction of the frequency of subsequent recurrent bleeding episodes. No significant improvement in the overall survival, however, has been documented.[55 – 61] Three large studies have compared long-term sclerotherapy with distal splenorenal shunt in the management of patients who have recovered from acute bleeding episodes.[62 – 64] Warren and coworkers[62] showed a markedly higher bleeding control rate with distal splenorenal shunt compared to sclerotherapy (3% vs. 53%) with no significant difference in early mortality. Two-year survival, however, was higher with sclerotherapy (84% vs. 59%). It is important to note that about one third of sclerotherapy patients failed treatment in this study and required surgery. Thus, the improved survival with sclerotherapy actually represents a combination of sclerotherapy and surgery.[62] Studies by Rikkers et al.[63] and Teres et al.[64] showed no difference in survival, a higher rebleeding rate with sclerotherapy, and a higher rate of encephalopathy with shunting. Other studies have shown similar results.[65]
PROPHYLACTIC SCLEROTHERAPY Prophylactic sclerotherapy for patients with esophageal varices who have never bled have failed to significantly reduce the incidents of recurrent bleeding or improve survival in several studies[66,67] and thus is generally not recommended. There are, however, a few proponents for such practice. Paquet[6] performed a study to evaluate the role of prophylactic sclerotherapy in cirrhotic patients considered at high risk
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for variceal bleeding. Patients were selected based on the size of the varies, the presence of cherry red spots, and poor clotting mechanism. At 3-year follow-up there was significant advantage for the sclerotherapy group compared to the control group regarding rebleeding and survival.[6] The NIEC trial suggests that a subpopulation of patients with esophageal varices is highly prone to hemorrhage. This study includes Child grade (as an index of liver function) variceal bleeding. Identifying such a “high-risk” group of patients is crucial in defining the role of prophylactic therapy.[5]
TRANSHEPATIC VARICEAL SCLEROSIS Another technique of variceal sclerosis involves percutaneous transhepatic catheterization of the portal vein with embolization of the coronary vein with a variety of sclerosants. This technique was introduced by Lunderquist, and Vang in 1974, and hypertonic glucose with thrombin was then used for sclerosis.[11] Subsequently, other agents have been used including sodium tetradecyl sulfate, absolute alcohol, gel foam strips, ivalon sponge, steel coils, and glue such as bucrylate. Generally 60 – 80% successful coronary vein occlusion with control of acute variceal bleeding has been reported. About 20–50% of these patients, however, suffered recurrent bleeding within varying time intervals.[68 – 70] The high rebleeding rate has been attributed to the rapid development of collaterals from the splenic hilum. Furthermore, the procedure has been complicated by a 20% incidence of portal vein thrombosis.[69] Gel foam pulmonary embolism has been hemoperitoneurn and bleeding from the tract in patients with coagulopathy. Presently, transhepatic embolization is not recommended as a first-line procedure in the management of patients with acute variceal bleeding. In addition to the mentioned risks, catheterization of the coronary vein in the acute setting is time consuming and requires special skills. It may, however, have a role in patients who have failed vasopressin infusion, sclerotherapy, and balloon tamponade. If successful, it can provide some time to better prepare the patient for a more definitive fonn of therapy. The procedure of transhepatic variceal obliteration has also been used as an adjunct to some shunt procedures to obliterate the coronary vein.
BALLOON TAMPONADE IN ACUTE VARICEAL BLEEDING As early as the 1950s, the Sengstaken-Blakemore tube has been used for control of variceal bleeding. The original tube with gastric and esophageal balloons as well as a gastric aspiration channel was later modified by adding an esophageal tube for continuous aspiration of secretions to prevent aspiration pneumonia.[71] Endotracheal intubation should precede placement of the Sengstaken-Blakemore tube to protect the airway following passage of the tube into the stomach, via the gastric balloon. The latter is then inflated with 200–300 cm3 of saline and pulled with the tube taped to
a fixation device such as a football helmet via a weight pulley system. If bleeding is not controlled by inflation of the gastric balloon alone, the esophageal balloon should then be inflated to a maximum pressure of 30– 40 mmHg and for no longer than 24 –48 hours. Temporary deflation of the esophageal balloon every 8 hours is recommended to avoid esophageal ulceration. The Sengstaken-Blakemore tube is associated with significantly high morbidity.[72 – 74] Lethal complications including esophageal perforation, asphyxia from upriding of the balloon into the pharynx, and aspiration pneumonia have been reported in 4–9% of cases. Up to 40% overall mortality has been reported. Because of such high morbidity and mortality associated with the Sengstaken-Blakemore tube, its use should be restricted to those patients whose variceal bleeding cannot be controlled by vasopressin and sclerotherapy.
SHUNTING PROCEDURES FOR PORTAL HYPERTENSION Decompressive shunts continue to play an important role in the management of portal hypertension for many patients.[75] Portosystemic shunts are considered major operative interventions, and thus patients should be carefully selected for these procedures.
INDICATIONS Nowadays, shunt surgery is rarely needed in an emergency situation. Vasopressin infusion, sclerotherapy, and balloon tamponade provide effective bleeding control in over 90% of cases. More recently, transjugular intrahepatic portosystemic shunt (TIPS) have further improved the chances of controlling variceal bleeding nonsurgically. For the rare patient who fails to respond to these measures, surgical intervention remains the option of last resort. In the long-term management of patients whose initial bleeding has been controlled, the majority of patients should initially be managed by sclerotherapy. Shunt surgery is resorted to in patients with good hepatic function (Child A or B patients) who are considered as “sclerotherapy failures.”[76] The exact definition of this term varies from one center to another but generally entails recurrent bleeding after three to six sclerotherapy sessions. Patients who are unable or unwilling to comply with a serial sclerotherapy regime are also included in this category. Gastric varices are very difficult to eradicate by endoscopic sclerotherapy, and these patients are best managed by surgical decompression.[77] Portal hypertensive gastropathy has been shown to be the source of bleeding in some patients. Obviously these patients are not candidates for injection sclerotherapy and should be considered for decompressive shunts.[78] Selected patients whose underlying liver disease is of excellent prognosis, and thus are expected to have a prolonged survival, might be better served with a decompressive distal splenorenal shunt than a long-term or life-term program of endoscopic follow-up and sclerotherapy. Examples include patients with congenital hepatic fibrosis, extrahepatic portal hypertension,
Chapter 72. Management of Portal Hypertension
and selected cases of schistosomal hepatic fibrosis (presinusoidal portal hypertension). Prophylactic portosystemic shunts are not indicated. Only one third of patients will have bleeding from their varices within 10 years of their detection. Studies have shown that despite protection against bleeding, prophylactic shunts provide absolutely no survival benefit over conservative measures. These patients tend to suffer from encephalopathy and eventually die of liver cell failure.[78,79]
TYPES OF SHUNT PROCEDURES Total Portosystemic Shunts These shunts are very effective in decompressing the splanchnic circulation and reducing portal pressure but result in loss of portal perfusion of the liver. The classic example of total portosystemic shunts is the end-to-side portocaval shunt. This procedure decompresses the splanchnic bed but does not decompress the obstructed liver sinusoids, and thus the intrahepatic sinusoidal pressure remains high. Portocaval shunts are technically easier to perform compared to distal splenorenal shunts. In these procedures the portal vein is identified in the free margin of the lesser omentum where it is isolated and dissected up to its bifurcation and mobilized sufficiently to allow an end-to-side or side-to-side anastomosis to the inferior vena cava without kinking or twisting. Side-to-side portocaval shunts, on the other hand, decompress both the splanchnic bed and the congested sinusoids. Like end-to-side shunts, side-to-side shunts result in total portal diversion resulting in normalization of the portal pressure but depriving the liver of the portal flow. Blood flow is reversed in the portal vein with side-to-side shunts so that it acts as an outflow tract for the obstructed sinusoids. In addition to bleeding control due to reduction of portal pressure, this results in excellent control. Other procedures that have been used to achieve total portal decompression include mesocaval and mesovenal interposition shunts. Mesocaval shunts are technically less demanding than portocaval shunts, hence they are may be preferable in emergency situations. This type of shunt also has the important advantage of avoiding dissection within the liver hilum and thus keeping the option for orthotopic liver transplant easily available should the need for it to arise at a future date. The central splenovenal shunt, whereby the spleen is removed and the central end of the splenic vein is anastomosed to the side of the left renal vein, has no hemodynamic advantage over portocaval shunt, since it results in total loss of portal blood flow to the liver. Besides removal of the spleen in patients with portal hypertension, it is often associated with excessive blood loss, particularly in patients with extensive perisplenic vascular adhesions. Total diversion of the portal flow to the liver has resulted in a postoperative encephalopathy rate of 20–70%. Furthermore, randomized trials comparing this procedure to medical management for variceal bleeding showed no significant difference in the overall survival, as the mortality from liver cell failure and encephalopathy almost equals that of recurrent
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bleeding in nonshunted patients. Another important disadvantage of the portocaval shunt in the present era of liver transplantation is that the hilar dissection needed for the portocaval shunt makes subsequent orthotopic liver transplantation technically difficult and hazardous. It is our opinion that total portocaval shunts have no place in the management of bleeding varices in the present time. In an attempt to obtain portal decompression without completely depriving the liver portal flow, the construction of “small bore” portocaval shunts was recommended. By reducing the portocaval stoma or reducing the size of the interposition graft between the portal or superior mesenteric vein and the inferior vena cava to 8 –10 mm diameter, portal pressure is reduced while the portal flow to the liver is maintained in 40 –80% of cases, thus minimizing the encephalopathy rates.[82 – 84] Other studies have failed to show a significant advantage over the standard protovacal shunts. Furthermore, like standard portocaval shunts, the procedure violates the right upper quadrant, which is a serious disadvantage for future transplant candidates.[85] With the exception of a few centers, the use of total shunts at present is limited to one of three indications: (1) emergency control of bleeding when nonsurgical means fail, (2) suitable cases of Budd-Chiari syndrome, and (3) patients with bleeding from ectopic varices sites such as ileostomy or colostomy sites (peristomal varices). A total shunt is required in such a case to decompress the whole splanchnic circulation.
Selective Portosystemic Shunts (DSRB) Unlike total shunts, which decompress the whole splanchnic circulation, selective shunts aim at decompression of the gastroesophageal area only to prevent variceal bleeding while maintaining portal flow to the cirrhotic liver. Distal splenorenal shunt (DSRS) (Fig. 72-4), first proposed by Warren in 1967, is the most commonly performed selective shunt at the present time.[86] Coronary caval shunt is another example of selective shunting procedures but is much less commonly utilized because of its high thrombosis rate.[87] We believe that distal splenorenal shunt is the shunt procedure of choice for patients with good liver function (Child A and B) who fail sclerotherapy for long-term management of bleeding varices.
HEMODYNAMICS OF DISTAL SPLENORENAL SHUNT Conceptually, this procedure is designed to decompress the variceal bed by normalizing the pressure in the splenic vein. This is achieved by transecting the splenic vein and anastomosing the splenic end to the side of the left renal vein. Following the creation of this shunt, venous return from the stomach is diverted away from the gastroesophageal varices to the decompressed short gastric and splenic veins. The operation is designed to disconnect the splenic from the superior mesenteric venous compartment. The idea is to preserve portal blood flow to the liver to eliminate or reduce the incidence of postshunt encephalopathy. To achieve this
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Figure 72-4.
Diagrammatic depiction of the distal splenorenal shunt.
anatomic separation between the decompressed splenic and the high-pressure mesenteric venous beds, all veins connecting these two compartments should be interrupted. This includes the coronary, gastroepiploic, and inferior mesenteric veins.
TECHNIQUE Exposure is equally well provided by a midline or a long left subcostal incision. Gastric devascularization is carried out along the greater curvature up to the short gastric vessels. These vessels are left intact to drain the gastroesophageal junction into the splenic vein. The right gastroepiploic vein is interrupted near the pyloric end of the greater curvature of the stomach. Through the lesser sac, the pancreas is mobilized along its inferior margin to expose and isolate the splenic vein. Careful handling is required to avoid tearing of the short pancreatic veins that drain directly into the splenic vein during this step. Mobilization of the splenic vein is started at its junction with the superior mesenteric vein and then is carried out towards the splenic hilum for a distance sufficient to allow bringing down the splenic vein to the left renal vein without kinking. Generally 4 –6 cm of the vein are required. More extensive mobilization of the splenic vein has been recommended by some authors (splenopancreatic disconnection) to avoid future formation of portosystemic collaterals along this route, which can reduce the shunt “selectivity” by time.[88 – 90] This rather theoretic benefit, however, has to be weighed against the risk of splenic vein tearing during such extensive mobilization and increased rate of rebleeding due to gastric congestion. The left renal vein is then identified in the retroperitoneum and mobilized. The left adrenal vein is ligated but the left gonadal vein may be left intact. The splenic vein is then transected as close as possible to its confluence
with the superior mesenteric vein. Leaving too long a stump may result in subsequent thrombosis that may extend to the portal vein. The cut end of the splenic vein is then anastomosed to the anteriosuperior aspect of the left renal vein in an end-to-side fashion using standard vascular technique. Attention is then directed to exposure and ligation of the coronary vein. This is best achieved by reflecting the stomach anteriorly and isolation of the vein in the peritoneal fold crossing between the upper border of the pancreas and the lesser curvature of the stomach. Postoperative care of distal splenorenal shunt patients includes careful fluid management. Unlike side-to-side portocaval shunts, distal splenorenal shunt does not decompress the hepatic sinusoids and thus may be complicated by the formation of ascites in the early postoperative period. Dietary sodium restriction is recommended, and most patients are given aldoctone 50 –100 mg daily. Lasix may be required for some patients.
RESULTS Distal splenorenal shunt has been shown to effectively control variceal bleeding in more than 90% of cases. Prospective trails comparing distal splenorenal shunt to total shunt showed equivalent bleeding control with no significant difference in survival.[90 – 92] Rebleeding after the DSRS is most often due to early shunt thrombosis. The most likely cause for this complication is kinking or twisting of the splenic vein, excessive tension at the suture line, or the use of a phlebitic or a small splenic vein (less that 6 mm in diameter). Late thrombosis of DSRS anastomosis is extremely rare and is usually a complication of recurrent alcoholic pancreatitis. Re-bleeding in the presence of a patient DSRS is rare (5 –10%). In most such patients, bleeding can be
Chapter 72. Management of Portal Hypertension
readily controlled sclerotherapy. As a result of maintained portal perfusion, the rate of encephalopathy is significantly lower after distal splenorenal shunt (generally less than 10%). Portal perfusion is maintained in distal splenorenal shunt in more than 90% of cases documented by angiographic studies (Fig. 72-5.) The ability of the shunt to maintain portal while effectively controlling variceal bleeding, i.e., “selectivity,” decreases with time in patients with alcoholic cirrhosis (Fig. 72-6.) Long-term studies have shown portal perfusion to be maintained in 90% of patients with nonalcoholic cirrhosis versus 50% of patients with alcoholic liver cirrhosis. Delayed reduction of portal perfusion to the liver is due to the progressive neoformation of portosystemic collaterals mainly involving intrinsic pancreatic and peupancreatic veins (pancreatic syphon). It is important to notice, however, that this loss of shunt selectivity with time, i.e., progressive diversion of portal flow, is not paralleled by progressive encephalopathy at the same rate. Unlike total shunts, the selective shunt is not designed to decompress the superior mesenteric or the sinusoidal venous bed. For this reason, postoperative ascites is not uncommon after this procedure. In most instances ascites responds readily to fluid restriction diuretic management. However, resistant ascites may be seen in DSRS patients with shunt occlusion or portal vein thrombosis. These complications can be readily recognized by angiographic or duplex studies. Another potentially serious complication is chylus ascites, resulting from injury to the major intestinal lymphatics during dissection in the vicinity of the superior of mesenteric vein. Chylus ascites can be readily recognized by the milky apperance of the ascites and the high lipid content of the ascitic fluid. Patients with chylus ascites usually respond after 2 – 4 weeks of repeated paracentesis and total parenteral nutrition. In conclusion, we believe that distal splenorenal shunt is the shunt procedure of choice. It should be employed whenever injection sclerotherapy fails to control bleeding provided the patients has good hepatic reserve and the operation is technically feasible. Because of the excellent long-term results with nonalcoholic cirrhosis regarding bleeding control, maintaining of portal perfusion, and survival, this subset of patients should be considered for distal splenorenal shunt earlier in the course of their disease.
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Figure 72-6. Venous phase of SMA injection showing delayed development of venous collaterals after DSRS with subsequent loss of portal blood flow to the liver.
NONSHUNT SURGICAL PROCEDURES A large variety of devascularization procedures have been described as surgical alternatives for patients with bleeding esophageal varices. The aim of these procedures is to interrupt collaterals between the high-pressure portal circulation and the variceal watershed area at the gastroesophageal junction. These procedures include gastroesophageal devascularization, esophageal transection, or a combination of the two procedures. Splenectomy is always added to decongest the splanchnic circulation.
Gastroesophageal Devascularization Devascularization of the distal esophagus and proximal stomach with ligation of the coronary vein and splenectomy was originally described by Hassab[93] for patients with schistosomal hepatic fibrosis in Egypt and the Middle East. Excellent results were reported with a very low incidence of recurrent bleeding and encephalopathy. Such results, however, could not be duplicated in the western studies dealing primarily with alcoholic and posthepatic liver cirrhosis.[94] Performing the operation via a transthoracic approach to allow extensive devascularization of the esophagus extending up to the inferior pulmonary vein also failed to improve results in the patients with alcoholic cirrhosis.
Esophageal and Gastric Transection Figure 72-5. Venous phase of SMA injection showing good liver portal perfusion after distal splenorenal shunt.
Transection of the esophagus and reanastomosis aims at interrupting the periesophageal and intramural collaterals.
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Currently the procedure is performed by use of stapling instruments, which transect and reanastomose the esophagus with a single action. The procedure is usually performed via an abdominal approach with the stapler introduced via a small gastrotomy incision. The stapler is fired about 2 cm proximal to the gastroesophageal junction. Proper sizing of the stapler and ensuring completeness of the two esophageal rings after removal of the stapler are crucial points to avoid the serious complications of leak and esophageal stenosis. Esophageal transection alone is generally effective for acute variceal bleeding but is followed by a very high rate of recurrent bleeding ranging between 50 and 70%.[95,96] This procedure is thus limited to selected unshuntable patients whose acute bleeding persists despite the previously described methods.
Combined Esophageal Transection and Devascularization Extensive esophagogastric devascularization combined with esophageal transection was described by Suguira and Futagawa in 1973.[97] The operation is performed via a twostage thoracotomy and abdominal approach. Excellent results were reported with an operative mortality of less than 5%, bleeding control of 97%, and minimal encephalopathy. Like the Hassab procedure, the results of the Suguira operation could not be reproduced in western series partly because of the variability of the extent of the devascularization process and partly because of the different underlying etiology of liver disease, being primarily alcoholic liver cirrhosis in these studies. Because of the much higher rate of recurrent bleeding with devascularization and transection procedures compared to shunt surgery, the role of these “nonshunt” operations is probably limited to good-risk patients (Child A or B) who fail sclerotherapy when the splanchnic venous anatomy precludes a shunt procedure. Examples include patients with portal vein thrombosis and patients who have already undergone an unsuccessful shunt operation.
Figure 72-7. Diagrammatic representation of the transjugular intrahepatic portosystemic shunt.
portal hypertension. Generally, a 10 –15 mm gradient is still present after completion of the procedure. As a direct consequence of the incomplete decompression, a high rate of recurrent bleeding (20%) is not surprising and is expected to increase with time. Second, the insertion of a metallic stent in the low-flow venous system is likely to be complicated by a high incidence of thrombosis, which is also likely to increase with time. The main indication for TIPS at the present time is for the short-term control of variceal bleeding in the small number of cirrhotic patients who are about to undergo liver transplantation. This is of particular value in patients with poor liver
TRANSJUGULAR INTRAHEPATIC PORTOSYSTEMIC SHUNT The concept of creating an intrahepatic portosystemic shunt (Figs. 72-7, 72-8) by creation of a tract between the portal vein and the inferior vena cava was first introduced by Rosch[98] in 1969 in the swine model. The procedure has subsequently gone through a series of modifications including introduction and improvement of the balloon-expandable stent. The Palmaz stent is now used to bridge the intrahepatic tract between the portal vein and the inferior vena cava and maintain its patency.[99,100] Several authors have then reported their experience with the procedure. It has proven efficacy in controlling acute variceal bleeding and is probably an effective therapy for intractable ascites.[101 – 104] Despite the high rate of technical success (over 90%), the procedure has several potential problems. Because of the small size of the intrahepatic portal vein and hepatic vein branches, the shunt does not result in complete relief of
Figure 72-8. Contrast injection in the portal vein showing flow across the TIPS into the hepatic vein.
Chapter 72. Management of Portal Hypertension
function who have failed more conservative measures and are not candidates for emergency surgery because of their liver status. In such cases, TIPS is a valuable alternative to tide the patient over the acute bleeding episode until liver transplantation is feasible. Long-term patency should not be an issue in this patient group. In this setting, TIPS is also advantageous over emergency portocaval shunts in avoiding technical difficulties with future transplantation when properly placed. Furthermore, portal decompression provided by the TIPS procedure may reduce the transfusion requirements during transplant surgery. Cases where misplacement or migration of the stent have been reported, however, may pose some technical difficulties for transplantation. Because of the high rate of rebleeding and stent occlusion with long-term followup, the value of TIPS in patients who are not considered candidates for liver transplantation is rather doubtful.
LIVER TRANSPLANTATION IN PORTAL HYPERTENSION Although sclerotherapy and shunt surgery have both reduced the risk of rebleeding in patients with esophageal varices, the overall survival of these patients remains poor because of the underlying liver disease, which is not addressed by either modality. With time, the majority of these patients continue to lose hepatic functional reserve and become incapacitated by encephalopathy, ascites, and coagulopathy. Liver transplantation emerged in the 1980s as the only reasonable option for cirrhotic patients with poor liver function. The dramatic improvement in surgical technique and immunosuppressive therapy over the past two decades has added transplantation as a safe therapeutic modality for these patients. Orthotopic liver transplantation is presently the technique of choice. While not considered an absolute contraindication anymore, portal vein thrombosis remains a high-risk surgical factor.[105] The use of a jump vein graft from the superior mesenteric vein or the superior mesenteric/splenic vein confluence to the recipient portal vein makes the procedure possible in some cases of portal vein thrombosis. Patients with extensive thrombosis of the portal tributaries are not suitable for this procedure. Previous portocaval shunts create tremendous technical difficulties in dismantling the shunt and preserving a portal vein of good quality for the anastomosis. It is thus crucial to avoid central (portocaval) shunts at all costs in a patient who is considered a potential candidate for liver transplantation. If a shunt procedure is needed as a bridge to transplantation, only peripheral shunts (that avoid the liver ilium) should be considered. As mentioned earlier, TIPS is also considered a safe bridge to liver transplantation in patients with poor liver function as it does not impinge on the hilum of the liver if properly placed.
RESULTS AND DIFFICULTIES Encouraging results have been reported from various centers.[106 – 109] Iwatsuki et al.[107] reported 79, 74 and 71%
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survival rates at 1, 3, and 5 years, respectively. For Child C patients, 2-year survival with liver transplantation is superior to shunt procedure, approaching 75%, vs. 30 –50% for shunt surgery. For good-risk patients (Child A, B) comparable survival rates are seen for both modalities at 2 years. At 5 years of follow-up, however, survival of shunt patients drops to 45 –50% compared to 71% after transplantation. While there is little doubt regarding the role of liver transplantation in patients with severe liver function impairment and bleeding esophageal varices, the procedure is surrounded by several difficulties that seriously limit the liberal use of this procedure as recommended by some of its proponents. The high cost, organ shortage, and morbidity of long-term immunosuppressive therapy are only some of these difficulties. In summary, our recommendation is that the initial treatment of patients with bleeding esophageal varices should be by endoscopic sclerotherapy. Failures should be managed according to the liver function status. Good-risk patients (Child A, B) are treated surgically. Our preference is for the distal splenorenal shunt whenever technically feasible. Patients with poor liver reserve are considered for orthotopic liver transplantation. TIPS may be placed for short-term bleeding control while the patient is being prepared for transplantation.
SCHISTOSOMIASIS AND PORTAL HYPERTENSION Schistosomiasis is an endemic disease in many African and Southeast Asian countries. Worldwide, schistosomiasis accounts for more cases of portal hypertension than any other intrinsic liver disease. The main histologic feature of hepatic schistosomiasis is fibrous tissue disposition around the terminal branches of the portal vein. There are two basic differences between schistosomal portal hypertension and portal hypertension secondary to alcoholic or viral liver disease: (1) schistosomiasis portal hypertension is presinusoidal in distribution; (2) in pure hepatic schistosomiasis, liver function is usually well preserved until the very late stages of the disease. The main cause of death in these patients is variceal bleeding. Studies have shown improved survival of schistosomal patients when variceal bleeding is successfully controlled. Similar studies in alcoholic and posthepatitic cirrhotics failed to show similar results because of the higher incidence of death from liver failure in these populations.[110] Acute management of variceal bleeding in schistosomal patients is the same as in other forms of portal hypertension. For long-term management, sclerotherapy with surgery as a safety net for sclerotherapy failure is the preferred method of treatment. This approach, however, may not achieve the same success rate as reported in the West regarding salvaging patients who have failed sclerotherapy, since many of these patients live in remote areas where emergency care may not be readily available. The most widely used operation for the treatment of schistosomal patients who fail injection treatment is splenectomy and gastric devascularization. Advocates of this procedure emphasize its relative simplicity compared to
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shunt procedures that require special skills which the average general surgeon may not possess. They also believe that removing the spleen helps to relieve the discomfort associated with massive enlargement of this organ as well as hypersplenism, which is a common hematologic finding in these patients. The main disadvantage of this procedure is the high incidence of rebleeding. The distal splenorenal shunt is our procedure of choice when surgical treatment is indicated in schistosomal portal hypertension. The incidence of rebleeding after this procedure is less than after splenectomy and gastric devascularization. From a technical point of view, splenic vein dissection is not as difficult as in patients with alcoholic pancreatitis because in schistosomiasis the pancreas is not usually inflamed. In some instances, however, massive splenomegaly may crowd the operative field and may be associated with extreme attenuation of the wall of the splenic and pancreatic veins. These technical difficulties can be ameliorated by temporary clamping of the splenic artery to decongest the operative field.
POSTHEPATIC PORTAL HYPERTENSION (BUDD-CHIARI SYNDROME) In this syndrome portal hypertension is caused by occlusion of the hepatic veins and/or the retrohepatic vena cava. The venoocclusive disease may be associated with generalized disorders that cause hypercoagulability such as myeloproliferative disorders, polycythemia vera, and protein C or protein S deficiency. In many cases, however, the etiology of venous thrombosis is not clear. Membranous webs obstructing the hepatic veins or IVC have been described in some patients presenting with this syndrome. In the acute form of this disease the patients present with signs and symptoms of progressive liver failure. This is often associated with massive ascites that may be difficult to control. Liver biopsy shows the characteristic histologic features of posthepatic portal hypertension, namely, sinusoidal congestion and, in the severe forms, central lobular necrosis. The treatment of patients presenting in the acute phase of the syndrome is mainly medical. Surgical decompression should be considered in patients with clinical evidence of progressive liver deterioration, particularly if associated with histologic changes suggestive of central lobular hepatic necrosis. The choice of operative procedure depends on the angiographic findings. If the IVC is patent, side-to-side portocaval shunt is the ideal operation. If the IVC is occluded, decompression of the portal venous system can only be achieved by a mesoatrial shunt. In this operation a Dacron graft is interposed between the superior mesenteric vein and the right atrium. Although mesoatrial shunts usually occlude within a year, they serve to protect the liver until spontaneous portosystem venous collaterals have had time to develop. In the chronic phase of Budd-Chiari syndrome, gastroesophageal variceal bleeding is the main cause of death. Initially, these patients are treated with sclerotherapy, but eventually they should be evaluated for liver transplants.
Two major issues will need to be considered in the evaluation process, namely the complexity of the transplant procedure in patients with occluded IVC, and the potential risk of recurrence of hepatic venous obstruction in the transplanted liver in patients with uncorrected hypercoagulable state.
PORTAL VEIN OCCLUSION The leading cause of portal vein occlusion in adults is liver cirrhosis. Other causes include pancreatitis and pancreatic malignancy. Perinatal portal vein thrombosis may be due to development aberrations or extension of the normal obliterative process from the umbilical vein and ductus venosus beyond their junction with the portal vein. Portal vein thrombosis in the newly born may also be secondary to omphalitis, generalized sepsis, or umbilical vein cannulation for exchange blood transfusion. In this form of portal hypertension, the pressure in the sinusoidal bed remains normal. As a result, collateral channels develop between the extra- and intrahepatic venous circulation. Angiographically, three distinct categories of portal venous obstruction can be recognized:[112] Type I, whereby the occlusion is limited to the hilum of the liver. This is the least common entity and is characterized by the formation of hilar caput medusa and marked enlargement of the cystic vein. Type II, whereby the main portal vein is occluded and replaced by multiple racemose collateral venous channels, the so-called cavernous malformation of the portal vein. Type III, which is the most common category and also the most extensive as the occlusive process involves the portal, the splenic, and the superior mesenteric veins (Figs. 72-9, 72-10). In patients with pure prehepatic portal hypertension, the liver function remains normal and the condition may remain asymptomatic until gastroesophageal variceal bleeding takes place. Sclerotherapy is more successful in such cases than in cirrhotics because patients with portal venous occlusion do not usually have defective blood coagulation. Surgery should be considered for patients in whom injection treatment has failed. In Type I and Type II patients who have a patent splenic and/or superior mesenteric vein, construction of an appropriate portosystemic shunt is the treatment of choice. Type III patients are not suitable candidates for shunt surgery, and the only surgical option for them is splenectomy and gastric devascularization.
SPLENIC VEIN THROMBOSIS Splenic vein thrombosis (SVT) is an infrequently recognized cause of gastroesophageal variceal bleeding.[111] In this condition the rise in venous pressure is limited to the splenic venous compartment including the short gastric and left
Chapter 72. Management of Portal Hypertension
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Figure 72-10. Splenoportogram showing hilar caput medusa with Type I portal vein occlusion.
Figure 72-9. Diagrammatic representation of types of portal vein occlusion: (A ) occlusion of portal vein at the hilum; (B ) occlusion of the main portal vein; (C ) occlusion of the portal vein, superior mesenteric vein, and splenic vein.
gastroepiploic veins. The rise in pressure in these venous channels is transmitted to their tributaries around the fundus and along the greater curvature of the stomach. As a result, two distinct venous pressure zones develop within the stomach, one hypertensive to the left and another normotensive to the right, the latter being drained by the unaffected coronary and venous channels that drain into the portal vein. The creation of a pressure gradiant within the stomach wall is the main hemodynamic feature of this form of portal hypertension. As a result, two sets of collaterals are formed: (1) portoportal collaterals between the veins draining the greater curvature and the veins draining the lesser curvature of the stomach; (2) portosystemic collaterals around the gastroesophageal junction. The first mechanism explains why gastric varices are more common in this syndrome than in the generalized form of portal hypertension. The clinical picture of SVT is fairly characteristic. The patient usually presents with hematemesis. History of pancreatitis together with endoscopic finding of extensive gastric varices should alert the treating physician to the possibility of SVT. The angiographic finding in the venous phase of splenic arteriography confirms the diagnosis. In addition to splenic venous obstruction, these studies show markedly dilated gastroepiploic veins. They also show left-toright transgastric venous flow as evidenced by sequential opacification of veins in this direction with the coronary vein being visualized in the late phases of the study followed by the portal vein (Fig. 72-11). The treatment of variceal bleeding secondary to SVT is surgical. Sclerotherapy is not likely to succeed because of the predominance of gastric varices in this condition. Splenectomy cures this form of portal hypertension. There are certain operative findings that should alert the surgeon to the diagnosis of SVT if this condition was not suspected prior to surgical exploration. These signs include markedly dilated gastroepiploic veins in contrast to normal-looking tributaries of the superior mesenteric vein, gross evidence of chronic pancreatitis, normal- appearing liver, and an enlarged spleen (Figs. 72-12, 72-13).
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either spontaneously or as a complication of a biliary enteric bypass created surgically to relieve coexisting bilary duct obstruction.
AORTIC SURGERY IN CIRRHOTICS WITH PORTAL HYPERTENSION
Figure 72-11. Delayed venous phase of SA injection in a patient with SVT. Notice the gastric varices and delayed opacification of the coronary and portal veins.
VARICES IN UNUSUAL LOCATIONS While the distal esophagus and fundus of the stomach are by far the most common sites for variceal formation, other potential locations include the duodenum, the intestine, and the biliary system.[113] Duodenal varices usually occur in the first or second part, hence they can be readily seen by endoscopy. The lesions should not be mistaken for duodenal neoplasms. Intestinal varices are often secondary to surgical adhesions between the bowel and abdominal wall. Intestinal varices may also be seen around iliostomies and colostomies as a result of formation of collaterals between the intestinal veins and adjacent veins of the abdominal wall. Varices in the biliary system are seen in patients with portal vein thrombosis
Figure 72-12.
The workup of patients for aortic surgery should include clinical and laboratory screening for evidence of liver cirrhosis and portal hypertension. The presence of these compounding problems should be considered in deciding for or against operative intervention in these patients. Thus, it may be wise to observe a 5 cm infrarenal aortic aneurysm in a cirrhotic as long as there is no radiologic evidence of significant aneurysm expansion. For larger aneurysms with reasonable expectation of life as far as the liver condition is concerned, endovascular aneurysm repair offers a reasonable alternative to open repair. The same principles apply to cirrhotics presenting with signs and symptoms of aortoiliac occlusive disease. Conservative management is advisable in such patients unless they present with limb-threatening ischemia. Again, the endovascular approach is preferred in such patients. Balloon angioplasty with or without stents should be used for lesions that are suitable for this form of treatment. In cirrhotic patients with aortic disease in whom the surgical treatment is the only feasible option, the operative approach should be modified to minimize the risk of intraoperative and postoperative complications. For aortoiliac occlusive disease, for example, an extraanatomic approach such as femorofemoral or axillofemoral offers a safer approach than an aortobifemoral bypass operation. In patients with good liver reserve in whom an aortic procedure is considered appropriate, it is imperative to minimize dissection around the aorta because of the increased risk of
Criteria for intraoperative diagnosis of SVT.
Chapter 72. Management of Portal Hypertension
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Figure 72-13. (A ) Markedly dilated gastroepiploic venous arcade in a patient with SVT. (B ) The contrast between a markedly dilated gastroepiploic venous arcade and normal looking intestinal veins in a patient with SVT.
bleeding and lymphatic leak. Any attempt to encircle the aorta in such patients carries the risk of injuring the congested retroaorticveins. For the same reason, in patients with aortic occlusive disease, end-to-side aortic anastomosis is potentially safer than the end-to-end technique. In addition to intraoperative bleeding, postoperative ascites is a major complicating factor in the care of cirrhotics who require aortic operation. Postoperative ascites adds considerably to the complexity of fluid and electrolyte management of these patients. Ascites may also leak through
the abdominal or groin incisions. Measures to avoid these potentially lethal complications include meticulous ligation of divided lymphatics and the use of the iliac instead of the femoral arteries for the distal anastomosis. Residual distal enternal iliac artery or common femoral artery stenosis can be balloon angioplastied intraoperatively. Finally, the TIPS procedure offers an attractive approach that may help to minimize operative blood loss during aortic surgery in cirrhotics and to reduce the incidence of troublesome postoperative ascites.
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from Esophagogastric Varices: A Prospective Controlled Randomized Trial. Hepatology 1985, 5, 584. Johansen, K.; Helton, W.S. Portal Hypertension and Bleeding Esophageal Varices. Ann. Vasc. Surg. 1992, 6, 553. Steigmann, G.F.; Goff, J.S.; Sun, J.H.; et al. Endoscopic Elastic Band Ligation for Active Variceal Hemorrhage. Am. Surg. 1989, 55, 124. Terblanche, J.; Northover, J.M.A.; Bornman, P.; et al. A Prospective Evaluation of Injection Sclerotherapy in the Treatment of Acute Bleeding from Esophageal Varices. Surgery 1979, 85, 239. Mac Dougall, B.R.D.; Theodossi, A.; Westaby, D.; et al. Increased Long-Term Survival in Variceal Hemorrhage Using Injection Sclerotherapy: Results of a Controlled Trial. Lancet 1982, 1, 124. Westaby, D.; Williams, R. The History of Injection Sclerotherapy for Esophageal Varices. Gastrointest. Endosc. 1983, 29, 303. Westaby, D.; Hayes, P.C.; Gimson, A.E.S.; et al. Controlled Clinical Trial of Injection Sclerotherapy for Active Variceal Bleeding. Hepatology 1989, 9, 274. The Copenhagen Esophageal Varices Sclerotherapy Project; Sclerotherapy After First Variceal Hemorrhage in Cirrhosis: A Randomized Multicenter Trial. N. Engl. J. Med. 1984, 311, 1594. Korula, J.; Balart, L.A.; Radvan, G.; et al. A Prospective Randomized Controlled Trial of Chronic Esophageal Variceal Sclerotherapy. Hepatology 1985, 5, 584. Terblanche, J.; Khan, D.; Campbell, J.A.H.; et al. Failure of Repeated Sclerotherapy to Improve Long-Term Survival After Esophageal Variceal Bleeding. Lancet 1983, 1, 1328. Warren, W.D.; Henderson, J.M.; Millikan, W.J.; et al. Distal Splenorenal Shunt Versus Endoscopic Sclerotherapy for Long-Term Management of Variceal Bleeding. Preliminary Report of a Prospective, Randomized Trial. Ann. Surg. 1986, 203, 454. Rikkers, L.F.; Burnett, D.A.; Volentine, G.D.; et al. Shunt Surgery Versus Endoscopic Sclerotherapy for Long-Term Treatment of Variceal. Early Results of a Randomized Trial. Ann. Surg. 1987, 206, 261. Teres, J.; Bordas, J.M.; Bravo, D.; et al. Sclerotherapy vs. Distal Splenorenal Shunt in the Elective Treatment of Variceal Hemorrhage: A Randomized Controlled Trial. Hepatology 1987, 7, 430. Spina, G.P.; Santambrogio, R.; Opocher, E.; et al. Distal Splenorenal Shunt Versus Endoscopic Sclerotherapy in the Prevention of Variceal Rebleeding. First Stage of a Randomized, Controlled Trial. Ann. Surg. 1990, 211, 178. Santangelo, W.C.; Dueno, M.I.; Estes, B.L.; et al. Prophylactic Sclerotherapy of Large Esophageal Varices. N. Eng. J. Med. 1988, 318, 814. The Veterans Affairs Cooperative Variceal Sclerotherapy Group; Prophylactic Sclerotherapy for Esophageal Varices in Men with Alcoholic Liver Disease. N. Eng. J. Med. 1991, 324, 1779. Bengmark, S.; Boesson, B.; Hoevels, J.; et al. Obliteration of Esophageal Varices by PTP. Ann. Surg. 1979, 190, 549.
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Gembarowicz, R.M.; Kelly, J.J.; O’Donnell, T.F.; et al. Management of Variceal Hemorrhage: Results of a Standardized Protocol Using Vasopressin and Transhepatic Embolization. Arch. Surg. 1980, 115, 1160. Mendez, G.; Russell, E. Gastrointestinal Varices: Percutaneous Transhepatic Therapeutic Embolization in 54 Patients. Am. J. Roentgenol. 1980, 135, 1045. Eldich, R.F.; Lande, A.J.; Goodale, R.L.; et al. Prevention of Aspiration Pneumonia by Continuous Esophageal Aspiration During Esophagogastric Tamponade and Gastric Cooling. Surgery 1968, 67, 405. Johansen, T.S.; Baden, H. Re-appraisal of the SengstakenBlakemore Balloon Tamponade for Bleeding Esophageal Varices. Results in 91 Patients. Scand. J. Gastroenterol. 1973, 18, 181. Novis, B.H.; Duys, P.; Barbezat, G.O.; et al. Fiberoptic Endoscopy and the Use of the Sengstaken Tube in Acute Gastrointestinal Hemorrhage in Patients with Portal Hypertension and Varices. Gut 1976, 17, 258. Teres, J.; Anastasio, C.; Bord, J.M.; et al. Esophageal Tamponade for Bleeding Varices: Controlled Trial Between the Sengstaken-Blakemore Tube and the Linton-Nachlas Tube. Gastroenterology 1978, 75, 566. Henderson, J.M. Portal Hypertension and Shunt Surgery. Adv. Surg. 1993, 26, 233. Warren, W.D.; Millikan, W.J. The Relative Role of Sclerotherapy vs. Surgical Procedures in Portal Hypertension. Adv. Surg. 1990, 23, 1. Sarin, S.K.; Kumar, A. Gastric Vances: Profile, Classification and Management. Am. J. Gastroenterol. 1989, 84, 1244. Terblanche, J. The Use of Sclerotherapy for the Management of Esophageal Varices in Portal Hypertension. Surg. Endosc. 1988, 2, 149. Conn, H.O.; Lindemuth, W.W.; May, L.J.; et al. Prophylactic Portacaval Anastomosis. A Tale of Two Studies. Medicine 1972, 51, 27. Resnick, R.H.; Chalmers, T.C.; Ishihara, A.M.; et al. Boston Interhospital Liver Group: A Controlled Study of the Prophylactic Portacaval Shunt: A Final Report. Ann. Intern. Med. 1969, 70, 675. Conn, H.O. Prophylactic Portacaval Shunts. Ann. Intern. Med. 1969, 70, 859. Rypins, E.B.; Sarfeh, I.J. The Influence of Portal Hemodynamics on Long-Term Survival of Alcoholic Cirrhotic Patients After Small Diameter Portacaval HGrafts. Am. J. Surg. 1988, 155, 152. Sarfeh, I.J.; Rypins, E.B.; Mason, G.R. A Systemic Appraisal of Portacaval H-Graft Diameters. Ann. Surg. 1986, 204, 356. Collins, J.C.; Sarfeh, I.J. Surgical Management of Portal Hypertension. West J. Med. 1995, 162, 527. Grace, N.D. Management of Portal Hypertension. Gastroenterologist 1993, 1, 39. Warren, W.D.; Salarn, A.A. Surgery for the Portal Hypertension of Cirrhosis: The Need for Change. Major Probl. Clin. Surg. 1974, 14, 127. Inokuchi, K. Selective Decompression of Esophageal Varices by a Left Gastric Venacaval Shunt. Ann. Surg. 1978, 10, 215.
88. Henderson, J.M.; Warren, W.D.; Millikan, W.J.; et al. Distal Splenorenal Shunt with Splenopancreatic Disconnection: A 4-Year Assessment. Ann. Surg. 1989, 210, 332. 89. Warren, V.V.D.; Millikan, W.J.; Henderson, J.M.; et al. Splenopancreatic Disconnection: Improved Selectivity of Distal Splenorenal Shunt. Ann. Surg. 1986, 204, 346. 90. Warren, W.D.; Millikan, W.J.; Henderson, J.M.; et al. Ten Years’ Portal Hypertensive Surgery at Emory. Ann. Surg. 1982, 195, 530. 91. Rikkers, L.F.; Rudman, D.; Galambos, J.T.; et al. Randomized Controlled Trial of the Distal Splenorenal Shunt. Ann. Surg. 1978, 187, 271. 92. Langer, B.; Rotstein, L.E.; Stone, R.M.; et al. A Prospective Randomized Trial of the Selective Distal Splenorenal Shunt. Surg. Gynecol. Obstet. 1980, 150, 45. 93. Hassab M.A. Gastroesophageal Decongestion and Splenectomy. Proceedings of the First National Symposium on Bilharziasis, Cairo, 1964; 201. 94. Barbot, D.J.; Rosato, E.F. Experience with the Esophagogastric Devascularization Procedure. Surgery 1987, 101, 685. 95. Abouna, G.M.; Bassiouny, H.; Al Nakib, B.M.; et al. The Place of the Suguira Operation for Portal Hypertension and Bleeding Esophageal Varices. Surgery 1987, 101, 91. 96. Orozco, H.; Juarez, F.; Uribe, M.; et al. Suguira Procedure Outside Japan: the Mexican Experience. Am. J. Surg. 1987, 152, 539. 97. Suguira, M.; Futagawa, S. A New Technique for Treating Esophageal Varices. J. Thorac. Cardiovasc. Surg. 1973, 56, 677. 98. Rosch, J.; Hanafee, W.N.; Snow, H. Transjugular Portal Venography and Radiologic Portocaval Shunt: An Experimental Study. Radiology 1969, 92, 1112. 99. Richter, G.M.; Noldge, G.; Roessle, M.; et al. Transjugular Intrahepatic Portacaval Stent Shunt: Preliminary Results. Radiology 1990, 174, 1027. 100. Richter, G.M.; Noldge, G.; Palmaz, J.C.; Roessle, M. The Transjugular Intrahepatic Portosystemic Stent Shunt (TIPSS): Results of a Pilot Study. Cardiovasc. Interventional Radiol. 1990, 13, 200. 101. Trover, P.C. Transjugular Intrahepatic Portosystemic Stent Shunt: Nonsurgical Therapy for Portal Hypertension. J. Ky. Med. Assoc. 1995, 93, 95. 102. Shiffman, M.L.; Jeffers, L.; Hooffigale, J.H.; et al. The Role of Transjugular Intrahepatic Portosystemic Stent Shunt for Treatment of Portal Hypertension and Its Complications: A Conference Sponsored by the National Digestive Diseases Advisory Board. Hepatology 1995, 22, 1591. 103. Crecelius, S.A.; Soulen, M.C. Transjugular Intrahepatic Portosystemic Shunts for Portal Hypertension. Gastroenterol. Clin. N. Am. 1995, 24, 201. 104. McCormick, P.A.; Dick, R.; Burroughs, A.K. Review Article the Transjugular Intrahepatic Portosystemic Shunt (TIPS) in the Treatment of Portal Hypertension. Aliment. Pharmacol. Ther. 1994, 8, 273. 105. Brems, J.J.; Hiatt, J.R.; Klein, A.S.; et al. Effect of a Priorportasystemic Shunt on Subsequent Liver Transplantation. Ann. Surg. 1989, 209, 51.
Chapter 72. Management of Portal Hypertension 106.
Henderson, J.M. Liver Transplantation for Portal Hypertension. Gastroenterol. Clin. N. Am. 1992, 21, 197. 107. Iwatsuki, S.; Starzl, T.E.; Todo, S.; et al. Liver Transplantation in the Treatment of Bleeding Esophageal Varices. Surgery 1988, 104, 697. 108. Starzl, T.E.; Demetris, A.J.; Van Thiel, D.H. Medical Progress: Liver Transplantation. N. Eng. J. Med. 1989, 321, 1014, (Part I). 109. Starzl, T.E.; Demetris, A.J.; Van Thiel, D.H. Medical Progress: Liver Transplantation. N. Eng. J. Med. 1989, 321, 1092, (Part I).
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CHAPTER 73
The Lymphatic System Timothy A. Miller Andrew E. Turk could lead to lymphedema. Sterling, in 1894, put forth his theories on filtration and absorption, which explained the pathophysiological process of lymphedema.[5] The first mention of congenital lymphedema was in 1892, when Milroy[6] described Milroy’s disease, and surgical causes of lymphedema were first noted by Halstead[7] in 1921. It is difficult to date the various medical approaches to the problem, but surgical approaches can be more easily documented. Lymphangioplasty, the first surgical procedure described in modern literature, was introduced in 1908 by Handley.[8] Kondoleon[9] suggested excision of muscle fascia, and in 1912 Charles described excision of skin and subcutaneous tissue with grafting. In 1917, Sistrunck[10] described a successful approach of subcutaneous and skin excision beneath flaps, and this was reintroduced in 1936 by Homans.[11] Thompson[12] suggested the deepithelialized dermal flap in 1962, Goldsmith et al.[13] the omental flap in 1967, and Rivero et al.[14] the lymphatic-venous anastomosis technique in the 1960s. Finally, O’Brien[15] proposed microsurgical reanastomosis in 1976.
LYMPHEDEMA: SIGNIFICANCE OF THE PROBLEM Lymphedema, or the presence of an abnormally large amount of fluid in the intercellular spaces of the body occurring because of lymphatic dysfunction, is as yet a very poorly understood entity in medicine. Its causes can be congenital or acquired. Chronic lymphedema has no real medical or surgical cure, although various means are available to control the extent of the swelling. It can have serious complications, such as recurrent cellulitis and, in rare instances, lymphangiosarcoma. A thorough understanding of the normal anatomy, physiology, pathophysiology, and current treatment options, along with their complications, is essential to finding a solution to this problem.
HISTORICAL ASPECTS Lymphedema was probably encountered clinically from the earliest beginnings of medical history. Hippocrates wrote of edema of the skin;[1] Paul of Aegina and Aretaeus of Cappadocia described “dropsy,” elephantiasis, and chronic pedal edema.[2,3] But while causes of edema secondary to infections and renal and vascular etiologies were identified as separate entities,[4] lymphedema as such was not recognized until much later.[5] Perhaps one reason for this is the largely microscopic nature of lymphatics, making them difficult to study or even recognize. And it was not until after the lymphatic system was described that the concept of lymphedema became known. There is evidence that the ancients saw lymph, but they did not correlate it with edema. Hippocrates and Aristotle spoke and wrote of “white blood” and “colorless fluid,” but they knew nothing of a lymphatic system, which was first described in 1626 by Gaspare Aselli. More than a century later, in 1787, Mascagni published the first systematic description of the lymphatic system. Hewson in 1744 and Cruikshank in 1789 were the first to postulate the involvement of this newfound lymphatic system in various pathological conditions and to suggest that its obstruction
PATHOPHYSIOLOGY An understanding of the anatomy and normal physiology of the lymphatic system is essential to a complete understanding of lymphedema pathophysiology.
Anatomy of the Lymphatic System It is generally agreed that lymphatics and lymph nodes arise from endothelial sprouting of the primordial venous system.[16,17] This development begins in four areas: the paired jugular and iliac sacs, the cisterna chyli, and the retroperitoneal system. These sacs develop peripherally between the third and eighth week of embryonic life and invade almost all tissues of the body with the major exceptions of the central nervous system, bone marrow, coating of the eye, internal ear, and intralobar portions of the liver. The thoracic duct results from the fusion of the cisterna chyli and the left jugular buds. The lymphatic channels and
Hobson/Wilson/Veith: Vascular Surgery: Principles and Practice, Third Edition, Revised and Expanded DOI: 10.1081/0819-9-120024957 Copyright q 2004 by Marcel Dekker, Inc.
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regional nodes of each extremity are eventually formed by this peripheral growth and drained either into the cisterna chyli (lower extremities) or directly into the thoracic ducts (upper extremities), which return lymph to the venous system. The lymphatics are similar to capillaries; however, the basement membrane, which is present in capillaries, is absent in the lymphatics. The lymphatic capillaries progress in size into collecting lymphatics. These form a valved system that connects to the original lymph nodes. The collecting lymphatics have intimal, medial, and adventitial layers, with elastic fibers and smooth muscle in the media in direct proportion to lymphatic size.
Leg Lymphatics The subcutaneous compartment (in which lymphedema occurs) is drained by three groups of lymphatics: a dermal plexus, collecting channels, and superficial lymphatic trunks. The intradermal lymphatics do not have valves and drain into the valved system lying in the deepest dermal level at the subcutaneous junction.[16] By means of collecting channels, the dermal plexus drains into main lymphatic trunks located on the surface of the muscle fascia. These are the lymphatics that are seen in lymphangiograms. There is a separate deep lymphatic system that drains the compartments and several channels located near bone. There is general agreement that the superficial and deep lymphatic systems are separate and communicate only under abnormal conditions, such as proximal obstruction.[18,19] As the deep vessels ascend, they maintain a constant diameter, and valves can be seen at regular (1 cm) intervals. About four vessels normally drain into the popliteal lymph nodes in the posterior knee, and four to six vessels ascend the thigh medially in the deep subcutaneous system to drain into the deep inguinal nodes. Some of the posterior trunks may bypass the popliteal nodes and enter into the superficial inguinal nodes. The superficial lymphatic system, which can more easily be studied by lymphangiography, drains into two pathways closely corresponding to the venous drainage of the leg. One system courses parallel to the greater saphenous vein, and a second drainage system parallels the lesser saphenous system. These trunks are also valved. They bifurcate, rejoin, and maintain the same diameter as they ascend the extremity. In the normal person, approximately eight vessels are seen along the medial aspect of the thigh. Some evidence exists that lymphatic channels draining the lower leg do not receive tributaries from the thigh. Lymphangiographic studies have shown that the skin and subcutaneous tissue of the thigh drains into the superior inguinal lymph nodes, while the lower leg drains into the more inferior inguinal nodes.[20] Because of this, in some patients with acquired lymphedema, the swelling may be limited to the lower leg. The inguinal nodes are divided into two groups: superficial (around the fossa ovalis) and deep (around the fatty tissue of the femoral sheath). These nodes drain proximally into the nodes around the iliac vessels. Although virtually all lymphatic flow passes through the inguinal nodes, it has been shown that lymph drainage can bypass these nodes and drain directly into the iliac area.[21]
Arm Lymphatics The superficial lymphatic channels appear anatomically similar to those in the leg, coursing along the general pattern of the basilic (medial aspect) and cephalic (lateral aspect) veins. At times they may join each other, but normally they course separately until they drain into axillary nodes.
Physiology of the Lymphatic System The lymphatic system serves a number of functions: drainage of a fraction of the macromolecular protein loss from the capillary circulation; removal of bacteria and foreign material; and transport of specific substances, such as vitamin K, from the gastrointestinal tract. Lymphatics at the capillary level are extremely permeable and have a low hydrostatic pressure compared to that of interstitial fluid.[21 – 24] Because of the marked permeability and hydrostatic differences as well as the valved nature of the system, lymph normally passes proximally and does not usually accumulate within the interstitium. Lymph is essentially an ultrafiltrate somewhat similar to plasma: it forms as a transudate resulting from the relatively high hydrostatic pressure of the arterial system. Over a 24-h period, approximately 50% of the circulating albumin can be lost from the arterial-capillary system.[24] Although the vast majority of that protein loss is resorbed into the venules by a combination of osmotic and hydrostatic forces, a minimal amount (approximately 0.1%) is not resorbed.[20] The lymphatic system is responsible for the return of this fraction of the macromolecular capillary loss. In the normal extremity, lymph contains 0.1 –0.5 g of total protein per 100 mL as compared to 6 g of protein per 100 mL in blood. Interestingly, in this dilute protein concentration, there is a disproportionately high ratio of albumin to globulin because of the higher molecular weight of globulin. This emphasizes the fact that lymph results from an ultrafiltration process across a semipermeable membrane. Once lymph enters a lymphatic from the extracellular spaces, it is not appreciably altered or concentrated.[25] Lymph flow proximally results from a combination of factors: interstitial pressure, the negative and positive fluctuation in the intraabdominal and intrathoracic cavities, and the adjacent compression of the arterial pulsations in muscular activity. The valves promote proximally directed flow. It is likely that compression of arterial pulsation and muscular contractions are particularly influential on the flow within the deep lymphatic system. There is some question as to whether lymphatic flow is assisted by an intrinsic contracture mechanism within the vessels themselves. One study demonstrated the presence of adrenergic receptors on the smooth muscle of the lymphatics, suggesting that spontaneous lymphatic contractility is an important force for the transportation of lymph.[26] The lymphatic vessels are known to contain muscle fibers as well as nerve endings. Several investigators have shown that the lymphatics of various laboratory animals respond to a variety of hormonal and chemical influences, and it seems likely that some function similar to peristalsis does exist.[27 – 31] If so, it would most critically affect the subcutaneous lymphatics that are not surrounded by muscle.
Chapter 73.
Lymphedema Lymphedema has several causes, but in all types there is impaired transcapillary fluid exchange and impaired transport of lymph. This ultimately results in an edematous and indurated extremity. Different factors characterize the acquired and primary (congenital) types of this condition, but in both, lymph drainage fails to keep up with production, resulting in accumulation of a relatively protein-rich interstitial fluid. In chronic lymphedema, total protein may be as high as 5 g/100 mL, compared to the normal value of 0.1–0.5 g/100 mL and the value of 0.9 g/100 mL in cardiac failure.[25] The high osmotic pressure secondary to the high protein concentration will further attract even greater amounts of fluid. A new balance of pressures is established at a higher level, and the increase in interstitial pressure in surrounding tissue compliance tends to increase lymph flow. Fibrosis of the extremity is of two types: (1) that resulting from the protein-rich edema fluid and (2) that due to depression of macrophage activity. The protein-rich environment results in the formation of edema by two mechanisms. First, edema occurs in areas of poorly oxygenated, stagnated fluid with accumulation of metabolic products. These metabolic disturbances induce the formation of fibrin and fibrous tissue. Second, the protein-rich environment favors the deposition of collagen, thus shifting the usual balance between collagen lysis and deposition toward deposition.[32] As mentioned, depression of macrophage activity is the second factor causing tissue fibrosis. In normal tissue, macrophages play a role in inducing collagen lysis. Studies show that macrophages in lymphedematous tissue are in a depressed state, and thus collagen lysis is also decreased. Knight et al.[33] demonstrated that lymphedematous fluid had a biochemical imbalance in favor of collagen deposition in the skin and that it therefore reduced lysis. All these factors combine to cause tissue fibrosis, which in itself further inhibits the ability of the lymphatic vessels to clear the excess fluid. Thus a cycle of further lymphedema and tissue fibrosis is perpetuated.[32]
CLINICAL PRESENTATION Lymphedema can be caused by several factors that can generally be categorized under acquired or primary (congenital) etiologies. Lymphedema is most commonly acquired from infections or parasitic etiologies; trauma to lymphatic channels secondary to burns, radiation, surgery, or direct injury; allergic reactions, resulting in lymphedema; trauma; and malignant etiologies.[34,35] Patients designated as having primary lymphedema are born with a reduced number of lymphatics or with lymphatics that are structurally abnormal. Although the etiologies vary, the clinical picture is similar. However, it can vary in severity from mild swelling of the extremity to seriously disabling or life-threatening complications such as recurrent cellulitis and lymphangiosarcoma. Early edema fluid accumulation results in a soft pitting type of edema, usually beginning in the ankle and gradually ascending. Modest increases in extremity diameter can be
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associated with substantial weight increases. Such patients typically complain of fatigue in the involved extremity. Corresponding with the duration of the lymphedema, the protein concentration of the edema fluid gradually increases. The combined lymphatic stasis and accumulation of interstitial fluid provide an ideal culture medium for bacteria. As many as 25% of patients have recurrent episodes of lymphangitis.[29] Attacks of lymphangitis account for a significant morbidity in some patients and can occur several times a year, often without preceding trauma. With progressive edema there is increased fibrosis of the connective tissue elements within the subcutaneous tissue in skin. The lymphangitis accelerates the process of fibrosis. In chronic lymphedema (elephantiasis, for example) the skin is thick and hyperkeratotic, and the entire extremity is indurated with nonpitting edema.
Primary Lymphedema As mentioned, primary lymphedema results from lymphatic abnormalities present at birth. This group of edemas can be categorized in several ways. Two methods of classification are (1) by age of onset and (2) by lymphangiographic findings. These will be discussed below. A third category comprising benign tumors of the lymphatics will be dealt with separately.
Classification by Age of Onset This is a purely arbitrary distinction, first employed by Kinmonth,[36] in which primary lymphedema is categorized into congenital lymphedema, lymphedema praecox, and lymphedema tarda based on the age of onset. While it is a useful classification, it may not be a true distinction pathophysiologically. Congenital lymphedema includes all forms of lymphedema present at birth. Presumably, this would also include benign lymphatic tumors, which are usually present at birth. These are considered separately below. Milroy’s disease is a specific subset of this category with the following characteristics: (1) it represents about 2% of the primary lymphedemas; (2) it has a familial pattern with an autosomal dominant inheritance pattern, thus affecting males and females almost equally; (3) its lymphangiographic pattern is usually one of hypoplasia; and (4) it usually affects the lower extremities.[36] Lymphedema praecox is generally manifest during adolescence, and it accounts for approximately 80% of patients with primary lymphedema. This may represent another form of congenital lymphatic system disease but with a later onset of symptoms.[36] Lymphedema tarda presents in middle age or after age 35. It is quite likely that the general category designated as “primary lymphedema” probably encompasses several conditions with varying and incompletely understood etiologies.
Classification by Lymphangiographic Findings Three general anatomic patterns of the lymphatic system have been described in patients with primary lymphedema: aplasia, hypoplasia, and hyperplasia (varicose).[37] The most
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common lymphangiographic finding is hypoplasia, seen in 70% of cases with primary lymphedema. In this form of lymphedema, when blue dye is injected, it spreads slowly into the web space. Occasionally a single superficial lymphatic channel can be seen. On radiographic examination after injection of contrast medium, typically one or two slightly enlarged lymphatic vessels may be seen. In the aplastic form (approximately 15%), the blue dye diffuses readily through the dermal plexus but remains confined to the dorsum of the foot and rarely extends above the ankle. Numerous dilated, tortuous channels that easily fill with contrast medium can be seen radiologically. Dermal backflow is almost always evident. The varicose type is thought to be the consequence of incompetent lymphatic valves. Lymphangiographic findings are generally correlated with the age of onset.[31] In those individuals who have the congenital form or an early onset of edema, the aplastic lymphangiographic form is usually found. The hypoplastic form predominates in patients with lymphedema praecox. Although most evidence seems to indicate that some anatomical abnormality is likely to be present in patients who have lymphedema, it is becoming apparent that this correlation is not absolute. In a lymphangiographic study of 200 patients, it was impossible to correlate the pathological lymphatic patterns and the clinical severity of the conditions.[38] In patients who have unilateral lymphedema, abnormal lymphangiographic findings on the clinically normal side are characteristic,[39] and although a substantial number of patients eventually develop bilateral swelling, others do not. It is therefore possible that, in addition to an anatomic abnormality, some functional derangement within the lymphatics exists.
Benign Tumors of Lymphatics Lymphangiomas are generally divided into three types: (1) lymphangioma simplex, composed of small, capillary-sized lymphatic channels; (2) cavernous lymphangioma, comprising dilated lymphatic channels, often with fibrous adventitial covering; and (3) cystic lymphangioma, or cystic hygroma. All three are felt to have their origin in the embryological development of the lymphatic system. Sabin[40] and later Goetsch[41] postulated that during the development of the lymphatic system, cell buds of lymphatic primordium occasionally fail to establish communication with veins, therefore resulting in isolated lymphatic spaces. Portions of the lymphatic system can become sequestered and retain the ability to produce lymph and form endothelial cysts. These lymphatic cysts slowly enlarge and infiltrate the surrounding tissues by pushing other structures aside. The tumors are all benign. The majority are present at birth, and 90% can be identified by the end of the first year of life.[42,43] The tend to grow in proportion to the growth of the child. They can greatly enlarge at times of infection. The most common of the three types of lymphangioma is the cystic hygroma. Hygromas appear as soft, cystic, discrete, nontender masses that transilluminate. They vary in size from a few millimeters to several centimeters. They can be located on any portion of the body; however, the majority are found in
the head and neck region. Hygromas of the neck, tongue, and intraoral regions can present significant problems with respiration in the newborn and on occasion require emergent excision. These lesions must be distinguished from hemangiomas, branchial cleft cysts, lipomas, and occasionally neoplasms such as rhabdomyosarcoma.[44]
Acquired Lymphedema The removal or destruction of the axillary or inguinal nodes by surgery, radiation, infection, tumor invasion, or other inflammation can produce lymphedema. The most common worldwide cause is direct infestation of the lymph nodes by the filarial parasite Wuchereria bancrofti;[31,36,45] however, the occurrence of permanent lymphedema complicating other infectious or inflammatory processes is unusual. Approximately 10 –15% of patients undergoing radical mastectomy develop significant postoperative arm swelling.[43,46,47] In a study of 200 operable breast cancer patients, it was found that radiation to the axilla after radical node dissection significantly increased the risk of postmastectomy lymphedema in the ipsilateral extremity.[48] There is a higher incidence in those patients undergoing radiation therapy, in obese patients, and in patients who have postoperative problems with wound healing. The swelling may not become clinically evident for as long as 1 year. This delay is the result of the ongoing fibrotic process, which further constricts and obstructs lymphatic drainage. The swelling generally begins in the upper arm and eventually may become massive. Lymphangiographic studies in acquired lymphedema demonstrate a varicose-type pattern with dilation of the lymphatic vessels and blockage at the area of the involved nodes. Lymphedema caused by malignant disease generally occurs late in the disease process, after there is extensive spread of tumor.
DIFFERENTIAL DIAGNOSIS In the vast majority of patients, the diagnosis of lymphedema can and should be made by history and physical examination. The gradual onset of edema beginning at the ankle and proceeding proximally over a period of several months unassociated with other symptoms is characteristic. In females, swelling classically occurs at the time of menarche or pregnancy. A major diagnostic problem is determining whether leg swelling is due to lymphatic or venous causes. The distinction can usually be made on clinical evidence. Edema secondary to venous disease demonstrates decreased capillary perfusion, characteristic dark brawny edema, and ulceration of the skin secondary to impaired perfusion and tissue anoxia. In lymphedema, capillary perfusion is unimpaired and ulceration is extremely rare, and the deep brown discoloration of venous problems is extremely unusual. Following a period of bed rest, lymphedema typically resolves in several days, whereas venous edema tends to improve within hours.
Chapter 73.
In very difficult diagnostic situations, venography is generally more informative than lymphangiography and considerably easier and safer to perform. Lymphangiography is tedious, difficult, and hazardous. In general, lymphangiographic findings will not influence the eventual medical or surgical management. Other techniques for the diagnosis of lymphedema include computed tomography (CT) scans. A characteristic “honeycomb” pattern is often seen in the subcutaneous compartment of lymphedematous extremities.[49,50] Lymphscintigraphy (using 99Tc-labeled antimony) has been effectively used for the diagnosis of lymphedema and as a test for the selection of microvascular surgery patients.[51 – 54] Two other uncommon conditions are lipedema and yellow nail syndrome (YNS). Lipedema, seen generally in women, is considered a lipodystrophy and is characterized by diffuse, symmetrical, nonpitting enlargement of the subcutaneous tissue of the extremity. A weight-reduction regime often has limited effectiveness, and surgery can be helpful in selected cases. First described in patients with lymphedema and yellow nails, YNS comprises the triad of yellow dystrophic nails, primary lymphedema, and bilateral effusions. It is also associated with an increased incidence of maxillary sinusitis. The etiology of YNS remains obscure.[55 – 57]
NONINVASIVE STUDIES Several approaches are available to evaluate the edematous extremity. The size can be evaluated by circumferential measurements and water volume displacement. To be meaningful, circumferential measurements should be standardized. Ideally, this involves taking the measurement after a full day’s activities from a bony reference point on the extremity. It should be emphasized that small variations in the circumference of the extremity represent substantial changes in fluid accumulation and weight. Measurements of water volume are more accurate though also more cumbersome.[27] Lymphatic function has been evaluated by the clearance of various radioisotopes, including gold (198Au), 99Tc-labeled dextran, and radioiodinated serum albumin (131I), or RIHSA. In normal individuals, approximately 80% of the RIHSA injected into the web space will be cleared in 24 h.[58] In those with lymphedema, the percentage is approximately half.[24,59,60] Clearance of RIHSA has also been used to document postoperative improvement in lymphatic function.[10,59 – 61] The contralateral extremity should not be used as a control in primary lymphedema because of the high incidence of bilateral lymphatic abnormalities. Variables such as volume of isotope injected, patient activity during the test, extremity position, and monitoring techniques (size of counter, time) must also be rigidly controlled and standardized.
LYMPHANGIOGRAPHY What is known of the gross anatomy of the peripheral lymphatics in both normal and disease states is defined
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through direct cannulation of the lymphatics.[62] The technique involves injecting 5 mL of an equal mixture of methylene blue and 1% lidocaine into the web spaces of the extremity. In the normal individual, the dermal lymphatics are outlined by this concentration of the dye. Once the superficial lymphatics are outlined by the blue dye, a transverse incision is made 2–3 in. proximal to the site of injection and the lymphatic channels are cannulated with a 27- to 30-gauge needle. Contrast material [such as ethiodized oil (Etiodol)] is then injected slowly into the lymphatic system. No more than 10 mL per leg or 5 mL per arm in given. Multiple radiographs are then obtained over the next 24 h to visualize the lymphatics. Since the superficial and deep lymphatics do not normally communicate, the deep lymphatics must be visualized separately. This is done in a similar fashion, except that the approach to the deep lymphatic chain is slightly posterior to the medial malleolus, near the area of the posterior tibial vessels.[36] While lymphangiograms are helpful, an experienced observer can gain considerable information simply from the rate of diffusion and the pattern of the methylene blue distribution. The potential complications of lymphangiography are many and include lymphangitis, wound infection, cellulitis, allergic reaction to the injected contrast material, pulmonary embolism of contrast material, and long-term staining of the extremity. Fever, chills, headache, nausea, vomiting, and arthralgia are common after this test. While a lymphangiograph can provide helpful information, it should not be considered a routine diagnostic procedure in evaluating lymphedema patients and should be performed only with a specific goal in mind. At this time a lymphangiogram has no possible therapeutic use.
MEDICAL TREATMENT Most patients with lymphedema are adequately managed without surgical intervention. The medical treatment is oriented toward the inciting event. Infectious causes in the acute phase are often managed with the appropriate antibiotic regimen combined with the principles of limb elevation and compression. Parasitic causes such as W. bancrofti and Brugia malayi are first treated with diethylcarbamazine, which eliminates the organisms from the blood. An anti-inflammatory and/or antihistamine is usually administered concurrently to control the allergic reactions to the dying parasite.[63] Also, as with all forms of lymphedema, limb elevation and compression should be used. Allergic causes are managed by withdrawal of the inciting agent and with antihistamines and anti-inflammatory agents. In cases of chronic lymphedema, however, neither the medical nor the surgical approach can provide a cure for the process. It is, therefore, imperative that the patient understand the chronicity of the condition as well as the importance of controlling the edema and preventing infection. Medical management can only attempt to improve lymphatic drainage by combining limb elevation, external compression, and the judicious use of diuretics and other
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selected medications, such as steroids and benzopyrones.[32,64,65] Certain measures can be taken by the patient. The patient should be instructed to avoid any unnecessary standing for long periods of time, to elevate the foot of the bed with 15-cm wood blocks, and to wear an elastic stocking conscientiously. The stocking should fit tightly; therefore the measurements of the individual patient should be taken after a period of bed rest when the extremity is smallest in diameter. A full-length stocking or leotard is often discarded by the patient because of inconvenience and discomfort. For most patients, a kneelength stocking is an excellent compromise. Intermittent compression machines of various types have been successful when used conscientiously, but they require a great deal of time and dedication.[66,67] They are no substitute for continuous compression stockings. Diuretics are occasionally effective in reducing the interstitial water load associated with lymphedema. To be most beneficial, diuretics should be taken intermittently, particularly in the premenstrual period. It is recommended that longer-acting thiazides be used in combination with a potassium-sparing diuretic over a 4-day period. Other medications, such as steroids injected into lymphatics, and benzopyrones have been reported to be useful in lymphedema.[32,64] Benzopyrones are known to stimulate macrophages,[32] and thus, theoretically, they could act to increase lysis of collagen through this mechanism. Clinical trials of benzopyrones show softening of lymphedematous tissue as well as modest decreases (0.5 cm over a 10month average) in the size of extremities with long-term use. They do not offer rapid relief but can slowly improve chronic high-protein lymphedema. In all, patients report subjective improvement in symptoms.[32,64,68 – 71] Generally, infection cannot be avoided. Patients should be instructed in meticulous foot care in order to avoid fungal infections. In patients with recurrent infectious episodes of unknown origin, prophylactic penicillin is the drug of choice; Streptococcus is the most common etiologic agent. When infection occurs, it must be treated early and aggressively. The patient should be restricted to bed rest, the extremity elevated, and antibiotics administered. Each inflammatory process exacerbates the fibrosis.
described over the last 70 years. There are two main categories of procedure: physiological and excisional (see Table 73-1). The physiological operations attempt to reconstruct lymphatic drainage either by introducing distant or local pedicle tissue or by employing microvascular techniques. The excisional operations remove varying amounts of subcutaneous tissue and skin. It should be emphasized that most pedicle flap procedures include a significant amount of excision.
Physiologic Operations Direct Lymphatic Reconstruction Lymphangioplasty was first proposed by Handley[8] in 1908. He implanted silk threads in the subcutaneous tissues in hopes of creating new lymphatic channels. In successive years various other synthetic materials have been used without success.[19,31,40,73,74] Their failure was largely related to the high incidence of infection and extrusion. It is difficult to conceive how valveless channels formed around a foreign body could ever drain lymph against gravity. Lymphaticovenous shunts were first proposed by Rivero[14] in 1967 when he surgically approximated a hemisectioned lymph node to the side of a vein. Early results were encouraging; however, fibrous ingrowth has consistently been noted within the first postoperative year.[75,76] Currently, work is still being done on lymphaticovenous anastomoses with clinical trials to evaluate the long-term patency.[77 – 84] Direct microvascular repair of lymphatics was proposed by O’Brien.[5] This approach is obviously the most direct method of lymphatic reconstruction in patients with obstructive or secondary lymphedema. Results are promising,[86 – 88] but some feel this approach may not attack all the problems of chronic lymphedema.[89] However, recently O’Brien et al.[90] demonstrated favorable long-term results after microlymphaticovenous anastomoses for the treatment of obstructive lymphedema. Microlymphaticovenous anastomosis has also been used for lymphedema of the breast, scrotum, and female genitalia.[91 – 93] Recent advances include venolymphatic
OPERATIONS
Table 73-1. Procedures for the Surgical Management of Lymphedema Described During the Last 70 Years
The operative approach to lymphedema must be considered in two categories: (1) operations to control chronic lymphedema and (2) the surgical approach to tumors of the lymphatic system.[72] Surgical intervention should be considered only after medical management has been attempted and has failed. Indications for surgery include functional impairment, cosmetic reasons, and recurrent lymphangitis. Patients frequently complain of fatigue related to the weight of the swollen extremity and an inability to control the size of the extremity. Cosmetic indications are strongest in adolescent females, who may develop severe psychological problems. The frustration encountered in the surgical management of lymphedema is reflected in the numerous procedures
Physiological Operations Direct lymphatic reconstruction Alloplastic implants Microlymphatic repair Lymph node – venous anastomosis Pedicle flaps Local skin flap Buried dermal flaps Omental flap Excisional Operations Total subcutaneous excision and skin grafting (Charles procedure) Subcutaneous excision beneath flaps
Chapter 73.
transfers[94] and harvesting a lymph-collecting system as a composite graft.[95 – 97]
Pedicle Flap Reconstruction Local skin flaps have been used, but they have not been successful, probably because only the dermal lymphatic plexus is transferred.[98,99] The simple excision of deep muscle fascia was one of the first operations attempted by Kondoleon[9] in the hope that the involved subcutaneous tissue would drain into the normal muscle and deep lymphatics. This was unsuccessful because of rapid fascial regrowth.[100] Thompson,[12] however, introduced a procedure in which a deepithelialized dermal flap was buried within the muscle with the expectation of achieving a permanent lymphatic communication between the subcutaneous tissue and uninvolved muscle compartment. Favorable results have been reported.[101,102] In fact, RIHSA clearance studies have documented improvement postoperatively.[19] It is important to note, however, that a substantial amount of skin and subcutaneous tissue is excised in this procedure.[19,31,103] It is, therefore, difficult to know how much of the postoperative improvement is due to the dermal flap versus the simple excision. A pedicle of omentum has been employed to serve as a new conduit for lymphatic flow.[13,38,62] Initial reports were encouraging; however, laboratory experiments have shown that no communication between the omentum and the extremity develops.[104,105] The omentum appears to be surrounded by a smooth bursalike sac at reoperation.[105] The lack of valves in the omental lymphatic system makes it an unlikely candidate for successful reconstruction. Moreover, the incidence of postoperative complications is significant.
Excisional Operations Total Subcutaneous Excision Originally described by Charles [106] in 1912 and commonly used since then,[107] the Charles operation is an extensive procedure that removes all skin, subcutaneous tissue, and deep fascia in the leg except in the foot. The bared muscle is covered by a split- or full-thickness graft. Splitthickness grafts initially appear satisfactory, but late scarring is extreme and the grafts are likely to be injured easily. They ulcerate frequently and develop a severe, hyperkeratotic, weeping, chronically infected dermatitis. The end result is almost always far worse than the original problem of lymphedema; therefore, we strongly oppose the use of splitthickness graft resurfacing after subcutaneous excision.[108] The full-thickness graft taken from the excised tissue is considerably more durable,[10] although it is a formidable challenge to achieve a complete take of full-thickness skin grafts over such a large area. Even when the grafts are successful, substantial scarring and chronic breakdown of these areas are not uncommon. In chronic, long-standing lymphedema where there is a substantial element of fibrosis, this may, however, be the only technically feasible procedure available. In some clinical situations, suction curettage has been suggested as a useful method in debulking lymphedematous
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limbs. Recent reports describe the use of suction curettage as an adjunct in surgical management of lymphedema.[109 – 111] It is difficult, however, to conceive how this method could be of significant value in the treatment of extremity edema of any magnitude without concomitant resection of the expanded skin envelope.
Staged Subcutaneous Excision Beneath Flaps Staged subcutaneous excision beneath flaps was originally described by Sistrunck[10] in 1917 and later popularized by Homans.[11] Improvement is directly related to the amount of skin and subcutaneous tissue removed and the postoperative care given each patient. The procedure is described to patients as a means of facilitating management of lymphedema and not as a cure, but results have been favorable. During the operation, as much subcutaneous tissue and skin care are removed as possible while attempting to maintain a viable skin flap and achieve primary wound healing.[112 – 115] An experience with 652 cases over 40 years has demonstrated the safety and efficacy of this approach.[116] In our own experience we have had favorable long-term results.[117]
Operative Technique Preoperative Care. Patients are placed at bed rest with extremity elevation until edema has largely resolved. This is usually begun at home, but the patient is admitted at least 4 days preoperatively. It generally takes 5 –14 days for edema to resolve, and this rate is dependent on the chronicity of the condition and amount of fibrosis present. Procedure in the Leg. All procedures utilize a pneumatic tourniquet placed as proximally as possible. Subcutaneous excision of the leg is done in two stages. The medial side is usually done first, and this involves the largest amount of resection. Anteriorly and posteriorly based skin flaps approximately 1.5–2 cm in thickness are elevated from the medial side of the extremity. The subcutaneous tissue is completely resected down to and including the muscle fascia. After excising the subcutaneous fat from the periosteum of the tibia, the deep fascial compartment of the calf is entered, affording a relatively avascular plane of dissection above the gastrocnemius muscle. Posteriorly, the sural nerve is identified and preserved. Dissection then proceeds superiorly over the knee and inferiorly to the ankle region above the fascia. The flap should not be developed beyond the anterior border of the medial malleolus. Because of the potential for avascular necrosis, ankle flaps are rarely longer than 6 cm. Substantial amounts of redundant skin (6 – 10 cm) and subcutaneous fat (400 –900 g) can be removed. The wound is then closed over a rubber suction drain, which is left in place a minimum of 5 days. Interrupted and continuous 4-0 nylon is used for closure without placement of any subcutaneous or dermal sutures. The second stage is done 2– 3 months later on the lateral aspect of the leg in similar fashion, taking care to preserve muscle fascia and the peroneal nerve or the sensory branches (superficial peroneal nerve) leading to the dorsum of the foot. These pierce the deep fascia about 4 –6 cm above the extensor
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retinaculum of the ankle. Specific areas of ankle swelling can be excised several months later through a separate incision. Procedures in the Arm. These are most commonly performed on postmastectomy patients. A medial excision is carried out from an incision extending from the distal ulna across the medial epicondyle through the posteromedial upper arm. Flaps about 1 cm thick are elevated to the midsagittal aspect of the forearm and tapered distally and proximally. The deep fascia is undisturbed. During the lateral dissection, which is usually done as a second stage, the dorsal sensory branches of the ulnar and radial nerves are identified and preserved. Considerable amounts of fat can be excised from the upper arm, and flaps can be thicker (1.5 –2 cm) in this area. Wide bands of redundant skin can be excised, and this can be carried up into the axilla with removal of the tourniquet. Suction catheters are placed as in the leg, and skin closure is performed as previously described. Postoperative Care. With both the procedure in the leg and that in the arm, the extremity is immobilized in a gauze dressing reinforced with a posterior splint and is kept elevated, 5 days for the arm and 8 days for the leg. The patient is measured for a form-fitting elastic stocking, and Ace wraps are used prior to this. After elevation, the arm can be placed in a sling. Dependency of the leg is begun on the ninth day and ambulation by the eleventh day, but only with either a firm leg wrapping or an elastic stocking in place.[118]
OUTCOME Eighty-five percent of patients treated by staged skin and subcutaneous excision have at least a 50% reduction in extremity size;[118] in addition, there is a decreased incidence of postoperative cellulitis (18%) and infection (4%). All patients have some recurrence of swelling after a full day’s work, with progressive swelling in 6%.[118] One year after surgery a twofold increase in the clearance of RIHSA has been documented, suggesting that the excision of substantial amounts of subcutaneous tissue somehow improves lymphatic function.[60,61,118] The mechanism and explanation of this improvement, however, is unclear at this time. Extensive surgical dissection may establish lymphatic venous anastomoses during the process of healing; the procedure may favorably alter the balance of lymph flow by effectively reducing the amount of lymph-forming tissue; the excision of substantial tissue and skin may result in external compression, effecting an increase in interstitial pressure much like elastic stockings, thus improving lymph flow. The discouraging fact remains that no procedure cures lymphedema. A degree of edema inevitably follows any operative procedure. In our opinion, compared to all available methods of surgical management, skin and subcutaneous excision is the most reliable, consistently beneficial, and uncomplicated means of surgically managing the symptoms of lymphedema.
Surgical Treatment of Benign Lymphatic Tumors
COMPLICATIONS
These tumors have already been described under “Clinical Presentation.” Here, we will deal with their treatment. Spontaneous remission of cystic hygroma, the most common form of lymphatic tumor, is extremely rare. Percutaneous aspiration of hygromas is usually followed by prompt recurrence and occasionally hemorrhage or development of infection. Introduction of sclerosing agents has been proposed, but the multiloculated nature of most hygromas makes this therapy unfeasible. Excision subsequent to sclerosis is technically difficult.[47] Radiation therapy has no place in the treatment of cystic hygroma. Treatment of cystic hygromas should be surgical excision, taking care to preserve all normal structures in the area. At times a staged excision in appropriate. These lesions are nonmalignant, and care should be taken to preserve all normal anatomy. Excision is usually deferred until the age of 6 months if there is no compression of the trachea or respiratory difficulty.[42,43] Lymphangioma simplex is similar in behavior to the cystic hygroma; however, it is more evenly distributed throughout the body, occurring more frequently in the extremities and trunk. Treatment is the same as for the cystic hygroma. Cavernous lymphangiomas likewise are amenable to surgical resection, usually when the child is a few years old. Often, they must be excised in stages. Lymphangiomas have also been reported in the small bowel, lungs, and solid viscera of the abdomen. Resection is necessary only if the lesions produce symptoms.
Complications of lymphedema can be categorized under those relating to the disease and those relating to its treatment (i.e., surgical complications).
Complications of Lymphedema These complications have already largely been described under “Clinical Presentation” and include such entities as recurrent cellulitis, lymphangitis, and fibrosis of the subcutaneous tissue. Lymphangiosarcoma can also be a complication of lymphedema.
Lymphangiosarcoma Stewart and Treves[119] described the association between postmastectomy lymphedema and lymphangiosarcoma in 1948. The malignant lesion of the lymphatics is nearly always associated with lymphedema, most commonly with postmastectomy lymphedema but also with filariasis.[24,39,85,106,120 – 122,124] The lesion generally appears approximately 10 years after the onset of lymphedema and pursues an aggressive, malignant course. Average survival is 19 months following initiation of treatment. The lesion is described as a reddish-purple discoloration or nodule and has been confused with Kaposi’s sarcoma. Satellite lesions are occasionally found, but the tumor spreads primarily by a hematogenous route.
Chapter 73.
The mainstay of therapy has traditionally been radical amputation.[121,123] Because of the very small number of these tumors, it is impossible to study the effects of various forms of therapy in randomized fashion. Successful treatment of other soft tissue sarcomas with preoperative radiation therapy and chemotherapy, with surgical excision, and with postoperative adjunct chemotherapy[122] justifies a similar approach in lymphangiosarcoma. There is, however, insufficient evidence to strongly recommend any one form of therapy for this highly malignant tumor, and prognosis remains poor.
Complications of Surgical Treatment Each surgical approach carries with it its own unique set of complications. Lymphangioplasty has the usual complications of infection and extrusion; lymphatic-venous anastomosis has the complications of fibrous ingrowth that ultimately results in failure, and omental flaps have been found to develop a bursa about the omentum. All these complications result in failure of the approach. Approaches
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shown to be successful also have associated complications. The Charles technique of complete skin and subcutaneous tissue removal followed by grafting can have the serious complications of late scarring, ulceration, and development of a hyperkeratotic, weeping, chronically infected dermatitis in the split-thickness grafted extremities. This can progress to the serious complication of amputation if not handled adequately.[108] Full-thickness skin-grafted extremities can have failure of total graft vascularization that, depending on severity, can have significant morbidity. Complications associated with staged subcutaneous excision beneath flaps are not as serious as those associated with the Charles procedure. These include ischemic necrosis of areas of the flap (6% in our series) and varying degrees of decreased sensitivity about 3 cm on either side of the incision. No alteration in hand or foot sensation or motor function has been noted in our series, although this is a possible complication.[118] Recurrence of edema to some extent is a complication of all lymphedema operations. This incidence and relative occurrence in all approaches has been previously described.
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48. Kissin, M.W.; della Rovere, G.Q.; Easton, D.; Westbury, G. Risk of Lymphoedema Following the Treatment of Breast Cancer. Br. J. Surg. 1986, 73, 580. 49. Hadjis, N.S.; Carr, D.H.; Banks, L.; Pflug, J.J. The Role of the CT in the Diagnosis of Primary Lymphedema of the Lower Limb. Am. J. Roentgenol. 1985, 144, 361. 50. Goltner, E.; Gass, P.; Haas, J.P.; Schneider, P. The Importance of Volumetry, Lymphscintigraphy and Computer Tomography in the Diagnosis of Brachial Edema After Mastectomy. Lymphology 1988, 21, 134. 51. Vaqueiro, M.; Gloviczki, P.; Fisher, J.; et al. Lymphscintigraphy in Lymphedema: An Aid to Microsurgery. J. Nucl. Med. 1986, 27, 1125. 52. Weissleder, H.; Weissleder, R. Lymphedema: Evaluation of Qualitative and Quantitative Lymphscintigraphy in 238 Patients. Radiology 1988, 167, 729. 53. Gloviczki, P.; Calcagno, D.; Schirger, A.; et al. Noninvasive Evaluation of the Swollen Extremity: Experiences with 190 Lymphscintigraphic Examinations. J. Vasc. Surg. 1989, 9, 683. 54. Golueke, P.J.; Montgomery, R.A.; Petronis, J.D.; et al. Lymphoscintigraphy to Confirm the Clinical Diagnosis of Lymphedema. J. Vasc. Surg. 1989, 10, 306. 55. Samman, P.D.; White, W.F. The “Yellow Nail” Syndrome. Br. J. Dermatol. 1964, 76, 153. 56. David, J.; Crawford, F.A., Jr.; Hendrix, G.H.; et al. Thoracic Surgical Implications of the Yellow Nail Syndrome. J. Thor. Cardiovasc. Surg. 1986, 91, 788. 57. Gupta, A.K.; Davies, G.M.; Haberman, H.F. Yellow Nail Syndrome. Cutis 1986, 37, 371. 58. Schirger, A.; Harrison, E.G.; Janes, J.M. Idiopathic Lymphedema: Review of 131 Cases. J. Am. Med. Assoc. 1962, 182, 14. 59. Emmett, A.J.; Barron, J.N.; Veall, N. The Use of I 131 Albumin Tissue Clearance Measurements and Other Physiological Tests for the Clinical Assessment of Patients with Lymphoedema. Br. J. Plast. Surg. 1967, 20, 1. 60. Miller, T.A.; Harper, J.D.; Longmire, W.P., Jr. The Management of Lymphedema by Staged Subcutaneous Excision. Surg. Gynecol. Obstet. 1973, 136, 1. 61. Miller, T.A. Surgical Management of Lymphedema of the Extremity. Plast. Reconstr. Surg. 1975, 56, 633. 62. Goldsmith, H.S.; de los Santos, R.; Beattie, E.J. Relief of Chronic Lymphedema by Omental Transposition. Ann. Surg. 1967, 166, 572. 63. Petersdorf, R.G.; Braunwald, E.; Adams, R.D., (Eds.) Harrison’s Principles of Internal Medicine; McGrawHill: New York, 1980; 895. 64. Fyfe, N.C.M.; Ruth, D.L.; Edwards, J.M.; Kinmonth, J.B. Intralymphatic Steroid Therapy for Lymphedema: Preliminary Studies. Lymphology 1982, 15, 23. 65. Clodius, L.; Deak, L.; Piller, N.B. A New Instrument for the Evaluation of Tissue Tonicity in Lymphedema. Lymphology 1976, 9, 1. 66. Zeliolrouski, A. Lympha-Press: A New Pneumatic Device for Treatment of Lymphedema of the Limbs. Lymphology 1980, 13, 68. 67. Zelikovski, A.; Deutsch, A.; Reiss, R. The Sequential Pneumatic Compression Device in Surgery for Lymphedema of the Limbs. J. Cardiovasc. Surg. 1983, 24, 122.
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Piller, N.B.; Clodius, L. The Use of a Tissue Tonometer as a Diagnostic Aid in Extremity Lymphedema: A Determination of its Conservative Treatment with Benzopyrones. Lymphology 1976, 19, 127. Piller, N.B. Conservative Treatment of Acute and Chronic Lymphedema with Benzopyrones. Lymphology 1976, 9, 132. Piller, N.B.; Morgan, R.G.; Casley-Smith, J.R. A Double-Blind, Crossover Trial of O-(Beta-Hydroxyethyl)-Rutosides (Benzopyrones) in the Treatment of Lymphedema of the Arms and Legs. Br. J. Plast Surg. 1988, 41, 20. Casley-Smith, J.R.; Casley-Smith, J.R. The Pathophysiology of Lymphedema and the Action of Benzopyrones in Reducing It. Lymphology 1988, 21, 190. Campisi, C.; Boccardo, F. Frontiers in Lymphatic Microsurgery. Microsurgery 1998, 18 (8), 462. Handley, W.S. Hunterian Lectures on the Surgery of the Lymphatic System. Br. Med. J. 1910, 1, 922. Silver, D.; Puckett, C. Lymphangioplasty: A Ten Year Evaluation. Surgery 1976, 80, 748. Calnan, J.S.; Reis, N.D.; Rivero, O.R.; et al. The Natural History of Lymph Node-to-Vein Anastomosis. Br. J. Plast Surg. 1967, 20, 134. Puckett, C. Evaluation of Lymphovenous Anastomosis in Obstructive Lymphedema. Plast. Reconstr. Surg. 1980, 66, 166. Baxter, T.J.; Gilbert, A.; O’Brien, B.M.; et al. The Histopathology of Microlymphatic Venous Anastomosis. Aust. N. Z. J. Surg. 1980, 50, 320. Fox, U.; Montersi, M.; Romangnoli, G. Microsurgical Treatment of Lymphedema of the Limbs. Int. Surg. 1981, 66, 53. O’Brien, B.; Shafiroff, B.B. Microlymphaticovenous and Resectional Surgery in Obstructive Lymphedema. World J. Surg. 1979, 3, 3. Puckett, C.L.; Jacobs, E.R.; Hurritz, J.S. Evaluation of Lymphovenous Anastomosis in Obstructive Lymphedema. Plast. Reconstr. Surg. 1980, 66, 116. Degni, M. New Technique of Lymphaticovenous Anastomosis for the Treatment of Lymphedema. J. Cardiovasc. Surg. 1978, 19, 577. Degni, M. New Microsurgical Technique of Lymphaticovenous Anastomosis for the Treatment of Lymphedema. Lymphology 1981, 14, 61. Jamal, S. Lymphovenous Anastomosis in Filarial Lymphedema. Lymphology 1981, 14, 64. Huang, G. Microlymphaticovenous Anastomosis for Treating Lymphedema of the Extremities and External Genitalia. J. Microvasc. Surg. 1981, 3, 32. Shafiroff, B.B.; Nightingale, G.; Baster, J.J.; O’Brien, B. Lymphatico Lymphatic Anastomosis. Ann. Plast. Surg. 1979, 3, 199. O’Brien, B.M.; Black, M.J.; Pagdestran, I. Role of Microlymphaticovenous Surgery in Obstructive Lymphedema. Clin. Plast. Surg. 1978, 5, 293. Krylov, V. Microlymphatic Surgery of Secondary Lymphedema of the Upper Limb. Ann. Chir. Gynecol. 1982, 71, 77.
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Daniller, A. Microsurgical Composite Tissue Transplantation. In Microlymphatic Surgery; Serafin, D., Buncke, H.J., Eds.; Mosby: St. Louis, Missouri, 1979. Clodius, L.; Piller, N.B.; Casley-Smith, J.R. The Problems of Lymphatic Microsurgery for Lymphedema. Lymphology 1981, 14, 69. O’Brien, B.M.; et al. Long-Term Results After Microlymphaticovenous Anastomoses for the Treatment of Obstructive Lymphedema. Plast. Reconstr. Surg. 1990, 85, 562. Huang, G.K.; Hu, R.Q.; Liu, Z. Microlymphaticovenous Anastomoses for Lymphedema of the Breast. Microsurgery 1985, 6, 32. Huang, G.K.; Hu, R.Q.; Liu, Z.; Pan, G.P. Microlymphaticovenous Anastomosis for Treating Scrotal Elephantiasis. Microsurgery 1985, 6, 36. Huang, G.K.; Hu, R.Q.; Shen, Y.L.; Pan, G.P. Microlymphaticovenous Anastomosis for Lymphedema of External Genitalias in Females. Surg. Gynecol. Obstet. 1986, 162, 429. Pho, R.W.H.; Bayon, P.; Tan, L. Adipose Veno-lymphatic Transfer for Management of Post-radiation Lymphedema. J. Reconstr. Microsurg. 1989, 5, 45. Ho, L.C.Y.; Lai, M.F.; Yeates, M.; Fernandez, V. Microlymphatic Bypass in Obstructive Lymphedema. Br. J. Plast Surg. 1988, 41, 475. Baumeister, R.G.; Siuda, S.; Bohmert, H.; Moser, E. A Microsurgical Method for Reconstruction of Interrupted Lymphatic Pathways: Autologous Lymph-Vessel Transplantation for Treatment of Lymphedemas. Scand. J. Plast. Reconstr. Surg. 1986, 20, 141. Yamamoto, Y.; Sugihara, T. Microsurgical Lymphaticovenous Implant: Treatment of Chronic Lymphedema. Plast. Reconstr. Surg. 1998, 101 (1), 157. Gillies, H.; Fraser, F.R. The Treatment of Lymphedema by Plastic Operation: A Preliminary Report. Br. Med. J. 1935, 1, 96. Smith, J.W.; Conway, H. Selection of Appropriate Surgical Procedures in Lymphedema: Introduction of Hinged Pedicle. Plast. Reconstr. Surg. 1954, 14, 347. Peer, L.A.; Shahgholi, M.; Walker, J.D., Jr.; MancusiUngaro, A. Modified Operation for Lymphedema of Leg and Arm. Plast. Reconstr. Surg. 1964, 14, 347. Sataguchi, S. Surgical Treatment of Chronic Lymphedema of the Extremities. Lymphology 1979, 12, 45. Tanape, T. The Surgical Treatment of Chronic Lymphedema of the Extremity. Lymphology 1979, 12, 47. Larson, D.L.; Coers, C.R.; Doyle, J.E.; et al. Lymphedema of the Lower Extremity. Plast. Reconstr. Surg. 1966, 38, 293. Danese, C.A.; Papaioannou, A.N.; Morales, L.E.; Mitsuda, S. Surgical Approaches to Lymphatic Blocks. Surgery 1968, 56, 821. Goldsmith, H.S. Long-Term Evaluation of Omental Transportation for Chronic Lymphedema. Ann. Surg. 1974, 180, 847. Charles, R.H. A System of Treatment; Churchill: London, 1912; Vol. 3. Dellon, A.L. The Charles Procedure for Primary Lymphedema. Plast. Reconstr. Surg. 1977, 60, 589.
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CHAPTER 74
Thoracic and Abdominal Vascular Trauma David V. Feliciano Kenneth L. Mattox
aortogram, spiral computed tomogram (CT), or transesophageal echocardiogram (TEE) is performed. A partial transection will lead to free bleeding into the pleural cavity, external bleeding (rarely), or a contained acute pulsatile (arterial)/nonpulsatile (venous) hematoma in the mediastinum or extrapleural, supraclavicular, or suprasternal area. A complete transection of one of these large vessels will lead to free bleeding from both ends of the vessel, or, rarely, thrombosis. Arteriovenous fistulas most commonly involve the innominate or subclavian vessels and are best localized on a thoracic aortogram.
Truncal vascular injuries are much less common than those involving peripheral vessels, and this has been particularly true in past military conflicts. In 1970, Rich et al.[1] noted that only 1.1% of 1000 arterial injuries in Vietnam involved the innominate or subclavian artery and only 3.9% involved the abdominal aorta, common iliac artery, or external iliac artery. Rapid improvements in civilian trauma care in the United States, especially the development of sophisticated prehospital systems and trauma centers, have allowed for the resuscitation and operative salvage of increasing numbers of patients with truncal vascular injuries over the past several decades. For example, the county hospitals in Houston treated 1117 noncardiac major cervicothoracic and 1895 major abdominal vascular injuries from 1958 to 1988.[2] These major cervical and truncal vascular injuries accounted for 52% of all cardiovascular injuries treated over the same period of time.
Diagnosis Three different clinical presentations have been noted in patients with penetrating wounds to the thoracic vessels.[4] First, some normotensive patients with wounds to the thoracic inlet, supraclavicular area, or superior mediastinum will be asymptomatic, have a normal chest x-ray, and have proximity only of a stab wound or missile track to the great vessels (Fig. 74-1). A second normotensive or slightly hypotensive group with wounds in the same area will present with a contained hematoma in the supraclavicular, suprasternal, or mediastinal area on physical examination and/or chest x-ray (Fig. 74-2). In either of these groups, further radiologic studies are necessary to verify and localize the aortic, arterial, or venous injury, as this will determine the operative approach. A thoracic aortogram performed via a retrograde femoral approach is the diagnostic method of choice. The role of spiral CT or transesophageal echocardiography as an alternative to a thoracic aortogram in patients with small penetrating vascular defects is unclear at this time. The successful use of these modalities, however, in detecting blunt tears or luminal thrombus in the thoracic aorta suggests that they may have increasing usage in the future in some of these stable wounded patients.[5 – 9] If an injury to the subclavian artery is suspected, another alternative to formal aortography would be to perform an emergency department
THORACIC VASCULAR TRAUMA— PENETRATING Thoracic vascular trauma includes injuries to the aorta and major branches, the pulmonary vessels, the superior and inferior vena cava, major veins at the thoracic inlet, the intercostal arteries, and the internal mammary artery. In trauma centers receiving large numbers of patients with penetrating wounds, injuries to these vessels account for 15–20% of all vascular injuries treated.[2,3]
Pathophysiology Penetrating wounds to the thoracic vessels cause defects in the wall or luminal irregularities with secondary thrombosis, partial or complete transections, or, on rare occasions, an arteriovenous fistula. A small defect in the arterial wall or a luminal irregularity can be visualized only if a thoracic
Hobson/Wilson/Veith: Vascular Surgery: Principles and Practice, Third Edition, Revised and Expanded DOI: 10.1081/0819-9-120024958 Copyright q 2004 by Marcel Dekker, Inc.
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Vascular Trauma
Figure 74-1. Proximity of missile to great vessels in superior mediastinum of asymptomatic patient. At thoracotomy, missile was found to be tamponading perforation of main pulmonary artery.
ipsilateral retrograde axillary or brachial arteriogram with a blood pressure cuff on the distal upper extremity inflated to 300 mmHg.[10] A third group of profoundly hypotensive patients with wounds to the thorax, especially to the sternal or parasternal area, or to one of the supraclavicular areas
does not need any diagnostic studies and should be moved to the operating room immediately. Should an unnecessary chest x-ray be performed, a mediastinal hematoma or significant hemothorax (lung outlined by clot in the pleural cavity) will be seen (Fig. 74-3).
Figure 74-2. Widening of superior mediastinum in modestly hypotensive patient with parasternal stab wound. Through-and-through injury to ascending aorta was repaired through a median sternotomy.
Chapter 74. Thoracic and Abdominal Vascular Trauma
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Figure 74-3. Large hemothorax in profoundly hypotensive patient with missile traversing the superior mediastinum and injuring the left innominate vein, left subclavian vein, left clavicle, and left first rib.
Management in the Emergency Department Because of possible involvement of the superior vena cava or other great veins in the upper thorax, reasonably stable patients with penetrating wounds above the nipples should have some intravenous lines placed in the lower extremities. With short large-bore (10-gauge or 8.5 French) catheters in peripheral veins, flow rates of crystalloids at 1.5 L/min are possible when an external pressure device is applied to a collapsible intravenous bag. Type-specific blood replacement is preferred, although universal donor O-negative blood is indicated in profoundly hypotensive or arrested patients. All fluids should be prewarmed, or fluids and blood should be infused through high-flow warmer units. The abdomen and lower extremities should also be covered with an external warming device. Profoundly hypotensive patients should be moved directly to the operating room for resuscitation and operation, and delays to insert intravenous catheters or perform chest x-rays are unacceptable in the modern era. An identification bracelet should be placed on the patient’s wrist, and one sample of intravenous blood should be drawn to allow for rapid identification of blood type and Rh as the patient is moved to the operating room. Any patient who arrives in cardiac arrest or in a moribund condition after sustaining a penetrating thoracic wound should have endotracheal intubation and a thoracotomy performed in the emergency department – unless the trauma operating room is nearby.[11] A wound in proximity to the superior mediastinum or suprasternal or supraclavicular areas may involve the great vessels rather than the heart. For this reason, an anterolateral thoracotomy in the third or fourth intercostal space (above the nipple) on the side of injury is indicated. For
right-sided wounds, a right anterolateral thoracotomy above the nipple (if injury to a subclavian vessel is suspected) should be supplemented by a transverse sternotomy performed with a Gigli saw and a left anterolateral thoracotomy at the lower edge of the male nipple to allow for crossclamping of the descending thoracic aorta (DTA). Use of an autotransfusion device to scavenge blood through the thoracotomy incision is always worthwhile. After evacuation of the hemothorax and manual dissection beneath the upper flap of the thoracic wall and sternum, the vascular wound can usually be visualized. Bleeding from beneath the upper pericardium mandates a longitudinal pericardiotomy in the midline.[12] A wound in the superior or inferior vena cava, ascending aorta, transverse arch, or pulmonary artery is best controlled by a finger or vascular clamp and repaired with 4 –0 or 5–0 polypropylene suture after the patient is moved to the operating room. Wounds of the subclavian vessels may cause exsanguinating hemorrhage into the pleural cavity, and manual compression or packing is applied to the bleeding site at the apex of the pleural cavity through either the high right or left anterolateral thoracotomy. Compression should also be applied to the supraclavicular fossa above as the patient is moved to the operating room. With major hemorrhage or air leak from the lung, an aortic vascular clamp should be applied across all hilar structures. In the operating room, any vascular repair performed in the emergency department is inspected and redone or buttressed as needed. Otherwise, formal vascular repair is performed as described above. The ends of the mammary vessels are ligated with 2-0 silk ties and the pleural cavities irrigated with antibiotic solution before insertion of thoracostomy tubes and closure of the chest wall and sternum.
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Vascular Trauma
Nonoperative Management There are now compelling data that nonocclusive peripheral arterial defects, especially focal narrowing or spasm, mural hematoma, or intimal flap, will heal without operation in 87 – 95% of patients.[13] Presumably, similar lesions in the great arteries of the thorax can also be managed without operation, though prospective data are limited at this time. This approach would appear to be most useful in patients with major visceral or vascular injuries requiring emergent operation in other areas of the body. As with nonoperative management of nonocclusive peripheral arterial defects, careful follow-up to document healing of the area of injury is necessary. The inability to detect enlargement of an observed lesion in the thorax on physical examination, however, mandates a repeat aortogram, arteriogram, or, perhaps, spiral CT. Because of the size of and flow through the thoracic aorta and other major thoracic arteries, observation of pseudoaneurysms of significant size or of arteriovenous fistulas from penetrating wounds is not recommended.
Operative Management Items which should be available in the operating room when the patient arrives include O-negative blood for transfusion if the patient has moderate or severe hypotension, autotransfusion machine, sternal saw, Gigli saw, complete cardiovascular tray, a variety of sizes of Dacron and polytetrafluoroethylene (PTFE) grafts, and appropriate vascular sutures. As hypothermia with secondary cardiac arrhythmias and coagulopathies occurs frequently in patients with penetrating thoracic vascular injuries, the preventive maneuvers listed in Table 74-1 are mandatory in the operating room. The patient should be in the supine position unless the track of a missile or knife is in proximity to the thoracic esophagus and DTA. In such a patient, a 308 elevation of the thorax on the side of the injury, usually the left, is appropriate. Skin preparation should include the anterior neck, thorax, and abdomen; the entire upper extremity on the side of a suspected or confirmed injury to the subclavian vessels; and one thigh to allow for harvest of the greater saphenous vein.
A variety of cervicothoracic incisions are available to obtain control of penetrating thoracic vascular wounds under semiemergent and elective circumstances (Fig. 74-4).[15] The choice of incision depends on the presumed track of the knife or missile or on the location of the vascular injury as seen on preoperative angiography.
Penetrating Wounds of the Innominate Vessels Exposure of the innominate artery is obtained through a median sternotomy and mobilization of the overlying left innominate vein. If a high anterolateral thoracotomy has been performed in the emergency department, a partial upper median sternotomy may be necessary to obtain complete exposure of the artery. Injuries to the artery have been evenly distributed among the upper, middle, and lower thirds in most series and are infrequently accompanied by injuries to the innominate veins.[16,17] Lateral arteriorrhaphy is the preferred technique, but bypass grafting from the ascending aorta to the distal innominate artery has been the most common form of repair in recent large civilian series.[16,17] The survival rate after penetrating injuries to the innominate artery is approximately 85%. Injuries to the left innominate vein occur three times more frequently than those to the short right innominate vein. Ligation has been the treatment in 80% of patients with penetrating wounds.[16,17]
Penetrating Wounds of the Intrathoracic Left Common Carotid Artery A median sternotomy is used to obtain proximal control, while distal control usually requires an extension of the
Table 74-1. Prevention of Hypothermia in Patients Undergoing Operation for Thoracic (or Abdominal) Vascular Injuries 1. Warm operating room to 858F (298C)[14] 2. Place turban or warming device on patient’s head 3. Cover both lower extremities except for some thigh (for retrieval of the greater saphenous vein) with a warming devicea 4. Infuse all fluids and blood through one of the rapid infusion warming units 5. Turn the cascade on the anesthesia machine to a high temperature immediately 6. Place warm saline around the exposed heart and in open pleural cavities during the sternotomy or thoracotomy a
Bair Hugger, Augustine Medical, Eden Praire, MN., or Warm Touch, Mallinckrodt Medical, St. Louis, MO.
Figure 74-4. Cervicothoracic incisions used for repair of injuries to the innominate artery or veins, common carotid arteries, or subclavian arteries or veins. (Copyright q Baylor College of Medicine, 1980. Used with permission.)
Chapter 74. Thoracic and Abdominal Vascular Trauma
incision along the anterior border of the left sternocleidomastoid muscle. Repair of the common carotid artery is preferred in patients treated immediately after wounding. In all patients with neurologic deficits short of coma, the only hope of improvement is with rapid revascularization.[18 – 20] While there has always been concern about the conversion of an ischemic to a hemorrhagic infarct, autopsies in some patients dying after carotid repair have documented that cerebral edema was the actual cause of death – and this is treatable in a critical care setting.[18] Patients presenting with coma appear to have a poor prognosis whether revascularization or ligation is performed, but hypotension may be a contributing factor and revascularization should be attempted.[18,20]
Penetrating Wounds of the Subclavian Vessels When the track of a missile or knife or the preoperative aortogram shows that the proximal right subclavian artery has been injured, the safest incision in the stable patient is a median sternotomy with a right supraclavicular extension.[15] Exposure of the entire right subclavian artery and vein is obtained by subperiosteal or complete removal of the medial two-thirds of the clavicle – not including the sternoclavicular joint–and division of the scalenus anticus muscle (Fig. 74-5). In a patient with the rare injury to the intrathoracic left subclavian artery, a high left anterolateral thoracotomy incision is indicated to obtain proximal control. Distal vascular control may then be obtained through the addition of
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a left supraclavicular incision. When the surgical team decides that exposure through these two incisions is inadequate, a median sternotomy incision has often been used to connect the other two. The “book” thoracotomy created by these three incisions is difficult to work through, as the flap only slides open rather than folding open like the pages of a book[21] (Fig. 74-4). Also, many patients with this incision are difficult to wean from the volume ventilator in the early postoperative period. More rapid exposure of the second or third portions of the right or left subclavian artery is attained by using the supraclavicular incision only and division of the clavicle with a Gigli saw. By grasping each end of the divided clavicle with a towel clip and lifting it away from the vascular injury, exposure is excellent and resection of the bone is avoided. After completion of the vascular repairs, the divided clavicle is repaired by insertion of a sternal wire with the knot facing anteriorly or by the application of an anterior dynamic compression plate. Even with proximal and distal control of the subclavian artery, there is often significant backbleeding into an injury of the first or second portion of the artery from the vertebral and internal mammary arteries and the thyrocervical trunk. In the patient who has exsanguinating hemorrhage from this area, loop control or ligation and division of these branches will decrease blood loss and allow for arterial repair in a relatively bloodless field. The subclavian artery is extremely fragile, and major iatrogenic injuries have occurred from the application of a vascular forceps or standard vascular clamp. Sudden movements of vascular clamps or the performance of an end-to-end anastomosis under tension must be avoided. Loss of any portion of the wall of the artery is treated with resection and end-to-end anastomosis or insertion of an autogenous saphenous vein or 6– 8 mm PTFE graft. The survival rate after injuries to the subclavian artery is approximately 87%. The subclavian vein is adherent to the periosteum of the clavicle and has many small branches in the supraclavicular area. Rapid mobilization of the clavicle and vein often causes more injuries than the original trauma, and ligation is appropriate in the unstable patient. Much as with major venous ligations in the lower extremities, elevation of the upper extremity for 5–7 days after ligation of the subclavian vein will dramatically decrease the incidence of chronic edema.
Penetrating Wounds of the Pulmonary Hilum
Figure 74-5. Excision of the medial clavicle (not including the sternoclavicular joint) will improve exposure of the second and third portions of the subclavian artery. (Copyright q Baylor College of Medicine, 1985. Used with permission.)
Injuries to the pulmonary hilum usually cause prehospital exsanguination. On rare occasions, an anterolateral thoracotomy in the fifth intercostal space in the emergency department and cross-clamping of the entire hilum will allow for transport of the patient to the operating room. An injury to several structures in the hilum is treated with an emergent pneumonectomy, which can be performed using classical individual ligation of hilar structures or by en bloc stapling using a 55 or 90 mm stapler with 3.5 mm staples.[22] In the report by Wagner et al.,[22] there was a 50% survival rate in 12 patients undergoing emergent trauma pneumonectomy for penetrating (#11) or blunt (#1) thoracic trauma. In 9 of those
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patients en bloc stapling was performed and 5 (56%) survived. A bronchopleural fistula developed in 2 of the survivors. The authors subsequently compared bronchial and pulmonary artery burst pressures in laboratory animals undergoing stapling versus ligation and found no significant differences.
THORACIC VASCULAR TRAUMA— BLUNT Blunt trauma to the thoracic vessels usually involves tears of the aorta or innominate artery. Since Parmley’s classic report from the Armed Forces Institute of Pathology in 1958, numerous articles have documented that 15– 23% of victims dying in motor vehicle crashes in the United States have rupture of the thoracic aorta at autopsy.[23 – 25] Of interest, a 12.7% incidence of rupture of the thoracic aorta was noted in a recent review of fatally injured pedestrians as well.[26] While a deceleration mechanism in motor vehicle crashes has always been cited as the most frequent cause of blunt rupture of the thoracic aorta, lateral impacts have been noted in 18 – 49.5% of series primarily involving autopsy case reviews in recent years.[27 – 29] These tears occur most frequently in both clinical and autopsy series at the isthmus of the thoracic aorta just beyond the origin of the left subclavian artery, but the exact reason for the frequency of this location is unknown. Various authors have postulated that differences in retropleural fixation between the transverse arch and DTA, upward displacement of the heart by sternal compression, increased intraluminal hydrostatic pressure, or a congenital weakness of tissues at the isthmus best explain the common location for this lesion.[27,30 – 33] Blunt tears of the ascending aorta accounted for 53.5% of all ruptures in unrestrained drivers in one Finnish autopsy series.[34] They are also occasionally noted in patients surviving vertical deceleration trauma, but the frequent occurrence of tamponade, exsanguination, or an associated cardiac injury precludes survival in most patients. Injury to the distal DTA is most commonly associated with significant fracture-dislocation of the lower thoracic spine.[35] The second most commonly injured thoracic vessel related to blunt deceleration trauma is the innominate artery.[36] Injury to this vessel usually occurs at its origin on the aorta and is probably related to hyperextension and rotation of the neck along with compression of the vessel between the upper sternum and vertebral column in frontal impact motor vehicle crashes.[16,17,37] Injuries to intercostal arteries may also occur when there are jagged fractures of the ribs resulting from blunt trauma. As these are systemic arteries with little supporting tissue, thoracotomy may occasionally be required to control hemorrhage from them.
Diagnosis Blunt thoracic vascular trauma, particularly injuries to the DTA, may have a subtle presentation in some patients. Items in the patient’s history that are suggestive of injury to these
vessels include the following: (1) history of a motor vehicle, motorcycle, or auto-pedestrian crash with an impact speed greater than 40– 45 mph; (2) history of sudden deceleration, particularly for the driver or front seat passenger in a motor vehicle crash;[37,38] (3) history of significant lateral impact type of motor vehicle crash;[29] (4) whether or not a shoulder harness type of restraint was worn by the victim, as such devices have been associated with injuries to the innominate, subclavian, and carotid arteries;[39 – 45] and (5) death of another victim in the same crash. Numerous symptoms and signs of blunt injury to the DTA have been described (Table 74-2). On physical examination, a presternal contusion is strongly suggestive of a thoracic vascular injury but has been noted in only 12–43% of such patients.[46,47] A precordial or interscapular systolic murmur (14% of patients) or decrease in femoral pulses (4%) is also reasonably specific for the presence of an aortic injury, but both are too rare to be of significant value.[46,47] Symbas et al.[48] have described the equally rare acute posttraumatic aortic coarctation syndrome in which there is increased blood pressure and pulse amplitude in the upper extremities in addition to the diminished femoral pulses described above. One interesting association noted in a retrospective study has been the fourfold increase in the incidence of aortic rupture when a pelvic fracture is present.[49] If the fracture was of the anterior-posterior compression type, the risk of an aortic injury was nine times greater than that in the overall blunt trauma population. Abnormalities noted on the admission chest x-ray or subsequent films are the most important diagnostic signs in patients with blunt thoracic vascular trauma (Fig. 74-6). A large number of radiologic signs suggestive of injury to the DTA have been reported, with widening of the superior mediastinum being the most commonly[30,38,50,51] (Fig. 74-7; Table 74-3). Since widening of the superior mediastinum is noted on routine chest x-rays of 3% of healthy supine individuals, the portable upright anteroposterior chest x-ray in the victim of blunt thoracic trauma is best performed with the patient leaning forward, away from the cassette.[52,53] This maneuver, originally described by Ayella et al.,[52] gives a more accurate view of the width of the superior mediastinum by duplicating the upper chest position in a standard posteroanterior chest x-ray. Also, many authors have commented on the importance of a greater than 8 cm widening of the superior mediastinum and obliteration of the aortic knob in detecting injury to the DTA.[46,47,50] It is of interest, however, that neither occurs with any greater frequency in patients with rupture of the aorta as compared to
Table 74-2. Clinical Signs Suggestive
of Blunt Injury to the Descending Thoracic Aorta Mark of steering wheel on anterior chest Interscapular murmur Decreased femoral pulses Upper extremity hypertension Paraparesis or paraplegia Tenderness over lower thoracic spine
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Table 74-3. X-Ray Signs Suggestive of Blunt Injury to the Descending Thoracic Aorta
Figure 74-6. Widening of the superior mediastinum on the chest x-ray of patient who was subsequently found to have an injury to the descending thoracic aorta.
those with normal aortograms.[36] And the definition of widening of the superior mediastinum is certainly variable, even among experienced radiologists.[53] Of interest, Woodring and King detected abnormalities in 30 of 32 patients (94%) with subsequently proven injuries to the thoracic aorta or brachiocephalic vessels using the first eight signs of mediastinal abnormality on a chest x-ray listed in Table 74-3[54]. Radiologic signs suggestive of blunt injury to the innominate artery include widening of the superior mediastinum, a pointed appearance of the right edge of the hematoma (also noted in some patients with rupture of the DTA), and a shift of the nasogastric tube to the left.[16,36] It is now accepted that a history of deceleration-type blunt trauma or a history of a significant lateral impact in a motor vehicle crash and an abnormal upright chest x-ray are indications for further diagnostic evaluation. It must be remembered, however, that a normal admission chest x-ray
Widened superior mediastinun . 8 cm on upright film Opacification of aortopulmonary window Deviation of the nasogastric tube to the right Deviation of the trachea to the right Depression of left mainstem bronchus Presence of apical pleural cap Widening of right paratracheal stripe Widening of paraspinal line Calcium layering in aortic arch or knob Massive left hemothorax Unilateral fracture of first rib and second rib or clavicle Severely displaced fracture of the first rib Bilateral first rib fractures Multiple rib fractures, especially with flail chest Fracture-dislocation of the sternum Fracture-dislocation of the lower thoracic spine
may be present in a small subset of patients with rupture of the DTA.[54 – 56] Therefore, the presence of an appropriate history in combination with unilateral fracture of the first rib and clavicle, a severely displaced fracture of the first rib, bilateral first rib fractures, multiple rib fractures, a flail chest, fracturedislocation of the sternum, fracture-dislocation in the lower thoracic spine, or paraparesis/paraplegia is an indication for further studies in the minds of most trauma surgeons, even when the superior mediastinum is not widened on the admission chest x-ray. In the absence of widening of the mediastinum, however, an isolated simple fracture of the first rib is not an indication for a thoracic aortogram. This is because injury to the DTA or innominate artery occurs with a similar frequency whether or not the first rib is fractured.[57 – 60] Once a decision is reached to pursue further diagnostic testing in the patient with possible blunt thoracic vascular injury, available options include spiral or helical computed tomography (CT), transesophageal echocardiography (TEE), digital subtraction angiography or aortography (DSA), and conventional biplane aortography. With increasing usage of spiral CT in the evaluation of many patients with major thoracic injury in recent years, guidelines have been developed to integrate this modality into standard diagnostic algorithms.[61] Mirvis et al. have suggested the following:[5] 1. 2.
3.
Figure 74-7. Rapidly expanding rupture of the descending thoracic aorta at the isthmus. Patient expired shortly after transfer to the trauma center. (From Feliciano DV and Rozycki GS.[51] Reproduced by permission.)
4.
Abnormal chest x-ray is followed by contrastenhanced spiral thoracic CT: Absence of mediastinal hemorrhage or direct signs of aortic injury by “high-quality” CT excludes the diagnosis of injury to the thoracic aorta. Direct evidence of injury to the thoracic aorta or other great vessel should be followed by aortography or thoracotomy, “based on the experience of the institution.” Spiral CT evidence of hemorrhage in the anterior mediastinum or paravertebral area in the absence of signs of injury to the thoracic aorta rules out injury to this structure.
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Evidence of mediastinal hemorrhage in the area of the thoracic aorta or great vessels without direct signs of vascular injury mandates aortography.
The enthusiastic adoption of spiral CT as a primary and, possibly, the sole diagnostic method to diagnose blunt injury to the thoracic aorta is based on recent data. In three recently published series, sensitivity was 100%, specificity 81.7 – 99.7%, and accuracy 86 –99.7%.[5,6,61] It is likely that more centers will proceed to nonoperative management or to operative repair based on the results of the spiral CT without confirmation by a thoracic aortogram. There is now a significant amount of data on the use of TEE in detecting blunt rupture of the thoracic aorta or a brachiocephalic vessel as well. The primary advantage of TEE is that it allows for examination of the thoracic aorta in a continuous fashion in any area of the hospital, including the emergency department, operating room, or intensive care unit. Buckmaster et al.[62] have described the use of TEE with color flow Doppler examinations in 121 of 160 patients with possible blunt injury to the thoracic aorta. There were equivocal studies in 3 patients, positive in 14 (all confirmed), and true-negative in the remainder. Of interest, there were one false-positive and four false-negative results in the 148 patients in the same series who underwent thoracic aortography (sensitivity 73%, specificity 99%). The obvious limitations to TEE include the following: (1) need to consult either cardiology or anesthesiology to perform the study; (2) operator dependent; (3) contraindication to esophageal intubation; (4) equivocal findings; (5) less than ideal visualization of the ascending aorta behind the right mainstem bronchus, branches of the transverse arch, and the DTA when a pneumothorax is present.[9,51,63] Thoracic aortography or intraarterial digital subtraction aortography (DSA) performed through a retrograde transfemoral or transaxillary/transbrachial (when femoral pulses are diminished) approach continues to be the standard of care that other diagnostic techniques are measured against. Most centers now use DSA, a study that can be performed in 15 – 30 min and has an accuracy of 97– 100%.[6,64,65] The major advantage to use of these techniques, in addition to accuracy, is the ability to detect and precisely localize injuries in all areas of the thoracic aorta and its branches. Visualizing a proximal extension of a rupture in the DTA into the transverse arch on aortography will alter the positioning of the patient and the operative approach, while failure to note this on any diagnostic study will prolong cross-clamp time on the thoracic aorta. In similar fashion, the 3.7% incidence of multiple lesions (two aortic tears or aortic tear in combination with injury to a brachiocephalic vessel) reported in Fisher’s review and continuing case reports documenting the same reinforce the importance or precise aortography performed by an experienced radiologist.[36,57 – 59,66,67] The disadvantage continues to be the inevitable delay as the interventional angiography team must be contacted and return to the hospital to complete this brief study. There is a emerging trend to use spiral CT as an intermediate step before thoracic DSA or even as a replacement for DSA, as previously noted, and it is likely that the use of DSA or conventional aortography will decrease significantly in the future.
Nonoperative or Delayed Operative Management There have been multiple case reports or small series since 1971 describing nonoperative or, more recently, delayed operative management in patients with blunt rupture of the thoracic aorta.[68] Historically, patients managed in this fashion have had severe associated injuries in which survival or meaningful recovery was in doubt at the time the injury to the thoracic aorta was diagnosed.[6,69 – 74] More recently, patients with associated injuries to the brain or lungs that would be adversely affected by cross-clamping of the thoracic aorta or systemic heparinization now have delays in operative management. This approach is similar to that used with nonoperative management of acute dissection of the thoracic aorta. When there is a suspicion of or diagnostic confirmation of an injury to the thoracic aorta in a normotensive patient, and nonoperative or delayed operative management is chosen, intravenous beta-blockers (esmolol, labetalol, or metoprolol) are administered. These are primarily indicated in patients with a pulse greater than 90 and a systolic blood pressure greater than 100 mmHg. With a goal of lowering wall shearing forces in the ruptured aorta, the beta-blocking agent chosen is titrated to a systolic blood pressure of 100 mmHg or a mean arterial blood pressure of 65 –75 mmHg.[6,72] Should the systolic blood pressure remain greater than 100 mmHg, an intravenous vasodilator such as nitroprusside is added. In the report by Pate et al.,[72] the medications described were “continued until traumatic rupture of the aorta is ruled out by further studies or until the aorta is cross-clamped at operation; it is continued chronically in patients in whom repair is deemed unsafe.” Should operative management be chosen in the patient with associated pulmonary contusions, a “trial” of operative positioning is worthwhile. If insertion of the double-lumen endotracheal tube, positioning of the patient in the right lateral decubitus position, and inflation of the occluding balloon in the left mainstem bronchus cause arterial desaturation, the operative repair should be delayed. Of interest, elective delayed operation was performed in 15 patients, while another 11 patients with blunt rupture of the thoracic aorta never had a repair in the report by Pate et al.[72] No patient managed with the antihypertensive protocol ruptured or died because of a delay in surgery or no repair at all.
Endovascular Stents for Repair of the Great Vessels There is widespread enthusiasm for the use of endoluminal stented grafts in treating artherosclerotic and posttraumatic lesions of the aortoiliac, femoral, and carotid systems.[75] Similar techniques have now been utilized to avoid operative repair of injuries to the subclavian and carotid arteries and the DTA.[76 – 81] In the most recent reports on endovascular stent grafts inserted into traumatic ruptures of the DTA, all patients did well with follow-up at 15 months in several.[78 – 84] Longterm studies evaluating the safety and patency of the endovascular approach to injuries of the thoracic aorta and great vessels are not available at this time.
Chapter 74. Thoracic and Abdominal Vascular Trauma
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Operative Management Equipment which should be available in the operating room when the patient arrives is the same as that for the patient with a penetrating thoracic vascular injury, depending on the preferred technique for repair of the innominate artery or DTA in a given institution.
Blunt Rupture of the Innominate Artery The patient is placed in the supine position, and the anterior and lateral neck and thorax as well as one thigh are prepared and draped. A median sternotomy and pericardiotomy will allow for exposure of the ascending aorta, including the contained hematoma at or just beyond the origin of the innominate artery. In the absence of significant intraoperative hypotension or an extensive injury to the arch simultaneously involving the origin of the left common carotid artery, neither cardiopulmonary bypass nor temporary shunts are needed for repair of the innominate artery.[16] A preclotted knitted Dacron graft 8– 12 mm in diameter is first sewn in an end-toside fashion to the ascending aorta proximal to the area of injury. After dissection of the bifurcation of the innominate artery distally and the area of injury proximally, vascular clamps are applied and the distal artery is transected proximal to the bifurcation. This allows retrograde flow from the right subclavian artery into the right common carotid artery during the period of clamping. The Dacron graft is then sewn to the distal end of the innominate artery and prograde flow is reestablished into the right subclavian and common carotid arteries. As a final step, the area of injury on the aortic arch is oversewn with Teflon pledgets (Fig. 74-8).
Blunt Rupture of the Descending Thoracic Aorta Operative techniques currently utilized include the following: (1) cross-clamping of the DTA around the tear with rapid repair (“clamp/repair”); (2) cross-clamping of the DTA with insertion of a sutureless intraluminal aortic prosthesis (“rigid intraluminal prosthesis”); (3) insertion of an external heparinbonded (triclodecylmethylammonium chloride heparin) shunt from the ascending aorta to the descending aorta or left femoral artery prior to cross-clamping of the DTA and repair (“external shunt”); (4) insertion of left femoral vein or left atrial and left femoral artery cannulas connected to a roller pump with or without an oxygenator (“left heart or atriofemoral bypass”); and (5) insertion of left atrial or superior pulmonary vein and left femoral artery cannulas connected to a Bio-Medicus centrifugal pump (Bio-Pump, Medtronic Bio-Medicus, Inc., Eden Prairie, MN). Each of the techniques listed has obvious disadvantages. The clamp/repair technique interrupts some blood flow to the thoracic spinal cord and may increase the risk of postoperative paraplegia or paraparesis. The intraluminal graft may be difficult to insert, has been known to dislodge, and may be a source of postoperative hypertension. Insertion of shunts or cannulas into the ascending or descending thoracic aorta or into the left atrium or superior pulmonary vein may result in bleeding during operation and leaks or pseudoaneur-
Figure 74-8. Technique of bypass grafting for repair of blunt injury to origin of the innominate artery (Copyrightq Baylor College of Medicine, 1981. Used with permission.)
ysms in the postoperative period. Whenever heparin is used in combination with a pump or pump and oxygenator, there is a risk of hemorrhage from other injured sites or at the aortic repair. In the operating room, a double-lumen endotracheal tube, a right radial artery line, and a Swan-Ganz catheter are inserted. It should be noted that attempts at awake intubation have resulted in fatal aortic rupture in some patients.[82] The patient is then placed in the right lateral decubitus position with the left hip externally rotated to allow for access to the abdomen and left groin.[83] The left hemithorax is entered through a posterolateral thoracotomy incision in the fourth or fifth intercostal space. The distal DTA is exposed inferior to the hematoma, and an umbilical tape is passed around the vessel. The transverse aortic arch is also encircled with an umbilical tape between the left common carotid and left subclavian arteries. Injury to the left vagus and recurrent laryngeal nerves should obviously be avoided during this maneuver. Control of the thoracic aorta at this level allows for safe repair of aortic tears that extend proximal to the origin of the left subclavian artery. The left subclavian artery is then encircled at its origin. When the “clamp/repair” technique is to be used, the surgeon should communicate with the anesthesiologist regarding the possible need for afterload modification during the period of aortic cross-clamping.[84] Large vascular clamps are then applied to the mid-arch, distal DTA, and left subclavian artery. A transverse aortotomy is performed; backbleeding from intercostal arteries is controlled by Silastic
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loops, balloon catheters, or ligation; and the area of injury is visualized. A partial-thickness tear not involving the entire circumference of the aorta can be primarily repaired on rare occasions with a continuous 3-0 or 4-0 polypropylene suture after mobilization of the proximal and distal ends of the vessel.[85] A more extensive tear is best repaired by insertion of a woven or impregnated Dacron graft, again utilizing a 3-0 or 4-0 continuous polypropylene suture for each anastomosis. With regards to the previously mentioned complication of paraplegia or paraparesis, cross-clamp times greater than 30 min are thought to increase the risk.[85 – 89] It is clear, however, that there is not a precise correlation between the two[84 – 87,90] (Table 74-4). An alternate and rarely used approach in recent years is insertion of a sutureless intraluminal aortic prosthesis. While experience with this prosthesis has primarily been in patients with dissecting or atherosclerotic thoracic aneurysms, several patients with rupture of the DTA have been treated as well.[91 – 93] The first problem reported with use of this prosthesis has been difficulty in inserting the proximal graft cuff (smallest graft available = 18 mm) into the relatively narrow lumen of the thoracic aorta in young trauma patients.[91,93] This has mandated removal of the proximal graft cuff and conversion to a standard sutured anastomosis in some patients.[92] The second problem has been sustained postoperative systolic hypertension thought to be due to the decrease in luminal size at the cuff site. In one of Grosso’s patients, a 40 mmHg decrease in systolic blood pressure was noted across the intraluminal graft on postoperative angiography.[94] Based on luminal size and thickness of the graft cuff, it appears that the sutureless intraluminal aortic prosthesis cannot be inserted into all young patients with traumatic rupture of the DTA. One of the time-honored approaches to repair of the injured DTA has been the insertion of a shunt from the proximal thoracic aorta or left atrium to the left femoral artery.[95] With use of a heparin-bonded shunt, neither heparinization nor use of a roller pump is necessary when the shunt is inserted into the proximal thoracic aorta. It is of interest, however, that the shunt does not prevent ischemic injury to the spinal cord in all patients.[87] This is also true of left atriofemoral bypass, in addition to the aforementioned problems related to insertion or dislodgment of cannulas.[84,96] Reports describing use of the Bio-Pump for atriofemoral bypass have been much more encouraging.[88,89,93,94,97-101] Once the left atrium (or left superior pulmonary vein) and left common femoral artery have been cannulated, the centrifugal pump maintains flow rates of 2– 3.5 L/min to the distal abdominal aorta below the clamp on the DTA without heparinization.
Table 74-4. Correlation of Aortic Cross-Clamp Times in Stable Patients with the Development of Postoperative Paraplegia Group ,30 min $30 min
Paraplegia
No paraplegia
p-value
1 15
60 109
0.02 0.02
Source: Fabian TC et al.[89] Reproduced with permission.
A report has described posterior cerebral infarcts in two partients who had aortic cross-clamp times of 44 minutes and 56 minutes while undergoing repair of the DTA using the centrifugal pump.[102] The authors suggested that systemic anticoagulation be considered if aortic cross-clamp times are likely to exceed 30 min. The variety of operative approaches for acute repair of the torn DTA, incomplete descriptions of associated injuries and causes of deaths in published series, and differences in reporting results have made it difficult to know the actual risks of early repair. A summary of recent reports is presented in Table 74-5. At the current time paraplegia rates following operation in reasonably sized series range from 1.5 to 23%. Mortality rates, which often reflect the magnitude of associated injuries, are 12 –25%.[88 – 90]
ABDOMINAL VASCULAR TRAUMA Abdominal vascular trauma includes injuries to the vessels in four separate areas of the abdomen as listed below: Zone 1—Midline retroperitoneum includes the supramesocolic area (suprarenal abdominal aorta, celiac axis, proximal superior mesenteric artery, proximal renal artery, and superior mesenteric vein), and the inframesocolic area (infrarenal abdominal aorta and infrahepatic inferior vena cava) Zone 2—Upper lateral retroperitoneum (renal artery and vein) Zone 3—Pelvic retroperitoneum (iliac artery and vein) Portal-Retrohepatic Area—Right upper quadrant (portal vein, hepatic artery, retrohepatic vena cava) The incidence of injury to major abdominal vessels in patients sustaining blunt abdominal trauma is estimated to be 5–10%.[103,104] In patients undergoing celiotomy for stab wounds of the abdomen, the incidence is approximately 10%.[105] When celiotomy is performed for gunshot wounds of the abdomen, injury to a named vessel occurs in approximately 25% of patients.[106]
Pathophysiology Penetrating wounds to the abdomen create the same types of injuries as seen in vessels of the thorax and extremities – namely, lateral wall defects with free bleeding or hematomas, partial or complete transection with free bleeding or thrombosis, and blast effects with intimal flaps and secondary thrombosis. Arteriovenous fistulas are rare and usually involve the portal and hepatic vessels or renal vessels in the upper abdomen or the iliac vessels in the lower abdomen. Blunt abdominal vascular injuries are generally caused by a direct anterior crushing or compression mechanism or a posterior blow to the spine. An intimal tear or flap may result and lead to thrombosis of a major vessel such as the superior mesenteric artery,[107] infrarenal abdominal aorta,[108,109] or iliac artery.[110,111] The “seat belt aorta” is the most dramatic example of an anterior crush leading to thrombosis.[108,109,112,113,114] Direct blows can also rupture major
Chapter 74. Thoracic and Abdominal Vascular Trauma
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Table 74-5. Current Results of Operative Repair for Blunt Rupture of the Descending Thoracic Aorta Technique Clamp/Repair External shunt Full bypass Partial bypass Centrifugal pump
Results
Hunt et al.[88]
Fabian et al.[89]
Paraplegia Death Paraplegia Death Paraplegia Death Paraplegia Death Paraplegia Death
6=37 ¼ 16:2% 9=37 ¼ 24:3% 1=6 ¼ 16:7% 1=6 ¼ 16:7%
12=73 ¼ 16:34% 11=73 ¼ 15:1% 0=4 ¼ 0% 0=4 ¼ 0% 1=22 ¼ 4:5% 5=22 ¼ 22:7% 3=39 ¼ 7:7% 5=39 ¼ 12:8% 2=69 ¼ 2:9% 10=69 ¼ 14:5%
2=43 ¼ 4:7% 7=43 ¼ 16:2%
vessels such as the superior mesenteric artery and vein at the base of the mesentery,[115] left renal vein over the abdominal aorta,[116] or the abdominal aorta itself,[117,118] leading to exsanguination or an acute pseudoaneurysm. In recent years, there have been numerous reports of iatrogenic injuries to abdominal vessels. Major causes have included diagnostic procedures such as angiography, abdominal operations such as retroperitoneal node dissections, spinal operations such as excision of a herniated disk, and insertion of vascular devices such as the intraaortic balloon.[119 – 121]
Diagnosis An abdominal vascular injury should be suspected in any patient with a penetrating wound between the nipples and upper thighs. The findings on physical examination will depend on whether a contained hematoma or active hemorrhage is present. Some patients will present with modest or moderate hypotension as the vasular injury is tamponaded in the retroperitoneum, base of the mesentery, or hepatoduodenal ligament. After an infusion of crystalloids, such patients may remain remarkably stable until the hematoma is opened at the time of laparotomy. This is particularly true in patients with injuries to major abdominal veins, including the inferior vena cava.[122] The history of a penetrating wound of the abdomen associated with a period of hypotension is an indication for an early laparotomy in the wounded patient. When hypotension resolves quickly with the administration of crystalloids or the source of modest hypotension is unclear because of the presence of other penetrating wounds or severe intoxication, further diagnostic tests that may be worthwhile include the following: (1) surgeon-performed ultrasound of the abdomen to confirm the presence of a hemoperitoneum; (2) local exploration of a stab wound to verify peritoneal penetration, followed by diagnostic peritoneal lavage; (3) flat-plate x-ray of the abdomen to verify peritoneal traverse of a missile; and (4) repeated physical examination to detect the onset of peritonitis. Other patients with penetrating wounds will present with profound hypotension and marked abdominal distension that increases during the period of resuscitation. The diagnosis of the abdominal catastrophe (multiple intraabdominal injuries; free bleeding from an abdominal vascular injury; major abdominal aortic or arterial injury with ineffective tamponade) secondary
Sweeney et al.[90] 1=65 ¼ 1:5% 9=71 ¼ 12%
to the penetrating wound is obvious and immediate operation is indicated. On rare occasions, loss of one femoral pulse may also be present on physical examination and is strongly suggestive of transection or thrombosis of the common or external iliac artery. As previously noted, blunt trauma to abdominal vessels may also cause significant intraabdominal hemorrhage when mesenteric vessels, peripancreatic branches of the portal vein, or the left renal vein are avulsed. Abdominal distension is usually less prominent in this group as compared to that from arterial injuries after pentrating wounds. Should there be any question about the presence of intraabdominal bleeding in the hypotensive patient who has suffered blunt trauma, a surgeonperformed ultrasound[123,124] or rapid diagnostic peritoneal lavage (supraumbilical in patients with pelvic fractures) is performed in the emergency department. In patients with intimal tears and secondary thrombosis of the renal artery, flank pain and gross or microscopic hematuria (70% of patients) may be the only findings suggestive of the diagnosis. Reasonably stable patients in this group or any patient with significant hematuria (more than 30 red blood cells per high-power field) after blunt abdominal trauma should undergo an abdominal CT. If only a renal contusion or superficial cortical laceration is present, a perirenal hematoma found at a subsequent laparotomy will not have to be opened. The presence of only proximal flow in the renal artery and rim enhancement by adrenal collaterals coupled with the absence of contrast in the kidney documents thrombosis of the renal artery. In patients with blunt pelvic fractures, persistent hypotension after application of an external fixator, and a negative surgeon-performed ultrasound or supraumbilical diagnostic peritoneal lavage, pelvic arteriography is useful to diagnose and treat deep pelvic arterial bleeders.
Management in the Emergency Department Prospective studies in urban areas have not demonstrated any survival advantage to the prehospital use of pneumatic antishock garments in patients with abdominal trauma.[125] A patient with a suspected abdominal vascular injury and application of the garment in the prehospital period should be rapidly transported to the operating room with the garment still inflated. The garment is removed when the anesthesiologist and surgeons have completed the usual preparations for laparotomy except for painting of the skin and draping.
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A patient arriving with abdominal distension and hypotension should have an identification bracelet applied and blood drawn for type and cross-match before being moved rapidly to the operating room. Multiple large-bore intravenous catheters can then be inserted in the upper extremities or veins at the thoracic inlet in the operating room. As described for patients with penetrating thoracic vascular wounds, fluids and blood should be infused through high-flow warming units. In contrast, the moribund or arrested patient should undergo an emergency department thoracotomy below the nipple (in contrast to patients with high thoracic wounds) to allow for cross-clamping of the descending thoracic aorta. This technique is performed in hospitals in which the operating room is geographically distant and has a salvage rate of only 2–3% in patients with abdominal trauma.[11]
Operative Management Equipment which should be available in the operating room when the patient arrives includes blood for transfusion, autotransfusion machine, aortic compressor, complete cardiovascular tray, sponge sticks with gauze sponges, balloon catheters, a variety of sizes of Dacron and PTFE grafts, and appropriate vascular sutures. The previously described warming maneuvers are initiated as the trunk from the chin to the knees is prepared and draped. A midline abdominal incision is made, all clots and free blood are removed with suction or manually evacuated, and a rapid inspection of the abdomen is made. Hemorrhage from solid organs or the mesentery is controlled by packing or clamps. Proximal and distal control with vascular clamps is obtained around any perforation in the abdominal aorta or other major artery, while the application of vascular clamps or sponge sticks for compression is used to control hemorrhage from the inferior vena cava or other major vein. Balloon catheters are occasionally useful to control hemorrhage from the abdominal aorta at any location or from the inferior vena cava, particularly at the confluence of the iliac veins or renal veins.[126] After hemorrhage is controlled, Babcock clamps, Allis clamps, or noncrushing intestinal clamps are applied to perforations in the gastrointestinal tract. Rapid one-layer closure of the perforations with 3-0 polypropylene suture is appropriate when only a few are present. This is also indicated when there is a contained retroperitoneal hematoma around the vascular injury. After the repairs of the gastrointestinal tract, the surgeon changes gloves and drapes, irrigates the abdominal cavity with saline and antibiotics, and performs the vascular repair. Should there be multiple perforations of the gastrointestinal tract or the need to cross-clamp a critical abdominal artery or vein, the vascular repair is performed first.
rotation of all left-sided abdominal viscera, including the left colon, left kidney, spleen, tail of pancreas, and fundus of the stomach. These organs are freed from their retroperitoneal attachments by a combination of sharp and blunt dissection (Fig. 74-9). This maneuver takes approximately 4 –5 min of operating time and exposes the entire abdominal aorta from the hiatus to the aortic bifurcation. If not performed carefully, damage to the kidney, posterior left renal artery, or spleen may result. As mobilization of the left kidney may cause anatomic distortion of an area of injury in the visceral abdominal aorta, some centers choose to leave the left kidney in the retroperitoneum during the medial mobilization.[127] Both the celiac nerve plexus and numerous lymphatics cover the supraceliac aorta and may prevent precise application of a proximal vascular clamp despite an adequate medial mobilization maneuver. Transection of the left crus of the diaphragm at the 2 o’clock position will allow for exposure of the distal descending thoracic aorta through the aortic hiatus and easier application of the proximal vascular clamp. In the patient with hemorrhage coming from the supramesocolic area, an aortic compression device should be applied.[128] More definitive proximal aortic control is obtained by manually dividing the lesser omentum, retracting the esophagus to the left, manually opening the aortic hiatus, and cross-clamping the supraceliac or descending thoracic aorta between the fingers of the left hand.[129] Distal control of the diaphragmatic or proximal visceral abdominal aorta may require ligation and division of the celiac axis. Repair of small perforating injuries of the suprarenal abdominal aorta is performed with a continuous 3-0 to 4-0 polypropylene suture in a transverse direction. Adjacent perforations are connected and closed in a similar fashion (Fig. 74-10), while more extensive injuries may require patch aortoplasty with PTFE. On rare occasions, the extent of the
Zone 1—Midline Supramesocolic Hematoma or Hemorrhage The midline retroperitoneum superior to and beneath the transverse mesocolon contains the suprarenal abdominal aorta, celiac axis, proximal superior mesenteric artery, proximal renal arteries, and proximal superior mesenteric vein. A hematoma in this area is approached by medial
Figure 74-9. Maneuver to expose abdominal aorta in plane behind left-sided intraabdominal viscera (Copyright q Baylor College of Medicine, 1981. Used with permission.)
Chapter 74. Thoracic and Abdominal Vascular Trauma
Figure 74-10. Drawing depicting two holes in abdominal aorta. The holes have been joined to facilitate transverse aortorrhaphy. (Copyright q Baylor College of Medicine 1984. Used with permission.)
defect in the suprarenal abdominal aorta will mandate repair with a 12 or 14 mm Dacron or PTFE interposition graft, as an end-to-end anastomosis is usually quite difficult to perform. Even in the presence of gastrointestinal contamination, the incidence of infection in a Dacron abdominal aortic graft inserted for trauma in a young healthy aorta is quite low (one patient reported since 1970).[130,131] Prior to release of the clamps on the suprarenal aorta in the shocky patient, the anesthesiologist should infuse fluids, blood, and bicarbonate to counteract the inevitable “washout” acidosis, much as in patients with repair of a ruptured abdominal aortic aneurysm. The retroperitoneum is then copiously irrigated with antibiotic solution and closed before any repairs of the gastrointestinal tract are performed. The survival rate for patients with injuries to the suprarenal abdominal aorta was 36% in one large series[132] (Table 74-6). Combined injuries to the suprarenal aorta and inferior vena cava had a 100% mortality in the same series. Injuries to the celiac axis are ligated, as there is no shortterm morbidity and repair is technically difficult. The injured superior mesenteric artery is usually repaired, however, as collateral circulation from the foregut and hindgut is often inadequate to maintain viability of the small bowel and right Table 74-6.
Survival After Arterial Injuries in the Abdomen
Vessel Suprarenal aorta Superior mesenteric artery Infrarenal aorta Renal artery Iliac artery
Survivors/ all patients
(%) Survival
54/155 67/116 43/93 19/22 145/236
34.8 57.7 46.2 86.7 61.4
Source: Modified from Feliciano et al.[130]
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colon in the trauma patient with shock. Control of the proximal superior mesenteric artery is obtained by the leftsided medial mobilization maneuver, while exposure of retropancreatic injuries may mandate complete transection of the neck of the pancreas. Distal injuries are approached through the base of the transverse mesocolon or mesentery. Lateral repair of the superior mesenteric artery is performed with 5–0 polypropylene suture. With destruction of the proximal artery, ligation is performed at the origin of the vessel on the visceral aorta. A saphenous vein or PTFE bypass graft is then sewn between the distal abdominal aorta (away from the pancreas) and the superior mesenteric artery beyond the area of ligation. In patients with profound shock and intraperative hypothermia, metabolic acidosis, and coagulopathies, the insertion of a temporary intraluminal shunt rather than a complex vascular repair is appropriate. The survival rate after repair of the injured superior mesenteric artery has averaged 58% in recent series[130,133] (Table 74-6). Injuries to the proximal renal artery are often associated with injuires to the visceral abdominal aorta, and survival rates are poor. More distal injuries are discussed below. The superior mesenteric vein injured near its junction with the splenic and portal veins is approached by transection of the neck of the pancreas, while more distal injuries are visualized at the base of the mesentery of the small bowel. Lateral venorraphy with 5-0 polypropylene suture is preferred, although some rather exotic repairs, including transposition of the splenic vein or saphenous vein grafting to the portal vein, have been described.[134] There are now data describing the excellent results attained with ligation of the severely injured vein. Stone et al.[135] have described the importance of vigorous fluid resuscitation in the postoperative period after ligation of the superior mesenteric (or portal) vein. This will reverse the peripheral hypovolemia that results from temporary splanchnic hypervolemia. The survival rate after repair of injuries to the superior mesenteric vein has averaged 72% in large series[130,135] (Table 74-7).
Zone 1—Midline Inframesocolic Hematoma or Hemorrhage The midline retroperitoneum inferior to the transverse mesocolon contains the infrarenal abdominal aorta and the infrarenal inferior vena cava. A patient with a hematoma or Table 74-7. Survival After Venous Injuries in the Abdomen
Vessel Superior mesenteric vein Infrahepatic inferior vena cava Suprarenal Renal Infrarenal Renal vein Iliac vein Portal vein
Survivors/all patients
(%) Survival
75/104
72.1
52/88 55/84 223/285 38/43 282/404 67/134
59.7 65.5 78.2 88.3 69.8 50.0
Source: Modified from Feliciano et al.[130]
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hemorrhage from this area should have proximal control of the abdominal aorta obtained just distal to the left renal vein at the base of the mesentery. Because of the size of the hematoma over an injured infrarenal abdominal aorta, manual dissection is required to expose the vessel. Repairs of the infrarenal abdominal aorta are similar to those described for the suprarenal abdominal aorta and result in a survival rate of approximately 46%[130] (Table 74-6). If there is not an injury to the aorta, then an injury to the infrarenal inferior vena cava should be suspected. The hematoma over an injured inferior vena cava frequently fills the right paracolic gutter, elevates the right colon, and leaks through its mesentery medially. While the infrarenal inferior vena cava can be exposed through the retroperitoneum in the midline, most trauma surgeons mobilize the retroperitoneal duodenum and right colon medially to expose the entire cava from the liver to the iliac veins (right medial mobilization maneuver) (Fig. 74-11). An isolated anterior or lateral perforation of the inferior vena cava is grabbed with a forceps or Allis clamp and a Satinsky vascular clamp is placed beneath it. Should the extent of hemorrhage preclude visualization of the perforation, sponge-stick compression or application of vascular clamps above and below the presumed area of injury is indicated. Simultaneous crossclamping of the infrarenal abdominal aorta will decrease the risk of hypotension secondary to loss of venous return. Isolated perforations are repaired in a transverse direction with continuous 5-0 polypropylene suture, frequently with two rows of sutures to ensure hemostasis. The posterior wall of the inferior vena cava is then mobilized to rule out a second perforation. On rare occasions, the perforation in the posterior wall can be repaired intraluminally by extending the length of the anterior perforation.
Figure 74-11. Drawing depicting exposure of infrahepatic inferior vena cava by right-sided medial mobilization maneuver.
Narrowing usually results when primary repair is used on large wounds of the inferior vena cava. Reconstruction of the narrowed area with a PTFE patch cavoplasty is indicated only in hemodynamically stable patients without a coagulopathy or hypothermia. This narrowing or even surgical ligation of the infrarenal inferior vena cava is well tolerated in young trauma patients if their ciculating volume is maintained and if both lower extremities are wrapped and elevated for the first 7–10 postoperative days (Fig. 74-12). Should ligation be performed, bilateral below-knee four-compartment fasciotomies are usually necessary and bilateral thigh fasciotomies are occasionally needed, as well. Injuries to the inferior vena cava at the confluence of the iliac veins are often difficult to visualize. For this reason, division of the right common iliac artery and mobilization of the overlying aortic bifurcation to the left may be necessary to complete the venous repair, followed by reanastomosis of the artery.[136] When the inferior vena cava is injured at its junction with the renal veins, it is usually necessary to pass silastic loops around both veins in addition to the usual clamp or sponge-stick control of the infrarenal and suprarenal cava before performing the repair.
Figure 74-12. Venogram illustrating total occlusion of the inferior vena cava following a simple vena cavorrhaphy for a single stab wound. Note collateral venous return via ascending lumbar veins toward the azygos system.
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Survival rates for patients with injuries to the inferior vena cava depend on which location of injury is being discussed. With wounds to the infrahepatic (no retrohepatic or suprahepatic injuries included) inferior vena cava, survival has averaged 70–78% in recent reviews. With injuries to the infrarenal inferior vena cava alone, survival has averaged 79%[130,137] (Table 74-7).
left renal vein is tolerated in many patients if the left adrenal and gonadal veins are intact; postoperative renal complications, however, do occur and may mandate late nephrectomy.[141] Survival rates for patients with injuries to the renal veins after penetrating trauma range from 42 to 88%, depending on the magnitude and number of associated injuries.[138,142]
Zone 2—Lateral Perirenal Hematoma or Hemorrhage
Zone 3—Lateral Pelvic Hematoma or Hemorrhage
Injury to the renal artery, renal vein, both, or the kidney should be suspected when a hematoma or hemorrhage is present in this location. In the patient who has suffered blunt abdominal trauma and who has had a normal IVP, renal arteriogram, or CT of the kidneys, there is no need to open the perirenal hematoma at a subsequent laparotomy. In the absence of preoperative CT screening, all perirenal hematomas found in patients with penetrating wounds are opened. Many centers continue to obtain silastic loop control of the midline renal artery and vein prior to entering a perirenal hematoma secondary to a penetrating wound. On the right side, mobilization of the duodenum will be necessary before the renal vein can be controlled. When there is active hemorrhage from a perirenal hematoma, midline control of the main vessels is too timeconsuming. The kidney is quickly mobilized out of the retroperitoneum, and a vascular clamp is applied to the hilar vessels under direct view. Repair of the injured renal artery after penetrating trauma is rarely attempted, as most patients are hypotensive and have multiple associated injuries. Techniques of repair that have been suggested but rarely utilized include bypass grafting from the aorta or hepatic artery on the right and transposition of the splenic artery on the left. In the hypotensive patient with multiple intraabdominal injuries, injury to the renal artery or both hilar vessels, and a normal contralateral kidney on intraoperative palpation, nephrectomy is the procedure of choice. The survival rate for patients with penetrating injuries to the renal artery is approximately 87%[130,138] (Table 74-6). As previously described, an intimal flap with secondary thrombosis of the renal artery may result from decelerationtype blunt trauma. In one study, 27% of the patients with this lesion had no hematuria, so the diagnosis has probably been missed on many occasions in busy trauma centers.[139] The modest enthusiasm for revascularization after blunt thrombosis is certainly justified based on the report by Haas et al.[140] In a series of five patients with a median warm ischemia time of 5 h (range 4.5 –36 h), revascularization was unsuccessful in restoring renal function in four. The technique of repair includes mobilization of the injured renal artery and ischemic kidney, segmental resection of the intimal disruption, and an end-to-end anastomosis with 6-0 polypropylene suture. After a period of acute tubular necrosis in the injured kidney, late renal function is studied by renal angiography, isotope renography, or CT or MRI angiography. Lateral venorrhaphy in a transverse direction with 5-0 polypropylene suture is indicated for small perforations of the renal veins. An extensive injury to the right renal vein mandates ligation and nephrectomy. Midline ligation of the
Injury to the iliac artery, iliac vein, or both may be present in this location. While penetrating wounds account for the majority of these injuries, major blunt abdominal trauma, including open pelvic fractures, has been seen more frequently in recent years.[110,111,143] All lateral pelvic hematomas are opened after penetrating wounds. The proximal common iliac arteries and veins are exposed by dividing the midline retroperitoneum over the bifurcation of the aorta. Silastic loops are easily passed around both the artery and the vein in young trauma patients without significant atherosclerosis. Distal vascular control is obtained just proximal to the inguinal ligament, where both external iliac vessels are readily exposed after the retroperitoneum is opened. Once proximal and distal vascular control has been obtained, the hematoma is opened. The silastic loops around the common iliac and external iliac vessels on one side are then elevated to allow for exposure and looping of the internal iliac vessels going down into the pelvis. In patients with hemorrhage, manual or laparotomy pad compression is utilized until proximal and distal vascular control is obtained. As ligation of either the common or external iliac artery will lead to a 40 –50% amputation rate in the hypotensive trauma patient, repair should be performed in patients without preterminal shock or a cardiac arrest. In addition to the standard forms of arterial repair, innovative approaches have included mobilization and use of the ipsilateral internal iliacartery to replace the injured external iliac artery and transposition of one iliac artery to the side of the contralateral iliac artery for a wound at the aortic bifurcation.[130,144] When the patient has an initial body temperature less than 358C, an arterial pH less than 7.2, or a base deficit less than 2 5 in the operating room, the insertion of a temporary intraluminal shunt to maintain distal perfusion is appropriate. This “damage control” technique allows for early transfer of the patient to the intensive care unit for rewarming, restoration of normal circulation, and correction of coagulopathies.[145] A problem unique to the pelvis in patients with penetrating injuries to both the gastrointestinal tract and the iliac artery is postoperative pelvic cellulitis or abscess formation in the area of the vascular repair. In the authors’ experience, both end-toend repairs and interposition grafts have suffered septic “blowouts” in the postoperative period. In patients with significant enteric or fecal contaminaton and the need for a complex repair (end-to-end anastomosis or interposition graft) of the iliac artery, an alternative approach is suggested. The injured artery is divided proximal to the area of perforation or transection, oversewn with a double row of continuous 4-0 or 5-0 polypropylene suture, and covered with
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retroperitoneum. As ischemic edema of the ipsilateral calf is inevitable, a four-compartment fasciotomy using two skin incisions should be performed. If the extremity appears to be ischemic in the operating room at the completion of the laparotomy or during the early postoperative period, an extraanatomic crossover femorofemoral bypass graft using an 8 mm externally supported PFTF is indicated. The survival rate is 80 –88% for tamponaded isolated injuries to the iliac artery, 50–60% for combined injuries to the iliac artery and vein, and 45% when there is free bleeding from the iliac artery into the peritoneal cavity. The overall survival rate in recent large series is 61 –62%[130,145,146] (Table 74-6). An injury to the iliac vein may be isolated between sponge sticks if the surgeon decides not to loop the vessel (Fig. 74-13). As previously noted, division of the right common iliac artery will aid in exposure of an injury to the confluence of the common iliac veins. A similar maneuver involving ligation and division of the internal iliac artery on the side of the pelvis will allow for improved exposure of an injury to the ipsilateral internal iliac vein.[147] Lateral repair of the external or common iliac vein is performed with a continuous 5-0 polypropylene suture, with the understanding that a narrowed area of repair will undoubtedly thrombose in
Figure 74-13. Drawing depicting temporary control of iliac venous injury using folded sponges above and below the injury and compressed against the posterior pelvis by the surgical assistant. (Copyright q Baylor College of Medicine, 1984. Used with permission.)
the postoperative period. Ligation of these vessels is well tolerated if the same precautions used after ligation of the inferior vena cava are applied. The survival rate for repair of an isolated injury to the iliac vein is 90–95%; this figure drops to 60 –70%, however, when other vascular injuries are also present. The overall survival rate in recent large series is 70%[130,146] (Table 74-7).
Portal/Retrohepatic Hematoma or Hemorrhage When there is a hematoma in or hemorrhage from the hepatoduodenal ligament, injury to the portal vein, hepatic artery, both, or a vascular injury in combination with an injury to the common bile duct is present. In either circumstance, a proximal vascular clamp is applied to the hepatoduodenal ligament (Pringle maneuver). If possible, a distal vascular clamp is applied to the ligament adjacent to the liver. Careful dissection is necessary to avoid injury to the common bile or hepatic duct during any vascular repairs. The portal vein is exposed by mobilizing the common bile duct to the left and stripping the lymphatic tissue off the right posterolateral aspect of the vessel. A perforation of the vein beneath the neck of the pancreas will once again require division of the gland between noncrushing clamps. Lateral repair of the portal vein is performed using a continuous 5-0 polypropylene suture. In addition to the standard techniques of repair for more extensive injuries, other innovative approaches have included transposition of the splenic vein, saphenous vein bypass graft around the ligated portal vein, and creation of an end-to-side portacaval shunt. The latter procedure may lead to hepatic encephalopathy and is not performed by the authors. Ligation for severe injuries is compatible with survival, as has been described by both Pachter et al.[148] and Stone et al.,[135] and is indicated in the hypothermic, acidotic patient with a coagulopathy. Significant amounts of fluids are then infused in the early postoperative period to reverse transient peripheral hypovolemia secondary to splanchnic hypervolemia, as previously noted.[135] With a blood flow of 1100 mL/min and a posterior position in the hepatoduodenal ligament, it is not surprising that the survival rate for patients with injuries to the portal vein in recent series has been approximately 50%[130,135,149,150] (Table 74-7). Injuries to the hepatic artery are rare, and ligation rather than repair is often indicated because of multiple associated visceral and vascular injuries in the right upper quadrant. Necrosis of hepatic parenchyma under mattress sutures obviously increases if the common hepatic artery or hepatic artery to the injured lobe is ligated. Penetrating wounds of the hepatic veins or retrohepatic vena cava or avulsions of the hepatic veins from blunt trauma are all rare but extremely lethal injuries. Most patients are hypotensive on admission and are found to have a massive retrohepatic hematoma extending to the infrahepatic area at laparotomy. When the hematoma is stable after penetrating or blunt trauma and there is no rupture with associated free bleeding into the peritoneal cavity, many experienced trauma
Chapter 74. Thoracic and Abdominal Vascular Trauma
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surgeons have in recent years chosen to leave the hematoma intact. In patients with profound hypotension and active hemorrhage from the retrohepatic area, therapeutic options include the insertion of perihepatic packs for compression or an attempt at repair. The packs are indicated whenever they control hemorrhage and certainly in any patient with hypothermia, a metabolic acidosis, and a coagulopathy before a repair has been started.[151] Failure of the packs to control retrohepatic hemorrhage mandates an attempt at repair using a direct lateral approach after mobilization of the overlying hepatic lobe, total hepatic vascular isolation, extensive hepatotomy down to the injured cava, or insertion of an atriocaval shunt. The lateral approach is useful in children and in selected adults with side perforations or avulsions of hepatic veins. Cross-clamping of the suprarenal aorta, hepatoduodenal ligament, suprarenal infrahepatic inferior vena cava, and suprahepatic vena cava isolates the liver but often worsens hypotension in the hypovolemic patient; satisfactory results have been obtained, however, with use of the technique in recent reviews.[152] An extensive hepatotomy should be utilized only by surgeons with significant experience in hepatic trauma. [153] Atriocaval shunting using a #36 thoracostomy tube or #8 endotracheal tube has been the most widely used approach in recent years (Fig. 74-14). Recent results with this technique have included a 50% survival in 8 patients with blunt hepatic vascular injuries[154] and a 33% survival in 18 patients not requiring resuscitative thoracotomy after penetrating wounds[155] (Table 74-7).
TRAUMA DAMAGE CONTROL It is now well recognized that prolonged complex thoracotomies or laparotomies for trauma decrease survival, particularly when a truncal vascular injury is present. When intraoperative hypothermia (, 34–358C), metabolic acidosis (pH , 7.1 – 7.2, base deficit , 2 15 mmol/L in patient , 55 years, or serum lactate . 5 mmol/L), or a coagulopathy (prothrombin time and/or partial thromboplastin time . 50% of normal) occurs, a “damage control” operative approach is indicated.[156] With thoracic vascular injuries, this would include temporary intraluminal shunting rather than a complex or prolonged repair of the common carotid or subclavian artery, ligation of major venous injuries, and towel clip or Esmarch silo closure of a thoracotomy or sternotomy incision. In the abdomen, this would include temporary intraluminal shunting rather than a complex or prolonged repair of the superior mesenteric or common or external iliac artery, ligation of major venous injuries (with the exception of the suprarenal inferior vena cava), and towel clip or intravenous bag silo closure of the celiotomy incision. As previously noted, correction of hypothermia, circulatory shock, and the inevitable coagulopathy are accomplished during the second phase of “damage control” in the surgical intensive care unit. Reoperation is performed when the patient has a body temperature . 368, correction of acidemia, and reasonably normal coagulation studies (prothrombin time , 15 s, partial thromboplastin time , 35 s or platelets . 50,000/mm 3 ).[157] Vascular reconstruction, visceral
Figure 74-14. Drawing depicting an atriocaval shunt inserted via a pursestring suture in the right atrial appendage. Note an extra hole has been placed in the intraatrial portion of the shunt. Also, note the location of umbilical tape tourniquets around the suprarenal infrahepatic inferior vena cava and intrapericardial inferior vena cava (Copyright q Baylor College of Medicine 1984. Used with permission.)
resection or repair, and attempted closure of the midline incision are the goals at this first reoperation.
SUMMARY Thoracic and abdominal vascular trauma now accounts for 30–40% of all vascular injuries seen in urban trauma centers. Patients present with luminal injuries diagnosed by arteriography or aortography, contained hematomas around perforations or transections, or exsanguinating hemorrhage into the pleural, peritoneal, or retroperitoneal areas. A variety
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of cervicothoracic incisions are available to approach thoracic vascular injuries, while numerous techniques of mobilization are used to expose intraabdominal vascular injuries. With early operation, rapid control of hemorrhage, and use of
adjuncts to prevent intraoperative hypothermia and reverse metabolic acidosis and coagulopathies, survival rates are exceptional considering the magnitude of injury.
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Part Ten.
Vascular Trauma
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Nitecki, S.; Karmeli, R.; Ben-Arieh, Y.; Schramek, A.; Torem, S. Seatbelt Injury to the Common Iliac Artery: Report of Two Cases and Review of the Literature. J. Trauma 1992, 33, 935. Buscaglia, L.C.; Matolo, N.; Macbeth, A. Common Iliac Artery Injury from Blunt Trauma: Case Reports. J. Trauma 1989, 29, 697. Dajee, H.; Richardson, I.W.; Iype, M.O. Seat Belt Aorta: Acute Dissection and Thrombosis of the Abdominal Aorta. Surgery 1979, 85, 263. Warrian, R.K.; Shoenut, J.P.; Iannicello, C.M.; Sharma, G.P.; Trenholm, B.G. Seatbelt Injury to the Abdominal Aorta. J. Trauma 1988, 28, 1505. Reisman, J.D.; Morgan, A.S. Analysis of 46 Intraabdominal Aortic Injuries from Blunt Trauma: Case Reports and Literature Review. J. Trauma 1990, 30, 1294. Courcy, P.A.; Brotman, S.; Oster-Granite, M.L.; Soderstrom, C.A.; Siegel, J.H.; Cowley, R.A. Superior Mesenteric Artery and Vein Injuries from Blunt Abdominal Trauma. J. Trauma 1984, 24, 843. Feliciano, D.V. Abdominal Vascular Injuries. Surg. Clin. N. Am. 1988, 68, 741. Matsubara, J.; Seko, T.; Ohta, T.; Shionoya, S.; Ban, I. Traumatic Aneurysm of the Abdominal Aorta with Acute Thrombosis of Bilateral Iliac Arteries. Arch. Surg. 1983, 118, 1337. Bass, A.; Papa, M.; Morag, B.; Adar, R. Aortic False Aneurysm Following Blunt Trauma of the Abdomen. J. Trauma 1983, 23, 1072. Rich, N.M.; Hobson, R.W. II; Fedde, C.W. Vascular Trauma Secondary to Diagnostic and Therapeutic Procedures. Am. J. Surg. 1974, 128, 715. McDonald, P.T.; Rich, N.M.; Collins, G.J., Jr.; Andersen, C.A.; Kozloff, L. Vascular Trauma Secondary to Diagnostic and Therapeutic Procedures: Laparoscopy. Am. J. Surg. 1978, 135, 651. Kozloff, L.; Rich, N.M.; Brott, W.H.; Collins, G.J., Jr.; McDonald, P.T.; Clagett, G.P.; Collins, J.T., Jr. Vascular Trauma Secondary to Diagnostic and Therapeutic Procedures: Cardiopulmonary Bypass and Intraaortic Balloon Assist. Am. J. Surg. 1980, 140, 302. Ingram, W.L.; Feliciano, D.V.; Renz, B.M.; Ansley, J.D.; Cushman, J.G.; Rozycki, G.S. Blood Pressure in the Emergency Department in Patients with Abdominal Vascular Injuries: Effect on Management and Prognostic Valve, Presented at the 55th Annual Meeting, American association for the Surgery of Trauma, Halifax, Nova Scotia, Canada, September 27 –30, 1995. Rozycki, G.S.; Ballard, R.B.; Feliciano, D.V.; Schmidt, J.A.; Pennington, S.D. Surgeon-Performed Ultrasound for the Assessment of Truncal Injuries: Lessons Learned from 1540 Patients. Ann. Surg. 1998, 228, 557. Rozycki, G.S.; Ochsner, M.G.; Feliciano, D.V.; Thomas, B.; Boulanger, B.R.; Davis, F.E.; Falcone, R.E.; Schmidt, J.A. Early Detection of Hemoperitoneum by Ultrasound Examination of the Right Upper Quadrant: A Multicenter Study. J. Trauma 1998, 45, 878. Mattox, K.L.; Bickell, W.; Pepe, P.A.; Burch, J.M.; Feliciano, D.V. Prospective MAST Study in 911 Patients. J. Trauma 1989, 29, 1104.
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Feliciano, D.V.; Burch, J.M.; Mattox, K.L.; Bitondo, C.G.; Fields, G. Balloon Catheter Tamponade in Cardiovascular Wounds. Am. J. Surg. 1990, 160, 583. Fry, W.R.; Fry, R.E.; Fry, W.J. Operative Exposure of the Abdominal Arteries for Trauma. Arch. Surg. 1991, 126, 289. Conn, J., Jr.; Trippel, O. II; Bergen, J.J. A New Atraumatic Aortic Occluder. Surgery 1968, 64, 1158. Veith, F.J.; Gupta, S.; Daly, V. Technique for Occluding the Supraceliac Aorta Through the Abdomen. Surg. Gynecol. Obstet. 1980, 151, 426. Feliciano, D.V.; Burch, J.M.; Graham, J.M. Abdominal Vascular Injury. In Trauma; Mattox, K.L., Feliciano, D.V., Moore, E.E., Eds.; McGraw-Hill: New York, 2000; 783–805. Lim, R.C., Jr.; Trunkey, D.D.; Blaisdell, F.W. Acute Abdominal Aortic Injury: An Analysis of Operative and Postoperative Management. Arch. Surg. 1974, 109, 706. Accola, K.D.; Feliciano, D.V.; Mattox, K.L.; Bitondo, C.G.; Burch, J.M.; Beall, A.C., Jr.; Jordan, G.L., Jr. Management of Injuries to the Suprarenal Aorta. Am. J. Surg. 1987, 154, 613. Accola, K.D.; Feliciano, D.V.; Mattox, K.L.; Burch, J.M.; Beall, A.C., Jr.; Jordan, G.L., Jr. Management of Injuries to the Superior Mesenteric Artery. J. Trauma 1986, 26, 313. Feliciano, D.V. Approach to Major Abdominal Vascular Injury. J. Vasc. Surg. 1988, 7, 730. Stone, H.H.; Fabian, T.C.; Turkelson, M.L. Wounds of the Portal Venous System. World J. Surg. 1982, 6, 335. Salam, A.A.; Stewart, M.T. New Approach to Wounds of the Aortic Bifurcation and Inferior Vena Cava. Surgery 1985, 98, 105. Burch, J.M.; Feliciano, D.V.; Mattox, K.L.; Edelman, M. Injuries of the Inferior Vena Cava. Am. J. Surg. 1988, 156, 548. Brown, M.F.; Graham, J.M.; Mattox, K.L.; Feliciano, D.V.; DeBakey, M.E. Renovascular Trauma. Am. J. Surg. 1980, 140, 802. Barlow, B.; Gandhi, R. Renal Artery Thrombosis Following Blunt Trauma. J. Trauma 1980, 20, 614. Haas, C.A.; Dinchman, K.H.; Nasrallah, P.F.; Spirnak, P. Traumatic Renal Artery Occlusion: A 15-Year Review. J. Trauma 1998, 45, 557. Rastad, J.; Almgren, B.; Bowald, S.; Eriksson, I.; Lundquist, B. Renal Complications to Left Renal Vein Ligation in Abdominal Aortic Surgery. J. Cardiovasc. Surg. 1984, 25, 432.
142. Wiencek, R.G.; Wilson, R.F. Abdominal Venous Injuries. J. Trauma 1986, 26, 771. 143. Smejkal, R.; Izant, T.; Born, C.; DeLong, W.; Schwab, W.; Ross, S.E. Pelvic Crush Injuries with Occlusion of the Iliac Artery. J. Trauma 1988, 28, 1479. 144. Landreneau, R.J.; Mitchum, P.; Fry, W.J. Iliac Arterial Transposition. Arch. Surg. 1989, 124, 978. 145. Cushman, J.G.; Feliciano, D.V.; Renz, B.M.; Ingram, W.L.; Ansley, J.D.; Clark, W.S.; Rozycki, G.S. Iliac Vessel Injury: Operative Physiology Related to Outcome. J. Trauma 1997, 42, 1033. 146. Burch, J.M.; Richardson, R.J.; Martin, R.R.; Mattox, K.L. Penetrating Iliac Vascular Injuries: Recent Experience with 233 Consecutive Patients. J. Trauma 1990, 30, 1450. 147. Vitelli, C.E.; Scalea, T.M.; Philips, T.F.; Sclafani, S.J.; Duncan, A.O. A Technique for Controlling Injuries of the Iliac Vein in the Patient with Trauma. Surg. Gynecol. Obstet. 1988, 166, 551. 148. Pachter, H.L.; Drager, S.; Godfrey, N.; LeFleur, R. Traumatic Injuries of the Portal Vein. The Role of Acute Ligation. Ann. Surg. 1979, 189, 383. 149. Graham, J.M.; Mattox, K.L.; Beall, A.C., Jr. Portal Venous System Injuries. J. Trauma 1978, 18, 419. 150. Ivatury, R.R.; Nallathambi, M.; Lankin, D.H.; Wapnir, I.; Rohman, M.; Stahl, W.M. Portal Vein Injuries. Noninvasive Follow-Up of Venorrhaphy. Ann. Surg. 1987, 206, 733. 151. Beal, S.L. Fatal Hepatic Hemorrhage: An Unresolved Problem in the Management of Complex Liver Injuries. J. Trauma 1990, 30, 163. 152. Buechter, K.J.; Sereda, D.; Gomez, G.; Zeppa, R. Retrohepatic Vein Injuries: Experience with 20 Cases. J. Trauma 1989, 29, 1698. 153. Pachter, H.L.; Spencer, F.C.; Hofstetter, S.R.; Liang, H.C.; Coppa, G.F. The Management of Juxtahepatic Venous Injuries Without an Atriocaval Shunt: Preliminary Clinical Observations. Surgery 1986, 99, 569. 154. Rovito, P.F. Atrial Caval Shunting in Blunt Hepatic Vascular Injury. Ann. Surg. 1987, 205, 318. 155. Burch, J.M.; Feliciano, D.V.; Mattox, K.L. The Atriocaval Shunt: Facts and Fiction. Ann. Surg. 1988, 207, 555. 156. Feliciano, D.V.; Moore, E.E.; Mattox, K.L. Trauma Damage Control. In Trauma; Mattox, K.L., Feliciano, D.V., Moore, E.E., Eds.; McGraw-Hill: New York, 2000; 907– 931. 157. Morris, J.A., Jr.; Eddy, V.A.; Rutherford, E.J. The Trauma Celiotomy: The Evolving Concepts of Damage Control. Curr. Prob. Surg. 1996, 33, 611.
CHAPTER 75
Vascular Injuries in the Neck and Thoracic Outlet Malcolm O. Perry
Trauma is the fourth leading cause of death in the United States: over 50 million injuries occur each year, and more than 100,000 people die as a result of these injuries. Although these patients frequently have multiple injuries, wounds of major vessels are the sole cause or a major contributing cause of many of the deaths.[1] In most situations there is little difficulty in ascertaining that the patient has a serious injury. Many of these people have multiple wounds, and a careful assessment of all injuries is required in order to establish priorities of care. This is particularly true of penetrating wounds of the brachiocephalic vessels, because not only is hemorrhage a threat, but interruption of blood flow to the brain may also produce serious neurological problems.
cavitation produced by a missile traveling at 150023000 ft/s is capable of damaging vessels remote from the wound tract. When such a blast cavity collapses, a suction effect is generated, which can draw surface structures such as bits of skin, clothing, or dirt along the wound tract. A high-velocity bullet or metal fragment can produce a great deal of tissue damage, especially if it strikes bone and all of the bullet’s energy is dissipated in the target. Moreover, splinters of bone may become secondary missiles and injure other structures. Such widespread damage may not be suspected on initial inspection because there may be only small entrance and exit wounds.
BRACHIOCEPHALIC VASCULAR INJURIES
ETIOLOGY
Most wounds of the cervical vessels and the thoracic outlet are caused by penetrating trauma,[2 – 5] and the common carotid artery is usually involved, the left more than the right (Table 75-1). Special problems are encountered in these patients when there is a vascular injury and a neurological deficit; there may also be wounds of the pharynx, esophagus, trachea, and major nerves. The neurological deficit associated with some of these injuries presents a unique and often perplexing problem. Unless technical problems occur during resuscitation and repair, the outcome in most patients will depend on the extent of the initial preoperative neurological deficit. Injuries of vessels in the thoracic outlet, at the base of the neck, present major problems regarding surgical exposure, because it may be necessary to open the chest in order to obtain proximal control of the great vessels arising from the arch of the aorta. The decision to open the chest early can be an important part of management. There are a number of vital structures in this area, and the danger of combined injuries of large arteries and veins is apparent. Wounds to vessels in these two areas are considered separately because of the technical requirements.
Major vascular wounds can occur in any environment, but the greatest incidence is seen in urban areas where violence is endemic. Penetrating trauma caused by knives and bullet wounds is more common than blunt trauma, although in some cases vascular wounds resulting from blunt trauma can be more difficult to diagnose and treat. Certain varieties of blunt trauma are particularly likely to result in vascular injury: steering wheel injuries, deceleration forces, falls, and crushing blows to the chest and root of the neck can be followed by serious vascular wounds.
MECHANISMS OF INJURY Most penetrating injuries are caused by stabbing or bullets traveling at a low velocity, and the damage is mainly confined to the wound tract. Knife wounds usually cause punctures, lacerations, and occasionally transactions, while bullets are more likely to sever the artery. The blast effect of highvelocity missiles may cause widespread damage because the
Hobson/Wilson/Veith: Vascular Surgery: Principles and Practice, Third Edition, Revised and Expanded DOI: 10.1081/0819-9-120024959 Copyright q 2004 by Marcel Dekker, Inc.
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Table 75-1. Brachiocephalic Vascular Injuries Artery Innominate Subclavian Axillary Aorta Common carotid Internal carotid External carotid Vertebral Total Vein Internal jugular Subclavian Innominate Total
8 38 43 11 56 19 19 7 201 53 50 17 120
CAROTID INJURIES It is helpful to divide patients with injuries to the carotid arteries into three groups for evaluation: group I, the first and largest group, contains those patients who have injuries of the common and internal carotid artery (ICA) but who have no neurological deficit.[6] Group II patients have a mild neurological deficit, and group III patients have a severe neurological deficit, which includes coma and hemiplegia. A significant number of these patients have other injuries, such as closed head trauma, which can especially distort the diagnostic picture. Such combined problems are particularly confusing when the indications for surgery are being considered—a precise neurological evaluation is mandatory before an operation is begun. The results of most studies strongly support surgical repair of all penetrating carotid artery injuries in patients who have either no neurological deficit or only a mild one; thus, all the patients in groups I and II would undergo repair of isolated carotid artery wounds.[6 – 9] This decision is easy to reach when the artery is bleeding briskly, but it may be more difficult to decide what to do when there is complete carotid artery occlusion without neurological symptoms or occlusion plus a profound stroke. In such a situation, technical problems encountered during surgery could conceivably produce additional brain damage, although in the reported experience this has been rare.[10 – 12] Failure to visualize an artery with arteriograms does not always mean that the vessel is occluded. A very slow flow of blood through a small channel may not be visualized even with good arteriographic techniques, but rapid-sequence computerized tomographic scanning or nuclear magnetic resonance studies can often clarify such situations. These studies will be especially important in patients who have sustained blunt trauma and in whom there may be hyperextension injuries of the distal ICA. In this situation, the ICA is forcibly stretched over the transverse process of C3 and the body of C2, a mechanism of injury that causes multiple transmural tears that predispose to thromboembolic events (Fig. 75-1). Until a neurological
Figure 75-1. Hyperextension injury of the internal carotid artery predisposes to thrombosis. The arrow marks the presence of a large mural clot in the distal internal carotid artery in a patient who had sustained blunt trauma. Resection and vein graft replacement were required.
problem appears in these patients, there may be little evidence of carotid artery injury. If such a lesion is untreated, it is likely to progress to complete occlusion, sometimes with extension of the clot into the cerebral arteries, producing a massive stroke.[13] Thromboembolism may supervene; middle cerebral artery emboli have been observed in such patients.
Evaluation and Preoperative Preparation The basic management of penetrating trauma to the neck is straightforward: wounds that pierce the platysma muscle and enter the anterior triangles of the neck are often best treated by surgical exploration.[14] It may be useful to divide penetrating wounds of the neck into three zones as suggested by Monson et al.[15] Although the exact levels vary according to the authorities who have suggested them, the modification proposed by Snyder is simple.[16] Zone III extends from the base of the skull to the angle of the mandible, zone II from the angle of the mandible to 1 cm above the head of the clavicle, and zone I from 1 cm above the head of the clavicle inferiorly to include the thoracic outlet. By clinical examination, it may
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be difficult to determine if injuries in zones I and III have damaged major vascular structures such as the carotid artery. In these situations, if the patients are hemodynamically stable, preoperative biplane arteriography is extremely useful. In selected patients with penetrating injuries in zone II who have no neurological deficit, operation may be performed without arteriography, although preoperative arteriography is helpful in the management of these patients as well. If there is a neurological deficit, a careful arteriographic study that includes biplane intracranial films is required. Some of these patients may have cerebral thromboembolism that will not respond to repair of cervical arterial wounds.
Diagnosis Those signs and symptoms that suggest arterial injury of vessels in the extremities apply equally to the neck, but unfortunately the cervical arteries are not directly accessible for examination of pulses, especially in patients with blunt trauma. Jernigan and Gardner[17] have described features suggesting that the patient has sustained blunt trauma to the carotid artery (Table 75-2). There may be very few signs of injury in these people, because less than half of the patients will have superficial evidence of blunt trauma (Fig. 75-2). Unless these patients present with neurological symptoms, blunt trauma to the carotid artery may not be apparent for several hours or much longer in some cases. Preoperative arteriograms are needed in these situations to expose such injuries, and arteriography should be used liberally in patients who have blunt or penetrating trauma to the neck and thoracic outlet.[18] Most major arterial wounds caused by penetrating trauma can be detected by examination, but adjunctive diagnostic studies such as ultrasound and arteriography can be helpful. Arteriograms in trauma patients are usually obtained for one of three reasons: to detect injuries not exposed by other means, to exclude the need for operation when no other indications exist, and to plan the operation, especially when special techniques are needed.
Operative Management Patients who have carotid artery injuries and continued prograde blood flow are candidates for surgical repair.[6] A patient who has complete occlusion of the ICA as a result of blunt trauma, who is not bleeding, and who has a severe neurological deficit accompanied by coma and hemiplegia may be best treated by nonoperative techniques or by ligation of the ICA if operation is required for other reasons. The Table 75-2. Clinical Features of Blunt Trauma Carotid Artery Injuries Hematoma of neck Horner’s syndrome Transient attack of ischemia Lucid interval Limb paresis in an alert patient Source: Modified from Jernigan WR, Gardner WC.[17]
Figure 75-2. A blow to the neck caused intimal fracture and transmural damage, which produced a small fusiform aneurysm (arrow ). Graft replacement of this section of the artery was necessary.
complete removal of thrombus in these situations is often difficult, and leaving behind residual clots may predispose to embolization, which extends the neurological damage. With isolated carotid wounds, extensive monitoring is not usually required, but a radial arterial line is helpful for measurements for arterial blood pressure and blood-gas tensions. General anesthesia, hypercapnia, and some neurological wounds interfere with cerebral autoregulation, and cerebral blood flow will then respond directly to changes in systemic arterial pressure. The maintenance of normal blood pressure is an important concept in the correct management of these situations. As in almost all cases of cervical trauma, the induction of anesthesia must be accomplished gently to prevent the dislodgment of tamponading clots, which might cause recurrence of bleeding or embolize into the intracranial circulation.[16] A variety of anesthetic agents are effective and safe; the final choice rests with the anesthesiologist. But drugs that are likely to cause hypotension are not desirable and should be avoided. Endotracheal intubation is required in these patients, and preoperative knowledge of laryngeal nerve function is essential; if this information is not known before the patient reaches the operating room, the vocal cords can be directly inspected during tracheal intubation. If the wound has not been accurately identified by preoperative arteriography, wide surgical exposure will be needed for exploration. The neurovascular structures are
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reached through the customary carotid incision made along the anterior border of the sternomastoid muscle, approaching the artery slightly from the anterolateral aspect to initially obtain control of the common carotid artery proximal to the area of suspected injury. Once the arterial wound is exposed, gentle digital pressure will usually control bleeding without clamping the vessel, thus minimizing the time of carotid artery occlusion. Injuries of the external carotid artery are usually clamped and repaired or ligated as indicated, and unless there is evidence that the external carotid artery is functioning as a major cerebral collateral, it often is sacrificed. It is usually neither grafted nor shunted during repair. Once the bleeding is controlled, the ICA backflow is assessed. Brisk, pulsatile backflow is usually evidence of adequate cerebral perfusion, but measurements of carotid artery stump pressures may be helpful. It has been suggested that back pressures greater than 70 mmHg indicate adequate cerebral perfusion; thus, such patients do not require additional support of cerebral circulation during the period of carotid artery occlusion necessary for repair.[1,12,16]Moreover, if the pressures are above 70 mmHg, the distal carotid cannot be cleared of clots, and ligation is necessary, these pressures should be adequate to prevent major stroke unless thromboembolism supervenes (Fig. 75-3). If the pressures are low or the backflow from the ICA is scanty and shunts are selected, a variety of techniques may be used, but the simple inlying straight-tube shunt is readily available. Unless the patient has multiple injuries or has injuries of the eye or central nervous system or has multiple fractures, most surgeons use systemic heparin when shunts are in place. However, it would seem more important to heparinize the patients if the distal carotid artery were filled with a stagnant pool of blood. Most studies of shunting and intraoperative heparinization during the repair of carotid artery injuries have failed to delineate clearly the need for and results of these maneuvers.[6 – 8] In the repair of arterial injuries, standard vascular techniques are used, but because of the importance of securing a smooth intimal surface in the carotid artery, resection and anastomosis are favored (Fig. 75-4). This is especially important with blunt trauma, because the wall damage is likely to be extensive. After resection, a repair without tension is required or an interposition graft is needed. Customarily, the saphenous vein is chosen to restore continuity in the carotid artery. If the defect in the proximal ICA is small, the distal external carotid can be ligated and this vessel substituted for the origin of the ICA, as illustrated in Fig. 75-5. If, because of low pressures or scanty backflow, a shunt is selected and a graft is also needed, the graft can be placed over the shunt prior to insertion; the shunt is then removed just before the anastomosis is completed, as shown in Fig. 75-6. Penetrating injuries of the ICA at the base of the skull are very difficult to expose, but division of the digastric muscle, resection of the styloid process, and, on occasion, temporary anterior subluxation of the mandible usually will permit visualization of the carotid as it enters the skull (Fig. 75-7). Lacerations at the carotid foramen that are too high to allow the placement of a vascular clamp distally can be controlled by inserting a balloon-tipped catheter through a separate incision in the artery, then advancing the catheter beyond the laceration and gently inflating the balloon to control
Figure 75-3. Lacerations of medium-sized or large vessels can be repaired by simple continuous suture techniques.
backbleeding.[1] Soft Fogarty catheters with attached threeway stopcocks can be used, or special balloon occlusion catheters can be designed for the carotid artery (these catheters are already in use no need to design new ones).
VERTEBRAL ARTERY INJURIES Wounds of the vertebral arteries are rare; these vessels, which enter the bony canal at the C6 level and exit at C2, are apparently protected from many injuries. In the past, without preoperative arteriograms vertebral artery damage was probably undetected unless discovered because of bleeding during exploration. Treatment consisted of proximal ligation, packing, and, on rare occasions, direct exposure and suture ligation.[11,12,15] Since preoperative arteriography is now employed more frequently to assess the damage accurately and to evaluate the collateral circulation, more vertebral artery wounds will probably be discovered.[12] Direct repair, even in the bony canal, is possible with modern vascular techniques. A penetrating injury to a dominant or single vertebral artery should be considered for repair. Continued bleeding or the late development of a false aneurysm or arteriovenous fistula are serious complications of such wounds. Traumatic occlusion of a small vertebral artery in a patient with normal connections into the circle of Willis is not likely
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Figure 75-4. Extensive wall damage to the artery is best repaired by resection and end-to-end anastomosis. Continuous sutures are commonly used, although in small arteries and in children interrupted suture techniques are preferred.
to cause serious problems and usually can be left alone. In such circumstances, treatment at operation customarily would be ligation only; therefore, the patient can be spared a rather difficult surgical exposure. With multiple injuries (carotid and vertebral), carotid repair is more important; if the patient has the more common cerebral vascular architecture, this should suffice.[1,16] In some patients the vertebral artery may be occluded by a percutaneously placed balloon to control bleeding.
Revascularization, with repair of all the damaged artery and complete removal of all clots, is seldom possible in patients who have total ICA occlusion as a result of blunt trauma.[10] If repair is attempted but incomplete, progressive neurological deterioration and death may occur. Restoration of flow to the carotid without clearing the distal artery is dangerous.[12]
Postoperative Care
Wounds of major veins frequently cause more troublesome bleeding than some arterial injuries.[2] The veins’ thin
Although any vascular repair is susceptible to bleeding, it is unusual in patients with arterial wounds unless there are multiple injuries or coagulation defects. Drains are not commonly employed in treating isolated wounds of the carotid arteries, but in selected patients with multiple cervical injuries, drains may be used for 12 h or so to prevent an accumulation of blood, which, if under tension, might cause compression of the artery. Postoperatively the patients must be carefully monitored for the appearance of neurological symptoms; any change is an indication for repeat arteriography to evaluate the status of repair and to assess the possibility of cerebral thromboembolism. Postoperative carotid artery occlusion rarely occurs. If it does, however, the patient should be returned immediately to the operating room for thrombectomy, correction of any technical errors, and immediate reestablishment of cerebral blood flow. In such situations it is best not to delay for arteriography because thrombosis and the possibility of stroke require immediate surgery. An expeditious restoration of flow is usually successful in preventing permanent neurological problems.[1] It appears that carotid ligation may be needed in only a small group: patients with complete ICA occlusion and severe neurological deficits including coma and hemiplegia.[6,7,11]
VENOUS INJURIES IN THE NECK
Figure 75-5. It may be possible to substitute the external carotid artery for the internal carotid in some situations. (From Perry MO.[1] Reproduced by permission.)
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bleeding, while more precise control is obtained with vascular clamps. Since there are few guidelines to assist in preoperative diagnosis, the extent of injury becomes evident only at surgery.[14] Ligation is almost always the treatment of choice for these wounds. In a few situations (bilateral internal jugular, innominate, and proximal subclavian vein injuries), suture repair may be chosen. Lateral or tangential sutures are effective in controlling the low-pressure bleeding and, if placed with care, will not seriously narrow the large vein if only a clean puncture or laceration is present. More extensive damage usually requires suture ligation because there are often associated injuries that take priority, and delays for complicated vein repairs are contraindicated.
INJURIES OF THE VESSELS OF ROOT OF THE NECK
Figure 75-6. When temporary inlying carotid shunts are needed in conjunction with vein grafting, this method is useful. The shunt also acts as a stent during the repair. (From Perry MO.[1] Reproduced by permission.)
walls, numerous fragile tributaries, and susceptibility to operative damage continue to present technical problems in isolation and control. Direct finger pressure, suction, and packing are usually effective methods to reduce the
The diagnosis of vascular injuries is obvious in the presence of specific findings such as profuse bleeding, large hematomas, weak or absent distal pulses, and continued intrathoracic hemorrhage, but up to one third of these patients have no specific diagnostic signs (Fig. 75-8). Those findings that suggest injuries to the great vessels, as listed in Table 75-3, may be of help in establishing the diagnosis. Most of the patients with penetrating wounds at the base of the neck and concomitant major arterial injuries have large hematomas or a wide mediastinum, but in some cases the signs may be more subtle. Persistent bleeding in the chest may be the only sign of injury to one of the great vessels. If the injured patient is stable, arteriography is helpful in precisely defining the extent and location of the wounds, but obtaining good biplane pictures of the arch and the great vessels is difficult because of overlapping images. Arteriography of these areas is not as reliable in excluding arterial penetration as it is in the extremities. Nevertheless, arteriograms are strongly recommended in patients who have injuries in zones I and III, not only to aid in diagnosis but also to plan the operation.
Figure 75-7. Improved exposure of the distal cervical internal carotid artery can be gained by anterior subluxation of the mandible. Dental wires can be used to hold the mandible in place if the teeth are normal, sparing the patient more extensive methods.
Chapter 75. Vascular Injuries in the Neck and Thoracic Outlet
Figure 75-8. The large arrow points to the false aneurysm of the right subclavian artery. The aneurysm is partially filled with laminated clot. The vertebral artery (small arrow ) arises from the posterior wall of the artery. Vein graft repair of the subclavian artery was performed.
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common carotid artery injury. With the exception of the left subclavian artery, all of the vessels from the aortic arch can be reached easily through this middle sternal incision, but, if necessary, the sternal splitting incision can be extended into the second or third interspace or a separate left thoracotomy incision may be opened to control the left subclavian artery at its origin. Direct control of bleeding usually can be accomplished by the common techniques of digital pressure until a vascular clamp can be put in place proximal to the injury. In some cases, in fact, small lacerations of large vessels can be controlled with direct finger pressure and then repaired by simply passing the vascular sutures beneath the occluding finger. In other situations where the wounds are not easily controlled, a balloon-tipped catheter may be inserted directly through the wound, inflated, and gently retracted to control bleeding temporarily while proximal vascular clamps are put in place. Once control is obtained, standard vascular techniques of repair are used. Lateral repair occasionally can be successful in large vessels, but if the wound cannot be closed without narrowing the artery, patch-graft angioplasty with autogenous tissue is indicated. More extensive wounds of the great vessels require resection and anastomosis; in many instances, an interposition plastic graft will be needed since suitably sized autografts are rarely available (Fig. 75-9). Unless there is heavy direct bacterial contamination, such plastic grafts are
Operative Management Injuries to major vessels in zone I may be particularly difficult to evaluate because the wound is not readily accessible for examination, yet direct exposure of a major vascular injury without obtaining proximal control can lead to fatal hemorrhage.[2,3,5] If the penetrating wound in zone I is thought to have injured the great vessels, proximal control via a middle sternal splitting incision is recommended before exposing the artery. Some authorities even suggest making a sternal splitting incision for all penetrating wounds that enter below the cricoid cartilage at the base of the neck or below C6; others suggest a more moderate approach. Most surgeons support the view that if a major vascular wound of the great vessels is strongly suspected, early thoracotomy is needed.[5] Similarly, if, during the course of cervical exploration of the carotid vessels, bleeding, hematoma, or blood staining of carotid sheath at the root of the neck is encountered, an immediate sternal splitting incision should be made to obtain control, because this may be the only sign of a proximal
Clinical Features of Injuries of Great Vessels in the Chest
Table 75-3.
Cardiac arrest Persistent or recurring hypotension Cardiac tamponade Wide mediastinum Recurrent hemothorax
Figure 75-9. Blunt chest trauma causing lung contusion and near-avulsion of the innominate artery (arrow ). Through a middle sternal splitting incision, a 10 mm knitted Dacron graft was sewed end to side to the ascending aorta and end to end to the undamaged distal innominate artery. The innominate origin was oversewn.
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Table 75-4. Mortality Rate for Penetrating Injuries of the Carotid Artery Neurological status on admission Group I Group II Group III
No deficit Mild deficit Severe deficit
Number
Deaths
49 8 15
0 1 5
satisfactory substitutes; but if there is heavy contamination and direct repair is deemed risky, a temporary remote bypass (axillary-axillary, subclavian-carotid, carotid-carotid) can be constructed to restore blood flow. Temporary shunt procedures to maintain cerebral perfusion while innominate and common carotid arteries are being repaired have been used infrequently, and although several reports allude to these maneuvers, none describe the indications or document the basis for their use.[2 – 5] As with the carotid artery, it appears that if there is a back pressure of 70 mmHg or greater in the common carotid or the innominate artery, temporary shunting procedures will not be required during the short time necessary to perform a direct repair. Similarly, heparinization has not been used with great frequency in these situations because of the presence of multiple wounds in many patients. The local instillation of heparin solutions (100 U.S.P. units of heparin per 10 mL of saline) has been found to be satisfactory in retarding local thrombosis during temporary occlusion while repairs are completed. Postoperatively, few surgeons use systemic anticoagulation in these patients. New applications of endovascular techniques may simplify the management of extensive vascular injuries. Stent-grafts may be helpful in treating large false aneurysms and arteriovenous fistulas, especially in the root of the neck and the mediastinum and other areas where exposure is difficult.[19]
Table 75-5. Mortality Rate for Blunt Trauma Carotid Artery
Injuries
All cases All carotid operations Immediate successful operations
Number
Deaths
Percent deaths
17 14 7
4 2 0
23 14 0
Results Accurate diagnosis obtained with arteriography and computed tomographic scanning combined with an aggressive surgical approach to these patients has produced quite satisfactory results. As shown in Table 75-4, penetrating carotid artery injuries often can be successfully managed if they are identified and repaired prior to the appearance of a neurological deficit. Blunt trauma to the cervical carotid vessels continues to present more difficult but not insoluble problems, as seen in Table 75-5, which lists the results obtained in the author’s series. In this small group of patients, early surgical repair appears to have been effective and relatively safe. Although some patients die because of hemorrhage, most of the problems that arise in patients who have been successfully resuscitated are due to neurological damage that occurred prior to treatment. Injuries of major vessels at the root of the neck continue to be formidable problems; the major threat remains exsanguinations either before or during operation. In stable patients, preoperative arteriography should reduce these risks, and innovative techniques such as nuclear magnetic resonance imaging may further improve diagnostic accuracy. Such methods, followed by an aggressive surgical approach with wide exposure to ensure control of hemorrhage, should result in continued improvement in care.
REFERENCES 1. Perry, M.O. The Management of Acute Vascular Injuries; Williams & Wilkins: Baltimore, 1981. 2. Flint, L.M.; Snyder, W.H.; Perry, M.O.; Shires, T. Management of Major Vascular Injuries in the Base of the Neck. Arch. Surg. 1973, 106, 407. 3. Hewitt, R.L.; Smith, A.D.; Becker, M.L.; et al. Penetrating Vascular Injuries of the Thoracic Outlet. Surgery 1974, 76, 715. 4. Lim, L.T.; Salctta, J.D.; Flanigan, D.P. Subclavia and Innominate Artery Trauma. Surgery 1979, 86, 890. 5. Reul, G.J.; Beall, A.C.; Jordan, G.L.; Mattox, K.L. The Early Operative Management of Injuries to the Great Vessels. Surgery 1973, 74, 862. 6. Thal, E.R.; Snyder, W.H.; Hays, R.J.; Perry, M.O. Management of Carotid Artery Injuries. Surgery 1974, 76, 955.
7. Liekweg, W.G.; Greenfield, L.J. Management of Penetrating Carotid Arterial Injury. Ann. Surg. 1978, 188, 587. 8. Bradley, E.L. Management of Penetrating Carotid Injuries: An Alternative Approach. J. Trauma 1973, 13, 248. 9. Teehan, E.P.; Padberg, F.T.; Thompson, P.N.; Lee, B.C.; Silva, M.; Jamil, Z.; Swan, K.C.; Hobson, R.W. Carotid Arterial Trauma: Assessment with the Glasgow Coma Scale (GCS) as a Guide to Surgical Management. Cardiovasc. Surg. 1997, 5, 196. 10. Yamada, S.; Kindt, G.W.; Youmans, J.R. Carotid Artery Occlusion Due to Nonpenetrating Injury. J. Trauma 1967, 7, 333. 11. Perry, M.O.; Snyder, W.H.; Thal, E.R. Carotid Artery Injuries Caused by Blunt Trauma. Ann. Surg. 1980, 1, 74. 12. Fry, R.E.; Fry, W.J. Extracranial Carotid Artery Injuries. Surgery 1980, 88, 581.
Chapter 75. Vascular Injuries in the Neck and Thoracic Outlet 13.
Mokri, B.; Piepgras, D.G.; Houser, O.W. Traumatic Dissections of the Extracranial Internal Carotid Artery. J. Neurosurg. 1988, 68, 189. 14. Roon, A.J.; Christensen, N. Evaluation and Treatment of Penetrating Carotid Injuries. J. Trauma 1979, 19, 391. 15. Monson, D.O.; Saletta, J.D.; Freeark, R.J. Carotid Vertebral Trauma. J. Trauma 1969, 9, 987. 16. Thal, E.R.; Snyder, W.H.; Perry, M.O. Vascular Injuries of the Extremities. In Rutherford RR (ed): Vascular Surgery. Saunders: Philadelphia, 1995; 713 –737.
17.
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Jernigan, W.R.; Gardner, W.C. Carotid Artery Injuries Due to Closed Cervical Trauma. J. Trauma 1971, 11, 429. 18. Perry, M.O. Injuries of the Brachiocephalic Vessels. In Vascular Surgery; Rutherford, R.R., Ed.; Saunders: Philadelphia, 1995; 705 – 713. 19. Marin, M.L.; Veith, F.J.; Panetta, T.F.; Cynamon, J.; Sanchez, L.A.; Schwartz, M.L.; Lyon, R.T.; Bakakow; Suggs, W.D. Transluminally Placed Endovascular Stented Graft Repair for Arterial Trauma. J. Vasc. Surg. 1994, 20, 466.
CHAPTER 76
Vascular Injuries of the Extremities Robert W. Hobson II Norman M. Rich 8-h period increase the risk of compartment syndromes, infection, and ultimate limb loss. Other complications associated with delayed treatment include local thrombosis, infection, and delayed recognition of arteriovenous fistulas and false aneurysms, which if present also mandate prompt surgical repair.
Successful management of extremity vascular trauma constitutes a major surgical challenge. Important lessons have been learned from military experience with regard to penetrating vascular injuries. Violence-prone civilian and urban population centers continue to be sources of penetrating gunshot wounds as well as injuries caused by sharp-edged instruments. Injuries due to blunt trauma also contribute substantially to the clinical experience; the association of major fractures or joint dislocations may complicate management of these vascular injuries. Finally, in some institutions, much vascular trauma is hospital-incurred or iatrogenic, being related to diagnostic or therapeutic interventional radiological procedures. The key aspects of the successful management of vascular trauma include control of hemorrhage, prompt diagnosis and initiation of resuscitative efforts, reduction of any unnecessary delays between injury and definitive care, and appropriate care of associated venous injuries, fractures, and neurological trauma. Delays in definitive vascular reconstruction beyond 6 – 8 h will reduce chances for ultimate rehabilitation of the patient’s injury and contribute to increased amputation rates. Prioritizing the care of the trauma victim is obviously a major consideration. In the victim of multiple trauma, control of the airway and care of thoracic injuries generally take first priority. If an intraabdominal injury is also suspected, peritoneal lavage and computed tomography (CT) will be of diagnostic value and exploratory laparotomy following thoracotomy may become appropriate. When an extremity vascular injury is also suspected, preoperative arteriographic assessment will be valuable in visualizing thoracic outlet and iliofemoral injuries; however, for injuries peripheral to the superficial femoral and axillobrachial arteries, operative arteriography may be not only more expeditious but also more valuable diagnostically. Depending on the patient’s status, the simultaneous exploration of suspected extremity vascular injuries at the time of exploratory laparotomy may be feasible and may minimize delays in definitive care. Immediate vascular reconstruction is recommended, as complications incurred as a result of delays beyond the 6- to
INCIDENCE AND PATHOPHYSIOLOGY Injuries to major arteries and veins were managed surgically and documented in isolated case reports or small clinical series during the late 1800s and early 1900s. The standardization of anastomotic techniques as described by Carrel, Guthrie, Murphy, Frouin, and others[1] represented a remarkable achievement, which, however, was not applied clinically in any large number of cases until the post –World War II era. Experience with vascular trauma was documented by DeBakey and Simeone[2] during World War II. These authors reported on the management of 2471 arterial injuries, only 3.3% of which were treated by vascular repair. Lateral arteriography was the principal means of repair, while only 3 of 81 cases were managed by end-to-end anastomosis. It was not until the Korean War that clinical experience suggested the feasibility of vascular reconstruction in the battlefield environment.[3 – 5] Of major importance was the efficiency of the medical evacuation system, which resulted in arrival of injured patients at definitive treatment centers well within the preferred 6- to 8-h time limit associated with improved success after vascular reconstruction. The availability of typespecific blood replacement and antibiotics as well as a better understanding of the resuscitation of the injured patient were important factors resulting in successful management and were applied to the civilian experience thereafter. The acceptance of vascular reconstruction for trauma during the Vietnam War and the careful clinical follow-up afforded by the Vietnam Vascular Registry confirmed the impression that these injuries were best treated by prompt surgical management.
Hobson/Wilson/Veith: Vascular Surgery: Principles and Practice, Third Edition, Revised and Expanded DOI: 10.1081/0819-9-120024960 Copyright q 2004 by Marcel Dekker, Inc.
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The importance of extremity vascular trauma relates to its high incidence in all reported series. Upper- and lowerextremity injuries accounted for 91% of the first 1000 traumatic vascular injuries reported by Rich and colleagues.[6] Major civilian series, reported by Perry and associates[7] and Drapanas et al.,[8] documented involvement of extremity vasculature in 87 and 84%, respectively. Principles of management will be comparable, although the pathophysiology of injury may differ. While blunt trauma accounted for only 1% of injuries in Vietnam, 10% of injuries were caused by blunt trauma in clinical series reported from Dallas[7] and New Orleans.[8] As a generalization, vascular injuries caused by penetrating trauma are usually more obvious in their presentation because of associated pulsatile bleeding, expanding hematomas, and peripheral pulse deficits. Diagnostic uncertainty can occur when the missile or sharp-edged instrument has passed in close proximity to a major artery or vein in the extremity or in cases of blunt trauma associated with closed fractures or joint dislocations.
DIAGNOSTIC CONSIDERATIONS Pulsatile bleeding, absence of peripheral pulses, and expanding hematomas are associated with arterial injury in a high percentage of cases. Of less significance in terms of accurate correlation with vascular injury are small or wellcontained hematomas, bruits, diminished but palpable pulses, or proximity injuries suggestive of vascular trauma but without the obvious confirmatory signs. However, experienced clinicians have recognized that the presence of peripheral pulses does not rule out major arterial injuries. Saletta and Freeark[9] also documented clinical findings suggestive of arterial injury in 57 patients with partially severed arteries. Fig. 76-1 demonstrates an example from our clinical experience with a through-and-through gunshot wound of the axillary artery with normally palpable brachial and radial pulses. The lack of specificity of some physical findings in arterial injury has stimulated use of contrast arteriography in suspected injuries, particularly when the missile or sharpedged instrument has come in close proximity to a major artery or vein in the extremity. Snyder et al.[10] Menzoian et al.,[11] and Geuder et al.[12] previously documented the indications and value of arteriography. Some features of the arteriographic assessment are apparent from our clinical practice. Arteriography for injuries peripheral to the superficial femoral and axillary arteries should not delay operative intervention, as operative arteriography can be equally valuable and will reduce delays in treatment. If arteriography is obtained prior to operation, biplanar views are recommended, since minimal radiographic changes accompany some significant vascular injuries. The incidence of unsuspected arterial injuries based on arteriographic assessment will range from 5 to 15%.[10 – 12] However, the high incidence of negative arteriograms has stimulated our group and others to reduce our dependency on contrast arteriography by use of noninvasive diagnostic studies.[13,14] Selective use of arteriography in those patients then becomes valuable to further characterize the injury. In some patients
Figure 76-1. (A ) This arteriogram shows a large pseudoaneurysm of the subclavian artery (arrow) just distal to the right vertebral artery, which occurred after an attempted subclavian vein catheter insertion. (B ) Following attempted stented graft placement through the right brachial artery, the pseudoaneurysm was excluded. Vertebral artery flow was maintained.
with intimal injuries or evidence of local arterial wall spasm, however, observation rather than operative management is indicated,[15,16] particularly when the degree of stenosis is # 75%[17] or is unassociated with reductions in distal segmental Doppler pressure measurements.[13] An example (Fig. 76-2) demonstrates the value of arteriography in a gunshot wound of the thigh in which the injury was suspected clinically because of diminished but palpable peripheral
Chapter 76.
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Figure 76-2. (A ) Axillary-subclavian artery arteriogram of a patient with a large pseudoaneurysm (open arrow ) after a stab wound to the chest resulting in a hemopneumothorax (arrow indicates chest tube ). (B ) Following transluminal insertion of the stent graft device, the pseudoaneurysm was repaired and flow was restored.
pulses and decreased Doppler ankle-to-arm index (0.8). Another arteriogram (Fig. 76-3) also documents the presence of a popliteal arterial injury caused by blunt trauma due to a fracture-dislocation of the knee, which, however, was not diagnosed arteriographically until 24 h after injury. Blunt injuries associated with fracture or dislocation about the knee indicate arteriography regardless of the status of peripheral pulses on physical examination. Geuder et al.[12] reported our vascular trauma series from Newark and considered the results of the management of proximity injuries by routine exploration during 1977–1980 by comparison with a program of management based on contrast arteriography during the period 1980 –1983. Treatment of 64 consecutive injuries before 1980 resulted in location of 8 vascular injuries on routine exploration, while 84 suspected injuries were studied arteriographically after 1980.
Of a suspected 12 injuries, 10 were confirmed on exploration, with two falsely positive arteriograms. Consequently, with the introduction of contrast arteriography, only 2 of 85 patients were explored unnecessarily, as compared with approximately 55 to 65 cases during the previous period. Further reduction in our dependency on contrast arteriography was reflected in data reported by Anderson et al.[14] Wounds due to sharp-edged instruments and gunshot wounds to the lateral thigh and arm were not associated with major arterial injury in the absence of clinical signs of arterial injury. Noninvasive vascular laboratory testing may also be helpful in the diagnosis of arterial and venous injuries. As previously reported by Lavenson and associates,[18] the Doppler ultrasound device may be used reliably to predict the viability of an extremity based on the presence or absence of distal audible flow signals after a vascular injury has been
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Figure 76-3. Recognition of this popliteal arterial injury in a patient with fracture-dislocation of the knee was delayed.
treated by ligation or repair. Furthermore, data on segmental Doppler pressures[3] and duplex ultrasound[14] demonstrated their potential for diagnosis of major vascular injuries as well as prospective follow-up for patients treated nonoperatively. In addition, the feasibility of endovascular repair of large intimal defects has been demonstrated experimentally[19] and clinically[20] and represents another option to be considered in these patients.
SURGICAL CONSIDERATIONS AND OVERVIEW Modern concepts in the initial care of the trauma patient include appropriate concern for ensuring an unobstructed airway, early resuscitation with intravenous crystalloid solutions administered through large-bore cannulas and supplemented by rapidly available type-specific crossmatched blood for transfusion, as well as prompt diagnosis of all injuries including extremity vascular trauma. Administration of a broad-spectrum antibiotic prior to operation and
during the perioperative period is recommended. Although prospective data demonstrating a significant clinical advantage in favor of prophylactic antibiotics is not as well established, their use seems justified and their routine administration is noted in most centers. Availability of an autotransfusion device is also a valuable asset, particularly in the patient with multiple trauma. Readministration of shed blood during early resuscitation has reduced transfusion requirements in patients with major vascular injuries. However, the availability of blood products—including packed cells, platelet packs, and fresh frozen plasma—also becomes crucial to the management of these patients and has facilitated repair of major thoracic, intraabdominal, and extremity vascular injuries. Use of interposition grafts in the repair of major extremity vascular injuries probably accounts for the most common form of treatment other than end-to-end anastomosis. We prefer reversed autogenous saphenous vein[1] for interposition grafting; however, some early enthusiasm for Dacron and polytetrafluoroethylene (PTFE) has been reported.[21] Early patency with PTFE was high, and infection was an unknown complication. Although experience with prosthetic grafts in combat injuries has been poor, this group of investigators also recommended use of synthetic prostheses, reporting acute massive hemorrhage and death due to graft dissolution in individual cases of exposed autografts as compared with initial suture-line disruptions or “herald” bleeds in patients with exposed prosthetic replacements. Nevertheless, on longterm follow-up, patency has been poor, particularly with PTFE,[21] demonstrating that its use represents a compromise as compared with use of the saphenous or other autologous veins. While regional anesthetic techniques may be useful in isolated injuries of the extremity vasculature, general anesthesia is usually required for these patients. Operative arteriography becomes essential in many instances prior to the vascular repair and as a routine diagnostic evaluation after arterial reconstruction to identify any unsuspected technical errors. Surgical exploration through elective incisions and clean tissue planes is recommended whenever feasible. Obtaining proximal control prior to direct exploration of the arterial injury may reduce blood loss, which can accompany direct surgical approaches, for example, to femoral triangle injuries. A suprainguinal incision with retroperitoneal exposure of the external iliac artery provides vascular control prior to a direct exploration over the femoral arterial injury. Under the premise that the vascular injury should be repaired as soon as possible, the arterial injury is generally repaired prior to skeletal fixation or repair of other major structures. However, in patients with unstable fractures associated with vascular injury but admitted promptly after the trauma, fracture stabilization may be accomplished primarily, thereby facilitating completion of the vascular reconstruction. The injured artery is controlled by application of atraumatic vascular clamps. Grossly injuried arterial ends are excised. However, additional arterial resection is not required beyond physically obvious disruptions, as microscopic changes of injury do not appear to influence ultimate patency.[22] Although backbleeding on release of the distal arterial clamp is suggestive of distal arterial patency, it does not rule out presence of distal
Chapter 76.
thrombi. Consequently, single passage of a Fogarty baloon catheter distally is recommended to retrieve any unsuspected thrombi. Distal intraarterial administration of heparin is then performed, prior to reapplication of the vascular clamps. Monofilament vascular suture of the 5-0 or 6-0 variety is recommended; the original or modified Carrel triangulation technique continues to be the recommended method for anastomosis. If the arterial repair is performed initially, it is essential that the general surgeon remain in the operating room to assist with the orthopedic aspects of the case so as to confirm patency of the repair after reduction and fixation of the fracture. Skeletal fixation can be accomplished with pins and external casting or with additional external fixation devices such as the Hoffman apparatus (Fig. 76-4). Associated major nerve injuries should be identified and tagged with nonabsorbable sutures or vascular clips; however, in the usual potentially penetrating wound, primary repair of these injuries is not recommended. Delayed repair 3 –6 weeks postoperatively is preferred. The associated popliteal or femoral venous injury should be repaired whenever possible,[23] particularly when lateral venorrhaphy, patch angioplasty, or end-to-end anastomosis can be accomplished. Although use of interposition grafts has not been uniformly accompanied by high patency rates,[24] autogenous repair with paneled and spiral interposition grafts has been associated with patency in over 70% of cases. Although ligation of venous injuries was the principal method of management in the post –World War I era, the reported advantage of improved limb salvage after venous ligation when an accompanying arterial injury were treated by ligation[25] was refuted by the important clinical report of the DeBakey and Simeone[2] after World War II. Furthermore, reported cases of venous gangrene caused by ligation of
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injured major veins, occurring in the presence of patent arterial repairs, stimulated surgeons to consider venous repair whenever possible or when there was evidence of peripheral venous hypertension.[5] The hemodynamics of acute femoral venous obstruction have been studied in the canine hindlimb,[26] and these studies have demonstrated the advantage of repair, particularly during the first 72 h after injury (Fig. 76-5). Currently, the only indication for venous ligation would be a case of multiple trauma where the added operative time required for venous repair might jeopardize the patient’s survival. Venous autografts are preferred in the repair of major venous injuries. Use of paneled[27] or spiral[28] vein grafts has also found application in femoral venous repairs where, for example, size mismatches occur between the saphenous vein and the common femoral vein. Recognizing the pathophysiology of venous injury, the recommendation[29,30] to repair major injured veins when evidence of peripheral venous hypertension exists is consistent with these laboratory research findings. As also emphasized by Rich and coworkers,[31] the incidence of posttraumatic venous insufficiency was reduced when popliteal venous injuries were repaired. In 55 patients whose popliteal venous injuries were treated with ligation, as compared to a similar number of injuries managed by repair, the incidence of postoperative edema was only 11% in the repair group as compared with 32% in patients treated by ligation. In addition, several authors have suggested that selected cases of femoral venous trauma[28 – 30] may be treated appropriately by venous repair. Fig. 76-6 is an example of a spiral vein graft used in repair of a common femoral venous injury, which was accompanied by substantial peripheral venous hypertension and a reduction in distal Doppler segmental pressures. Femoral venous injuries can be treated successfully, and patency rates in excess of 70% have been reported.[28 – 30]
Figure 76-4. Use of the Hoffman external fixator in this combined tibial-fibular fracture facilitated care. A popliteal-to-distal posterior tibial bypass was performed to maintain limb viability.
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Adjunctive measures including external pneumatic calf compression,[32,33] administration of low molecular weight Dextran,[34] and use of distal arteriovenous fistulas[34,35] may be helpful in maintaining graft patency. In cases of combined arterial and venous injury, the use of fasciotomy, although somewhat controversial, has merit.[36] Although clinical assessment of compartment hypertension is accurate in many cases, the use of soft tissue pressure measurements[37] can supplement and assist with defining indications for fasciotomy. Fig. 76-7 demonstrates technical considerations in the performance of fasciotomy as recommended by Patman and Thompson.[38] Fasciotomy employing a lateral incision and fibulectomy (Fig. 76-8), as recommended by Ernst and Kaufer,[39] may also be performed in selected cases.
ENDOVASCULAR TREATMENT FOR VASCULAR INJURIES OF THE EXTREMITIES
Figure 76-5. Hemodynamics of acute femoral venous obstruction in the canine hindlimb. (From Hobson et al.[26] Reproduced by permission.)
Figure 76-6. Use of a spiral vein graft for reconstruction of the common femoral vein. (From Hobson et al.[28] Reproduced by permission.)
In the last 8 years, endovascular treatment methods have proven to be of value in the management of traumatic and iatrogenic vascular injuries of the extremities, including those associated with some false aneurysms and some arteriovenous fistulas.[40 – 46] These endovascular treatments include the use of small artery coil embolization when trauma to a small arterial branch is causally related to a false aneurysm or arteriovenous fistula. They also include the insertion of endovascular grafts or covered stents when defects in major arteries produce false aneurysms or arteriovenous fistulas.[41 – 46] Endovascular grafts have been used effectively to repair injuries to femoral arteries with durable patency in excess of 5 years. However, the advantages of these endovascular graft repairs of traumatic false aneurysms and arteriovenous fistulas are particularly striking when the subclavian, innominate, or iliac arteries are involved.[42,43,45] Standard operative approaches to traumatic vascular lesions of these arteries can be challenging and difficult, particularly if these lesions occur in patients with serious medical comorbidities or complex injuries involving other organs. Our experience has shown that such central arterial injuries can be treated more simply and effectively by the use of endovascular grafts inserted via a remote access site. The insertion of such grafts requires digital fluoroscopic guidance and catheter-guidewire skills. Although some surgeons may consider these requirements burdensome, they also facilitate the use of balloon catheters to gain proximal control.[47] This may be particularly advantageous in patients with infection, scarring, or multiorgan trauma.[47] Endovascular treatment of some traumatic vascular lesions has already been proven safe, effective, and in some cases superior to standard open surgical techniques. We believe that usage of endovascular techniques to gain control of and treat iatrogenic and traumatic arterial injuries will become more widespread as vascular surgeons develop familiarity and facility with these methods.
Chapter 76.
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Figure 76-7. Performance of fasciotomy through limited skin incisions is demonstrated. (From Patman and Thompson.[38] Reproduced by permission.)
Figure 76-8. Fasciotomy of all compartments may also be accomplished by use of a lateral incision and fibulectomy. (From Ernst and Kaufer.[39] Reproduced by permission.)
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SPECIFIC ARTERIAL INJURIES, UPPER EXTREMITY Subclavian Artery Injuries to the subclavian vasculature are unusual, but they do occur most frequently as a result of penetrating trauma; however, massive blunt trauma that disrupts the chest wall may also account for such injuries. Although considerable progress has been made in obtaining a better understanding of the regional surgical anatomy and preferred methods of caring for these injuries, the infrequent occurrence of subclavian arterial trauma has resulted in only modest experience for any individual surgeon. Rich and associates[6] reported only 8 subclavian arterial injuries among the first 1000 arterial injuries reported from Vietnam, and most collected series[7,8] document an occurrence of less than 5%. Numerous surgical approaches to the subclavian artery have been developed since Halsted[48] originally demonstrated the feasibility of resecting a subclavian arterial aneurysm following resection of the medial two thirds of the clavicle. The concept of a limited sternotomy combined with a supraclavicular incision and division of the clavicle laterally was emphasized by Shumacker[49] as well as Steenberg and Ravitch.[50] Amato et al.[51] recommended extending the incision to the third intercostal space by transecting the first two costal cartilages, thereby broadening the available exposure. Injuries in this area can be controlled by direct surgical approaches with pressure over the injured subclavian vasculature; however, occasionally, right anterior thoracotomy for control of the innominate or proximal subclavian arteries and left anterior thoracotomy for control of the proximal subclavian artery may be necessary as a life-saving measure in the emergency room. The diagnosis of these injuries may sometimes be difficult. Obviously, patients with evidence of bleeding, expanding hematoma, and pulse deficits require immediate operative intervention; however, patients with blunt trauma accompanied by first- or second-rib fractures may require arteriography to identify possible subclavian arterial injuries as well as innominate or carotid injuries. The validity of arteriography in these cases is not immediately comparable to the experience in identification of other peripheral arterial injuries. These features were also documented by Flint and colleagues,[52] who reported absence of obvious physical findings in nearly one third of injuries. The operative exposure of patients with injuries in this area also has been emphasized by Mansberger and Linberg[53] and Flint and coworkers.[52] The concept of an initial incision over the clavicle with its medial resection and the extension of the incision, should it prove inadequate, has been emphasized. Generally the incision with clavicular resection may be an initial consideration unless precise knowledge of the location of the injury has been obtained on preoperative arteriography. If a carotid injury is suspected, an incision anterior to the sternomastoid muscle for control of this vascular injury may be of additional importance. The transclavicular incision allows adequate exploration of the right subclavian artery and vein, while the distal two thirds of the left subclavian artery can be visualized after clavicular resection. Extension of this incision into a modified or limited median sternotomy by extending the incision into the third intercostal space allows
further visualization of the innominate artery and vein as well as the proximal left subclavian. Once vascular control has been obtained, resection of the damaged artery with end-toend anastomosis is commonly possible. Although interposition grafts of autogenous saphenous vein are preferred, Dacron and PTFE prostheses can be utilized in selected cases. Operative management and surgical complications have been reported by Rich and colleagues.[54]
Axillary Artery Although vascular injuries in the upper extremity account for approximately 35% of extremity vascular trauma, the axillary artery, like the subclavian artery, is uncommonly injured, accounting for no more than 2–8% of extremity vascular injuries.[6] The axillary artery begins at the lateral edge of the first rib and is divided into three parts by the pectoralis minor muscle. The potential for collateralization about the shoulder will affect therapy of this injury. In addition, the brachial plexus is adjacent to the area, and the cords surround the axillary artery, making accompanying neurological injury common. Etiologically, penetrating trauma is the most common cause of injury.[6 – 8] However, other unusual blunt injuries can be caused by crutch ambulation and direct axillary arterial trauma.[55] Incisions for exposure of the axillary artery are best performed with the patient in the supine position with the arms abducted at about 608. Proximal control of the injury may be obtained by an infraclavicular incision, with control of the axillary artery just beyond the lateral edge of the first rib. Distal control can then be obtained below the tendon of the pectoralis major muscle. Division of the tendon will frequently facilitate operative exposure, in many instances helping to gain access to an injury near or behind the muscle. Division of the pectoralis minor tendon similarly may be helpful. Once control of the injury has been obtained, end-to-end anastomosis may be possible or an interposition saphenous vein graft may be considered. As reviewed by Peacock and Proctor,[56] repair of these arterial injuries as well as other upper-extremity injuries can be accomplished with minimal limb loss; however, the neurological deficits caused by cord or more peripheral neural injuries constitute the major source of long-term disability. In this regard, the ends of the injured nerve should be tagged with nonabsorbable sutures, delaying repair preferably for 3–6 weeks. The major exception to this recommendation would be the clean knife wound, in which case neurological repair may be undertaken primarily.
Brachial Artery Brachial arterial injuries constitute the most common upper extremity injury, varying in their incidence from 10 to 30% in military and civilian clinical service.[6 – 8] Knowledge of the anatomy of the brachial artery, an extension of the axillary artery, is crucial when indications for repair and the anticipated results are considered. Amputation rates vary considerably for injuries above and below the profunda brachial artery. During the World War II experience,[2] the amputation rate was 56% when ligation occurred above this level and only 26% when ligation was below the origin of this major muscular collateral artery. The amputation rate was
Chapter 76.
reduced to less than 5% in the Vietnam experience[6] due to prompt routine repair, and in some civilian series amputation has not been reported after repair.[56] Pathophysiological brachial arterial injuries can occur from penetrating trauma as well as blunt trauma. However, in some institutions, injury to the brachial artery due to radiological procedures such as arch or coronary arteriography as well as placement of intraarterial therapeutic catheters may constitute the most common cause of injury.[57] Blunt trauma should also be considered in the unusual supracondylar fracture of the humerus,[58] in which anterior displacement of the upper humoral section can lacerate or contuse the brachial artery. Following reduction of the fracture, clinical evaluation is required to assess peripheral pulses or local signs of injury. Arteriography may also be necessary for diagnosis in selected cases. Once a brachial artery injury has been diagnosed, surgical exploration is best obtained through a longitudinal incision along the course of the artery just medial to the biceps groove and then extended across the antecubital fossa as needed in an S-shaped fashion. The median nerve as well as the brachial and antecubital veins are in close proximity to the artery, and care must be taken to avoid injury to these associated structures. Division of muscular branches is adequate to allow end-to-end anastomosis in most cases; however, interposition grafts may be required and should be used liberally to avoid tension or stenosis at the anastomoses. Brachial catheterization injuries occur primarily as a result of intimal damage caused by catheter trauma with subsequent arterial thrombosis, aggravated in some cases by inadequate surgical technique in the closure of the brachial arteriotomy. Repairs can usually be performed under local anesthesia. Proximal control can be obtained with ease through an incision in the biceps groove, extending inferiorly to expose the distal brachial bifurcation as may become necessary. In most instances, repair of the intimal flap or resection with end-to-end anastomosis is possible and should be done immediately upon discovery of the injury. Subsequent development of false aneurysms or infection increases the technical difficulties of repair. Delayed repair also frequently requires more extensive revascularization using saphenous vein grafts, which is unusual in primary repairs.
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incisions made directly over these arteries. Since the size of the ulnar and radial arteries may be as small as 1 or 2 mm, care must be taken in accomplishing end-to-end anastomoses with use of fine monofilament vascular suture aided by magnification. Depending on the injury, vein-patch angioplasty is preferable to lateral arteriorrhapy and interposition saphenous vein grafting. Using a venous segment at the ankle also constitutes the most reasonable approach. Associated fractures need stabilization, and this can generally be accomplished by external fixation. Fasciotomy may be required in many cases; however, fasciotomy frequently becomes a part of the surgical exploration. When fasciotomy is indicated for blunt traumatic injuries or combined arterial and venous injuries, the incision should be placed on the volar surface of the forearm from the wrist to the elbow. The lacertus fibrosus should be incised to help decompress the distal brachial artery and median nerve. Operative arteriography for identification of any unsuspected technical errors is also important in brachial, radial, or ulnar arterial injuries.
SPECIFIC ARTERIAL INJURIES, LOWER EXTREMITY Lower-extremity vascular injuries accounted for as many as 60% of the cases in Vietnam,[6] while incidence data from civilian series range from 30 to 50% of cases.[7,8] The high amputation rate associated with common femoral and popliteal arterial injuries has focused attention on the care of these cases. Current diagnostic considerations are outlined in Table 76-1, while the elements of surgical management are outlined in Table 76-2.
Common Femoral and Profunda Femoris Arteries The importance of the common femoral and profunda femoris arteries is underscored by the World War II experience, during which amputation rates exceeded 80% for common femoral arterial injuries treated by ligation,[2] making this the most critical artery supplying the lower extremity. Other compli-
Radial and Ulnar Arteries
Table 76-1.
Although these injuries account for only 6.1% of all arterial injuries documented in World War II,[2] civilian series[6] may include injuries to these arteries in as many as 20% of cases. Collateralization between these arteries will allow ligation of an injured ulnar or radial artery in most cases without development of ischemia or subsequent symptoms of effort discomfort. However, ligation of these injuries from the World War II experience[2] resulted in an incidence of limb loss of 9% with radial ligation and 11% with ulnar ligation. When both vessels were ligated because of arterial injury, the amputation rate rose to 39%. Local compression of the injured site will control bleeding. Tourniquets are generally not recommended because of the abuse that can occur if therapy is delayed several hours. The distal brachial, radia, or ulnar arteries can be explored through
Preoperative arteriography is recommended in cases of diagnostic uncertainly: visualization of small intimal defects or segmental arterial spasm indicates nonoperative management and clinical follow-up using noninvasive techniques. In the presence of abnormal Doppler segmental pressure measurements or duplex scans demonstrating hemodynamically significant abnormalities, preoperative arteriography is recommended, followed by surgical repair as indicated. Operative arteriography as needed is preferred over preoperative studies for injuries peripheral to the axillary and common femoral arteries. Operative arteriography is also recommended after repair to identify any unsuspected technical errors.
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Recommendations for the Care of Vascular Trauma of the Extremity
Table 76-2.
Selective preoperative or operative arteriography can be performed if the site of injury is in doubt. Use of Doppler segmental pressures and duplex scanning will reduce dependency on arteriography in cases of proximity injuries near major arteries. Wound debridement and control of the injured artery and veins; excision of grossly injured artery only. Retrieval of any distal thrombus by Fogarty catheter. Local injection of heparin distally in the absence of associated significant ophthalmic, intracranial, or intraabdominal intrathoracic trauma. Consider systemic heparin on admission for isolated injuries in the upper and lower extremity if ischemia is present on admission. Arterial reconstruction accomplished without tension or stenosis of the suture line; otherwise, interposition grafting is indicated, preferably with autogenous saphenous vein. Operative arteriography is recommended to identify any unsuspected technical errors after repair. Soft tissue coverage of the vascular repair and selected use of fasciotomy. Management of associated injuries including fractures, venous trauma, and nerve injury.
cations associated with surgical management of common femoral arterial injuries include thrombosis of the vascular repair, hemorrhage, and amputation.[3] Loss of the profunda femoris artery as the major collateral in the lower extremity upon ligation of the common femoral artery probably accounts for the reported high amputation rate. Similar injuries in the superficial femoral artery treated by ligation resulted in amputation in only about 50% of cases.[2] Isolated injuries to the profunda femoris artery are not associated with a significant rate of amputation; however, these injuries become increasingly important because of the opportunity for collateralization through this artery in more elderly patients who develop atherosclerotic peripheral vascular disease. Combined femoral arterial and venous injuries involving the femoral triangle are common in instances of penetrating trauma. In the presence of venous hypertension, common femoral venous repair may be a necessary addition to the endto-end anastomosis or interposition graft in the common femoral artery. Blunt trauma as well as transfemoral catheterizations constitute other common causes for femoral arterial injuries in civilian practice. Blunt trauma to the femoral triangle can result in arterial contusion or intimal disruption, leading to lower-limb ischemia. As with brachial arterial injuries, the transfemoral catheter injury can frequently be repaired under local anesthesia and generally has the same pathophysiological etiology as injuries to the brachial or axillary arteries. Results are uniformly good if management is undertaken promptly. In traumatic injuries of the common femoral artery managed in Vietnam,[3] amputation rates were reduced from the nearly 80% observed in World War II to 15% because of routine vascular repair. Operative exposure of the common femoral and profunda femoris arteries can generally be achieved by longitudinal
incisions over the groin and medial thigh. However, direct exposure can result in substantial blood loss; extension of the incision into the inguinal crease and superiorly will permit extraperitoneal exposure of the external iliac artery for proximal control. An alternative can be the performance of a separate inguinal incision for the same purpose of gaining proximal control of the iliac artery. Elements of the repair of an arterial injury, once it has been identified, are outlined in Table 76-2.
SUPERFICIAL FEMORAL ARTERY Isolated injuries to the superficial femoral artery are relatively common and closely approximate the incidence of brachial arterial injuries. The location of the artery adjacent to the femur results in substantial injuries when a femoral fracture accompanies the trauma. As also emphasized by the World War II experience, the association of fracture with any lowerextremity vascular injury increases the risk of amputation, probably due to more extensive soft-tissue and venous injuries. The surgical management of these injuries requires proximal and distal control and usually necessitates general anesthesia, with the potential for requiring of exploration from the external iliac artery to below the level of the knee. Exploration may be accomplished through a longitudinal incision placed anterior to the sartorius muscle; it need not be adjacent to the entrance or exit wounds. Local bleeding can usually be controlled with pressure. Use of an operative tourniquet may be valuable in selected cases. Once proximal and distal control have been obtained, standard vascular repair by lateral arteriorrhaphy, end-to-end anastomosis, or interposition grafting is indicated. Occasionally, repair of a superficial femoral venous injury will be necessary based on the presence of peripheral venous hypertension. Employing the operative management outlined in Table 76-2, the surgeon can anticipate excellent results provided that reconstruction is accomplished within the first 6 h after injury. Although we have recommended use of autografts for combat casualties, experience with civilian vascular trauma has emphasized the indications for synthetic materials such as Dacron or PTFE, and these can be used to expedite repair in selected instances if a saphenous vein is not available. The amputation rate as reported from World War II for ligation of superficial femoral arterial injuries was about 55%. This complication was reduced to 12% in Vietnam, with the availability of routine battlefield repair. Other complications associated with femoral arterial injuries relate to arteriovenous fistulas as well as false aneurysms.[59] Prompt recognition of these complications and their repair by well-accepted vascular techniques can also result in excellent results and reduce disability.
POPLITEAL AND INFRAPOPLITEAL ARTERIES The importance of proper management of popliteal arterial injuries relates to the high amputation rate, nearly 75% among World War II casualties, when treated by ligation.[2]
Chapter 76.
Despite the availability of well-trained surgeons in Vietnam, the amputation rate remained at approximately 30% for combat casualties.[60] Principles learned during the management of these difficult injuries, however, have translated to much reduced amputation rates among civilian vascular injuries. More recent civilian series have documented consecutive injuries without amputation.[61,62] Snyder[63] emphasized the important elements of successful management. These follow the general outline for the management of extremity vascular trauma (Table 76-2), with the addition of several specialized considerations. Diagnosis is at times misleading, particularly in blunt trauma or fracture dislocations. Arteriography can be extremely valuable; however, it can be accomplished in the operating room with proximal control of the distal superficial femoral or proximal popliteal artery. If the lower extremity injury is isolated, systemic heparinization should be considered as part of the admission management in a way comparable to that used for the management of acute arterial insufficiency due to thromboembolism or atherosclerotic occlusion. This will, of course, prevent propagation of distal thrombus and should improve limb salvage. Timing of revascularization is perhaps critical, and consideration for shunting should be given on exploration of the injury, particularly in isolated popliteal arterial injuries or in those instances where surgical delays may result in exceeding the preferred 6-h limit. Although end-to-end anastomoses are frequently employed with brachial and superficial femoral arterial injuries, interposition grafting is required in most popliteal injuries. Provided these techniques are utilized, the anticipated results are excellent and we can look forward, in our civilian experience, to substantial improvement over the amputation rates reported from Vietnam. When injury has extended to the tibioperoneal trunk or involved injury to two or three of the tibial arteries, relatively high amputation rates have been reported.[1,64,65] Associated
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fractures and soft-tissue injuries also contribute to higher amputation rates. In the vascular trauma series from Newark,[64,65] amputation was required in blunt injuries (41%) to two or three tibial arteries, while amputation was uncommon (3%) with penetrating injuries. Conversely, no amputations were needed in a series of consecutive popliteal arterial injuries.[64] Stabilization of lower-extremity fractures may be greatly facilitated by the use of external fixation devices such as the Hoffman apparatus, and these have essentially extended our ability to repair and manage some injuries of this kind. Again, delays in reconstruction constitute a source of substantial morbidity and in some series have accounted for the higher amputation rates. Although we recommend repair of the arterial injuries initially, followed by orthopedic fixation, it is in this group of injuries that the fracture may be unstable enough that initial stabilization of the fracture is preferred. As reported from our recent experience,[65] ligation of single tibial injuries did not result in amputation. Some two-vessel injuries did well; however, when the peroneal artery is the single patent artery, reconstruction of the anterior or posterior tibial artery is recommended. Revascularization was required in all cases of three-vessel injury. However, distal bypass to the single anterior or posterior tibial artery was usually sufficient. Injuries in this group, which are associated with substantial soft-tissue and skeletal injury, should be considered for primary amputation. However, the criteria for this decision are ill defined and the clinical situation is fortunately infrequent. If the lower extremity is also denervated, particularly in cases of plantar anesthesia, replantation should be avoided, as results have not been satisfactory in terms of ultimate functional rehabilitation. Consequently, primary amputation in a few selected injuries should be considered, but only in those with substantial soft-tissue and skeletal injury accompanied by denervation.
REFERENCES 1. 2.
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4. 5.
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Rich, N.M.; Spencer, F.C. Vascular Trauma; Saunders: Philadelphia, 1978. DeBakey, M.E.; Simeone, F.A. Battle Injuries of Arteries in World War II: An Analysis of 2,471 Cases. Ann. Surg. 1946, 123, 534. Hughes, C.W. Acute Vascular Trauma in Korean War Casualties: An Analysis of 180 Cases. Surg. Gynecol. Obstet. 1954, 99, 91. Hughes, C.W. The Primary Repair of Wounds of Major Arteries. Ann. Surg. 1955, 141, 297. Spencer, F.C.; Grewe, R.V. The Management of Acute Arterial Injuries in Battle Casualties. Ann. Surg. 1955, 141, 304. Rich, N.M.; Baugh, J.H.; Hughes, C.W. Acute Arterial Injuries in Vietnam: 1,000 Cases. J. Trauma 1970, 10, 359. Perry, M.O.; Thal, E.R.; Shires, G.T. Management of Arterial Injuries. Ann. Surg. 1971, 173, 403.
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Drapanas, T.; Hewitt, R.L.; Weichert, R.F.; Smith, A.D. Civilian Vascular Injuries: A Critical Appraisal of Three Decades of Management. Ann. Surg. 1970, 172, 351. Saletta, J.D.; Freeark, R.J. The Partially Severed Artery. Arch. Surg. 1968, 97, 198. Snyder, W.H.; Thal, E.R.; Bridges, R.A.; et al. The Validity of Normal Arteriography in Penetrating Trauma. Arch. Surg. 1978, 113, 424. Menzoian, J.O.; Doyle, J.E.; LoGerfo, F.E.; et al. Evaluation and Management of Vascular Injuries of the Extremities. Arch. Surg. 1983, 118, 93. Geuder, J.W.; Hobson, R.W.; Padberg, F.T.; et al. Role of Contrast Arteriography in Suspected Arterial Injuries of the Extremities. Ann. Surg. 1985, 51, 89. Johansen, K.; Danies, M.; Howey, T.; et al. Objective Criteria Accurately Predict Amputation Following Lower Extremity Trauma. J. Trauma 1990, 30, 568.
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14. Anderson, R.J.; Hobson, R.W.; Lee, B.C.; et al. Reduced Dependency on Arteriography for Penetrating Extremity Trauma: Influence of Wound Location and Noninvasive Vascular Studies. J. Trauma 1990, 30, 1059. 15. Gomez, G.A.; Kries, D.J., Jr.; Ratner, L.; et al. Suspected Vascular Trauma of the Extremities: The Role of Arteriography in Proximity Injuries. J. Trauma 1986, 26, 1005. 16. Frykberg, E.R.; Vines, F.S.; Alexander, R.H. The Natural History of Clinically Occult Arterial Injuries: A Prospective Evaluation. J. Trauma 1989, 29, 577. 17. Neville, R.F.; Padberg, F.T., Jr.; DeFouw, D.; et al. The Arterial Wall Response to Intimal Injury in an Experimental Model. Ann. Vasc. Surg. 1992, 6, 50. 18. Lavenson, G.S.; Rich, N.M.; Strandness, D.E., Jr. Ultrasonic Flow Detector Value in the Management of Combat Incurred Vascular Injuries. Arch. Surg. 1971, 103, 644. 19. Neville, R.F.; Yasubara, H.; Watanabe, B.I.; et al. Endovascular Management of Experimental Arterial Intimal Defects: A Comparison by Arteriography, Angioscopy, and Intravascular Ultrasound. J. Vasc. Surg. 1991, 13, 496. 20. White, G.H.; White, R.A.; Kopchok, G.E.; et al. Endoscopic Intravascular Surgery Removes Intraluminal Flaps, Dissections, and Thrombus. J. Vasc. Surg. 1990, 11, 280. 21. Feliciano, D.V.; Mattox, K.L.; Graham, J.M.; Bitondo, C.G. Five-Year Experience with PTFE Grafts in Vascular Wounds. J. Trauma 1985, 25, 71. 22. Rich, N.M.; Manion, W.C.; Hughes, C.W. Surgical and Pathological Evaluation of Vascular Injuries in Vietnam. J. Trauma 1969, 9, 279. 23. Rich, N.M.; Collins, G.J.; Hobson, R.W. Venous Injuries in the Extremities: Combined Arterial and Venous Injuries. In Venous Trauma: Pathophysiology, Diagnosis, and Surgical Management; Hobson, R.W., Rich, N.M., Wright, C.B., Eds.; Futura: Mt. Kisco, New York, 1983; 145 – 190. 24. Meyer, J.P.; Walsh, J.J.; Schuler, J.J.; et al. The Early Fate of Venous Repair Following Civilian Vascular Trauma: A Clinical, Hemodynamic, and Venographic Assessment. Ann. Surg. 1987, 206, 458. 25. Makins, G.H. Gunshot Injuries to the Blood Vessels; Bristol, England: Wright, 1919. 26. Hobson, R.W.; Howard, E.W.; Wright, C.B.; et al. Hemodynamics of Canine Femoral Venous Ligation: Significance in Combined Arterial and Venous Injuries. Surgery 1973, 74, 824. 27. Earle, A.S.; Horshey, J.S.; Villavicencio, J.L.; Warsen, R. Replacement of Venous Defects by Venous Autografts. Arch. Surg. 1960, 80, 116. 28. Hobson, R.W.; Yeager, R.A.; Lynch, T.G.; et al. Femoral Venous Trauma: Techniques for Surgical Management and Early Results. Am. J. Surg. 1983, 146, 220. 29. Agarwal, N.; Shah, P.M.; Claus, R.H.; et al. Experience with 115 Civilian Venous Injuries. J. Trauma 1982, 22, 827. 30. Schramek, A.; Hashmona, M.; Farbstein, J.; Adler, O. Reconstructive Surgery in Major Vein Injuries in the Extremities. J. Trauma 1975, 15, 816. 31. Rich, N.M.; Hobson, R.W. II; Collins, G.J., Jr.; Anderson, C.A. The Effect of Acute Popliteal Venous Interruption. Ann. Surg. 1976, 183, 365.
32. Hobson, R.W.; Lee, B.C.; Lynch, T.G.; et al. Use of Pneumatic External Compression in Femoral Venous Reconstruction. Surg. Gynecol Obstet. 1984, 159, 284. 33. Hobson, R.W.; Croom, R.D.; Rich, N.M. Influence of Heparin and Low Molecular Weight Dextran on the Patency of Vein Grafts in the Venous System. Ann. Surg. 1973, 178, 773. 34. Hobson, R.W.; Wright, C.B. Peripheral Side-toSide Arteriovenous Fistula: Hemodynamics and Application in Venous Reconstruction. Am. J. Surg. 1973, 126, 411. 35. Levin, P.M.; Rich, N.M.; Hutton, J.E., Jr.; et al. The Role of Arteriovenous Shunts in Venous Reconstruction. Am. J. Surg. 1971, 122, 183. 36. Padberg, F.T.; Hobson, R.W. Fasciotomy in Acute Limb Ischemia. Semin Vasc. Surg. 1992, 5, 52. 37. Perry, M.O. Compartment Syndromes and Reperfusion Injury. Surg. Clin. N. Am. 1988, 68, 853. 38. Patman, R.D.; Thompson, J.E. Fasciotomy in Peripheral Vascular Surgery. Arch. Surg. 1970, 101, 663. 39. Ernst, C.B.; Kaufer, H. Fibulectomy-Fasciotomy: An Important Adjunct in the Management of Lower Extremity Arterial Trauma. J. Trauma 1971, 11, 365. 40. Panetta, T.F.; Sclafani, S.J.A.; Goldstein, A.S.; et al. Percutaneous Transcatheter Embolization for Arterial Trauma. J. Vasc. Surg. 1985, 2, 54. 41. Marin, M.L.; Veith, F.J.; Panetta, T.F.; et al. Percutaneous Transfemoral Stented Graft Repair of a Traumatic Femoral Arteriovenous Fistula. J. Vasc. Surg. 1993, 18, 299. 42. Marin, M.L.; Veith, F.J.; Panetta, T.F.; et al. Transluminally Placed Endovascular Stented Graft Repair for Arterial Trauma. J. Vasc. Surg. 1994, 20, 466. 43. Patel, A.V.; Marin, M.L.; Veith, F.J.; et al. Endovascular Graft Repair of Penetrating Subclavian Artery Injuries. J. Endovasc. Surg. 1996, 3, 382. 44. Parodi, J.C. Endovascular Repair of Abdominal Aortic Aneurysms and Other Arterial Lesions. J. Vasc. Surg. 1995, 21, 549. 45. Ohki, T.; Veith, F.J.; Marin, M.L.; et al. Endovascular Approaches for Traumatic Arterial Lesions. Semin. Vasc. Surg. 1997, 10, 272. 46. Ohki, T.; Veith, F.J.; Kraas, C.; et al. Endovascular Therapy for Upper Extremity Injury. Semin. Vasc. Surg. 1998, 11, 106. 47. Veith, F.J.; Sanchez, L.A.; Ohki, T. Technique for Obtaining Proximal Intraluminal Control When Arteries Are Inaccessible or Unclampable Because of Disease or Calcification. J. Vasc. Surg. 1998, 27, 582. 48. Halsted, W. Ligation of the First Portion of the Left Subclavian Artery and Excision of a Subclavico-Axillary Aneurysm. Bull. Johns Hopkins Hosp. 1892, 3, 93. 49. Shumacker, H.B., Jr. Operative Exposure of the Blood Vessels in the Superior Anterior Mediastinum. Am. Surg. 1948, 127, 464. 50. Steenburg, R.W.; Ravitch, M.M. Cervico-thoracic Approach for Subclavian Vessel Injury from Compound Fracture of the Clavicle: Considerations of SubclavianAxillary Exposures. Ann. Surg. 1963, 157, 839. 51. Amato, J.J.; Vanecko, R.M.; Yao, S.T.; Weinberg, M., Jr. Emergency Approach to the Subclavian and Innominate Vessels. Ann. Thorac. Surg. 1969, 8, 537.
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Flint, L.M.; Snyder, W.H.; Perry, M.O.; Shires, G.T. Management of Major Vascular Injuries in the Base of the Neck: An 11 Year Experience with 146 Cases. Arch. Surg. 1973, 106, 407. Mansberger, A.R.; Linberg, F.J. First Rib Resection for Distal Exposure of Subclavian Vessels. Matas R: Traumatic Aneurysm of the Left Brachial Artery:. . . Incision and Partial Excision of Sac: Recovery. Phila. Med. News 1888, 53, 462. Rich, N.M.; Hobson, R.W. II; Jarstfer, B.S.; Geer, T.M. Subclavian Artery Trauma. J. Trauma 1973, 13, 485. Abbott, W.M.; Darling, R.C. Axillary Artery Aneurysms Secondary to Crutch Trauma. Am. J. Surg. 1973, 125, 515. Peacock, J.B.; Proctor, H.J. Factors Limiting Extremity Function Following Vascular Injury. J. Trauma 1977, 17, 532. Rich, N.M.; Hobson, R.W. II; Fedde, C.W. Vascular Trauma Secondary to Diagnostic and Therapeutic Procedures. Am. J. Surg. 1974, 128, 715. MacLean, L.D. The Diagnosis and Treatment of Arterial Injuries. Can. Med. Assoc. J. 1963, 88, 1091.
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Rich, N.M.; Hobson, R.W. II; Collins, G.J., Jr. Traumatic Arteriovenous Fistulas and False Aneurysms: A Review of 558 Lesions. Surgery 1975, 78, 817. Rich, N.M.; Baugh, J.H.; Hughes, C.W. Popliteal Artery Injuries in Vietnam. Am. J. Surg. 1969, 118, 531. Lim, L.L.; Michuda, M.S.; Flanigan, D.P.; Pankovich, A. Popliteal Artery Trauma: 31 Cases Without Amputation. Arch. Surg. 1980, 115, 1307. Shah, D.M.; Corson, J.D.; Karmody, A.M.; et al. Optimal Management of Tibial Arterial Trauma. J. Trauma 1988, 28, 228. Snyder, W.H. Vascular Injuries Near the Knee: An Updated Series and Overview of the Problem. Surgery 1982, 91, 502. Yeager, R.A.; Hobson, R.W. II; Lynch, T.G.; et al. Popliteal and Infra-Popliteal Arterial Injuries: Differential Management and Amputation Rates. Am. Surg. 1984, 50, 155. Padberg, F.T.; Rubelowsky, J.J.; Hernandez-Maldonado, J.J.; et al. Infra-popliteal Artery Injury: Prompt Revascularization Affords Optimal Limb Salvage. J. Vasc. Surg. 1992, 16, 877.
CHAPTER 77
Iatrogenic Vascular Injuries Charles D. Franco Jamie Goldsmith Takao Ohki Frank J. Veith Vascular injuries occur during many types of interventions including oncological,[1] gynecological,[2] neurosurgical or orthopedic,[3 – 8] and, more recently, minimally invasive or laparoscopic surgery.[9,10] However, the majority of iatrogenic vascular injuries confronting clinicians are due to the increased use of percutaneous diagnostic and therapeutic procedures.[11,12] This is particularly true with the larger catheters in use for transluminal angioplasty[13,14] and intraaortic cardiac assist devices.[15,16] The pattern of injury is also changing as more complex procedures are being performed in patients with diffuse, advanced atherosclerosis. If not recognized and treated appropriately, iatrogenic vascular injuries may threaten life and limb. The frequency and severity of injury, requirements for complicated repairs, and therapeutic results are often related to the underlying arterial disease in these patients. When possible, therefore, operative repair should be preceded by studies to define the nature and extent of injury and to visualize the proximal and distal arterial tree. Since repair can often be difficult and demanding, it should be performed by a surgeon experienced in the operative treatment of extensively diseased arteries. A predilection for the iliofemoral segment as the site of injury exists because of the relative accessibility and, therefore, frequent use of the femoral artery as well as its common involvement by atherosclerotic disease. Arterial injuries may present with excessive bleeding, pseudoaneurysm formation, acute ischemia, or arteriovenous fistula.[17] This chapter reviews our experience with diverse arterial complications requiring surgical intervention following various types of percutaneous transfemoral artery procedures, including infrarenal angiography, peripheral angioplasty, cardiac catheterization, coronary angioplasty, and aortic balloon pump insertion. The advent of ultrasound-guided compression therapy in recent years has permitted nonsurgical treatment of many femoral artery injuries.[18] Similarly, the development of endovascular techniques has enabled minimally invasive approaches for repair of less accessible arterial injuries.[19] We then review some of the
common iatrogenic vascular injuries that occur in the upper extremity as well as causes of iatrogenic injury during peripheral revascularization.
ARTERIAL INJURIES FOLLOWING PERCUTANEOUS TRANSFEMORAL PROCEDURES In our series,[20] angioplasty of the iliac or infrainguinal arteries was the most frequent cause of injury, followed by cardiac catheterization. Infrarenal arteriography, coronary angioplasty, and intraaortic balloon pump insertion accounted for the remainder (Table 77-1). Approximately one fourth of the vascular complications occurred in the iliac arteries and three fourths in the femoral arteries (Table 77-2). The most severe injuries occurred in the iliac arteries, requiring a major arterial reconstruction rather than a simple repair in 79% of the cases. Interposition or bypass grafts and endarterectomy with or without a patch angioplasty were usually indicated. Pseudoaneurysm was by far the most common presentation, accounting for more than half of the injuries. Arterial dissections, thrombotic occlusions, and lacerations with persistent bleeding occurred in a similar number of cases. Massive arterial disruptions, arteriovenous fistulas, and hematomas occurred in a small number of patients (Table 77-2). Diagnosis of suspected arterial injuries may be established by physical assessment, noninvasive vascular studies, and arteriography when indicated. Physical examination is the most important element. The presence or absence of distal pulses, thrill, bruit, expanding hematoma, or pulsatile mass— as well as regional signs of ischemia or systemic signs of acute blood loss—are critical to evaluation. The following paragraphs outline the presentation, diagnosis, and management of specific types of injuries. A summary of the surgical
Hobson/Wilson/Veith: Vascular Surgery: Principles and Practice, Third Edition, Revised and Expanded DOI: 10.1081/0819-9-120024961 Copyright q 2004 by Marcel Dekker, Inc.
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Table 77-1. Causes of Iatrogenic Arterial Injuries Peripheral angiography Peripheral angioplasty Cardiac catheterization Coronary angioplasty Intraaortic balloon pump
Iatrogenic Arterial Injuries Produced by Percutaneous Femoral Procedures
Table 77-2.
6 22 16 5 6
Total
Location of injury Type of injury
55
Source: Franco et al.[20]
interventions required for treatment of these injuries is provided in Table 77-3.
Pseudoaneurysm Dissection Thrombosis Laceration Rupture AV fistula Hematoma Total
Pseudoaneurysms The diagnosis of pseudoaneurysm is suggested by palpation of a pulsatile mass and may be confirmed by duplex Doppler scanning (Fig. 77-1) or arteriography (Fig. 77-2). Although ultrasonography is accurate in the diagnosis of pseudoaneurysm, it does not provide the anatomic information obtainable from an arteriogram. Intravenous digital subtraction technique may be preferable to standard arteriography because it is less invasive. Most iliofemoral pseudoaneurysms are in the range of 1–3 cm, but some may be as large as 4 –5 cm or more. Approximately 60% of femoral pseudoaneurysms will resolve spontaneously, but no variables have been identified to reliably predict which ones will thrombose.[21,22] Traditionally, early surgical repair has been advocated to avoid complications such as rupture, hemorrhage, and thrombosis of the native artery.[23] However, surgery has been largely replaced by ultrasound-guided compression therapy of these lesions since it was first described in 1991.[18] This modality can be highly successful (55 –98%) with few complications and rare early or late recurrences.[18,24 – 29] The technique of ultrasound-guided compression repair is dependent upon the obliteration of arterial flow into the pseudoaneurysm by occluding the communicating tract to the underlying artery. Compression is maintained for 10- to 20Table 77-3.
CIA
EIA
CFA
SFA
Total
0 0 1 0 0 0 0
1 5 3 1 3 0 0
23 2 2 5 0 2 2
5 0 0 0 0 0 0
29 7 6 6 3 2 2
1
13
36
5
55
CIA = common iliac artery; EIA = external iliac artery; CFA = common femoral artery; SFA = superficial femoral artery. Source: Franco et al.[20]
min intervals and for periods of up to 2 h until flow is no longer detected within the pseudoaneurysm. It is usually not necessary to impede flow in the underlying artery. Limitations of the procedure are hand fatigue and patient discomfort. The patient is maintained at bedrest for 6 h following successful treatment, and a repeat duplex is performed within the ensuing days to confirm persistent thrombosis. The rate of success is not influenced by aneurysm size or age, dimensions of the communicating tract, vessel of origin, obesity, or presence of associated hematoma. Failure rate is high in patients receiving therapeutic doses of anticoagulants.[28,29] In patients requiring surgical intervention, proximal control of pseudoaneurysms can usually be obtained directly through the groin. Very large ones sometimes require a separate, retroperitoneal approach for proximal control. Most pseudoaneurysms can be repaired by lateral suture of the arterial communication, which commonly measures 2 –5 mm. Conditions imposed by underlying chronic disease occasionally mandate an adjunctive procedure such as an endarterectomy or a patch angioplasty, particularly if it appears that closure of the defect in the arterial wall would compromise the lumen.
Treatment of Arterial Injuries Produced by Percutaneous Femoral Procedures Treatment of injury
Type of injury
LS
GRF
PAT
END
THR
EVC
Total
Pseudoaneurysm Dissection Thrombosis Laceration Rupture AV fistula Hematoma
27 0 0 5 0 2 0
0 4 3 1 3 0 0
2 2 0 0 0 0 0
0 1 0 0 0 0 0
0 0 3 0 0 0 0
0 0 0 0 0 0 2
29 7 6 6 3 2 2
34
11
4
1
3
2
55
Total
LS = Lateral suture; GRF = interposition or bypass graft; PAT = patch; END = endarterectomy; THR = thrombectomy; EVC = evacuation. Source: Franco et al.[20]
Chapter 77.
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Figure 77-2. Intravenous digital subtraction angiogram of a common femoral artery pseudoaneurysm. (From Franco et al.[20] Reproduced by permission of Surgery.)
Thrombotic Occlusions Thrombotic occlusions present with varying degrees of regional ischemia, depending on the level and extent of occlusion. Thrombectomy alone was successful in the treatment of only half of the cases in our series.[8] Therefore, we routinely obtain a postinjury arteriogram to define the segments involved and to evaluate the inflow and outflow vessels should a bypass be necessary. Thrombotic occlusion of the iliac artery is more likely to require a bypass than thrombosis of the femoral artery. Only one of the four iliac thromboses in our series[8] could be treated by thrombectomy alone; severe atherosclerotic disease of the involved segments was the indication for bypass in the others.
Figure 77-1. B-mode ultrasound image of a common femoral artery pseudoaneurysm measuring 33 mm. (From Franco et al.[20] Reproduced by permission of Surgery.)
Arterial Dissections Arterial wall dissections generally follow use of the larger catheters required for transluminal angioplasty or intraaortic cardiac assist devices. Dissections present with a pulse deficit and signs of regional ischemia. Urgency of operative repair is dictated by the severity of ischemia. Postinjury arteriography should be performed to demonstrate the nature and extent of arterial injury as well as to define the inflow and outflow tracts. Operative strategy is determined by the location and extent of dissection. Longer, more extensive lesions usually require a bypass graft. The surgical approach depends on selected inflow and outflow sites based on a postinjury arteriogram. Local procedures, such as endarterectomy or patch angioplasty, may be utilized for shorter, less extensive dissections and obviously require a direct approach to the involved segment.
Arterial Lacerations Most iliofemoral artery lacerations presenting with uncontrolled bleeding are located in the common femoral artery, usually anterior but occasionally tangential, posterior, or multiple and measuring 2 –5 mm in size. Occasionally they occur in the deep or superficial femoral arteries or in another large branch. These injuries are more frequent following transluminal angioplasty because of the larger catheters used and because multiple catheter exchanges are usually necessary. Diagnosis is usually suggested by an expanding hematoma, a decrease in hematocrit, or systemic signs of acute blood loss. On occasion, however, massive retroperitoneal bleeding may occur, producing systemic signs of major blood loss without any discernible groin hematoma. Patients, particularly those with difficult femoral punctures, must be monitored closely for a decrease in hematocrit or signs of hemodynamic instability. A duplex scan will usually demonstrate active extravasation through an arterial wall defect and a surrounding collection. In contrast to lacerations that cause pseudoaneurysms, bleeding from these lacerations
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is uncontained, usually associated with hypotension, and almost always requires urgent surgery. Arterial lacerations can usually be repaired with a simple lateral suture technique. In some instances, multiple arterial wall defects may be produced, necessitating a patch or an interposition graft for repair.
coincidentally on a subsequent arteriogram in the other. Although a duplex scan can detect the fistula, we routinely obtain preoperative arteriography to better define the lesion anatomically. Proximal and distal control of both the artery and vein are essential. Lateral suture repair of both the arterial and venous defects, usually located within a small associated pseudoaneurysm, is commonly sufficient.
Arterial Rupture In our experience, all arterial ruptures occurred during attempts at transluminal balloon angioplasty of external iliac atherosclerotic lesions.[8] Arterial rupture is a highly morbid injury, and prompt recognition is essential. These injuries present immediately with manifestations of acute blood loss and a blush of contrast on fluoroscopy, representing extravasation around the involved segment (Fig. 77-3). Another manifestation of arterial rupture is persistent pain after the angioplasty balloon has been deflated. The angioplasty balloon should be reinflated at the level of injury to control hemorrhage by intraluminal tamponade. These patients require active resuscitation and preparation for emergency surgery. The operative approach always requires a standard retroperitoneal dissection. Intraluminal tamponade should be maintained until direct control is obtained proximal and distal to the injury. The severity of this injury requires exclusion of the injured segment and bypass or interposition grafting to restore vascular continuity.
Arteriovenous Fistulas Arteriovenous fistulas may or may not be symptomatic. In our series, both were asymptomatic and were detected by the presence of a thrill and bruit in one case and found
Figure 77-3. Massive arterial disruption of the external iliac artery with dye extravasation. (From Franco et al.[20] Reproduced by permission of Surgery.)
OPERATIVE APPROACH We preferentially use a groin approach for all femoral and distal-half external iliac artery lesions. Access for the latter is provided by a technique that releases the inguinal ligament and allows retraction of the abdominal wall anteriorly and superiorly (Fig. 77-4). This is accomplished by dividing the overlying deep fascia parallel to the inguinal ligament. The medial three fourths of the inguinal ligament is a free aponeurotic margin and is easily retracted. The lateral one fourth is continuous with the iliopsoas fascia,[30] which may be incised to gain further exposure as high as the iliac bifurcation in some cases. All divided fascial layers should be reapproximated during closure. A standard retroperitoneal approach for control of the iliac arteries is used when (1) injury is proximal to the distal half of the external iliac artery, (2) a massive pseudoaneurysm precludes adequate proximal control in the groin, (3) a large abdominal panniculus in an obese patient prohibits adequate exposure through the groin, or (4) extensive scarring in the groin impedes dissection. Proximal and distal vascular control was obtained solely through a groin incision in 45 (85%) patients, including 6 (11%) in whom access to the distal external iliac artery was obtained by release and retraction of the inguinal ligament. A separate standard retroperitoneal incision was necessary for control in 10 (18%) patients because of proximal injury, massive pseudoaneurysm, morbid obesity, or extensive groin scarring.
Figure 77-4. Exposure of the distal external iliac through a groin incision using a new technique of inguinal ligament release. (From Franco et al.[20] Reproduced by permission of Surgery.)
Chapter 77.
Our technique for release and retraction of the inguinal ligament facilitates exposure and control of distal iliac and proximal femoral arterial lesions. This approach may simplify management and, in some cases, obviate the need for more extensive retroperitoneal dissection or routine division of the inguinal ligament.[31] Depending on pelvic architecture, this technique will allow exposure of the external iliac artery proximally as far as its origin in some patients.
ENDOVASCULAR APPROACH The evolution of endovascular techniques has fostered the development of minimally invasive strategies in obtaining proximal arterial control. Endovascular techniques are useful in circumstances that render open dissection and extraluminal control hazardous. Such circumstances may be due to scarring or infection in the area where proximal control is to be obtained or heavy circumferential, ringlike calcification and plaque formation, which prevent all clamps from occluding the vessel lumen. An endovascular approach is also useful when there are associated injuries to other structures in the vicinity.
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Others have advocated the use of intraluminal balloon catheter occlusion,[32 – 35] but positioning of these balloon catheters has been difficult to control precisely, and their insertion without a hemostatic sheath has been associated with considerable blood loss. Veith et al.[36] describe their technique in 20 patients during a 2-year period with 15 external iliac/common femoral, 2 common iliac, and 3 subclavian/axillary occlusions. An unclampable artery was the indication for performing this technique in 8 of the 20 patients and was found only in the external iliac/common femoral segments. Intense scarring or infection was the indication for endovascular occlusion in another 8 patients in which there were one subclavian, one common iliac, and 6 external iliac/common femoral segment occlusions. Proximal arterial control was obtained in all patients with virtually no blood loss. The planned operation was performed successfully in all patients, and there were no complications such as dissection or plaque disruption. The technique involves open surgical exposure of an artery distal to the site where proximal control is required. An 18gauge needle is inserted in the exposed artery and a floppytipped guidewire is inserted through the needle, which is then removed. A 6F or 7F hemostatic sheath and dilator are introduced over the guidewire (Fig. 77-5). If the arteries are
Figure 77-5. (A ) Diagram of patient with heavily scarred groin from previous surgery. To perform femorodistal bypass only the anterior surface of the distal common femoral artery must be dissected. Site of guidewire and sheath insertion is indicated by asterisk. (B ) Guidewire has been inserted short distance through needle. Needle has been removed; hemostatic sheath and its dilator are being advanced over guidewire. Rotating sheath and dilator as a unit as they are advanced facilitates entrance through arterial wall. (From Veith et al.[36])
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Figure 77-6. After removal of dilator, directional catheter (Berenstein) is inserted through sheath over wire. Then under fluoroscopic guidance, wire is advanced well into external iliac artery. (From Veith et al.[36])
atherosclerotic or tortuous, intraluminal guidewire passage can be facilitated and made safer with a directional catheter and fluoroscopic guidance (Fig. 77-6). When the guidewire is inserted well proximal to the site of intended proximal control, the hemostatic sheath and guidewire are advanced over the wire to the desired level (Fig. 77-7). The guidewire and dilator are removed, and an appropriate-sized standard balloon catheter is passed through the hemostatic sheath. The position of the balloon within the arterial tree and the location of branches can be assessed by injecting radiopaque contrast into the flush/injection port of the sheath and placing a small amount of dilute contrast in the balloon. After the balloon catheter is accurately positioned at the optimal site for proximal occlusion, the sheath is retracted while the balloon catheter is kept fixed so that the balloon is no longer within the sheath. The balloon is inflated until the arterial inflow is occluded (Fig. 77-8). Distal and branch control can be obtained with standard surgical techniques or, if these are not possible, by inserting additional intraluminal balloon catheters after the artery is opened. The sheath is then
removed and the intended arterial reconstruction or repair is performed. If this is a bypass, the original guidewire/sheath insertion site can be extended proximally and distally to function as the proximal arteriotomy (Fig. 77-9).
VASCULAR COMPLICATIONS DUE TO INTRAAORTIC BALLOON PUMP CATHETERS As mentioned earlier, complications are more frequent with the larger catheters in use for balloon angioplasty and for intraaortic balloon counterpulsation.[13 – 16] The complication rate for the latter catheters ranges from 4 to 43%.[15,37 – 41] These catheters present a problem not only because of their larger size and inherent propensity for arterial injury, but also because they are indwelling for extended periods of time and may result in ischemic complications secondary to arterial
Figure 77-7. Catheter is removed, leaving wire and sheath in place. Dilator is replaced, and sheath and dilator are advanced over wire well into external iliac artery. (From Veith et al.[36])
Chapter 77.
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Figure 77-8. Dilator is removed along with guidewire, leaving sheath within iliac artery. Balloon catheter is advanced within sheath. After appropriate positioning of balloon with fluoroscopic guidance and contrast injection as needed, sheath is partially withdrawn, and balloon is inflated to occlude external iliac artery and two of its branches (inset). (From Veith et al.[36])
occlusion by the catheter itself or by thrombus formation around the catheter. Limb ischemia is usually evident during the first day of counterpulsation, but additional patients may develop limb ischemia during the next several days, as demonstrated by Alderman et al.[39] They found no further incidence of limb ischemia in patients requiring 5 or more days of counterpulsation. Limb ischemia resolved in two thirds of their patients after balloon removal alone, and one third required vascular surgery. Surgical intervention usually consisted of thromboembolectomy or simple suture repair. Occasionally, a vein patch angioplasty or interposition graft was necessary. When intraaortic balloon counterpulsation
must be continued in patients with limb-threatening ischemia, a femoro-femoral bypass may be very useful.[15] Randomized, prospective studies[40,41] have demonstrated a significant decrease in vascular complications when these devices are placed by open surgical technique as compared to the percutaneous technique. This difference, however, may be attributed more to the method of removal than insertion, since in the open technique a Fogarty thromboembolectomy balloon is routinely passed through the iliofemoral vessels and a sutured arteriotomy closure is performed.[42] In fact, Cutler et al.[43] reported complications only in patients who had percutaneous removal of the catheter and had no
Figure 77-9. After obtaining distal arterial control, sheath is removed and site of its entrance extended as arteriotomy for distal bypass. Balloon catheter remains in place and provides proximal control. It can be removed as last few stitches of proximal anastomosis are tightened (inset ). If catheter-sheath introduction site is not extended as orgin of bypass, it can be closed primarily with sutures. (From Veith et al.[36])
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complications following surgical removal. Various studies have found that female gender,[39,41,44] peripheral vascular disease,[39,44] diabetes,[39,41] and hypertension[41] are significant predictors of vascular complications.
IATROGENIC ARTERIAL INJURIES OF THE UPPER EXTREMITY The large number of diagnostic, therapeutic, and monitoring procedures has dramatically increased the incidence of iatrogenic arterial injuries in the upper extremity during the last two to three decades. The most common iatrogenic cause for upper extremity ischemia is brachial arteriotomy for cardiac catheterization.[45] Although reports are quite variable, ranging from 0.3%[46] to 28%,[47] most large contemporary studies report incidences between 0.6 and 4%.[48 – 52] The true incidence of upper extremity arterial complications, however, is probably higher than that reported, since many patients may remain asymptomatic despite brachial artery occlusion because of the extensive collateral circulation present in the arm.[47] Factors found to contribute to occlusive complications include the size of the arteriotomy at closure, use of heparin, duration of the diagnostic procedure, and the number of catheter exchanges.[53,54] Other factors that contribute to iatrogenic complications include a second catheterization through the same brachial artery site,[49] difficulty of catheter passage,[55] the presence of an atherosclerotic plaque at the arteriotomy site,[54,55] and, finally, the experience of the person performing the catheterization.[52] Iatrogenic brachial artery injuries include thrombosis, dissection, pseudoaneurysm or persistent bleeding from a laceration, and arteriovenous fistula. Most lesions are limited to or near the arteriotomy site, but occasionally a more proximal lesion may be present in the axillary or subclavian segments. It is important to consider this possibility, since it may be the cause of recurrent thrombosis after a local brachial artery procedure has been performed. The mechanisms of injury following arterial catheterization have been well described.[47,56] Narrowing or stenosis of the artery may occur during closure of the arteriotomy. This complication may be reduced by use of a transverse arteriotomy and careful closure with interrupted sutures rather than a pursestring suture. A second type of injury occurs when thrombus that has formed a sleeve around the catheter is scraped or wiped off when the catheter is withdrawn from the artery. This complication may be more frequent during a lengthy procedure or when proper anticoagulation is not maintained. Another form of injury is intimal or vessel wall dissection, which may progress to perforation or laceration of the arterial wall if instrumentation is excessive. A fourth type of injury, described by Karmody et al.[56] as a “catheter lesion,” consists of endothelial erosion or denudation frequently accompanied by fracture of the underlying internal elastic lamina.[57] This lesion is always found on the posterior wall of the artery and is usually within 1.5 cm proximal to the site of catheter entry. This is presumably the area where mechanical damage is most pronounced by abutment of the catheter tip and the site of
maximal pressure from the side of the catheter as it is being manipulated in the vessel. Surgical intervention is clearly indicated when arterial injury is manifest by acute ischemic symptoms. Management of asymptomatic patients, however, has been controversial in the past, with some authors advocating a nonoperative approach.[58] Symptoms are unlikely to develop unless the arm-forearm pressure gradient is greater than 50 mmHg,[59] but it is difficult to predict which patients will eventually become symptomatic. Nearly half of all patients who are initially asymptomatic despite brachial artery occlusions will develop ischemic symptoms; half of these patients will have symptoms severe enough to require vascular reconstruction.[51] When performed early, surgical therapy usually requires only thrombectomy, arteriotomy revision, or local resection with primary anastomosis or vein graft interposition.[49,50,60] If surgery is delayed for more than a day following the injury, the rate of reocclusion increases from 2 to 12%[60] and significant neurologic complications may ensue.[48] If the condition is allowed to become chronic, surgical treatment of the lesion becomes more complex and a bypass of the occluded segment will generally be necessary, using autogenous saphenous vein as the conduit of choice. The success rate for upper extremity arterial bypasses is greater than 90% when the outflow is not severely limited.[45,61] Surgical repair of injuries proximal to the axillo-brachial affecting the intrathoracic arterial segments may require complex exposure techniques including claviculectomy, sternotomy, or thoracotomy. Surgical repair may also be rendered more hazardous secondary to a large hematoma with distorted anatomy, a false aneurysm, or venous hypertension when an arteriovenous fistula is present. Endovascular techniques, including the use of coil embolization, intravascular stents, and stented grafts or covered stents, have been developed for the treatment of traumatic and iatrogenic vascular injuries. The use of endovascular techniques is particularly appealing in these circumstances because repair can be performed from a remote access site, obviating the need for direct surgical exposure of the injury site, thus reducing morbidity and mortality.
IATROGENIC PEDIATRIC ARTERIAL INJURIES Nontraumatic arterial occlusions are rare in children; they may result from cardiogenic embolization or spontaneous arterial thrombosis secondary to dehydration, polycythemia, infection or congestive heart failure. Acute ischemia in children is more likely to be secondary to trauma by a variety of mechanisms,[63 – 65] but the majority are iatrogenic,[66] especially in children younger than 2 years.[67] Iatrogenic pediatric vascular injuries most commonly occur secondary to arterial catheterization for diagnostic or monitoring purposes such as umbilical artery catheterization, transfemoral arteriography or cardiac catheterization, and needling procedures for arterial blood samples.[66,68] Upper extremity iatrogenic arterial injuries are rare in children, reflecting the trend away from brachial artery puncture for invasive procedures.[68 – 71]
Chapter 77.
Pediatric arterial injuries pose special problems and considerations not encountered in the adult.[72] The inability of very young patients to communicate their symptoms coupled with the rapid development of collateral blood flow often obscures the severity of underlying ischemia. Moreover, surgeons may be reluctant to recommend surgical repair in infants and children due to the diminutive size of their vessels. However, the importance of normal arterial perfusion has been underscored by numerous reports documenting subsequent limb growth retardation as a result of uncorrected circulatory impairment, even when there is no symptomatic evidence of ischemia. [73 – 76] Late revascularization, although controversial, generally does not correct limb length discrepancies.[73,74,77,78] Transfemoral cardiac catheterization accounts for 26 – 67% of pediatric iatrogenic arterial injuries.[67,79,80] The use of systemic heparinization while the catheter is in position significantly reduced the incidence of thrombotic complications in a randomized, prospective study.[67] This study also demonstrated a significantly higher rate of thrombotic occlusions in younger patients. No patient older than 10 years developed complications, whereas patients younger than 10 years had a complication rate of 40%. It is thought that the mechanism of arterial occlusion at the insertion site, or distally after embolization, is the formation of fibrin sleeves on catheters and eventual stripping of these sleeves during catheter removal.[81] Percutaneous methods of arterial puncture are associated with a lower incidence of thrombotic complications as compared to cannulation via an open arteriotomy.[71] Although a high incidence of thrombi has been shown angiographically following umbilical artery cannulation, most investigators report clinical complications of less than 5%.[82,83] The most serious and almost uniformly fatal complication is aortic occlusion.[84,85] Umbilical artery catheters also cause thrombotic complications in the lower
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extremities, renovascular hypertension, aortic pseudoaneurysms, hemoperitoneum, and urologic complications.[86 – 89] The incidence of complications can be reduced by using hypothrombogenic catheter materials with end-holes, heparin drips, and a high aortic position.[84] Arterial spasm following cannulation is frequently a cause for transient perfusion deficits in children, particularly in younger patients.[79] However, investigators have demonstrated the presence of arterial thrombosis in all cases when pulse deficits persist beyond 3–8 h.[68,69] Heparinization is generally recommended during the waiting period. Surgical intervention should be considered if the perfusion deficit persists beyond this observation period. The decision to intervene should not be based solely upon the presence or absence of a femoral pulse since a pulse may be present despite thrombus situated at the femoral bifurcation, which can be easily removed. In addition, more distal occlusions may sometimes be treated by thromboembolectomy or even bypass procedures.[65,77] The clinical approach to iatrogenic pediatric arterial injuries outlined by Flanigan et al. produced reasonable success in their experience.[80] All patients with aortic thrombosis should be heparinized and undergo immediate surgical intervention. Children with loss of pulse but without aortic occlusion should be heparinized and observed for 6 h. Patients without a femoral pulse after 6 h should undergo surgery since thrombus was found in all such cases. Patients with a femoral pulse but with distal ischemia can be studied by ultrasound to identify patients with distal common femoral artery thrombus since they can also be treated relatively easily. More distal occlusions were generally treated nonoperatively with heparin therapy, although a more aggressive approach may be indicated in older children. Fibrinolytic therapy may also be considered in some patients. Although controversial, later revascularization may be effective in some patients for relief of limb length discrepancies.[66,74,78]
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Ross, R.S. Arterial Complications. Circulation 1968, 37 (Suppl. 3), 39. Brener, B.J.; Couch, N.P. Peripheral Arterial Complications of Left Heart Catheterization and Their Management. Am. J. Surg. 1973, 125, 521. Babu, S.C.; Piccorelli, G.O.; Shah, P.M.; et al. Incidence and Results of Arterial Complications Among 16,350 Patients Undergoing Cardiac Catheterization. J. Vasc. Surg. 1989, 10, 113. McCollum, C.H.; Mavor, E. Brachial Artery Injury After Cardiac Catheterization. J. Vasc. Surg. 1986, 4, 355. Kitzmiller, J.W.; Hertzer, N.R.; Beven, E.G. Routine Surgical Management of Brachial Artery Occlusion After Cardiac Catheterization. Arch. Surg. 1982, 117, 1066. Menzoian, J.O.; Corson, J.D.; Bush, H.L.; LoGerfo, F.W. Management of the Upper Extremity with Absent Pulses After Cardiac Catheterization. Am. J. Surg. 1978, 135, 484. Nicholas, G.G.; DeMuth, W.E. Long-Term Results of Brachial Thrombectomy Following Cardiac Catheterization. Ann. Surg. 1976, 183, 436. Armstrong, P.W.; Parker, J.O. The Complications of Brachial Arteriotomy. J. Thoracic Cardiovasc Surg. 1971, 61, 424. Machleder, H.I.; Sweeney, J.P.; Barker, W.F. Pulseless Arm After Brachial Artery Catheterization. Lancet 1972, 1, 407. Bolasny, B.L.; Kileen, D.A. Surgical Management of Arterial Injuries Secondary to Angiography. Ann. Surg. 1971, 6, 962. Karmody, A.M.; Zaman, S.N.; Mirza, R.A.; Bousvaros, G. The Surgical Management of Catheter Injuries of the Brachial Artery. J. Thorac Cardiovasc Surg. 1977, 73, 149. Karmody, A.M.; Lempert, N.; Jarmolych, J. The Pathology of Post-Catheterization Brachial Artery Occlusion. J. Surg. Res. 1976, 20, 601. Kottke, B.A.; Fairbairn, J.F.; Davis, G.D. Complications of Aortography. Circulation 1964, 30, 843. Barnes, R.W.; Peterson, J.L.; Krugmire, R.B., Jr.; et al. Complications of Brachial Artery Catheterization: Prospective Evaluation with the Doppler Ultrasonic Velocity Detector. Chest 1974, 66, 363. Kline, R.M.; Hertzer, N.R.; Beven, E.G.; et al. Surgical Treatment of Brachial Artery Injuries After Cardiac Catheterization. J. Vasc. Surg. 1990, 12, 20. McCarthy, W.J.; Flinn, W.R.; Yao, J.S.T.; et al. Result of Bypass Grafting for Upper Limb Ischemia. J. Vasc. Surg. 1986, 3, 741. Ohki, T.; Veith, F.J.; Kraas, C.; Latz, E.; Sanchez, L.A. Endovascular Therapy for Upper Extremity Injury. Semin. Vasc. Surg. 1998, 11, 106. Braly, B.D. Neonatal Arterial Thrombosis and Embolism. Pediatr. Surg. 1965, 58, 869. Meagher, D.P., Jr.; Defore, W.W.; Mattox, K.L.; et al. Vascular Trauma in Infants and Children. J. Trauma 1979, 19, 532. Richardson, J.D.; Fallat, M.; Nagaraj, H.S.; et al. Arterial Injuries in Children. Arch. Surg. 1980, 116, 685. Smith, C.; Green, R.M. Pediatric Vascular Injuries. Surgery 1981, 90, 20. Freed, M.D.; Keane, J.F.; Rosenthal, A. The Use of Heparinization to Prevent Arterial Thrombosis After
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Percutaneous Cardiac Catheterization in Children. Circulation 1974, 50, 565. White, J.J.; Talbert, J.L.; Haller, J.A. Peripheral Arterial Injuries in Infants and Children. Ann. Surg. 1968, 167, 757. Mansfield, P.B.; Gazzania, A.B.; Litwin, S.B. Management of Arterial Injuries Related to Cardiac Catheterization in Children and Young Adults. Circulation, XLH 1970, 501. Hohn, A.R.; Craenen, J. Arterial Pulses Following Percutaneous Catheterization in Children. Pediatrics 1969, 43, 617. Rubenson, A.; Jacobsson, B.; Sorensen, S.E. Treatment and Sequelae of Angiographic Complications in Children. J. Pediatr. Surg. 1979, 14, 154. Shaker, I.J.; White, J.J.; Signer, R.D.; et al. Special Problems of Vascular Injuries in Children. J. Trauma 1976, 16, 863. Bassett, F.H. III; Lincoln, C.R.; King, T.D.; et al. Inequality in the Size of the Lower Extremity Following Cardiac Catheterization. South Med. J. 1968, 61, 1013. Bloom, J.D.; Mozersky, D.J.; Buckley, C.J.; et al. Defective Limb Growth as a Complication of Catheterization of the Femoral Artery. Surg. Gynecol. Obstet. 1974, 138, 524. Jacobsson, B.; Carlgren, L.E.; Hedvall, G.; et al. A Review of Children After Arterial Catheterization of the Leg. Pediatr. Radiol. 1973, 1, 96. Currarino, G.; Engle, M.A. The Effects of Ligation of the Subclavian Artery on the Bones and Soft Tissues of the Arms. J. Pediatr. 1965, 67, 808. Whitehouse, W.M., Jr.; Coran, A.G.; Stanley, J.C.; et al. Pediatric Vascular Trauma: Manifestations, Management, and Sequelae of Extremity Arterial Injury in Patients Undergoing Surgical Treatment. Arch. Surg. 1976, 111, 1269. Klein, M.D.; Coran, A.G.; Whitehouse, W.M., Jr.; et al. Management of Iatrogenic Arterial Injuries in Infants and Children. J. Pediatr. Surg. 1982, 17, 933. Mortensson, W. Angiography of the Femoral Artery Following Percutaneous Catheterization in Infants and Children. Acta Radiol. Diag. 1976, 17, 581. Flanigan, D.P.; Keifer, T.J.; Schuler, J.J.; Ryan, T.J.; Castronuovo, J.J. Experience with Iatrogenic Pediatric Vascular Injuries. Ann. Surg. 1983, 198, 430. Formanek, G.; French, R.S.; Amplatz, K. Arterial Thrombus Formation During Clinical Percutaneous Catheterization. Circulation 1970, 41, 833. Goetzman, B.W.; Stadalnik, R.C.; Bogren, H.G.; et al. Thrombotic Complications of Umbilical Artery Catheters: A Clinical and Radiographic Study. Pediatrics 1975, 56, 374. O’Neill, J.A., Jr.; Neblett, W.W. III; Born, M.L. Management of Major Thromboembolic Complications of Umbilical Artery Catheters. J. Pediatr. Surg. 1981, 16, 972. Flanigan, D.P.; Stolar, C.J.H.; Pringle, K.C.; et al. Aortic Thrombosis Following Umbilical Artery Catheterization. Arch. Surg. 1982, 117, 371. Marsh, J.L.; King, W.; Barrett, C.; et al. Serious Complications After Umbilical Artery Catheterization for Neonatal Monitoring. Arch. Surg. 1975, 110, 1203.
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86. Merten, D.F.; Vogel, J.M.; Adelman, R.D.; et al. Renovascular Hypertension as a Complication of Umbilical Arterial Catheterization. Radiology 1978, 126, 751. 87. Spangler, J.G.; Kleinberg, F.; Fulton, R.E.; et al. False Aneurysm of the Descending Aorta. A Complication of Umbilical Artery Catheterization. Am. J. Dis. Child. 1979, 131, 1258.
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Miller, D.; Kirkpatrick, B.V.; Kodroff, M.; et al. Pelvic Exsanguination Following Umbilical Artery Catheterization in Neonates. J. Pediatr. Surg. 1979, 14, 264. 89. Stevens, P.S.; Mandell, J. Urologic Complications of Neonatal Umbilical Arterial Catheterization. J. Urol. 1978, 120, 605.
CHAPTER 78
Vascular Complications Related to Drug Abuse Richard A. Yeager Robert W. Hobson II Creighton B. Wright Drug abuse in the United States is endemic to all parts of society. In 1990 an estimated 28 million Americans used illicit drugs, and many of these individuals injected substances intravenously.[1] Recent statistics indicate that overall the incidence of drug abuse may be decreasing.[2 – 4] Obviously, however, abuse of illicit drugs remains a major problem in the United States today. Cocaine-related emergency room episodes continue to increase, methamphetamine (“crank”) abuse has reached epidemic proportions in some areas,[5] and heroin use is spreading among the multiethnic populations of our major cities.[6] The unfortunate persistance of parenteral drug abuse in our society provides surgeons with a challenging array of pulmonary, cardiac, and vascular complications, either directly or indirectly related to the drug injections.[7] The compulsion and ingenuity of drug addicts allows any part of the body to be a potential injury site.[7 – 12] Even the repeated intracardiac injection of illicit drugs has been reported.[13] Heroin obviously is well recognized as a frequently abused intravenous drug, but the list includes cocaine, other narcotics, barbiturates, nonnarcotic analgesics, and amphetamines.[7,14] Various drug combinations are also popular. For example, intravenous cocaine users frequently combine the drug with heroin (“speedball”).[15] In addition to the systemic effects of these drugs, direct injections can cause vascular injury and limb ischemia by a variety of mechanisms, including local vascular trauma and infection, distal emboli, as well as chemical injury. Often the excipients (talc, cornstarch, or fillers) of oral preparations or the agent used to “cut” the heroin (quinine, barbiturates, or lactose) do as much or more vascular damage than the drug itself.[14,16] Surgeons should be aware of the myriad of vascular problems associated with drug abuse and be prepared to manage them. This chapter will review the spectrum of vascular injuries related to parenteral drug abuse, including pathophysiology, clinical presentation, and management.
OVERVIEW OF THE CLINICAL PROBLEM The drug abuse population presents several difficult management problems. History concerning time factors, type of drug, method of preparation, and mode of injection may be lacking or inaccurate. This is often due to either the patient’s deceptive behavior or the clouded sensorium related to chronic drug usage. Outpatient therapy and follow-up is inconsistent due to poor patient compliance, which may compromise treatment protocols. Deep venous thrombosis due to drug injection, for example, is probably best treated by hospitalization and heparinization for 2 weeks,[17] since shorter courses of heparin followed by outpatient warfarin therapy is seldom a feasible option in this noncompliant patient population.[13] Peripheral venous access for phlebotomy or drug therapy is frequently unavailable due to dermal scars and peripheral venous sclerosis secondary to repeated injections. Often the patient is knowledgeable about his or her own best available venous access, and this information should be solicited. Furthermore, when surgical repair of drug-related vascular injuries is required, autogenous veins are often of inadequate quality for interposition grafting or even patch angioplasty.[18] Consideration should be given to the use of autogenous arterial grafts[19,20] in this situation, although common synthetic prostheses such as polytetrafluoroethylene (PTFE) or Dacron are also utilized. The use of synthetic materials, however, may be associated with attendant problems of infection in an already immunologically compromised host (Fig. 78-1).[21] Treating physicians should be aware that communicable diseases such as hepatitis and tuberculosis are prevalent among the drug abuse population.[22,23] In addition, 5–33% of intravenous drug users in the United States are infected with the human immunodeficiency virus (HIV); seroprevalence is as high as 60% in sections of New York City.[24,25] When drug users present with localized infections requiring
Hobson/Wilson/Veith: Vascular Surgery: Principles and Practice, Third Edition, Revised and Expanded DOI: 10.1081/0819-9-120024962 Copyright q 2004 by Marcel Dekker, Inc.
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infected venous pseudoaneurysms. Furthermore, pulmonary vascular complications can occur as a direct result of venous injections.[27]
Superficial Venous Thrombosis and Associated “Puffy Hand” Repeated injection into the superficial veins causes sclerosis and thrombosis of the veins due to chronic mechanical and chemical trauma. Although lymphatic obstruction due to injected particulate debris is of primary importance,[28] the eventual obliteration of the entire superficial venous drainage is a contributing factor in causing the “puffy hand” syndrome described in drug addicts.[8] Other causes of acute hand swelling in the drug addict include infection, lesions related to “skin popping,”[29] compartment syndrome,[30] bullous skin lesions related to barbiturate overdose,[31] and acute arterial injection.[32] After other causes are ruled out, treatment for acute puffy hand should include elevation, antibiotics, and anticoagulation. A number of these patients will develop intractable hand and arm swelling, for which compression support sleeves are useful.
Deep Venous Thrombosis
Figure 78-1. Infected pseudoaneurysm at PTFE-superficial femoral arterial anastomosis in drug abuser with obturator foramen bypass.
surgical drainage, preoperative plain radiographs of the planned operative field are recommended. These wounds may harbor broken needle tips, which obviously pose a risk to the operating team.[23] Heroin nephropathy with renal failure may be encountered in the drug addict.[26] Vascular shunts—created for hemodialysis access as well as other subcutaneous vascular grafts—are frequently adapted for drug abuse injections by this population. Eventual graft infections commonly occur, necessitating removal of the prosthesis. For this reason, peritoneal dialysis is considered an alternative to hemodialysis in any renal failure patient with a history of drug abuse. Consequently, the drug abuse patient presents many unique and challenging management problems that demand innovative diagnostic and therapeutic approaches. It is hoped that a better understanding of the potential clinical problems and management alternatives will improve medical and surgical care for this group.
VASCULAR COMPLICATIONS RELATED TO INTRAVENOUS DRUG INJECTION The intravenous abuse of drugs can lead to several local venous complications, including superficial vein thrombosis, deep venous thrombosis, septic thrombophlebitis, and
Once the drug abuser has sclerosed all superficial veins, she or he resorts to injecting the deep veins.[33,34] The most popular sites are the femoral, axillosubclavian, and jugular veins.[35] Repeated mechanical and chemical trauma to the venous wall ultimately leads to thrombus formation (Figs. 78-2 and 78-3). Treatment includes elevation and heparin anticoagulation for 2 weeks. Long-term outpatient warfarin therapy is rarely a practical alternative in this population.
Septic Thrombophlebitis Venous thrombosis with a superimposed infection is a more complex problem. Septic thrombophlebitis results when local venous injury occurs with either thrombosis or hemorrhage associated with hematoma formation. Organisms are then introduced into or around the thrombus, usually at the time of drug injection. In general, most infections seen in addicts appear to be related to their injection habits and not due to the contamination of heroin or drug paraphernalia.[36 – 38] Staphylococcus aureus is the most common causative organism of septicemia in these cases. Skin contamination is a likely source for the sepsis. The incidence of staphylococcal carriers among people who undergo chronic drug injection is reported to be high.[38] Sterile preparation of the skin prior to drug injection is seldom practiced, and addicts often use saliva or unsterile water as a mixing medium for their drugs. In addition, the addict is prone to develop infections since chronic narcotism can inhibit phagocytosis and lymphocyte-mediated immunity.[7,8,39] The natural history of untreated septic thrombophlebitis includes persistent bacteremia as well as septic pulmonary emboli resulting in lung abscesses. The incidence of infected pulmonary emboli associated with septic thrombophlebitis reportedly ranges from 7 to 30%.[40,41] Persistent bacteremia
Chapter 78.
Figure 78-2.
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Axillary venous thrombosis related to the injection of illicit drugs.
can also lead to endocarditis, with its attendant complications. One series of 100 patients with septic thrombophlebitis was characterized as being 46% drug abusers. Local pain was the most common (83%) complaint, while erythema or edema constituted the most common physical signs (63%).[40] Experience from burn centers confirms that septic thrombophlebitis can be difficult to detect, often presenting as occult septicemia.[42] Therefore a high index of suspicion for septic thrombophlebitis should be maintained in managing a drug abuser. Blood cultures are usually positive, and confirmation of venous thrombosis generally requires either duplex ultrasonography or contrast venography. The treatment of septic thrombophlebitis depends on whether the infection involves the superficial or deep venous system. A superficial suppurative phlebitis is managed with excision of the vein, systemic antibiotics, and open wound drainage. Delayed primary wound closure is recommended. Initial management of deep venous septic thrombophlebitis includes heparin anticoagulation and antibiotics. If clinical improvement is observed, therapy is continued. Intravenous antibiotics are continued for 3 – 6 weeks in order to prevent bacterial endocarditis, and intravenous heparin anticoagulation is usually maintained for at least 2 weeks.[17,43]
In cases where a clinical response to antibiotics and heparin is lacking, patients may undergo venous exploration with either excision or ligation of the involved vein.[44,45] Weinberg and Pasternak[45] recommend ligation of the subclavian vein at the junction with the internal jugular vein for septic thrombophlebitis involving the subclavian vein. Extraction of infected thrombus by balloon thrombectomy has also proved beneficial in clearing the sepsis.[46] Gram’s stain and culture of the thrombus assists with diagnosis. In cases involving intrathoracic veins, positive diagnosis based on thrombectomy may indicate thoracotomy or sternotomy for venous exploration, drainage, or venous ligation.[44] Transvenous infrarenal vena caval filters may be employed in cases of septic thrombophlebitis if venous ligation is imprudent or not feasible.[46 – 48]
Infected Venous Pseudoaneurysms The combination of local infection and repeated needle trauma can destroy the venous wall, with eventual pseudoaneurysm formation. Venous pseudoaneurysms are occasionally utilized as preferred sites for repeated drug injections. Two patients in our practice presented with expanding purulent groin masses
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Figure 78-3.
Femoral venous thrombosis related to illicit drug injection.
associated with surrounding cellulitis and induration. Aspiration of the masses demonstrated sanguinopurulent content. Arteriography failed to confirm an arterial false aneurysm. Both patients were explored and found to have infected femoral venous pseudoaneurysms.[49] Venography prior to exploration might have demonstrated the extent of pathology as well as the venous anatomy. Surgical treatment consists of drainage of associated abscess, proximal and distal venous ligation with excision of involved vein, and extraction of septic thrombi.[50]
Angiothrombotic Pulmonary Hypertension Pulmonary hypertension and cor pulmonale also occur with intravenous drug abuse.[12] Chronic pulmonary arterial
embolization of particulate debris is the pathogenesis. The “blue velvet syndrome,” as documented by Wendt and coauthors,[51] involves the intravenous injection of paregoric and talc-containing tripelennamine (PBZ). Pathologic study of the lungs confirms angio-occlusive lesions associated with a diffuse pulmonary vascular sclerosis as well as intravascular talc crystals. Other reports have documented pulmonary granulomatosis resulting from intravenous injection of talccontaining drugs intended for oral use.[52,53] The tablets most commonly used for intravenous injection after crushing and dissolving are methylphenidate (Ritalin), methadone, tripelennamine, propoxyphene (Darvon), phenmetrazine (Preludin), and amphetamines.[52] Pathophysiologically, these conditions are comparable to the injection of excipients into the extremity arterial circulation.
Chapter 78.
Dyspnea is the usual symptom resulting from the pulmonary talc granulomatosis.[52] A normal chest roentgenogram does not rule out the presence of extensive pulmonary talc granulomatosis, although pulmonary opacities may be radiographically evident.[54] Even with total obliteration of the lumina of many smaller pulmonary arteries, pulmonary infarcts are infrequent.[52] The diagnosis should be considered in any drug addict with cardiopulmonary distress. Lung biopsy will often confirm the diagnosis.
ARTERIAL INJURY AND EXTREMITY GANGRENE RELATED TO DRUG ABUSE Repeated attempts at deep venous injection eventually result in inadvertent arterial puncture. Brachial or femoral arterial injections are most frequent. Upper extremity arterial injections result in the syndrome referred to as a “hand trip.” Maxwell and coauthors[9] accurately describe this as a burning pain in the region supplied by the injected artery. A hyperemic flush is noted in the same region. Signs and symptoms of ischemia predominate, with pain, edema, cyanosis, and gangrene. The etiology of the ischemia and gangrene has been the focus of much interest and some controversy. Ischemia can be related to direct mechanical arterial wall injury resulting in intimal flap, arteriovenous fistula, or pseudoaneurysm. Other pathophysiologic mechanisms for ischemia related to the drugs or excipients include vasospasm, chemical endarteritis, and particulate embolization. The end result is platelet aggregation, distal arterial thrombosis, and ischemic necrosis. The degree of tissue loss is often dependent on the type of drug injected, the concentration, and the time delay before treatment.
Pathophysiology Vasoconstriction VanderPost[55] is credited with first reporting the damaging effects of intraarterial drug injection. He reported digital gangrene related to an inadvertent ulnar artery injection of 10% thiopental sodium during anesthesia. Others have reported various extremity complications related to intraarterial barbiturate injections.[56,57] The initial clinical reports stimulated experimental work on the pathophysiology of arterial drug injections. An early hypothesis proposed vasoconstriction as a primary factor resulting in gangrene. Studies done by Kinmonth and Shepherd,[58] however, demonstrated that the vasoconstriction seen with injections of 5% thiopental lasted only about 30 s. Using a rabbit-ear model, the investigators found that sympathectomy and heparin were of benefit in decreasing the area of tissue necrosis, while vasodilators were of no benefit. Tissue necrosis was related to thiopental concentration. A contrasting report by Burn[59] suggested that thiopental provoked a release of norepinephrine from the arterial wall, causing vasoconstriction. In a model
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measuring gangrene in the mouse tail, pretreatment with reserpine resulted in a decrease in the observed amount of tissue necrosis. However, Ellertson and coworkers[60] studied a rabbit-ear model with angiography and could identify no spasm of the central artery of the ear with proximal ligation and injection of 10% thiopental. They did notice venospasm and venous thrombosis, which they proposed as the key factor in the development of gangrene. Subsequent studies by these investigators demonstrated significant reduction of tissue necrosis with the use of heparin but not with reserpine.[61] Additionally, Alix and coworkers[62] and then Wright and colleagues[14] studied flow alterations after various drug injections in the hind limb of a canine model as well as the lower extremity of a subhuman primate. Barbiturates, amphetamines, narcotics, and narcotic analgesics were studied. Most drugs caused an increase in femoral arterial blood flow unaccompanied by any evidence of vasoconstriction. Some species variation was noted in that amphetamine-caused vasoconstriction in the dog but had no effect on limb blood flow in the subhuman primate. Although most experimental evidence suggests that vasoconstriction following drug injection may not be the primary factor leading to tissue necrosis, clinical benefit has been reported with the use of reserpine when administered early following parenteral drug injection.[63] Additional recent experimental evidence suggests that a component of the tissue injury following intraarterial drug injection is mediated by thromboxane release, leading to vasoconstriction and platelet aggregation. Agents aimed at blocking the release or inhibiting the production of thromboxane have proved experimentally beneficial in preventing tissue necrosis.[64]
Chemical Endarteritis Some drugs have a direct toxic effect on the artery, resulting in endothelial destruction and interstitial edema.[65,66] Engler et al.[67] observed early arterial wall inflammation associated with canine femoral arterial drug injections. These findings have led to work investigating the effect of steroids on arterial drug injection. Enloe and coworkers[68] used a rabbit-ear model as described by Kinmonth and Shepherd[58] and measured the effect of intraarterial hydroxyzine to produce gangrene. They found the immediate injection of lidocaine or papavarine was of some benefit, but intraarterial dexamethasone prevented gangrene. In addition, Buckspan and coinvestigators[65] found that pharmacologic doses of dexamethasone (Decadron) significantly reduced gangrenous changes due to intraarterial thiopental (Pentothal) in a rabbit-ear model. The clinical experience of Maxwell and coauthors[9] also invoked a chemical endarteritis with barbiturate injections causing endothelial damage of capillaries, arterioles, and arteries. They did not use steroids in their treatment regimen; however, Gaspar and Hare[66] utilized dexamethasone in their series of patients with gangrene due to drug injection. Recently Treiman and coauthors[69] reported on 48 patients with extremity ischemia following intraarterial drug injection. Their treatment protocol included anticoagulation as well as
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dexamethasone, 4 mg intravenously every 6 h for several days.
Particulate Embolization Particulate embolization is an important factor in the degree of tissue loss secondary to an intraarterial drug injection.[14,16] When oral preparations are mixed with water and injected, the excipients (talc, cornstarch, fillers, emulsives) are often more injurious than the drug itself. Wright and coinvestigators[14] found that intraarterial injections of suspensions of cornstarch and talc produced reductions of femoral arterial flow in the subhuman primate. Subsequential femoral arteriograms demonstrated microvascular obstruction in digital arteries with proximal propagation of thrombus. Polarizing microscopy of gangrenous tissues from drug addicts has documented numerous refractile bodies in the small arteries.[16] Additionally, retinal circulation emboli have been reported in drug addicts.[70]
Barbiturate Crystallization Certain classes of drugs may have unique biochemical features which augment the pathophysiology. For instance, barbiturates in aqueous solution are alkaline (pH 10.6–11.4). However, with a decrease of the pH into the physiologic range, crystallization occurs. Brown and coinvestigators[71] studied various in vitro preparations and concluded that, following barbiturate injection into blood, acid crystals form which cause intimal damage and initiate red cell hemolysis and platelet aggregation. The higher the concentration of the barbiturate, the more likely is crystal formation. These
crystals in association with platelet aggregates may cause a mechanical block of small arterioles.[71 – 73] The frequency of vascular complications related to barbiturates is probably underestimated, since barbiturate is often used to “cut” heroin.[9] Maxwell and coauthors[9] proposed a schematic representation for the pathophysiology of intraarterial barbiturate injection (Fig. 78-4).
Summary of Pathophysiology Ischemia and gangrene related to intraarterial drug injection involve several mechanisms simultaneously. Unfortunately, critical factors affecting the degree of tissue loss— namely, the type of drug injected, the concentration, and the time delay before treatment—cannot be controlled by the surgeon. Nevertheless, an understanding of the pathophysiology will help the surgeon design a proper management protocol. An arterial injection may be followed by a transient period of arterial or venous spasm associated with microembolization of particulate matter, platelet aggregation, and secondary distal thrombosis. Most reported data do not support arterial spasm as a significant factor in the pathophysiology of untoward effects caused by intraarterial drugs of abuse,[14,58] although Ryan and coauthors[13] emphasize that, when endothelial drug exposure is prolonged, even transient vasospasm may be of importance. In addition, vasodilators have proved clinically beneficial when administered early following intraarterial drug injection.[63,74] Often chemical arteritis also occurs, resulting in endothelial cell injury and subsequent vascular thrombosis.[9,67,68] Other factors that may relate to the degree of tissue loss include prolonged tourniquet time or extremity arterial compression
Figure 78-4. Schematic representation of pathophysiology of intraarterial barbiturate injection. (From Maxwell et al.[9] Copyright 1972 by American Medical Association. Reproduced by permission.)
Chapter 78.
due to abnormal posturing during an obtunded state. Also, systemic drugs may cause hypotension, which will further reduce extremity blood flow and possibly contribute to local drug exposure.
Management Management of an acute intraarterial drug injection includes initial resuscitation with normalization of cardiac output and peripheral perfusion, tetanus prophylaxis, and elevation for edema, as well as extremity immobilization. The early evaluation should include segmental ultrasonic Doppler pressures of the extremities as well as Doppler evaluation of the palmar or pedal arches and digits. Compartment pressures should be measured as clinically appropriate;[30] if elevated, a fasciotomy should be performed. Early arteriography is indicated to rule out arterial injury or thrombosis at the injection site and to evaluate distal arterial spasm or occlusion. If an arterial injury is identified at the site of injection (thrombosis, intimal flap, pseudoaneurysm, arteriovenous fistula), either early or delayed surgical repair is planned, depending on the type of injury, the degree and etiology of the distal ischemia, and the extent of local sepsis. A major arterial thrombosis accompanied by severe distal ischemia obviously requires prompt surgical intervention; however, management of a small arteriovenous fistula may be delayed until resolution of infection and local edema has occurred. Generally most arterial drug injections with accompanying distal ischemia should be acutely managed with intravenous heparin anticoagulation, which will maintain patent collaterals and inhibit further propagation of thrombus.[69] Also, the antiplatelet and rheologic properties of low molecular weight dextran support a rationale for its use.[16,66,69,75] Additionally, if the patient is seen within a few hours of injection and spasm is noted angiographically, vasodilators are probably useful.[63,74,76] Thrombolytic agents are another therapeutic modality to consider in the treatment of drug-related vascular injury, since anecdotal success has been reported.[49,74,77] Recently Silverman and Turner[74] reported success using combination therapy consisting of vasodilators, heparin, and streptokinase in three patients with hand ischemia related to intraarterial drug injection. There is also experimental and clinical evidence that steroids are beneficial for patients with intraarterial drug injection, and additional clinical trials seem indicated.[65,66,67] In addition, a variety of miscellaneous therapeutic interventions, such as stellate ganglion and brachial plexus blocks, have been recommended for the management of intraarterial drug injection.[58,75,78] Brachial plexus block theoretically provides analgesia as well as sympathetic blockade. Regional block obviously can result in local hematomas when the patient is anticoagulated,[79] although Ryan and coauthors[78] recommended a continuous brachial plexus block with an indwelling catheter in a heparinized patient. Often, long after intraarterial drug injection, a drug addict will present with demarcating tissue necrosis. Treatment at this time involves antibiotics, tetanus prophylaxis, local debridement, and even amputation designed to preserve maximal tissue function.
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VASCULAR COMPLICATIONS RELATED TO COCAINE ABUSE Cocaine hydrochloride is a fine white powder derived from the leaves of the plant Erythroxylon coca. It may be abused by either intravenous injection or nasal inhalation. In addition, the alkaloidal or “crack” form of cocaine is heat stable and able to be smoked.[80] Cocaine use acutely increases heart rate and blood pressure and induces both vasospasm and platelet activation.[81 – 83] Vascular complications associated with cocaine abuse are varied and include stroke (both ischemic and hemorrhagic), myocardial infarction, peripheral vascular thromboses, mesenteric ischemia, and thoracic aortic dissection.[15,82,84 – 89] A number of pulmonary complications related to cocaine abuse have also been reported, including pulmonary hemorrhage and infarction.[80] In addition, a form of accelerated atherosclerosis has been linked to cocaine abuse.[90]
ARTERIAL INFECTIONS RELATED TO DRUG ABUSE Koch[91] in 1851 described a patient with an infected aneurysm involving the superior mesenteric artery, but it was Osler[92] who introduced the term mycotic aneurysm in 1885 to describe peripheral aneurysms resulting from embolization due to endocarditis. Although the term mycotic aneurysm is still used to describe arterial infections of all types, the recommended classification of Wilson and coauthors[93] retains Osler’s original term only for those arterial infections resulting from emboli of endocardial origin. Most arterial infections of an extremity encountered in drug addicts are accurately classified as traumatic infected pseudoaneurysms.[93]
Clinical Problems Infectious complications are the major cause of hospitalization of drug addicts and account for 15% of their deaths.[94,95] Infected pseudoaneurysms are serious vascular complications usually involving the femoral or brachial artery. These are common sites for repeated needle injections. The process usually involves direct mechanical arterial injury by needle puncture or laceration or due to arterial wall injection of drug resulting in transmural necrosis. In addition, injections with contaminated needles introduce bacteria to the site of arterial injury. Less commonly, direct extension of a groin abscess results in arterial wall destruction and development of an infected false aneurysm. In addition, septicemia originating from a remote focus may result in arterial wall seeding, either through the vasa vasorum or onto injured endothelium. Therefore mesenteric and other visceral mycotic aneurysms typically occur in the drug addict following an episode of sepsis or endocarditis. Huebl and Read[96] reported on three heroin addicts with infected femoral pseudoaneurysms. All three were success-
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fully managed with arterial ligation and drainage. Several reports have followed documenting numerous anatomic sites of involvement.[7,9,97 – 106] Besides femoral and brachial pseudoaneurysms, other arterial infection sites reported in drug addicts include superior mesenteric,[102] carotid,[98] subclavian,[103,107] radial,[104] pulmonary,[7] external iliac,[104] inferior mesenteric,[108] and abdominal aorta.[109] Clinical presentation of an extremity arterial infection usually includes local pain and swelling at the site. Typically the site of repetitive needle injections will have extensive dermal scanning.[104] Infected femoral pseudoaneurysms are usually larger than simple groin abscesses, and they exhibit expansile pulsation laterally.[98,101] Duplex ultrasonography is useful in differentiating pseudoaneurysm from other inflammatory groin masses.[110] An obvious danger with infected pseudoaneurysms, particularly in the groin, is that the diagnosis will not be considered and the surgeon will proceed with incision and drainage, followed by profuse hemorrhage, which may be very difficult to control. A high index of suspicion is therefore urged, and preoperative arteriography is recommended to confirm the diagnosis. Abnormalities were noted in 29 of 30 arteriograms performed in one series of mycotic aneurysms.[104] It is noteworthy that intravenous drug abusers are likely to be chronically colonized with pathologic staphylococcal strains; specifically, Staphylococcus aureus continues to be the most common causative organism cultured in these patients.[38,104] In one series of infected pseudoaneurysms, infection was caused by this organism in more than 70% of the cases.[104] Initial aspiration and Gram’s stain will help in antibiotic selection prior to the culture report. The emergence of methicillin-resistant Staphylococcus makes the use of antibiotic sensitivities mandatory.[111] Mesenteric and other visceral mycotic aneurysms that occur in the drug addict are often related to endocarditis. Clinical suspicion for bacterial or fungal endocarditis should be high when sepsis occurs in any drug abuser.[8,112 – 117] Cardinal clinical findings with endocarditis include positive blood cultures and a changing heart murmur. With right-sided endocarditis, however, septic pulmonary emboli commonly can occur in the absence of cardiac murmurs. A septic pulmonary arteriovenous fistula has also been reported in a drug addict with right-sided valvular endocarditis. Left-sided endocarditis often presents with peripheral emboli resulting in peripheral arterial seeding. This can result in mycotic aneurysms at sites throughout the circulation, including
Table 78-1.
visceral arteries such as the superior[102] and inferior[108] mesenteric arteries. These patients often present as diagnostic problems with vague abdominal complaints.[49,118] Abdominal CT scanning and arteriography are both useful diagnostic tools in such drug abuse patients. A prompt diagnosis of mesenteric or other visceral mycotic aneurysms will potentially result in early surgical intervention and a successful outcome.[118]
Management The drug abuse patient presenting with an inflamed mass located near a major artery is considered to have an infected pseudoaneurysm until proved otherwise. Information derived from needle aspiration of these frequently ill-defined masses is likely to be misleading, but duplex ultrasonography is a useful, initial diagnostic test. Since these cases may be associated with a significant risk for limb loss, it seems prudent to recommend the liberal use of arteriography not only to confirm the diagnosis but also to help plan the surgical approach. The preferred surgical management for any infected pseudoaneurysm (upper or lower extremity) includes proximal and distal arterial ligation with drainage or excision of the involved artery. Limb-threatening ischemia of the upper extremity is not likely, especially when involvement is distal to the profunda brachii artery.[23,104,109] Upperextremity revascularization, when required, can usually be accomplished utilizing an autogenous tissue graft within the area of infection.[101,105] By contrast there is a significant risk of lower extremity amputation in patients with infected femoral pseudoaneurysms. Some authors have reported an amputation rate ranging from 20 to 30% when femoral bifurcation ligation is required.[104,119] In a remarkable series recently reported by Ting and Cheng,[120] however, 34 infected femoral pseudoaneurysms treated with ligation and aneurysm excision resulted in no limb loss. It is noteworthy that 24 of these pseudoaneurysms involved the femoral bifurcation. Padberg et al.[121] also recommend primary ligation in all cases and consider revascularization only when there is an absent distal Doppler signal. Surgical results reported for infected femoral pseudoaneurysm are summarized in Table 78-1. Since the vast majority of patients will maintain limb viability following infected femoral pseudoaneurysm ligation and excision, a
Surgical Results for Infected Femoral Pseudoaneurysms Due to Parenteral Drug Abuse
Surgical treatment of pseudoaneurysm Ligation and excision without revascularization Excision with in situ prosthetic bypass Excision with in situ autogenous revascularization Excision with remote prosthetic bypass
Number of patients
Postoperative wound hemorrhage
Prosthetic graft sepsis
AVOR amputation
172
12 (7%)
—
26 (15%)
5 25
2 (40%) 7 (28%)
4 (80%) —
1 (20%) 1 (4%)
40
1 (3%)
7 (18%)
4 (10%)
Ref. 18, 49, 96, 98, 101, 102, 104, 119–124 104, 106, 121 49, 101, 102, 104–106, 119, 121–123 18, 98, 104, 106, 119, 121–125
Chapter 78.
strategy employing selective revascularization seems appropriate. Successful excision of the infected femoral pseudoaneurysm requires proximal control, which may be obtained at the level of the inguinal ligament. When the inflamed mass extends above the inguinal ligament, proximal control of the external iliac artery is recommended through a lower-quadrant extraperitoneal incision. The artery is divided and ligated at this level. If feasible, distal control of the superficial femoral artery is obtained before entering the infected aneurysm and controlling the profunda femoris artery from within.[18] Ligation of normal uninvolved arterial segments is recommended. In the experience of Johnson and coauthors,[104] bleeding following ligation and excision of infected groin pseudoaneurysms occurred in 12.5% of cases, and hemorrhage was usually due to failure of a ligature placed on infected arterial segments. Patients with involvement of the femoral bifurcation are the most likely to require revascularization. In situ reconstruction utilizing autogenous vein may be employed,[49] although suitable vein is seldom available and the potential for postoperative hemorrhage due to vein graft sepsis is well recognized. Therefore revascularization, when indicated, is most often performed with a synthetic prosthesis routed through clean tissue planes either lateral to the groin or medially via the obturator foramen.[98,124,126] Unfortunately, subcutaneous grafts in this population are often used as sites for drug injection, resulting in a high incidence of subsequent graft infection (Table 78-1; Fig. 78-1). Ledgerwood and Lucas[100] reported on the management of three patients (two drug addicts) with aneurysmal abscess involving the carotid artery. The patients were treated with antibiotics and proximal carotid arterial ligation followed by delayed distal ligation and drainage. No patient experienced a neurologic deficit. Measurement of carotid stump pressure is useful in determining the safety of carotid arterial ligation. A systolic stump pressure in excess of 70 mmHg indicates adequate collateral hemispheric blood flow; carotid arterial ligation under these circumstances is acceptable.[127] In cases of lower stump pressures, autogenous reconstruction, if feasible, is recommended.[20]
Table 78-2.
Vascular Complications Related to Drug Abuse
1115
VASCULITIS RELATED TO DRUG ABUSE Numerous drugs of abuse have been linked to various types of arteritis. Citron and coworkers[128] reported a series of drug abusers who developed a necrotizing angiitis indistinguishable from periarteritis nodosa. Most of these patients abused methamphetamine alone or in combination with heroin or lysergic acid diethylamide. These patients developed pancreatitis, renal failure, hypertension, pulmonary edema, and/or neuropathy. Arteriography demonstrated arterial aneurysms and sacculations in various organ systems including kidney, liver, pancreas, and small bowel. Biopsy demonstrated a panarteritis of small and medium-sized arteries, with fibrinoid necrosis and luminal thrombosis.[128] Other links between drug abuse and arteritis include a cerebral arteritis reportedly attributed to the abuse of amphetamines[129 – 132] and cocaine[133,134] as well as heroin alone[135] or in combination with lysergic acid diethylamide.[136] The pathogenesis of drug abuse vasculitis may relate to the presence of circulating immune complexes and their deposition on blood vessel walls.[137 – 140] This leads to complement activation, migration of polymorphonuclear leukocytes, and release of lysosomal enzymes, which results in arterial wall damage.[139] The diagnosis should be suspected in any patient with a drug history who presents with signs and symptoms suggesting involvement of the renal, hepatobiliary, gastrointestinal, or central nervous systems. Treatment obviously includes cessation of the drugs. Symptoms related to drug-induced vasculitis have reportedly improved in patients treated with prednisone.[133,137]
ERGOTISM During the Middle Ages, ergotism occurred in epidemics across central and eastern Europe.[141] Its etiology was later found to be related to the ingestion of rye bread contaminated by the fungus Claviceps purpurea, an ergot-producing mold.
Pharmacologic Properties of Ergot Derivatives Action
Class Amino acid alkaloids Ergotamine tartrate Dihydrogenated amino acid alkaloids Dihydroergotamine Dihydroergotoxine Amino alkaloids Ergonovine and methylergonovine
Vasoconstriction
Oxytocic
Most active
Highly active but of delayed onset, not active orally
Active
Active
Active but less than above None
Active on pregnant human uterus
Most active
Most active
Slight
Most active
None
?
Source: Merhoff and Porter.[14] Reproduced by permission.
Alpha blocker
Sympatholytic
1116
Part Ten.
Vascular Trauma
Symptoms included diarrhea, abdominal cramps, vomiting, headache, convulsion, coma, and peripheral ischemia.[142] The characteristic burning sensation in the feet and hands associated with ergotism came to be known as “St. Anthony’s fire.”[143,144] Present-day ergot poisoning is an iatrogenic disease related to an overuse of medications containing ergot alkaloids usually prescribed for migraine headaches, postpartum hemorrhage, or deep venous thrombosis prophylaxis. The pathophysiology of ergotism is related to vasoconstriction. The classification of the ergot derivatives and their pharmacologic properties have been tabulated by Merhoff and Porter (Table 78-2).[141] Common among these is ergotamine tartrate (Cafergot), a migraine headache medication. Additionally, methysergide (Sansert), a semisynthetic ergot alkaloid prescribed for migraine headaches, can also cause severe vasoconstriction. Another ergot derivative reportedly associated with limb ischemia is dihydroergotamine, which is used in combination with heparin for prophylaxis of deep venous thrombosis.[145 – 148] Bagby and Cooper[149] have described three clinical settings in which ergot intoxication may occur. They include the chronic ingestion of therapeutic doses, the acute ingestion of excessive amounts, and the acute ingestion of small amounts by individuals with hypersensitivity to the drug. Symptomatic vasospasm is most common in the extremities, although it may involve any organ system.[141] Ergot-induced vasospasm involving the renal,[150] carotid,[151,152] mesenteric,[153] and coronary[154] arteries has been reported. A high index of suspicion is necessary to make the diagnosis of ergot-induced vasospasm, since many patients will not volunteer a history that ergot derivatives were ingested.[155] Arteriography usually demonstrates involvement of large and medium-sized arteries with abruptly tapered smooth stenosis associated with significant collaterals.[142,156] Arterial thrombosis is uncommon, while
extremity arterial spasm is usually bilateral and symmetrical.[157] In the lower extremities, spasm may begin at the level of the common iliac arteries, although the femoral and popliteal arteries are more commonly involved (Figs. 78-5 and 78-6).[157] Extensive laboratory and clinical investigation has resulted in an abundance of data concerning the pharmaco-
Figure 78-5. Bilateral and symmetrical profunda and distal superficial femoral arterial spasm due to ergot intoxication.
Figure 78-7. Patient depicted in Figs. 78-5 and 78-6 after cessation of ergotamine tartrate.
Figure 78-6. Bilateral and symmetrical popliteal and tibial arterial spasm due to ergot intoxication.
Chapter 78.
logic properties of ergotamine. It is well documented that ergotamine is bound to the alpha receptors, and attempts to experimentally displace it with phenoxybenzamine have been unsuccessful.[141,158] Additionally, ergotamine has been shown to be a vasoconstrictor even in the sympathectomized limb,[159,160] although direct sympathetic blockade using conduction anesthetic techniques as well as regional sympathectomy have both been reported to be of clinical benefit.[161 – 163] Clinical improvement of ergotism has also been reported using a variety of parenteral vasodilators including alcohol, papaverine, sodium nitroprusside, tolazoline, prostaglandins, and nitroglycerin.[142,161,164 – 169] In addition, orally administered vasodilating agents such as prazosin and diltiazem have proven beneficial.[170,171] Even hydrostatic arterial dilatation using balloon catheters has
Vascular Complications Related to Drug Abuse
1117
reportedly reversed ergotamine-induced peripheral vasospasm.[148,172] Central to the treatment of ergotism, however, is discontinuance of the drug. Improvement can be expected in a matter of days once metabolism of the drug is complete (Fig. 78-7).[141] In the presence of severe ischemia and impending tissue loss, heparinization is recommended to assist in the maintenance of patent collaterals, thereby preventing propagation of thrombus.[141] Additionally, sodium nitroprusside is currently the vasodilating drug of choice for patients with threatened tissue loss.[173] It is noteworthy that the recurrence of limb ischemia due to ergotism has been documented after discontinuance of intravenous sodium nitroprusside.[160,166]
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Abuse: Case Reports and Literature Review. Am. J. Gastroenterol. 1997, 92, 1053. Perron, A.D.; Gibbs, M. Thoracic Aortic Dissection Secondary to Crack Cocaine Ingestion. Am. J. Emerg. Med. 1997, 15, 507. Wohlman, R.A. Renal Artery Thrombosis and Embolization Associated with Intravenous Cocaine Injection. South. Med. J. 1987, 80, 928. Bacharach, J.M.; Colville, D.S.; Lie, J.T. Accelerated Atherosclerosis, Aneurysmal Disease, and Aortitis: Possible Pathogenetic Association with Cocaine Abuse. Int. Angiol. 1992, 11, 83. Kolodgie, F.D.; Virmani, R.; Cornhill, J.F.; Herderick, E.E.; Smialek, J. Increase in Atherosclerosis and Adventitial Mast Cells in Cocaine Abusers: An Alternative Mechanism of Cocaine-associated Coronary Vasospasm and Thrombosis. J. Am. Coll. Cardiol. 1991, 17, 1553. Koch, L. Ueber Aneurysma Der Arteriae Mesenterichae Superioris in Inaug Dural-Abhandlung; JJ Barfus’ Schen Universitats Buchdruckerei: Erlangen, 1851; 5 – 23. Osler, W. The Gulstonian Lectures on Malignant Endocarditis. Br. Med. J. 1885, 1, 467. Wilson, S.E.; VanWagenen, P.; Passaro, E., Jr. Arterial Infection. Curr. Probl. Surg. 1978, 15, 6. Hau, T.; Kallick, C.A. Surgical Infections in Drug Addicts. World J. Surg. 1980, 4, 403. Wiegers, S.E.; Plehn, J.F.; Rejail-Khorasani, A.; Knowlton, A.A. Purulent Pericarditis and Ventricular Pseudoaneurysm in an Intravenous Drug Abuser. Am. Heart J. 1988, 116, 1635. Huebl, H.C.; Read, R.C. Aneurysmal Abscess. Minn. Med. 1966, 49, 11. Joseph, W.L.; Fletcher, H.S.; Giordano, J.M.; Adkins, P.C. Pulmonary and Cardiovascular Implications of Drug Addiction. Ann. Thorac. Surg. 1973, 15, 263. Fromm, S.H.; Lucas, C.E. Obturator Bypass for Mycotic Aneurysm in the Drug Addict. Arch. Surg. 1970, 100, 82. Willoughby, C.P.; Evans, E.; Stoker, T.A.M.; Gabriel, R. Arterial Hemorrhage in a Drug Addict. Br. Med. J. 1973, 2, 307. Ledgerwood, A.M.; Lucas, C.E. Mycotic Aneurysm of the Carotid Artery. Arch. Surg. 1974, 109, 496. Anderson, C.B.; Butcher, H.R., Jr.; Ballinger, W.F. Mycotic Aneurysms. Arch. Surg. 1974, 109, 712. Yellin, A.E. Ruptured Mycotic Aneurysm: A Complication of Parenteral Drug Abuse. Arch. Surg. 1977, 112, 981. Ho, K.L.; Rasseich, Z.S. Mycotic Aneurysm of the Right Subclavian Artery: Complication of Heroin Addiction. Chest 1978, 74, 116. Johnson, J.R.; Ledgerwood, A.M.; Lucas, C.E. Mycotic Aneurysm: New Concepts in Therapy. Arch. Surg. 1983, 118, 577. Tuckson, W.; Anderson, B.B. Mycotic Aneurysms in Intravenous Drug Abuse: Diagnosis and Management. J. Natl. Med. Assoc. 1985, 77, 99. Welch, G.H.; Reid, D.B.; Pollock, J.G. Infected False Aneurysms in the Groin of Intravenous Drug Abusers. Br. J. Surg. 1990, 70, 330.
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Miller, C.M.; Sangiuolo, P.; Schanzer, H.; et al. Infected False Aneurysms of the Subclavian Artery: A Complication in Drug Addicts. J. Vasc. Surg. 1984, 1, 684. Lau, J.; Mattox, K.L.; DeBakey, M.E. Mycotic Aneurysm of the Inferior Mesenteric Artery. Am. J. Surg. 1979, 138, 443. Collins, G.J., Jr.; Rich, N.M.; Hobson, R.W. II; et al. Multiple Mycotic Aneurysms Due to Candida Endocarditis. Ann. Surg. 1977, 186, 136. Helvie, M.A.; Rubin, J.M.; Silver, T.M.; Kresowik, T.F. The Distinction Between Femoral Artery Pseudoaneurysms and Other Causes of Groin Masses: Value of Duplex Doppler Sonography. Am. J. Roentgenol. 1988, 150, 1177. Barg, N.L.; Supena, R.B.; Fekety, R. Persistent Staphylococcal Bacteremia in an Intravenous Drug Abuser. Antimicrob. Agents. Chemother. 1986, 29, 209. Louria, D.B.; Hensle, T.; Rose, J. The Major Medical Complications of Heroin Addiction. Ann. Intern. Med. 1967, 67, 1. Cherubin, C.E.; Baden, M.; Kavaler, F.; et al. Infective Endocarditis in Narcotic Addicts. Ann. Intern. Med. 1968, 69, 1091. Ramsey, R.G.; Gunar, R.M.; Tobin, J.R., Jr. Endocarditis in the Drug Addict. Am. J. Cardiol. 1970, 25, 608. Stimmel, B.; Donoso, E.; Dack, S. Comparison of Infective Endocarditis in Drug Addicts and Non Drug Users. Am. J. Cardiol. 1973, 32, 924. Scalcini, M.C.; Sanders, C.V. Endocarditis from Humanto-Human Transmission of Staphylococcus aureus. Arch. Intern. Med. 1980, 140, 111. Light, J.T., Jr.; Hendrickson, M.; Sholes, M.; et al. Acute Aortic Occlusion Secondary to Aspergillus Endocarditis in an Intravenous Drug Abuser. Ann. Vasc. Surg. 1991, 3, 271. Friedman, S.G.; Pogo, G.J.; Moccio, C.G. Mycotic Aneurysm of the Superior Mesenteric Artery. J. Vasc. Surg. 1987, 6, 87. Reddy, D.J.; Smith, R.F.; Elliott, J.P., Jr.; et al. Infected Femoral Artery False Aneurysms in Drug Addicts: Evolution of Selective Vascular Reconstruction. J. Vasc. Surg. 1986, 3, 718. Ting, A.C.W.; Cheng, S.W.K. Femoral Pseudoaneurysms in Drug Addicts. World J. Surg. 1997, 21, 783. Padberg, F., Jr.; Hobson, R. II; Lee, B.; Anderson, R.; Manno, J.; Breitbart, G.; Swan, K. Femoral Pseudoaneurysm from Drugs of Abuse: Ligation or Reconstruction? J. Vasc. Surg. 1992, 15, 642. Cheng, S.W.K.; Fok, M.; Wong, J. Infected Femoral Pseudoaneurysm in Intravenous Drug Abusers. Br. J. Surg. 1992, 79, 510. Levi, N.; Rordam, P.; Jensen, L.P.; Schroeder, T.V. Femoral Pseudoaneurysms in Drug Addicts. Eur. J. Vasc. Endovasc Surg. 1997, 13, 361. Patel, K.R.; Semel, L.; Clauss, R.H. Routine Revascularization with Resection of Infected Femoral Pseudoaneurysms from Substance Abuse. J. Vasc. Surg. 1988, 8, 321. Patel, K.R.; Semel, L.; Clauss, R.H. Routine Revascularization with Resection of Infected Femoral Pseudoaneurysms from Substance Abuse (Letter). J. Vasc. Surg. 1989, 10, 358.
126. Leather, R.P.; Karmody, A.M. A Lateral Route for ExtraAnatomical Bypass of the Femoral Artery. Surgery 1977, 81, 307. 127. Ehrenfeld, W.K.; Stoney, R.J.; Wylie, E.J. Relation of Carotid Stump Pressure to Safety of Carotid Artery Ligation. Surgery 1983, 93, 299. 128. Citron, B.P.; Halpern, M.; McCarron, M.; et al. Necrotizing Angiitis Associated with Drug Abuse. N. Engl. J. Med. 1970, 283, 1003. 129. Halpern, M.; Citron, B.P. Necrotizing Angiitis Associated with Drug Abuse. Am. J. Roentgenol. Radium Ther. Nucl. Med. 1971, 111, 663. 130. Margolis, M.T.; Newton, T.H. Methamphetamine (“Speed”) Arteritis. Neuroradiology 1971, 2, 179. 131. Rumbaugh, C.L.; Bergeron, R.T.; Fang, H.C.H.; McCormick, R. Cerebral Angiographic Changes in the Drug Abuse Patient. Radiology 1971, 101, 335. 132. Brust, J.C.M. Vasculitis Owing to Substance Abuse. Neurol. Clin. 1997, 15, 945. 133. Krendel, D.A.; Ditter, S.M.; Frankel, M.R.; Ross, W.K. Biopsy-Proven Cerebral Vasculitis Associated with Cocaine Abuse. Neurology 1990, 40, 1092. 134. Scully, R.E.; Mark, E.J.; McNeely, W.F.; McNeely, B.U. Case Records of the Massachusetts General Hospital. Weekly Clinicopathological Exercises. Case 27-1993. N. Engl. J. Med. 1993, 329, 117. 135. King, J.; Richards, M.; Tress, B. Cerebral Arteritis Associated with Heroin Abuse. Med. J. Aust. 1978, 2, 444. 136. Lignelli, G.J.; Buchheit, W.A. Angiitis in Drug Abusers. N. Engl. J. Med. 1971, 284, 111. 137. Heazlewood, J.J.; Bochner, F.; Craswell, P.W. Hallucinogenic Drug Induced Vasculitis. Med. J. Aust. 1981, 1, 359. 138. McAllister, H.A., Jr.; Mullick, F.G. The Cardiovascular System. In Pathology of Drug-Induced and Toxic Disease; Riddel, R.H., Ed.; Churchill Livingstone: New York, 1982; 201–228. 139. Fauci, A.S.; Haynes, B.F.; Katz, P. The Spectrum of Vasculitis: Clinical, Pathologic, Immunologic, and Therapeutic Considerations. Ann. Intern Med. 1978, 89, 660. 140. Alarcon-Segovia, D. The Necrotizing Vasculitides: A New Pathogenetic Classification. Med. Clin. N. Am. 1977, 61, 241. 141. Merhoff, G.C.; Porter, J.M. Ergot Intoxication: Historical Review and Description of Unusual Clinical Manifestations. Ann. Surg. 1974, 180, 773. 142. Henry, L.G.; Blackwood, J.S.; Conley, J.E.; Bernhard, V.M. Ergotism. Arch. Surg. 1975, 110, 929. 143. Fitzgerald, B. Saint Anthony’s Fire or Carpal Tunnel Syndrome? (A Case of Iatrogenic Ergotism). Hand 1978, 20, 82. 144. Magee, R. Saint Anthony’s Fire Revisited—Vascular Problems Associated with Migraine Medication. Med. J. Aust. 1991, 154, 145. 145. Gatterer, R. Ergotism as Complication of Thromboembolic Prophylaxis with Heparin and Dihydroergotamine. Lancet 1986, 2, 638. 146. Seifert, K.B.; Blackshear, W.M., Jr.; Cruse, C.W.; et al. Bilateral Upper Extremity Ischemia After Administration of Dihydroergotamine-Heparin for Prophylaxis of Deep Venous Thrombosis. J. Vasc. Surg. 1988, 8, 410.
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Ashenburg, R.J.; Phillips, D.A. Ergotism as a Consequence of Thromboembolic Prophylaxis. Radiology 1989, 170, 375. Baader, W.; Herman, C.K.; Johansen, K. St. Anthony’s Fire: Successful Reversal of Ergotamine-Induced Peripheral Vasospasm by Hydrostatic Dilutation. Ann. Vasc. Surg. 1990, 4, 597. Bagby, R.J.; Cooper, R.D. Angiography in Ergotism: Report of Two Cases and Review of the Literature. Am. J. Roentgenol. Radium Ther. Nucl. Med. 1972, 116, 179. Fedotin, M.S.; Hartman, C. Ergotamine Poisoning Producing Renal Artery Spasm. N. Engl. J. Med. 1970, 283, 518. Richter, A.M.; Banker, V.P. Carotid Ergotism, a Complication of Migraine Therapy. Radiology 1973, 106, 339. Lazarides, M.K.; Karageorgiou, C.; Tsiara, S.; Grillia, M.; Dayantas, J.N. Severe Facial Ischaemia Caused by Ergotism. J. Cardiovasc. Surg. 1992, 33, 383. Berman, J.K.; Brown, H.M.; Foster, R.I.; Grisell, T.L. Massive Resection of the Intestine. J. Am. Med. Assoc. 1947, 135, 918. Goldfischer, J.D. Acute Myocardial Infarction Secondary to Ergot Therapy. N. Engl. J. Med. 1960, 262, 860. Maples, M.; Mulherin, J.L.; Harris, J.; Dale, W.A. Arterial Complications of Ergotism. Am. Surg. 1981, 47, 224. Yater, W.M.; Cahill, J.A. Bilateral Gangrene of Feet Due to Ergotamine Tartrate Used for Pruritus or Jaundice. J. Am. Med. Assoc. 1936, 106, 1625. Ancalmo, N.; Ochsner, J.L. Peripheral Ischemia Secondary to Ergotamine Intoxication. Arch. Surg. 1974, 109, 832. Innes, I.R. Identification of the Smooth Muscle Excitatory Receptors for Ergot Alkaloids. Br. J. Pharmacol. 1962, 19, 120. Bluntschli, H.J.; Goetz, R.H. The Effect of Ergot Derivatives on the Circulation in Man with Special Reference to Two New Hydrogenated Compounds (Dihydroergotamine and Dihydroergocomine). Am. Heart. J. 1948, 35, 873. Andersen, P.K.; Christensen, K.N.; Hole, P.; et al. Sodium Nitroprusside and Epidural Blockage in the Treatment of Ergotism. N. Engl. J. Med. 1977, 296, 1271.
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London, M.; Magora, F.; Rogel, S. Acute Ergot Poisoning. Angiology 1970, 21, 515. Hudgson, P.; Hart, J.A.L. Acute Ergotism: Report of a Case and Review of the Literature. Med. J. Aust. 1964, 2, 589. McLoughlin, M.G.; Sanders, R.J. Ergotism Causing Peripheral Vascular Ischemia. Rocky Mt. Med. J. 1972, 69, 45. Thompson, W.S.; McLure, W.W.; Landowne, M. Prolonged Vasoconstriction Due to Ergotamine Tartrate. Arch. Intern. Med. 1950, 85, 691. Ahlgren, I.; Haeger, K.; Nylander, G. Imminent Gangrene of the Leg After Ergot Poisoning. Angiology 1968, 19, 354. Carliner, N.H.; Denune, D.P.; Finch, C.S., Jr.; Goldberg, L.I. Sodium Nitroprusside Treatment of ErgotamineInduced Peripheral Ischemia. J. Am. Med. Assoc. 1974, 227, 308. Cranley, J.J.; Krause, R.J.; Strasser, E.S. Impending Gangrene of All Four Extremities Secondary to Ergotism. N. Engl. J. Med. 1963, 269, 727. Tfelt-Hansen, P.; Ostergaard, J.R.; Gothgen, I.; et al. Nitroglycerin for Ergotism: Experimental Studies In Vitro and in Migraine Patients and Treatment of an Overt Case. Eur. J. Clin. Pharmacol. 1982, 22, 105. Edwards, R.J.; Fulde, G.W.O.; McGrath, M.A. Successful Limb Salvage with Prostaglandin Infusion: A Review of Ergotamine Toxicity. Med. J. Aust. 1991, 155, 825. Dagher, F.J.; Pais, S.O.; Richards, W.; Queral, L.A. Severe Unilateral Ischemia of the Lower Extremity Caused by Ergotamine: Treatment with Nifedipine. Surgery 1985, 97, 369. Cobaugh, D.S. Prazosin Treatment of ErgotamineInduced Peripheral Vascular Ischemia. J. Am. Med. Assoc. 1980, 244, 1360. Shifrin, E.; Olschwang, D.; Perel, A.; Diamont, Y. Reversal of Ergotamine-Induced Arteriospasm by Mechanical Intra-Arterial Dilation. Lancet 1980, 2, 1278. Wells, K.E.; Steed, D.L.; Zajko, A.B.; Webster, M.W. Recognition and Treatment of Arterial Insufficiency from Cafergot. J. Vasc. Surg. 1986, 4, 8.
CHAPTER 79
Complex Regional Pain Syndromes (Posttraumatic Pain Syndromes: Causalgia and Mimocausalgia) Ali F. AbuRahma
Posttraumatic pain syndromes, most often called reflex sympathetic dystrophy or causalgia, remain one of the most poorly understood and frequently misdiagnosed entities encountered in clinical practice. These painful syndromes can develop following irritation or damage to peripheral nerves in a variety of settings, and in the susceptible patient the initiating event may be relatively insignificant, even obscure. The associated vascular signs of these syndromes often convince the referring physician that he or she is dealing primarily with a painful vascular condition. Reflex sympathetic dystrophy (RSD) or causalgia is a disorder characterized by severe chronic refractory burning pain, usually occurring in a previously injured extremity. The symptom complex can range from burning pain, swelling, and trophic changes of the extremity to contractures and muscle atrophy. Various terms have been used to describe this entity (Table 79-1), which can be considered an exaggerated response of the extremity to trauma. The typical response includes intense and prolonged pain, delayed functional recovery, and vasomotor and trophic changes. The term causalgia should be used to denote a syndrome of burning pain. Sympathetic hyperactivity is noted as coldness and sweating of the injured extremity associated with allodynia and hyperalgesia following major nerve injury. The discomfort usually responds to sympathetic nerve blocks or sympathectomy. In 1864, Mitchell, Morehouse, and Keen[1] described the syndrome subsequently referred to as causalgia (from the Greek kausos, heat; algos, pain). Their observations were made in the course of treating American Civil War soldiers suffering gunshot wounds of the extremities. Their description remains a classic:
trivial burning to a state of torture, which can hardly be credited, but which reacts on the whole economy, until the general health is seriously affected. The part itself is not subject to an intense burning sensation, but becomes exquisitely hyperesthetic so that a touch or a tap of the finger increases the pain. Exposure to the air is avoided by the patient with a care which seems absurd, and most of the bad cases keep the hands constantly wet, finding relief in moisture rather than in the coolness of the application. As the pain increases, the general sympathy becomes more marked. The temper changes and grows irritable, the face becomes anxious and has a look of weariness and suffering. The sleep is restless, and the constitutional condition reacting on the wounded limb exasperates the hyperesthetic state so that rattling of a newspaper, a breath of air, another’s step across the ward, the vibration caused by a military band, or a shock of the feet in walking, give rise to increase of pain. At last the patient grows hysterical if we may use the only term which covers the fact. He walks carefully, carries the limb tenderly with a sound hand, he is tremulous, nervous, and has all kinds of expedients for lessening the pain. Minor causalgia and mimocausalgia are terms that were introduced to identify the syndrome when it was not the result of nerve injury[2] Lankford and Thompson[3] reclassified minor causalgia as involving a purely sensory nerve. Minor and major traumatic dystrophy describe the intensity of the syndrome when it develops after an injury that does not involve damage to a peripheral nerve. The shoulder-hand syndrome is a reflex sympathetic dystrophy that involves the entire upper extremity. A number of painful disabilities of the shoulder following coronary occlusion, hemiplegia, and other afflictions of the upper extremity have been grouped into a category designated shoulder-hand syndrome. This was
The great mass of sufferers described this pain as superficial, but others said it was also in the joints, and deep in the palms. If it lasted long, it was referred finally to skin alone. Its intensity varies from the most
Hobson/Wilson/Veith: Vascular Surgery: Principles and Practice, Third Edition, Revised and Expanded DOI: 10.1081/0819-9-120024963 Copyright q 2004 by Marcel Dekker, Inc.
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originally described by Steinbrocker and coworkers,[4] who pointed out that 15% of patients with myocardial infarction developed persistent pain in the shoulder, arm, wrist, or hand at some time during their recovery. Many different states could result in reflex vasomotor disturbances, pain, muscle spasms, and atrophy of the upper extremity, and that the pathophysiological mechanisms were related to afferent stimulation of an internuncial pool located within the spinal cord. Sudeck’s atrophy is a posttraumatic reflex dystrophy with bone involvement shown on roentgenograms.
Terms Used to Describe Posttraumatic Pain Syndromes
Table 79-1.
Acute atrophy of bones Algodystrophy Algoneurodystrophy Causalgia Causalgia-like states Disuse phenomenon Homans’ minor causalgia Major causalgia Mimocausalgia Minor causalgia Mitchell’s causalgia Painful osteoporosis Posttraumatic dystrophy Posttraumatic fibrosis Posttraumatic neurovascular pain syndrome Posttraumatic osteoporosis Posttraumatic pain syndrome Posttraumatic painful osteoporosis Posttraumatic spreading neuralgia Posttraumatic sympathalgia Posttraumatic sympathetic dysfunction Posttraumatic sympathetic dystrophy Posttraumatic vasomotor disorders Reflex neurovascular dystrophy Reflex dystrophy Reflex dystrophy of the extremities Reflex nervous dystrophy Reflex sympathetic dystrophy Shoulder-hand syndrome Steinerocher’s shoulder-hand syndrome Sudeck’s atrophy Sudeck’s osteodystrophy Sudeck’s syndrome Sympathalgia Sympathetic neurovascular dystrophy Traumatic angiospasm Traumatic edema Traumatic neuralgia Traumatic vasospasm
NEW CLASSIFICATION AND TERMINOLOGY The consensus committee that met in Orlando, Florida, in November 1993 determined that there was a need for revision of the taxonomic system for RSD.[5] There was a consensus that the term RSD had lost any clinical or research utility because of widespread indiscriminate use with no regard to diagnostic or descriptive criteria. The relationship to the sympathetic nervous system was felt to be inconsistent and the “reflex” implied by the terminology has never been demonstrated. It was also felt that the term “dystrophy” was used imprecisely and may not be present consistently. RSD had also become a nondiscriminating diagnosis for patients showing a resistance to therapy or some elements of neuropathic pain.[6] Accordingly, the nomenclature complex regional pain syndrome (CRPS) was developed to replace the previous terms of causalgia and RSD. CRPS is likely to be a spectrum of conditions with somewhat similar clinical manifestations that are often grouped together for the sake of clinical utility.[7] The main characteristic of this syndrome involves dysfunction and pain of duration or severity out of proportion to those expected from the initiating event. The cause of this pain syndrome and the pathophysiology are poorly understood. As a result, it was decided against incorporating casual or mechanistic implications, such as the role of the sympathetic nervous system, into the new nomenclature. The new classification was based on a descriptive method that would allow for future modifications as indicated by new scientific findings.[5,6] The following is a summary of the definition of this syndrome (CRPS): 1.
2.
Complex indicates the dynamic and varied nature of the clinical presentation within a single person over time, and among persons with seemingly similar disorders. It also includes the features of autonomic, cutaneous, motor, inflammation, and dystrophic changes, which distinguish this syndrome from other forms of neuropathic pain. Regional indicates the wider distribution of the clinical symptoms and findings beyond the area of the original lesion. This is considered a key characteristic of this syndrome. The distal part of the limb is usually affected, but it may occur in other parts of the body, e.g., the face or torso, and may spread to other body parts.
3.
Pain is the hallmark characteristic of this syndrome. It is out of proportion to the initiating event and includes spontaneous burning pain and thermal or mechanistically induced allodynia.
Two types of CRPS have been recognized: type I, which corresponds to the old term reflex sympathetic dystrophy, and type II, which corresponds to the term causalgia. The definitions of both types I and II contain an exclusion criterion that prevents inclusion of those patients with pain and findings physiologically, anatomically, and temporally proportionate to some form of injury. The terms sympathetically maintained pain (SMP) and sympathetically independent pain (SIP) were not considered as separate entities, but as descriptions of types of pain that can be found in a variety of pain disorders, including types I and II CRPS.
Chapter 79.
The following are the diagnostic criteria of type I CRPS (formerly RSD), as adapted from Stanton-Hicks et al.[5] and Merskey and Bogduk[8]: 1. 2.
3.
4.
It is a syndrome that follows an initiating noxious event. There is evidence of edema, skin blood-flow abnormality, or abnormal sudomotor activity in the region of the pain since the initiating event. Spontaneous pain or hyperalgesia/allodynia exists beyond the territory of a single peripheral nerve(s) and is disproportionate to the initiating event. The diagnosis is excluded by the presence of conditions that would otherwise account for the degree of dysfunction and pain.
The diagnostic criteria of type II CRPS (formerly causalgia) include: 1.
2.
3.
It is a syndrome that follows nerve injury; otherwise, it is similar to type I in all other aspects. Spontaneous allodynia or pain occurs and is not necessarily limited to the region of the injured nerve. There is evidence of edema, temperature changes, skin blood-flow changes, abnormal sudomotor activity, and motor dysfunction in the region of the pain since the initiating event. The diagnosis is excluded by the presence of conditions that would otherwise account for the degree of dysfunction and pain.
ETIOLOGY Three precipitating causes of CRPS have been identified: traumatic – fracture, dislocation, sprain, crush injury, burns, and iatrogenic injuries; nontraumatic – prolonged bed rest, neoplasm, metabolic bone disease, thrombophlebitis, myocardial infarction, and cerebral vascular accident; and idiopathic. Most cases of CRPS are posttraumatic. The proportion of causalgia cases to the total number of nerve injuries ranges from 1.8% to 12%.[9] The incidence of CRPS in trauma patients ranges between 0.05% and 5%.[10] CRPS has also been reported in 0.2 –11% of patients with Colles’ fracture,[11] and in 12– 20% of patients with hemiplegia.[12] The incidence of CRPS in myocardial ischemia patients varies between 5% and 20%, but appears to be decreasing, probably due to early mobilization.[13]
PATHOPHYSIOLOGY The exact pathogenesis remains obscure but probably involves a self-sustaining reflex among sympathetic afferents, sympathetic efferents, and possibly sensory afferents, allowing for direct cross-stimulation and pain cycle formation. The mechanism is not known but may be enzymatic, biochemical, or bioelectric in nature. The result is prolonged production of pain impulses. The occurrence of
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RSD is accompanied by hyperactivity of the sympathetic system. Two theories have been proposed to explain it. One proposes a peripheral mechanism by which the pain is felt; the other, a central mechanism at the central nervous system level. Other investigators propose a combination of the two. Most of these theories were developed to explain the causalgic pain associated with nerve injury. Most popular is the belief that “artificial synapses” occur at the site of nerve injury. First proposed by Doupe and associates,[14] the theory states that RSD results from development of an artificial synapse between adjacent fibers of the injured peripheral nerve at the point of injury. As a result, efferent sympathetic impulses generate afferent impulses in sensory fibers passing back to the spinal cord. This would explain the beneficial effect of the efferent sympathetic blockade in these patients. Such artificial synapses have been demonstrated experimentally in crushed nerves,[9] and the interruption of sympathetic efferent impulses may explain the warm, red, and dry extremity seen initially in cases of major causalgia. Devor[15] also presented experimental evidence to support the peripheral injury theory. He suggested that nerve injury or damage to Schwann cells or the axons results in local sprout outgrowths or demyelination, further leading to the acquisition of chemosensitivity by the demyelinated segment of nerve sprout and the acquisition of ectopic pacemaker-like activity. This “pacemaker” will discharge spontaneously and in response to depolarizing stimuli. Circulating catecholamines and those from sympathetic efferent fibers also activate the pacemaker and augment the discharge. Livingstone supported the central nervous system theory,[16] proposing the presence of an abnormal level of activity or increased stimulation of the internuncial neuronal pool located in the posterior horn of the spinal cord. The central effects excited peripheral effects such as spasm, vasomotor disturbance, and other changes in the tissues. These then stimulated once again the sensory afferents, setting up a feedback cycle. The “gate control” theory of pain is more recent.[17] In the substantia gelatinosa of the dorsal horns of the spinal cord, the synapses between the peripheral nerves and those that relay their impulses up the long tracts to the brain are modulated by sympathetic input. Simplified for the sake of explanation, it is as if a gate existed at this point of relay and transmission that controls the relationship between the number or frequency of incoming peripheral impulses and the number or frequency of outgoing pulses reaching the brain. High-frequency stimulation of the latter pathways in awake patients is always reported as burning pain. Thus, if the gate is open, an effect of increased sympathetic activity, sensations of, for example, touch or pressure, which would normally result in lowerfrequency impulses being relayed to the brain, might be perceived as burning pain because of the higher frequency of impulses getting through the open gate.
Sympathetically Maintained Pain and Sympathetically Independent Pain As indicated earlier, the sympathetic nervous system may or may not play a role in the pain associated with CRPS. Because of the lack of scientific understanding of the pathophysiology,
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it was decided not to include mechanistic implications, such as the sympathetic nervous system, in the new nomenclature of CRPS. The original term, sympathetically maintained pain, was described as a pain state maintained by the sympathetic nervous system.[18] The terms SMP and SIP were not considered separate disorders, but descriptions of the types of pain that can be found in a variety of pain disorders, including types I and II CRPS. The term SMP was used for the pain that is maintained by sympathetic efferent innervation or by circulating catecholamines or by neurochemical action. It was also felt that SMP is that aspect of pain that can be relieved by pharmacologic blockades or local anesthetic block of the sympathetic ganglia that serve the painful area.[19] SIP refers to the pain state that is not maintained by the sympathetic nervous system. SMP may vary over a period of time, and a patient may have a pain syndrome in which part of the pain is sympathetically maintained and another part is sympathetically independent, i.e., the patient has both SIP and SMP at the same time. A patient may have SMP at one time, only to have SIP at a later time.[7] Haddox[7] indicated that an important point of this definition is that SMP may be a feature of several types of painful entities and is not a requirement of any one entity. Both pain states may include, but are not limited to, CRPS, phantom pain, herpes zoster, neuralgias, and metabolic neuropathies.[5] SMP, accordingly, may or may not be present in a patient with CRPS, i.e., CRPS has strict inclusion criteria, but the presence or absence of SMP is not one of these. SMP, therefore, is not an equivalent term for causalgia or RSD. There is a provision for some conditions to be present in several variants, such as nerve injury plus type II CRPS, or a nerve injury with SMP, in which sympathetic block relieves some of the pain, but the presentation does not contain sufficient features for the full CRPS diagnosis.[6]
3.
4.
5.
6.
Signs 1.
Diagnosis In November 1993, the consensus committee of the American Pain Syndrome was unable to develop a uniform listing of symptoms and signs because of the variability of the clinical criterion.[20] However, the following criteria, adapted from Wilson et al.,[21] can be used to describe the symptoms of CRPS: 1.
2.
Pain is a requirement for the diagnosis of CRPS. This pain is reported in the affected extremity and is disproportionate to the expected clinical course following the initial event. It may be spontaneous or evoked and is usually reported as burning pain or diffuse pain, and is not consistent with the distribution of a peripheral nerve, even if the initial injury involved a peripheral nerve. This important distinguishing feature separates CRPS from other causes of pain, or more specific neuropathic pain disorders. The pain may be reported as throbbing or aching, intermittent or continuous, and exacerbated by physical or emotional stresses. The patient often adopts a protective posture to protect the affected extremity. Sympathetic dysfunction is reported as a sudomotor or vasomotor instability in the affected extremity compared with the unaffected extremity. This
dysfunction may vary from time to time and the patient may report that the extremity is warm and red or cold and blue, purple or mottled. Veldman et al.[22] reported that 92% of patients had altered skin temperature. Sweating, particularly of the palms or soles, may be reported as increased, decreased, or unchanged. Normal sympathetic function may be present at certain times. Sensory changes are usually reported at some stage and include allodynia and hyperesthesia in the region of the pain. Allodynia may occur in response to thermal stimulation (cold or warm), deep pressure, light touch, or joint movement. Swelling may be reported at any stage of this syndrome. This swelling is typically peripheral and may be intermittent or permanent and may be exacerbated in the dependent position of the extremity. There can also be pitting or brawny edema. Trophic changes of the skin may be reported later in the course of the syndrome. The nails may be atrophic or hypertrophic. Hair growth and texture may be decreased or increased, and the skin may become atrophic. Motor dysfunction may include dystonia, tremor, and loss of strength of the affected muscle groups. Joint swelling and stiffness may also be reported, particularly of the digits.
2.
3.
4.
Sensory examination: Allodynia may be evaluated by applying nonnoxious stimuli to the affected extremity (warm, cold, light touch, deep pressure, joint movement) and comparing it with the normal extremity. Hyperalgesia can be evaluated by comparing sensory reports from noxious stimulation between the normal area and the painful area. Vasomotor examination: Simultaneous temperature measurements of both the affected and unaffected extremities must be made with symmetrical points. The temperature of the digit pads, palm/sole, and forearm/calf should be measured with noncontact thermometry or thermography. Serial measurements should be made because peripheral temperature varies widely under normal circumstances. Skin color can also be evaluated visually or by pulse oximetry. Sudomotor examination: Resting heat output may be estimated by skin impedance[23] or quinizarin testing or cobalt blue,[24] or as part of the quantitative sudomotor reflex test (QSRT),[25] which measures resting sweat output by hygrometry and changes evoked by iontophoresis of acetylcholine into the skin.[26] Edema: Edema is generally judged by clinical impression by comparing one extremity to the other since most volume-displacement methods that provide quantitative estimates of the extent of the edema and allow objective measurement of the results of treatment can be cumbersome.
Chapter 79.
5. 6.
7.
Trophic changes: The skin, hair, and nails of the affected side is compared to the unaffected side. Motor dysfunction: The presence of dystonia, tremor, and changes in strength can be measured clinically. Objective measurements should be done (e.g., apposition and opposition pinch strength, grip, weight-bearing on lower extremity). Psychological changes: No psychometric instrument has been validated in the treatment of CRPS. The psychiatrist or psychologist generally uses familiar instruments as part of the initial assessment and follow-up.
Drucker and colleagues[27] recognized three clinical stages of causalgia: 1.
2.
3.
Acute—this stage is reversible and is characterized by constant, immediate aching or burning, disproportionate pain associated with edema, hyperalgesia, and hyperhidrosis. Patchy osteoporosis is demonstrated after 1–2 months. At this stage, satisfactory results can be expected with a chemical sympathetic block, the benefits of which often last beyond the normal duration of the block. Spontaneous resolution may occur in this stage, particularly with therapeutic support. Dystrophic—by 3 months, edema becomes indurated and the limb becomes cool, pale, and cyanotic. The pain becomes continuous, and diffuse osteoporosis is usually demonstrated. This course is usually marked by a fixed response to chemical sympathetic block, and patients rarely experience spontaneous resolution. Atrophic—pain spreads beyond the area of injury and becomes fixed. Trophic changes occur, including atrophy of the skin and fingertips with fixed joint contractures. Radiographs show severe demineralization and ankylosis. Osteoporosis can develop in any of the stages of CRPS and is termed Sudeck’s atrophy. Osteoporosis developed in 31% of the patients described by Drucker and colleagues.[27]
By stage III, the likelihood that irreversible changes are present is high, and treatment will most likely fail. With prompt treatment, patients in stages I or II may eventually receive permanent relief of their pain. Sympathectomy may not be required in stage I. However, for patients in stage III, the likelihood of a poor result is increased and sympathectomy may not give lasting relief. CRPS or reflex sympathetic dystrophy can occur in any age group, with a female-to-male ratio of 2:1 Although RSD has been reported in children,[28,29] it is not as disabling as in adults, with minimal roentgenographic or bone scan changes, and the response is usually better with conservative therapy. Persistent pain, that is, out of proportion to that expected from the initial extremity injury, is an important clue in the diagnosis of CRPS. Radiological findings of RSD may take several weeks to develop. Osteoporosis and abnormal bone scans (Technetium 99) can be found in the majority of patients with RSD.[30 – 32] Asymmetrical blood flow is usually seen, with most patients
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showing increased flow and uptake, while a few show diminished flow and uptake. The diagnosis of causalgia is certain when the clinical presentation includes superficial burning pain in the distribution of a single somatic sensory nerve, hyperesthesia, vasomotor abnormalities, radiographic evidence of osteoporosis, and a good response to sympathetic blockade. However, this classic picture can be reliably expected only in major causalgia. In minor or mimocausalgia, certain clinical features may be minimal or absent, though the response to sympathetic block may still be reliable. In fact, the ultimate relief obtained by surgical sympathectomy is predictable by careful documentation of the response to sympathetic blockade.
Assessment of Sympathetic Block It is often difficult to judge whether or not a complete sympathetic block has been obtained, especially when vascular disease is present. A significant increase in warmth, whether subjective or objective, cannot always be registered. Increased filling of the veins is a sign of sympathetic block, which is worth looking for, since the venous system is less often the site of pathological changes than the arterial system. A positive Horner’s syndrome following stellate ganglion blockade is not an indication of a complete sympathetic block of the upper limb and the head. It merely demonstrates that the sympathetic chain in the neck has been blocked. Objective signs of a complete sympathetic block are an appreciably increased skin temperature compared with the side not blocked, an increase in arterial pulsations demonstrated by oscillometry or plethysmography, and abolished secretion of sweat in the hand or foot. The presence of sympathetic vasomotor tone may be assessed by noting the response of the digit pulse amplitude to a deep breath. Normally, the pulse amplitude is attenuated with such a maneuver, whereas patients with autosympathectomy, as in diabetes mellitus, surgical sympathectomy, or advanced ischemia, may lose this vasoconstrictive reflex.
Stellate Ganglion Block Technique In the stellate ganglion block technique, the patient is placed supine, with the head slightly raised and extended backward on a pillow (Fig. 79-1). With a finger inserted between the sternocleidomastoid muscle and the trachea, the most easily palpated transverse process is sought, which is usually at the sixth level of the thyroid cartilage. A local anesthetic wheal is raised with a fine needle over the transverse process. Using two fingers, the anesthesiologist presses down between the sternocleidomastoid muscle and the common carotid artery on one side and the thyroid, trachea, and esophagus on the other. One finger palpates the transverse process and at the same time allows the insertion of a fine-gauge needle, 5– 8 cm long, toward this transverse process until needle contact is made with it. The needle must not penetrate any tissue that offers appreciable resistance. With the needle resting on the transverse process, the point of the needle is withdrawn a few millimeters and fixed. After careful aspiration, 15 –20 mL of 0.25% Marcaine (bupivacaine hydrochloride) is injected to
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Figure 79-1. Stellate ganglion block technique. Note the position of the needle.
bathe the stellate ganglion that lies at the level of C7 –D1. A positive Horner’s syndrome consisting of ptosis, miosis, enophthalmos, and anhidrosis occurring with block of the stellate ganglion is, however, not a guarantee of complete block of the sympathetic innervation of the upper extremity and the head. It merely demonstrates that the sympathetic chain in the neck has been blocked.
Lumbar Sympathetic Block Techniques Pharmacological block of the lumbar chain using conventional local anesthetic agents merely requires that the tip of the needle is placed into the perisympathetic space from the back. Landmarks for this block are L1, which is situated at the level of the junction of the 12th rib and the erector spinae muscles, and L4 –L5, at the level of a line drawn between the posterior iliac crests. Preferably, the patient should lie in the lateral position with the waist supported either by a pillow or by breaking the table so that the vertebral column is curved in the lateral plane in order to widen spaces between the transverse processes on the upper side (Fig. 79-2). Wheals are raised opposite the spinous processes of L2 and L4 7 –10 cm lateral to the midline. A 19-gauge needle 12 –18 cm long, with a depth marker on it, is introduced through the wheal and directed 45 degrees cranially or caudally so that it strikes the transverse process of the vertebra lying above or below it. Upon making contact with bone, the marker is pushed down to the skin and the needle is withdrawn. In a patient of normal size, the marker is moved so that its position for that point is double the distance between the skin and the transverse process. In thin patients, the length of needle introduced should be slightly increased, and in stout patients, slightly decreased. The distance from the tip of the needle to the marker will correspond roughly to the distance between the skin and the ventrolateral aspect of the vertebral body. The needle is inserted between the transverse processes and directed more medially, but at right angles to the skin, in the
Figure 79-2. nique).
Lumbar sympathetic block (three-needle tech-
sagittal plane. This space will be found approximately opposite the corresponding spinous process. If the needle strikes bone when the marker is close to the skin, the point will be in contact with the lateral aspect of the body of the vertebra. The bevel of the needle should face the body of the vertebra so that slight bending of the needle will allow it to slip forward to lie adjacent to the sympathetic chain. The position of the needle may be checked by x-ray, but with experience, this becomes unnecessary. Complete sympathetic blockade may be obtained with a single injection of 15 cc of Marcaine at the level of L2. Better results can be obtained using two or even three needles, one point inserted at L2 and the other(s) at L3 and L4 (Fig. 79-2).
Differential Diagnosis Pain disproportionate to the particular extremity wound suggests CRPS. However, not all pain is CRPS (causalgia or mimocausalgia). Other conditions must be ruled out, including arterial occlusion, venous thromboembolism, erythromelalgia, tight cast or dressing, infection, acute compression from edema, fibrositis, myositis, tenosynovitis, septic arthritis, collagen vascular disorders, muscle strains, sprains, postmenopausal osteoporosis, osteomyelitis, fascial herniation, peripheral neuropathy, radiculitis, hysterial conversion reaction, and malingering. A careful history and physical examination should exclude arterial ischemia in
Chapter 79.
a patient with a painful, tender, cold extremity. If the pulses are not easily felt, assessment by Doppler examination or another noninvasive vascular laboratory test would be helpful. Other conditions can also be excluded by a through clinical examination and appropriate investigations. In the differential diagnosis of CRPS, one of the most important diagnoses to consider is that of nerve entrapment. Causalgic-like pain may also occur if a nerve is caught in a suture, entrapped by a scar, or compressed by surrounding structures. The former obviously must be considered in causalgic pain appearing immediately postoperatively, but since nerve irritation or injury can occur by any compressing or pinching mechanism, there may be a causalgic component to the pain associated with any nerve compression. This is important because relief of the compression may only partially relieve the pain, and the causalgic component may persist. If peripheral nerve entrapment is suspected, there will often be a “trigger point” where the focal application of pressure will cause sharp pain. The pain will be relieved by the infiltration of a small amount of local anesthetic at this point. The pain of peripheral neuritis is often burning and associated with hyperesthesia and vasomotor phenomena. The process here is more diffuse in location and gradual in onset, without a history of trauma or some other discrete precipitating event. Patients presenting with Drucker’s stage II may be thought to have Raynaud’s syndrome. However, in the latter, the symptoms are intermittent, primarily related to cold exposure, and relieved by warmth. Furthermore, hyperesthesia is rare, and the pain is not usually severe or burning in character. As stated earlier, the clinical diagnosis of major or minor causalgia is greatly strengthened by a positive response to sympathetic blockade. The degree of pain relief a patient enjoys with such a block is an excellent predictor of the degree of relief that can be expected postoperatively should sympathectomy be undertaken.[33] Some caution should be exercised here, however, because sympathectomy can give some degree of nonspecific relief of almost any pain, including ischemic pain.[31,34] However, causalgic pain is usually dramatically relieved by sympathetic blockade (e.g., 75– 100% relief), whereas other pain usually receives only mild to moderate (25–50%) relief. The diagnosis of major versus minor causalgia is usually based on the history of the injury, the degree and characteristics of the pain and associated findings, and the response to treatment. Patients with major causalgia have a clear-cut history of nerve injury, present earlier with a fullblown classic picture, and have a better response to treatment. Patients with minor causalgia usually present later, because their initiating event is more obscure, and their clinical features may be less obvious. Treatment response may be less dramatic and less long-lasting, but this may be due, at least in part, to delay in presentation or recognition, and therefore, to treatment.
Treatment The basis for proper treatment of this syndrome is early recognition and prevention. Early mobilization of an injured extremity in patients known to be susceptible to CRPS, such
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as those with hemiplegia or myocardial infarction, is critical. When early sympathetic dystrophy changes occur, pain relief and active use of the hand, arm, or leg are indicated. Passive motion by the therapist should be avoided, as it may increase the pain and edema. Narcotics should be avoided. Splinting the hand in a functional position may be helpful. If such measures as heat, elevation, analgesics, anti-inflammatory agents, diuretics, vasodilators, and steroids are not effective in relieving the symptoms promptly, or if the symptoms become intensified over the course of several days, one should proceed directly to sympathetic blocks, which are both diagnostic and therapeutic. Desensitization of the hyperalgesic area should be begun, first stroking the area with wisps of cotton and slowly progressing to coarser objects. Trigger points, if noted, should be injected with local anesthetic or steroid mixtures. A nonsteroidal anti-inflammatory agent is begun and continued long-term. A short course of high-dose steroids may be helpful as well.[11,32] Elavil (amitriptyline hydrochloride) is recommended by Benson[35] in a dose of 50–75 mg nightly or divided during the day, with 150 mg maximum. Benson also recommended a phenothiazine such as Prolixin (fluphenazine hydrochloride), which potentiates any narcotic, possesses an analgesic property of its own, and depresses the response to peripheral stimuli. The recommended dosage is 1 mg three times daily, but doses up to 10 mg daily can be used. A sympatholytic drug such as Dibenzyline (phenoxybenzamine hydrochloride) should be begun at 10 mg daily and increased to 40 mg daily as tolerated. Intensive physical therapy should be initiated for patients with an inadequate response to the above measures. This should include a full range of motion exercises and whirlpool bath exercises. Timely physical therapy can be very helpful in patients with CRPS. Trudel and associates[36] reported good results in 88% of RSD patients treated with physical therapy. Transcutaneous electrical nerve stimulation (TENS) has been used in patients with RSD.[37] The results with this treatment have been mixed; however, since this method is rapid and safe, it should be tried before more aggressive treatment is used. Success or failure of this device in the hands of an experienced examiner will be apparent by the third to fifth treatment.[38] A course of steroids should be tried in patients with a poor response to physical therapy and/or TENS. Kozin and collaborators[32] reported a fair to excellent response to steroids in 63 of 67 of RSD patients. A daily dose of 60 mg of prednisone is usually used, which is tapered every 3 days by 5 mg, for a total therapy duration of about 5 weeks. Sympathetic ganglion blockade has been one of the most widely recommended treatments for patients with RSD.[39 – 41] Satisfactory results have been reported in 50 –80% of patients. The sooner the sympathetic blockage is started, the better the prognosis. A sympathetic block performed within the first few weeks of symptoms may give long-lasting relief. In early cases, relief of pain may last beyond the duration of the block and may even be curative. Blocks should be repeated until the pain is controlled. If the results of the sympathetic blocks are equivocal, a control block with normal saline may be performed. When relief from repeated sympathetic blocks becomes less effective and the response is dramatic but of shorter duration, surgical sympathectomy should be considered. Early sympathectomy will prevent
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the occurrence of irreversible trophic changes, which may become refractory even to sympathectomy if the syndrome is prolonged. A chemical sympathectomy using an injection of phenol or alcohol can be used in surgical high-risk patients. It should not be used in the upper extremity because of the proximity of the brachial plexus to the cervical sympathetic chain. Drucker and coworkers suggested that long delays prior to sympathectomy may jeopardize a good outcome.[27] A similar experience was noted in our series,[33] but Mockus’s group[40] concluded that there was no correlation between the duration of preoperative symptoms and the degree or duration of pain relief. In this series, a good response to the sympathetic block was required before proceeding with sympathectomy. This may explain their conclusion. Several authors have reported complete relief of symptoms in 60 – 100% of patients during a follow-up period of 6 months to 17 years.[2,27,40] Results were better when surgery was done within 6 months of the initial injury. Failure of treatment was seen most often in patients with advanced stages of RSD or in those with incomplete sympathetic denervation. Injections of alcohol and phenol have been used rather than sympathectomy in an attempt to produce lasting sympathetic denervation. However, there is a significant incidence of incomplete or transient sympathetic block with this approach. Its risks include painful neuralgia and inflammation with scarring, all of which make subsequent surgery more difficult.[42] Radiofrequency ablation has been advocated as a more precise method of achieving percutaneous sympathetic denervation.[43] Admittedly, it represents an advance over phenol or alcohol blocks, but its effect is still not as complete or durable as sympathectomy, and its local reaction would seriously interfere with subsequent sympathectomy. Furthermore, its requires a general anesthetic. Such methods have been justified primarily because of the morbidity of sympathectomy, particularly transthoracic sympathectomy, which may cause significant postthoracotomy discomfort. However, this objection is no longer valid now that the procedure can be safely and precisely done through a thoracoscope[44 – 46] and the patient discharged the following day. Through the modern thoracoscope, with its view enlarged on a video screen, and using instruments such as those developed for laparoscopic cholecystectomy, removal of T2 and T3 and division of the rami to the lower part of the stellate ganglion can be performed with precision and safety in the absence of inflammation and scarring. Others reported good results with laparoscopic lumbar sympathectomy.[47] In view of this development, and the fact that lumbar sympathectomy is so well tolerated, any percutaneous method that does not produce a complete and lasting sympathectomy cannot be condoned because it precludes safe sympathectomy later. As will be seen below, if sympathectomy is limited to those obtaining excellent relief from a sympathetic block produced by local anesthetic, it produces long-term relief in nearly 90% of patients.[33,40]
define a role for sympathectomy in causalgia.[50 – 52] In 1951, Mayfield[51] reported on 75 patients with causalgia treated and followed for 5 years; 73 of the 75 patients had significant early pain relief, and in 63% this was sustained for 5 years. In the other 37%, the pain relief was significantly improved, but not completely gone at 5 years. In Thompson’s 1979 series of 147 patients, 27 patients with causalgia were treated with sympathectomy; and among 120 patients with minor causalgia, 55 were treated with sympathectomy and 65 with medical management; 82% of the patients had excellent pain relief, 11% had good pain relief, and 7% had a poor result. Residual symptoms, however, largely secondary to associated injuries were present in 31%.[53] Mockus et al.[40] reported their experience in treating 31 patients. All patients in this series were evaluated preoperatively with sympathetic block, and 97% of the patients obtained a satisfactory level of immediate pain relief. In extended follow-up, this level of pain relief was sustained in 94%. In a similar, more recent series of 28 patients, we[33] reported a 95% long-term success rate in patients with an excellent response to a trial block. Olcott and associates also reported a 91% good to excellent result in 35 patients.[54] An interesting subgroup of patients was identified in the last two reports.[33,40] In the first series,[40] patients with causalgic pain persisting after disc surgery formed a subgroup of 12 patients for whom sympathectomy offered a therapeutic benefit equal to that in other patients. These cases constituted more than half of those in whom lumbar sympathectomy was performed; this relates both to a high index of suspicion and indoctrination of local neurosurgeons. In the second series,[33] 10 patients (36% of the total) had lumbar discectomy, and they too reported uniformly excellent results. Once called “arachnoiditis” and thought to be due to inflammation and nerve sheath irritation following disc surgery, it probably relates to residual nerve damage that occurs before nerve root compression is relieved by removal of the herniated nucleus pulposis. Clearly, the recognition of causalgia as a potential component of lumbar disc pain, its persistence after discectomy, and its potential relief by sympathectomy has not been well recognized in the English literature.
Results of Sympathectomy
Stage II
The first reports of surgical sympathectomy for causalgia were probably those of Spurling in 1930[48] and Kwan in 1935.[49] Clinical series from World War II helped to clearly
Physical therapy, TENS, and steroid therapy should be combined in these patients. Sympathetic blocks and surgical sympathectomy should be considered if these measures fail.
CONCLUSION In summary, the following are the generally acceptable guidelines for the treatment of patients with RSD.
Stage I Physical therapy with or without the TENS unit is usually useful. A local nerve or sympathetic block may be necessary for patients who experience severe pain and are unable to undergo physical therapy. If these measures fail, a course of steroid therapy should be given.
Chapter 79.
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Diagnostic Criteria for Reflex Sympathetic Dystrophy
Stage III
Table 79-2.
Steroid therapy or sympathetic blockade and surgical sympathectomy should be considered, but may be unsuccessful. Manipulation of joint contracture under general anesthesia, antidepressants, and vocational guidance may also be used. Cooney et al.[55] summarized their treatment protocol as follows: their first step was to differentiate between sympathetic pain and somatic pain (Table 79-2). The use of the RSD score can be helpful. If the pain is somatic, treatment options include isolated nerve block, continuous nerve block, TENS (external), direct electrical nerve stimulation (internal), and nerve ablation. If pain is sympathetic in origin, treatments should include protection of limb (garment or splint) combined with active use, sympathetic blocks (single or continuous), and finally sympathectomy.
Clinical symptoms and signs 1. Burning pain 2. Hyperpathia or allodynia 3. Temperature or color changes 4. Edema 5. Hair or nail growth changes Laboratory results 6. Thermometry or thermography 7. Bone radiograph 8. Three-phase bone scan 9. Quantitative sweat test 10. Response to sympathetic block Interpretation: If total of positive findings equal: . 6 Probable reflex sympathetic dystrophy 3 – 5 Possible reflex sympathetic dystrophy , 3 Unlikely reflex sympathetic dystrophy
Complications Failure to promptly recognize and appropriately treat causalgic pain is one of the most tragic complications because it often results in a complicated clinical course with irreversible changes, including wasting of the skin and muscles, fixed joint contractures, and severe demineralization of bone, as well as a missed opportunity for relief by sympathectomy. The complications of sympathectomy itself have been described in depth by the author.[33] Intraoperative complications can be avoided by meticulous attention to the
Complex Regional Pain Syndromes
anatomic relationships and normal variations of anatomy among the most frequently injured structures: the genitofemoral nerve, ureter, lumbar veins, aorta, and inferior vena cava. The most frequent postoperative complication is postsympathectomy neuralgia, which, though frequent, almost always resolves spontaneously.[34,40]
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19. Campbell, J.N. Complex Regional Pain Syndrome and the Sympathetic Nervous System. Pain 1996—An Updated Review. IASP Refresher Courses on Pain Management Held in Conjunction with the 8th World Congress on Pain, IASP Press: Seattle, 1996; 89 – 96. 20. Gibbons, J.J.; Wilson, P.R. RSD Score: Criteria for the Diagnosis of Reflex Sympathetic Dystrophy and Causalgia. Glin. J. Pain 1992, 8, 260– 363. 21. Wilson, P.R.; et al. Diagnostic Algorithm for Complex Regional Pain Syndromes. In Reflex Sympathetic Dystrophy: A Reappraisal. (Progress in Pain Research and Management); Janig, W., Stanton-Hicks, M., Eds.; IASP Press: Seattle, 1996; Vol. 6, 93 – 105. 22. Veldman, P.H.J.M.; Reynen, H.M.; Arntz, I.E.; et al. Signs and Symptoms of Reflex Sympathetic Dystrophy: Prospective Study of 829 Patients. Lancet 1993, 342, 1012 –1016. 23. Schondorf, R. The Role of the Sympathetic Skin Response in the Assessment of Autonomic Function. In Clinical Autonomic Disorders; Low, P.A., Ed.; Little, Brown: Boston, 1993; 231 – 241. 24. Fealey, R.D. The Thermoregulatory Sweat Test. In Clinical Autonomic Disorders; Low, P.A., Ed.; Little, Brown: Boston, 1993; 217 – 229. 25. Low, P.A.; Pfeifer, M.D. Standardization of Clinical Tests for Practice and Clinical Trials. In Clinical Autonomic Disorders; Low, P.A., Ed.; Little, Brown: Boston, 1993; 2887–296. 26. Low, P.A.; Wilson, P.R.; Sandroni, P.; et al. Reflex Sympathetic Dystrophy: A Reappraisal, Progress. In Pain Research and Management; Janig, W., Stanton-Hicks, M., Eds.; IASP Press: Seattle, 1996; Vol. 6, 40 – 43. 27. Drucker, W.R.; Hubay, C.A.; Holden, W.D.; et al. Pathogenesis of Post-Traumatic Sympathetic Dystrophy. Am. J. Surg. 1959, 97, 454– 465. 28. Bernstein, B.H.; Singsen, B.H.; Kent, J.T. Reflex Neurovascular Dystrophy in Childhood. J. Pediatr. 1978, 93, 211– 215. 29. Silber, T.J.; Majd, M. Reflex Sympathetic Dystrophy Syndrome in Children and Adolescents: Report of 18 Cases and Review of the Literature. Am. J. Dis. Child. 1988, 142, 1325 –1330. 30. Kozin, R.; Genant, H.K.; Bekerman, C.; et al. The Reflex Sympathetic Dystrophy Syndrome. II. Roentgenographic and Scintigraphic Evidence of Vilaterality and of Periarticular Accentuation. Am. J. Med. 1976, 60, 332– 338. 31. Davidoff, G.; Werner, R.; Cremer, S.; et al. Predictive Value of the Three-Phase Technetium Bone Scan in Diagnosis of Reflex Sympathetic Dystrophy Syndrome. Arch. Phys. Med. Rehabil. 1989, 70 (2), 135– 137. 32. Kozin, F.; Ryan, L.M.; Carerra, G.F.; et al. The Reflex Sympathetic Dystrophy Syndrome. III. Scintigraphic Studies, Further Evidence for the Therapeutic Efficacy of Systemic Corticosteroids and Proposed Diagnostic Criteria. Am. J. Med. 1981, 70, 23– 30. 33. AbuRahma, A.F.; Robinson, P.A.; Powell, M.; et al. Sympathectomy for Reflex Sympathetic Dystrophy: Factors Affecting Outcome. Ann. Vasc. Surg. 1994, 8, 372– 379. 34. Barnes, R. The role of Sympathectomy in the Treatment of Causalgia. J. Bone Jt. Surg. 1953, 35B, 172.
35. Benson, W.F. Discussion of the Presentation by Chuinard RG at Annual Meeting; American Society for Surgery of the Hand: Atlanta, GA, 1980. 36. Trudel, J.; deWolfe, V.G.; Young, J.R.; et al. Disuse Phenomenon of the Lower Extremity: Diagnosis and Treatment. J. Am. Med. Assoc. 1963, 186, 1129– 1131. 37. Meyer, G.A.; Fields, H.L. Causalgia Treated by Selective Large Fibre Stimulation of Peripheral Nerve. Brain 1972, 95, 163– 168. 38. Wilson, R.L. Management of Pain Following Peripheral Nerve Injuried. Orthop. Clin. N. Am. 1981, 12, 343 – 359. 39. Loh, L.; Nathan, P.W. Painful Peripheral States and Sympathetic Blocks. J. Neurol. Neurosurg. Psychiatry 1978, 41, 664– 671. 40. Mockus, M.; Rutherford, R.B.; Rosales, C. Sympathectomy for Causalgia: Patient Selection and Long-Term Results. Arch. Surg. 1987, 122, 668– 672. 41. Subbarao, J.; Stillwell, G.K. Reflex Sympathetic Dystrophy Syndrome of the Upper Extremity: Analysis of Total Outcome of Management of 125 Cases. Arch. Phys. Med. Rehabil. 1981, 62, 549– 554. 42. Ramos, M.; Almazan, A.; Lozano, F.; et al. Phenol Lumbar Sympathectomy in Severe Arterial Disease of the Lower Limb: A Hemodynamic Study. Int. Surg. 1983, 68, 127. 43. Noe, C.E.; Haynsworth, R.F., Jr. Lumbar Radiofrequency Sympatholysis. J. Vasc. Surg. 1993, 17, 801. 44. Appleby, T.C.; Edwards, W.H., Jr. Thoracoscopic Dorsal Sympathectomy for Hyperhidrosis: Technique of Choice. J. Vasc. Surg. 1992, 16, 121. 45. Horgan, K.; O’Flanagan, S.; Duignan, P.J.; et al. Palmar and Axillary Hyperhidrosis Treated by Sympathectomy by Transthoracic Endoscopic Electrocoagulation. Br. J. Surg. 1984, 71, 1002. 46. Malone, P.S.; Cameron, A.L.P.; Rennie, J.A. Endoscopic Thoracoscopic Sympathectomy in the Treatment of Upper Limb Hyperhidrosis. Ann. Coll. Surg. Engl. 1986, 68, 93. 47. Kathouda, N.; Wattanasirichaigoon, S.; Tang, E.; Yassini, P.; Ngaorungsri, U. Laparoscopic Lumbar Sympathectomy. Surg. Endosc. 1997, 11 (3), 257– 260. 48. Spurling, R.G. Causalgia of the Upper Extremity: Treatment by Dorsal Sympathetic Ganglionectomy. Arch. Neurol. Psychiatry (Chir.) 1930, 23, 704. 49. Kwan, S.T. The Treatment of Causalgia by Thoracic Sympathetic Ganglionectomy. Ann. Surg. 1935, 101, 222. 50. Kirklin, J.W.; Chenoweth, A.E.; Murphy, F. Causalgia: A Review of Its Characteristics, Diagnosis, and Treatment. Surgery 1947, 21, 321. 51. Mayfield, F.H., Causalgia; Charles C Thomas: Springfield, IL, 1951. 52. Shumaker, H.B., Jr.; Abramson, D.I. Post-Traumatic Vasomotor Disorders. Surg. Gynecol Obstet. 1949, 88, 417. 53. Thompson, J.E. The Diagnosis and Management of PostTraumatic Pain Syndromes (Causalgia). Aust. N.Z. J. Surg. 1979, 49 (3), 299. 54. Olcott, C.; Eltherington, L.G.; Wilcosky, B.R.; et al. Reflex Sympathetic Dystrophy—The Surgeon’s Role in Management. J. Vasc. Surg. 1991, 14 (4), 488– 492. 55. Cooney, W.P. Somatic Versus Sympathetic Mediated Chronic Limb Pain: Experience and Treatment Options. Hand Clini. 1997, 13, 355– 361.
CHAPTER 80
Compartment Syndrome David A. Kulber Geoffrey S. Tompkins Jonathan R. Hiatt have supported the unified concept that compartment syndrome and Volkmann’s contracture are related entities resulting from increased intracompartmental pressure and ischemia of compartmental tissue.
Acute compartment syndrome is defined alternatively as 1) a condition in which increased pressure within a limited space compromises the circulation and function of tissues within that space or 2) a condition in which high pressure within a closed fascial space reduces capillary blood perfusion below a level necessary for tissue viability. Recurrent compartment syndrome, also known as chronic or exertional compartment syndrome, is characterized by pain and sometimes loss of nerve function, which recur with exercise and abate if exercise is discontinued.[1] Contracture is a complication of compartment syndrome resulting from necrosis of the muscles of the distal segment of a limb. The crush syndrome, an extreme form of compartment syndrome, results from severe blunt trauma or prolonged compression of skeletal muscle leading to myonecrosis.
PATHOPHYSIOLOGY Most investigators agree that the principal abnormality causing compartment syndrome is an increase in intracompartmental pressure producing ischemia of muscles and nerves. Critical factors that influence the magnitude of neuromuscular damage include the level of intracompartmental pressure, duration of the pressure increase, local changes that impair the restoration of blood flow, and tolerance of the given tissue to ischemia. Because of the complex mechanisms involved in the compartment syndrome, there remains a debate about the absolute levels of compartment pressure that result in neuromuscular damage.
HISTORICAL CONSIDERATIONS The consequences of compartmental ischemia were first described by Richard von Volkmann in 1881.[2] Volkmann’s ischemic contracture in the forearm was attributed to arterial insufficiency and venous stasis resulting from tight bandaging of an injured extremity. In 1906, Hildebrand speculated that hydrostatic fluid transudation caused increased pressure and compromise of the circulation in the condition he termed “Volkmann’s ischemic contracture.”[3] Jonh B. Murphy advocated fasciotomy in 1914, attributing compartmental ischemia to increased intracompartmental pressure.[4] The importance of vascular injury was recognized and investigated. In 1926, Jepson reported on venous occlusion and tight bandaging in the dog and demonstrated the preventive value of early fasciotomy.[5] Increased experience with arterial injury during World War II led Foisie[6] and Griffiths[7] to speculate on the etiologic role of arterial spasm in the newly recognized entity of lower extremity compartment syndrome. In 1966, Seddon was first to fully describe lower extremity compartment syndromes and their clinical importance.[8] In recent years, clinical and laboratory studies
Microcirculation Capillary blood flow is regulated by a gradient between arterial and venous pressure (A-V gradient). Factors acting to decrease the A-V gradient, which in turn may cause compartmental ischemia, include increased venous pressure, arteriolar closure, impaired capillary flow, vasospasm, and increased capillary permeability. Venous capillary closure is a mechanical effect dependent only upon tissue pressure immediately surrounding capillaries. The critical closure theory proposes that arterioles may close under tissue pressure less than mean arterial pressure (MAP).[9] The degree of arteriolar closure at a given tissue pressure depends upon vessel size, level of vasomotor tone, and intravascular pressure. The “no reflow” phenomenon suggests that swollen cells cause compression and narrowing of the vascular lumen.[10] Injured capillary endothelium may cause narrowing by the formation of intravascular blebs. Trapping of red blood cells
Hobson/Wilson/Veith: Vascular Surgery: Principles and Practice, Third Edition, Revised and Expanded DOI: 10.1081/0819-9-120024964 Copyright q 2004 by Marcel Dekker, Inc.
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in the narrowed capillaries also contributes to impaired reflow. Vasospasm may result from injury, when traction upon an artery stretches its media and stimulates contraction. Also, increased intracompartmental pressure itself has been found to induce arterial spasm by a nonsympathetically mediated antidromic reflex. Capillary permeability has been associated with reperfusion injury.[11] In ischemic tissues, adenosine triphosphate is converted to adenosine monophosphate, which in turn is catabolized to hypoxanthine. When oxygen is reintroduced into hypoxic tissue, the reduction of hypoxanthine to xanthine ensues rapidly, and an excess of superoxide radical is produced.[12] Toxic oxygen metabolites damage cell membranes through lipid peroxidation, thus resulting in increased capillary permeability. It has been observed that more muscle damage occurs from 3 hours of partial ischemia than from total ischemia because of this reperfusion injury effect.[13,14]
Compartmental Pressure The resting intracompartmental pressure in humans has been shown to be 4 ^ 4 mmHg in humans,[15] and the normal capillary pressure ranges from 17 to 40 mmHg.[16] In canine histological studies, the lowest level of pressure reported to cause muscle necrosis was 30 mmHg maintained for 8 hours.[17] The conduction velocity in the canine peroneal nerve showed a significant decline at 30 mmHg and complete conduction block at 50 mmHg.[18] Local blood flow begins to decrease significantly at tissue pressures in the 40 –50 mmHg range and approaches zero at the 60–80 mmHg range or when externally applied pressure is less than 20 –30 mmHg below MAP.[19 – 21] This was demonstrated in a clinical series reported by Matsen:[22] no patient with a pressure measured at less than 45 mmHg showed residual sequelae of compartmental syndrome, while all patients who had a maximum pressure greater than 55 mmHg displayed significant losses of neuromuscular function. The authors concluded that because of the large individual variation in tolerance of elevated intracompartmental pressure, it would be difficult to define a critical pressure above which treatment should be instituted because of the large individual variation in tolerance of elevated intracompartmental pressure. Recent studies have suggested that determination of the difference between the mean arterial and compartmental pressures (DP) is more useful than the absolute tissue-pressure.[23] Duration of the elevation of pressure is as important as the absolute level of pressure in the pathogenesis of compartment syndromes. Tissue pressures which are tolerated initially may ultimately produce neuromuscular damage if allowed to persist for extended periods.[22]
ETIOLOGY The causes of compartment syndrome may be classified as intrinsic or extrinsic[24] (Table 80-1). Intrinsic causes are those which produce an increased compartment content. Extrinsic causes occur when the volume of the compartment is decreased.
Table 80-1. Causes of Acute Compartment Syndromes Extrinsic Mechanical constriction (casts, dressings, pneumatic trousers) Surgical closure of fascial defects Environmental injuries (frostbite, burns) Intrinsic Edema Ischemia-reperfusion (vascular injury, thrombosis/ embolism, tourniquet) Limb compression-immobilization (drug overdose, positioning during general anesthesia) Hemorrhage Trauma (vessel, bone, soft tissue injuries) Bleeding disorders Anticoagulant therapy Source: Ref. 32.
Traumatic injuries of muscle, bone, and soft tissues account for the majority of intrinsic causes. Tibial fractures and supracondylar humeral fractures in children are often associated with compartment syndromes and contractures. Thirty-six to 45% of all compartment syndromes result from lower extremity fractures,[25] and 30% of arterial injuries and 14% of severe venous injuries have been reported to result in compartment syndromes.[26] Reperfusion injury after significant periods of ischemia is another cause.[27] Extrinsic causes include casts, bandages, thermal injuries, and frostbite. Recent case reports have documented a wide variety of additional causes of compartment syndrome. These include tumors, hemophilia and other bleeding disorders, lithotomy positioning during surgery, intraaortic balloon pulsation, transaxillary arteriograms, pneumatic antishock trousers, snakebites, closed intramedullary nailing, drug abuse, ruptured Baker’s cyst, systemic capillary leak syndrome, and exercise.[24,28 – 30]
DIAGNOSIS Physical Examination Acute Compartment Syndrome Areas at risk for compartment syndrome include not only common sites such as the forearm and the leg, but also less common ones such at buttocks, thighs, feet, deltoid, and hands. The prompt diagnosis and management of acute compartment syndrome requires a high degree of suspicion, repeated documented examination at frequent intervals, additional studies where indicated, and treatment based on available information without unnecessary and potentially hazardous delay and observation. In one series, clinical grounds alone were sufficient to identify 16–21 patients in need of treatment, and all recovered without sequelae, while residual neuromuscular deficits occurred in the 5 whose clinical indications for treatment were ignored.[31] The clinical diagnosis of acute compartment syndrome is suggested by the presence of a number of subjective and
Chapter 80.
Measuring and Monitoring Techniques Acute Compartment Syndrome Elevated interstitial pressure is one of the earliest signs of acute compartment syndrome.[24] The measurement of an increase in tissue pressure will suggest the diagnosis in its early stages; however, all available clinical data should be considered in making a final diagnosis. Patients who require pressure monitoring include those who are unresponsive due to head injury, are uncooperative or unable to verbalize (intoxicated, intubated, children), or have peripheral or central nerve injuries. Compartment pressure monitoring also should be used in patients with indeterminate clinical findings.[36] The absolute level of pressure at which fasciotomy is indicated has not been established. A number of factors should be considered in interpreting the compartmental pressure data, including the clinical setting, the type of catheter system, and the recognition that actual compartment pressure is the sum of all internal and external components (dressings, armboards, and limb positioning).[37,38]
Chronic Compartment Syndrome Chronic compartment syndrome of the leg is the type most frequently encountered, although forearm syndromes have
Features Distinguishing Clinical Entities
Tense compartment Pain with stretch Paresthesia or anesthesia Paresis or paralysis Pulses intact Source: Ref. 60.
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been reported. These syndromes are usually the consequence of muscular overuse in athletes. Compartment volume can increase by as much as 20% as a result of increased capillary hydrostatic and interstitial osmotic pressures. Chronic compartment syndrome can also occur after acute and/or chronic venous insufficiency and blunt extremity trauma.[33,34] Patients will typically complain of aching and cramping of the leg in the distribution of the involved compartment. These symptoms will abate between periods of exercise, and physical examination in the pain-free patient may be entirely normal. In patients who are symptomatic at the time of exam, muscle herniation may be identified by a palpable fullness and tenderness in the involved compartment. Neurologic deficits also may be detectable at this time. Usually, the diagnosis of chronic compartment syndrome requires the measurement of compartment pressures before, during, and after exercise. Recently, thallium-201 SPECT imaging of the leg has proven useful for precise localization of the ischemic compartment involved in chronic compartment syndrome.[35] The differential diagnosis includes vascular insufficiency, tendonitis, periostitis, and stress fracture.
variable signs and symptoms. These include pain, motor deficits, sensory abnormalities, swelling, and others. Pain is a common clinical finding. Patients often complain of pain out of proportion to the external physical findings, which is worsened by stretch of the muscles in the involved compartment(s). Motor weakness presenting as paresis and paralysis in the muscles of the involved compartment is often difficult to interpret in the acute setting. Because nerve tissue is more sensitive to ischemia than muscle, purely ischemic muscle weakness should appear later in the course of compartment syndrome than other signs of ischemia, particularly neural deficits. Motor deficit is an indication of irreversible damage to muscle and nerve in the compartment. Sensory abnormalities of the nerves coursing through the affected compartment(s), both subjective and measured, are considered by many authors to be the most reliable physical signs of compartmental ischemia. The subjective changes reported may range from paresthesia to hypoesthesia to anesthesia. Recommended neurologic tests include two-point discrimination, pinprick, light touch, and vibratory sensation. Palpation of a tense compartment is uniformly recognized as the crucial sign in the diagnosis of acute compartment syndrome. Its importance cannot be overstated, because it is an easily observed measure of increased intracompartmental pressure, which may be elicited independent of the patient’s neurological status, including level of consciousness. Finally, it distinguishes acute compartment syndrome from acute arterial insufficiency and peripheral nerve injury (Table 80-2). Other findings which may be useful in diagnosis of compartment syndrome include raised erythematous patches and bullae containing serosanguineous fluid.[32] While assessment of distal arterial pulses is important, a number of clinical series have shown that peripheral pulses and capillary refill may remain intact in patients with compartment syndrome because tissue damage occurs before compartmental pressure exceeds the arterial pressure.[16] The differential diagnosis of acute compartment syndrome includes arterial injury, nerve injury, osteomyelitis, tenosynovitis, cellulitis, and thrombophlebitis. Certain features distinguish these entities (Table 80-2).
Table 80-2.
Compartment Syndrome
Compartment syndrome
Arterial occlusion
Neurapraxia
+ + 1 + +
2 + + + 2
2 2 + + +
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Chronic Compartment Syndrome Patients who are symptomatic and suspected of having chronic compartment syndrome usually show elevations in pressure to 80 mmHg and greater when stressed, and pressures remain elevated for several minutes after exercise. However, chronic compartment syndrome may exist in patients with an appropriate clinical history whose compartment pressures rise only to 30 –40 mmHg with exercise but show a delay in returning to normal levels after exercise.[3,39]
Catheter Systems Needle Manometer The needle manometer technique advocated by Whitesides[21] is the oldest catheter technique (Fig. 80-1). Pressure is applied through a syringe into the IV tubing until tissue pressure is overcome, and the saline meniscus is observed to move as fluid enters the muscle compartment. This pressure is then read from the manometer as tissue pressure.
Infusion The infusion technique proposed by Matsen[22] measures the pressure required to maintain a slow (0.7 mL/day) saline infusion into the muscle compartment being studied. This method measures the tissue resistance and can be used for continuous monitoring for several days.
Wick Catheter Fibrils of polyglycolic acid suture protrude from the bore of the catheter, acting as a wick to provide more surface area for fluid equilibration and also to prevent ball-valve obstruction of the catheter. This permeation of the wick permits contact with a large volume of tissue fluid. Interstitial
fluid pressure is transmitted into a catheter filled with sterile, heparinized saline. The advantages of the wick system include accuracy and reproducibility greater than those obtained with the needle manometer method in comparison studies.[15]
Slit Catheter The slit catheter, described by Rorabeck,[40] employs a 20cm polyethylene tube with 3-mm symmetrical slits cut in its end, which is connected via tubing to a plastic transducer dome. This technique was found to be as accurate as the wick catheter in immediate measurement and more accurate than the wick catheter or needle manometer for continuous measurement over 24 hours.
STIC Catheter The solid-state transducer intracompartment (STIC) catheter, designed by the McDermott group,[41] has its transducer within the catheter tip so that it is automatically equilibrated with the compartment being tested. The STIC catheter is easier to equilibrate, insert, maintain, and interpret. It also was reported to be more sensitive than the wick catheter, registering pressure fluctuations occurring with movement of the patient’s toes.
Supplemental Studies Nerve stimulation and conduction studies may be useful in unconscious or uncooperative patients or in those in whom it is difficult to distinguish neurapraxia from paralysis.[22] Electromyography has been shown to be helpful in evaluating the extent of muscle necrosis and neurogenic paresis, and it can also detect nerve entrapment, a frequent complication of Volkmann’s contracture. Noninvasive vascular studies such as ankle-brachial index and duplex studies may quantitate the degree of ischemia and demonstrate decreased venous filling and distorted compartmental architecture caused by swelling or hematoma.[42] Nuclear magnetic resonance spectrometry has been used in animal models to determine diminution of blood flow severe enough to cause cellular metabolic derangements.[43] Thallium-201 SPECT imaging may be useful in localizing excertional compartment syndrome.[35]
TREATMENT OF ACUTE COMPARTMENT SYNDROME
Figure 80-1. Needle manometer for intracompartmental pressure measurement.
Systemic derangements of oxygenation and fluid volume must be corrected at the outset. Attention should then be directed to the position of the limb and to the dressings. The affected limb should be stabilized and placed at the level of the heart to minimize venous congestion while preserving arterial inflow. Bandages, splints, and casts should be inspected and loosened or split.
Chapter 80.
Fasciotomy Surgical Principles Fasciotomy remains the definitive treatment of compartment syndrome. Indications for fasciotomy[36] include (1) compartmental pressure greater than 30 mmHg associated with signs of compartmental ischemia such as nerve dysfunction or muscle weakness, (2) prolonged coma with compression of the limb, (3) major soft tissue or orthopedic injury, and (4) vascular injuries and operations in which arterial inflow is diminished or absent, significant ischemia occurs before revascularization (6 hours) or arterial and venous injuries coexist. Prophylactic fasciotomy is used for elective tibial operations such as tibial osteotomy, leg lengthening, and tibial bone grafts. Fasciotomy prior to arterial repairs in shotgun wounds or crush injuries is recommended. Stabilization of fractures before vascular repair avoids disruption of anastomoses. Because fasciotomy converts a closed fracture into an open one, rigid external fixation should be applied. Use of an indwelling arterial shunt avoids ischemia of the distal extremity during fracture reduction and fixation, after which the definitive vascular repair may be done.[44] Prompt and liberal use of fasciotomy will minimize ischemic damage and diminish the chance of complications.[45] Favorable functional results have generally been reported only if the operation is performed with 12– 24 hours following onset of signs and symptoms.[46] Debridement of muscle is kept to a minimum because it is extremely difficult to assess viability macroscopically. It has been recommended that no muscle be excised within the first 72 hours after injury. This approach avoids debridement of marginally viable muscle with the potential for regeneration.[27] The only exception is crush syndrome, where necrotic muscle must be removed to minimize systemic derangements. Epimysiotomy, or incision of the fibrous muscle sheath, is recommended for any muscle not showing rapid revascularization after fasciotomy. This is often required in the buttock and deltoid compartments, where fascial and epimysial fibers blend.[47]
Wound Care Wounds are usually packed open, and the limb is splinted. Primary closure can be attempted if post fasciotomy compartment pressures return to noncritical levels. Contracture is inhibited by active and passive range-of-motion exercises. Wound closure is performed after 3 – 7 days, either by delayed primary skin closure or split-thickness skin grafting.[24] The shoelace technique may be used to achieve delayed primary closure without the need for a skin graft.[48]
Outcome Factors affecting outcome include underlying atherosclerotic disease, anemia, and hypovolemia. Infection is the principal complication of fasciotomy and may result in amputation and death. However, Rush has reported a minimal incidence of wound infection in a series of open fasciotomies and has emphasized that persistent ischemia and systemic disease are the usual causes of morbidity and mortality.[49]
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Other complications of fasciotomy include reduction in active muscle strength, chronic neuropathy, and leg swelling. Reperfusion injury from release of products of muscle necrosis into the systemic circulation may follow fasciotomy or arterial repair. Hyperkalemia, acidosis, and myoglobinuric renal failure may result from myonecrosis. Postfasciotomy hemorrhage is a stubborn problem seen occasionally in patients who required the procedure because of intracompartmental bleeding. These patients often have systemic disorders causing bleeding, such as hematologic malignancy or thrombocytopenia of other etiologies. Consultation from an experienced hematologist should be obtained.
Adjunctive Therapy Free radical scavengers have been shown to reduce skeletal muscle necrosis after reperfusion injury. In the animal model, Bulkley et al.[50] has demonstrated a significant decrease in compartment pressures after reperfusion in animals treated with free radical scavengers Ricci et al.[51] also found a significant reduction of muscle injury by using free radical scavengers in reperfusion injury, but there was no preservation of normal neuromuscular function. Hypertonic mannitol has been shown to lower interstitial pressure by osmotic diuresis and scavenging of free oxygen radicals. [52] Several experimental studies have shown mannitol to be useful in treatment of compartment syndrome. In a clinical series, Shah used hypertonic mannitol in conjunction with revascularization procedures for thromboembolism, and only 3 of 24 patients required fasciotomy, compared to 13 of 17 untreated patients.[51,53] In a recent study of the use of hypertonic mannitol for treatment of acute ischemia-reperfusion injuries in 186 patients over a 5-year period, the authors concluded that mannitol may have a protective effect, decrease the need for fasciotomy, and minimize neuromuscular dysfunction.[48]
CHRONIC COMPARTMENT SYNDROME Fasciotomy is the treatment of chronic compartment syndrome. Prior to this, the patient should have plain radiographs and a technetium bone scan to search for stress fractures or other pathology. The duration of symptoms also is a factor in the decision to operate. Reneman[54] believes that the duration should be “months, not weeks,” and Detmer[55] discourages operation when symptoms have been present for less than one year. Although symptoms from chronic compartment syndrome may temporarily improve with rest, physiotherapy, and anti-inflammatory medications, most authors report failure of nonoperative management in true chronic compartment syndrome. In properly selected patients, results from fasciotomy are generally good. Bilateral fasciotomies, frequently the subcutaneous type, are often required. Turnispeed found that patients treated by open fasciectomy instead of subcutaneous fasciotomy had fewer early postoperative wound complications and late recurrences.[34] The prognosis
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for return to a high level of athletic performance following surgical treatment of chronic compartment syndrome is quite good.[39]
structures are branches of the peroneal and posterior tibial vessels.
Compartments of the Foot
COMPARTMENT SYNDROMES OF THE LOWER EXTREMITY Anatomy Compartments of the Leg (Anterior, Lateral, Deep, Superficial) The anterior compartment is most prone to development of compartment syndrome. Its fascial boundaries are the crural fascia anteriorly, intermuscular septum laterally (separating the lateral compartment), and the interosseous membrane between tibia and fibula posteriorly. The muscles of the anterior compartment are dorsiflexors (tibialis anterior, extensor digitorum brevis, extensor hallucis longus, and peroneus tertius) and are innervated by the deep peroneal nerve, whose cutaneous distribution is the web space between the great and second toe. The vascular supply is from the anterior tibial artery. The neurovascular bundle is bounded by the tibialis anterior, extensor hallucis longus, and the interosseous membrane. The lateral or peroneal compartment is the second most frequently involved in compartment syndromes. Its boundaries are the crural fascia anteriorly and laterally, the anterior intermuscular septum and fibula medially, and the posterior intermuscular septum separating the superficial posterior intermuscular compartment posteriorly. The muscle contents of the lateral compartment (peroneus longus and brevis) are innervated by the superficial peroneal nerve, whose cutaneous distribution is primarily the middorsal aspect of the foot. There are no major vessels in this compartment. Of the two posterior compartments, the deep posterior is more frequently involved in compartment syndrome. This compartment is bounded by the tibia, interosseous membrane, and fibula anteriorly and the transverse intermuscular septum separating the superficial compartment posteriorly. The muscles of the deep compartment are the tibialis posterior, flexor digitorum longus, and flexor hallucis longus. These are innervated by the tibial nerve, which emerges from the compartment and gives rise to the medial and lateral plantar nerves of the foot, as well as the medial calcaneal nerve. The posterior tibial vessels course with the tibial nerve in a neurovascular bundle just deep to the transverse intermuscular septum. The superficial compartment is covered posteriorly by the crural fascia and is bounded anteriorly by the transverse intermuscular septum. The muscles of the compartment, the gastrocnemius, soleus, and plantaris, are unique in receiving innervation from the tibial nerve, which travels outside of their compartment. The only nerve within the superficial compartment is the sural, which supplies the cutaneous region over the lateral dorsum of the foot and the lateral malleolar region via its lateral calcaneal branch. The only vascular
The foot is described classically as having four compartments (medial, central, lateral, and interosseous); however, recent injection studies have demonstrated at least nine compartments.[56,57] Communication has been demonstrated to exist between the deep posterior compartment of the leg and the calcaneal compartment of the foot, thus explaining the development of deep posterior compartment syndromes in patients with calcaneal and talar fractures.[58]
Other Compartments The gluteal, ililiacus-psoas, and anterior and posterior thigh compartments are rarely involved in compartment syndromes. Their anatomy is reviewed elsewhere.[59]
Fasciotomy Techniques—Leg Subcutaneous (Closed) Fasciotomy The subcutaneous or limited skin incision fasciotomy has been used to treat chronic compartment syndromes but has only limited utility in the treatment of acute compartment syndrome. The method of Detmer[55] for the anterior compartment involves scissor-stripping of the fascia through three transverse incisions, leaving the compartment widely open as verified by finger inspection. Advocates of this technique deem it to be the preferred treatment for selected cases with only moderate swelling and propose that its advantages include avoidance of large infection-prone skin defects which might become infected, delay healing time, or require skin grafts for closure. The weakness of subcutaneous fasciotomy is that the skin itself may become the limiting envelope in extremity swelling. It also does not provide adequate decompression of all muscle compartments.
Fibulectomy-Fasciotomy Transfibular fasciotomy with fibulectomy is intended to provide better exposure for more thorough decompression than is achieved by closed fasciotomy.[60,61] Extensive fibular resection may be accomplished through a single extensive posterolateral incision allowing access to all muscle compartments and neurovascular structures from the popliteal fossa to the ankle. It has been reported that fibulectomy is of particular importance in the patient who has sustained significant venous injury, where avoidance of a medial incision or multiple incisions is crucial to minimize interruption of venous drainage. There are several drawbacks to this procedure. It requires extensive muscle stripping and dissection under regional or general anesthesia, eliminating it as a bedside procedure. Also, the potential exists for vascular damage, because branches of anterior tibial and peroneal vessels crossing the lower third of the fibula must be ligated. Because of these and other complications, fibulectomy is rarely warranted.
Chapter 80.
Parafibular Fasciotomy The parafibular approach (Fig. 80-2; see also Fig. 80-4A), described by Matsen,[22] is used to decompress all four compartments if an acute compartment syndrome develops in any one of them. A single incision is made from the neck of the fibula to the lateral malleolus, and the lateral compartment is then opened. Retraction of the anterior skin exposes the anterior compartment fascia, which is then opened with care to avoid the superficial peroneal nerve. The posterior skin is retracted to expose and open the fascia of the superficial compartment. The final step is to retract the lateral compartment anteriorly and to release the soleus from the fibular shaft and retract it posteriorly, exposing the deep posterior compartment fascia, which is then opened.
Double-Incision Fasciotomy The double-incision fasciotomy (Figs. 80-3, 80-4B) was originally described by Mubarak[36] and Owen[62] and has been modified. The anterolateral incision extends 20 – 25 cm midway between the fibular shaft and the tibial crest, approximately over the anterior intermuscular septum. Skin edges are undermined proximally and distally to allow visualization of most of the compartment fascia. A transverse incision is made in the fascia to identify the anterior intermuscular septum and to locate the superficial peroneal nerve in the lateral compartment adjacent to the septum. The anterior compartment is then opened with scissors,
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proceeding proximally toward the patella and distally toward the great toe. The lateral compartment fasciotomy is made in line with the fibular shaft, directing the scissors toward the proximal and distal fibular landmarks. The fasciotomy thus remains posterior to the superficial peroneal nerve. The second, posteromedial incision is 20 –25 cm in length and is placed 2 cm posterior to the posterior margin of the tibia, avoiding injury to the saphenous nerve and vein. Skin flaps are raised, and the saphenous structures are retracted anteriorly. Another transverse fascial incision is used to identify the posterior intermuscular septum between superficial and deep posterior compartments. The tendon of the flexor digitorum longus in the deep compartment and the Achilles’ tendon in the superficial compartment are identified. The superficial compartment fasciotomy is carried as far proximally as possible, then distally behind the medial malleolus. The deep compartment is next opened from distal to proximal beneath the soleus. If the soleus attaches distally to more than half of the tibia, it should be released.
Fasciotomy Techniques—Foot Dorsal Incision The dorsal approach for fasciotomy, described by Mubarak and Owen,[63] is performed by making two longitudinal incisions placed medial to the second and lateral to the fourth metatarsals, thus creating a wide bridge
Figure 80-2. Parafibular fasciotomy. (A ) Lateral incision exposing the lateral compartment fascia. (B ) Skin retraction exposing anterior compartment fascia. (C ) Superficial posterior compartment exposed. (D ) Exposure and incision of the deep posterior compartment fascia.
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are separated from remaining structures by a thin fascia. In the proximal volar compartment are the lacertus fibrosus of the biceps and pronator teres; the distal edge is the transverse carpal ligament. The muscular contents of the compartment are the superficial muscles named above and the deep group: flexor digitorum superficialis and profundus, flexor pollicis longus, and pronator quadratus. The principal motor supply to these muscles is the median nerve, with the ulnar nerve contributing to half of the flexor digitorum profundus. The compartment contains both radial and ulnar arteries before the former exits beneath the thumb abductors to form the dorsal arch, and the latter travels into the palm to form the superficial palmar arch.
Dorsal Compartment The dorsal compartment is also bounded medially, laterally, and posteriorly by antebrachial fascia. Ulna, radius, and interosseous membrane form its anterior border. Muscles in the dorsal compartment include extensor carpi ulnaris, extensor digitorum communis, abductor pollicis longus, and extensor pollicis longus and brevis. The motor nerve to these muscles is the posterior interosseous branch of the radial. Figure 80-3. Double-incision fasciotomy. (A ) Anterolateral skin incision; exposure of septum and superficial peroneal nerve; anterior and lateral compartment fascial incisions. (B ) Posteromedial skin incision; exposure of posterior intermuscular septum; superficial and deep compartment fascial incisions.
of skin. Dissection is carried down to the bone longitudinally with minimal subcutaneous disruption. Once bone is encountered, further longitudinal dissection is performed in each interosseous space, reaching the medial and lateral compartments.
Medial Incision The long plantar medial incision provides access to all fascial compartments. The incision follows the length of the inferior surface of the first metatarsal and enters the medial compartment between the metatarsal and the abductor hallucis muscle. Retraction of the abductor hallucis muscle permits access to the other compartments by gentle blunt dissection, as described by Myerson.[57]
COMPARTMENT SYNDROMES OF THE UPPER EXTREMITY Anatomy Volar Compartment The flexor or volar compartment of the forearm is bounded by antebrachial fascia anteriorly, medially, and laterally and by radius, interosseous membrane, and ulna posteriorly. In the distal aspect of this compartment, the superficial muscles almaris longus, flexor carpi ulnaris, and flexor carpi radialis
Other Compartments The third compartment of the forearm, the so-called “mobile wad,” is composed of brachioradialis and extensors carpi radialis longus and brevis. Other compartments in the upper extremity include the deltoid, biceps, and triceps.[59]
The Hand The palm consists of hypothenar and thenar compartments as well as four dorsal and three volar interosseous compartments. The finger is enclosed in tight investing fascia of the skin at the flexor creases.[64] Isolated compartment syndrome of the hand is rare and is often associated with injury to the forearm and wrist. The carpal tunnel should also be released at the time of fasciotomy.
Fasciotomy Techniques—Arm Incisions for decompression of the upper limb, particularly the forearm, should be made with anticipation of the possible need for later tendon transfers should muscle infarction become progressive despite decompression.[65] Volar decompression is performed through a single incision beginning proximal to the antecubital fossa, extending to the midpalm, and including a carpal tunnel release. In cases of median nerve dysfunction, three areas where compression may occur should be explored, including the lacertus fibrosus (always released during fasciotomy), the proximal edge of pronator teres, and the proximal flexor digitorum superficialis. The dorsal compartment is decompressed through a longitudinal incision over the dorsal forearm, shorter than the volar incision, and skin edges are undermined proximally and distally. The entire length of the dorsal fascia should be incised.
Chapter 80.
Figure 80-4.
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Techniques seen in cross section: (A ) parafibular fasciotomy; (B ) double-incision fasciotomy.
It has been recommended that pressure in the dorsal compartment should be measured prior to and after volar decompression, and fasciotomy should be performed if compartment pressure exceeds 30 mmHg. The “mobile wad” does not normally require decompression, but if necessary, it
can be decompressed through a volar curvilinear incision.[32,65,66] Compartment syndromes of the hand most often are the result of crush injuries or burns. Treatment of subsequent posttraumatic contracture may be challenging and complex.[67]
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ABDOMINAL COMPARTMENT SYNDROME When abdominal pressure becomes elevated to pathologic levels, abdominal compartment syndrome (ACS) may occur. ACS includes the following features: 1) elevated ventilatory pressures; 2) elevated central venous pressure; 3) decreased urine output; 4) massive abdominal distention; 5) reversal of these derangements with abdominal decompression. Two recent reviews provide outstanding summaries of this syndrome.[68,69] Intraperitoneal (abdominal) pressure, usually expressed in mmHg, is approximately zero and may be measured using direct and indirect techniques. The most commonly used direct technique is the electronic insufflator system, used for measurement of the pressures produced with carbon dioxide pneumoperitoneum for laparoscopic operations. With indirect techniques, pressures are measured across the wall of an intra-abdominal structure via an indwelling device. Bladder pressure is used most commonly today. The bladder serves as a passive diaphragm for volumes of 50 – 100 mL, and bladder pressures have been shown to correlate with IAP for pressures ranging from 5 to 70 mmHg. Operationally, the indwelling bladder catheter is connected to manometer system, and IAP may be measured at the bedside in a rapid and simple system. Causes of ACS may be acute and chronic. Acute causes are spontaneous, postoperative, traumatic, and iatrogenic. Acute and chronic causes are listed in Table 80-3. Mortality of ACS is as high as 40% in collected reports. Most cases of ACS occur in association with major trauma, with or without a major vascular injury; multifactorial mechanisms are responsible for posttraumatic ACS. These mechanisms include hypoperfusion of the viscera with hemorrhagic shock; large-volume fluid resuscitation; tight abdominal closures, sometimes with packing, in patients who have undergone exploratory laparotomy; and the use of positive pressure ventilation. The contents of the abdominal compartment may be increased markedly with swollen intestines, ongoing coagulopathic hemorrhage, and the use of packs for tamponade of bleeding surfaces.
Table 80-3.
Causes of Abdominal Compartment Syndrome
Acute Peritonitis Intra-abdominal abscess Ileus or intestinal obstruction Ruptured abdominal aortic aneurysm Intra-abdominal bleeding Tight abdominal closure Abdominal packing Mesenteric vascular occlusion Pneumoperitoneum
Chronic Ascites Tumors Pregnancy Peritoneal dialysis
Major pathophysiologic effects are associated with increased IAP. The abdominal wall becomes stiffer, and compliance falls in a linear fashion. Venous return is diminished because of decreased IVC flow and elevation of the diaphragm. Diaphragmatic elevation produces increased ventricular filling pressures and decreased cardiac compliance, hindering return of blood to the heart. Visceral blood flow declines linearly with increasing IAP. Perfusion of mesenteric arteries, intestinal mucosa, and liver are diminished, with resultant visceral ischemia, which may be quantified using gastric tonometry. Renal blood flow, glomerular filtration rate, and urine output are diminished. Oliguria is a hallmark of ACS and occurs as a consequence of decreased cardiac output and compression of the aorta, renal arteries, and veins, but not of the ureter. The thoracic cavities are compressed by the abdominal distention, and lung compliance falls. Elevated ventilatory pressures, like oliguria, are hallmarks of the syndrome. Pulmonary artery pressures and pulmonary vascular resistance are increased. Arterial blood gas derangements include hypoxemia, hypercarbia, and acidosis. Hemodynamic changes also are marked. Cardiac output is depressed because of markedly diminished stroke volumes, despite compensatory tachycardia. Preload is decreased, because of decreased venous return and increased intrathoracic pressure, and afterload is increased, because of elevated systemic vascular resistance. Central venous and pulmonary capillary wedge pressures also are increased. Treatment of ACS is surgical and requires abdominal decompression and closure of the abdominal wall. The effects of abdominal decompression are dramatic, with immediate improvement in cardiac, respiratory, and renal function. Prior to decompression, aggressive efforts are directed to restoration of intravascular volume with blood and products and maximization of oxygen delivery. Invasive hemodynamic monitoring and large-bore vascular access are essential. Coagulation defects and hypothermia should be corrected insofar as possible; however, ACS may develop during massive resuscitation after operation for major injury. When clinical deterioration is marked, with anuria, ventilatory dysfunction, and hemodynamic instability, abdominal decompression may be needed before the therapeutic goals have been reached. Options for abdominal closure at the time of decompression include open packing, skin closure, or prosthetic closure. Open packing has risks of fistulization, evisceration, and massive fluid loss. The skin may be closed over open fascia using sutures or towel clips, but the risk here is of recurrent compression. Prosthetic closures are used most frequently. Various types of prosthetic mesh are available, but as these are quite expensive, the use of a sterilized, open 3 L irrigation bag, sutured to fascia or skin, is preferred by many surgeons. Abdominal reclosure is performed 4 –7 days following decompression. Surgical options include definitive closure of the abdominal wall at this time, or a staged closure with mesh or skin grafts may be chosen. If the closure is staged, definitive closure is performed at a minimum of 3 –6 months postoperatively.
Chapter 80.
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44. Thomas, D.D.; Wilson, R.F.; Wiencek, R.G. Vascular Injury About the Knee, Improved Outcome. Am. Surg. 1989, 55, 370– 377. 45. Myers, S.I.; Harward, T.R.S.; Maher, D.P.; et al. Complex Upper Extremity Vascular Trauma in an Urban Population. J. Vasc. Surg. 1990, 12, 305– 309. 46. Rorabeck, C.H. Treatment of Compartment Syndromes of the Leg. J. Bone J. Surg. 1984, 66B, 93–97. 47. Eaton, R.G.; Green, W.T. Epimysiotomy and Fasciotomy in the Treatment of Volkmann’s Ischemic Contracture. Orthop. Clin. N. Am. 1972, 3, 175– 186. 48. Berman, S.S.; Schilling, J.D.; McIntyre, K.E.; Hunter, G.C.; Bernhard, V.M. Schoelace Technique for Delayed Primary Closure of Fasciotomies. Am. J. Surg. 1994, 167, 435– 436. 49. Rush, D.S.; Frame, S.B.; Bell, R.M.; et al. Does Open Fasciotomy Contribute to Morbidity and Mortality After Acute Lower Extremity Ischemia and Revascularization? J. Vasc. Surg. 1989, 10, 343– 350. 50. Perler, B.A.; Tohmeh, A.G.; Bulkley, G.B. Inhibition of the Compartment Syndrome by the Ablation of Free Radical-Mediated Reperfusion Injury. Surgery 1990, 108, 40– 47. 51. Ricci, M.A.; Graham, A.M.; Corbisiero, R.; et al. Are Free Radical Scavengers Beneficial in the Treatment of Compartment Syndrome After Acute Arterial Ischemia? J. Vasc. Surg. 1989, 9, 244– 250. 52. Better, O.S.; Zinman, C.; Reis, D.N.; et al. Hypertonic Mannitol Ameliorates Intracompartmental Tamponade in Model Compartment Syndrome in the Dog. Nephron 1991, 58, 344–346. 53. Buchbinder, D.; Karmody, A.M.; Leather, R.P.; Shah, D.M. Hypertonic Mannitol, Its Use in the Prevention of Revascularization Syndrome After Acute Arterial Ishchemia. Arch. Surg. 1981, 116, 14– 21. 54. Reneman, R.S. The Anterior and the Lateral Compartment Syndrome of the Leg Due to Intensive Use of the Muscles. Clin. Orthop. 1975, 113, 69– 80. 55. Detmer, D.E. Chronic Leg Pain. Am. J. Sports Med. 1980, 8, 141–144.
56. Manoli, A. Compartment Syndromes of the Foot: Current Concepts. Foot Ankle 1990, 10, 340– 344. 57. Myerson, M. Diagnosis and Treatment of Compartment Syndrome of the Foot. Orthopedics 1990, 13, 711– 717. 58. Myerson, M.S.; Berger, B.I. Isolated Medial Compartment Syndrome of the Foot: A Case Report. Foot Ankle Int. 1996, 17, 183– 185. 59. Garfin, S.R. Anatomy of the Extremity Compartments. In Compartment Syndromes and Volkmann’s Contracture; Mubarak, S.J., Hargens, A.R., Eds.; W.B. Saunders: Philadelphia, 1981; 17 – 46. 60. Enst, C.B.; Kaufer, H. Fibulectomy-Fasciotomy: An Important Adjunct in the Management of Lower Extremity Arterial Trauma. J. Trauma 1971, 11, 365– 380. 61. Kelly, R.P.; Whitesides, T.E. Transfibular Route for Fasciotomy of the Leg. J. Bone Jt. Surg. 1967, 49A, 1022– 1023. 62. Mubarak, S.J.; Owen, C.A. Double Incision Fasciotomy of the Leg for Decompression in Compartment Syndromes. J. Bone Jt. Surg. 1977, 59A, 184– 187. 63. Mubarak, S.J.; Owen, C.A. Compartmental Syndrome and Its Relation to the Crush Syndrome: A Spectrum of Disease. Clin. Orthop. 1975, 113, 81–89. 64. Ouellette, E.A.; Kelly, R. Compartment Syndromes of the Hand. J. Bone Jt. Surg. Am. 1996, 78, 1515– 1522. 65. Carter, P.R. Crush Injury of the Upper Limb: Early and Late Management. Orthop. Clin. N. Am. 1984, 14, 719– 747. 66. Gelberman, R.H. Compartmental Syndromes of the Forearm: Diagnosis and Treatment. Clin. Orthop. 1981, 161, 252– 261. 67. Tajima, T. Treatment of Post-traumatic Contracture of the Hand. J. Hand Surg. 1988, 13B, 118– 129. 68. Burch, J.M.; Moore, E.E.; Moore, F.A.; Franciose, R. The Abdominal Compartment Syndrome. Surg. Clin. 1996, NA76, 883– 842. 69. Schein, M.; Wittmann, D.H.; Aprahamian, C.C.; Condon, R.E. The Abdominal Compartment Syndrome: The Physiological and Clinical Consequences of Elevated Intra-Abdominal Pressure. J. Am. Coll. Surg. 1995, 180, 745– 753.
CHAPTER 81
Principles of Vascular Access Surgery Robert S. Bennion Samuel E. Wilson From the beginning, the full potential of hemodialysis for the long-term treatment of patients with chronic renal failure was limited by the lack of a means for repeated access to the vascular system. At the outset, it was necessary for repeated cutdowns to be made on an artery and vein for each dialysis, following which the vessels were ligated. The duration of a course of dialysis was, therefore, limited to the treatment of acute renal failure. W. J. Kolff, the designer of the first practical dialysis machine, observed in 1944, “when a preparation of the arteries was necessary (all veins being ruined) very persistent hemorrhages arose from the subcutaneous tissue owing to the heparine. . .. After the 12th dialysis became a failure, the artery being damaged, the urea percentage of the blood rapidly rose to 640 mg percent whereupon death followed.”[1] Scribner, Dillard, and Quinton[2] (an internist, a surgeon, and an engineer) in 1960 introduced the first successful apparatus for provision of reasonably long-term cannulation of an artery and vein using an external Silastic shunt. This was widely adopted over the succeeding 6 years, up to the time Cimino and coworkers[3] reported their success, in 1966, with the autologous, subcutaneous arteriovenous fistula. This “arterialized” superficial arm vein could be repeatedly cannulated, and it has stood the test of time, remaining today the best method for provision of long-term vascular access. As is shown in Fig. 81-1, the number of patients in the United States requiring hemodialysis more than doubled in the years between 1986 and 1995 to well over 160,000. During 1995 (the last year for which data are available), over 50% of the patients on hemodialysis had their dialysis via a functioning bridge fistula, while somewhat less than 20% had dialysis by a functioning subcutaneous ateriovenous fistula (see Fig. 81-2). In about 30% of patients, either permanent or temporary central venous catheters were used. In addition, the availability of vascular access is also an important consideration in the treatment of patients needing long-term administration of anticancer medication and other drugs, for total parenteral nutrition, and for the treatment of patients by means of plasmapheresis.
PHYSIOLOGY OF ARTERIOVENOUS FISTULAS An arteriovenous (AV) fistula has local and systemic, hemodynamic and nonhemodynamic effects. These vary, depending on whether the fistula is acute or chronic, and are modified by the anatomical configuration of the fistula and by how far proximally or distally it is sited on the vascular tree. A fistula may be formed directly between an adjacent artery and vein or, if these vessels are separated, by connecting them with a conduit limb of variable diameter or length. When the connecting limb is very short, as in a Cimino fistula, the flow through the fistula, when plotted in relation to the fistula diameter, increases following a sigmoid curve with increasing diameter of the fistula.[5] There is little flow through the fistula until its diameter exceeds 20% of that of the proximal artery. From then onward, flow increases rapidly with small changes in fistula diameter until the diameter reaches 75% of the proximal arterial diameter. Following that, there are only small increases in flow with increasing fistula diameter. In all fistulas, the direction of blood flow in both the proximal artery and vein is normal. With small fistulas (by definition, these have a diameter of less than 75% of the proximal arterial lumen), the blood flow in the distal vein and artery is in the normal direction. However, this is usually reversed in large fistulas (diameter greater than 75% of the arterial lumen). Fistulas that are to be utilized for therapeutic purposes are constructed so that they are of the large variety. This ensures the greatest blood flow and decreases the likelihood of fistula clotting. Fistulas formed between the radial or posterior tibial artery and a vein have blood flow rates of 150–500 mL/min. Grafts attached to larger arteries such as the femoral or axillary have flow rates of 500–1500 mL/min through them. When a fistula is opened, there is a fall in peripheral resistance, which leads to a decrease in the proximal fistula artery pressure and which is compensated for by an increase in cardiac output. Proximal arterial flow then increases, and, accompanying this, there is an increase in proximal venous
Hobson/Wilson/Veith: Vascular Surgery: Principles and Practice, Third Edition, Revised and Expanded DOI: 10.1081/0819-9-120024965 Copyright q 2004 by Marcel Dekker, Inc.
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Figure 81-1. Number of patients with end-stage renal disease by treatment modality, 1986 – 1995. (Modified from U.S. Renal Data System 1997 Annual Report.[4])
outflow that is not accompanied by a significant rise in central venous pressure because of the large capacity of the venous system. The highest blood pressure in the distal artery is usually only about two thirds of systemic pressure, which is nevertheless higher than that at the fistula opening. Therefore, flow is often retrograde in the distal artery. Valves in the veins direct blood flow cardiad and result in an initially high peripheral venous pressure. “Arterialization” of the veins leads to dilation and valvular incompetence, which may cause distal venous hypertension.
Blood in the distal fistula vein flows retrograde until at some point the valves are able to withstand the pressure. The blood in the distal vein is carried cardiad by venous collaterals, which open off the vein. With time, there is significant increase in the number of collateral vessels formed between the proximal and distal arteries and the proximal and distal veins. In the arterial system these are stimulated by the pressure differences across the bed, and in the venous system, the hypertrophy to accommodate the large retrograde flow. Ligation of the distal fistula artery reduces the degree of development of collateral arterial vessels.
Figure 81-2. Percentage of patients receiving hemodialysis by method of dialysis, 1995. (Modified from U.S. Renal Data System 1997 Annual Report.[4])
Chapter 81.
Venous collaterals develop more extensively than do arterial ones, and they accommodate the considerable retrograde venous flow that follows as incompetence of the valves occurs. Ligation of the proximal fistula artery decreases flow through the fistula and peripheral vascular bed, an effect that is much less pronounced with a chronic fistula in which large collaterals have been stimulated to develop. These maintain blood flow through the distal vascular bed and the fistula to a much greater extent than does flow through the proximal fistula artery. In small fistulas, there is a gradual buildup of platelets and fibrin along the fistula tract; these are replaced by smooth muscle and fibrous tissue and eventually result in fistula closure. With time, in larger fistulas, there is lengthening and dilation of the proximal and distal veins and the proximal artery in addition to the vascular collaterals. The proximal artery develops smooth-muscle hypertrophy in addition to dilation, and then it elongates. Later the muscle atrophies, and the vessel becomes tortuous and aneurysmal. In the vein, there is an increase in smooth-muscle and fibrous tissue of the subintimal layer. Eventually it may develop atherosclerosis. The vein dilates for up to 8 months following construction of an AV fistula. In addition to the foregoing changes, there is an increase in the temperature of the tissues surrounding an AV fistula because of increased flow in the adjacent collaterals. AV fistulas have been used to treat discrepancies in limb lengths in children. The increased collateral flow stimulates bone growth. A large AV fistula may produce congestive cardiac failure. To compensate for the increased fistula flow, the pulse, stroke volume, and cardiac output increase, and there is increased vasoconstriction of other parts of the vascular bed. Blood may be “stolen” from the vascular bed peripheral to the fistula, producing symptoms of ischemia. This happens when fistula blood flow equals about one third of the prefistula cardiac output. Heart failure occurs when the fistula flow is 20– 50% of the cardiac output.
SHORT-TERM VASCULAR ACCESS
Principles of Vascular Access Surgery
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thrombosis or infection. These patients are thus maintained while a further permanent site is constructed or the failed site is salvaged. Percutaneous subclavian vein catheterization was first reported by Aubaniac, a French military surgeon, in 1952.[6] Initially, central venous lines were used for intravenous (IV) access, central venous pressure monitoring,[7] and total parenteral nutrition.[8] In addition to these three functions, this list has been expanded to include venous access for chemotherapy infusion, left heart and pulmonary artery pressure monitoring, temporary dialysis, and multiple lumen vascular access channel catheters for complicated medical and surgical critical care patients.
Anatomy A thorough knowledge of the structures of the thoracic inlet is necessary to proceed with percutaneous central venous catheterization. The subclavian vein meets the internal jugular vein behind the sternoclavicular joint bilaterally. On the right side this confluence forms the superior vena cava. On the left side it forms the innominate vein, which carries the left-sided venous blood, entering the superior vena cava just cephalad to the right atrium. The cephalic vein lies uniformly in the deltopectoral groove and joins the subclavian vein in such a way that it is difficult to direct a guide wire or catheter into the proximal subclavian vein. Generally, the cephalic vein or external jugular vein is used for access by cutdown approach (Fig. 81-3). The anterior scalene muscle separates the subclavian artery and brachial plexus, which are posterior to this muscle, from the subclavian vein, which lies anterior to the muscle (Fig. 81-4). The scalene muscle helps protect the subclavian artery and brachial plexus from injury during needle insertion. The thoracic duct enters the left subclavian vein near its confluence with the left internal jugular vein. The lymphatic vessel on the right enters in the same position but is much smaller. Topographically, the subclavian vein lies on a straight line between the sternal notch and the junction of the medial and middle third of the ipsilateral clavicle immediately dorsal (posterior) to the clavicle. The vein enters the thorax between the clavicle and first rib. The internal jugular vein may be
Percutaneous Central Venous Cannulation Techniques Although acute hemodialysis in the past was carried out primarily with external AV shunts, these have now been essentially replaced by percutaneously placed central venous catheter hemodialysis. Blood is withdrawn from the cannulated vein, passed through the dialyzer, and returned to the patient by a peripheral vein or via the second lumen of a double-lumen catheter. The indications for the use of percutaneous venous cannulation are for acute renal failure, for exogenous poisoning, and, in addition, for patients with chronic renal failure who require emergency dialysis as their initial treatment because of advanced uremia. This technique is also available for patients who have a permanent vascular access site that has developed a complication such as
Figure 81-3. Central venous anatomy of the thoracic outlet. (From Wilson and Owens.[5] Used with permission.)
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Figure 81-4. Costoclavicular scalene triangle demonstrating position of subclavian vein between clavicle and first rib.
found lateral to the carotid pulse and enters the thorax between the sternal and clavicular heads of the sternocleidomastoid muscle bilaterally. These surface landmarks are essential to know for safe percutaneous central venous catheter placement.
Approaches There are two approaches to percutaneous central venous access. In the direct approach the catheter enters the subclavian vein through a direct percutaneous puncture site. In the indirect approach the catheter enters the subclavian vein from a subcutaneous tunnel. Direct Approach. Direct central venous access is obtained by cannulating the subclavian or internal jugular vein percutaneously with a polyethylene, polyurethane, or Teflon catheter and advancing the catheter into the superior vena cava. A Seldinger guide wire may or may not be used, depending on the equipment being utilized. The Seldinger technique involves percutaneous vascular access by threading a catheter over a previously placed thin guide wire. The wire is advanced through a small needle that has been inserted through the skin into a vessel (artery or vein). The indication for direct vascular approach includes the following: monitoring of central venous pressure; pulmonary artery pressure; hyperalimentation; temporary dialysis; and intravenous access in patients with poor peripheral veins or critical care patients in need of multiple intravenous portals. The available armamentarium includes single-, double-, or triplelumen catheters, each with its appropriate indication and insertion technique. The 16-gauge catheter was the first one commonly used for direct percutaneous central venous access. This polyethylene catheter was inserted through a 14-gauge needle into the subclavian or internal jugular vein and advanced into the superior vena cava. Recently, this catheter has been used less frequently for several reasons. The insertion needle is 14gauge and is potentially dangerous because of its large size. The catheter, which is inserted through the needle, may be accidentally sheared off by the sharp edges of the needle. The catheter is quite brittle and less flexible, creating a situation that predisposes to the formation of a fibrin sheath around the catheter.[9] These catheters are considered to increase the risk of thromboembolic phenomena.
Direct subclavian vein venipuncture is usually performed in a minor-surgery room under local anesthesia with the patient sedated and the operative site prepared and draped to maintain sterile conditions. An operating room table is useful to maintain the patient in the Trendelenburg position so as to distend the subclavian vein or internal jugular vein. If possible, IV fluid is administered to expand the venous compartment to ensure that the patient is normovolemic. A useful sign in the head-down position is that the intravascular volume is adequate if the operator can see the external jugular vein dilated with blood. A pillow may be placed in the midline of the patient’s back to drop the shoulders posteriorly and to position the central veins anteriorly. The patient’s head is turned to the opposite side. The operator’s index finger is placed in the sternal notch, and the thumb is placed under the clavicle at a point between the medial and middle third of the clavicle (Fig. 81-5). A cutaneous wheal of local anesthetic is made at this area. The distance between the index finger and the thumb represents the proximal subclavian vein and its union with the internal jugular vein to form the superior vena cava behind the sternoclavicular joint. The 14-gauge needle is connected to a 10-mL syringe without a Luer lock. The needle is inserted into the skin at the wheal, directed medially toward the sternal notch, while posteriorly sliding the needle under the clavicle and aspirating on the syringe as the needle is advancing. When the subclavian vein is entered, a “flashback” of venous blood fills the syringe. One stops for a second to be quite sure the blood is dark red and the piston of the syringe is not rising as it would if the subclavian artery were entered. The bevel of the needle is turned down, and the patient performs a Valsalva maneuver. This increases the central venous pressure and prevents air from entering the needle when the syringe is disconnected. The syringe is removed, and the intracatheter is inserted into the needle and advanced, gently rotating the catheter as it progresses into the subclavian vein. When the catheter is in place, the 14-gauge needle is withdrawn from
Figure 81-5. Technique for percutaneous puncture of subclavian vein. (From Wilson and Owens. [5] Used with permission.)
Chapter 81.
the skin and the plastic needle guard is immediately snapped on to protect the needle from lacerating the catheter. Now the metal stylet is removed from inside the catheter, and the catheter is connected to IV fluids. When the IV bag is lowered beneath the level of the operating room table, blood will be seen in the IV tubing if the catheter is properly placed. In addition, flow rates of the IV will tell the operator if the catheter is properly positioned. The plastic needle guard is sutured to the skin with 3-0 monofilament suture, and the insertion site is dressed. A postinsertion x-ray is always taken to be sure the catheter is in the superior vena cava and not turned upward into the jugular vein. In addition, one must be sure that a pneumothorax has not been created with the needle insertion. The technique for placing the catheter in the superior vena cava from the internal jugular vein is similar. The index finger is placed in the space between the sternal and clavicular heads of the sternocleidomastoid muscle just cephalad to the clavicle. A wheal of local anesthetic is made approximately a third of the way up into the neck at the lateral border of the sternocleidomastoid muscle. The needle is inserted in the wheal at the lateral border of the muscle aimed at the index finger just deep to the clavicle. All other aspects of internal jugular cannulation are identical to the infraclavicular subclavian approach. The internal jugular approach is easier and safer because the risk of pneumothorax is less. The patients, however, find it very uncomfortable because there is catheter motion with head movement. To prevent the catheter motion, the patient’s neck must be splinted, which becomes quite uncomfortable after a short period of time. The direct subclavian vein catheterization may be accomplished utilizing the Seldinger technique. Some of the newer percutaneous central venous catheters are made from soft, pliable, nonthrombogenic Silastic or Teflon, which is so supple that it must be inserted into position over a thin guide wire (Fig. 81-6). Either the subclavian vein or the internal jugular vein may be used, but because these catheters are tolerated for long periods of time, the subclavian approach is favored. There are many kits available that contain all the required equipment. These catheters may contain single, double, or triple lumens for dialysis or critical care patients in need of IV access. These catheters are placed, using x-ray or preferably C arm control. The patient is prepared and draped as noted above, including Trendelenburg position, running IV, pillow in the back midline, head turned away from operative side, and having the patient perform a Valsalva maneuver when the needle hub is exposed to room air. The external jugular vein is used as a measurement of intravascular volume. A wheal of local anesthetic is made in the dermis, sited just caudal to the junction of the middle and medial third of the clavicle, and an 18-gauge needle on a syringe is inserted into the skin through this wheal, aimed medially toward the sternal notch and angled posteriorly, deep to the clavicle. As the needle is advanced, bevel downward, negative pressure is placed on the syringe until there is a “flashback” of dark venous blood in the syringe. The piston of the syringe will not self-rise if the needle is in the vein. The patient is now asked to perform a Valsalva maneuver, and the syringe is removed from the needle. The J-shaped soft end of the guide wire, which is Teflon-coated, is
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straightened by a plastic tip deflector and is inserted into the 18-gauge needle and advanced into the subclavian vein, rotating the wire as it is advanced. At this point, an x-ray or C arm is used to assure the correct position of the guide wire in the superior vena cava. After appropriate maneuvering of the wire into proper position, both the tip deflector and the insertion needle are removed. Using a venotomy dilator inserted over the guide wire, or a number 11 blade, the skin opening is enlarged to permit the catheter to enter the skin. The venotomy dilator is then removed, and the Silastic or Teflon catheter is inserted over the guide wire. If a multiplelumen catheter is used, it is important to have either heparinized saline, 100 units per milliliter, or IV fluids prepared for all the IV portals. The catheter is also advanced using a rotational motion. Before attempting to advance the catheter over the guide wire, care must be taken to see that the guide wire reaches the IV connector side of the catheter for both traction and protection from pushing the wire into the venous system, while the catheter is being advanced over it. When the catheter is in the appropriate position, the guide wire is removed and the catheter is secured with a monofilament suture and connected to the appropriate IV tubing. Recently a breakaway or peel-away Teflon sheath has been made available to introduce over the guide wire, allowing a catheter to be inserted into the sheath after the guide wire is removed. This sheath is then pulled apart and removed. Although there is little advantage to this technique, where direct percutaneous access is performed, the breakaway or peel-away sheath is indispensable when inserting buried reservoirs, infusion pumps, Hickman catheters, or pacemakers by the percutaneous central venous method (Fig. 81-7). Indirect Approach. The indirect percutaneous catheterinsertion technique to catheterize the central venous system evolved through pacemaker technology. When pacemakers were placed in subcutaneous pouches, the pacemaker lead had to be inserted under direct vision into the peripheral vein, such as the cephalic vein in the deltopectoral groove, the external jugular vein, or the internal jugular vein. Occasionally, the cephalic vein was too small to accept the lead wire, or the lead wire could not be placed and advanced from the external jugular vein into the superior vena cava. At this point, a cutdown to reach the subclavian or internal jugular veins was necessary. The problem was solved with the development of the breakaway –peel-away sheath, which permitted percutaneous insertion of the pacemaker lead into the superior vena cava from the subclavian vein entry point and then allowed complete coverage of the lead in the subcutaneous pocket. The percutaneous technique has become so popular that the cutdown technique for placing a pacemaker lead in the cephalic vein under direct vision is losing its appeal as surgeons become more comfortable with the percutaneous subclavian vein catheterization technique. The technique is now used for routine insertion of Hickman catheters through a subcutaneous tunnel for chemotherapy, hyperalimentation, or vascular access and in the near future will be used for selfcontained infusion pumps for systemic constant infusion of heparin, insulin, morphine, or chemotherapy.
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Figure 81-6. Seldinger technique for introducing catheters. (From Wilson and Owens.[5] Used with permission.)
The initial procedure is similar, no matter which device is being inserted. A permanent pacemaker lead introducer set with breakaway or peel-away sheath is necessary. The patient is prepared and draped as noted previously. The head of the bed is lowered until the vein can be seen to fill. A wheal of local anesthetic is placed in the dermis caudal to the junction of the middle and medial third of the clavicle, and an 18gauge needle is inserted into the skin and aimed medially toward the sternal notch and posteriorly deep to the clavicle.
The J-shaped soft end of the Teflon-coated guide wire is straightened by a plastic tip deflector and inserted into the 18gauge needle and advanced into the subclavian vein, rotating the wire as it is advanced. At this point an x-ray or C arm is used to assure the correct position of the guide wire in the superior vena cava. The patient should have electrocardiogram monitoring, for the guide wire may cause ventricular arrhythmias if it is advanced into the right ventricle. At this point, the insertion needle and the guide wire tip straightener
Figure 81-7.
Needle, guide wire, and catheter introduced. The sheath is peeled off the catheter after introduction.
Chapter 81. Principles of Vascular Access Surgery 1151
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are removed and the wire is left alone, care being taken not to pull it out. A pocket or tunnel must be made for the specific device that is being inserted. For the pacemaker, self-contained reservoir, or self-contained infusion pump, a subcutaneous pocket is created on the ipsilateral pectoral region. The pocket should be caudad to the incision so that the device will lie below the incision when the wound is closed and the patient is upright. The Hickman catheter is a 90-cm silicone rubber catheter with a Dacron cuff 30 cm from the Luer lock end. The Dacron cuff is buried in a subcutaneous tunnel so that fibrous tissue will grow into the cuff for stabilization and to retard septic complications. Two stab wounds are required to create a subcutaneous tunnel for the Hickman catheter. A stab wound is made on the precordium and at the exit site near the guide wire. Using local anesthesia, a tunnel is created between the two stab wounds. The Hickman catheter, which has been flushed with heparinized saline, 100 U.S.P. units of heparin per milliliter, is inserted into the precordial stab wound and brought out of the stab wound near the guide wire. The catheter is advanced so that the Dacron cuff is in the subcutaneous tunnel. The Hickman catheter is now measured and cut so that the tip of the catheter following the course of the subclavian vein (plus innominate vein on the patient’s left side) and superior vena cava will lie at the level of the right third rib. With the apparatus in position (pacemaker, reservoir, pump, or Hickman catheter), attention is again turned to the guide wire. Over the guide wire, insert the sheath introducer assembly. Using a twisting motion, advance the sheath introducer assembly over the guide wire. Leaving the sheath in place, remove the guide wire and the introducer. Venous blood will come out from inside the sheath. From the pocket or tunnel develop a subcutaneous path for the lead or catheter to enter the breakaway sheath. This may require a small incision where the sheath enters the skin. Introduce the lead or catheter into the sheath and advance into position (Fig. 81-8). Break the sheath by pulling it apart. Withdraw the sheath as the peeling continues. If the lead or catheter withdraws from the sheath as the sheath is being peeled and withdrawn, reinsert the catheter gently and continue peeling. The wounds are now closed with interrupted subcuticular absorbable sutures (Fig. 81-9). Patients are placed on prophylactic antibiotics immediately prior to and 24 h postoperatively. The Hickman catheter, reservoir, or pump is aspirated and flushed with heparinized saline to ensure proper function. When using the percutaneous subclavian approach for central venous access, care must be taken when patients are obese, emphysematous, or hypovolemic. The side of a patient with a healed clavicular fracture or mastectomy should be avoided for attempts at percutaneous subclavian vein access. Occasionally, a patient will be seen with occlusion of the superior vena cava. These patients are obviously poor candidates. A preoperative venogram should be performed if the surgeon feels there is a risk of superior vena cava occlusion. It is probably best to avoid a side of the chest that has previously undergone radiation therapy.
Figure 81-8. Catheter is introduced through sheath. (From Wilson and Owens.[5] Used with permission.)
Complications Early complications of percutaneous central venous catheterization are due to technique. Pneumothorax is the most often seen. Later complications are usually related to sepsis or central venous thrombosis. Septic complications are more common in multiple lumen catheters and less frequent in vascular access devices that are completely buried, as compared to the Hickman catheter, which exits from the patient. Catheter sepsis may be heralded only by fever, tachycardia, or glucose intolerance. Treatment of catheterrelated bacterial infection usually requires removal of
Figure 81-9. Position of central venous catheter suitable for hyperalimentation placed via cephalic vein for long-term access. (From Wilson and Owens.[5] Used with permission.)
Chapter 81.
the foreign body. Subclavian vein thrombosis is generally not symptomatic. Other complications are listed in Table 81-1.
Other Sites The percutaneous access sites used for emergency hemodialysis or other procedures may include the femoral vessels. The femoral vein is cannulated in the groin using local infiltration anesthesia. Following insertion of a 16-gauge cannula into the vein, a guide wire is threaded through the cannula into the common iliac vein or the inferior vena cava. The guide wire should not be forced. If resistance is met, it is withdrawn a little and a further attempt at free passage made. The catheter is then passed over the free end of the guide wire into the iliac vein or inferior vena cava. Percutaneous venous cannulation provides a means for the immediate dialysis of a patient. The external catheter may be removed following the course of dialysis, reducing the chance of infection. Catheter thrombosis between dialyses is prevented by infusion of low-dose heparin for the duration of the catheter’s use. Blood flows of up to 200 mL/min can be achieved via these catheters, making this method of dialysis as efficient as others. The technique does not increase cardiac workload, unlike external AV shunts or internal AV fistulas. Table 81-1.
Complications of Percutaneous Vascular Access
Early Thoracic Pneumothorax Tension pneumothorax Subcutaneous emphysema Hemothorax Hydrothorax Hemomediastinum Hydromediastinum Arterial Subcutaneous hematoma Arterial laceration Pseudoaneurysm Venous Venous laceration Air embolism Catheter embolism Lymphatic Thoracic duct laceration Cardiac Arrythmia Perforation and tamponade Neurologic injury Brachial plexus Phrenic nerve Vagus nerve Recurrent laryngeal nerve Catheter misplacement
Late Catheter obstruction Thoracic Hydrothorax Hydromediastinum Venous Air embolism Central vein thrombosis Superior vena cava syndrome Hepatic vein thrombosis Cardiac Arrhythmia Coronary sinus thrombosis Lymphatic Lymphatic fistula Chylothorax Septic Catheter sepsis Septic thrombosis Suppurative thrombophlebitis
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These catheters may be changed after a period of days by reinsertion of the guide wire along the existing catheter, withdrawal of the older catheter, and its replacement with a clean catheter by the Seldinger technique. With the development of Silastic catheters, which reduce the likelihood of catheter thrombosis, and because of the lower risk of infection of a catheter placed in the subclavian vein rather than in the groin, subclavian catheters can be left in situ or replaced and provide dialysis access over an interval of several weeks. This obviates the need for repeated needle punctures.
LONG-TERM VASCULAR ACCESS The best long-term access is made by utilization of the patient’s own vessels to construct an autogenous subcutaneous AV fistula. Failing this, biological conduits such as bovine carotid artery heterograft or human umbilical vein or synthetic materials such as polytetrafluorethylene (PTFE) are used to bridge the distance between suitable arteries and veins.
Subcutaneous AV Fistula The autogenous AV fistula of the Cimino type is associated with the longest useful patency and lowest rate of infection and is least likely to thrombose. For construction, it requires an artery large enough to support a high rate of blood flow and veins that will “arterialize” and thus dilate. The fistula is unobstrusive and does not interfere significantly with patient activities, unlike the Scribner shunt. It does, however, require 3–5 weeks following its construction for maturation of the veins into large, thick-walled vessels that can be repeatedly and reliably punctured (Fig. 81-10). It may not be feasible to construct a Cimino fistula in a patient who has small fragile veins or a paucity of veins, possibly as the result of previous episodes of thrombophlebitis or sclerosis following intravenous injections. It is also difficult to construct in patients who have an obese arm. The fistula is easier to construct and more likely to remain patent in a patient who has prominent veins, such as a manual worker. The radial artery may not be large enough to maintain flow through the fistula in patients with advanced atherosclerosis. This is a pertinent consideration in the diabetic patient with renal failure. Again, as with the Scribner shunt, it should be determined before construction that the hand circulation can be maintained by the ulnar artery alone, using the maneuver described previously. Cimino fistulas have up to a 90% useful patency rate at 12 months, which falls to about 75% at 4 years. Once failure occurs, they can, uncommonly, be surgically revised for extended longevity. Fistulas may clot during an episode of hypotension or because of restriction of the venous outflow of the arm by clothing, a sphygmomanometer cuff, or a tourniquet. In addition, flow through the fistula is reduced by advancing atherosclerosis in the feeding artery and can ultimately fall to a critically low level at which the fistula thromboses.
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Figure 81-10.
Compartment Syndrome, Vascular Access, Malformations, and Transplantation
Well-developed (“arterialized”) Cimino fistula. (From Wilson and Owens.[5] Used with permission.)
Following construction of an AV fistula in the arm, swelling may be seen in the hand. This is usually easily managed by elevating the hand on a pillow for a time. Rarely, severe venous hypertension follows the development of valvular incompetence in the distal fistula venous bed. Very uncommonly a forearm fistula “steals” blood from the distal arterial circulation, leading to hand ischemia. The fistula is constructed using local infiltration anesthesia or alternatively a brachial plexus nerve block. Patients with progressive renal failure may have their fistula formed and matured beforehand, in anticipation of the need for maintenance hemodialysis. This is done when their creatinine clearance falls to 10 mL/min. Before constructing a Cimino fistula, the arm pulses are carefully palpated, and a sphygmomanometer cuff is applied around the upper arm to restrict venous outflow and aid visualization of the venous anatomy. The veins are marked out using an indelible pen. It is preferable to construct the Cimino fistula in the nondominant arm. This aids in training the patient for regular hemodialysis, should this eventuate. At operation, a longitudinal incision is made in the skin overlying the radial artery. The cephalic vein is dissected out from the subcutaneous fat, ligating any tributaries as necessary so that it lies alongside the radial artery without kinking or producing any stenosis. Following this, the radial artery is dissected and mobilized, taking care not to avulse any of its smaller branches since this produces a periarterial hematoma, which can interfere with the construction of an adequate fistula. The artery and vein are anastomosed together in one of four configurations (Fig. 81-11): (1) The side-to-side anastomosis is the easiest to do well and is associated with the highest fistula flow rate. (2) The arterial end to vein side reduces turbulence and the likelihood of distal arterial steal but is associated with a lower flow rate. (3) The vein end to
arterial side results in the highest proximal venous flow and minimal distal venous hypertension but is technically more difficult to construct. (4) The end-to-end anastomosis combines the least likelihood of development of distal arterial steal and venous hypertension with the lowest fistula flow rate of the four configurations. The fistula is made utilizing about a 1-cm-long venotomy and arteriotomy. If valves are present in the vein at the site of the venotomy, they are resected with small scissors. Fine suture material such as 7-0 prolene is used for the anastomosis, taking care to tie the knots on the outside of the vessels. A continuous suturing technique is employed, starting at the midpoint of the posterior wall, with the side-toside anastomosis.
Figure 81-11. Configurations of artery and vein in Cimino fistula. (From Wilson and Owens.[5] Used with permission.)
Chapter 81.
Before completing the anastomosis, a coronary artery dilator is passed proximally in the artery and vein to ascertain that no stenosis has been produced by suturing at the vessel junctions. Any bleeding occurring after the vascular clamps have been released is usually controlled by the application of firm pressure with a swab for several minutes. Only if this fails is the bleeding site controlled by insertion of additional fine sutures. These can lead to further bleeding from the needle tracks and increase the likelihood of inadvertently narrowing the anastomosis. After the operation is successfully completed, a strong thrill should be palpable. If there is vigorous arterial pulsation but no thrill, outflow obstruction is suspected, and one should confirm that there is no stenosis in the vein. Part of the anastomosis is dismantled and a small, simple rubber or Fogarty catheter is passed into the vein. If a stricture is felt, it may be dilated by bougies or by blowing up the balloon on the Fogarty catheter. In some patients it is not possible to construct the standard Cimino fistula at the wrist. If the patient is thin, the proximal cephalic vein is easily seen at the elbow and may be used for anastomosis to the brachial artery in the cubital fossa. A transverse incision is made a little proximal to the cubital fossa, and the brachial artery is mobilized distally to the level of the bicipital tendon. The median nerve lies medial and posterior to the artery and should be protected. The anastomosis between the artery and vein is limited to about a length of 5–7 mm to reduce the chances of developing a steal syndrome, which is more likely here. At times, the basilic vein can be mobilized from the level of the wrist to the middle of the forearm and then tunneled subcutaneously for anastomosis to the radial artery. It is also possible to anastomose the basilic vein to the ulnar artery, but this should not be done if there has been a previous radiocephalic fistula in that arm because of the high chance of compromising the circulation to the hand, since the radial artery is usually occluded. The Cimino fistula may function for many years. Eventually it may fail due to sclerosis of the veins as a result of repeated venipuncture or following renal transplant, when changes occur in the blood that restore coagulation to normal. It is not wise to discard an AV fistula following renal transplant because dialysis may be necessary during episodes of acute rejection or if there is failure of the kidney. Reoperation to salvage a failed Cimino fistula is commonly unsuccessful. Failure is usually most expeditiously managed by construction of another access site. If another Cimino fistula cannot be constructed or the old site revised, then a prosthetic bridge fistula is constructed.
Bridge Fistulas Bridge fistulas constructed from graft materials are a good alternative to the radiocephalic fistula. They can be formed between almost any artery and vein, are easily accessible under the skin for reliable needle puncture, and can be used for dialysis earlier than the AV autogenous fistula. These fistulas take on various configurations. If the vein and artery are close to each other, the bridge material may run in a loop or lie in a U configuration. If the artery and vein are some distance apart, the bridge graft lies in a straight or curved line. Care should be taken to avoid kinking of the
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fistula material, and in particular, it should not pass over joints where flexion will restrict flow and lead to graft clotting. Oneyear patency rates of 75 –80%, comparable to those of the Cimino fistula, have been reported with PTFE grafts. The larger the artery used to provide flow through the fistula, the lower the rate of fistula thrombosis. For this reason, thigh fistulas, using the common or superficial femoral artery, are less likely to clot. In addition, they can be easily utilized by the patient, who has both hands free, for home dialysis, but they have the major disadvantage of a higher postoperative infection rate. Location of the fistula in the arm is almost always the first-choice site and is the mandatory position in the older patient with significant leg vessel artherosclerosis or the obese patient who has dermatitis in the groin. A variety of biological and prosthetic materials have been used for bridge fistula construction. These include bovine carotid artery, human umbilical vein, homologous saphenous vein,[10] and synthetic materials. Of these, the PTFE graft has proved particularly successful and is currently the most commonly used material for bridge fistulas. The bovine heterograft was developed over a decade ago, by enzyme debridement of fresh bovine carotid arteries, followed by tanning with dialdehyde.[11] A 6- to 10-mL internal diameter graft about 40–50 cm long results. The material is pliable and easily sutured. At one time, it was thought that bovine heterografts should be utilized primarily rather then a Cimino fistula. However, some 5 years after introduction of bovine grafts, it was evident that they were prone to infection and aneurysm formation. Progressive degeneration of the graft material occurs so that the whole graft tends to undergo aneurysmal dilation or forms nonanastomotic aneurysms. This was seen more often in grafts anastomosed between proximal larger vessels, probably due to the increased material damage associated with higher b1ood flow rates. These grafts also develop stenosis at the venous anastomosis in company with other prosthetic materials, which leads to graft blood flow restriction and then clotting. The early enthusiasm for bovine heterografts has evaporated. The human umbilical vein graft was prepared in the hope that it would overcome the deficiencies of bovine carotid grafts.[12] It was believed it would be nonimmunogenic. The graft is prepared by tanning the human umbilical vein, collected automatically at the time of infant delivery, with either dialdehyde starch or glutaraldehyde, which converts it into a more rigid collagen tube. The material retains a critical surface tension level similar to that of autogenous saphenous vein. Thus, it was thought that it would also be more resistant to thrombus formation than synthetic grafts or modified bovine grafts. However, as with bovine heterografts, enthusiasm for this material as a bridge fistula has greatly waned due to consistently high thrombosis rates from inflow and outflow stenosis and aneurysmal dilatation. Expanded PTFE has become the most commonly used material for construction of bridge fistulas. PTFE handles well, does not require preclotting, is widely available, and has a long shelf life and high patency rate. PTFE bridge fistulas are currently noted to have 12-month patency rates between 50 and 60% compared to more than 70% patency for autogenous AV fistulas over the same time frame.[13] Fortunately, should a PTFE graft thrombose, it can usually be successfully treated by either surgical and/or pharmacological thrombectomy.
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Infection of PTFE grafts occurs in up to 10%. Over two thirds of these infections are found within the first 4 months of use, and the majority require removal of the graft for resolution. To minimize chances of bacterial seeding and infecting the replacement fistula, the infected graft is removed some days before establishing another bridge fistula elsewhere. If the infection involves the anastomosis, it is not uncommon that the artery will need to be ligated, and if this is the common femoral or brachial artery with the anastomosis immediately proximal to the bifurcation multiple vessels may need to be tied off, exposing the patient to the risk of limb ischemia. The diameter of the bridge graft is selected to be larger than that of the supply artery to ensure maximum fistula flow. The size, if too large, also increases the likelihood of developing high-output cardiac failure and distal limb ischemia. Experience has shown that grafts of 6 mm in diameter provide good flow and retain their patency while being uncommonly associated with the foregoing complications. In the arm, a 6-mm graft is usually selected, so that the large graft-to-artery ratio provides maximal flow. Distal limb tissue perfusion is also affected by the degree of atherosclerosis that has developed in the distal arterial tree, and this is a significant consideration in the older patient who is being prepared for a thigh bridge fistula. If this is a concern, then a preoperative angiogram may be helpful in planning further patient management. However, if the patient’s ankle blood pressure is 80% or more of his or her brachial blood pressure and he or she has no history of claudication, then distal ischemia is unlikely to follow if a bridge fistula is constructed. Bridge fistulas have been formed between most of the suitably sized superficial arteries and veins. After subcutaneous implantation, the prosthesis can be readily palpated and punctured. Puncture should, if possible, be delayed until the prosthesis has been incorporated in the surrounding tissue. The puncture sites then tend to “heal,” making extravasation and perigraft hematoma formation less likely than in the unincorporated prosthesis (Fig. 81-12). Puncture of a graft in the first 24 h after implantation is not only possible but often necessary.* For patient comfort, ease of handling by the patient or nurse, and safety, bridge fistulas are best placed in the arm. In the arm, a bridge fistula can be constructed between the radial artery and cephalic or basilic vein in the cubital fossa (straight) (Fig. 81-13), the cephalic or basilic veins and the brachial artery (loop) (Fig. 81-14), and the axillary vein and brachial artery (straight) (Fig. 81-15). The conduit is tunneled through the subcutaneous tissue on the radial side of the forearm to allow the arm to lie comfortably during dialysis. Bridge fistulas in the arm have a shorter useful patency than those in the thigh, since clotting is more likely because of the lower fistula flow rates. On the other hand, bridge fistulas in the arm are less likely to become infected than thigh fistulas, which are in proximity to the bacteria of the heavily colonized groin skin. In the thigh, the initial bridge fistula is constructed between the femoral artery proximal to its exit from the
Figure 81-12. Perigraft hematoma—the result of early puncture (arrow ) before the graft was tissue-incorporated.
adductor canal and the proximal saphenous or femoral vein (Fig. 81-16). Upon failure, the arterial end of the fistula can be moved to the more proximal femoral artery. With long-term hemodialysis, the surgeon can be called on to create multiple vascular access sites, because each will eventually fail. It is conceivable that some patients could potentially outlive their available limb access sites. Then an AV fistula between the axillary vein and artery has been employed. Complications in this central site are serious and difficult to manage.
COMPLICATIONS OF AV FISTULAS Thrombosis
*Creation of the subcutaneous tunnel using a tunneler of the same size as the graft will result in a tight fit, making extravasation less likely should hemodialysis be required early on.
The most common complication is fistula or graft thrombosis. The likelihood of this occurring depends on the type of shunt, the site of the AV anastomosis, the prosthetic material used, and the diameter of patient’s veins and arteries.
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Figure 81-15. PTFE bridge fistula between brachial artery and axillary vein. (From Wilson and Owens. [5] Used with permission.)
Figure 81-13. PTFE bridge fistula between radial artery and cephalic or basilic vein in cubital fossa. (From Wilson and Owens.[5] Used with permission.)
The autogenous Cimino fistula thromboses early following construction in about 10 –15% of patients. This may be due to poor vessels (an atherosclerotic radial artery or small veins) or technical factors such as obstruction at the venous anastomosis. With time, the Cimino fistula is more likely to
Figure 81-14. PTFE bridge fistula between brachial artery and cephalic or basilic veins. (From Wilson and Owens.[5] Used with permission.)
remain patent than a bridge fistula. However, in the initial period, the bridge fistula has a higher patency rate. Thrombosis occurring 3 months or more following construction of a Cimino fistula is commonly due to fibrosis of the veins, following the repeated trauma of needle punctures. Late thrombosis of a prosthetic graft, however, is usually due to “intimal hyperplasia” producing stenosis of the venous outflow. When late clotting of a Cimino fistula occurs, it may be most expedient to convert it to a bridge prosthetic fistula. Late thrombosis of a graft due to intimal hyperplasia in the vein adjacent to the prosthetic venous anastomosis occurs with PTFE and other prosthetic materials. Differences in
Figure 81-16. Position of femorosaphenous bridge fistula. (From Wilson and Owens.[5] Used with permission.)
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compliance between the vein and the prosthetic material result in turbulence and hydraulic trauma to the vein. At times, outflow obstruction is appreciated early before the graft thomboses by the dialysis nurse who observes a rise in pressure at the venous end of the conduit or notes that the blood in the venous chamber is becoming dark during dialysis. Following this observation, a “shuntogram” is obtained. This is a radiography in which contrast material is injected into the conduit. Thrombosis of a bridge fistula is managed by either surgical or pharmacological thrombectomy or both, which can salvage between 40 and 70% of grafts. Surgical thrombectomy is best performed through an incision sited near the venous end of the graft. A graft that has been in situ for a long time often has a well-formed fibrous capsule, and dissection of this can lead to tearing of the PTFE material. A 2-cm-long incision is made in the graft just proximal to the venous anastomosis. The patient is heparinized, and a small Fogarty embolectomy catheter is passed into the vein to remove any thrombus. This maneuver has dislodged clot into the venous and pulmonary circulation. If this fails to restore good flow in the graft, it is then necessary to explore the arterial end to remove clots. If these maneuvers result in good flow and good pulsation with a strong thrill, then the operation may be terminated. However, if this does not occur, then an angiogram should be obtained to determine if there is any correctable stenosis at the arterial or venous ends of the fistula. Such a lesion at the venous anastomosis is managed by a patch angioplasty or constructing a more proximal venous anastomosis or grafting from the fistula to a more proximal vein. Percutaneous transluminal angioplasty in selected cases has not been successful in management of venous runoff stenosis in our experience. Beginning nearly 10 years ago, techniques for percutaneous nonsurgical management of vascular graft thrombosis were developed. These have included thrombolysis with urokinase, mechanical clot maceration and embolization, and hydrodynamic thrombectomy. These techniques are reported to be equally capable of salvaging thrombosed bridge fistulas with low morbidity. All these techniques use balloon angioplasty with or without stenting to treat the cause of the thrombosis. Although multiple procedures are often required, secondary patency rates near 70% have been reported.[14] However, a recent prospective, randomized study looking at long-term success following surgical and percutaneous thrombectomies demonstrated longer patency if the graft is surgically thrombectomized rather than relying on percutaneous techniques.[15]
Infection Infection is second to cardiovascular disease as a cause of mortality and morbidity in patients on chronic dialysis. The highest rate of infection is found with external shunts, while the lowest is with the Cimino fistula. Needling of fistulas can produce a hematoma, which then becomes infected with skin organisms. Involvement of the anastomatic site with infection may lead to endovasculitis, septicemia, and metastatic abscess formation.
Grafts may become infected at the time of implantation from skin organisms and poor aseptic technique. To lower the likelihood of this, perioperative antibiotics effective against skin organisms, particularly Staphylococcus epidermidis and Staphylococcus aureus, are routinely used. On occasion, a superficial soft tissue infection overlying a graft will resolve; however, graft infections usually require removal of the prosthetic material for complete resolution. Grafts are thought to be more resistant to infection once they have become incorporated and a pseudointimal lining has formed. When a graft is infected and is to be removed for control of the infection, plans are made for implantation of a new graft at a different site. An interval of a few days should be allowed between removal and implantation of the new graft for resolution of the associated bacteremia and cellulitis, thus reducing the chances of “seeding” and infecting the new graft. In some cases of graft infection limited to a needle puncture site, a length of the graft may be excised and a replacement segment tunneled through uninfected tissues to join the remaining proximal and distal ends.
Congestive Heart Failure With a large AV communication fed by a moderately large artery, there is a considerable increase in venous return to the heart, which maintains the increased cardiac output necessary to sustain fistula flow. This can eventually lead to heart failure. When cardiac failure develops, it may be treated quite simply by “banding” of the fistula. This is done by encircling the prosthetic graft with a 1-cm cuff of Teflon. The arterial end of the prosthesis may be narrowed by placing several interrupted sutures to achieve the same effect. The flow through the graft is reduced to a level of 300 –400 mL/min. Reduction of the blood flow to lower levels is likely to lead to graft thrombosis.
Vascular Insufficiency A vascular steal syndrome occurs uncommonly. It is seen with side-to-side fistulas constructed at the wrist. Reversed flow in the distal radial artery increases as the fistula ages, and the collaterals hypertrophy between the proximal and distal arteries, elevating the blood pressure in the distal artery. Thus, a significant pressure gradient develops between the distal artery and fistula itself, stealing blood from the more peripheral muscle beds. The patient experiences ischemic pain in the hand, which is often more severe during hemodialysis. Vascular steal has also been observed in patients with fistulas formed between the femoral artery and saphenous vein in the leg. The steal may be corrected in the hand by ligation of the radial artery immediately distal to the fistula, converting it from a side-toside to an end-to-side anastomosis.
Venous Hypertension An AV fistula is a planned means for raising pressure locally in the venous system. However, venous hypertension may occur in the tissues distal to the fistula. In the time
Chapter 81.
Figure 81-17.
Principles of Vascular Access Surgery
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Pseudoaneurysms may develop at needle puncture sites as shown in this 2-year-old PTFE graft.
immediately following construction of the fistula, occurrence of a significant elevation of pressure in the distal venous channels is prevented by competent venous valves. With the valvular incompetence that eventually develops, there is retrograde distal venous flow, and the higher pressure is transmitted distally up to a null point where there is no venous flow and the valves are competent. The pressure is dissipated by the opening of a large venous collateral bed. In some patients there is marked swelling of the hand, discoloration, and pigmentation of the skin comparable to that seen in venous stasis disease in the leg. In long-standing cases, venous stasis ulceration may be seen. The treatment is ligation of the vein immediately distal to the fistula. An end-vein –to–side-artery fistula, which is slightly more difficult to construct, would obviate development of this problem. However, many surgeons prefer initially to make a side venous anastomosis, reasoning that should the extremely rare problem of venous hypertension develop, the distal vein can then be easily ligated. Massive edema of the entire extremity after construction of an AV fistula signifies proximal major venous obstruction.
Vascular Access Neuropathy A small number of patients with a Cimino fistula report symptoms of carpal tunnel syndrome. These symptoms are
especially noticeable during the night. If this syndrome is suspected, its existence may be proved by nerve conduction velocity studies. There will be a reduction in median nerve conduction time across the carpal ligament. Carpal tunnel syndrome possibly arises because of increased venous pressure in the hand, leading to tissue edema and compression of the median nerve. Another theory is that it is due to a vascular steal, producing ischemia of the nerve. Some evidence for this etiology comes from the observation that ligation of the radial artery distal to the AV fistula has improved the symptoms. This syndrome has been managed in a few patients by division of the carpal ligament similar to the proven treatment for the median nerve compression occurring in patients not on dialysis.
Aneurysms Vascular prostheses may develop pseudoaneurysms secondary to needle puncture and perigraft hematoma (Fig. 81-17) formation or true aneurysmal dilation of the whole graft. The latter is thought to be the result of degeneration and “fatigue” of the graft material itself. If the pseudoaneurysm is not infected, it can be managed by local excision and repair of the graft or excision of the graft segment with interportion position of a new length of material.
REFERENCES 1. 2.
Graham, W.B. Historical Aspects of Hemodialysis. Transplant. Proc. 1997, 9, 1. Quinton, W.E.; Dillard, D.; Scribner, B.H. Cannulation of Blood Vessels for Prolonged Hemodialysis. Trans. Am. Soc. Artif. Intern. Organs 1960, 6, 104.
3.
Brescia, M.J.; Cimino, J.E.; Appel, K.; Harwich, B.J. Chronic Hemodialysis Using Venipuncture and Surgically Created Arteriovenous Fistula. N. Engl. J. Med. 1966, 275, 1089. 4. U.S. Renal Data System, USRDS 1997 Annual Data Report; The National Institutes of Health, National Institute
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5.
6. 7.
8. 9.
10.
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of Diabetes and Digestive and Kidney Diseases: Bethesda, Maryland, 1977. Owens, M.L.; Bower, R.W. Physiology of Arteriovenous Fistulas. In Vascular Access Surgery; Wilson, S.E., Owens, M.L., Eds.; Year Book Medical Publishers: Chicago, 1980. Aubaniac, R. L’injection Intraveineuse Sousclaviculaire: Advantages et Technique. Presse Med. 1952, 60, 1456. Wilson, J.N.; Grow, J.B.; Demong, C.V.; et al. Central Venous Pressure in Optimal Blood Volume Maintenance. Arch. Surg. 1962, 85, 563. Dudrick, S.J.; Ruberg, R.L. Principles and Practice of Parenteral Nutrition. Gastroenterology 1971, 61, 901. Peters, W.R.; Bush, W.H., Jr.; McIntyre, R.D.; Hill, L.D. The Development of Fibrin Sheath on Indwelling Venous Catheters. Surg. Gynecol. Obstet. 1973, 137, 43. May, J.; Tiller, D.; Johnson, J.; Ross-Sheil, A.G. Saphenous Vein Arteriovenous Fistula in Regular Dialysis Treatment. N. Engl. J. Med. 1969, 280, 770.
11. Sterling, W.A.; Hazel, L.T.; Diethelm, A.G. Vascular Access for Hemodialysis by Bovine Graft Arteriovenous Fistulas. Surg. Gynecol. Obstet. 1975, 141, 69. 12. Dardik, H.; Ibrahim, I.M.; Dardik, I. Arteriovenous Fistulas Constructed with Modified Human Umbilical Cord Vein Graft. Arch. Surg. 1976, 111, 60. 13. Culp, K.; Flanigan, M.; Taylor, L.; Rothstein, M. Vascular Access Thrombosis in New Hemodialysis Patients. Am. J. Kidney Dis. 1995, 26, 341. 14. Cohen, M.A.H.; Kumpe, D.A.; Durham, J.D.; Zwerdlinger, S.C. Improved Treatment of Thrombosed Hemodialysis Access Sites with Thrombolysis and Angioplasty. Kidney Int. 1994, 46, 1375. 15. Marston, W.A.; Criado, E.; Jaques, P.F.; et al. Prospective Randomized Comparison of Surgical Versus Endovascular Management of Thrombosed Dialysis Access Grafts. J. Vasc. Surg. 1997, 26, 373.
CHAPTER 82
Vascular Anomalies: Hemangiomas and Malformations Hugh H. Trout III Sandra Eifert
pediatricians, pediatric surgeons, plastic surgeons, dermatologists, neurosurgeons, hand surgeons, otolaryngologists, orthopedists, neuroradiologists, and radiologists specializing in computed tomography (CT), magnetic resonance imaging (MR), and/or angiography. Interestingly, in contrast to Europe, vascular surgeons in the United States see relatively few of these patients, but those they are faced with often have complex lesions that are beyond their purview. It is beyond the scope of this chapter to provide a comprehensive review of the entire field of vascular anomalies. The goal is to provide an overview of the field, including methods of diagnosis and treatment of those lesions that a vascular surgeon is most likely to encounter. Specifically, there is no discussion of vascular anomalies involving the neurological system—an entire field in itself— and we have only briefly mentioned visceral malformations involving the lungs, liver, and gastrointestinal tract. No one physician has sufficient knowledge to care for the entire array of vascular anomalies. Because multiple specialists often need to be involved with evaluation and treatment of these complex and unusual anomalies, it should be emphasized that centers with a special interest and expertise in caring for patients with these lesions do exist and are often a valuable resource for consultation. Interestingly, because of the nature of the problems, battles over specialty turf are unlikely to occur.
INTRODUCTION Past efforts to characterize congenital vascular anomalies (vascular anomalies are, by definition, congenital even if not apparent at birth) are replete with eponyms and descriptive terms that are antiquated, incorrect, and misleading. In 1976, an International Workshop for the Study of Vascular Anomalies was established with biannual meetings, and in 1992, an organization evolved out of this group called the International Society for the Study of Vascular Anomalies (ISSVA). By 1996 the ISSVA had agreed on a classification system that makes biological sense (as we currently understand it).[1] This system is also simple and correlates with history, physical examination, and behavior. While modifications of this system will undoubtedly occur as the emerging role of angiogenesis factors, immunohistochemical cellular markers, and genetic influences are further elucidated, the present classification system is now sufficiently developed to allow accurate predictions of prognosis and assessment of the risk/benefit of various treatment options. The importance of nosology (systematic classification of diseases) cannot be overstated. Prior to the general acceptance of this system it was almost impossible to glean much information from the medical literature regarding vascular lesions because different authors described similar lesions differently and grouped disparate lesions together. Accordingly, diagnosis and prognosis were usually hopelessly muddled and treatment was often inappropriate or detrimental. Adding to the problems of understanding vascular anomalies, patients with these anomalies are seen by many specialists, depending on the age of the patient and the location and extent of the lesion. We are, however, hardpressed to pick a specialty, with the probable exception of gerontology, whose members do not occasionally see these patients. The specialists that are commonly consulted are
AVOIDING COMMON MISCONCEPTIONS Hemangiomas are tumors of infancy and childhood. They grow rapidly after birth and regress between 1 and 8 years of age. The term “hemangioma” should not be used to describe adult lesions (see below). This is not a simple
Hobson/Wilson/Veith: Vascular Surgery: Principles and Practice, Third Edition, Revised and Expanded DOI: 10.1081/0819-9-120024966 Copyright q 2004 by Marcel Dekker, Inc.
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semantic issue but goes to the point that misuse of the term “hemangioma” leads to confusion and inaccurate assessment and often improper treatment. Treatment of high-flow vascular anomalies should never include proximal arterial occlusion, by either ligation or embolization (the only exception would be if operative removal were planned within the next few days). Proximal arterial occlusion stimulates dilatation of collateral arteries and expansion of the lesion. This will make later arteriography or ablative embolization much more difficult. Such treatment can make a limb ischemic as well. Moreover, even if symptoms are relieved by proximal arterial occlusion, this relief will surely be transient and measured in months, not years. The term “congenital arteriovenous fistula” is confusing and should rarely be used. If so, it should be used with care and precision. An arteriovenous (AV) fistula connotes a single communication between an artery and a vein. While it is possible that a congenital vascular anomaly can consist of a single communication between an artery and a vein, it is exceedingly rare. If it is documented, treatment is the same as that for an acquired AV fistula, i.e., ablation of the communication. Arteriovenous fistulas, defined as a single communication between an artery and a vein, are almost always acquired post–traumatic lesions. Sometimes it can be difficult to distinguish a mature acquired AV fistula from an arteriovenous malformation (AVM), the congenital lesion composed of numerous arteriovenous communications. Since acquired arteriovenous fistulas differ from arteriovenous malformations in etiology, prognosis, and treatment, it is particularly important to distinguish the two. The acquired, single communication, arteriovenous fistula, often seen by vascular surgeons in the United States, is discussed in Chapter 76. The term Klippel-Trenaunay-Weber syndrome to describe a complex-combined lesion is a superb example of one of the problems with eponyms. They can often serve as convenient shorthand descriptions of complex anomalies, but only when the meaning of the eponym is well established and broadly accepted. Klippel-Trenaunay is a slow-flow complex lesion, whereas Parkes-Weber is a fast-flow complex lesion. The triple eponym Klippel-Trenaunay-Weber is imprecise and does not reflect what the authors originally accurately described. Klippel-Trenaunay-Weber, therefore, obfuscates rather than enlightens and it should not be used. Most vascular anomalies can be diagnosed with a careful history and physical examination. Diagnosis of the remainder relies on radiological imaging studies such as ultrasound sonography, CT, and MRI. Additionally, these studies are often helpful in determining the extent of the lesion (almost always more extensive than detected by physical examination) and in predicting prognosis.
CLASSIFICATION Vascular anomalies are divided into two broad categories: tumors and vascular malformations. Tumors are divided into hemangiomas and more aggressive types (hemangioendothelioma, angiosarcoma). Vascular malformations are
subdivided into slow-flow and fast-flow lesions and complex-combined forms (Table 82-1). As a rule, eponyms should be avoided, but it is somewhat helpful to apply eponyms as a shorthand description for some of the more complex vascular malformations. Some eponyms are used in this chapter, but only after detailed characterization.
HEMANGIOMAS Clinical Characteristics Hemangiomas are the most common tumors of infancy and early childhood. They do not appear to occur in adults. They may be present at birth as a small dot, macular lesion,
Table 82-1.
Classification of Congenital Vascular
Anomalies Tumors Hemangiomas Other (hemangioendotheliomas, “tufted angioma,” angioscarcoma) Malformations Slow-flow Capillary (CM) Port-wine stain Sturge-Weber syndrome Capillary-lymphatic malformation (CLM) Circumscribed “Angiokeratomas” Telangiectasias Essential telangiectasia Rendu-Osler-Weber syndrome Ataxia telangiectasia (Louis-Bar syndrome) Cutis marmorata telangiectasia congenital Lymphatic (LM) Localized Diffuse Venous (VM) (CVM) (AVM) Localized Diffuse Fast-flow Arterial (AM) (AVF) (AVM) Complex-combined Slow-flow Klippel-Trenaunay syndrome (CVM, CLVM of limb or trunk with hypertrophy) Solomon syndrome (CM, VM, intracranial AVM, epidermal nevi, osseous, defects, tumors) Proteus syndrome (CM, VM, macrodactyly, hemihypertrophy, lipomas, pigmented nevi, scoliosis) Maffucci syndrome (LVM, enchondromas) Fast-flow Parkes-Weber syndrome (CLAVM with AVF) Source: Adapted from Fishman S.J.; Mulliken, J.B. Hemangiomas and Vascular Malformations of Infancy and Childhood. Pediatr. Clin. N. Am. 1993; 40, 1191.
Chapter 82.
bruise-like patch, or a pale spot. More commonly, they appear during the first few weeks after birth, proliferate rapidly with an increased endothelial turnover in the superficial dermis for the first year, and then regress. Involution is usually completed by age 12. They affect females more commonly than males (ratio , 3:1).[2] Most hemangiomas are small, single tumors involving only the skin. These involute uneventfully, leaving normal or slightly blemished skin. Immunohistochemical cellular markers demonstrate the hemangioma’s life cycle. During the proliferative phase, the tumor has a high expression of factors that reflect active angiogenesis: vascular endothelial growth factor (VEGF), basic fibroblast growth factor (bFGF), urokinase, type IV collagenase, and proliferating cell nuclear antigen (PCNA).[3] Conversely, during the involving phase, tissue inhibitor metalloproteinase 1 (TIMP 1), an antiangiogenic factor, is expressed.[3] Mast cells that are present during late proliferation and the early involuting phases may have a role in secreting modulators that downregulate hemangiogenesis.[4,5] While the precise role of known and yet to be discovered angiogenic and antiangiogenic factors is not fully elucidated in hemangiomas, they have been shown to be of diagnostic use in differentiating hemangiomas from vascular malformation and may prove to be helpful in treatment.[6] Perhaps 10 – 20% of hemangiomas are problematic, causing distortion, ulceration, or destruction. Even small hemangiomas can threaten vision or the airway. Gastrointestinal hemangiomas present with bleeding, and larger ones can threaten vital organs. Hepatic hemangiomas, both single and multiple, may present with congestive heart failure, anemia, and hepatomegaly. A thrombocytopenic coagulopathy [Kasabach-Merritt phenomenon (KMP)] may also occur in tumors that have a lymphatic component as well.[1] The thrombocytopenia is profound (less than 10,000/mm3), and biopsy reveals a histopathologic diagnosis of kaposiform endothelioma.[7] This is a life-threatening entity (30 –40% mortality) and mandates treatment.
Diagnosis Rarely a hemangioma is fully grown at birth.[8] Many present as a small cutaneous mark at birth, but the usual presentation is a tumor presenting shortly after birth (median 2 weeks) and growing rapidly for the first 6– 8 months. A deep hemangioma (often incorrectly called a “cavernous hemangioma”) can mimic a lymphatic or venous malformation. Ultrasonography or magnetic resonance (MR) will differentiate these lesions. A hemangioma can also be confused with a capillary malformation (“port-wine stain”), but the hemangioma has prominent draining veins and will regress. Pyogenic granulomas, tiny acquired cutaneous lesions, can be confused with hemangiomas, but they rarely appear appear before 6 months of age. They grow in a stalk and often bleed or form an eschar. If uncertainty remains, ultrasonography or MR will distinguish the hemangioma from the vascular malformations.[1] Ultrasonic examination with color Doppler hemangiomas in the proliferative phase demonstrates a parenchymatous mass with a high-flow anomaly. MR shows high flow in the
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proliferative phase and, during involution, demonstrates a slow-flow tumor with some fatty tissue replacement.[9,10] Angiography is only used for embolization of a hemangioma, causing high-output cardiac failure. Biopsy is necessary if there is any suspicion that the vascular tumor is malignant.
Treatment The overwhelming majority of hemangiomas will grow and regress completely, leaving little evidence of their past existence. Family requests (and often demands) for definitive treatment of larger hemangiomas or those that cause an obvious cosmetic deformity are frequent and understandable. Nonetheless, thorough explanation is necessary to convince parents not to insist on treatment of these infants and children except for tumors that will cause psychosocial problems in children approaching school age. Some authors still advocate chemotherapy, cryotherapy, radiation therapy, or ligation of feeder vessels, but these treatments may be harmful and should be withheld except in rare life-threatening circumstances. Certain specific indications for intervention include: (1) rapidly growing facial lesions that cause marked facial distortion, (2) lesions with bleeding, ulceration, or infection, (3) lesions that interfere with normal physiologic function (vision, breathing, eating, hearing), (4) large hemangiomas (usually hepatic) that cause congestive heart failure or bleeding, or (5) more aggressive vascular tumor causing thrombocytopenia (Kasabach-Merritt phenomenon).
Corticosteroids The mechanism by which corticosteriods accelerate the involution of hemangiomas is not known; it has been observed that some cortisone analogs inhibit the growth of new vessels. Corticosteriod therapy is effective (30 –60% of the time) primarily during the proliferative phase but has little efficacy or indication once the quiescent or involuting phase begins.[11] Corticosteriod therapy is currently, in most instances, considered to be the first-line treatment for problematic or endangering hemangiomas. The complications of short-term steroid therapy are few and not long-lasting in most infants and children. As greater understanding of the role of angiogenic and antiangiogenic factors is gained, more effective agents with fewer adverse side effects will be available.
Interferon-a Interferon-a-2a was developed as an antiviral agent. When tested in patients with acquired immunodeficiency syndrome (AIDS), it was noticed that Kaposi’s sarcoma, the vascular tumor associated with the AIDS virus, regressed. Subsequent investigations revealed that interferon inhibits the movement of capillary endothelium in vitro. Moreover, interferon-a inhibits angiogenesis in mice. As a consequence of these observations, interferon-a-2a has been used in a number of patients with life- or vision-threatening hemangiomas that did not respond to corticosteroids.[12] Interferon-a-2b is equally efficacious.[13] To date, a high success rate of initiating
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regression has been observed, though the side effects of treatment have been substantial (fever, neutropenia, and superficial skin necrosis). Because of these side effects, corticosteroids are generally tried before interferon-a.
Embolization Embolization can occasionally be useful when coricosteroids and interferon-a have failed and the infant is in congestive heart failure; this is usually caused by hepatic hemangiomas.[8]
Excision On occasion, removal of a bleeding or ulcerated hemangioma is necessary. Localized excision of a hemangioma of the eyelid may be an indication for resection to prevent astigmatic amblyopia.
Cryotherapy Cryotherapy causes tissue damage and scarring and does not retard growth of the deep portion of the hemangioma.
Radiation Therapy Though proliferating hemangiomas, with their rapid endothelial turnover, are exquisitely sensitive to radiation, the long-term consequences (radiation burns, bone atrophy, and later malignancy) make this therapeutic modality one to avoid except for life-threatening hepatic hemangiomas that are unresponsive to corticosteroids and interferon-a.
Ligation of Feeder Vessels This procedure is usually ineffective at controlling growth. It results in loss of angio access for subsequent study or embolization; moreover, the goal of reducing flow to the hemangioma can almost always be achieved with embolization techniques when necessary to preserve life or organ viability.
Laser Therapy Pulsed dye laser treatment of superficial hemangiomas does not hasten involution but will lighten the bright red color. Laser therapy can cause ulceration, depigmentation, and tiny pock-like scars. Despite its popularity, there is no evidence that laser therapy, at least as delivered by current methods, results in a better cosmetic result, and some evidence suggests that the results may be worse. Laser therapy will lighten some superficial hemangiomas, but these are the very tumors that leave near-normal skin after regression. It is probably safer and certainly cheaper to restrict use of the laser for recalcitrant ulcerated hemangiomas. Laser is very effective in treatment of residual telangiectasia in the involuting and involuted phase.
MALFORMATIONS Vascular malformations are congenital errors in vascular morphogenesis. They are categorized by the nature of their predominant vascular channels. Some are clinically apparent at birth, but other types appear later, usually by the fourth decade. Because of the late appearance, they are often called “acquired lesions,” but in fact they most likely develop from a dormant analog, present since birth. Capillary malformations (CMs) are best exemplified by the port-wine stain familar to all because of the obvious cosmetic disfigurement when involving the face. CMs can be combined with an arterial (AM), venous (VM), or lymphatic (LM) abnormality, but by themselves they present no clinical problem, only cosmetic, though obviously this alone can have profound consequences. Lymphatic malformations are lowflow lesions and may cause difficulties because of their location or size, but are rarely life-threatening. Venous and arterial malformations, singly or in combination with other malformations (such as LMs), are more difficult to classify because of their myriad presentations. A clinically useful way to think about venous and arterial malformations is to view them as a spectrum from a simple venous aneurysm or single dilated vein extending to a highly complex and large lesion primarily composed of tortuous veins with or without lymphatics moving to simple arterial anomalies (the beginning of the high-flow end of the spectrum) and extending to the complex arterial lesions (arteriovenous malformations). Each of the four major categories of vascular malformations (CM, LM, VM, and AM) has a particular histopathologic appearance. Capillary lesions are composed of regular, ectatic, thin-walled channels located in the papillary and upper reticular dermis. Venous malformations are composed of thin-walled vessels, lined by sparse irregular bands of smooth muscle. These channels often contain thrombi and phleboliths. Lymphatic anomalies are histologically similar to venous anomalies, contain a pale acidophilic fluid, and are composed of variable sized channels with walls of variable thickness that contain both smooth and striated muscular elements; tiny foci of lymphatics are typically found. The arterial vessels of an arteriovenous malformation are dysplastic and consist of thickened walls and discontinuous elastic lamina, with hyperplastic smooth muscle fibers within the media.[14] The cause of most vascular malformations is unknown. The field of molecular genetics has provided some information about four inherited autosomal dominant vascular disorders, and further advances may shed light on the causes of the sporadic malformation forms that, in turn, may lead to new methods of treatment.[1] Usually one type of malformation is markedly predominant, but combinations among the four types also occur with frequency. It is of considerable clinical importance to distinguish a malformation (which will not regress) from a hemangioma (which will regress). Moreover, it is also clinically important to distinguish a low-flow malformation from a high-flow vascular malformation, since the former gives rise to clinical difficulties primarily by virtue of the organ structures it involves, whereas a high-flow malformation tends to be more destructive locally, can cause cardiac
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strain because of substantial arteriovenous shunting, and is more difficult to extirpate.
CAPILLARY MALFORMATIONS—LOW FLOW General Considerations The “port-wine stain” and other telangiectasias are examples of CMs. They may be associated with deeper and more extensive vascular anomalies, and when they are, it is the other associated anomaly that usually determines prognosis and treatment.
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Options for Treatment Treatment is for appearance or because of soft tissue/skeletal overgrowth. Excision and skin grafting, full or partial thickness, is used only in patients with severe fibrovascular thickening. Skin expansion with subcutaneous balloons prior to excision can be useful for small to moderate-sized lesions that involve areas in which this approach is applicable. Laser therapy is effective in improving cosmetic appearance in 70 –80% of patients. Facial lesions respond better than truncal CMs. The flashlamp pulsed-dye laser is the current standard.[15] Efforts to vary those parameters based on the anatomy and pathophysiology of the lesion hold hope for continued improvement in the results.[16] Efforts to inject a substance that concentrates in the lesion (a photosensitizer) and becomes toxic to the endothelium when exposed to light at varying wavelengths (photochemotherapy) have shown promise as well.[17]
Signs and Symptoms The stains or other telangiectatic lesions are readily apparent. When they are not accompanied by other vascular or neural anomalies, they cause no symptoms. They can, of course, also reflect the presence of the far more serious neurological entity, ataxia telangiectasia (AT), or the pulmonary, gastrointestinal, and/or brain lesions associated with the RenduOsler-Weber syndrome.
Diagnostic Evaluation These malformations require no diagnostic evaluation unless other anomalies, such as eye or brain involvement with Sturge-Weber syndrome, are suspected.
Differential Diagnosis The diagnosis is almost always readily obvious in a neonate. A fading macular stain, also known as a nevus flammeus neonatorum (salmon patch, angel’s kiss, etc.), is often misdiagnosed as a “port-wine stain.” In contrast to a CM, a fading macular stain usually involves the nuchal region, blanches when compressed, becomes more apparent when the infant cries, and tends to regress uneventfully within a few years. Occasionally a macular, telangiectatic hemangioma can also be confused with a CM. Usually, however, the hemangioma is usually darker and raised with prominent draining veins. Moreover, when the hemangioma either enlarges or involutes, the differentiation from a CM is established, as the latter remains essentially unchanged.
Natural History CMs do not regress, expand, or cause symptoms, but they often darken in color, particularly in the oracofacial region. Most CMs are harmless, but occasionally they signal the presence of more ominous underlying congenital abnormalities such as Sturge-Weber, Klippel-Trenaunay, and Parkes Weber syndromes.
LYMPHATIC MALFORMATIONS— LOW FLOW General Considerations Lymphatic malformations are composed of dysplastic lymphatic vessels. They are low-flow lesions and cause difficulties because of their location and size but are rarely life-threatening. Most common are microcystic lymphatic malformations, formerly called “lymphangiomas.” Macrocystic, formerly called “cystic hygroma,” and combined forms can occur as well. They are benign tumors, consisting of multiple lymphatic vessels and vesicles. Lymphatic abnormalities are frequently associated with other vascular anomalies, and they may involve skin and soft tissues. The majority of lymphatic anomalies are present at birth or become evident before 2 years of age. They do not show involution. They may be located in the face, neck, trunk, and limbs and are often accompanied by skeletal and soft tissue overgrowth. Complications caused by lymphangiomas are cellulitis and lymphangitis, characterized by massive swelling, pain, and hyperemia. The primary consequence is a fibrotic change of tissues due to the lymphatic fluid storage in the soft tissue and an increase in oncotic pressure. The skin over these malformations is continuously stretched such that the fibers lose their elasticity.
Treatment Infection within a LM should be treated promptly with antibiotics. Large cysts can be aspirated and infused with sclerosant agents, though recurrence is common with sclerosants alone. Excision, often preceded by sclerosant therapy, is the only “cure,” but incomplete excision will allow transected lymphatic channels to regenerate. Osteotomy/ ostectomy of the affected bone region may be indicated if there is an abnormal relationship between bone and lymphatic malformation.
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Another common type of lymphatic anomaly may cause lymphedema, which represents an extraordinary amount of lymphatic fluid stored in the interstitial tissue. The origin of this lymphatic anomaly may be a structural or functional defect. Two distinct types occur: primary (congenital) and secondary (acquired) lymphedema. Primary lymphedema is defined as lymphedema that is caused by an inborn defect of the lymphatic system such as aplasia or hypoplasia of lymphatics resulting in an storage of lymphatic fluid in the interstitial tissue. Hypoplasia is by far more common. Primary lymphedema can be subdivided into three clinical groups: (1) congenital lymphedema is present at birth; (2) lymphedema praecox is characterized by a clinical onset between puberty and age 35; (3) lymphedema tarda is defined as an outbreak after age 35. Secondary lymphedema is an acquired form that is usually secondary due to infection, for instance filiarisis, as well as thrombophlebitis or trauma. Treatment options depend on the individual circumstances. Treatment of cellulitis consists of intravenous antibiotics. In primary and secondary lymphedema therapy with compression stockings or pneumatic compression devices may be helpful for years but may be less useful as the subcutaneous tissues fibrose. There is some belief that pneumatic compression may not be as effective as once thought. Massage therapy offers some promise as an effective treatment and deserves further study as to its role in controlling swelling. On occasion, because of recurrent complications or increasing bulk, surgical management may be necessary. To provide optimal conditions for a resection of these tissues, strict compression should be performed for weeks before the operation to reduce the size of the involved area. This should be followed by a generous resection of the affected tissues. If open lymphatic channels are found, they should be implanted into regional veins, otherwise they regenerate and the soft tissue mass will recur.
VENOUS MALFORMATIONS— LOW FLOW General Considerations Some venous malformations can be life-threatening because of their size or involvement of an organ, most frequently the liver or upper airway. Bleeding from venous malformations involving the gastrointestinal tract can also exceedingly difficult to control. In most instances, however, venous malformations cause problems because of their cosmetic appearance, bulk, the organ(s) they involve, or their association with other anomalies, especially the Klippel-Trenaunay syndrome. Included are simple venous anomalies such as absence or hypoplasia of named veins, duplications, valvular anomalies, abnormal venous enlargements — either single or multiple — or spongy growths, sometimes erroneously referred to as “cavernous hemangiomas.” These spongy venous malformations may occur as isolated lesions, or they may occur in conjunction with other anomalies (see syndromes below).
It is these spongy lesions that most often give rise to debate about prognosis and appropriate treatment.
Signs and Symptoms The signs and symptoms of a particular VM depends on the location. Primary venous varicosities associated with a paucity or absence of venous valves is an example of a venous malformation. Likewise the left renal vein can pass behind the aorta or it can divide into two veins, one going anterior to the aorta, the other passing posteriorly. Except for those situations where the venous anomaly gives rise to varicose veins or to swelling of an extremity, most go undetected until discovered on an imaging study, during an operation, or at autopsy. The venous anomaly that often elicits attention, however, is the mass lesion. This lesion can present with a cosmetic defect, with pain from compression of surrounding tissues, thrombosis of blood in some of its channels, or stasis changes in the extremity. Spongy venous malformations do not pulsate, have a thrill, or have a bruit. Though they are somewhat soft and compressible, the mass cannot be made to disappear completely with compression and will often expand when in a dependent position. Large venous malformations can also be associated with a low-grade disseminated intravascular coagulopathy (DIC).
Diagnostic Evaluation Though ultrasonography with color Doppler is useful to separate slow-flow from fast-flow lesions, it is operator dependent and does not adequately characterize the extent of the lesion. The diagnostic test that best helps in the differential diagnosis is MRI, with and without enhancement, as this will distinguish between low- and high-flow lesions (T2-weighted sequences will show a high-intensity signal, brighter than fat, reflecting lakes of stagnant blood).[18,19] Formal imaging with venography is usually not particularly helpful in characterizing the lesion. If, however, excision of a large mass or a mass that intimately involves critical structures is contemplated, it may be of advantage to obtain an arteriogram, depending on the clinical presentation. Arteriography will demonstrate the absence of large arterial feeder vessels, though it is rarely necessary for diagnostic purposes.
Differential Diagnosis The vascular lesion that might be confused with a spongy venous malformation by those inexperienced with these anomalies is the arterial malformation. The venous malformation does not pulsate, has no bruit, and its flow can be demonstrated by ultrasonography or MRI. An arteriovenous malformation, in contrast, does pulsate, has a bruit, and its fast flow can be demonstrated by MRA. On occasion venous channels within a venous malformation will thrombose, causing the mass to become larger, firmer, and tender. This is not typical of a malignancy, but, if uncertainty persists, MRI will usually be diagnostic, and, if necessary, biopsy may be indicated.
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Natural History VMs grow commensurately with the individual. They are usually present at birth, though some may first appear in the second or third decades of life and sometimes even later. They may expand in response to trauma, menarche, pregnancy, or hormone manipulation such as birth control pills. Venous malformations may periodically develop thrombi in some of these dilated channels, presumably on the basis of sluggish blood flow. These thromboses can be quite painful, analogous to the symptoms of patients with superficial phlebitis. The extremities can be involved with extensive venous malformations. Those often involve muscle[18] and may be associated with demineralization and skeletal hypoplasia as well.[20] These pure VMs are distinguished from KlippelTrenaunay syndrome by the absence of limb hypertrophy and capillary-lymphatic vesicles. They are of particular concern because they often have coagulation abnormalities characterized by a localized intravascular coagulopathy that can present as a low-grade disseminated intravascular coagulopathy. Platelet count is around 100,000/mm3. Fibrinogen levels, presence of fibrin split products, and D-dimers from peripheral citrated blood confirms the diagnosis of a chronic consumptive coagulopathy. [1] Similar findings can be observed in patients with extensive lymphatic malformations. Treatment with low molecular weight heparin reduces the incidence of bleeding. This low-grade DIC should be looked for prior to any procedure.
Options for Treatment Many VMs do not require treatment. If the lesion is in an extremity and produces minor to moderate symptoms, wellfitting support hose may provide sufficient relief. Low-dose antiplatelet therapy (aspirin) may reduce the incidence of symptomatic phlebitis in those with a prior history of thrombosis within the redudant or dilated veins provided a localized intravascular coagulopathy has been ruled out. Intralesional sclerosing agents for VMs include hypertonic saline, sodium tetradecyl sulfate, sodium morrhuate, ethanolamine, Ethiblocw,[21] and absolute alcohol.[22] Ethibloc is a vegetable protein mixed with alcohol that stimulates autolysis of tissue. It is biodegradable and cleared by phagocytosis, though, on occasion, it does provoke a considerable inflammatory response soon after injection. It is used in Europe but has not yet been approved for use in the United States by the FDA. Because of its toxicity to all tissues, absolute alcohol for ablation of venous malformations should be restricted to use by interventional radiologists with considerable experience with this agent. Moreover, claims of “cure,” regardless of treatment modality, should be regarded with skepticism until 5- to 10-year follow-up imaging studies are available. As a general rule, most patients have few symptoms. Those with head and neck VMs often notice stiffness in the morning, and those with VMs involving the limbs will experience heaviness after exercise or after prolonged standing. The risk of causing permanent damage to normal tissues and the low probability that an entire venous malformation
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can be obliterated with sclerosing techniques argues against routine use. Excision can be effective for a well-localized VM, more often surgical removal is done for VM after sclerotherapy. The indications for treatment are bleeding, chronic ulceration, pain, marked cosmetic deformity, or symptoms arising from compression of adjacent structures. If cure—rather than palliation for a local problem—is the goal, it is important that the lesion be completely excised or recanalization may occur. Cryotherapy and radiation therapy are not effective.
Outcome of Management Venous malformations that are completely excised do not recur. Those that are extensive and are not amenable to complete excision may persist and, indeed, possibly enlarge after incomplete excision or sclerotheraphy. As indicated above, however, most venous malformations do not require treatment and remain relatively quiescent.
ARTERIAL MALFORMATIONS— HIGH FLOW General Considerations At one end of the spectrum of arterial malformations are the abnormalities of position or structure such as duplications, hypoplasias, stenoses, aneurysms (congential, not atherosclerotic), and arterial ectasias. Next are the congenital arteriovenous fistulae (AVFs) that have only one or very few arteriovenous communications. It is not certain that these exist; if they do, they are exceedingly rare. This lesion is congenital and can easily be confused with the far more common arteriovenous fistula that is acquired, usually after trauma. Such a congenital lesion is indistinguishable, except by history, from an acquired arteriovenous fistula. The clinical relevance of this entity is that a malformation (congenital) that consists of only a single or a few arteriovenous communications is amenable to treatment by excisional or nonexcisional techniques that excise or obliterate that communications(s), just as for an acquired arteriovenous fistula. An AVM, with multiple microscopic arterial and venous communications, is the most difficult arterial anomaly to treat. These lesions are divided into localized, truncal, and diffuse arteriovenous malformations. The localized lesions can resemble VMs and CMs, particularly in their early stage in that they are composed of a mass of very small communications between arteries and veins. The resistance within this mass is high, the feeder arteries are small, and shunting of blood is modest. Truncal arteriovenous malformations have large inflow arteries and dilated outflow veins.The multiple arteriovenous communications tend to involve the head, neck, and upper limb. They are discrete, demonstrable by arteriography, usually involve major arteries, and are high flow. Diffuse arteriovenous malformations have large inflow arteries with rapid filling of the surrounding venous tree on
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angiography. The communications involve the lower limb more than the upper. The communications are extensive and are themselves difficult to demonstrate by arteriography because of the near instantaneous shunting from the arterial system to large venous tributaries.
Signs and Symptoms Clinical staging of AVMs is documented by the clinical staging system of Schobinger:[23] Stage I: Stage I: Stage III: Stage IV:
Blush/stain, warmth, and AV shunting by continuous Doppler or 20 MHz color Doppler Same as stage I, plus enlargement, tortuous tense veins, pulsations, thrill, and bruit Same as above, plus either dystrophic changes, ulceration, bleeding, persistent pain, or destruction Same as Stage II, plus cardiac failure
Arteriovenous malformations pulsate, have a palpable thrill, and have loud and extensive bruits present. They may cause symptoms by compression of surrounding structures, by ulcerating, by “stealing” or shunting blood away from distal tissues, or rarely by causing congestive heart failure (Stage IV). They may be relatively circumscribed and accessible to embolization or excision, or they may be diffuse and involve one or more vital structures extensively. If ulceration occurs (Stage III), the etiology is either a shunting of blood away from the ulcerated area or is an increase in venous pressure near the area of the ulceration, almost identical to that seen in patients with chronic venous insufficiency.
Diagnostic Evaluation The diagnosis of an AVM usually can be made on clinical criteria of a pulsatile mass of long duration in the absence of a history of trauma. Progression of an AVM can be monitored by duplex scanning; the extent of this highly vascular mass is probably best determined by MRI.[19] If therapy is contemplated or if the possibility of an acquired arteriovenous fistula is present, an arteriogram is necessary.
Differential Diagnosis The lesion most likely to be mistaken for an arteriovenous malformation is an acquired arteriovenous fistula. If a history of trauma is present, an arteriogram will be necessary to look for the distinguishing characteristic of a single arteriovenous communication, the hallmark of an acquired arteriovenous fistula. An arteriovenous malformation may possess a single arteriovenous communication, but this is exceedingly rare. Also, arteriovenous malformations can coexist with other abnormalities, the most common being Parkes Weber syndrome (discussed below).
Natural History Arteriovenous malformations may be observed in infancy but are often missed by those unfamiliar with vascular anomalies. They can lie dormant for many years, sometimes
becoming obvious as late as the third or fourth decade, but most become apparent in childhood or adolescence. Some remain fairly quiescent, cause few symptoms, and require no treatment. Increased cardiac output is common due to shunting of blood from the arterial tree to the venous system without passing through a capillary bed. This increased cardiac workload, however, is generally well tolerated for many years. Arteriovenous malformations cause moderate symptoms due to their size or due to compression of surrounding tissues. Others cause ulceration of overlying skin, either by diversion of arterial blood or by increasing local venous pressure. Arteriovenous malformations can also cause pain due to shunting-induced distal ischemia or due to compression of surrounding structures. Although it is unusal, large malformations can cause marked increases in cardiac output and symptomatic congestive heart failure. Finally, massive arteriovenous malformations, usually seen in infancy or childhood, can cause death, either from cardiac failure or from organ failure, usually hepatic.
Options for Treatment No treatment is probably best for those patients who are asymptomatic or have minimally symptomatic lesions. Resection, 24 – 28 hours after embolizaton, may be necessary for those lesions that are symptomatic are relatively localized or for those that have overlying nonhealing or recurrent ulcerations. If the ulceration is thought to be secondary to venous hypertension, local excision of the tissues beneath the ulceration, skin grafting, and long-term external support may reduce the incidence of recurrent ulceration. Microvascular flaps of normal distal tissue are often needed after resection. Embolization may be helpful in situations in which excision is planned within 2 or 3 days. Also, embolization can be useful in those moderately to severely symptomatic patients in whom excision is not possible because of the extent or location of the lesion. Many different embolic agents are used. Wires or coils are easy to insert but usually are positioned too proximal in the feeder arteries. As a consequence collateral vessels develop, and little, if any, benefit is derived. Polyvinyl alcohol foam (Ivalonw) particles are permanent and have been popular in the past. It is difficult, however, to inject the correct size as some of the particles pass through the malformation and go to the lung, whereas others occlude the small feeder vessels and do not fill the nidus of the malformation. Cyanoacrylates (super glue) have been used quite successfully to fill arteriovenous malformations, particularly cerebral, and good to excellent long-term palliation has been attained. Unfortunately, this substance is exceedingly difficult to work with as the catheters used to inject the cyanoacrylate can occasionally be glued to the lesion; few invasive radiologists are truly masters of this medium. A sclerosing agent, ethyl alcohol, is highly toxic, easy to inject, but difficult to control. It is painful, can cause thrombosis as it passes into the venous system, and can damage normal tissues if they are exposed to high concentrations.
Chapter 82.
Nerves and the central nervous system are particularly susceptible to injury. Notwithstanding all these cavcats, if administered by an experienced radiologist, ethyl alcohol can be a highly effective agent in controlling some of the more extensive and complex malformations.[24,25] A word of caution: short-term results of embolization may appear exceedingly promising. Good long-term follow-up studies, however, are sparse. Of those that exist, most imply that embolization may be a temporizing therapy and that the indications for treatment should be carefully considered prior to initiating embolization.
Outcome of Management Outcome of management is almost entirely dependent on the extent of involvement of the AVM with vital structures. Embolization will be deleterious if the major arterial feeders are obstructed as this will promote dilatation of collateral vessels and will not reduce lesion size or the amount of shunting. If the embolization is effective in obliterating the major portion of the arteriovenous communications (i.e., the nidus of the arteriovenous malformation), it will sometimes reduce the shunting and may reduce the size of the mass. Even highly successful embolization should be thought of as a temporizing modality that may be all that is necessary for controlling mass size or pain, but by itself should not be considered curative. Excision of an AVM will be curative if the entire mass is removed. Excision should never be undertaken lightly; there is the possibility of massive blood loss or damage to critical structures, even in the hands of highly skilled and experienced surgeons. Moreover, because these anomalies are often extensive and involve essential organs or structures, complete excision is frequently not possible. Partial excision may be successful as palliation, but it can also result in promoting dilatation of collaterals or in rendering adjacent or distal tissue ischemic. As a consequence, thorough preoperative assessment, careful planning of the operation, meticulous operative technique, and modest expectations should be the hallmark for excisional therapy of arteriovenous malformations.
COMPLEX-COMBINED MALFORMATIONS General Considerations Vascular malformations can be occur in association with other development abnormalities. The use of eponyms has generally confused rather than clarified, especially in the field of congenital vascular lesions. Nevertheless, until our understanding of many of the syndromes that have been described increases, eponyms are a convenient shorthand for discussion purposes. Many vascular malformation syndromes have been described. For the most part they are exceedingly rare or they have little relevance to vascular surgeons. Two, Klippel-Trenaunay and Parkes Weber, however, are not rare and will occasionally be seen by vascular surgeons. The following discussion of vascular malformations combined
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with other congenital lesions will be restricted to these two syndromes.
Klippel-Trenaunay and Parkes Weber Syndromes Klippel-Trenaunay (CVM, CLVM limb/trunk with hypertrophy, rare hypotrophy) is a complex-combined slow-flow vascular malformation. It is characterized by a capillarylymphatico-venous malformation involving an extremity (usually lower) with limb or trunk hypertrophy. The typical presentation is a patient with capillary staining of the skin, varicose veins, particularly involving the lateral aspect of the extremity, and an enlarged (length or girth) extremity. Variations include superficial or deep venous anomalies, bony or soft tissue limb asymmetry, usually hypertrophy.[26,27] A similar condition is the pure venous malformations that also involve an extremity. The pure venous malformations are separate from the Klippel-Trenaunay syndrome in that pure venous malformations do not have a lymphatic component with soft tissue hypertrophy and there is no limb disparity. This differentiation is important because the pure venous malformation patient is more likely to develop coagulation abnormalities. Parkes Weber (CAVM, CAVF, CLAVM limb) is less common and is characterized by a capillary (dermal) malformation and an arterial malformation(s) involving an extremity with limb (lower more often than upper) bony or soft tissue hypertrophy and congenital varicose veins. The primary difference between Klippel-Trenaunay and Parkes Weber is the type of malformation and the flow rate. Because the malformation is venous, patients with Klippel-Trenaunay syndrome have normal blood flow to the affected extremity and generally have a good to excellent prognosis. In contrast, patients with Parkes Weber syndrome have increased blood flow to the involved extremity with AV shunting. Pain, ulceration, and increased cardiac output with associated cardiac enlargement are often encountered in patients with the Parkes Weber syndrome. Treatment of patients with Klippel-Trenaunay syndrome consists primarily of educating patients and their families to the favorable prognosis and of counseling about external support garments. Occasionally venous ulcers may develop secondary to venous hypertension at the level of the ankle. Local measures (sclerotherapy, removal of underlying veins) designed to reduce this venous hypertension may be necessary if the compressive therapies usually employed for venous ulcers are not successful. Removal of varicose veins of some of the venous malformation can be achieved with symptomatic improvement, though, as with most vascular anomalies, caution and modest expectations should govern invasive maneuvers (it is important to determine that an intact deep venous system is present before excision of the superficial veins). An exception is the need for epiphysiodesis to arrest growth in the adolescent with a significant limb length disparity. Treatment of patients with Parkes Weber syndrome is difficult. Because the limb length disparity is usually much more severe in patients with Parkes Weber syndrome than it is in those with Klippel-Trenaunay syndrome, epiphyseal arrest
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procedures are more common. On occasion, in patients with extensive arteriovenous involvement, it may be necessary to advice amputation to control pain caused either by distal ischemia or by involvement of nerves by the mass of the arteriovenous malformation. In general, despite heroic and often ingenious attempts to control the arteriovenous component, efforts to do so, either by embolization or by an operation, have been notoriously unsuccessful and have often seemed only to hasten the need for amputation. Here again, operative or embolic treatment should be reserved for specific and compelling reasons.
bility of completely erradicating most of them, the chronic nature of the problems they cause, and the difficulty of treatment of most of them, patients with vascular anomalies are probably best served by referral to centers who have a variety of specialists with experience in diagnosing and treating them. Most often those who reserve invasive treatment for well-established indications will achieve the best functional results. Much has been learned about these lesions, especially how to classify them so that treatment and prognosis can be better understood. As our understanding of molecular genetics improves, along with better imaging techniques, we will have even better insight and have more ways to provide effective treatments.
SUMMARY Vascular anomalies are unusual, and their diagnosis and treatment are not broadly understood by most physicians, especially those who only occasionally treat them. Because of their myriad and complex presentations, the impossi-
ACKNOWLEDGMENTS The authors wish to thank Dr. J. B. Mulliken for his advice and comments on an earlier draft.
REFERENCES 1. Enjolras, O.; Mulliken, J.B. Vascular Tumors and Vascular Malformations (New Issues). Adv. Dermatol. 1997, 13, 375– 423. 2. Fishman, S.J.; Mulliken, J.B. Hemangiomas and Vascular Malformations of Infancy and Childhood. Pediatr. Clin. N. Am. 1993, 40, 1177– 1200. 3. Takahashi, K.; Mulliken, J.B.; Kozakewich, H.P.; Rogers, R.A.; Folkman, J.; Ezckowitz, R.A. Cellular Markers That Distinguish the Phases of Hemangioma During Infancy and Childhood. J. Clin. Investig. 1994, 93, 2357 –2364. 4. Glowacki, J.; Mulliken, J.B. Mast Cells in Hemangiomas and Vascular Malformations. Pediatrics 1982, 70, 48– 51. 5. Pasyk, K.A.; Cherry, G.W.; Grabb, W.C.; Sasaki, G.H. Quantitative Evaluation of Mast Cells in Cellularly Dynamic and Adynamic Vascular Malformations. Plast. Reconstr. Surg. 1984, 73, 69– 77. 6. Folkman, J. Clinical Applications of Research on Angiogenesis. N. Engl. J. Med. 1995, 333, 1757– 1763. 7. Mulliken, J.B. Vascular Anomalies. In Grubb and Smith’s Plastic Surgery, 5th Ed.; Aston, S.J., Beasley, R.W., Thorne, C.H.M, Eds.; Lippincott-Raven Publishers: Philadelphia, 1997. 8. Boon, L.M.; Enjolras, O.; Mulliken, J.B. Congenital Hemangioma: Evidence for Accelerated Involution. J. Pediatr. 1996, 128, 329. 9. Huston, J., 3d.; Forbes, G.S.; Ruefenacht, D.A.; Jack, C.R.; Lie, J.T.; Clay, R.P. Arteriovenous Malformations of the Head and Neck: Natural History and Management. Mayo Clin. Proc. 1992, 67, 739– 747. 10. Meyer, J.S.; Hoffer, F.A.; Barnes, P.D.; Mulliken, J.B. Biological Classification of Soft-Tissue Vascular Anomalies: MR Correlation. Am. J. Roentgenol. 1991, 157, 559– 564. 11. Enjolras, O.; Riche, M.C.; Merland, J.J.; Escande, J.P. Management of Alarming Hemangiomas in Infancy: A Review of 25 Cases. Pediatrics 1990, 85, 491–498.
12. Ezekowitz, R.A.; Mulliken, J.B.; Folkman, J. Interferon Alfa-2a Therapy for Life-Threatening Hemangiomas of Infancy. N. Engl. J. Med. 1992, 326, 1456– 1463. 13. Tamayo, L.; Ortiz, D.M.; Orozco-Covarrubias, L.; DuranMcKinster, C.; Mora, M.A.; Avila, E.; Teixeira, F.; RuizMaldonado, R. Therapeutic Efficacy of Interferon Alfa-2b in Infants with Life-Threatening Giant Hemangiomas. Arch. Dermatol. 1997, 133, 1567 –1571. 14. Mulliken, J.B.; Fishman, S.J. Vascular Anomalies: Hemangiomas and Malformations. In Pediatric Surgery; 5th Ed. O’Neill, J.A., Jr., Rowe, M.I., Grosfeld, J.L., Fonkalsrud, E.W., Coran, A.G., Eds.; Mosby Yearbook Inc.: St. Louis, MO, 1998; Vol. 2, 1940. 15. Morelli, J.G.; Huff, J.C.; Weston, W.L. Treatment of Congenital Telangiectatic Vascular Malformations with the Pulsed-Dye Laser (585 nm). Pediatrics 1993, 92, 603– 606. 16. van Gemert, M.J.; Nelson, J.S.; Milner, T.E.; Smithies, D.J.; Verkruysse, W.; de Boer, J.F.; Lucassen, G.W.; Goodman, D.M.; Tanenbaum, B.S.; Norvang, L.T.; Svaasand, L.O. Noninvasive Determination of Port Wine Stain Anatomy and Physiology for Optimal Laser Treatment Strategies. Phys. Med. Biol. 1997, 42, 937– 950. 17. Lin, X.X.; Wang, W.; Wu, S.F.; Yang, C.; Chang, T.S. Treatment of Capillary Vascular Malformation (Port-Wine Stains) with Photochemotherapy. Plast. Reconstr. Surg. 1997, 99, 1826– 1830. 18. Enjolras, O.; Ciabrini, D.; Mazoyer, E.; Laurian, C.; Herbreteau, D. Extensive Pure Venous Malformations in the Upper or Lower Limb: A Review of 27 Cases. J. Am. Acad. Dermatol. 1997, 36, 219–225. 19. Burrows, P.E.; Laor, T.; Paltiel, H.; Robertson, R.L. Diagnostic Imaging in the Evaluation of Vascular Birthmarks. Dermatol. Clin. 1998, 16, 455– 488.
Chapter 82. 20.
Boyd, J.B.; Mulliken, J.B.; Kaban, L.B.; Upton, J. 3d.; Murray, J.E. Skeletal Changes Associated with Vascular Malformations. Plast. Reconstr. Surg. 1984, 74, 789– 797. 21. Gorriz, E.; Carreira, J.M.; Reyes, R.; Gervas, C.; Pulido, J.M.; Pardo, M.D.; Maynar, M. Intramuscular Low Flow Vascular Malformations: Treatment by Means of Direct Percutaneous Embolization. Eur. J. Radiol. 1998, 27, 161– 165. 22. de Lorimier, A.A. Sclerotherapy for Venous Malformations. J. Pediatr. Surg. 1995, 30, 188– 193. 23. Mulliken, J.B. Vascular Anomalies. In Grabb and Smith’s Plastic Surgery, 5th Ed.; Aston, S.J., Beasley, R.W., Thorne, C.H.M., Eds.; Lippincott-Raven Publishers: Philadelphia, 1997; 201.
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Yakes, W.F.; Rossi, P.; Odink, H. How I Do It. Arteriovenous Malformation Management. Cardiovase. Interv. Radiol. 1996, 19, 65– 71. 25. Jackson, J.E.; Mansfield, A.O.; Allison, D.J. Treatment of High-Flow Vascular Malformations by Venous Embolization Aided by Flow Occlusion Techniques. Cardiovasc. Interv. Radiol. 1996, 19, 323– 328. 26. Jacob, A.G.; Driscoll, D.J.; Shaughnessy, W.J.; Stanson, A.W.; Clay, R.P.; Gloviczki, P. Klippel-Trenaunay Syndrome: Spectrum and Management. Mayo Clin. Proc. 1998, 73, 28– 36. 27. Berry, S.A.; Peterson, C.; Mize, W.; Bloom, K.; Zachary, C.; Blasco, P.; Hunter, D. Klippel-Trenaunay Syndrome. Am. J. Med. Genet. 1998, 79, 319– 326.
CHAPTER 83
Vascular Aspects of Organ Transplantation Jorge Ortiz T. S. Dulkanchainun D. K. Imagawa combined heart and lung transplantation. After appropriate preoperative evaluation of the donor’s heart and lung function, including chest x-ray, electrocardiogram, echocardiogram and/or coronary angiography, the procurement team proceeds with a standard median sternotomy. Direct evaluation of the pericardial fluid, coronary arteries, ventricular function, and possible congenital abnormalities may help to determine whether the organs are suitable for transplantation. The heart is usually prepared early in the procedure in the event that a rapid procurement becomes necessary due to donor instability. The sternal retractor handle is placed cephalad to clear the operative field for the abdominal procurement. Even when thoracic organs are not recovered, the long midline thoracoabdominal incision is generally utilized to improve the exposure of the abdominal viscera as well as provide exposure for cardiac resuscitation in the unstable donor. After adequate mobilization of the heart, the superior vena cava (SVC) and inferior vena cava (IVC) are dissected free, and tissue is cleared from between the ascending aorta and main pulmonary artery. Once this is accomplished, rapid procurement can be performed if necessary (Fig. 83-1).[1] When the abdominal dissection is complete, including placement of perfusion cannulas, a cardioplegia cannula is placed and secured in either the midportion of the ascending aorta or the innominate arterial trunk. If lung procurement is planned, the midportion of the main pulmonary artery is also cannulated at a site that depends on the type of lung transplant procedure that is planned. When all organ procurement teams are ready, the SVC is ligated proximally and divided. To prevent infusion of liver preservation solution into the heart, a clamp is placed across the IVC at the level of the diaphragm and divided between the clamp and right atrium (Fig. 83-2). This prevents the preservation solution from venting into the pericardium and allows for the exposure required for the remaining dissection in order to preserve appropriate vascular cuffs, especially when simultaneous lung bloc procurement is to be attempted.[2] A large-bore catheter placed in
INTRODUCTION The science of solid organ transplantation has evolved significantly. Breakthroughs in the field of immunology and infectious disease have permitted the use of more potent immunosuppressants that have lowered the rate of rejection while not significantly increasing complications. These advances have led to an expansion of transplantation indications. Technical advances have also led to multiorgan cadaveric procurements and living donation. Patients thought to have anatomic contraindications (such as portal vein thrombosis in liver transplantation) have also benefited from this growth. The following is a brief overview of organ transplantation with specific attention paid to vascular issues. Organ procurement, transplantation, complications, and special technical considerations are all reviewed.
VASCULAR ASPECTS OF ORGAN PROCUREMENT Knowledge of standard and aberrant vascular anatomy as well as proper technique is essential for successful procurement of organs for transplantation. The actual procurement approach is dictated by the organs to be recovered as well as the condition of the donor (i.e., living, stable cadaveric, or unstable cadaveric). The following sections have been highlighted for multiorgan procurement in a stepwise fashion in the order of standard organ removal.
Cardiac and Lung Procurement The heart can be recovered alone as part of a multiple organ procurement as well as a composite heart and lung graft for
Hobson/Wilson/Veith: Vascular Surgery: Principles and Practice, Third Edition, Revised and Expanded DOI: 10.1081/0819-9-120024967 Copyright q 2004 by Marcel Dekker, Inc.
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Figure 83-1. Adequate mobilization of the heart is accomplished by clearing tissue from between the ascending aorta and the main pulmonary artery and dissecting free the SVC and IVC. (Illustration by Ann Mamanee.)
the infrarenal IVC allows for a controlled drainage of the cava while preventing flooding of the abdominal operative field from a divided IVC. The aortic crossclamp is placed with the initiation of both cardioplegia infusion and pulmonary preservation infusion. To vent the left heart as the perfusate returns through the pulmonary veins, the tip of the left atrial appendage is excised.[1] The heart and lungs are then bathed in ice cold saline solution while the preservation solution infusions are completed. The aortic and pulmonic cannulas are then removed and both vessels divided at the site of the cannula insertion. If no pulmonary procurement is planned, the pulmonary veins are transected at the pericardium. For combined cardiac and pulmonary procurement, an incision through the left atrium may be necessary in order to provide an adequate atrial cuff for anastomoses at time of lung transplantation.[2] The donor organs are then placed in sterile saline-filled jars and securely placed in at least two sequential sterile, cold saline-filled plastic bags, which are then transported in an ice chest.
Liver Retrieval The following technique can be used by less experienced surgeons in an expeditious manner while placing any aberrant vasculature at a lower risk for injury. This technique can only be used when the pancreas is not being procured. After isolation and cannulation of the aorta proximal to the common iliac bifurcation, the duodenum is Kocherized to expose the IVC. Precooling flush can be accomplished through cannulation of the SMV, IMV, or splenic vein. The left triangular ligament is then divided, the supraceliac aorta is clamped, and the infusion of University of Wisconsin solution is begun.[3] The perfusate may be vented through a divided IVC into the pericardium or through a controlled drainage of the infrarenal IVC via a large-bore catheter as described earlier. The entire abdominal cavity is then bathed with saline slush to ensure proper cooling of all organs for procurement. Dissection begins along the lesser curvature of the stomach remaining lateral to any potential replaced hepatic branches from the left gastric artery (Fig. 83-3). The diaphragm is then
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Figure 83-2. To prevent venting of liver preservation solution into the heart or pericardium, a clamp is placed across the IVC at the level of the diaphragm and divided between the clamp and right atrium. (Illustration by Ann Mamanee.)
divided down to the esophagus. Attention is turned to the porta hepatis with division of the gastroduodenal, right gastric artery, and the common duct. The gallbladder is flushed at this points. A posterior window is made in the gastroduodenalhepatic node pancreatic neck triangle, which will expose the portal vein. In the midst of the pancreas the portal vein is cut distal to its trifurcation. Dissection continues at a 1 o’clock orientation until the splenic artery is located and divided approximately 2 cm from the celiac axis. The adrenal gland, diaphragmatic crura, and connective tissues are all cut, exposing the aorta. Returning to the porta hepatis, scissors are used to cut along the Kocherized duodenum staying lateral to any potential replaced right hepatic artery (Fig. 83-4). The SMA and celiac axis are cut off the aorta and remain on the same Carrel patch. The inferior vena cava is divided above the renal veins and the liver is then lifted out of the body.[3] The back table involves cleaning the superior and inferior vena cava and the portal vein. If the SMA is found not to have a replaced right hepatic artery, it is removed. The hepatic artery is followed to the gastroduodenal orifice. All vessels
directed toward the liver hilum are preserved. Reconstruction of aberrant vasculature will be discussed in the following section. This can be performed either on the back or “front” table.[4] Standard techniques that involve more “warm” dissection are employed when liver and pancreas are both procured. This involves the careful delineation of hepatic arterial anatomy before the flush is begun. The distal aorta is dissected, as is the supraceliac aorta. The IMV, SMV, or portal vein cephalad to the pancreas is prepared for cannulation depending on the surgeon’s preference. The right gastric and the gastroduodenal arteries are ligated and divided. The hepatic artery is dissected. The splenic and left gastric arteries are ligated and divided. The portal vein is dissected to reveal the confluence of the splenic and superior mesenteric veins: this involves ligation of the coronary vein. After cannulation the celiac axis is removed from the aorta, the portal vein is cut at its confluence, the IVC is cut above the renal veins, and the suprahepatic vena cava is cut as it enters the heart.[5] Vascular issues arise when there are replaced vessels from the SMA.
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Figure 83-3. A replaced or aberrant left hepatic artery commonly arises from the left gastric artery, but may also arise from the splenic artery or the aorta. (Illustration by Ann Mamanee.)
Replaced vessels from the gastric or gastroduodenal arteries do not affect procurement technique. Careful dissection of a right replaced artery from the superior mesenteric artery is mandatory in order to ensure proper blood supply of both the pancreas and the liver. Many transplant centers advocate enbloc procurement of the liver and pancreas and subsequent back table division.[5] However, if the organs are to be sent to different centers, this is not feasible. Since liver transplantation is more urgent, the vascular integrity of the liver takes precedence over that of the pancreas.
Reduced Liver Donation Because of donor-organ shortages, new strategies to expand the donor pool have been explored. These include reducing a whole organ in order to size-match it to smaller recipients, dividing a whole organ between an adult and a child, dividing a graft between two adults, and living related donation. The size reduction helps the child at the expense of those adults
waiting on the transplant list, therefore shifting the shortage from the pediatric population to the adult population. The technique for splitting grafts for an adult and a child and living donation of the left lateral segment to a child is the same. It is now believed that better graft function results from in situ splitting instead of ex vivo splitting.[6] Vascular structures are more easily identified, cold ischemia minimized, and the body’s coagulation cascade is used most effectively. The first vascular structure isolated is the left hepatic vein. Next, the dissection of the left hepatic artery is performed, paying special attention to the artery to segment 4. The entire left portal vein is then isolated with careful ligation of branches to the caudate lobe. The portal vein branches to segment 4 are ligated and divided to the right of the umbilical fissure. After total vascular control the liver parenchyma is divided. The liver is split between segment 4 and segments 2 and 3. The right graft is removed with the cava and the left graft is drained by the left hepatic vein (Fig. 83-5).[7] Splitting of the donor organ into grafts suitable for two adults is performed similarly. The parenchyma is divided
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Figure 83-4. A replaced or aberrant right hepatic artery can commonly arise from superior mesenteric artery, but can arise from the right gastric as well as the gastroduodenal artery or directly from the aorta. (Illustration by Ann Mamanee.)
along the line from the gallbladder fossa to the IVC. The left graft now comprises segments 2, 3, and 4.[8] Living donation of a graft from an adult to another adult entails a formal right hepatic lobectomy or left lobectomy in the donor. The right hepatic vein with segments 5, 6, 7, and 8 is transplanted into the recipient. Alternatively, segments 2, 3, and 4 with the left hepatic vein can be transplanted. Reduction of grafts are performed on the back table. The technique is similar to any resection performed for other indications. Aberrant vasculature must be respected, and small arteries and veins should be carefully tied. The resected surface is often treated with fibrin glue before implantation.[7]
Pancreas Retrieval The pancreas is usually procured after the liver and before the kidneys. Before the aorta is cannulated, the hepatic artery is dissected from the hepatoduodenal ligament to the celiac axis. The gastroduodenal and right gastric arteries are ligated and divided. The splenic artery is isolated just proximal to its dorsal pancreatic branch. Depending on preference, the lesser sac can be opened at this time or after the liver has been removed. It is important to carefully ligate the branches of the pancreas leading to the retroperitoneum as they will bleed
profusely at reperfusion. The portal vein is divided to allow enough length for transplantation of both the liver and pancreas. The SMV and IMV are carefully tied. The superior mesenteric artery is removed from the aorta. After intestinal transection, the gland is removed with the C-loop of duodenum and the spleen.[9] On the back table the spleen is removed and the tail is carefully tied. The duodenum is trimmed and the stapled edges oversewn. The portal vein is prepared to provide enough length for anastomosis. The splenic artery and superior mesenteric artery are located on the craniad portion of the gland. These arteries are then anastamosed to a Y-graft of common, internal, and external arteries procured from the donor. The internal iliac is sewn to the splenic and the external is sewn to the SMA, allowing for one arterial anastomosis in the recipient.[10]
Kidney Retrieval In cadaveric donors both kidneys can be procured doubly or singly, or as part of a total abdominal evisceration for multiorgan transplantation with separation on the back table. The kidneys can be removed after the liver and pancreas have been recovered or as an independent procedure if those organs
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Figure 83-5. The liver is split between segment 4 and segments 2 and 3, as the right graft is removed with the vena cava and the left graft is drained by the left hepatic vein. (Illustration by Ann Mamanee.)
are not suitable for donation. Kidney procurement is initiated after suprarenal division of the aorta and IVC. The standard (or double) technique involves isolation and division of the ureters at the level of the bladder. On the left side the ureter is medially mobilized through a rent created in the sigmoid mesentery. After the right ureter has been medially mobilized, the two kidneys are dissected laterally, avoiding the hilum. When both kidneys and ureters are safely in the midline, both organs (including the inferior vena cava and the aorta) can be excised off of the vertebral column (Fig. 83-6). On the back table the kidneys are viewed posteriorly. The left renal vein is cut at its junction with the inferior vena cava. Next the aorta is incised on its posterior side along the midline. The renal arteries leading to each kidney are visualized and protected. A small Carrel patch is made for later anastomosis. The kidneys can now be measured and evaluated for abnormalities.[11] In the single technique, after the suprarenal cava and aorta have been cut, the left renal vein is separated from the IVC. The connective tissue on the anterior portion of the aorta is dissected free. Carefully, the aorta is divided at the anterior midline (Fig. 83-7). Arterial cuffs are created around the renal orifices for later anastomosis. The left renal vein and artery remain with the left kidney. The right renal vein and the inferior vena cava and right renal artery remain with the right kidney. The mobilization of the ureters and the dissection about the lateral aspect of both kidneys is performed in the same fashion as the double technique. When the kidneys have been procured during an abdominal evisceration, the entire block is reoriented on the back table so the anterior organs are now posterior. The ureters have been
cut from the bladder bilaterally. The kidneys are dissected laterally to medially. The posterior aortae, which is anterior now, is incised along the midline (Fig. 83-8). Carrel patches are then fashioned. The left renal vein is separated from the cava as previously described. The kidneys are now separated from the remaining bloc of organs.[11] Before living kidney donation, a spiral CT scan or MR angiogram is performed to evaluate the vascular anatomy and collecting system. If this is equivocal, a renal angiogram is performed. Although the left kidney is usually preferred, the kidney with the least amount of anatomic variation is used for donation. The open technique involves a flank incision. On the left side the gonadal vein is ligated as it enters the renal vein. On the right side the gonadal vein is ligated as it enters the inferior vena cava. The adrenal vein is also divided. The renal artery is visualized after anterior mobilization of the kidney. At this point it is traced as far towards the aorta as possible. The vascular pedicle of the kidney is ligated after transection of the ureter and demonstration of excellent urinary output.[1] The laparascopic technique employs the same vascular principles with the assistance of vascular clips and staples.[12] Left-sided procurement is usually favored due to the greater length of the renal vein, which facilitates an easier anastomosis.
Small-Bowel Retrieval The small bowel can be procured as part of an abdominal evisceration for subsequent separation on the back table or
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Figure 83-6. In the standard, or “double,” technique, the inferior vena cava and the aorta are excised off of the vertebral column. (Illustration by Ann Mamanee.)
obtained individually after recovery of the liver and pancreas. The graft is based on a vascular pedicle using the SMV or portal vein. The SMA provides arterial supply. When the pancreas is also to be utilized for transplantation, it is imperative to obtain suitable iliac grafts for extension of the pedicle.[11]
growth factor for the vein to prevent circumferential narrowing.[13,14] For the arterial reconstruction the usual site in the recipient is the proper hepatic artery at the level of the gastroduodenal artery. This junction is spatulated to provide a greater circumference for connection to the donor hepatic artery, celiac trunk, or a Carrel patch to the aorta.
Vascular Surgical Technique of Liver Transplantation
Vascular Surgical Technique of Pancreas Transplantation
The number of venous anastomoses performed depends on the method of recipient hepatectomy. If performed conventionally, the recipient vena cava is excised and the reconstruction involves the suprahepatic vena cava, the IVC, and the portal vein. In the “piggyback” technique, the recipient vena cava is preserved and the reconstruction involves the suprahepatic cava and the portal vein. The IVC is ligated. These two (or three) anastomoses are performed using the intima eversion technique with two running nonabsorbable sutures that are eventually tied to each other (Fig. 83-9). When the portal vein reconstruction is complete an air knot is tied to provide a
Most transplant centers place the pancreas intraabdominally on the right side because of the more anterior orientation of the vessels on this side (Fig. 83-10). The portal vein is anastomosed to the external iliac vein in end-to-side fashion. It is imperative that the branches of the internal iliac vein are all ligated so that there will be less tension and therefore less risk of venous thrombosis. Some centers perform the venous anastomosis to the SMV in order to prevent potential hyperinsulinemia by having direct portal drainage. At least 2 cm of portal vein are necessary for an adequate reconstruction. For the arterial reconstruction the external iliac artery is
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Figure 83-7. In the single technique, the aorta and IVC are divided above the aortic bifurcation and split anteriorly to expose the posterior wall so that Carrel patches can be fashioned safely. (Illustration by Ann Mamanee.)
anastomosed to the splenic and SMA, which have undergone Y-plasty with a donor iliac graft.[15,10]
Vascular Surgical Technique of Kidney Transplantation The kidney is usually placed in an iliac fossa of the surgeon’s preference. The right-sided iliac vessels are more anterior and may afford greater exposure. The preparation of the vessels involves meticulous ligation of lymphatics to avoid postoperative lymphocele. When a suitable length of external iliac artery and vein are prepared, the anastomosis is performed with a fine (5-0 or 6-0) nonabsorbable suture in an end-to-side fashion. The simplest technique involves splaying the recipient vessel at four points and then sewing outside to inside donor to recipient (“ship to shore”). In this manner the back wall is safe and any potential plaques on the recipient artery are plicated to the wall instead of being dislodged. Another technique involves sewing the proximal wall from
the inside and then completing the distal wall in the usual fashion. The arterial anastomosis is usually about 1 cm cephalad to the venous reconstruction.[10,16] Alternatively, the arterial anastomosis can be performed end to end between the renal artery and the mobilized and divided recipient hypogastric artery (Fig. 83-11). The development of a new surgical instrument, the AutoSuture VCS disposable clip applier system (United States Surgical Corporation, Norwalk, Connecticut) allows the completion of an everting anastomosis with a series of clips. This is believed to lessen the amount of warm ischemia time and is reportedly quite easy to learn.[17] However, further experience is needed to fully evaluate this new modality.
Vascular Surgical Technique of SmallBowel Transplantation The anastomoses in this procedure vary with the organ clusters transplanted. The small bowel can be implanted
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Figure 83-8. When the kidneys have been procured during an abdominal evisceration, the entire block is reoriented on the back table, and the posterior aorta (which is anterior now) is incised along the midline to allow Carrel patches to be fashioned. (Illustration by Ann Mamanee.)
singly, with the liver, with the liver and pancreas, or as part of a multivisceral block (cluster of grapes). The enbloc vascular reconstruction involves arterial connection between donor aorta and recipient aorta, venous reconstruction between the suprahepatic vena cava of the donor and the hepatic vein confluence of the recipient. Liver –small bowel and liver–
Figure 83-9.
pancreas –small bowel reconstructions are performed similarly. Small intestine –alone transplantation involves end-toside anastomosis of the donor SMA to the aorta of the recipient. Frequently the donor thoracic aorta is used as an interposition graft.[3] The SMV is anastomosed to a suitably prepared section of recipient portal vein.[18]
Venous end-to-end anastomoses are performed via an intimal eversion technique. (Illustration by Ann Mamanee.)
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Figure 83-10. The pancreas is usually placed intraabdominally on the right side because of the more anterior orientation of the vessels. (Illustration by Ann Mamanee.)
VASCULAR COMPLICATIONS IN ORGAN TRANSPLANTATION Liver Transplantation Arcuate Ligament Syndrome This is diagnosed when a significant reduction (or disappearance) of blood flow within the donor hepatic artery is noted during the expiratory phase of the respiratory cycle. This compression can be released by division of the median arcuate ligament. If this does not suffice, an aortohepatic graft may be required.
Hepatic Artery Thrombosis The incidence of hepatic artery thrombosis after liver transplantation ranges from 2 to 8% in adults. It is higher in the pediatric population. These patients can present in fulminant hepatic necrosis with bacteremia, hemodynamic instability, and markedly elevated liver enzymes. They can also show a more indolent course with relapsing bacteremia, milder elevations of liver enzymes, and hepatic abscesses demonstrated on CT scan or ultrasound. Later presentation
may be primarily biliary in nature. These patients experience cholangitis, bile duct strictures, and bile leaks. Finally, patients may be asymptomatic with only minimal elevations of enzymes. The diagnosis of hepatic artery thrombosis is made on duplex scanning and angiography.[19] A newer modality yet to be completely evaluated is spiral computerized tomography. When patients present with fulminant hepatic necrosis, the graft should be removed and a new organ transplanted. A patient may remain anhepatic for up to 14 hours until a new organ can be located. If the thrombosis is found in the early postoperative period, and the patient is not in fulminant failure, urgent rearterialization should be performed. Patients with biliary strictures can be maintained with antibiotics and percutaneously placed stents. Patients with localized necrosis may benefit from resection. Unfortunately, in the majority of patients (50–70%) retransplantation is necessary.[19]
Hepatic Artery Stenosis The clinical presentation is usually an insidious decrease in graft function or the onset of biliary complications. It may result from rejection, clamp injury, or cold preservation injury. This can be treated with percutaneous transluminal
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Figure 83-11. The renal arterial anastomosis can be performed end to end between the renal artery and the mobilized and divided recipient hypogastric artery. (Illustration by Ann Mamanee.)
angioplasty, rearterialization, or, if necessary, retransplantation.[19]
Hepatic Artery Pseudoaneurysms The gold standard for diagnosis is angiogram. Screening is performed with duplex or CT scan. Often the initial presentation is gastrointestinal bleeding. Usually these aneurysms are involved with local infection. The treatment involves resection of the infected area and revascularization if possible. Frequently retransplant is necessary.[19]
Portal Vein Stenosis and Thrombosis This may manifest with liver dysfunction or signs of portal hypertension such as an upper gastrointestinal bleed. The gold standard for diagnosis is angiogram. Screening is performed with duplex or CT scans. The treatment is with percutaneous transluminal angioplasty. If unsuccessful, retransplantation is necessary.[20]
Suprahepatic Caval Stenosis This can result from poor anastomotic technique or kinking of the anastomosis. The patient may present with liver dysfunction and new-onset ascites. The diagnosis is confirmed on angiogram and screened for with duplex. Treatment is with percutaneous radiologically guided dilatation. This can be done serially. If this fails, operative correction is necessary.[21]
Infrahepatic Caval Stenosis This can present with lower extremity edema and kidney dysfunction. After clinical suspicion is aroused, the diagnosis is made with ultrasound and confirmed with angiography. IVC stenosis can be treated with serial dilatations that result in excellent long-term patency.[21]
Pancreas Transplantation Vascular thrombosis represents the leading cause of nonimmunologic graft loss in pancreas transplantation with
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a reported incidence ranging from 10 to 35%.[22] The symptoms of arterial thrombosis include a sharp rise in blood glucose, a drop in serum amylase, and decreased urinary amylase. The symptoms of venous thrombosis include a sharp rise in blood glucose, a rise in serum amylase, and tenderness over the graft. In late graft thrombosis, the graft can remain in place as it often has developed collateral vessels and may still function. In early graft thrombosis graft pancreatectomy may be necessary if invasive radiologic or surgical maneuvers fail. Some surgeons believe that extensive mobilization of the external iliac vein, which includes ligation of the internal iliac vein, is necessary to avoid anastomotic tension and subsequent thrombosis.[15]
sclerosis, clamp injury, and faulty surgical technique. The diagnosis is confirmed with ultrasound and angiogram. The treatment of choice is percutaneous transluminal angioplasty. If this is not feasible, surgical repair is necessary. Unfortunately, there is a significant rate (20–30%) of graft loss following attempted surgical repair.[23]
Arteriovenous Fistulas These often result as a complication of biopsy. Presentation is usually with persistent hematuria. The diagnosis is confirmed with duplex. The treatment of choice is radiologic occlusion.[23]
Kidney Transplantation Hemorrhage Early hemorrhage can result from faulty anastomotic technique or more commonly from hilar vessels that were in spasm at the time of closure. Hypotension that is not responsive to saline boluses combined with decreasing hematocrit and a rapidly filling drain (if placed) warrants immediate investigation. Coagulation parameters should be checked and judiciously corrected. Early exploration is frequently necessary to save the graft and patient’s life; therefore needless delays should be avoided.[23] Late hemorrhage can also result from an aneurysmal disruption. These aneurysms usually are caused by bacterial or fungal infections of persistent hematomas. Other sequelae of aneurysms include thrombosis, embolus, or distal limb ischemia. Definitive diagnosis is made with angiogram, and surgical repair is required. This involves excision of the abnormal vessels and reapproximation with healthy, noninfected tissues. Occasionally a synthetic graft or autogenous saphenous vein is used in order to bridge this gap.[1]
Renal Artery Thrombosis Renal artery thrombosis is usually heralded by a sudden decrease in urine output and a simultaneous increase in creatinine. The diagnosis is confirmed by ultrasound and angiogram. Early thrombosis is often the result of an intimal flap or damage incurred during procurement or engraftment. Late thrombosis is usually due to rejection or progression of a stenotic segment. Early diagnosis may allow for repair of the artery and possible salvage of the graft.[23]
Renal Vein Thrombosis Renal vein thrombosis may present with deteriorating kidney function, proteinuria, or hematuria. It may result from progression of iliofemoral vein thrombosis. If the iliofemoral venous thrombosis cannot be treated with thrombolytic therapy before the development of renal vein thrombosis, the graft will probably be lost.[1,23]
Renal Artery Stenosis Renal artery stenosis is a late complication that manifests with hypertension, slowly rising creatinine, and polycythemia. It can result from rejection, progression of athero-
SPECIAL VASCULAR CONSIDERATIONS IN ORGAN TRANSPLANTATION Kidney Transplantation Multiple Donor Renal Arteries Multiple renal arteries are found in 18 –30% of donors. When multiple arteries can be safely procured from cadaveric donors, it is easiest to perform the anastomosis to one aortic cuff that contains the orifices of both vessels.[12] When the arteries are on separate patches, they can be sewn together for subsequent implantation. If this cannot be performed, two separate anastomoses are necessary. Alternatively, a Y-plasty can be performed using a hypogastric bifurcation interposition graft. Other techniques for bench reconstruction include anastomosing the smaller artery to the larger in an end-to-side fashion. If the vessels are similar in size, a side-to-side anastomosis can be performed before subsequent connection to the iliac vessel. It is imperative to maintain the integrity of lower pole arteries in order to prevent calyceal necrosis. This can sometimes be ensured by an end-to-end anastomosis between polar artery and the recipient inferior epigastric artery.[24] However, the use of these grafts has been associated with increased incidence of vascular complications.
Short Renal Artery Optimal mobilization of the recipient iliac vessels is imperative in order to guarantee a safe anastomosis. The short renal artery can be extended with the use of a donor iliac artery or the internal iliac artery of the recipient.[10]
Short Right Donor Renal Vein In the cadaver the right renal vein is procured intact with the IVC. If the vein is too short, a cuff of IVC can be used to extend the vessel. Alternatively, the left renal vein orifice and proximal caval orifice can be oversewn and the anastomosis performed between the recipient external iliac vein and the donor IVC. It is sometimes helpful to fully mobilize the common and external iliac veins by dividing the internal iliac venous branches.[10]
Chapter 83.
Vascular Anastomoses to Prosthetic Material Not uncommonly, a surgeon is called upon to anastomose the renal artery to a limb of an aortic graft that was previously placed because of aneurysmal or atherosclerotic disease. The arterial anastomosis is not technically demanding. The venous anastomosis is often difficult because of perivascular fibrosis that subsequently results in hemorrhage and/or thrombosis with graft loss. The results of this surgery are frequently poor due to these technical issues and the advanced physiological and chronological age of the patient.[25]
Suboptimal Recipient Vessels When a potential recipient presents with a history and physical consistent with significant atherosclerotic, aneurysmal disease, or venous thrombosis, it is prudent to evaluate the iliac vessels with duplex scanning. Frequently, the decision to place the kidney on a particular side is influenced by these examinations. Unfortunately, these lesions are sometimes found unexpectedly in the operating room. Aneurysms and stenotic segments can be repaired and the renal artery anastomosed into the prosthetic graft. If a soft area free of atherosclerosis cannot be found, endarterectomy may be necessary. If the iliac (external and internal) artery or vein are completely unsuitable, jump grafts can be used to the aorta or IVC. The graft can be synthetic or a previously procured donor iliac artery.[26]
Pancreas Transplantation Unsuitability of Donor Iliac Grafts If the donor iliac grafts are unavailable because of unsuitability or use by the liver transplant team, a Y-graft that includes the brachiocephalic, carotid, and subclavian arteries can be used. Bigam et al. reported use of the innominate artery as an extension graft when the Y-graft was too short to reach to the external iliac artery.[28] Similarly, donor iliac vein grafts have been used to extend the portal vein anastomosis.
Liver Transplantation Portal Vein Thrombosis Most commonly, portal vein flow can be reestablished by venous thrombectomy. This is not without risks; an iatrogenic tear in the midst of the pancreas can precipitate a rapidly fatal
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outcome. If thrombectomy fails, a donor iliac graft can be tunneled from the recipient SMV to the donor portal vein.[28] If the SMV is thrombosed, a mesenteric tributary can be used for portal inflow.[29] The renal vein has also been used to establish portal integrity. If these maneuvers are unsuccessful, the donor portal vein can be sewn to the recipient vena cava.[30] Multivisceral transplantation may be necessary as a very last resort.
Inadequate Recipient Hepatic Artery Donor iliac arteries provide reliable conduits for revascularization in liver transplantation. They usually are used from the infrarenal aorta and routed either above or below the pancreas. Less often the supraceliac aorta is employed.[31] This area can be very technically difficult to access and can result in significant blood loss. Additionally, the graft can originate from the iliac arteries (frequently an extension graft is necessary). The use of the splenic artery for revascularization has also been described.[32]
Anomalous Donor Hepatic Arteries Normal anatomy is encountered in only 40% of donors.[4] The left hepatic artery may arise from the left gastric or splenic artery, or from the aorta. The right hepatic artery can arise from the right gastric, the SMA, the gastroduodenal arteries, or the aorta. An anomalous left hepatic artery or right hepatic artery arising from the right gastric or gastroduodenal artery does not require special reconstruction as the celiac axis can still be used for anastomosis. When the right hepatic artery arises from the SMA it can be cut and anastomosed to the splenic or gastroduodenal arteries. Alternatively, the SMA patch can be joined to the celiac patch, and then the splenic or distal end of the SMA used for anastomosis to the recipient.[14]
CONCLUSION As the field of transplantation continues to grow, new innovations will become necessary. Improvements in the treatment of hepatitis B and C, better preservation solutions, increased donor awareness, and continued technical advancement have maximized donor utilization and optimized recipient outcomes. It must be emphasized, however, that sound surgical judgment and knowledge of standard and aberrant anatomy are essential for successful surgical results.
REFERENCES 1.
Mittal, V.K.; Toledo-Pereyra, L.H. Vascular Aspects of Organ Transplantation. Vascular Surgery: Principles and Practice, 2nd ed.; Lippincott, 1996; Chap. 82. 2. Flye, M.W. Donor Management. Multiple Cadaveric Organ Recovery; W.B. Saunders, 1995; Chap. 48. 3. Olson, L.; Davi, R.; Barnhart, J.; Burke, G.; Ciancio, G.; Miller, J.; Tzakis, A. Non-Heart-Beating Cadaver Donor
Hepatectomy: “The Operative Procedure.” Clin. Transplant. 1999, 13, 98– 103. 4. Yanaga, K.; Tzakis, A.G.; Starzl, T.E. Personal Experience with the Procurement of 132 Liver Allografts. Transplant. Int. 1989, 2 (3), 137– 142. 5. Emre, S.; Schwartz, M.E.; Miller, C.M. The Donor Operation. In Transplantation of the Liver; Busuttil,
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R.W., Klintmalm, G.B., Eds.; W.B. Saunders, Chap. 39, 393 – 396. Busuttil, R.W.; Goss, J.A. Split Liver Transplantation. Ann. Surg. 1999, 229 (3), 313– 321. Goss, J.A.; Yersiz, H.; Shackleton, C.R.; Seu, P.; Smith, C.V.; Markowitz, J.S.; Farmer, D.G.; Ghobrial, R.M.; Markmann, J.F.; Arnaut, W.S.; Imagawa, D.K.; Colquhoun, S.D.; Fraiman, M.H.; McDiarmid, S.V.; Busuttil, R.W. In Situ Splitting of the Cadaveric Liver for Transplantation. Transplantation 1997, 64 (6), 871– 877. Hashikura, Y.; Kawasaki, S. Recent Advances in LivingRelated Liver Transplantation and in Liver Transplantation for Patients with Liver Cirrhosis and Hepatocellular Carcinoma. Nippon Geka Gakkai Zasshi 1998, 99 (11), 754– 758. Hakim, N.S.; Papalois, V.E. Successful Procurement of 50 Pancreatic Grafts Using a Simple and Fast Technique. Int. Surg. 1998, 83, 327– 329. Jerius, J.T.; Murillo, D.; Taylor, R.J. Vascular Reconstruction of Transplant Organs. Problems in General Surgery; Lippincott, Williams & Wilkins: Philadelphia, 1998; Vol. 15. No. 3, 21 – 30. Yanaga, K.; Podesta, L.G.; Broznick, B.; Shapiro, R.; Steiber, A.C.; Makowka, L. Chapter 3: Multiple Organ Recovery for Transplantation. Atlas of Organ Transplantation; Gower Medical Publishing, 1992. Kuo, P.C.; Cho, E.S.; Flowers, J.L.; Jacobs, S.; Bartlett, S.T.; Johnson, L.B. Laparsocopic Living Donor Nephrectomy and Multiple Renal Arteries. Am. J. Surg. 1998, 176, 559–562. Strieber, A.C.; Makowka, L.; Starzl, T.E. Chapter 7: Orthotopic Liver Transplantation. Atlas of Organ Transplantation; Gower Medical Publishing, 1992; 7.12 – 7.51. Klintmalm, G.B.; Busuttil, R.W. The Recipient Hepatectomy and Grafting. In Transplantation of the Liver; Busuttil, R.W., Klintmalm, G.B., Eds.; W.B. Saunders, Chap. 40, 405– 418. Tyden, G.; Groth, C.G. Chapter 8: Pancreas Transplantation. Atlas of Organ Transplantation; Gower Medical Publishing, 1992; 8.4– 8.11. Shapiro, R.; Simmons, R.L. Renal Transplantation. Atlas of Organ Transplantation; Gower Medical Publishing, 1992; Chap. 4, 4.6– 4.9. Jones, J.W. A New Anastomotic Technique in Renal Transplants Reduces Warm Ischemia Time. Clin. Transplant. 1998, 12, 70– 72. Hoffman, A.L.; Lee, K.K.W.; Schraut, W.H. Small Bowel and Multivisceral Organ Transplantation. Atlas of Organ Transplantation; Gower Medical Publishing, 1992; 9.4 – 9.8. Imagawa, D.K.; Busuttil, R.W. Technical Problems: Vascular. In Transplantation of the Liver; Busuttil, R.W., Klintmalm, G.B., Eds.; W.B. Saunders, 1996; Chap. 63, 626– 632.
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Olthoff, K.M.; Busuttil, R.W. Venous Anomalies Including Portal Vein Thrombosis and Prior Portosystemic Shunts. In Transplantation of the Liver; Busuttil, R.W., Klintmalm, G.B., Eds.; W.B. Saunders, 1996; Chap. 46, 465 – 473. Colquhoun, S.D.; Busuttil, R.W. Graft Failure: Cause, Recognition, and Treatment. In Transplantation of the Liver; Busuttil, R.W., Klintmalm, G.B., Eds.; W.B. Saunders, 1996; Chap. 61, 607 – 615. Sansalone, C.V.; Aseni, P.; Follini, M.L.; Rosetti, O.; Slim, A.O.; Colella, G.; Di Benedetto, F.; Rombola, G.; Rondinara, G.F.; Dc Carlis, L.; Brunati, C.; Meroni, A.; Confalonieri, R.; Civati, C.; Forti, D. Early Pancreas Retransplantation for Vascular Thrombosis in Simultaneous Pancreas – Kidney Transplants. Transplant. Proc. 1998, 30, 253– 254. Danovitch, G.M. Handbook of Kidney Transplantation; Little, Brown: Boston, 1996. Oesterwitz, H.; Strobelt, D. Extracorporeal Microsurgical Repair of Injured Multiple Donor Kidney Arteries Prior to Cadaveric Allotransplantation. Eur. Urol. 1985, 11, 100– 105. Van der Vliet, J.A.; Naafs, D.B.J.; van Bockel, J.H.; Kootstra, G.; Boll, A.P.M.; Barendregt, W.B.; Buskens, F.G.M. Fate of Renal Allografts Connected to Vascular Prostheses. Clin. Transplant. 1996, 10, 199– 202. Oesterwitz, H.; Strobelt, D. Extracorporeal Microsurgical Repair of Injured Multiple Donor Kidney Arteries Prior to Cadaveric Allotransplantation. Eur. Urol. 1985, 11, 100– 105. Delpin, E.S.; Delpin, E.S. Brief Report: Successful Extension of the Transplant Renal Vein with a Synthetic Vascular Graft. Bol. Asoc. Med. P. R. 1997, 89 (10– 12), 206– 207. Bigam, D.; Hemming, A.; Sanabria, J.; Cattral, M. Transplantation 68 (2), 314– 315. Shaw, B.W., Jr.; Iwatsuki, S.; Bron, K.; Starzl, T.E. Porta Vein Grafts in Hepatic Transplantation. Surg. Gynecol. Obstet. 1985, 161, 66. Tzakis, A.; Kirkegaard, P.; Pinna, A.; Jovine, E.; Evangelos, P.; Misiakos, E.; Maziotti, A.; Dodson, F.; Khan, F.; Nery, J.; Rasmussen, A.; Fung, J.; Ruiz, P.; Demetris, A. Liver Transplantation with Cavoportal Hemitransposition in the Presence of Diffuse Portal Vein Thrombosis. Transplantation 1988, 65 (5), 619– 624. Shaked, A.A.; Takiff, H.; Bussutil, R.W. The Use of the Supraceliac Aorta for Hepatic Arterial Revascularization in Transplantation of the Liver. Surg. Gynecol. Obstet. 1991, 173, 198– 202. Figueras, J.; Torras, J.; Arandal, I.; Rafecas, A.; Fabregat, J.; Ramos, E.; et al. Revascularization of Liver Grafts with Recipient Splenic Artery in Liver Transplantation. Transplant. Proc. 1995, 27, 2313– 2314.
CHAPTER 84
Vascular Surgical Techniques Frank J. Veith
This chapter provides illustrations and accompanying descriptions of standard techniques and operations used in vascular surgery. These include techniques for dissecting, incising, and repairing injured arteries and veins; methods for vascular anastomoses and bypass grafting; and one surgeon’s standard techniques for performing relatively uncomplicated, common venous and arterial operations. The methods described and illustrated represent one way of performing these operations. Other vascular surgeons may have different and even better ways of doing the same procedures, and indeed some of these are discussed and illustrated in other chapters in this volume. Moreover, the techniques that are illustrated in this chapter may not apply to every case, and certainly other special methods are required to deal with the more complex and complicated pathologic patterns of disease that seem to make up an increasing proportion of vascular surgical practice. However, the methods that are shown work well for the standard patterns of vascular pathology that require surgical treatment. The techniques shown are included to provide students and resident trainees with some of the details involved in one surgeon’s way of performing these standard vascular operative procedures.
Hobson/Wilson/Veith: Vascular Surgery: Principles and Practice, Third Edition, Revised and Expanded DOI: 10.1081/0819-9-120024968 Copyright q 2004 by Marcel Dekker, Inc.
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ARTERIAL DISSECTION 1 2 3
The periadventitial tissue is grasped with forceps and incised with scissors. This may be done in several layers. The artery is then freed from its surrounding areolar tissue layers using a combination of blunt and sharp dissection. Care is taken to avoid injury to all arterial branches. Small crossing veins traverse some of these periadventitial layers. These are isolated, doubly ligated, and divided, as shown.
Arterial Incision 4
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An arterial segment is isolated between clamps in such a way that its lumen is filled with blood. A knife is then used to make the arteriotomy. Care is taken to keep the knife cut directly perpendicular to the lumen of the artery, so that the incision in the artery is straight and not skewed or tangential. The point of the knife is used to cut the artery, using light pressure and multiple strokes. If the arterial wall is thickened with disease, a mosquito clamp is inserted into the artery to define the lumen, and the straight cut, which is perpendicular to the wall, is continued between the blades of the clamp as shown. If a scissors is used with a diseased, thick-walled artery, such as the one shown, then jagged, skewed openings in the artery and its various diseased layers may occur and anastomosis rendered more difficult. The ends of the arteriotomy should be fashioned at approximately 458 angles so that there is no undermining of the media or the adventitia and the intimal layer can be clearly visualized for placement of stitches. If the arterial wall is relatively normal, a small Pott’s scissors or microscissors can be used to complete the arteriotomy.
Suture Closure of Arteriotomy 7
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Both limbs of a double-armed atraumatic monofilament suture are placed from within outward at each end of the arteriotomy and then tied. One arm of one suture is then run to the center of the incision. It should be noted that in performing the arteriotomy and suture closure, no excision of intima or endarterectomy is performed and all layers are cut evenly. The suture originating at the other end of the arteriotomy is also run to the center of the incision, where it is tied to the first suture.
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END-TO-END VASCULAR ANASTOMOSIS 1
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End-to-end anastomosis of arteries is accomplished by approximating the ends of the two arteries with occluding atraumatic clamps. A double-armed atraumatic monofilament suture is placed at either lateral side of the artery. Care is taken to include equal bites of all layers of the arterial wall in each passage of the needle. With good light and exposure, the three layers of the arterial wall can be clearly visualized. The two corner stitches are tied. One arm of the suture is then run along the anterior wall of the artery to the opposite corner and tied. By rotating the vascular clamps and appropriately manipulating the corner sutures, the anastomosis is turned over, exposing the posterior wall. One of the sutures is then run to the opposite corner and tied to the free end of the opposite corner suture. Again, care is taken with each bite to include equal-sized portions of each layer of the arterial wall. The completed anastomosis is shown.
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END-TO-SIDE VASCULAR ANASTOMOSIS 1
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Sutures are placed at the two ends of the planned anastomosis. Care is taken to place these stitches from within outward in each structure and to catch all layers of both the vein graft and the artery. The intimal layer is particularly important in this regard. Double-armed 6-0 polypropylene atraumatic sutures are used. The apex suture is tied while the opposite-end suture is left untied. One arm of the apex suture is run to the midportion of one side of the anastomosis. Small, even bites of all layers are taken with each stitch of the running suture. The opposite limb of the suture is run along the opposite lateral margin of the anastomosis to its midportion. The suture in the opposite end is tied, and both arms of this suture are run to the midportions of the anastomosis, where they are tied to the suture from the opposite end. Good visualization of the inside and the outside of the artery must be obtained when each bite is taken so that the suture will catch and fix the intimal layer. In general the arterial wall should not be grasped with forceps but should be only pushed with the closed forceps to provide visualization. It is also important that the closed or open forceps be used to stabilize the artery as the needle is being passed through it. This can be accomplished without grasping the artery, simply by using the forceps as a pusher or foil.
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REPAIR OF LACERATED INFERIOR VENA CAVA; REPAIR OF LACERATED ARTERY OR VEIN Repair of Lacerated Inferior Vena Cava 1
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A knife wound of the inferior vena cava is shown. This is controlled by emptying the segment of cava containing the laceration by sponge stick pressure proximally and distally. Finger pressure, or pressure with a tonsil sucker, is used to control bleeding from branches entering the injured venous segment. When this is done the vein may be dissected free proximally and distally and clamps applied, although this is often not necessary. When the edges of the laceration can be clearly visualized and the adjacent wall of the vein is dissected from surrounding tissue, the edges of the laceration are grasped with a forceps and a Satinsky clamp is placed to isolate the laceration. The laceration is then closed with a running 4-0 or 5-0 vascular polypropylene suture in a dry field precisely approximating the edges. If the laceration is through and through the inferior vena cava, the far wall must also be repaired. This can be accomplished after the inferior vena cava is emptied of blood by approximating the laceration in the far wall from within the vena cava through the laceration in the near wall. To accomplish this, one must get an absolutely dry field; it may be necessary to isolate the vessel proximal and distal to the injury and apply vascular clamps. It may also be necessary to isolate and ligate branches that drain into that segment. The temptation to grasp the bleeding vena cava in a pool of blood should be resisted, particularly before the vessel is cleanly dissected. Pressure control and emptying of the injured vein should be the theme of technical management.
Repair of Lacerated Artery or Vein Types of Vascular Injury and Methods of Repair 4
5 6
7
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9 10 11
A small puncture wound or minor laceration of an artery is shown. This is frequently the type of injury encountered from an arteriographic procedure. The injury is controlled by finger pressure until the artery is controlled by the application of clamps and the injury repaired. Simple interrupted sutures through all layers of the arterial wall, or the adventitia and media, are adequate to control the injury and maintain patency of the artery. A more extensive and somewhat jagged, although clean, laceration is shown. This can result from a knife wound or injury with a similar sharp object. Bleeding is controlled by pressure until the artery remote from the injury is isolated and controlled with clamps. All branches entering into the intervening segment also must be isolated and controlled. If the laceration is clean and there is no contusion of the adjacent edges of the laceration, it may be repaired by a simple running suture. Sutures are placed from within outward at both ends of the laceration and then run to the center, where they are tied. A contused arterial wound is shown. An injury such as this can be produced by a bullet wound or other blunt trauma. In the injury depicted there is loss of arterial wall substance, and tissue adjacent to the defect is damaged. All injured artery wall must be excised by cutting the artery along the lines shown. This leaves inadequate length of artery to approximate without tension. Accordingly, a prosthetic graft or autologous vein graft must be used. This can be inserted as an interposition graft, as shown. Alternatively, if exposure is impaired or there is excessive surrounding tissue damage or contamination, the debrided arterial ends are ligated and a remote bypass graft is carried out to restore arterial continuity.
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REPAIR OF LACERATED FEMORAL ARTERY 1
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If the injury is thought to be complex, proximal control of the iliac artery through a suprainguinal retroperitoneal incision is advisable. While this is rapidly being accomplished, bleeding from the femoral artery laceration is controlled with finger pressure. Even with occlusion of the external iliac artery, bleeding from the groin will be brisk due to the multiple branches of the deep femoral artery. However, finger pressure can control this bleeding while the superficial femoral artery is dissected and clamped. It is sometimes necessary to get clamp control of the deep femoral artery as well, so that accurate approximation of the lacerated femoral artery can be accomplished. Occasionally, if only one or two sutures are required, digital or suckerpressure will control bleeding from the deep femoral artery so that the sutures can be accurately placed. More complex injuries require clamp control of all branches. In some instances of false aneurysm due to injury at the time of arteriography, the false aneurysm can simply be entered with a vertical incision in the groin and bleeding from the anterior wall of the femoral artery controlled with digital pressure. The artery can then be dissected proximally in the groin, and suture control of the bleeding point can be obtained. If the patient is obese or a complex injury is suspected, proximal control via the external iliac is advisable.
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INFERIOR VENA CAVA PLICATION 1
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A retroperitoneal incision in the right flank is made at about the level of the umbilicus, or midway between the costal margin and the iliac crest. Care is taken to extend this incision across the lateral one-half to one-third of the rectus sheaths to provide better medial exposure. The three oblique abdominal muscles are cut in the direction of the skin incision, and the anterior and posterior rectus sheath is also incised. Rarely is it necessary to divide the rectus muscle. After dividing the transversalis fascia, it is possible to enter the retroperitoneal plane and strip the peritoneum from the deeper layers of the abdominal wall. This is first accomplished superiorly and then inferiorly. Finally, the peritoneum is swept away from the posterior parietes. In the course of this, the psoas muscle is visualized and serves as an important landmark.
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INFERIOR VENA CAVA PLICATION (cont.) 5
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By using three mechanical retractors, which are fixed to the operating table, and fitting them with appropriate 1- or 2-in. Deaver retractors, the retroperitoneal fatty tissue and edges of the incision can be retracted superiorly and inferiorly. The peritoneal cavity and its contents, along with the ureter, can be retracted strongly in a medial direction. The fatty areolar tissue overlying the inferior vena cava is then incised and dissection continued in the periadventitial plane of the inferior vena cava. By pushing the inferior vena cava gently to the patient’s left and putting tension on the surrounding fatty areolar tissue, the right-side lumbar veins can be visualized and protected from injury. By gently holding the inferior vena cava to the patient’s right, using the fingers of the surgeon’s left hand, and tensioning the fatty areolar tissue to the patient’s left, it is possible to visualize the left-side lumbar veins and protect them from injury. Once the position of the lumbar veins is known, it is possible to compress the vena cava in the lateral plane with an atraumatic vascular forceps. A large C clamp is placed behind the vena cava to grasp a red rubber catheter, which has been cut appropriately for the purpose. Into the other end of this catheter the posterior half of the vena caval clip is inserted so that it can be drawn around the back of the cava. The clip is then closed and tied, completing the operation. The retroperitoneum is allowed to collapse over the cava. The retractors are removed and the wound is closed in layers.
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SAPHENOUS VEIN LIGATION AND STRIPPING 1
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4 5 6
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9 10 11 12 13
The anatomy of the varicose greater saphenous vein is shown, together with the three skin incisions that are typically required. The upper incision should start directly over the femoral pulse and extend medially in a diagonal fashion as shown. (All three incisions may be somewhat shorter than shown.) Additional incisions may be required if a perforator is suspected or the stripper does not pass a particular point. The position of the saphenous nerve adjacent to the vein is also shown in the ankle area. Great care must be taken to protect this from injury so as to avoid saphenous neuritis. As the oblique incision in the groin is deepened in the fatty tissue, a large venous structure will be encountered. The position of the femoral artery should be carefully identified by palpating the femoral pulse; care should be taken to avoid injury to this vessel and the femoral vein. Once it has been confirmed that the first large venous structure encountered is in fact the greater saphenous vein, it can be divided between clamps as shown. Both ends of the divided saphenous vein are separated and dissected free. Their branches are clamped, doubly ligated, and divided. The fossa ovalis is identified by the small arterial branch that defines its lower border. The junction of the saphenous vein with the common femoral vein is clearly identified, and the saphenous vein is clamped a few millimeters away from this junction. Without pulling firmly on the saphenous vein and tenting up the adjacent walls of the common femoral vein, the vein is ligated with #00 silk. A second suture is placed on the greater saphenous vein just beyond the first tie. The two ligatures on the saphenous vein are shown in position, without any deformity being created in the common femoral vein. A vertical incision is then made just anterior to the medial malleolus. The saphenous vein and saphenous nerve are identified, and the nerve is protected from injury. Branches in this area are ligated, and then the saphenous vein is divided between clamps. An opening is made in the proximal end of the distal saphenous vein so that the small end of the stripper can be inserted. The remaining distal end of the saphenous vein is ligated and the stripper is tied in place. Traction is exerted in a cephalad direction. As the stripper is being drawn toward the patient’s head, a snug-fitting sterile elastic bandage is applied to the area from which the vein is being removed, thereby controlling avulsed tributaries. Positions of typical incisions in the leg are also shown. Through these small incisions, previously marked clusters of varicosities can be removed. In the illustration, a twisting motion of a clamp avulses one such small cluster. A slightly larger incision is made to remove a bigger cluster. Where possible, identifiable branches are ligated and the thin-walled varices are avulsed. This shows the appearance of the veins as they are removed and the branches connecting with the deeper system are ligated. This shows a larger incision, and division and ligation of a probable communicating branch. Through these incisions all major venous clusters are excised and avulsed. A subcuticular absorbable suture is used to close all incisions. It provides the best cosmetic result.
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CAROTID ENDARTERECTOMY 1
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The position of the patient, with the head turned away from the side of the incision, is shown. A thyroid pillow should be placed beneath the shoulders, and the head of the patient should be draped free with the anesthesiologist placed at the side of the operating table, so that the surgeon and his or her assistant can stand on either side of the table—which is rotated toward the assistant to provide equally good access to both surgeons. The incision is placed along the anterior border of the sternomastoid and curved slightly posterior in its upper portion to avoid injury to the marginal mandibular branch of the facial nerve. After the incision is deepened through the subcutaneous fat and platysma, the anterior border of the sternomastoid muscle is defined and the wound edges are retracted with a self-retaining retractor. The anterior surface of the internal jugular vein is defined and the common facial branch is identified and dissected free. This vein is divided between ligatures. In the event that the vein is short, the divided ends may be oversewn. Division of the common facial vein allows the internal jugular vein to be retracted laterally and posteriorly and held with the self-retaining retractor. The upper angle of the wound is then retracted with an army-navy retractor, which can be held in a secure position with a robot arm, avoiding the need for a second assistant in this operation. The position of the common facial vein is a rough guide to the carotid bifurcation. The fascial investments of the carotid artery are then grasped with forceps, tensioned, and incised to expose the underlying adventitia of the carotid artery. As this incision is extended superiorly, care is taken to identify the hypoglossal nerve and protect it from injury. Once this is identified and protected, the anterior belly of the digastric muscle is identified and retracted superiorly with the army-navy retractor. The common carotid artery, the superior thyroid artery, the external carotid artery, and the internal carotid artery are then dissected free in their periadventitial plane and encircled with vessel loops. Care is taken to dissect the surrounding tissue away from the carotid artery so that it will be manipulated minimally. (This is so that the risk of embolization will be minimized.) Care should be taken to dissect the internal carotid artery as far as necessary to isolate at least 1 cm distal to the palpable disease. This upper dissection of the internal carotid artery can be facilitated by isolating, ligating, and dividing small arteries and veins which hold the hypoglossal nerve posteriorly. Once these small vessels are divided, the hypoglossal nerve can be swept anteriorly and medially. This provides access to the upper reaches of the internal carotid artery. The patient is given systemic heparin [1 mg (100 IU)/kg]. Atraumatic vascular clamps are then placed gently across the common and external carotid arteries, and the superior thyroid artery is controlled with a doubled vessel loop. A needle is then inserted in the common carotid artery below palpable disease and the stump pressure is measured. According to the surgeon’s preference, the stump pressure measurement, the EKG recordings with carotid clamping, and the patient’s clinical and radiographic presentation, a decision is made regarding the need for shunt protection of the brain during endarterectomy. A gently applied atraumatic clamp is placed across the internal carotid artery well distal to any palpable disease, and an incision is made in the common and internal carotid artery in a longitudinal direction. Entrance is gained into the lumen of the internal carotid artery distal to the disease and into the common carotid artery proximal to the disease. In between, the incision in the artery is deepened to the surface of the plaque. The adventitial and a portion of the medial layers of the carotid artery are grapsed with fine atraumatic forceps and the appropriate endarterectomy plane defined. Ideally this is just deep to the circular muscle fibers within the media of the vessel. Using an endarterectomy spoon or dissector, this plane is further defined and the core of the diseased artery is dissected free proximally and distally. This dissection is continued in circumferential fashion until it proceeds proximal to the obvious atheromatous plaque in the common carotid artery. The core of the artery is then transected through relatively normal intima and media. This frees the proximal end of the plaque, which can then be placed under tension to further facilitate the endarterectomy of the external carotid artery. This is accomplished by eversion with inferior traction on the clamp controlling the external carotid. Generally the atheroma within the external carotid separates with this eversion technique. However, it is sometimes necessary to transect the atheroma sharply to end the removal of the plaque from the external carotid. Occasionally it may be necessary to make a separate longitudinal incision in the external carotid to ensure maintenance of flow to this important vessel. Following transection of the external carotid attachments of the plaque, the endarterectomy can continue up the internal carotid artery. The arteriotomy in the internal carotid artery should extend well above the upper level of the plaque, which is frequently most extensive on the posterior wall. Once the upper border of the plaque is defined, the endarterectomy may be completed by transecting the plaque through normal intima, as indicated by the dashed line in Fig. 7. Sometimes transection of the distal end of the plaque is unnecessary since it will feather out and come away from the distal intima as the plaque is freed under gentle tension. If any free intimal or medial edge is detected at the site of the upper limit of the endarterectomy, this free edge is secured with “U” stitches placed with the knot tied on the outside of the internal carotid artery. Although some surgeons feel that placement of these “U” stitches is almost never necessary, we employ them frequently. If placed with care they do not distort the vessel or its lumen, and they certainly may provide protection against upward dissection of an intimal flap. After all plaque is removed and the distal end of the endarterectomy secured, care is taken to examine the endarterectomized segment of the artery to remove all loose circular muscle fragments and other debris so that no material is present which could possibly embolize. This maneuver is facilitated by using fine forceps and copious amounts of saline irrigation. The longitudinal arteriotomy is enclosed with fine polypropylene 6-0 sutures. These are generally begun at both ends of the arteriotomy and carried to the central portion, where they are tied. If these sutures are placed carefully and encompass small bites of the endarterectomized arterial wall, the arterial closure can be accomplished without narrowing. Although some surgeons routinely use a vein or PTFE patch, we do not use it routinely in primary cases. If a patch is necessary, we favor use of an accessory saphenous vein from the thigh or PTFE. Rupture of ankle vein has been reported in a few cases, and we would not advocate use of this material. Before flow is reestablished, both the internal and common carotid arteries are flushed to remove luminal debris. When the arteriotomy is closed, an effort is made to exclude all intraluminal air, and clamps are removed first from the external and common carotid artery so that debris will be carried up this vessel. Only after release of these two clamps is the internal carotid artery clamp removed.
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CAROTID ENDARTERECTOMY (cont.) 10 11 12
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In the event that a shunt is necessary, one possible technique for its insertion is shown. Small Rummel tourniquets are positioned around the internal carotid and common carotid arteries. After the longitudinal incision is made in these arteries, the internal carotid artery vascular clamp is removed and the occluded shunt is gently inserted into a normal portion of this artery. The Rummel tourniquet is gently tightened to secure the shunt in place, and the clamp occluding the shunt is released momentarily to assure adequate backflow from the internal carotid artery and appropriate positioning of the distal end of the shunt. The clamp on the shunt is replaced. After controlling the common carotid artery with finger compression, the common carotid artery clamp is removed. The common carotid artery is then flushed by a momentary release of the finger pressure, and the proximal end of the shunt is passed down the common carotid artery between the fingers. The common carotid artery Rummel tourniquet is tightened and the clamp is removed from the shunt, restoring flow to the internal carotid artery. The endarterectomy is then performed in the standard fashion. This is somewhat more difficult with the shunt in place. However, it can be accomplished in an unhurried fashion with the same technical care as already described. If the dissection in the internal carotid artery has proceeded high enough, a very adequate end point can almost always be obtained and its adequacy assured by direct visual inspection.
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CAROTID ENDARTERECTOMY (cont.) 15
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To remove the shunt upon completion of the endarterectomy, the arteriotomy in the common carotid and internal carotid artery is closed for as long a distance as possible. These closures are begun at both ends of the arteriotomy and continue toward the midportion, leaving the central part of the arteriotomy open to allow removal of the shunt. The shunt is clamped in its midportion and the distal Rummel tourniquet is released. The distal end of the shunt is then carefully removed from the artery. The rush of blood aids in the removal of luminal debris. The internal carotid artery is then gently clamped. With finger control of the common carotid artery again established, the proximal Rummel tourniquet on the common carotid artery is released and the shunt is removed. Clamp control of the common carotid artery is then established after flushing that vessel. Traction is placed on the two suture ends defining the unclosed portion of the arteriotomy. Taking great care to avoid intraluminal air, a small partially occluding vascular clamp is placed just under the open portion of the arteriotomy. Flow is then reestablished up the external carotid artery by releasing the clamps on this vessel. After a moment of this flow the internal carotid artery clamp is released, reestablishing flow to the brain. The midportion of the arteriotomy closure is then accomplished and the partially occluding clamp is removed. After securing adequate hemostasis, a few #0000 polyglycolic acid sutures are used to approximate lymphoareolar tissue over the carotid artery. The platysma and skin are then closed in layers. We generally employ a small closed suction drain for 24 h, although this is not routinely deemed necessary.
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AORTIC ANEURYSM REPAIR 1
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More than 95% of aortic aneurysms involve the infrarenal segment of the abdominal aorta. Aneurysms of the infrarenal aorta and iliac arteries can be approached via an anterior transperitoneal route or via a left-sided retroperitoneal route with the left side of the patient slightly elevated and the left upper extremity affixed to the ether screen. For more standard abdominal aortic and iliac aneurysms, we favor the anterior transperitoneal approach, using a long midline incision which is extended superiorly above the xiphoid in the skin and fascial layers and to the pubis inferiorly. For aortic aneurysms that involve the segment of the aorta that gives rise to the renal arteries or the superior mesenteric and celiac arteries, we favor a retroperitoneal transpleural approach with the upper lateral portion of the incision extending into the eighth or ninth intercostal space (see Plates 17– 20). After the abdomen is opened, the intraperitoneal and retroperitoneal viscera are explored thoroughly, the small bowel is retracted to the right, and the transverse colon is retracted superiorly. This exposes the posterior peritoneum overlying the segment of the aorta below the inferior mesenteric artery. Just above this area, the ascending or fourth portion of the duodenum and the ligament of Treitz can be identified. A T-shaped incision is made in the peritoneum. This begins over the lower extent of the aortic aneurysm, which in the example shown extends inferiorly only to the aortic bifurcation. The incision is extended superiorly midway between the duodenum and the inferior mesenteric vein. In its upper portion it is converted to a T-shaped incision which parallels the lower border of the pancreas. The inferior mesenteric vein is carefully identified, isolated, and divided so that the lower border of the pancreas may be freed beneath the peritoneal incision and retracted superiorly, thereby providing access to the neck of the aneurysm, the left renal vein, and the pararenal segment of the aorta if this is necessary. After this incision is completed, the abdominal viscera are controlled with packs and self-retaining retraction devices. These can consist of a large ring-shaped retractor, which allows retraction of the abdominal wound laterally and the transverse colon and mesocolon superiorly, as depicted. This ring retraction device must be supplemented by two deeply placed Deaver retractors, which, with appropriate packing, allow the small bowel and duodenum to be retracted to the right and craniad and the transverse and descending colon to be retracted to the left and craniad. These two Deaver retractors may be held by surgical assistants but are best held in a fixed position by robot-arm retractors, which can be affixed to the operating table. Alternatively, a special self-retaining retraction device (Omni-tract) designed for aortic surgery can be used. This device is shaped in the form of a wishbone, which is affixed securely to the operating table. The apex of this wishbone is placed over the sternum; various retracting elements may then be secured to the wishbone. Once retraction is secured, the retroperitoneal fatty areolar tissue overlying the aneurysm is incised in the midline, using a rightangle clamp and coagulating cautery to control the small arterial and venous bleeders in this layer. As dissection in this plane proceeds superiorly, the left renal vein is identified and its lower border defined. It is sometimes necessary to dissect this vein circumferentially so that it can be encircled with a loop and retracted superiorly. However, this is not always necessary. To aid in the mobilization and retraction of the left renal vein, it is sometimes necessary to divide the genital branch or branches and a posterior lumbar branch which is often present.
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AORTIC ANEURYSM REPAIR (cont.) 5 6
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With the lower border of the left renal vein identified and in some cases with it appropriately retracted in a craniad direction, the fascial investing layer just outside the adventitia of the aorta is incised after elevating this layer with forceps. It is then possible in most instances to dissect the lateral walls of the aorta using a combination of blunt finger dissection and occasional sharp dissection to divide resistant bands or small branches arising from this segment of the aorta. Such small branches most often represent accessory renal arteries; if these are less than 2 mm in diameter, they may be ligated and divided to facilitate aortic mobilization. It is generally not necessary to dissect the aorta completely on its posterior aspect, although some surgeons still do so. Adequate anterior and lateral mobilization of the aorta, if it is extensive enough, will usually facilitate clamp control of the aorta proximal to the aneurysm. Circumferential aortic dissection, although it may facilitate clamp control and suturing, can also lead to bleeding. For that reason we no longer perform this dissection routinely. The areolar tissue just superficial to the adventitia of the common iliac arteries is grasped with forceps, placed under tension, and sharply incised. This allows periadventitial dissection of the iliac arteries anteriorly and laterally on both sides. For reasons already mentioned we do not routinely dissect these vessels circumferentially either. After administration of systemic heparin [1 mg (100 IU)/kg], appropriate atraumatic vascular clamps are then applied to the proximal infrarenal aorta and distal common iliac arteries. A doubled vessel loop may be placed on the inferior mesenteric artery as it emerges from the aneurysm. Generally the application of clamps is such that the aorta and iliac arteries are compressed in a lateral direction. However, if these vessels are calcified and tortuous, compression of the vessels in an anteroposterior direction may be more easily accomplished. This is particularly true if the infrarenal aorta just proximal to the aneurysm deviates to the right. An effort is made to use vascular clamps, which are shaped in such a fashion that the handles do not obscure the operative field. Some surgeons favor placement of the distal clamps first to minimize the chance of distal embolization of clot and atheromatous material. Although this is advantageous from a theoretical perspective, the placement of distal clamps before the aneurysm is decompressed by a proximal clamp is sometimes technically difficult. This is particularly true when the aneurysm is large and involves the iliac arteries. After clamp placement in a fashion that obliterates the aneurysmal pulse is completed, the aneurysm is incised along its anterior surface and this incision is extended laterally in both directions at the superior and inferior ends of the aneurysm, as indicated by the dashed lines. This incision is generally best accomplished with the coagulating cautery to minimize bleeding from small vessels in the aneurysm wall and surrounding areolar tissue. The lumen of the aneurysm is entered. It is advantageous to utilize some form of cell-saving or autotransfusion device throughout these cases to minimize the need for homologous blood transfusion.
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AORTIC ANEURYSM REPAIR (cont.) 9 10
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Clot within the lumen of the opened aneurysm is then mobilized with finger dissection and removed. This exposes the orifices of lumbar arteries and other aortic branches, which can backbleed vigorously into the opened aneurysmal sac. This bleeding is controlled by oversewing the orifices of these branches with figure-of-eight #000 silk sutures. Although some large aneurysms have no patent arteries that require such control, other aneurysms have many branches. Bleeding from this source can be quite substantial. If bleeding from the inferior mesenteric artery is brisk and the inferior mesenteric artery is small, the orifice of this vessel may be oversewn as well. However, if this artery is large and there is only a trickle of backbleeding from it, consideration should be given to reimplantation of this vessel into the wall of the aortic graft. This is particularly true if there is stenotic or occlusive disease involving the celiac and superior mesenteric arteries. Often, however, the orifice of the inferior mesenteric artery is occluded; no attention need be directed to this vessel as long as flow is reestablished to at least one of the internal iliac arteries. An appropriate-sized aortic graft is selected for use. A variety of woven or knitted Dacron grafts or PTFE grafts may be used. If an uncoated knitted Dacron graft is employed, it must be carefully preclotted. To minimize bleeding through the graft wall, we use a collagen-coated knitted graft (Hemashield), which bleeds minimally and is easy to handle. Suturing of the graft is best accomplished with #00 polypropylene sutures with large needles. The suture is begun posteriorly as shown. This suture is tied with two or three throws, and suturing is continued laterally in both directions. The posterior wall of the aorta need not be completely divided. Some surgeons favor the loose placement of five or six of the posterior sutures in a parachute fashion followed by tensioning of these sutures to approximate the graft to the aortic wall. This technique may favor careful placement of the sutures, but care must then be taken to assure adequate tensioning of all suture loops. After placement of one posterolateral quadrant of sutures, the opposite posterolateral quadrant is completed. The two anterior quadrants of the suture line are then completed in similar fashion. Note the large size of the suture bites, which are placed through all layers of the aortic wall. The sutures are then tied anteriorly.
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AORTIC ANEURYSM REPAIR (cont.) 14
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The graft is then clamped temporarily and the proximal aortic clamp released to flush debris from the lumen and to test the suture line. Any bleeding points in the suture line are reinforced and the aorta is reclamped. After appropriate tensioning of the graft, it is transected and the distal anastomosis completed in a fashion similar to the proximal anastomosis. Just before completion of this anastomosis, the iliac clamps are released to allow flushing of debris from these vessels. After suitable volume replacement, one of the iliac clamps is removed to test the anastomoses for leaks. Once both anastomoses are found to be intact, the proximal clamp is carefully released, monitoring the patient’s systemic arterial pressure and replacing blood volume as needed. Heparin is reversed with protamine, and the interior of the aneurysm is again checked for bleeding. Not uncommonly a well-controlled lumbar orifice will begin to bleed again with release of the aortic and iliac clamps. Once the interior of the aneurysm is free of bleeding, the aneurysm wall is closed over the graft and, where possible, the suture lines, with #000 polyglycolic acid sutures. The retroperitoneum is then reapproximated so that neither the aneurysm wall nor either suture line can come into contact with the duodenum or small bowel. Closure of the retroperitoneum is often facilitated by release of the self-retaining retraction devices. It is not necessary to completely close the upper portion of the retroperitoneal incision. (In fact, this is often impossible.) In the event that a retroperitoneal layer cannot be interposed between the graft and its suture lines, it may be necessary to use a flap of retroperitoneal fat or omentum.
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AORTIC ANEURYSM REPAIR (cont.) 17
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The aneurysmal incisions for managing a large right common iliac and a small left common iliac aneurysm are shown. Clamp control on the right is at the level of the internal and external iliac arteries. Often a single Satinsky clamp can be used to accomplish the same end, particularly if the iliac aneurysm is redundant and these two branches come off posteriorly. A single atraumatic clamp is placed on the distal left common iliac artery where it is of relatively normal caliber. The opened aortic and iliac aneurysms can be seen and the completed suture lines of the aortic bifurcation graft are shown. Anastomosis on the right is to the iliac bifurcation. On the left it is to the mid –common iliac artery. Similar techniques for performing these anastomoses and the aortic anastomoses are employed. Aneurysm closure and retroperitoneal closure are accomplished in the same fashion as that already outlined for a simple aortic aneurysm. Care is taken to assure adequate hemostasis before all wounds are closed.
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AORTIC ANEURYSM REPAIR (cont.) Retroperitoneal Transpleural Approach The retroperitoneal transthoracic approach is particularly helpful when exposure of the pararenal or suprarenal abdominal aorta is required or when the transperitoneal approach is rendered difficult or impractical because of extreme obesity, previous operative scarring, or the presence of stomas. Although infrarenal aneurysms can be approached via an incision extending into the eleventh intercostal space and not entering the pleura, we prefer a higher transpleural incision for pararenal or suprarenal aneurysms. 19
20 21,22
The patient is positioned to obtain 308 of elevation of the left hip and 908 of elevation of the left shoulder. A gentle Sshaped incision is made starting midway between the pubis and the umbilicus and extending across the costal margin into the left eighth or ninth intercostal space. The abdominal and thoracic muscles and fascia are cut in line with the skin incision. The transversalis fascia is incised laterally to enter the retroperitoneal space. The peritoneum and its contents are bluntly separated from the overlying muscles and fascia, which are cut so that the peritoneal sac can be retracted medially.
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AORTIC ANEURYSM REPAIR (cont.) 23 24
The intercostal muscles are divided, the pleura is entered, and the costal margin is divided. The ribs are retracted with a Fininchetto rib spreader. When more cranial exposure is required, it may be necessary to divide a portion of the left leaf of the diaphragm at its periphery. Below the diaphragm, further blunt dissection posteriorly, inferiorly, and superiorly frees the peritoneum and its contained structures so that they can be retracted medially along with the left kidney, which is displaced anteriorly and medially. This exposes the retroperitoneal lymphoareolar tissue overlying the aorta. Self-retaining retractors are extremely helpful in maintaining this exposure. A large lumbar branch extending posteriorly from the left renal vein is often present and must be divided between ligatures (inset).
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AORTIC ANEURYSM REPAIR (cont.) 25
The fatty areolar tissue overlying the aorta contains many small vessels. This tissue is elevated with a right-angle clamp, coagulated with electrocautery, and divided to expose the aorta posterolaterally. Once the periadventitial plane of the aorta below the renal arteries is entered, finger dissection permits this vessel to be cleared anteriorly and posteriorly to facilitate clamp placement if the aorta is not aneurysmal at this level (inset). Care must be exercised not to injure the inferior vena cava medially, and such injuries may be avoided by not passing a clamp circumferentially around the aorta. To expose the anterior surface of the distal aorta, its bifurcation, and the common iliac arteries, the inferior mesenteric artery has been ligated and divided to facilitate medial retraction of the ureter as well as the peritoneal sac and its contained viscera.
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AORTIC ANEURYSM REPAIR (cont.) 26 27 28
If further aortic exposure above the renal arteries is required, as in the case depicted, the muscle fibers from the left crus of the diaphragm are incised with electrocautery after being elevated with a right-angled clamp. This gives access to the periadventitial plane of the suprarenal aorta and facilitates dissection of the superior mesenteric and celiac arteries if necessary. Sufficient aortic dissection anteriorly and posteriorly can also be accomplished to allow safe clamp placement at whatever level is dictated by the nature of the patient’s pathology. Inferiorly, the peritoneum, its contents, and the left ureter have been mobilized and retracted medially to expose the left common iliac artery and its branches. By careful blunt finger dissection in the plane just anterior to these vessels, it is possible to free up the peritoneal sac and its contents and retract them anteriorly and to the patient’s right to expose the right common iliac artery and the origins of its branches. Again, this is facilitated greatly by using appropriate self-retaining retraction techniques, which enable sufficient dissection to allow clamp placement on the right and left internal and external iliac arteries. Circumferential dissection of these vessels through this approach is dangerous, unnecessary, and poses the risk of major venous injury. After administration of heparin and application of clamps in the location dictated by the patient’s pathology, the aneurysm is opened and clot is removed. Lumbar arteries are controlled by suture ligature from within, and the appropriate graft is inserted using techniques similar to those illustrated in the transperitoneal approach. In the case shown, the left renal artery would have to be reimplanted into the aortic graft or revascularized with a graft.
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AORTOFEMORAL BYPASS FOR OCCLUSIVE DISEASE 1 2
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Aortobifemoral bypass is performed on patients with aortic and extensive bilateral iliac disease, which produces severe lower extremity ischemia. A long midline incision extending upward along the xiphoid process is made. The abdomen is carefully and systematically explored. The small bowel is retracted to the right and the posterior peritoneum is incised over the aortic bifurcation. This incision is extended superiorly alongside the ascending portion of the duodenum, dividing the ligament of Treitz. This incision is placed midway between the duodenum and the inferior mesenteric vein. The retroperitoneal incision is made in the shape of a “T” superiorly along the base of the transverse mesocolon, paralleling the lower border of the pancreas. After the posterior peritoneum is incised, the small bowel and other intraperitoneal viscera are packed off within the abdominal cavity and held in place with self-retaining retractors. A ring retractor and two mechanical retractors, which are affixed to the table, are shown in the illustration. Alternatively, a Stoney retractor (Omni-tract) can be used and is probably the best method for providing aortic exposure. These self-retaining retraction devices provide steady, safe retraction and allow optimal exposure without the requirement for multiple assistants. Once the posterior peritoneum is incised and the viscera retracted, the aorta can be seen or palpated through the retroperitoneal fatty areolar tissue.
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AORTOFEMORAL BYPASS FOR OCCLUSIVE DISEASE (cont.) 4 5
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This retroperitoneal fatty areolar tissue contains a number of small blood vessels and is best incised with electrocautery. The incision in this tissue is begun anterior to the aorta. Once the adventitia of the aorta is visualized in the midportion of the retroperitoneal incision, the opening in the retroperitoneal fatty areolar tissue is continued cephalad and caudad by elevating this tissue with a right-angle clamp and incising it with the coagulating electrocautery. The aorta is then dissected free anteriorly and laterally using a combination of blunt and sharp dissection. Superiorly, this dissection extends posteromedially and posterolaterally. However, it is not necessary to free the posterior wall of the aorta completely. The common femoral artery is exposed through a vertical groin incision placed over the course of the common femoral artery. If no femoral pulse can be felt, the occluded artery can usually be palpated as a firm tubular structure. If this is not possible, the incision is made midway between the pubic tubercle and the anterior superior iliac spine. This incision is deepened through the subcutaneous tissue and fascia layers. The femoral sheath is then incised and the artery dissected free in the periadventitial plane. Care is taken to clamp and ligate all identifiable lymphatics, and lymph nodes are freed around their periphery but not transected. The skin excision extends over the groin crease. In the upper end of the wound, the inguinal ligament is identified, freed medially and laterally, and retracted superiorly. Crossing venous branches may have to be clamped and ligated. The common femoral bifurcation is identified by the decreasing diameter of the femoral artery, and the superficial and deep femoral arteries are dissected free circumferentially.
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AORTOFEMORAL BYPASS FOR OCCLUSIVE DISEASE (cont.) 8
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By elevating the inguinal ligament a tunnel between the retroperitoneal dissection within the abdomen and the groin is fashioned using primarily finger dissection. Care is taken to avoid injury to veins which may cross over the external iliac artery, as shown in Fig. 7. A similar tunnel is made on the left side by passing the fingers behind the sigmoid mesentery. These tunnels should parallel the course of the subjacent arteries and should be as close to their periadventitial plane as possible. In this way, damage to the ureters and other retroperitoneal vessels is minimized. Prior to occlusion of any major artery, hemostasis is assured and the patient is given 1 mg (100 IU) per kg of intravenous heparin. A large atraumatic vascular clamp is placed entirely across the aorta just below the lower border of the renal vein, which is clearly identified. A second large curved atraumatic vascular clamp is then placed (Figs. 9, 10) so as to occlude the distal aorta and all lumbar arteries entering the aortic segment posteriorly. The inferior mesenteric artery, if patent, is occluded by tensioning a doubled Silastic vessel loop and affixing it to the drapes with a clamp. The anterior wall of the aorta is then opened with a #15 scalpel blade. Once the aortic lumen is clearly identified, a small right-angle clamp is placed within the lumen to elevate all layers of the aortic wall and thereby facilitate a clean incision in this vessel. We favor side-to-end proximal aortic anastomoses so that all possible remaining pelvic circulation can be preserved. Some surgeons favor end-to-end proximal anastomosis with oversewing of the distal divided end of the aorta. There is, however, no convincing evidence that such a procedure is superior in any way to side-to-end proximal aortic anastomosis. The position of the aortic clamps and their shape is clearly shown. The end sutures, which are usually of #00 or #000 polypropylene, have been placed through the aorta and the beveled aortic bifurcation graft. In general, large atraumatic needles (MH) facilitate this procedure. These end sutures are tied, and the suture is run around from the lower and upper ends of the anastomosis and tied at the midportion on either side. Once the proximal aortic anastomosis is completed, the graft is clamped and the aortic clamps are removed. Any bleeding points at the anastomosis are controlled with interrupted sutures. Removal of the aortic clamps at this time is advisable to test the proximal anastomosis for leaks and to restore any remaining pelvic circulation. In general, smaller-sized grafts appear to perform better than larger grafts. Most patients can be treated with a 16 £ 8 or 14 £ 7 mm graft. We favor the use of collagen-coated knitted Dacron grafts when larger grafts are required and the use of PTFE bifurcation grafts when smaller grafts are required. In almost every instance the proximal anastomosis is placed in the portion of the aorta between the renal arteries and the inferior mesenteric artery since the aorta below that level is so commonly involved with disease. Although one might be tempted to use a partially occluding clamp on the aorta, this is not advisable. In almost all of these patients, the aorta is thick-walled, and crossclamping is necessary to allow easy access to the lumen and adequate suture placement. When the occlusion in the aorta extends up to the renal arteries, no distal clamp is necessary. The anastomosis can still be carried out to the infrarenal aortic segment after the thrombus is removed. This is facilitated by digital control of the suprarenal aorta. More recently we have been using suprarenal or supraceliac control to allow a more deliberate disobliteration of the infrarenal aorta in these cases. If the aorta is heavily calcified, this process usually stops below the renals and the immediate infrarenal segment can be safely cross-clamped. To occlude the distal vessels, the heavily calcified aorta often must be cracked; this can be accomplished if appropriate care is used.
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AORTOFEMORAL BYPASS FOR OCCLUSIVE DISEASE (cont.) 11 12
13
14
Note that the single barrel of the bifurcation graft is kept short to avoid kinking of the limbs. The proximal end of the graft is cut at approximately 458 so that it will lie flush on the aorta without kinking. A long, gently curved clamp is then passed, under finger control, through the previously dissected tunnels from the groin to the retroperitoneal incision where the limbs of the graft are carefully grasped within the point of the clamp so that there are no projecting stumps of the graft to catch on retroperitoneal soft tissue. The grafts are then pulled inferiorly through the tunnel and subjected to mild tension. Angled atraumatic vascular clamps are then placed to occlude the common femoral, deep femoral, and superficial femoral arteries. A linear arteriotomy in the common femoral artery is made to expose the origin of the deep femoral artery. If this is undiseased, a standard end-to-end anastomosis is carried out in the same fashion as shown for the proximal aortic anastomosis. However, the suture bites are much smaller and require placement with greater care, so that even bites of all layers are taken and there is no narrowing of the outflow artery lumen. Particular care is taken to be sure that all sutures catch adequate bites of intima so that no distal flaps are left. Each stitch must be placed under direct vision. If there is significant disease at the origin of the deep femoral artery, as shown in the inset, the arteriotomy is extended across this disease and the graft placed over the opened lumen. We do not favor performing an endarterectomy in this circumstance, but rather prefer extending the arteriotomy across the disease and placing the graft as a patch over the stenotic segment. If a long, deep femoral artery occlusion or stenosis is present, this may be treated with a long vein patch and the graft may be placed into this. If endarterectomy is carried out, care must be taken to tack down the distal intima. After all clamps are removed, the heparin is reversed and hemostasis is assured. The wounds are then closed in layers. Care is taken to close one or more layers of fascia or fatty tissue over the graft and to obliterate dead space. The retroperitoneum is closed in such a way that a lateral peritoneal flap of connective tissue or peritoneum is interposed between the duodenum and the graft-to-aorta anastomosis. If this cannot be accomplished, omentum is interposed between the anastomosis and the duodenum.
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AORTOFEMORAL BYPASS FOR OCCLUSIVE DISEASE (cont.) Retroperitoneal Approach This approach is useful in brittle, old patients and when the standard transperitoneal approach is rendered difficult because of previous operative scarring, infection, or the presence of stomas. 15
16
17
18
In thin patients, abdominal aortic exposure can be obtained via a curved incision beginning over the rectus muscle, halfway between the pubis and the umbilicus, and extending to the tip of the 11th rib. In fatter, more muscular patients, this incision is extended into the 10th or 11th interspace, with division of the intercostal muscles in that interspace. The pleura need not be entered. If more proximal aortic exposure is required, we favor a transpleural approach via a higher interspace (see Aortic Aneurysm Repair, Retroperitoneal Transpleural Approach, Plates 17 and 18). The incision is deepened through the abdominal muscle layers until the transversalis fascia is exposed laterally and superiorly. This is incised to expose the retroperitoneal fat. The peritoneum and its contents are bluntly freed from the overlying muscles and fascia superiorly, inferiorly, and medially to facilitate incision in the remaining layers of the abdominal wall (see Plate 17). The peritoneum and its contained viscera are then freed from the underlying psoas muscle and retracted medially along with the accompanying left ureter. This exposes the lymphoareolar tissue overlying the aorta. This tissue contains many small vessels and is best incised using electrocautery to control troublesome bleeding. Once the periadventitial plane of the aorta is entered, this vessel can be dissected anteriorly and on both sides using blunt and sharp dissection, so that adequate exposure for proximal clamp placement can be obtained. Prior to administering heparin and placing these clamps, standard vertical groin incisions are made to expose the femoral arteries and usually the proximal deep femoral artery, as illustrated in the standard transperitoneal procedure.
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AORTOFEMORAL BYPASS FOR OCCLUSIVE DISEASE (cont.) 19
20
Tunnels are created between the groin incisions and the retroperitoneal incision using blunt finger dissection and taking particular care to make the right-sided tunnel just anterior to the right common and external iliac arteries, so as to avoid injury to any structures anterior to these vessels. Once the dissection is completed, heparin is administered and the aorta is cross-clamped proximally. A long curved clamp is placed posteriorly to occlude retrograde bleeding from the iliac and lumbar arteries. The aorta is opened longitudinally (or transected), and the remainder of the operation is performed in a fashion similar to that illustrated and described for the transperitoneal approach.
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FEMOROPOPLITEAL BYPASS 1
2
3
4
The positioning of the extremity and location of the skin incisions are shown. If the greater saphenous vein in the thigh and upper leg is to be used as the graft, the skin incision is made directly over the course of that vein and deep subcutaneous flaps are raised to reach the appropriate arteries. Alternatively, if a prosthetic graft is to be used, skin and subcutaneous incisions placed directly over the appropriate arteries are employed. The positions for the above-knee and below-knee access routes to the popliteal artery from a medial approach are shown. The above-knee incision is placed along the anterior border of the sartorius muscle. The below-knee incision parallels the posterior border of the tibia. The above-knee access route to the popliteal artery is shown after the skin and subcutaneous tissue have been incised. The fascial incision is then made along the anterior border of the sartorius muscle, just deep to which can be felt the adductor tendon. The sartorius muscle is freed from the deeper structures and retracted with a self-retaining retractor. Care is taken to avoid injury to the blood supply and nerve supply to the sartorius muscle. The deep fascia of the popliteal space is then grasped with forceps and sharply incised. This exposes the popliteal fat, which is carefully separated by blunt and sharp dissection. Any crossing veins are cauterized or ligated. The popliteal neurovascular bundle can then be palpated as it emerges from the adductor muscle. By grasping the outer tissues of this bundle with forceps and elevating it, its superficial fascial investments can be incised.
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FEMOROPOPLITEAL BYPASS (cont.) 5
6 7
8
9
10
11
Additional fascial layers overlie the periadventitial plane around the artery. In these layers course many small veins which connect the main veins that accompany the popliteal artery. By sharply dividing these fascial investments, it is possible to visualize the crossing veins. These can be carefully ligated and divided to clearly define the periadventitial plane of the popliteal artery. After division of these veins, the popliteal artery can be circumferentially dissected in its periadventitial plane and elevated using Silastic loops. A groin incision over the common, superficial, and deep femoral arteries is made in a standard fashion. A subsartorial tunnel is then created, using blunt dissection with the fingers. If the tunnel is too long for the fingers to meet, a plastic chest-tube container can be used to complete this tunnel. Once the tunnel has been created, the backs of the fingers should be in contact with the indurated surface of the diseased artery to confirm the correct location of the tunnel. The greater saphenous vein is carefully harvested by a long incision placed directly over it. All branches are carefully identified and ligated so as not to constrict the vein or prevent its free enlargement as it is gently dilated. Balanced saline solution (Hank’s) or chilled heparinized blood is used to irrigate the vein and gently distend it. This process is facilitated with a long plastic catheter with a well-rounded tip passed into the vein. In a sequential fashion, 2- to 3-cm segments of the vein can be isolated by gentle finger pressure and distended to identify leaks. Passage of the catheter also identifies recanalized previously thrombophlebitic segments, which cannot be found in any other way and which, if present, make a vein unsatisfactory for use. The vein is then immersed in the chilled solution until the surgeon is ready to use it. After heparin is administered systemically [1 mg (100 IU)/kg], the segment of popliteal artery selected for the distal anastomosis is isolated by the careful and gentle application of atraumatic vascular clamps. Care is taken to avoid excessive closing pressure on these clamps as well as torsion, since a diseased popliteal artery can easily be injured. Small branches entering the selected segment are occluded by microclips. The area for the arteriotomy is selected by careful palpation of the vessel. An effort to use the least diseased portion of the artery is made. However, in many instances no segment or wall of the popliteal artery is completely free of atherosclerotic involvement. The point of a new #15 scalpel blade is used to make the arteriotomy. Once the lumen of the artery has been entered, a fine mosquito clamp is inserted and opened so that the knife cut in the arterial wall will be clean and sharp and evenly placed through all layers of the diseased artery. Often the arterial incision is placed across a known stenosis in the artery to widen the stenotic area and improve outflow via the distal anastomosis. The anastomosis is then completed using 6-0 polypropylene sutures. These stitches are begun at the heel and the toe. Each stitch is placed through all layers of the artery and vein, taking particular care to include even bites of the intimal layers. The suturing is continued from both ends toward the center of the anastomosis on each side. The sutures are tied at the midportion of each wall of the anastomosis.
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FEMOROPOPLITEAL BYPASS (cont.) 12
13 14
15
16
17
A long, gently curved aneurysm clamp is then placed through the previously defined tunnel and the graft is pulled retrograde from the popliteal incision through the tunnel to the groin incision, taking particular care to avoid twisting or kinking the graft. All occluding devices in the popliteal artery are removed, and the graft and outflow tract are flushed with heparinized saline solution. The proximal anastomosis to the common femoral artery is completed in a fashion similar to that already described (see Plate 3, Figs. 1–5). If the proximal superficial femoral artery is free of atherosclerotic involvement, the proximal anastomosis may be constructed to the latter vessel. Use of this vessel minimizes the length of good autologous saphenous vein that is required. Grafts originating from the superficial femoral artery have acceptable long-term patency rates which are comparable to those of grafts originating from the common femoral artery. Similarly, if vein length is limited, the proximal anastomosis may be constructed to the deep femoral artery as long as it is free of significant disease. If a marked stenosis is present at the origin of the deep femoral artery, the graft may be inserted across this stenosis. If the common femoral artery is very thick-walled and diseased, the proximal anastomosis can sometimes be facilitated by sewing a vein patch into the diseased segment and then inserting the proximal end of the vein graft into this patch. This technique is particularly useful if the proximal end of the vein (which was previously the most peripheral portion of the greater saphenous vein) is small. If suitable autologous vein is not present in the ipsilateral lower extremity or if the patient has a limited life expectancy (3– 4 years), it is perfectly acceptable to use a 6-mm PTFE graft for above-knee femoropopliteal bypass. Furthermore, if the femoropopliteal bypass is inserted into an isolated or blind popliteal artery segment, the surgeon may elect to use a PTFE graft and save the vein for a simultaneous or subsequent sequentialinfrapopliteal bypass. The position of the skin incision for access to the below-knee popliteal artery is shown. Great care must be taken to avoid injury to the greater saphenous vein, which frequently crosses the operative field. This must be carefully freed and protected from injury. The deep investing fascia of the leg is incised. As this incision extends superiorly, the tendons of the gracilis muscle and the semitendinosus muscle cross the field. These may be divided to provide better exposure.
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FEMOROPOPLITEAL BYPASS (cont.) 18
19 20
21 22 23
24
The popliteal space is entered and the neurovascular bundle palpated in the upper portion of the depths of the wound. The popliteal vein is the most superficial structure. Often dissection of the artery is facilitated by isolating the popliteal vein and retracting it with a Silastic loop. The neurovascular bundle in the inferior portion of the wound is deep to the soleus muscle. The arcing upper border of this muscle, which inserts on the posterior surface of the tibia, can clearly be seen and felt. A finger or right-angle clamp can be placed deep to this muscle, and it can be incised over the finger or clamp to expose the distal popliteal artery and its trifurcation. By ligating and dividing branches of the popliteal vein, this vessel can be retracted anteriorly or posteriorly to expose the underlying artery and its branches. In this view one can see the origin of the anterior tibial artery, the tibioperoneal trunk and its terminal branches, and the peroneal and posterior tibial arteries. The anterior tibial artery is usually larger than shown in this drawing. Any or all of these branches can be freed circumferentially and encircled with Silastic loops. The origin of the anterior tibial artery is best seen after ligation of one or more accompanying anterior tibial veins. After administration of systemic heparin, suitable gentle clamp or clip application isolates the most disease-free portion of the artery. This is incised with a scalpel blade. A meticulous anastomosis of the vein or PTFE graft to the artery is made. Great care is taken to visualize every suture bite and to be sure that equal portions of all layers of the artery and vein wall are caught in every stitch. PTFE grafts to the below-knee popliteal artery should be used only in poor-risk patients or in those in whom ipsilateral autologous vein is not available. The completed distal anastomosis is shown after removal of all occluding instrumentation.
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FEMOROPOPLITEAL BYPASS (cont.) 25
26 27
This shows the method for constructing the portion of the tunnel behind the knee. This tunneling should be carried out by blunt finger dissection, with the backs and tops of the fingers being placed against the popliteal vessels so that the graft will pass in the depths of the popliteal fossa. Usually this tunnel is constructed before the patient is given heparin. The graft is then passed retrograde behind the knee, using a large curved clamp, inserted under finger guidance, to draw the vein from the below-knee incision to a small above-knee incision and then to the groin. This figure shows the position of the graft in its anatomic tunnel. Before performing the proximal anastomosis, the knee should be fully extended to allow appropriate tensioning of the graft and to permit the graft to be cut at precisely the right level so that it will be neither overly taut nor redundant with the knee at full extension. Heparin is reversed with protamine, and meticulous hemostasis is obtained throughout all wounds. These are then closed in layers without drainage. The in situ vein graft bypass technique has received a great deal of attention recently. There is no evidence whatsoever that this technique provides superior results in femoropopliteal bypasses. Randomized, prospective comparisons of in situ and reversed vein grafts in the femoropopliteal position have shown that the two grafting techniques produce comparable results; accordingly, we favor use of reversed vein grafts for femoropopliteal bypass. For tibial bypasses, many of which can be performed with short reversed vein grafts, we favor the latter procedure. However, it is possible that long bypasses from the upper thigh to the lower leg have better patency rates when they are performed as an in situ graft if the vein is small (,3.0 mm in distended diameter). However, this remains to be proved conclusively.
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AXILLOFEMORAL BYPASS 1
2
3
4
5
The position of the patient and locations of the incisions are shown. The right axillary artery is less likely to be involved with significant disease and is chosen preferentially to provide inflow. However, some of our recent data have shown that approximately 25% of candidates for axillofemoral bypass have significant unsuspected axillary or subclavian artery disease, and we presently advocate preoperative arch arteriography, via a translumbar approach, to determine the presence or absence of inflow disease and to guide the surgeon in the choice of which axillary artery to use. Although many surgeons advocate the performance of routine axillobifemoral bypass even if the symptoms are restricted to one lower extremity, we have found that axillounifemoral bypasses have patency rates similar to those of axillobifemoral bypasses. We therefore perform a unilateral procedure if a patient’s predominant symptoms are restricted to only one lower extremity. The pattern of disease for which an axillofemoral bypass might be employed is shown. Severe and extensive aortic and bilateral iliac disease of a sort not suitable for percutaneous transluminal angioplasty is present. The axillary incision is placed over the proximal axillary artery and is approximately parallel to the fibers of the pectoralis major muscle. The skin incision is deepened through the subcutaneous tissue and the fascia of the pectoralis major muscle. The fibers of the latter muscle are separated and retracted with a self-retaining retractor. The borders of the pectoralis minor muscle are defined. A finger or right angled clamp is then placed beneath the muscle, and this muscle is divided as close to its insertion on the coracoid process as possible. Either scissors or cautery can be used for this maneuver. The axillary artery is identified as it courses among the components of the brachial plexus. The periadventitial plane of this artery is identified, and the artery is carefully dissected free in a circumferential manner. Silastic vessel loops are placed around the artery to elevate it and to facilitate circumferential dissection of a 5- to 7-cm segment of artery. Care is taken to avoid injury to the large thin-walled branches which arise from the proximal portion of the axillary artery. An effort is made to dissect the most proximal portion of the artery so that it can be used for the anastomosis. After a groin incision is made with exposure of the inguinal ligament, as already described (see Plate 22, Fig. 7), the tunneling procedure between the two incisions is performed. This is begun by blunt finger dissection, under the pectoralis major muscle and as close to the chest wall as possible, via the axillary incision. Blunt finger dissection to start the tunnel from the groin incision is also performed. This tunnel must be superficial to the inguinal ligament and aponeurosis of the external oblique muscle.
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AXILLOFEMORAL BYPASS (cont.) 6
7
8
9
Any of several varieties of tunneler may be used to join the axillary and femoral incisions. An intermediate skin incision midway along the tunnel is generally unnecessary. We have found that a plastic chest-tube container serves as a very effective tunneler; this is shown in the illustration. However, a variety of other instruments can be used just as well. The tunneler is passed, under finger control, from below upward and retrieved from the axillary incision, taking care to guide the tunneler away from the axillary neurovascular structures. The closed tip of the plastic tube is then cut off with heavy scissors, as shown by the short broken line. If a bilateral femoral procedure is to be employed, the opposite groin is also opened, the femoral arteries are dissected circumferentially, and a tunnel created in the subcutaneous plane between the two groin incisions. Care is taken to place this tunnel superficial to the inguinal ligaments and abdominal musculature and just above the pubic symphysis. The tunneler is left in place but withdrawn slightly (2 –4 cm) so that it can later be retrieved for use. The patient is given intravenous heparin [1 mg (100 IU)/kg]. The axillary artery is carefully elevated and occluded with gently applied atraumatic vascular clamps. The axillary artery is a very thin-walled structure that is easily damaged; these clamps should be placed with extreme care. Microclips are used to occlude the smaller branches of the axillary artery, and tensioned double-looped Silastic loops affixed to the drapes are used to occlude the larger branches. The vascular clamps are rotated slightly to expose the anteroinferior portion of the axillary artery, and a longitudinal incision is made in that artery using the techniques already shown. If the artery is perfectly normal, as it often is, a scissors may be used to create the incision or extend it to its ends. If, on the other hand, the artery is diseased, the knife-and-clamp technique already illustrated (Plate 30, Fig. 22) should be used. Double-armed 5-0 or 6-0 polypropylene sutures are placed in the corners of the arteriotomy. A 6-mm PTFE graft is anastomosed to the artery using careful suturing technique as already described for other anastomoses. The opened end of the tunneler is then pushed into the wound.
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AXILLOFEMORAL BYPASS (cont.) 10 11
12
A long bronchoscopy grasping forceps is then placed through the tunneler, and the graft drawn from above downward (Figs. 9–10). The right femoral anastomosis is then completed in a standard fashion. This anastomosis can be either in the common femoral artery or extended across the origin of the deep femoral artery if there is disease at that site. Alternatively, the anastomosis can be entirely into the deep femoral artery if the proximal portion of that artery is extensively diseased. The left femoral anastomosis is completed in a similar way. Finally, the femorofemoral graft is anastomosed to the axillary limb. The positions of these anastomoses are clearly shown. The nature and location of the disease in the femoral arteries determines the exact location of the graft-to-artery femoral anastomoses. If disease is present at the origin of the deep femoral artery, the arteriotomy is placed across this disease, and the graft used to enlarge the orifice (see Plate 36, Figs. 3 and 5). Heparin is reversed with protamine, hemostasis is obtained, and the wounds are closed in layers, with an effort to close as much soft tissue over the anastomotic areas as is possible. This is particularly important in the groin, since the anastomosis is not deep to any muscular layers.
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FEMOROFEMORAL BYPASS 1
2
This figure shows the typical pattern of disease for which femorofemoral bypass is an effective operative treatment. Unilateral iliac occlusive disease is present, with minimal involvement of the aorta and contralateral iliac arteries. Incisions over both femoral arteries are made and extended upward over the inguinal ligament. These incisions are deepened to expose the inguinal ligaments. Once these have been identified, finger dissection is used to create a tunnel superficial to the external oblique and above the symphysis of the pubis. Care is taken to avoid dissecting deep to the inguinal ligament.
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FEMOROFEMORAL BYPASS (cont.) 3
4
5
Self-retaining retractors are placed to hold the edges of the wound apart and to elevate the inguinal ligament. To accomplish the latter maneuver, a robot arm and an army-navy retractor can be used. After isolating the common, deep, and superficial femoral arteries, control of patent arteries is obtained with atraumatic vascular clamps gently applied so as not to injure the vessels. No clamp is necessary for the occluded superficial femoral artery. Small microclips are used to occlude branch vessels without injuring them. After administration of intravenous heparin, the arteriotomy is made as already described (see Plate 30, Fig. 22). In the instance shown, a stenosis is present at the origin of the right deep femoral artery; accordingly, the incision in the artery is made across this stenosis. No endarterectomy is carried out. After the anastomosis of the 6-mm PTFE tubular graft to the right common and deep femoral artery is completed, the right-side vascular clamps are removed and the graft is clamped. It is then drawn through the tunnel, and an arteriotomy in the left common femoral artery is made along the line indicated. Both anastomoses have now been completed. The position of the graft, in a gentle C-shaped arc, is shown. After hemostasis is assured and the heparin reversed, the wounds are carefully closed in layers, so that as many soft tissue layers as possible cover the graft and dead space is eliminated.
ACKNOWLEDGMENT The illustrations in this chapter were drawn by Lauren Keswick, M.S., and Charles M. Stern. Many were reproduced from the section “Vascular Surgical Techniques,” by Frank J. Veith, which appeared in an Atlas of Surgical Techniques, by Marvin L. Gliedman, published by McGraw-Hill in 1990.
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Index
Abdominal aortic aneurysm, 631 – 638 colorectal tumors, 636 – 637 concomitant intra-abdominal pathology, 636 diagnosis, 632 – 634 endovascular grafts for, 364 – 371 anatomic selection criteria, 371 –374 Ancure Guidant EVT, 365 – 366 AneuRx Graft, 366 aneurysm size, patient selection based on, 374–375 bifurcated modular graft, deployment technique of, 369 – 371 construction, 364 – 365 endoleaks, 379 – 380 equipment for endovascular grafting, 367 Excluder, 366 fully supported vs. partially supported grafts, 365 high-risk patients, 374 Montefiore Endovascular Graft System, 366–367 operating room, basic setup of, 367 patient selection, 371 preoperative imaging, 371 self-expanding vs. balloon-expandable stents, 364– 365 single components vs. multiple component, 365 Talent Endovascular Bifurcated Spring Graft, 366 technical considerations, 367 – 368 Vanguard Endovascular Aortic Graft, 366 vascular access, techniques to obtain, 368– 369 Zenith, 366 gallbladder disease, 637 hindgut, pelvic perfusion, maintenance of, 636 homograft replacement, development of procedure, 6
[Abdominal aortic aneurysm] horseshoe kidney, 636 inflammatory aneurysms, 636 juxtarenal aneurysm, 635 ligation for, development of procedure, 6 medical risk assessment, 639 operative techniques, 634 pathogenesis, 631 – 632 planning distal anastomosis, 635 – 636 renal tumors, 637 repair with prosthetic grafts, development of procedure, 6 results of open repair, 634 –635 ruptured, 637– 638 Abdominal aortic arteriography, 191 –197 Abdominal aortic surgery, colonic ischemia complicating, 856 – 857 Abdominal compartment syndrome, 1142 Abdominal vascular trauma, 1058 –1065 diagnosis, 1059 emergency department management, 1059– 1060 operative management, 1060 pathophysiology, 1058 – 1059 Abdominal vein thrombosis, 970 Abnormal blood flow, hemodynamics, 81–101 aneurysms, 97 – 98 arterial obstructive lesions, circulatory effects, 87 – 91 after exercise, 91 during exercise, 88 – 90 at rest, 88 – 89 arteriovenous fistulas, 95 – 97 therapy, 96– 97 basic hemodynamics, 81 – 87 energy losses, 84– 86 arterial stenoses, 86 flow pulses, 91 – 93 hemodynamic resistance, 86 – 87 kinetic energy, 82 potential energy, 81 – 82 pressure, 91 – 93
1261
[Abnormal blood flow, hemodynamics] shear, effect on arterial wall, 97 therapy, 93 –95 collateral dilation, 95 direct arterial surgery, 93 – 95 reducing viscosity, 95 sympathectomy, 95 vasodilators, 95 total fluid energy, 82 – 84 Above-knee amputation, 566 – 567 ACAS (see Asymptomatic Carotid Artery Study) Access, 342– 343 Activated protein C resistance, 281 – 282 Acute arterial insufficiency, 405 – 412 diagnosis, 406 –408 etiology, 405 pathophysiology, 405 – 406 Acute atrophy of bones, 1124 Acute mesenteric ischemia, 839 – 844 angiography, 843 – 844 clinical presentation, 842 conditions associated with, 841 diagnostic studies, 842 – 844 historical background, 839 – 840 laboratory findings, 842 mesenteric vasoconstriction, pathophysiology of, 841 – 842 other diagnostic modalities, 843 patient population, 840 radiographic signs, 842 – 843 selection of patients, 844 treatment plan, 844 operative management, 845 –846 postoperative care, 846 principles of management, 844 – 845 types of, 840– 841 arterial causes, 840 venous causes, 840 – 841 Acute mesenteric vascular disease, 839– 859 acute mesenteric ischemia, 839 – 844 colonic ischemia, 852 – 854
1262
Index
Acute peripheral arterial occlusion, results of thrombolysis in, 300 – 301 Adjunctive endovascular procedures, 395– 404 catheter pressure localization, arterial stenoses, 398– 399 completion arteriography, 396 – 398 digital fluoroscopy, 395 – 396 basic principles, 395 cine loop playback, 396 magnification, 396 roadmapping, 396 subtraction, 395 – 396 fluoroscopically assisted thromboembolectomy, 399 – 400 intraoperative balloon angioplasty, stenting, 401–402 intraoperative thrombolysis, 400 – 401 preprocedure arteriography, 398 proximal arterial control, using balloon catheter, 399 standard vascular operations, techniques to facilitate, 396–402 Adventitia, artery wall, 34– 35 Adventitial cystic disease, popliteal artery, 513– 516 clinical presentation, 515 etiology, 514 history, 513– 514 incidence, 514 laboratory evaluation, 515 pathophysiology, 514 – 515 treatment, 515– 516 Age, as risk factor for atherosclerosis, 56– 57 Age-related changes in artery wall, 36 – 37 Air-filled plethysmograph, 115 Alcohol consumption incidence of coronary heart disease, 63 as risk factor for atherosclerosis, 63 Algodystrophy, 1124 Algoneurodystrophy, 1124 Alimentary tract tumors, angiography, 183– 185 Allen test, 108 American Venous Forum, 232 Amputation, in dysvascular patient, 555– 573 above-knee, 566 – 567 for acute ischemia, 555 – 556 at ankle, 561– 562 below-knee, 562 – 565 contraindications to, 563 complications, 569 – 570 in diabetic patient, 555 – 556 digital plethysmography, 559 hip disarticulation, 567
[Amputation, in dysvascular patient] incidence, 555 indications for, 555 laser Doppler flowmetry, 559 level of, 558– 560 nuclear magnetic resonance spectroscopy, 559 photoplethysmography, 559 postoperative care, 567 –568 preoperative management, 556 –557 previous reconstructive surgery, effect on amputation level, 558 prosthesis fitting, 568 segmental blood pressure, 559 skin perfusion pressures, 559 skin temperature measurement, 559 surgery, 557– 558 surgical techniques, 560 –567 through-knee amputation, 565 – 566 of toe, 560– 561 ray amputation of toe, 561 transphalangeal level, 560 transmetatarsal amputation of forefoot, 561 Amputee, vascular, rehabilitation, 575– 594 amputation levels, 576 amputation prevention, 592 computer-aided design-computerassisted manufacturing, 579 – 580 energy consumption during gait, amputees, 591 – 592 exoskeletal versus endoskeletal, 579 follow-up care, 598 incidence, 575 –576 phantom pain, 590 – 591 postoperative management, 577 – 578 preprosthetic phase of management, 578 prognosis, 576 prosthetic components, 580 – 584 articulated foot-ankle assembly, 583 dynamic response, energy-storing feet, 580– 583 foot-ankle assembly, 580 transtibial prosthetic sockets, 584 prosthetic knees, 588 – 590 prosthetic phase of management, 578– 579 prosthetic prescription, 579, 592 – 593 transfemoral amputee, 593 transtibial amputee, 592 – 593 suspension variations transfemoral amputees, 588 transtibial amputee, 584, 585 transfemoral prosthesis, 584 – 587 treatment, 592
Anabolic steroids, drug interactions, 289 Anatomical bypass grafts, 442 – 445 Anesthesia, 342 – 343 Aneurysm, 97 – 98 angiography, 172 – 173 from arteriovenous fistulas, 1159 extracranial carotid artery, 803 – 809 atherosclerotic carotid aneurysms, 804 clinical presentation, 804 – 805 differential diagnosis, 807 effects of, 804 incidence, 803 investigation of, 805 pathology of, 803 – 804 reconstructive approach, 806 – 807 results of surgery, 808 simple ligation, 806 surgical anatomy, carotid arteries, 807– 808 surgical treatment, 806 –808 traumatic carotid artery aneurysms, 804 treatment, 805 formation of, 45 – 47 infected, 669–693 abdominal aorta, 680 – 682 aorta, 672 bacteriologic studies, 677 – 678 bacteriology, 674 – 676 carotid artery, 673 colonized aneurysms, 676 contemporary classification, 670 diagnosis, 677 – 678 endovascular infection, 676 endovascular repair, 682 extraanatomic reconstruction, 680– 682 extremities, 674 fungal infection, 676 histology, 671 incidence, 670– 671 laboratory data, 677 microbial arteritis, 671 – 672 microbiology, 674 mycotic aneurysms, 670 – 671 natural history, 676 – 677 operative findings, 679 operative management, 679 – 680 pathogenesis, 671 postoperative management, 684, 685, 686 preoperative management, 679 radiologic studies, 678 – 679 salmonella infection, 675 in situ reconstruction, 681 – 682 terminology, 669 – 670
Index [Aneurysm] treatment, 679 – 689 unusual bacteria, 675 visceral arteries, 673 – 674, 682– 684 occlusive disease, vascular injuries, endovascular grafts, 363 – 394 physical exam, 107 –108 popliteal artery, 653 – 657 asymptomatic aneurysms, 654 – 655 clinical features, 653 diagnosis, 653 – 654 epidemiology, 653 management, 654 – 656 results, 656 surgery, 655– 656 symptomatic aneurysms, 654 thrombolytic therapy, 655 splanchnic artery, 659 – 667 celiac artery aneurysms, 665 gastric, gastroepiploic aneurysms, 665– 666 gastroduodenal, pancreaticoduodenal aneurysms, 665 hepatic artery aneurysm, 661 – 662 intestinal branch artery aneurysms, 666 splenic artery aneurysms, 659 – 661, 660– 661 superior mesenteric artery aneurysms, 662– 665 Angiography, 169 – 210, 345– 346 abdominal aortic arteriography, 191– 197 aneurysms, 172 – 173 angiographic catheters, 171 arterial portography, 177 carotid-cerebral, 202 – 203 celiac arteriography, 182 contrast agents, 169 – 171 dissecting aneurysm, 173 – 174 gastrointestinal bleeding, 185 –187 hepatic venography, 179 – 182 lower extremity arteriography, 191– 197 lower extremity venography, 197 – 200 mesenteric arteriography, 182 mesenteric ischemia, 187 – 188 acute mesenteric ischemia, 188 chronic ischemia, 187 – 188 mesenteric venography, 177 interpretation of, 179 portal venography, 177 portal venous access, 182 pulmonary, 175 – 177 renal arteriography, 188 – 191 superior vena cava venography, 201– 202
[Angiography] thoracic aortography, 171 – 172 transhepatic venous access, 182 transjugular intrahepatic portal catheterization, 177 – 179 trauma, 182– 183 tumors, 183– 185 alimentary tract tumors, 183 – 185 hepatic tumors, 185 pancreatic tumors, 183 upper extremity arteriography, 200 –201 upper extremity venography, 201 – 202 Angioscopy, 346 Angiospasm, traumatic, 1124 Angiothrombotic pulmonary hypertension, from intravenous drug injection, 1110– 1111 Ankle, amputation at, 561 – 562 Anticoagulant therapy, 285 – 296, 700– 701 anticoagulation, complications of, 293– 294 arterial thromboembolism prophylaxis against, 291 – 292 therapy for, 291 atherosclerosis, 242 coagulation mechanism, 285 direct thrombin inhibitors, 289 – 290 hirudin, pharmacokinetics of, 290 physical properties, 289 – 290 heparin, 286– 287 complications of, 293 low molecular weight heparins, 286– 287 mode of action, 286 – 287 physical properties, 286 – 287 unfractionated heparins, 286 – 287 heparin-like agents, 286 –287 low molecular weight heparinoids, 287 pharmacokinetics, 287 oral anticoagulants, drug interactions with, 289 pharmacokinetics low molecular weight heparins, 287 unfractionated, 287 platelet function inhibitors, 290 aspirin, 290 clopidogrel, 290 glycoprotein IIb/IIIa inhibitors, 290 ticlopidine, 290 venous thromboembolism, prophylaxis against, 292– 293 venous thromboembolism therapy, 290– 291 vitamin K antagonists, 287 – 289 drug interactions, 288 – 289 mode of action, 288
1263
[Anticoagulant therapy] pharmacokinetics of warfarin, 288– 289 physical properties, 287 warfarin anticoagulation, reversal of, 294 complications, 293 – 294 monitoring, 289 Anticoagulation therapy, complications of, 293– 294 Antioxidants, 240 for atherosclerosis, 266 vitamins, 68 –69 Antiplatelet agents, 303 – 308 antiplatelet drugs, 304 – 306 aspirin, 304– 305 administration, 304 – 305 dosage, 304–305 efficacy, 304– 305 mechanism of action, 304 for prevention of thromboembolic complications, 305 complications, 305 glycoprotein IIb/IIIa inhibitors, 305– 306 with oral anticoagulants, 305 platelet function, 303 – 304 arterial wall, interaction with, 304 coagulation cascade, interaction with, 303– 304 side effects, 305 thienopyridines, 306 in venous disease, 305 Antithrombin deficiency, 274– 275 clinical presentation, 275 diagnosis, 275 Antithrombotic therapy, evaluation of, 700– 706 Anti-tissue plasminogen activator, 277 Antyllus, contribution of, 1 Aorta atherosclerosis, medical management, 251– 252 infection, 672 Aortic aneurysm abdominal, 631 – 638 historical developments in treatment of, 5–6 repair, 1210– 1227 thoracoabdominal, 641 – 651 diagnosis, 643– 644 etiology, 641– 642 natural history, 642 – 643 operative treatment, 645 – 648 postoperative care, 649 preoperative evaluation, 644 – 645 results, 649– 650
1264
Index
Aortic arch, occlusive disease of branches of, 765– 770 aortic arch syndromes, 765 cervical reconstructions, 766 – 767 cross-over bypasses, 767 – 768 diagnosis, 765 surgical management, 765 – 766 thoracic reconstruction, 769 – 770 upper midsternotomy, 770 Aortic atherosclerosis, 45 Aortic endograft, development of procedure, 4 Aortic occlusive disease, historical developments in treatment of, 3 Aortobifemoral bypass general principles of, 443 technique of, 443– 444 Aortoenteric fistula, with aortoiliofemoral occlusive disease, 448 Aortofemoral bypass, for occlusive disease, 1228– 1239 Aortoiliac, femoropopliteal occlusive disease, combined, 495 – 511 combined endovascular, surgical revascularization, 504 – 506 combined inflow, outflow procedures, 501 endovascular grafts, 506 evaluation, 496 – 501 incidence, 496 inflow assessment, 496 – 498 proximal aortic reconstruction, clinical outcome of, 496 treatment options, 501 – 506 Aortoiliac aneurysm repair, penis, 881– 882 Aortoiliac endarterectomy, 442 development of procedure, 3 Aortoiliac inflow, adequacy of noninvasive studies, 119 arteriovenous fistula, 119 pseudoaneurysm, 119 pseudoaneurysm, 119 Aortoiliac occlusive disease endovascular graft repair, 380 – 386 arterial trauma, 385 – 386 endovascular grafts, 380 graft insertion, location of stent deployment in bilateral iliac disease, 380– 381 operative technique, 381 – 384 results of endovascular grafting, 384 for treatment of vascular trauma, 384 historical developments in treatment of, 3–4 penis, operations for, 880 – 881
Aortoiliofemoral occlusive disease, 439– 454 algorithm for intervention, 441 – 442 aortoenteric fistula, 448 clinical diagnosis, 440 coagulation complications, 446 – 447 complications, 446 – 450 cauda equina ischemia, 450 conservative treatment, 441 deterioration of prosthesis, 448 false aneurysm formation, 447 graft infection, 447 hemorrhage, 447 – 448 historical aspects, 439 local nonvascular complications, 448– 449 lymphatic fistula, lymphocele, 448 myocardial infarction, 446 objective diagnosis, 440 –441 arteriography, 441 direct pressure measurements, 441 noninvasive assessment, 440 – 441 pathophysiology, 439 – 440 acute obstruction, 440 chronic atherosclerosis, 439 – 440 hypoplastic aorta, 440 occlusive mid-aneurysmal disease, 440 percutaneous transluminal angioplasty, 442 pulmonary problems, 446 remote ischemic vascular complications, 449– 450 renal problems, 446 results, 445–446 sexual dysfunction, 449 Sigmoid colon ischemia, 449 spinal cord, 450 stroke, 446 surgical treatment, 442 – 445 anatomical bypass grafts, 442 – 445 aortoiliac endarterectomy, 442 endovascular bypass, 445 extra-anatomical bypass grafts, 445 general principles of aortobifemoral bypass, 443 juxtarenal occlusion, 445 laparoscopic aortobifemoral bypass, 445 multilevel occlusive disease, 444 – 445 technique of aortobifemoral bypass, 443– 444 transfusion, 445 systemic complications, 446 – 447 trash foot, 449– 450 unilateral limb occlusion, 448 ureteric obstruction, 449
Aortorenal bypass with autogenous vein, development of procedure, 7 Arcuate ligament syndrome, 1182 Arizona hinshawii, aneurysm infection, 674 Arm lymphatics, 1038 Arrhythmias, perioperative cardiovascular risk, 319 Arterial allografts, 612 Arterial diseases, clinical examination, 103– 106 acute arterial occlusion, 105 atheroembolism, 105 peripheral arterial disease, 103 –104 popliteal artery entrapment, 105 Raynaud’s phenomenon, 106 reflex sympathetic dystrophy, 105 – 106 thoracic outlet syndrome, 105 vasculitis, 104 Arterial dissection, 1188 – 1189 arterial incision, 1188 –1189 suture closure of arteriotomy, 1188– 1189 Arterial injury lower extremity, 1089– 1090 pediatric, iatrogenic, 1102 – 1103 upper extremity, 1088– 1089 Arterial insufficiency, acute, 405 – 412 cerebral ischemia, 411 diagnosis, 406 – 408 etiology, 405 fibrinolytic therapy, complications of, 410 ischemia, signs of, 406 ischemic manifestations, evolution of, 410– 411 laboratory assessment, 407 pathophysiology, 405 – 406 patient evaluation, 407 revascularization, complications of, 409 treatment, 408 –410 embolectomy technique, 408 fasciotomy, 410 fibrinolytic therapy, 410 postoperative anticoagulation, 408 upper extremity ischemia, 411 visceral ischemia, 411 Arterial lacerations, iatrogenic, 1097– 1098 Arterial malformations, 1167 –1169 diagnostic evaluation, 1168 differential diagnosis, 1168 natural history, 1168 options for treatment, 1168 – 1169 outcome of management, 1169 signs, symptoms, 1168
Index Arterial obstructive lesions, circulatory effects, 87 – 91 pressure-flow relationships after exercise, 91 during exercise, 88 –90 at rest, 88 – 89 Arterial occlusion, acute, clinical examination, 105 Arterial physical exam, 106 – 108 Allen test, 108 aneurysms, 107 – 108 bruit, 107 examination of skin, 108 – 109 exercise testing, 108 leg elevation, 108 pulse, 106– 107 thoracic outlet maneuvers, 109 Arterial portography, 177 Arterial rupture, iatrogenic, 1098 Arterial surgery, for abnormal blood flow, 93– 95 Arterial thromboembolism prophylaxis against, 291 – 292 therapy for, 291 Arterial thrombolysis, 299 – 300 Arterial trauma, endovascular grafts for, Montefiore experience, 386 Arterioarterial atherothrombotic microemboli, lower limb, 427 –458 clinical diagnosis, 431 – 432 diagnostic investigations, 432 – 434 during fibrinolytic therapy, 435 – 437 incidence, 427 –428 medical management, 435 sources of microemboli, 428 – 429 surgical management, 434 – 435 Arteriotomy, suture closure of, 1188 – 1189 Arteriovenous fistula, 95 – 97, 937– 938 iatrogenic, 1098 noninvasive studies, pseudoaneurysm, 119 physiology of, 1145– 1147 therapy, 96 – 97 Artery, lacerated, repair of, 1194 Artery wall nutrition, 35– 36 Artery wall structure, 31 – 35 adventitia, 34 –35 intima, 31 – 33 media, 33 – 34 Ascites, 1017 Aspirin, 290, 304 – 305, 332 administration, 304 –305 dosage, 304– 305 efficacy, 304– 305 mechanism of action, 304 for prevention of thromboembolic complications, 305
Assessment of outcomes, 221 – 226 application of, 225 disease, impact of, 221 – 222 disease-specific instruments, 224 – 225 EuroQol, 224 generic outcomes assessment tools, 223– 224 generic quality of life instruments, 224 Medical Outcomes Study, 224 Nottingham Health Profile, 224 patient-based outcomes assessment parameters, 222– 223 Quality of Well-Being Scale, 224 Sickness Impact Profile, 224 Asymptomatic aneurysms, 654 –655 Asymptomatic Carotid Artery Study, 7 Atherectomy, peripheral, 351 – 362 Auth Rotablator, 357 – 359 indications, 351 Atheroembolism, clinical examination, 105 Atherosclerosis artery wall structure adventitia, 34 – 35 intima, 31 – 33 media, 33 – 34 atherosclerotic lesion structure fatty streaks, 37 – 39 fibrous plaques, 39 – 40 lesion complications, 40 – 41 carotid artery, intima-media thickness, 261 cellular modifications in endothelium, 21 – 22 macrophage, 24 – 25 platelets, 25 – 26 smooth muscle, 22 – 24 disease process complicated lesion, 16 experimental animals, studies in, 16–17 fatty streak, 15 fibrous plaque, 15 – 16 lesions, 15 – 16 plaque rupture, 16 endothelium endothelial cell culture, 21 – 22 endothelial responses, 22 enlargement of arteries with, 42 epidemiology, 55 – 79 antioxidant vitamins, 68 –69 cardiovascular death rates, age-specific, 62 coronary artery disease, incidence, 62 fibrinogen level, risk of cardiovascular disease by, 61 fish consumption, 66
1265
[Atherosclerosis] Framingham Study of Evolution of Atherothrombotic Brain Infarction, 58 gender, 55 – 56 ischemic heart disease death rates, United States, 57 lipoprotein cholesterol levels, according to alcohol consumption, 63 omega-3 fatty acids, 66 Pooling Project, 58 racial predisposition, 55 – 56 risk factors, 56 – 70 smoking, risk of cardiovascular disease by, 59 thrombosis, 69 – 70 Veterans Administration Cooperative Study Group on Antihypertensive Agents, 58 Western Collaborative Group Study, 58 human angioplasty, 330 hypotheses of atherogenesis lipids, 19 response-to-injury hypothesis, 17 – 19 risk factors, 19 – 21 medical management, 235 – 247, 249– 272 anticoagulant therapy, 242 antioxidants, 240, 266 antiplatelet therapy, 242 aorta, 251– 252 approach to treatment, 238 atherosclerotic plaque, 235 – 236 Bezafibrate Coronary Angiographic Intervention Trial, 264 calcium channel blockers, 258 – 259 carotid artery, 251 Cholesterol-Lowering Atherosclerosis Study, 253 complicated plaques, progression to, 238 controlled clinical trials, 252 – 261 coronary artery, 251 – 258 diabetes mellitus, 241 exercise, 241– 242 fatty streaks, 236 –237 femoral artery, 252 fibrous plaque, 237 – 238 folic acid supplementation, 242 gelatinous plaques, 237 gene therapy, 242– 243 Heidelberg Study, 258 homocysteine supplementation, 242 hyperlipidemias, drug therapy for, 239– 240 hypertension, 240 – 241
1266
Index
[Atherosclerosis] infection, 242 International Nifedipine Trial on Antiatherosclerotic Therapy, 259 LDL-Apheresis Atherosclerosis Regression Study, 259 lesion arrest or regression, 238 Lifestyle Heart Trial, 258 Lipid Coronary Angiographic Trial, 265 Lipid-Lowering Antiatherosclerosis Therapies Trial, 252 medical management, 238 –239 Monitored Atherosclerosis Regression Study, 256 Montreal Study, 259 Multivitamins and Probucol Trial, 266 National Heart, Lung, and Blood Institute, Type II Coronary Intervention Study, 252 plaque evolution, 236 Post Coronary Artery Bypass Graft Trial, 260 Probucol Angioplasty Restenosis Trial, 266 Program on Surgical Control of Hyperlipidemias, 260 recent antiatherosclerosis interventions, 261– 266 renal artery, 251 smoking, 240 St. Thomas’ Atherosclerosis Regression Study, 254 Stanford Coronary Risk Intervention Project, 254 triglyceride-rich lipoproteins, 261– 266 uncontrolled studies, 251 – 252 University of California, San Francisco, Specialized Center of Research, Intervention Trial, 254 viral infection, 242 pathophysiology, 15 –29, 31 –54 age-related changes in artery wall, 36– 37 aneurysm formation, 45 – 47 aortic atherosclerosis, 45 artery wall nutrition, 35 – 36 artery wall structure, 31 – 35 atherosclerotic arteries, enlargement, 42 atherosclerotic lesion structure, 37– 41 carotid bifurcation plaques, 44 – 45 cellular modifications in, 21 – 26 configuration of lesions, 41 – 42
[Atherosclerosis] coronary artery atherosclerosis, 47– 48 disease process, 15 – 17 future directions, 26 – 27 hypotheses of atherogenesis, 17 – 21 localization, atherosclerotic lesions, 42– 44 quantitative evaluation, 48 – 49 superficial femoral artery stenosis, 47 platelets other factors, 25 – 26 platelet-derived growth factor, 25 regression in experimental animal models, 249– 251 in humans, 251– 261 risk factors, 56 – 57 alcohol consumption, incidence of coronary heart disease, 63 behavior patterns, 68 diabetes, 20 diabetes mellitus, 66 – 67 hypercholesterolemia, 19 – 20 hyperhomocystinemia, 68 hyperlipidemia, 61 – 66 hypertension, 20, 57 – 58 male sex, 20, 57 obesity, 67 – 68 physical inactivity, 67 –68 smoking, 20, 58 –61 stress, 68 smooth muscle lipid metabolism, 23 – 24 smooth-muscle proliferation, 22 – 23 surgical management, 259 – 261 uncontrolled studies femoral artery, 251 popliteal artery, 251 Atherosclerotic lesion structure, 37 – 41 Atrophy of bones, acute, 1124 Auth Rotablator, 352, 357 – 359 Autogenous vein, aortorenal bypass with, development of procedure, 7 Axillary artery, injury, 1088 Axillary vein thrombosis, 882 – 902 Axillobifemoral bypass, development of procedure, 4 Axillofemoral bypass, 1250 – 1255 development of procedure, 4 Axillofemoral grafts, 532 – 534 results, 539 technique, 532– 534 Axillopopliteal extraanatomic bypass, 536– 538 Axillo-subclavian venous stenosis, 1008
Babcock, W.W., 8 Balloon catheter for embolectomy, development of procedure, 4 Balloon-assisted stent placement, development of procedure, 4 Balloons, 343 –344 Barbiturate crystallization, 1112 Barbiturates, drug interactions, 289 Barnett, Henry, 7, 8 BECAIT (see Bezafibrate Coronary Angiographic Intervention Trial) Behavior patterns, atherosclerosis, 68 Behcet’s disease, 922– 923 Below-knee amputation, 562 – 565 contraindications to, 563 Bergan, John, 5 Bernhard, Victor, 5 Beta-adrenergic blockers, 1020 Bezafibrate Coronary Angiographic Intervention Trial, 264 Biological grafts, 612 Blaisdell, F. William, 4 Blakemore, Arther, 5 Bleeding esophageal varices, management of, 1019 Blinding, clinical trial, 214 Blood flow, abnormal, hemodynamics, 81– 101 aneurysms, 97 – 98 arterial obstructive lesions, circulatory effects, 87 – 91 after exercise, 91 during exercise, 88 – 90 at rest, 88 – 89 arteriovenous fistulas, 95 – 97 therapy, 96– 97 basic hemodynamics, 81 – 87 energy losses, 84– 86 arterial stenoses, 86 flow pulses, 91 – 93 hemodynamic resistance, 86 – 87 kinetic energy, 82 potential energy, 81 – 82 pressure, 91 – 93 shear, effect on arterial wall, 97 therapy, 93 – 95 collateral dilation, 95 direct arterial surgery, 93 – 95 reducing viscosity, 95 sympathectomy, 95 vasodilators, 95 total fluid energy, 82 – 84 Bracco, as contrast agent, 170 Brachial artery, injury, 1088 – 1089 Brachiocephalic vascular injuries, 1071 Bridge fistulas, 1155– 1156 Brucella, aneurysm infection, 674
Index Bruit, examination of, 107 Budd-Chiari syndrome, 1010 – 1011 Button bar on computer, 233 Bypass aortofemoral, for occlusive disease, 1228– 1239 axillofemoral, 1250– 1255 femorofemoral, 1256– 1259 femoropopliteal, 1240 – 1249 Calcium channel blockers, for atherosclerosis, 258–259 Calisthenics, metabolic equivalent level for, 317 Campylobacter fetus, aneurysm infection, 674 Canadian Society for Vascular Surgery, 232 Capillary malformations, 1165 diagnostic evaluation, 1165 differential diagnosis, 1165 natural history, 1165 options for treatment, 1165 signs, symptoms, 1165 Cardiac procurement, for transplantation, 1173– 1174 Cardiovascular death rates, age-specific, 62 Carnitine, 311 Carotid extracranial, aneurysms, 803 – 809 atherosclerotic carotid aneurysms, 804 clinical presentation, 804 – 805 differential diagnosis, 807 effects of, 804 incidence, 803 investigation of, 805 pathology of, 803 – 804 reconstructive approach, 806 – 807 results of surgery, 808 simple ligation, 806 surgical anatomy, carotid arteries, 807– 808 surgical treatment, 806 – 808 traumatic carotid artery aneurysms, 804 treatment, 805 occlusive disease, extracranial, 745 – 764 angiography, 751 asymptomatic stenosis, efficacy of carotid endarterectomy, clinical trials on, 757– 758 carotid artery stenting, 760 –761 carotid endarterectomy, description of, 751– 756 clinical presentation, 750 – 751 historical perspective, 747 – 748
[Carotid] indications for, 758 – 760 pathogenesis, 748 – 750 randomized clinical trials, 756 symptomatic stenosis, efficacy of carotid endarterectomy, clinical trials, 756–757 ulcerative lesions, 729 – 736 angiography, 732 – 733 classification, 731– 732 definitions, 730 historical development, 729 –730 medical management, 733 natural history, 732 noninvasive testing, 733 pathophysiology, 730 – 731 presentation, 731 surgical management, 733 – 735 Carotid arteriography, vs. duplex imaging, 135– 138 Carotid artery, 783 – 793 internal, spontaneous dissecting hematoma, 788 – 791 intima-media thickness, 261 Carotid atherosclerosis, medical management, 251 Carotid bifurcation plaques, 44 – 45 Carotid body tumors, 811 – 821 clinical presentation, 812 – 813 complications, 817 – 819 diagnostic considerations, 813 – 814 pathophysiology, 812 prognosis, 817 surgical technique, 816 – 817 therapeutic considerations, 814 – 816 Carotid endarterectomy, 1204 – 1209 external, 795–802 clinical presentation, operative technique, 799– 800 external carotid artery occlusion, 800– 801 external carotid artery occlusion prevention, 800– 801 treatment, 801 Carotid infection, 673, 683 Carotid injuries, 1072– 1074 diagnosis, 1073 evaluation, 1072 –1073 operative management, 1073 – 1074 Carotid kink, 786 – 788 Carotid loop, 783 – 786 Carotid pathology, 711 – 727 carotid plaques, evolution of, 717 – 719 cerebral infarction, mechanism of, 715– 717 endarterectomy, post-carotid, recurrent stenosis, 719– 722
1267
[Carotid pathology] population surveys, 714 – 715 postmortem, 714 symptomatic, versus asymptomatic plaques, 715– 717 Carotid stenoses, asymptomatic, first surgical benefit documentation, 7 Carotid stenosis Doppler quantitation, 129 – 132 first operation for, 8 Carotid surgery, cerebral protection during, 737– 743 electroencephalography, 738 – 739 high-risk conditions, 737 intraoperative monitoring, 738 patient selection, 737 perioperative stroke, 737 –738 regional anesthesia, 739 – 740 Carotid-cerebral angiography, 202 – 203 Carrea, Raul, 7, 8 Carrel, Alexis, 2 Catheter angiographic, 171 pressure localization, arterial stenoses, 398– 399 Causalgia, 1123– 1132 diagnosis, 1126 etiology, 1125 pathophysiology, 1125 –1130 signs, 1126– 1127 stellate ganglion block technique, 1127– 1128 sympathetic block, assessment of, 1127 sympathetically maintained pain, sympathetically independent pain, 1125– 1126 terminology, 1124– 1125 Causalgia-like states, 1124 Cavernosometry, cavernosal artery occlusion pressure, penis, 880 Celiac aneurysms, 665 Celiac arteriography, 182 Cellular modifications in atherosclerosis, 21– 26 endothelium, 21– 22 endothelial cell culture, 21 – 22 endothelial responses, 22 macrophage, 24 – 25 platelets, 25 – 26 other factors, 25 – 26 platelet-derived growth factor, 25 smooth muscle, 22 – 24 lipid metabolism, 23 – 24 smooth-muscle proliferation, 22 –23 Cellular response to injury, 327 – 328 endothelium, 327
1268
Index
[Cellular response to injury] increased response of SMCs to mitogens, 328 inflammation, 328 medial SMC proliferation, 328 platelets, 327 proliferation of SMCs in intima, 328 SMC migration, 328 smooth-muscle cells, 327 – 328 Celsius, contribution of, 1 Cerebral angiography, development of procedure, 7 Cerebral infarction, mechanism of, 715– 717 Cerebral ischemia, 411 Cerebral protection during carotid artery surgery, 737–743 electroencephalography, 738 – 739 high-risk conditions, 737 intraoperative monitoring, 738 patient selection, 737 perioperative stroke, 737 – 738 regional anesthesia, 739 – 740 Cerebrovascular disease (see also under specific disorder) historical developments in treatment of, 7–8 Cervical rib, 889 Chemical endarteritis, 1111 – 1112 Chlamydia pneumoniae, atherosclerosis and, 242 Chloramphenicol, drug interactions, 289 Cholesterol age-related changes in artery wall, 36– 37 alcohol consumption and, 63 aneurysm formation, 45 – 47 anticoagulant therapy, 242 antioxidant vitamins, 68 – 69 antioxidants, 240, 266 antiplatelet therapy, 242 aorta, 251– 252 aortic atherosclerosis, 45 approach to treatment, 238 artery wall nutrition, 35 –36 artery wall structure, 31 – 35 adventitia, 34– 35 intima, 31 – 33 media, 33 – 34 atherosclerotic arteries, enlargement, 42 atherosclerotic lesion structure, 37 – 41 fatty streaks, 37 – 39 fibrous plaques, 39 – 40 lesion complications, 40 – 41 atherosclerotic plaque, 235 – 236 Bezafibrate Coronary Angiographic Intervention Trial, 264
[Cholesterol] calcium channel blockers, 258 – 259 cardiovascular death rates, age-specific, 62 carotid artery, 251 intima-media thickness, 261 carotid bifurcation plaques, 44 – 45 cellular modifications in, 21 – 26 endothelium, 21 – 22 macrophage, 24 – 25 platelets, 25 –26 smooth muscle, 22– 24 Cholesterol-Lowering Atherosclerosis Study, 253 complicated plaques, progression to, 238 configuration of lesions, 41– 42 controlled clinical trials, 252 – 261 coronary artery, 251 – 258 coronary artery atherosclerosis, 47 – 48 coronary artery disease, incidence, 62 diabetes mellitus, 241 disease process, 15 – 17 complicated lesion, 16 experimental animals, studies in, 16– 17 fatty streak, 15 fibrous plaque, 15 – 16 lesions, 15 – 16 plaque rupture, 16 endothelium endothelial cell culture, 21 – 22 endothelial responses, 22 enlargement of arteries with, 42 epidemiology, 55 – 79 exercise, 241–242 fatty streaks, 236 – 237 femoral artery, 252 fibrinogen level, risk of cardiovascular disease by, 61 fibrous plaque, 237 – 238 fish consumption, 66 folic acid supplementation, 242 Framingham Study of Evolution of Atherothrombotic Brain Infarction, 58 future directions, 26 – 27 gelatinous plaques, 237 gender, 55 –56 gene therapy, 242 – 243 Heidelberg Study, 258 homocysteine supplementation, 242 human angioplasty, 330 hyperlipidemias, drug therapy for, 239– 240 hypertension, 240 – 241 hypotheses of atherogenesis, 17 – 21 lipids, 19
[Cholesterol] response-to-injury hypothesis, 17 – 19 risk factors, 19 – 21 infection, 242 International Nifedipine Trial on Antiatherosclerotic Therapy, 259 ischemic heart disease death rates, United States, 57 LDL-Apheresis Atherosclerosis Regression Study, 259 lesion arrest or regression, 238 Lifestyle Heart Trial, 258 Lipid Coronary Angiographic Trial, 265 Lipid-Lowering Antiatherosclerosis Therapies Trial, 252 lipoprotein cholesterol levels, according to alcohol consumption, 63 localization, atherosclerotic lesions, 42– 44 medical management, 235 – 272 Monitored Atherosclerosis Regression Study, 256 Montreal Study, 259 Multivitamins and Probucol Trial, 266 National Heart, Lung, and Blood Institute, Type II Coronary Intervention Study, 252 omega-3 fatty acids, 66 pathophysiology, 15 – 29 plaque evolution, 236 platelets other factors, 25 –26 platelet-derived growth factor, 25 Pooling Project, 58 Post Coronary Artery Bypass Graft Trial, 260 Probucol Angioplasty Restenosis Trial, 266 Program on Surgical Control of Hyperlipidemias, 260 quantitative evaluation, 48 – 49 racial predisposition, 55 –56 recent antiatherosclerosis interventions, 261– 266 regression in experimental animal models, 249– 251 in humans, 251– 261 renal artery, 251 risk factors, 56– 70 age, 56 – 57 alcohol consumption, incidence of coronary heart disease, 63 behavior patterns, 68 diabetes, 20 diabetes mellitus, 66 – 67 hypercholesterolemia, 19 –20
Index [Cholesterol] hyperhomocystinemia, 68 hyperlipidemia, 61 – 66 hypertension, 20, 57 – 58 male sex, 20, 57 obesity, 67 – 68 physical inactivity, 67 –68 smoking, 20, 58– 61 stress, 68 smoking, 240 risk of cardiovascular disease by, 59 smooth muscle lipid metabolism, 23 – 24 smooth-muscle proliferation, 22 – 23 St. Thomas’ Atherosclerosis Regression Study, 254 Stanford Coronary Risk Intervention Project, 254 superficial femoral artery stenosis, 47 surgical management, 259 – 261 thrombosis, 69 – 70 triglyceride-rich lipoproteins, 261 – 266 uncontrolled studies, 251 – 252 femoral artery, 251 popliteal artery, 251 University of California, San Francisco, Specialized Center of Research, Intervention Trial, 254 Veterans Administration Cooperative Study Group on Antihypertensive Agents, 58 viral infection, 242 Western Collaborative Group Study, 58 Cholesterol-Lowering Atherosclerosis Study, 253 Cholestyramine, 64 drug interactions, 289 Chronic compartment syndrome, 1137– 1138 Chronic pulmonary hypertension, 975 Chronic venous insufficiency, 937– 947, 979– 990 acquired venous disease, 982 primary, 982 secondary, 982 anatomic distribution, influence of, 986– 988 arteriovenous fistula theory, 937– 938 classification, 980–981 clinical examination, 110 clinical manifestations of, 154 – 155 congenital, 981 congenital disease, 982 cytokine regulation, tissue fibrosis, 942– 943 deep veins, 988 dermal fibroblast function, 943 – 944
[Chronic venous insufficiency] diffusion block theory, 938 etiologies, 981 historical theories, 937 leukocyte activation, 938 – 939 macroscopic alterations, 945 matrix metalloproteinases, inhibitors in venous ulcer healing, 944 – 945 natural history, application, 988 – 989 natural history of development of, 982– 986 perforator disease, 986 – 987 primary disease, 982 – 984 secondary disease, 984 – 986 segmental disease, patterns of, 988 segmental distribution, effect of, 986 stasis dermatitis, dermal fibrosis, pathophysiology of, 941 – 944 superficial veins, 986 ulceration, 989 venous microcirculation, 939 – 941 endothelial cell characteristics, 940 extracellular matrix alterations, 941 types, distribution of leukocytes, 940– 941 venous stasis theory, 937 Chronic visceral ischemia, 861 – 875 anatomic considerations, 861 clinical presentation, 861 – 862 nonoperative therapy, 869 – 870 pathophysiology, 862 – 863 recurrent visceral ischemia, 870 –873 revascularization options, 863 – 869 autogenous antegrade bypass, 864– 865 bypass, 864– 867 endarterectomy, 867 – 869 prosthetic antegrade bypass, 865 –867 reimplantation, 863 – 867 retrograde bypass, 864 Cigarette smoking (see Smoking) Cilazapril, 332 Cilostazol, 309 – 310 clinical use, 309 – 310 mechanism, 309 Cine loop playback, digital fluoroscopy, 396 Cirrhotics with portal hypertension, aortic surgery, 1030– 1031 Citrobacter, aneurysm infection, 674 CLAS (see Cholesterol-Lowering Atherosclerosis Study) Clinical examination, 103 – 106 vascular system, 103 – 112 acute arterial occlusion, 105 Allen test, 108 aneurysms, 107 – 108
1269
[Clinical examination] arterial diseases, 103 – 106 arterial physical exam, 106 – 108 atheroembolism, 105 bruit, 107 chronic venous insufficiency, 110 deep vein thrombosis, 110 – 114 examination of skin, 108 – 109 exercise testing, 108 history, 110–112 leg elevation, 108 lymphangitis, 112 lymphatic disease, 111 – 112 lymphedema, 111 – 112 peripheral arterial disease, 103 – 104 physical exam, 111 physical examination, 112 popliteal artery entrapment, 105 pulse, 106– 107 Raynaud’s phenomenon, 106 reflex sympathetic dystrophy, 105– 106 superficial vein thrombosis, 110 thoracic outlet maneuvers, 109 thoracic outlet syndrome, 105 thrombosis, 110 – 111 varicose veins, 110, 111 vasculitis, 104 venous insufficiency, 111 venous system examination, 109 – 111 Clinical trial costs, 216– 217 design, 211– 220 blinding, 214 patient selection, 213 presentation of results, 215 – 216 randomization, 214 statistical design, 214 – 215 therapeutic regimens, 213 – 214 economic analysis, 217 – 218 ethics, 216 future trends, 218 limitations, 216 – 217 types of clinical trials, 211 – 212 Clofibrate, 64 drug interactions, 289 Coagulation mechanism, anticoagulants, 285 Cocaine abuse, vascular complications related to, 1113 Colestipol, 64 Colitis, fulminating universal, 857 Collateral dilation, abnormal blood flow, 95 Colon carcinoma colitis associated with, 857 lesions mimicking, 857
1270
Index
Colonic ischemia, 852 – 854 associated with colon carcinoma, 857 causes of, 854 clinical presentation, 853 –854 complicating abdominal aortic surgery, 856– 857 diagnosis, 854– 857 fulminating universal colitis, 857 general principles of management, 855 historical background, 852 irreversible lesions, management of, 856 ischemic strictures, management of, 856 lesions mimicking colon carcinoma, 857 manifestations of, management of late, 856 pathophysiology of, 853 reversible lesions, management of, 855– 856 Colonized aneurysms, 676 Color flow imaging, duplex scanning, venous reflux detection, 164 Colorectal tumors, 636 – 637 Color-encoded technology, for noninvasive study of peripheral vascular disease, 114– 115 Color-flow duplex imaging, 134 – 135 Common carotid artery, intrathoracic left, penetrating wounds of, 1052 –1053 Communications on computer, 229 Compartment syndrome, 1133 – 1144 abdominal compartment syndrome, 1142 chronic compartment syndrome, 1137– 1138 diagnosis, 1134– 1136 catheter systems, 1136 measuring, monitoring techniques, 1135– 1136 physical examination, 1134 – 1135 supplemental studies, 1136 etiology, 1134 historical considerations, 1133 of lower extremity, 1138– 1140 anatomy, 1138 fasciotomy techniques-foot, 1139– 1140 fasciotomy techniques-leg, 1138– 1139 pathophysiology, 1133 – 1134 compartmental pressure, 1134 microcirculation, 1133 – 1134 treatment, 1136– 1137 adjunctive therapy, 1137 fasciotomy, 1137 of upper extremity, 1140– 1141 anatomy, 1140 fasciotomy techniques-arm, 1140– 1141
Completion arteriography, 396 – 398 Complex regional pain syndromes, 1123– 1132 diagnosis, 1126 etiology, 1125 lumbar sympathetic block techniques, 1128 differential diagnosis, 1128 – 1129 treatment, 1129 –1130 pathophysiology, 1125 – 1130 signs, 1126– 1127 stellate ganglion block technique, 1127– 1128 sympathectomy, results of, 1130 sympathetic block, assessment of, 1127 sympathetically maintained pain, sympathetically independent pain, 1125– 1126 terminology, 1124– 1125 Complex-combined malformations, 1169 Complicated plaques, progression to, 238 Computers, 227 – 234 affiliated vascular societies, with linked pages, 232 American Venous Forum, 232 applications, 228 – 229 communications, 229 database management, 228 spreadsheets, 229 wordprocessing, 228 button bar, 233 Canadian Society for Vascular Surgery, 232 Eastern Vascular Society, 232 future enhancements, 233 Internet, 229– 234 Joint Council of Society for Vascular Surgery, 231 Medline, 231 Midwestern Vascular Surgical Society, 232 New England Society for Vascular Surgery, 232 North American Chapter of International Society for Cardiovascular Surgery, 231 overview, 227– 228 Peripheral Vascular Surgery Society, 232 power bar, 232– 233 searching for data, 231 searching medical literature, 233 – 234 Society for Clinical Vascular Surgery, 232 Southern Association for Vascular Surgery, 232 Vascular Home Page, 231 – 232
[Computers] vascular societies’ administrative office, communicating with, 230 – 231 Western Vascular Society, 232 Conduction disturbances, 319 Congenital vascular malformation, noninvasive diagnosis, 165 Congestive heart failure from arteriovenous fistulas, 1158 perioperative cardiovascular risk, 318 Conray-60, as contrast agent, 170 Contrast agents, angiography, 169 – 171 Cook, Inc., Zenith, development of, 366 Cooley, Denton, 5, 8 Cooper, Ashley, 1, 6 Cooperative Study of Renovascular Hypertension, 6 Coronary artery atherosclerosis, 47 – 48 medical management, 251 – 258 Coronary artery disease, incidence, 62 Costs, of clinical trial, 216 – 217 Crafoord, Clarence, 2, 3 Crawford, E. Stanley, 6, 7, 8 Cycling, metabolic equivalent level for, 317 Dardik, Herbert, 5 Dark Ages, medical treatments during, 1 Database management on computer, 228 Davis, J.B., 8 DeBakey, Michael, 5, 6, 7, 8 Deep femoral artery surgery, 545 – 553 anatomy, 545 angiographic techniques, 547 distribution of disease, 546 – 547 indications for, 547 – 549 to lower amputation level, 553 operative technique, 549 – 551 results, 551– 552 Deep vein thrombosis, 929 – 935, 963–978 abdominal vein thrombosis, 970 anticoagulation, 967 chronic, pulmonary hypertension, 975 clinical examination, 110 – 114 clinical resolution of thrombosis, 932 diagnosis, 965– 966 fibrin, assay of, 966 impedance plethysmography, 965– 966 radioactive-labeled fibrinogen, 966 ultrasound, 965 venography, 966 effect of treatment, 932 –933 fibrinolysis, 967 – 968 future therapeutic possibilities, 933 history, 929 from intravenous drug injection, 1108
Index [Deep vein thrombosis] pathogenesis, 929 – 930 changes in vessel wall, 930 hypercoagulability of blood, 930 stasis, 930 pathophysiology, 963 – 964 postthrombotic limb, 932 prophylaxis, 966 – 967 pulmonary thromboembolism, 970– 975 arterial blood gases, 971 central venous pressure, 971 chest radiography, 971 diagnosis, 970 – 972 electrocardiography, 971 lung scan, 971– 972 management, 973 – 974 overview, 970 pathophysiology, 972 – 973 pulmonary arteriography, 972 pulmonary embolectomy, 974 – 975 subclavian vein thrombosis, 970 surgical approaches, 968 – 969 operative thrombectomy, 968 vena cava interruption, 968 – 969 thrombophlebitis migrans, 970 thrombus resolution, 930 –931 monocyte in thrombus resolution, 931 organization, natural lysis, 930 – 931 recanalization, 931 treatment, 967 – 969 Dermal fibrosis, stasis dermatitis, pathophysiology of, 941 – 944 Descending thoracic aorta, blunt rupture of, 1057– 1058 Design of clinical trial, 211 – 220 costs, 216– 217 economic analysis, 217 – 218 ethics, 216 future trends, 218 limitations, 216 – 217 trial design, 212– 216 blinding, 214 patient selection, 213 presentation of results, 215 – 216 randomization, 214 statistical design, 214 – 215 therapeutic regimens, 213 – 214 types of clinical trials, 211 – 212 Desmodus rotundus, plasminogen activator, 299 Deterioration of prosthesis, with aortoiliofemoral occlusive disease, 448 Devascularization, 1026 DeWeese, Marion S., 6, 7, 8, 9 Dexamethasone, 332
Diabetes amputation, 555 – 556 atherosclerosis, 241 peripheral vascular disease, 601 – 610 infection, 603– 604 ischemia, 604– 608 lower extremity arterial disease, 603– 608 neuropathy, 603 pathophysiology, 601 – 602 as risk factor for atherosclerosis, 66 – 67 Diazoxide, drug interactions, 289 Digital fluoroscopy, 395 – 396 basic principles, 395 cine loop playback, 396 magnification, 396 roadmapping, 396 subtraction, 395 – 396 Digital gangrene, patient presentation, 907– 908 Digital ischemia, 912 Digital plethysmography, for amputation, 559 Diltiazem, 332 Dipyridamole, 332 Direct arterial surgery, for abnormal blood flow, 93–95 Direct thrombin inhibitors, 289 – 290 pharmacokinetics of hirudin, 290 physical properties, 289 – 290 Disease process, atherosclerosis, 15 –17 experimental animals, studies in, 16 –17 lesions, 15 – 16 complicated lesion, 16 fatty streak, 15 fibrous plaque, 15 – 16 plaque rupture, 16 Disease-specific instruments, 224– 225 Dissecting aneurysm, angiography, 173– 174 Disuse phenomenon, 1124 dos Santos Joao Cid, 2, 5 Raynaldo, 3 Dotter, Charles, 4 Dressing, metabolic equivalent level for, 317 Drug abuse, vascular complications from, 1107– 1121 arterial infections, 1113 – 1115 arterial injury, extremity gangrene, 1111– 1113 barbiturate crystallization, 1112 chemical endarteritis, 1111 – 1112 particulate embolization, 1112 pathophysiology, 1111 – 1113 vasoconstriction, 1111
1271
[Drug abuse, vascular complications from] cocaine abuse, vascular complications related to, 1113 ergot derivatives, pharmacologic properties of, 1115 ergotism, 1115– 1117 intravenous drug injection, 1108 – 1111 angiothrombotic pulmonary hypertension, 1110– 1111 deep venous thrombosis, 1108 infected venous pseudoaneurysms, 1109– 1110 septic thrombophlebitis, 1108 – 1109 superficial venous thrombosis, “puffy hand,” 1108 management, 1113 vasculitis, related to drug abuse, 1115 D-thyroxines, drug interactions, 289 Dubost, Charles, 5, 6 Dunphy, J. Englebert, 3, 7 Duplex imaging clinical applications, 132 – 134 color flow imaging, venous reflux detection, 164 in ultrasonography, 127 – 129 for venous disease diagnosis, 162 – 163 vs. carotid arteriography, 135 – 138 Dystrophy, posttraumatic, 1124 Dysvascular patient, amputation in, 555– 573 above-knee amputation, 566 – 567 for acute ischemia, 555 – 556 at ankle, 561–562 below-knee, 562 – 565 contraindications to, 563 complications, 569 – 570 in diabetic patient, 555 – 556 digital plethysmography, 559 hip disarticulation, 567 incidence, 555 indications for, 555 laser Doppler flowmetry, 559 level of, 558– 560 nuclear magnetic resonance spectroscopy, 559 photoplethysmography, 559 postoperative care, 567 – 568 preoperative management, 556 – 557 previous reconstructive surgery, effect on amputation level, 558 prosthesis fitting, 568 segmental blood pressure, 559 skin perfusion pressures, 559 skin temperature measurement, 559 surgery, 557– 558 surgical techniques, 560 – 567 through-knee amputation, 565 – 566
1272
Index
[Dysvascular patient, amputation in] of toe, 560– 561 ray amputation of toe, 561 transphalangeal level, 560 transmetatarsal amputation of forefoot, 561 Eascott, Felix, 7 Eastern Vascular Society, 232 Economic analysis, of clinical trial, 217– 218 Edema, traumatic, 1124 Edwardsiella, aneurysm infection, 674 Embolectomy, balloon catheter for, development of procedure, 4 Embolic arterial occlusions, lower extremity, historical developments in treatment of, 5 Enalapril, 332 Encephalopathy, 1017 Endarterectomized superficial femoral artery, femorofemoral bypass with, development of procedure, 4 Endarterectomy carotid, 1204– 1209 external carotid, 795 – 802 case reports, 798– 799 clinical presentation, 796 – 800 collaterals, anatomy of, 796 external carotid artery occlusion, 800– 801 hemodynamics, 796 internal carotid artery occlusion, 795– 796 natural history, 795 – 796 occlusion prevention, 800 – 801 occlusion treatment, 801 operative technique, 799 – 800 results of operative series, 796 –797 post-carotid, recurrent stenosis, 719– 722 restinosis after, 331 – 332 patency after, 332 Endograft exclusion of traumatic arterial disruptions, pseudoaneurysms, development of procedure, 4 Endoscopic variceal sclerosis, 1020 Endothelial cell culture, 21 – 22 seeding, 615– 616 Endothelium, in atherosclerosis, 21 – 22 endothelial cell culture, 21 – 22 endothelial responses, 22 Endovascular bypass, 445 Endovascular graft, 363 – 394 abdominal aortic aneurysms, 364 – 371 anatomic selection criteria, 371 – 374
[Endovascular graft] Ancure Guidant EVT, 365 – 366 aneurysm size, patient selection based on, 374–375 bifurcated modular graft, deployment technique of, 369 – 371 construction, 364 – 365 endoleaks, 379 – 380 equipment for endovascular grafting, 367 Excluder, 366 fully supported vs. partially supported grafts, 365 high-risk patients, 374 Montefiore Endovascular Graft System, 366–367 operating room, basic setup of, 367 patient selection, 371 preoperative imaging, 371 self-expanding vs. balloon-expandable stents, 364– 365 single components vs. multiple component, 365 Talent Endovascular Bifurcated Spring Graft, 366 technical considerations, 367 – 368 Vanguard Endovascular Aortic Graft and AneuRx Graft, 366 vascular access, techniques to obtain, 368– 369 Zenith, 366 for arterial trauma, Montefiore experience, 386 history of, 363– 364 Endovascular graft repair, aortoiliac occlusive disease, 380 – 386 arterial trauma, 385 – 386 endovascular grafts, 380 graft insertion, location of stent deployment in bilateral iliac disease, 380– 381 operative technique, 381 –384 results of endovascular grafting, 384 for treatment of vascular trauma, 384 Endovascular infection, 676 Endovascular surgical training, 341 – 342 Endovascular technology, future of, 347– 348 Endovascular therapies for arterial disease, historical developments in treatment of, 4 End-to-end vascular anastomosis, 1190– 1191 End-to-side vascular anastomosis, 1192– 1193 Energy losses, in hemodynamics, 84 – 86 arterial stenoses, 86
Enlargement, atherosclerotic arteries, 42 Enterobacter, aneurysm infection, 674 Enterococcus, aneurysm infection, 674 Epidemiology, atherosclerosis, 55 – 79 antioxidant vitamins, 68– 69 cardiovascular death rates, age-specific, 62 coronary artery disease, incidence, 62 fibrinogen level, risk of cardiovascular disease by, 61 fish consumption, 66 Framingham Study of Evolution of Atherothrombotic Brain Infarction, 58 ischemic heart disease death rates, United States, 57 lipoprotein cholesterol levels according to alcohol consumption, 63 alcohol consumption and, 63 omega-3 fatty acids, 66 Pooling Project, 58 racial predisposition, 55 –56 risk factors, 56– 70 age, 56 – 57 alcohol consumption, incidence of coronary heart disease, 63 behavior patterns, 68 diabetes mellitus, 66 – 67 hyperhomocystinemia, 68 hyperlipidemia, 61 – 66 hypertension, 57 – 58 male sex, 57 obesity, 67 – 68 physical inactivity, 67 – 68 smoking, 58 – 61 stress, 68 sexual predisposition, 55 – 56 smoking, risk of cardiovascular disease by, 59 thrombosis, 69 – 70 Veterans Administration Cooperative Study Group on Antihypertensive Agents, 58 Western Collaborative Group Study, 58 Equipment, 343 – 345 Erection, physiology of, 877 Ergot derivatives, pharmacologic properties of, 1115 Ergotism, 1115– 1117 Escheria coli, aneurysm infection, 674 Esophageal, gastric transection, 1025– 1026 Esophageal varices, 1016 – 1017 bleeding, management of, 1019 Estrogens, 64 Ethacrynic acid, drug interactions, 289 Ethanol, drug interactions, 289
Index Ethics, in clinical trials, 216 EuroQol, 224 Evolution of vascular surgery, 1 – 14 antiquity to end of nineteenth century, 1–2 aortic aneurysms, 6 aortic occlusive disease, 3 cerebrovascular disease recognition, 7 cerebrovascular disease surgical treatment, 8 early twentieth century, 2 – 3 early twenty-first century, gene therapy, 9 endovascular therapies for arterial disease, 4 femoral arterial occlusive disease, 5 femoral artery aneurysm, 6 last fifty years of twentieth century, 3– 9 aortic aneurysms, 5 – 6 aortoiliac arteriosclerotic occlusive disease, 3 – 4 cerebrovascular disease, 7 – 8 embolic arterial occlusions, lower extremity, 5 infrainguinal arteriosclerotic occlusive disease, 4 – 5 renal artery occlusive disease, 6 splanchnic artery occlusive disease, 6–7 venous disease, 8– 9 nonanatomic revascularization of lower extremities, 4 popliteal arterial occlusive disease, 5 popliteal artery aneurysm, 6 renal artery disease, 7 splanchnic artery disease, 7 tibial arterial occlusive disease, 5 venous disease, 8 Examination of vascular system, 103 –112 arterial diseases, 103 – 106 acute arterial occlusion, 105 atheroembolism, 105 peripheral arterial disease, 103 – 104 popliteal artery entrapment, 105 Raynaud’s phenomenon, 106 reflex sympathetic dystrophy, 105– 106 thoracic outlet syndrome, 105 vasculitis, 104 arterial physical exam, 106 – 108 Allen test, 108 aneurysms, 107 – 108 bruit, 107 examination of skin, 108 – 109 exercise testing, 108 leg elevation, 108 pulse, 106–107
[Examination of vascular system] thoracic outlet maneuvers, 109 lymphatic disease, 111 – 112 history, 111– 112 lymphangitis, 112 lymphedema, 111 – 112 physical examination, 112 physical exam, 111 thrombosis, 111 varicose veins, 111 venous insufficiency, 111 venous system examination, 109 – 111 chronic venous insufficiency, 110 deep vein thrombosis, 110 – 114 history, 110 superficial vein thrombosis, 110 thrombosis, 110 – 111 varicose veins, 110 Exercise, atherosclerosis and, 241 –242 Exercise testing, 108 Expanded polytetrafluoroethylene, 614– 615 Extended profundoplasty, development of procedure, 5 External carotid endarterectomy, 795 – 802 clinical presentation, 796 – 800 case reports, 798 – 799 operative technique, 799 – 800 results of operative series, 796 – 797 external carotid artery occlusion, 800– 801 background data, 800 prevention, 800– 801 treatment, 801 internal carotid artery occlusion, 795– 796 anatomy of collaterals, 796 hemodynamics, 796 natural history, 795 – 796 Extraanatomic bypass, 527 – 543 axillofemoral grafts, 532 – 534 results, 539 technique, 532– 534 axillopopliteal extraanatomic bypass, 536– 538 femorofemoral grafts, 528 –532 results, 530– 532 technique, 529– 530 graft materials, 528 hemodynamic consideration, 520 indications for, 527 obturator foramen bypass grafts, 536 technique, 536 thoracic aorta to femoral artery bypass, 534– 536 Extra-anatomical bypass grafts, 445 Extracellular matrix, 329
1273
Extracranial carotid artery aneurysms, 803– 809 clinical presentation, 804 – 805 differential diagnosis, 807 effects of, 804 incidence, 803 investigation of, 805 pathology of, 803 – 804 atherosclerotic carotid aneurysms, 804 traumatic carotid artery aneurysms, 804 reconstructive approach, 806 – 807 results of surgery, 808 simple ligation, 806 surgical anatomy, carotid arteries, 807– 808 surgical treatment, 806 – 808 treatment, 805 Extracranial carotid artery bifurcation, arteriosclerosis of, 7 Extracranial carotid artery occlusive disease, 745– 764 angiography, 751 asymptomatic stenosis, efficacy of carotid endarterectomy, clinical trials on, 757– 758 carotid artery stenting, 760 – 761 carotid endarterectomy, description of, 751– 756 clinical presentation, 750 – 751 historical perspective, 747 – 748 indications for, 758 – 760 pathogenesis, 748 – 750 randomized clinical trials, 756 symptomatic stenosis, efficacy of carotid endarterectomy, clinical trials, 756– 757 Extracranial vascular disease, symptomatic, 695– 710 anticoagulant therapy, 700 –701 antithrombotic therapy, evaluation of, 700– 706 completed, 699 – 700 platelet antiaggregant drugs, clinical trials of, 705– 706 platelet-suppressant therapy, 704 – 705 progressing stroke, 699 thrombolytic therapy, 701 – 704 transient ischemic attacks, 695 – 699 atheromatous material, 698 hemodynamic pathogenesis, 698 – 699 natural history, 699 platelet-fibrin emboli, 698 thromboembolic pathogenesis, 698 Extracranial-intercranial arterial bypass, development of procedure, 8
1274
Index
Extracranial-intracranial arterial bypass, development of procedure, 8 Extrahepatic presinusoidal portal hypertension, 1015– 1016 Extremity, vascular injuries, 1081 – 1093 diagnostic considerations, 1082 – 1084 endovascular treatment, 1086 – 1087 pathophysiology, 1081 – 1082 surgical considerations, 1084 –1086 Extremity gangrene, from drug use, 1111– 1113 barbiturate crystallization, 1112 chemical endarteritis, 1111 – 1112 particulate embolization, 1112 pathophysiology, 1111 – 1113 vasoconstriction, 1111 False aneurysm formation, with aortoiliofemoral occlusive disease, 447 Fasciotomy, 410 compartment syndrome, 1137 Fatty streak, 15, 37 – 39, 236– 237 Femoral aneurysm ligation, development of procedure, 6 Femoral artery aneurysm, historical developments in treatment of, 6 atherosclerosis, medical management, 251, 252 injury, 1089– 1090 lacerated, repair of, 1196 –1197 occlusive disease, historical developments in treatment of, 5 stenosis, superficial, 47 superficial, injury, 1090 Femoral endarterectomy, development of procedure, 5 Femoral popliteal bypass, reversed autogenous saphenous vein, development of procedure, 5 Femoral vein ligation, development of procedure, 8 Femoral-popliteal-tibial occlusive disease, 455– 484 aggressive approaches to limb salvage, 478 amputation level, 477 angiographic evaluation, 459 – 460 arteriographic outflow characteristics, 477 cost-benefit ratio, 477– 478 differential diagnosis, 457 – 458 durability of angioplasty, 475 economic impact of limb salvage, 478 femoral-popliteal-tibial occlusive disease, clinical presentation, 455– 458
[Femoral-popliteal-tibial occlusive disease] limb salvage, 474 – 475 immediate limb salvage, 474 late limb salvage, 474 – 475 lytic agents, 476 – 477 medical considerations, 460 new developments, 478 – 480 in diagnostic techniques, 479 in endovascular devices, 479 intraoperative adjunctive techniques, 480 for lower extremity vein bypasses, 479– 480 in tibial, pedal bypasses, 479 newer interventional treatments, 457 operative mortality, 473 – 474 patency, arterial reconstructive operations, 475 patient evaluation, 458 – 460 physical examination of extremity, 458– 459 noninvasive vascular laboratory tests, 459 pulse examination, 458 – 459 systemic factors, 459 reoperations, 476 results, 468–477 staging, 456– 457 surgical considerations, 460 – 462 axillopopliteal bypass, 461 femoropopliteal bypass, 460 graft material, 461 – 462 infrapopliteal bypass, 460 – 461 profundoplasty, 461 in situ vs. reversed saphenous vein grafts, 462 treatment, 460 – 469 upper extremity veins, 462 –463 angioplasty, 467 bypasses to ankle, foot arteries, 463– 464 drug treatment, 464 failing graft, 466–467 foot lesions, 464 operative technique, 462 – 463 reoperation, 465 – 466 Femoral-tibial bypass with vein, development of procedure, 5 Femorofemoral bypass, 1256 – 1259 development of procedure, 4 with endarterectomized superficial femoral artery, development of procedure, 4 Femorofemoral grafts, 528 – 532 results, 530–532 technique, 529– 530 Femoropopliteal bypass, 1240 –1249
Femoropopliteal occlusive disease, aortoiliac, combined, 495 – 511 Fibrinogen level, risk of cardiovascular disease by, 61 Fibrinolysis, 297 – 298 complications of, 410 deep vein thrombosis, 967 – 968 Fibrinolytic system defects, 276 – 277 clinical presentation, 276 – 277 methods of testing, 277 Fibrolase, 299 Fibromuscular dysplasia, 923 – 926 Fibrosis, posttraumatic, 1124 Fibrous plaque, 15 –16, 39– 40, 237– 238 Fields, William, 7, 8 Fish consumption, atherosclerosis and, 66 Fish oils (see Omega-3 fatty acids) Fisher, Miller, 7 Flow pulses, hemodynamics, 91 – 93 Fluoroscopically assisted thromboembolectomy, 399 – 400 Fogarty, Thomas, 4, 5 Folic acid supplementation, atherosclerosis, 242 Forefoot, transmetatarsal amputation of, 561 Framingham Study of Evolution of Atherothrombotic Brain Infarction, 58 Freeman, Norman, 3, 4, 6, 7 Fungal infection, 676 Galbraith, G., 8 Galen, contribution of, 1 Gallbladder disease, 637 Gangrene digital, patient presentation, 907 – 908 extremity, from drug use, 1111 – 1113 barbiturate crystallization, 1112 chemical endarteritis, 1111 – 1112 particulate embolization, 1112 pathophysiology, 1111 – 1113 vasoconstriction, 1111 Gardening, metabolic equivalent level for, 317 Gastroduodenal, pancreaticoduodenal aneurysms, 665 Gastroepiploic aneurysms, 665 –666 Gastroesophageal devascularization, 1025 Gastrointestinal bleeding, angiography, 185– 187 Gelatinous plaques, 237 Gemfibrozil, 64 Gender, atherosclerosis, 55 – 57 Gene therapy, 9 atherosclerosis, 242 –243
Index Generic outcomes assessment tools, 223– 224 Generic quality of life instruments, 224 Glycoprotein IIb/IIIa inhibitors, 290, 305– 306 Goldblatt, Harry, 2, 7 Golf, metabolic equivalent level for, 317 Gore, W.L. and Associates, Excluder, 366 Goyanes, Jose, 2, 6 Graft infection with aortoiliofemoral occlusive disease, 447 prosthetic, 621– 629 aortic, aortoiliac bypass grafts, 624– 625 aortobifemoral bypass grafts, 625– 626 diagnosis, 623 endoscopy, 624 imaging studies, 623 – 624 incidence, 621 laboratory studies, 623 management, 624 microbiology, 622 – 623 pathogenesis, 621 – 622 peripheral bypass graft infections, 626 physical examination, 623 Greenfield, Lazar J., 8, 9 Griseofulvin, drug interactions, 289 Gross, Robert, 2, 3 Grove, W.J., 8 Gruntzig, Andreas, 4, 6, 7 Guida, P.M., 4 Guidewires, 343 Guthrie, Charles C., 2 Haemophilus, aneurysm infection, 674 Hall, Karl, 5 Hauer, G., 8 Heidelberg Study, 258 Hemangiomas, 1163– 1164 clinical characteristics, 1163 diagnosis, 1163 treatment, 1163– 1164 corticosteroids, 1163 cryotherapy, 1164 embolization, 1164 excision, 1164 interferon-alpha, 1163– 1164 laser therapy, 1164 ligation of feeder vessels, 1164 radiation therapy, 1164 Hemodialysis patients, venous stenosis in, 1008– 1010 Hemodynamic resistance, 86 – 87
Hemodynamics abnormal blood flow, 81– 101 aneurysms, 97 – 98 arterial obstructive lesions, circulatory effects, 87 – 91 arteriovenous fistulas, 95 – 97 basic hemodynamics, 81 – 87 collateral dilation, 95 direct arterial surgery, 93 – 95 energy losses, 84 – 86 flow pulses, 91 – 93 hemodynamic resistance, 86 – 87 kinetic energy, 82 potential energy, 81 – 82 pressure, 91 –93 reducing viscosity, 95 shear, effect on arterial wall, 97 sympathectomy, 95 therapy, 93– 95 total fluid energy, 82 – 84 vasodilators, 95 distal splenorenal shunt, 1023 –1024 Hemorrhage, with aortoiliofemoral occlusive disease, 447 –448 Heparin, 286– 287, 332– 333 complications of, 293 low molecular weight heparins, 286 –287 mode of action, 286 – 287 physical properties, 286 – 287 unfractionated heparins, 286 – 287 Heparin-induced thrombosis, 278 – 280 clinical presentation, 279 diagnosis, 279 treatment, 279 –280 Heparin-like agents, 286 – 287 Hepatic artery, infected aneurysm, 682 Hepatic artery aneurysm, 661 – 662 clinical presentation, 661 investigations, 661 –662 operations, 662 Hepatic artery pseudoaneurysms, 1183 Hepatic artery stenosis, 1182 – 1183 Hepatic artery thrombosis, 1182 Hepatic tumors, angiography, 185 Hepatic venography, 179 –182 Hexabrix, as contrast agent, 170 Hills, climbing, metabolic equivalent level for, 317 Hindgut, pelvic perfusion, maintenance of, 636 Hip disarticulation, 567 Hippocrates, contribution of, 1 Hirudin, 332 pharmacokinetics of, 290 History of vascular surgery antiquity to end of nineteenth century, 1 –2
1275
[History of vascular surgery] aortic aneurysms, 6 aortic occlusive disease, 3 cerebrovascular disease recognition, 7 cerebrovascular disease surgical treatment, 8 early twentieth century, 2 – 3 early twenty-first century, gene therapy, 9 endovascular therapies for arterial disease, 4 femoral arterial occlusive disease, 5 femoral artery aneurysm, 6 last fifty years of twentieth century, 3 – 9 aortic aneurysms, 5– 6 aortoiliac arteriosclerotic occlusive disease, 3 – 4 cerebrovascular disease, 7 – 8 embolic arterial occlusions, lower extremity, 5 infrainguinal arteriosclerotic occlusive disease, 4 – 5 renal artery occlusive disease, 6 splanchnic artery occlusive disease, 6–7 venous disease, 8 – 9 nonanatomic revascularization of lower extremities, 4 popliteal arterial occlusive disease, 5 popliteal artery aneurysm, 6 renal artery disease, 7 splanchnic artery disease, 7 tibial arterial occlusive disease, 5 venous disease, 8 Hobson, Robert, 7, 8 Holden, William, 2 Homans, John, 3, 8 Homans’ minor causalgia, 1124 Homocysteine supplementation, atherosclerosis, 242 Homograft replacement abdominal aortic aneurysm, development of procedure, 6 thoracic aortic aneurysm, development of procedure, 6 thrombosed aortic bifurcation, development of procedure, 3 Horseshoe kidney, 636 Howell, W.H., 3 Human umbilical cord vein allograft, 613 Hunter, John, 1 Husni, E.A., 8 Hypaque, as contrast agent, 170 Hypercoagulability clinical presentation, 274 guidelines for identifying, 273 – 274
1276
Index
Hyperhomocystinemia, as risk factor for atherosclerosis, 68 Hyperlipidemia artery wall structure adventitia, 34– 35 intima, 31 – 33 media, 33 – 34 atherosclerotic lesion structure fatty streaks, 37 – 39 fibrous plaques, 39 – 40 lesion complications, 40 – 41 carotid artery, intima-media thickness, 261 cellular modifications in endothelial cell culture, 21– 22 endothelial responses, 22 endothelium, 21 – 22 lipid metabolism, 23 – 24 macrophage, 24 – 25 platelet-derived growth factor, 25 platelets, 25 – 26 smooth muscle, 22 – 24 smooth-muscle proliferation, 22 – 23 disease process experimental animals, studies in, 16– 17 fatty streak, 15 fibrous plaque, 15 – 16 lesions, 15 – 16 plaque rupture, 16 drug therapy for, 239 – 240 enlargement of arteries with, 42 epidemiology, 55 – 79 antioxidant vitamins, 68 – 69 cardiovascular death rates, age-specific, 62 coronary artery disease, incidence, 62 fibrinogen level, risk of cardiovascular disease by, 61 fish consumption, 66 Framingham Study of Evolution of Atherothrombotic Brain Infarction, 58 gender, 55– 56 ischemic heart disease death rates, United States, 57 lipoprotein cholesterol levels, according to alcohol consumption, 63 omega-3 fatty acids, 66 Pooling Project, 58 racial predisposition, 55 – 56 risk factors, 56 – 70 smoking, risk of cardiovascular disease by, 59 thrombosis, 69 – 70
[Hyperlipidemia] Veterans Administration Cooperative Study Group on Antihypertensive Agents, 58 Western Collaborative Group Study, 58 human angioplasty, 330 hypotheses of atherogenesis lipids, 19 response-to-injury hypothesis, 17 – 19 risk factors, 19 – 21 medical management, 235 –272 anticoagulant therapy, 242 antioxidants, 240, 266 antiplatelet therapy, 242 aorta, 251– 252 approach to treatment, 238 atherosclerotic plaque, 235 –236 Bezafibrate Coronary Angiographic Intervention Trial, 264 calcium channel blockers, 258 – 259 carotid artery, 251 Cholesterol-Lowering Atherosclerosis Study, 253 complicated plaques, progression to, 238 controlled clinical trials, 252 –261 coronary artery, 251 – 258 diabetes mellitus, 241 exercise, 241– 242 fatty streaks, 236– 237 femoral artery, 252 fibrous plaque, 237 – 238 folic acid supplementation, 242 gelatinous plaques, 237 gene therapy, 242 –243 Heidelberg Study, 258 homocysteine supplementation, 242 hyperlipidemias, drug therapy for, 239– 240 hypertension, 240 – 241 infection, 242 International Nifedipine Trial on Antiatherosclerotic Therapy, 259 LDL-Apheresis Atherosclerosis Regression Study, 259 lesion arrest or regression, 238 Lifestyle Heart Trial, 258 Lipid Coronary Angiographic Trial, 265 Lipid-Lowering Antiatherosclerosis Therapies Trial, 252 medical management, 238 – 239 Monitored Atherosclerosis Regression Study, 256 Montreal Study, 259 Multivitamins and Probucol Trial, 266
[Hyperlipidemia] National Heart, Lung, and Blood Institute, Type II Coronary Intervention Study, 252 plaque evolution, 236 Post Coronary Artery Bypass Graft Trial, 260 Probucol Angioplasty Restenosis Trial, 266 Program on Surgical Control of Hyperlipidemias, 260 recent antiatherosclerosis interventions, 261– 266 renal artery, 251 smoking, 240 St. Thomas’ Atherosclerosis Regression Study, 254 Stanford Coronary Risk Intervention Project, 254 triglyceride-rich lipoproteins, 261– 266 uncontrolled studies, 251 – 252 University of California, San Francisco, Specialized Center of Research, Intervention Trial, 254 viral infection, 242 pathophysiology, 15 – 29, 31– 54 age-related changes in artery wall, 36– 37 aneurysm formation, 45 – 47 aortic atherosclerosis, 45 artery wall nutrition, 35 – 36 artery wall structure, 31– 35 atherosclerotic arteries, enlargement, 42 atherosclerotic lesion structure, 37– 41 carotid bifurcation plaques, 44 – 45 cellular modifications in, 21 – 26 configuration of lesions, 41 – 42 coronary artery atherosclerosis, 47– 48 disease process, 15 – 17 future directions, 26 – 27 hypotheses of atherogenesis, 17 –21 localization, atherosclerotic lesions, 42– 44 quantitative evaluation, 48 – 49 superficial femoral artery stenosis, 47 regression in experimental animal models, 249– 251 in humans, 251– 261 as risk factor for atherosclerosis, 61 – 66 risk factors age, 56 – 57
Index [Hyperlipidemia] alcohol consumption, incidence of coronary heart disease, 63 behavior patterns, 68 diabetes, 20 diabetes mellitus, 66 – 67 hypercholesterolemia, 19 – 20 hyperhomocystinemia, 68 hyperlipidemia, 61 – 66 hypertension, 20, 57 – 58 male sex, 20, 57 obesity, 67 – 68 physical inactivity, 67 –68 smoking, 20, 58– 61 stress, 68 surgical management, 259 – 261 uncontrolled studies femoral artery, 251 popliteal artery, 251 Hypertension atherosclerosis and, 240 – 241 perioperative cardiovascular risk, 319– 320 portal, 1015– 1035 acute variceal bleeding, balloon tamponade in, 1022 ascites, 1017 beta-adrenergic blockers, 1020 bleeding esophageal varices, management of, 1019 cirrhotics with portal hypertension, aortic surgery, 1030– 1031 combined esophageal transection, devascularization, 1026 diagnostic workup, 1018 encephalopathy, 1017 endoscopic variceal sclerosis, 1020 endoscopy, 1018 esophageal, gastric transection, 1025– 1026 esophageal varices, 1016– 1017 extrahepatic presinusoidal portal hypertension, 1015– 1016 gastroesophageal devascularization, 1025 hemodynamics, distal splenorenal shunt, 1023– 1024 indications, 1022– 1023 injection schedule, long-term prevention of rebleeding, 1021 intrahepatic presinusoidal portal hypertension, 1015 laboratory testing, 1018 liver biopsy, 1019 liver transplantation in portal hypertension, 1027
[Hypertension] long-term injection sclerotherapy, results of, 1021 medical treatment, 1019 – 1020 nonshunt surgical procedures, 1025– 1026 organic nitrates, 1020 pathogenesis, 1015 pathophysiology of portal hypertension, 1016 portal vein occlusion, 1028 posthepatic portal hypertension, 1028 postsinusoidal portal hypertension, 1016 prophylactic sclerotherapy, 1021– 1022 radiographic studies, 1018 – 1019 results, 1021, 1024– 1025 resuscitation, patient monitoring, 1019 schistosomiasis, portal hypertension, 1027– 1028 selective portosystemic shunts, 1023 shunt procedures, types of, 1023 shunting procedures for portal hypertension, 1022 sinusoidal portal hypertension, 1016 splenic vein thrombosis, 1028 – 1029 technical aspects, 1020– 1021 technique, 1024 total portosystemic shunts, 1023 transhepatic variceal sclerosis, 1022 transjugular intrahepatic portosystemic shunt, 1026–1027 variceal banding, 1021 variceal injection sclerotherapy, banding, complications of, 1021 varices in unusual locations, 1030 vasopressin analogue, 1020 renovascular aortorenal bypass, 831 characteristics of, 824 – 825 effect of operation on, 832 medical therapy, 826 – 827 nephrectomy, 831 – 832 noninvasive studies, 119 operative techniques, 828 – 832 percutaneous transluminal dilation, 828 postoperative care, 832 preoperative preparation, 828 therapeutic options, 826 – 827 thromboendarterectomy, 831 treatment of, 826 – 832 as risk factor for atherosclerosis, 57 – 58 secondary, renal artery occlusion, establishment of importance of, 7
1277
Hyperthrombotic states, 273 – 284 activated protein C resistance, 281 – 282 antithrombin deficiency, 274–275 clinical presentation, 275 diagnosis, 275 anti-tissue plasminogen activator, 277 clinical presentation, 274 fibrinolytic system defects, 276 – 277 clinical presentation, 276 – 277 methods of testing, 277 heparin-induced platelet aggregation, patient management, 280 heparin-induced thrombosis, 278 –280 clinical presentation, 279 diagnosis, 279 treatment, 279 – 280 hypercoagulability, guidelines for identifying, 273 – 274 lupus anticoagulant, 280 – 281 clinical syndrome, 281 diagnosis, 281 treatment, 281 protein C, 277– 278 methods of testing, 278 protein S deficiency, 278 tissue plasminogen activator, 277 Hypoplastic aorta, 440 Iatrogenic vascular injuries, 1095 – 1106 arterial lacerations, 1097 – 1098 arterial rupture, 1098 arteriovenous fistulas, 1098 endovascular approach, 1099 – 1100 iatrogenic pediatric arterial injuries, 1102– 1103 intraaortic balloon pump catheters, vascular complications due to, 1100– 1102 operative approach, 1098 – 1099 percutaneous transfemoral procedures, arterial injuries following, 1095– 1098 pseudoaneurysms, 1096 thrombotic occlusions, 1097 upper extremity, iatrogenic arterial injuries of, 1102 Iliac bypass, development of procedure, 4 Iliac vein stents, 1007– 1008 Iliopopliteal bypass, development of procedure, 4 Imaging, 345– 347 (see also Noninvasive studies) duplex, 132– 135 venous reflux detection with, 164 vs. carotid arteriography, 135 – 138 operative, 138– 139 postoperative, 138 – 139
1278
Index
[Imaging] preoperative, 371 radiologic, 774 real-time B-mode, 127 ultrasound, 774 Impact of disease, assessment of outcomes, 221– 222 Impedance plethysmography, deep vein thrombosis, 965 – 966 Impotence noninvasive studies, 121, 878 operations specifically for, 882 – 883 Impregnated grafts, 616 In situ saphenous vein arterial bypass, 485– 494 arteriovenous fistulas, 491– 492 development of procedure, 5 history of, 485 introduction of new valve cutter, 5 preoperative saphenous vein anatomy, 485– 486 results, 494 surgical technique, 486 – 489 technical requirements, 489 – 491 venous spasm, 491 Indomethacin, drug interactions, 289 Infected aneurysms, 669 –693 abdominal aorta, 680 –682 endovascular repair, 682 extraanatomic reconstruction, 680– 682 in situ reconstruction, 681 – 682 aorta, 672 bacteriologic studies, 677 – 678 bacteriology, 674 – 676 carotid artery, 673 colonized aneurysms, 676 contemporary classification, 670 diagnosis, 677– 678 endovascular infection, 676 extremities, 674 fungal infection, 676 histology, 671 incidence, 670– 671 laboratory data, 677 microbial arteritis, 671 – 672 histology, 672 incidence, 671 pathogenesis, 672 microbiology, 674 mycotic aneurysms, 670 –671 natural history, 676 –677 operative findings, 679 operative management, 679 – 680 pathogenesis, 671 postoperative management, 684 aortic aneurysms, 685
[Infected aneurysms] peripheral aneurysms, 685 visceral artery aneurysms, 686 preoperative management, 679 radiologic studies, 678 – 679 arteriography, 679 computed tomography, 678 –679 plain films, 678 ultrasound, 678 salmonella infection, 675 terminology, 669 – 670 treatment, 679 – 689 unusual bacteria, 675 visceral arteries, 673 – 674, 682–684 carotid artery, 683 extremity vessels, 683 – 684 hepatic artery, 682 other visceral vessels, 682 – 683 superior mesenteric artery, 682 Infected graft, prosthetic, 621 –629 aortic, aortoiliac bypass grafts, 624 – 625 aortobifemoral bypass grafts, 625 – 626 diagnosis, 623 endoscopy, 624 imaging studies, 623 – 624 incidence, 621 laboratory studies, 623 management, 624 microbiology, 622 – 623 pathogenesis, 621 – 622 peripheral bypass graft infections, 626 physical examination, 623 Infected venous pseudoaneurysms, from intravenous drug injection, 1109– 1110 Infection, from arteriovenous fistulas, 1158 Inferior vena cava lacerated, repair of, 1194 – 1195 plication, 1198– 1201 Inflammatory aneurysms, 636 Infrahepatic caval stenosis, 1183 Infrainguinal arteriosclerotic occlusive disease, historical developments in treatment of, 4 – 5 Infrainguinal bypass, vein mapping for, noninvasive studies, 120 –121 Infrapopliteal artery, injury, 1090 – 1091 Injection sclerotherapy, long-term, 1021 Innominate artery, blunt rupture, 1057 Innominate artery endarterectomy, development of procedure, 8 Innominate-subclavian-carotid arterial bypass, development of procedure, 8 INTACT (see International Nifedipine Trial on Antiatherosclerotic Therapy)
International Nifedipine Trial on Antiatherosclerotic Therapy, 259 Internet, 229– 234 Intestinal branch artery aneurysms, 666 Intestinal ischemia, chronic description of, by Dunphy, 7 development of operative treatment, 7 Intima, artery wall, 31 – 33 Intraaortic balloon pump catheters, vascular complications due to, 1100– 1102 Intracavernous injection, penis, 879 Intrahepatic presinusoidal portal hypertension, 1015 Intraluminal graft repair, thoracoabdominal aneurysms, development of procedure, 6 Intraluminal stripper, for vein removal, development of, 8 Intraoperative balloon angioplasty, stenting, 401– 402 Intravascular ultrasound, 346 Intravenous drug injection, 1108 –1111 angiothrombotic pulmonary hypertension, 1110– 1111 deep venous thrombosis, 1108 infected venous pseudoaneurysms, 1109– 1110 septic thrombophlebitis, 1108 – 1109 superficial venous thrombosis, “puffy hand,” 1108 Ionic dimeric contrast agent, 170 Ionic monomeric contrast agents, 170 Ischemia acute, amputation in, 555 – 556 chronic, angiography, 187 – 188 digital, 912 heart disease death rates, United States, 57 manifestations, evolution of, 410 – 411 mesenteric, acute, 839 – 844 angiography, 843 – 844 arterial causes, 840 clinical presentation, 842 conditions associated with, 841 diagnostic studies, 842 – 844 historical background, 839 – 840 laboratory findings, 842 mesenteric vasoconstriction, pathophysiology of, 841 – 842 operative management, 845 – 846 other diagnostic modalities, 843 patient population, 840 postoperative care, 846 principles of management, 844 – 845 radiographic signs, 842 – 843 selection of patients, 844
Index [Ischemia] treatment plan, 844 types of, 840– 841 venous causes, 840 – 841 signs of, 406 vertebrasilar, 771 – 782 anatomy, 772– 773 arterial pathology, 773 common carotid, to subclavian artery, bypass for, 774 – 775 common carotid to distal vertebral artery bypass, 777 – 779 distal vertebral artery external carotid, transposition of to vertebral artery, 779 – 780 left subclavian artery, transthoracic repair of, 775– 776 occipital artery, transposition of to distal vertebral artery, 780 proximal subclavian artery, surgical reconstruction of, 774 – 776 proximal vertebral artery, transposition of to common carotid artery, 776– 777 subclavian artery, transposition of to common carotid artery, 775 subclavian to vertebral artery bypass, 777 ultrasound, radiologic imaging, 774 vertebral artery, 776 – 780 vertebral/proximal subclavian artery reconstruction, 774 visceral, chronic, 861 – 875 anatomic considerations, 861 autogenous antegrade bypass, 864– 865 bypass, 864– 867 clinical presentation, 861 – 862 endarterectomy, 867 –869 nonoperative therapy, 869 – 870 pathophysiology, 862 – 863 prosthetic antegrade bypass, 865 – 867 recurrent visceral ischemia, 870 – 873 reimplantation, 863 –867 retrograde bypass, 864 revascularization options, 863 – 869 Ischemic strictures, management of, 856 Isovue, as contrast agent, 170 Jacobson, Julius H. II, 8 Jaretzki, Alfred, 5, 6, 8, 703 Joint Council of Society for Vascular Surgery, 231 Jordan, G.L., 8 Julian, O.C., 8 Juxtarenal aneurysm, 635 Juxtarenal occlusion, 445
Kahn, S. F., 4 Kawasaki’s disease, 921– 922 Kidney retrieval, for transplantation, 1177– 1178 Kidney transplantation, 1184 – 1185 arteriovenous fistulas, 1184 hemorrhage, 1184 multiple donor renal arteries, 1184 renal artery stenosis, 1184 renal artery thrombosis, 1184 renal vein thrombosis, 1184 short renal artery, 1184 short right donor renal vein, 1184 – 1185 suboptimal recipient vessels, 1185 for transplantation, vascular surgical technique of, 1180 Kinetic energy, in hemodynamics, 82 Kinks, carotid artery, 783 – 793 Kistner, Robert, 8, 9 Klass, J., 7 Klebsiella, aneurysm infection, 674 Klippel-Trenaunay syndrome, 1169 – 1170 Krayenbuhl, Hugh A., 8 Kunlin, Jean, 2, 4, 5, 8, 9 LAARS (see LDL-Apheresis Atherosclerosis Regression Study) Laparoscopic aortobifemoral bypass, 445 LDL-Apheresis Atherosclerosis Regression Study, 259 Leadbetter, W.F., 7 Leather, Robert, 5 Leg elevation, in clinical examination, 108 Leg lymphatics, 1038 Leriche, Rene, 2, 3 Lesions, atherosclerotic, 15 – 16 complicated lesion, 16 fatty streak, 15 fibrous plaque, 15 – 16 plaque rupture, 16 Lester, Savage, 4 Leukocyte activation, venous insufficiency, 938 Lifestyle Heart Trial, 258 Ligation, saphenous vein, 1202 –1203 Linton, Robert, 3, 8 Lipid Coronary Angiographic Trial, 265 Lipid metabolism, in atherosclerosis, 23–24 Lipid-lowering agents, 333 Lipid-Lowering Antiatherosclerosis Therapies Trial, 252 Lipoprotein cholesterol levels (see also Atherosclerosis) alcohol consumption and, 63 Literature, medical, computer searches, 233– 234
1279
Liver donation, reduced, for transplantation, 1176– 1177 Liver retrieval, for transplantation, 1174– 1176 Liver transplantation, 1185 anomalous donor hepatic arteries, 1185 inadequate recipient hepatic artery, 1185 portal hypertension, 1027 portal vein thrombosis, 1185 for transplantation, vascular surgical technique of, 1179 vascular complications, 1182 – 1185 arcuate ligament syndrome, 1182 hepatic artery pseudoaneurysms, 1183 hepatic artery stenosis, 1182 – 1183 hepatic artery thrombosis, 1182 infrahepatic caval stenosis, 1183 portal vein stenosis, thrombosis, 1183 suprahepatic caval stenosis, 1183 Localization, atherosclerotic lesions, 42– 44 LOCAT (see Lipid Coronary Angiographic Trial) Long-term vascular access, 1153 – 1156 bridge fistulas, 1155– 1156 subcutaneous arteriovenous fistulas, 1153– 1155 Lovastatin, 332 Low molecular weight heparinoids, 287 pharmacokinetics, 287 Low molecular weight heparins, pharmacokinetics, 287 Lower extremity arterial disease, with diabetes, 603– 608 infection, 603–604 neuropathy, 603 Lower extremity arterial injuries, 1089– 1090 Lower extremity arteriography, 191 – 197 Lower extremity chronic venous insufficiency, 991–1002 incompetence of deep veins, operations for, 995– 996 valvuloplasty, 995 – 996 venous transposition, valve transplantation, 996 incompetent perforating veins, interruption, 992 – 995 endoscopic techniques, 992 – 995 patient selection, 992 preoperative tests, 992 preoperative evaluation, 991 superficial reflux, ablation of, 992 surgical treatment, 991 preoperative evaluation, 991 venous obstruction, operation for, 996– 1000
1280
Index
[Lower extremity chronic venous insufficiency] bypass for femoropopliteal venous occlusion, 996– 997 for common femoral or iliac vein obstruction, 998 – 999 prosthetic femorocaval, iliocaval, or inferior vena cava bypass, 999– 1000 results, 998– 999 Lower extremity compartment syndrome, 1138– 1140 Lower extremity embolic arterial occlusions, historical developments in treatment of, 5 Lower extremity revascularizations, use of in human umbilical vein grafts, 5 Lower extremity systolic pressure, normal values, 115 Lower extremity venography, 197 – 200 Lower limb, arterioarterial atherothrombotic microemboli, 427 –458 clinical diagnosis, 431 – 432 diagnostic investigations, 432 – 434 during fibrinolytic therapy, 435 – 437 incidence, 427– 428 medical management, 435 sources of microemboli, 428 – 429 surgical management, 434 – 435 Lumbar sympathectomy, 595 – 599 chemical sympathectomy, 598 complications, 598 effects of, 595 operative technique, 596 – 598 patient selection, 595 – 596 Lumbar sympathetic block techniques, 1128 complex regional pain syndromes, 1128 differential diagnosis, 1128 – 1129 sympathectomy, results of, 1130 treatment, 1129– 1130 Lung procurement, for transplantation, 1173– 1174 Lupus anticoagulant, 280 – 281 clinical syndrome, 281 diagnosis, 281 treatment, 281 Lymphangiography, 1041 Lymphangiosarcoma, 1044 – 1045 Lymphangitis, clinical exam, 112 Lymphatic disease, clinical exam, 111– 112 history, 111– 112 lymphangitis, 112 lymphedema, 111 – 112 physical examination, 112
Lymphatic fistula, with aortoiliofemoral occlusive disease, 448 Lymphatic malformations, 1165 – 1166 treatment, 1165– 1166 Lymphatic system, 1037– 1048 acquired lymphedema, 1040 anatomy arm lymphatics, 1038 leg lymphatics, 1038 lymphatic system, 1037– 1038 benign lymphatic tumors, surgical treatment of, 1044 benign tumors of lymphatics, 1040 clinical presentation, 1039 complications, 1044 differential diagnosis, 1040 – 1041 historical aspects, 1037 lymphangiography, 1041 lymphangiosarcoma, 1044 –1045 lymphedema, 1037 medical treatment, 1041– 1042 noninvasive studies, 1041 operations, 1042– 1044 direct lymphatic reconstruction, 1042– 1043 excisional operations, 1043 – 1044 operative technique, 1043– 1044 pedicle flap reconstruction, 1043 physiologic operations, 1042 – 1043 staged subcutaneous excision beneath flaps, 1043 total subcutaneous excision, 1043 outcome, 1044 pathophysiology, 1037 – 1038 physiology, 1038 lymphedema, 1039 primary lymphedema, 1039 – 1040 classification by age of onset, 1039 classification by lymphangiographic findings, 1039– 1040 surgical treatment, complications of, 1045 Lymphedema, 1037, 1039 acquired, 1040 clinical exam, 111 – 112 primary, 1039 –1040 classification by age of onset, 1039 classification by lymphangiographic findings, 1039– 1040 Lymphocele, with aortoiliofemoral occlusive disease, 448 Lyons, C., 8 Lytic therapy, 1003– 1014 literature, 1006– 1007 patient selection, 1004 – 1006 thrombolytic therapy, 1003 – 1007
Macrophage, in atherosclerosis, 24 –25 Magnification, digital fluoroscopy, 396 Major causalgia, 1124 Male sex, as risk factor for atherosclerosis, 57 Mallinckrodt, as contrast agent, 170 Marin, Michael, 4 MARS (see Monitored Atherosclerosis Regression Study) Martin, Peter, 5 Matas, Rudolph, 2 Matrix metalloproteinases, inhibitors in venous ulcer healing, 944 – 945 Matus, Rudolph, 6 Maynard, E.P., 7 McCaughan, J.J., 4 McLean, Jay, 3 Meadox Corporation, Vanguard Endovascular Aortic Graft, development of, 366 Media, artery wall, 33 – 34 Medical literature, computer searches, 233– 234 Medical Outcomes Study, 224 Medline, 231 Medtronic Corporation, AneuRx Graft, development of, 366 Mefenamic acid, drug interactions, 289 Meprobamate, drug interactions, 289 Mesenteric arteriography, 182 Mesenteric ischemia acute, 839– 844 angiography, 188, 843 – 844 arterial causes, 840 clinical presentation, 842 conditions associated with, 841 diagnostic studies, 842 – 844 historical background, 839 – 840 laboratory findings, 842 mesenteric vasoconstriction, pathophysiology of, 841 – 842 operative management, 845 – 846 other diagnostic modalities, 843 patient population, 840 postoperative care, 846 principles of management, 844– 845 radiographic signs, 842 – 843 selection of patients, 844 treatment plan, 844 types of, 840– 841 venous causes, 840 – 841 angiography, 187 – 188 acute mesenteric ischemia, 188 chronic ischemia, 187 – 188 Mesenteric vascular disease, acute, 839– 859
Index Mesenteric vasoconstriction, pathophysiology of, 841– 842 Mesenteric venography, 177 interpretation of, 179 Metabolic equivalent level for, 317 Microbial arteritis, 671 – 672 histology, 672 incidence, 671 pathogenesis, 672 Microcirculatory dysfunction, skeletal muscle ischemia, 413 – 426 hyperpermeability, mechanisms of signal transduction in, 414 – 415 microvascular dysfunction, mechanisms of, 417– 422 endothelial, vascular wall cells, 417– 418 endothelium-leukocyte interactions, 419– 420 leukocytes, 418 microvascular permeability, 414 – 417 biochemical bases, 414 nitric oxide synthase, 416 – 417 phosphorylation, 415 –416 Microemboli, atherothrombotic, arterioarterial, lower limb, 427– 458 clinical diagnosis, 431 – 432 diagnostic investigations, 432 – 434 during fibrinolytic therapy, 435 – 437 incidence, 427 –428 medical management, 435 sources of microemboli, 428 – 429 surgical management, 434 – 435 Midwestern Vascular Surgical Society, 232 Mikkelsen, W.P., 7 Mimocausalgia, 1123 – 1132 diagnosis, 1126 etiology, 1125 pathophysiology, 1125 – 1130 signs, 1126– 1127 stellate ganglion block technique, 1127– 1128 sympathetic block, assessment of, 1127 sympathetically maintained pain, sympathetically independent pain, 1125– 1126 terminology, 1124– 1125 Minor causalgia, 1124 Mitchell’s causalgia, 1124 Mobin-Uddin, Kazi, 8, 9 Molins, Mahelz, 7 Monitored Atherosclerosis Regression Study, 256 Moniz, Egas, 3, 7
Montefiore experience, endovascular grafts for arterial trauma, 386 results, 386 technique, 386 Montreal Study, 259 Moore, S.W., 4 Morris, George, 8 Mott, Valentine, 2 Multilevel occlusive disease, 444 – 445 Multivitamins and Probucol Trial, 266 Murphy Guillermo, 7 John, 2 MVP Trial (see Multivitamins and Probucol Trial) Mycobacterium, aneurysm infection, 674 Mycotic aneurysms, 670 – 671 histology, 671 incidence, 670 – 671 pathogenesis, 671 Myocardial infarction, 446 Naftidrofuryl, 311 Nalidixic acid, drug interactions, 289 NASCET (see North American Symptomatic Carotid Endarterectomy Trial) Neck root of, vessels of, injuries of, 1076– 1078 vascular injuries in, 1071 –1079 etiology, 1071 mechanisms of injury, 1071 Neointimal hyperplasia, 325 – 340 atherosclerosis, human angioplasty, 330 cellular response to injury, 327 – 328 endothelium, 327 increased response of SMCs to mitogens, 328 inflammation, 328 medial SMC proliferation, 328 platelets, 327 proliferation of SMCs in intima, 328 SMC migration, 328 smooth-muscle cells, 327 – 328 embryology, 325 – 326 extracellular matrix, 329 injury response, 326 – 329 models, 326– 327 mediators, 328– 329 growth factors, 328 hormonal factors, 328 – 329 mechanical factors, 329 patency after endarterectomy, 332 preventive strategies, 332 – 334 ACE inhibitors, 333 drug delivery methods, 334
1281
[Neointimal hyperplasia] heparin, 333 lipid-lowering agents, 333 photodynamic therapy, 333 radiation, 333– 334 prospective agents to inhibit formation of, 332 prosthetic bypass grafts, neointimal hyperplasia in, 331 restenosis after endarterectomy, 331– 332 thrombosis, 329 vein bypass grafts, neointimal hyperplasia in, 330–331 Nephrectomy, for renovascular hypertension, development of procedure, 7 Neuralgia, traumatic, 1124 Neurovascular dystrophy, reflex, 1124 Neurovascular pain syndrome, posttraumatic, 1124 New England Society for Vascular Surgery, 232 Niacin, 64 Nifedipine, 332 Nocturnal penile tumescence monitoring, 880 Nomenclature, 341 – 350 Nonanatomic revascularization of lower extremities, historical developments in treatment of, 4 Noninvasive studies aortoiliac inflow, adequacy of arteriovenous fistula, 119 pseudoaneurysm, 119 vascular pathology of popliteal fossa, 119 cerebrovascular diagnosis, 123 – 167 (see also under specific modality) chronic venous insufficiency, clinical manifestations of, 154 – 155 color-flow duplex imaging, 134 –135 Doppler quantitation, carotid stenosis, 129– 132 Doppler ultrasound, 125 – 127 duplex ultrasonography, 127 – 129 future developments, 142 – 147 historical perspective, 123 – 125 morphology, 139 – 140 natural history, 140 – 142 operative imaging, 138 – 139 pathology, 139 – 140 postoperative imaging, 138 –139 real-time B-mode imaging, 127 varicose veins, clinical classification of, 154 venous diseases diagnosis, 155 – 165 congenital vascular malformation, 165
1282
Index
[Noninvasive studies] duplex imaging, 132 – 138 duplex scanning, 162 – 163 instrumentation color-encoded technology, 114 – 115 duplex technology, 114 – 115 systolic pressure of lower extremity, normal values, 115 transcutaneous Doppler, 113 – 114 noninvasive techniques, 158 – 165 peripheral arterial occlusive disease, diagnosis, 116 – 118 peripheral vascular disease, 113 – 122 aortoiliac inflow, adequacy of, 118– 119 arterial reconstruction, follow-up after, 118 clinical applications, 116 – 121 infrainguinal bypass graft surveillance, 120 instrumentation, 113 –116 mesenteric ischemia, 119 – 120 peripheral arterial occlusive disease, 116– 118 photoelectric plethysmograph, 116 plethysmography, 115 – 116 renovascular hypertension, 119 sexual impotence, 121 vein mapping, for infrainguinal bypass, 120– 121 phlebography, 157 plethysmography, 158 air-filled plethysmograph, 115 strain-gauge plethysmograph, 116 radioisotope techniques, 157 – 158 scanning technique, 163 – 164 ultrasound techniques, 160 – 162 venous outflow obstruction, 158 venous reflux, 158– 160 venous reflux detection, duplex scanning, color flow imaging, 164 venous thrombosis conditions associated with, 154 lower extremities, clinical manifestations, 153 – 154 radiographic signs of, 157 Nonionic monomeric contrast agents, 170 Nonocclusive mesenteric ischemia, 847 North American Chapter of International Society for Cardiovascular Surgery, 231 North American Symptomatic Carotid Endarterectomy Trial, 7, 8 Northway, O., 8 Nottingham Health Profile, 224
Nuclear magnetic resonance spectroscopy, for amputation, 559 Nycomed, as contrast agent, 170 Obesity, as risk factor for atherosclerosis, 67– 68 Obturator foramen bypass grafts, 536 technique, 536 Occlusive mid-aneurysmal disease, 440 Omega-3 fatty acids, 66 atherosclerosis and, 66 OmniCath, 352, 356 –357 Omnipaque, as contrast agent, 170 Operative imaging, 138 – 139 Oral antibiotics, drug interactions, 289 Oral anticoagulants, drug interactions, 289 Oral contraceptives, drug interactions, 289 Organ transplantation, 1173 –1186 kidney transplantation, 1184 – 1185 arteriovenous fistulas, 1184 hemorrhage, 1184 multiple donor renal arteries, 1184 renal artery stenosis, 1184 renal artery thrombosis, 1184 renal vein thrombosis, 1184 short renal artery, 1184 short right donor renal vein, 1184– 1185 suboptimal recipient vessels, 1185 liver transplantation, 1185 anomalous donor hepatic arteries, 1185 arcuate ligament syndrome, 1182 hepatic artery pseudoaneurysms, 1183 hepatic artery stenosis, 1182 – 1183 hepatic artery thrombosis, 1182 inadequate recipient hepatic artery, 1185 infrahepatic caval stenosis, 1183 portal vein stenosis, thrombosis, 1183 portal vein thrombosis, 1185 suprahepatic caval stenosis, 1183 organ procurement, 1173 – 1181 cardiac, lung procurement, 1173– 1174 kidney retrieval, 1177– 1178 kidney transplantation, vascular surgical technique of, 1180 liver retrieval, 1174– 1176 liver transplantation, vascular surgical technique of, 1179 pancreas retrieval, 1177 pancreas transplantation, vascular surgical technique of, 1179 – 1180 reduced liver donation, 1176 – 1177 small bowel transplantation, vascular surgical technique of, 1180 – 1181
[Organ transplantation] small-bowel retrieval, 1178 – 1179 pancreas transplantation, 1185 unsuitability of donor iliac grafts, 1185 vascular complications, 1182 – 1184 kidney transplantation, 1184 liver transplantation, 1182 – 1185 pancreas transplantation, 1183 – 1184 Organic nitrates, 1020 Osteoporosis painful, posttraumatic, 1124 posttraumatic, 1124 O’Toole, James, 7, 8 Oudot, Jacques, 3, 4 Outcomes assessment, 221 – 226 application of, 225 disease, impact of, 221 – 222 disease-specific instruments, 224 – 225 EuroQol, 224 generic outcomes assessment tools, 223– 224 generic quality of life instruments, 224 Medical Outcomes Study, 224 Nottingham Health Profile, 224 patient-based outcomes assessment parameters, 222 – 223 Quality of Well-Being Scale, 224 Sickness Impact Profile, 224 Oxyphenbutazone, drug interactions, 289 Paget-Schroetter syndrome, 898 – 901 Pain syndromes, complex, regional, 1128 complications, 1131 differential diagnosis, 1128 – 1129 sympathectomy, results of, 1130 treatment, 1129– 1130 Painful osteoporosis, 1124 Palma, Eduardo, 5, 8, 9 Palmaz, Julio, 4 Pancreas retrieval, for transplantation, 1177 Pancreas transplantation, 1183 – 1185 for transplantation, vascular surgical technique of, 1179– 1180 unsuitability of donor iliac grafts, 1185 Pancreatic tumors, angiography, 183 Pare, Ambrose, 1 Parkes Weber syndrome, 1169 – 1170 PART (see Probucol Angioplasty Restenosis Trial) Patient selection, for clinical trial, 213 Patient-based outcomes assessment parameters, 222 – 223 Pediatric arterial injuries, iatrogenic, 1102– 1103
Index Penile brachial pressure indices, 878 Penile microvascular surgery, 883 –884 Penile plethysmographic pulse volume recordings, 878 Pentoxifylline, 310 – 311 clinical use, 310 – 311 mechanism, 310 Percutaneous central venous cannulation techniques, 1147– 1153 anatomy, 1147– 1148 approaches, 1148– 1152 complications, 1152– 1153 Percutaneous coaxial dilation, development of procedure, 4 Percutaneous renal artery balloon dilation, development of procedure, 7 Percutaneous transluminal angioplasty, 442 development of procedure, 4 Perforating veins, incompetent endoscopic interruption of, development of procedure, 8 subfascial division, development of procedure, 8 Perioperative evaluation, cardiac risk, 315– 324 arrhythmias, 319 assessment, 316 – 320 conduction disturbances, 319 congestive heart failure, 318 hypertension, 319 – 320 perioperative management, 320 – 321 hemodynamic monitoring, 321 medical management, 320 – 321 surgical procedure, 320 predictors, perioperative cardiovascular risk, 316 valvular heart disease, 319 Perioperative management, cardiac risk, 320– 321 hemodynamic monitoring, 321 medical management, 320 –321 surgical procedure, 320 Peripheral arterial disease, clinical examination, 103 – 104 Peripheral atherectomy, 351 – 362 atherectomy devices, 351 – 359 Simpson AtheroTrak, 351 – 355 Auth Rotablator, 352, 357 – 359 complications, 354 – 355 indications, 351 OmniCath, 352, 356 – 357 Simpson Athero-Cath, 352 TEC, 352 Transluminal Extraction Catheter, 355– 356 complications with, 356
Peripheral vascular disease aortoiliac inflow, adequacy of arteriovenous fistula, 119 pseudoaneurysm, 119 vascular pathology of popliteal fossa, 119 diabetes, 601 – 610 lower extremity arterial disease, 603– 608 pathophysiology, 601 – 602 instrumentation color-encoded technology, 114 –115 duplex technology, 114 – 115 systolic pressure of lower extremity, normal values, 115 transcutaneous Doppler, 113 – 114 lower extremity arterial disease infection, 603– 604 ischemia, 604– 608 neuropathy, 603 noninvasive studies, 113 –122 aortoiliac inflow, adequacy of, 118– 119 arterial reconstruction, follow-up after, 118 clinical applications, 116 – 121 infrainguinal bypass graft surveillance, 120 instrumentation, 113 – 116 mesenteric ischemia, 119 – 120 peripheral arterial occlusive disease, 116– 118 photoelectric plethysmograph, 116 plethysmography, 115 – 116 renovascular hypertension, 119 sexual impotence, 121 vein mapping, for infrainguinal bypass, 120–121 peripheral arterial occlusive disease, diagnosis, 116 –118 plethysmography air-filled plethysmograph, 115 strain-gauge plethysmograph, 116 Peripheral Vascular Surgery Society, 232 Phantom pain, 590 – 591 Phenylbutazone, drug interactions, 289 Phlebography, 157 Photodynamic therapy, 333 Photofixation, graft, 616 Photoplethysmography, for amputation, 559 Physical exam, 111 Physical inactivity atherosclerosis, 67– 68 as risk factor for atherosclerosis, 67 – 68 Pickering, George, 7 Plain films, 678
1283
Plaque evolution, 236, 717 – 719 (see also Atherosclerosis) Plaque rupture, 16 Platelet antiaggregant drugs, clinical trials of, 705– 706 Platelet function, 303 – 304 arterial wall, interaction with, 304 coagulation cascade, interaction with, 303– 304 Platelet function inhibitors, 290 aspirin, 290 clopidogrel, 290 glycoprotein IIb/IIIa inhibitors, 290 ticlopidine, 290 Platelet in atherosclerosis, 25 – 26 platelet-derived growth factor, 25 Platelet-derived growth factor, 25 Platelet-suppressant therapy, 704 – 705 Plethysmograph air-filled, 115 strain-gauge, 116 Plethysmography, 158 impedance, deep vein thrombosis, 965– 966 Plication, inferior vena cava, 1198 – 1201 Pneumococcus, aneurysm infection, 674 Polyester grafts, 614 Polymers, new, 616 Polytetrafluoroethylene expanded, 614– 615 extruded grafts, introduction of, 5 Pooling Project, 58 Popliteal adventitial cystic disease, 513– 516 clinical presentation, 515 etiology, 514 history, 513– 514 incidence, 514 laboratory evaluation, 515 pathophysiology, 514 – 515 treatment, 515– 516 Popliteal aneurysm, 653 – 657 asymptomatic aneurysms, 654 – 655 clinical features, 653 diagnosis, 653–654 epidemiology, 653 excision, development of procedure, 6 historical developments in treatment of, 6 management, 654 – 656 results, 656 surgery, 655– 656 symptomatic aneurysms, 654 thrombolytic therapy, 655 Popliteal atherosclerosis, medical management, 251
1284
Index
Popliteal entrapment, 516 – 523 classification, 517– 518 clinical evaluation, 519 – 520 clinical examination, 105 diagnosis, 520 history, 516– 517 pathophysiology, 518 – 519 prevalence, 518 results, 520 treatment, 520 Popliteal fossa, vascular pathology, noninvasive studies, 119 Popliteal injury, 1090– 1091 Popliteal occlusive disease, historical developments in treatment of, 5 Portal hypertension, 1015 – 1035 acute variceal bleeding, balloon tamponade in, 1022 ascites, 1017 bleeding esophageal varices, management of, 1019 cirrhotics with portal hypertension, aortic surgery, 1030– 1031 diagnostic workup, 1018 encephalopathy, 1017 endoscopic variceal sclerosis, 1020 endoscopy, 1018 esophageal varices, 1016 – 1017 extrahepatic presinusoidal, 1015 – 1016 hemodynamics, distal splenorenal shunt, 1023– 1024 indications, 1022– 1023 injection schedule, long-term prevention of rebleeding, 1021 intrahepatic presinusoidal, 1015 laboratory testing, 1018 liver biopsy, 1019 liver transplantation in, 1027 long-term injection sclerotherapy, results of, 1021 medical treatment, 1019 –1020 beta-adrenergic blockers, 1020 organic nitrates, 1020 vasopressin analogue, 1020 nonshunt surgical procedures, 1025– 1026 combined esophageal transection, devascularization, 1026 esophageal, gastric transection, 1025– 1026 gastroesophageal devascularization, 1025 pathogenesis, 1015 pathophysiology of, 1016 patient monitoring, 1019 portal vein occlusion, 1028 posthepatic, 1028
[Portal hypertension] postsinusoidal, 1016 prophylactic sclerotherapy, 1021 – 1022 radiographic studies, 1018 –1019 results, 1021, 1024– 1025 schistosomiasis, portal hypertension, 1027– 1028 selective portosystemic shunts, 1023 shunt procedures, types of, 1023 shunting procedures for, 1022 sinusoidal, 1016 splenic vein thrombosis, 1028 – 1029 technical aspects, 1020– 1021 technique, 1024 total portosystemic shunts, 1023 transhepatic variceal sclerosis, 1022 transjugular intrahepatic portosystemic shunt, 1026– 1027 variceal banding, 1021 variceal injection sclerotherapy, banding, complications of, 1021 varices in unusual locations, 1030 Portal vein occlusion, 1028 Portal vein stenosis, thrombosis, 1183 Portal venography, 177 Portal venous access, hepatic venography, 182 Portosystemic shunts selective, 1023 total, 1023 POSCH (see Program on Surgical Control of Hyperlipidemias) Post Coronary Artery Bypass Graft Trial, 260 Post-carotid endarterectomy, recurrent stenosis, 719– 722 Posthepatic portal hypertension, 1028 Postoperative imaging, 138 – 139 Postsinusoidal portal hypertension, 1016 Posttraumatic pain syndromes, 1123 – 1132 complications, 1131 diagnosis, 1126 differential diagnosis, 1128 – 1129 etiology, 1125 pathophysiology, 1125 – 1130 signs, 1126– 1127 stellate ganglion block technique, 1127– 1128 sympathectomy, results of, 1130 sympathetic block, assessment of, 1127 sympathetically maintained pain, sympathetically independent pain, 1125– 1126 terminology, 1124– 1125 terms describing, 1124 treatment, 1129– 1130 Potential energy, in hemodynamics, 81 – 82
Power bar on computer, 232 – 233 Pravastatin, 64 Praxilene (see Naftidrofuryl) Predictors, perioperative cardiovascular risk, 316 Predinisolone, 332 Presentation of results, clinical trial, 215– 216 Presinusoidal portal hypertension extrahepatic, 1015– 1016 intrahepatic, 1015 Pressure, hemodynamic, 91 – 93 Probucol Angioplasty Restenosis Trial, 266 Procurement, of lung for transplantation, 1173– 1174 Profunda femoris artery, injury, 1089– 1090 Profundoplasty, 545 – 553 anatomy, 545 angiographic techniques, 547 distribution of disease, 546 – 547 indications for, 547 – 549 to lower amputation level, 553 operative technique, 549 – 551 results, 551– 552 Program on Surgical Control of Hyperlipidemias, 260 Prophylactic sclerotherapy, 1021 – 1022 Prostaglandins, 311 Prosthesis, 579 articulated foot-ankle assembly, 583 components, 580 – 584 dynamic response, energy-storing feet, 580– 583 fitting, 568 foot-ankle assembly, 580 transfemoral, 584 –587 transtibial amputee, suspension variations, 585 mechanical suspension, 585 suction suspension, 584 transtibial prosthetic sockets, 584 Prosthetic graft infection, 621– 629 aortic, aortoiliac bypass grafts, 624– 625 aortobifemoral bypass grafts, 625– 626 diagnosis, 623 endoscopy, 624 imaging studies, 623 – 624 incidence, 621 laboratory studies, 623 management, 624 microbiology, 622 – 623 pathogenesis, 621 – 622
Index [Prosthetic graft] peripheral bypass graft infections, 626 physical examination, 623 neointimal hyperplasia in, 331 Prosthetic knee, 588 – 590 Prosthetic materials for vascular conduits, 611– 619 arterial, venous xenografts, 613 –614 arterial allografts, 612 biological grafts, 612 current recommendations, 615 endothelial cell seeding, 615 – 616 expanded polytetrafluoroethylene, 614– 615 graft thromboreactivity, 611 –612 human umbilical cord vein allograft, 613 impregnated grafts, 616 new polymers, 616 photofixation techniques, 616 polyester grafts, 614 synthetic grafts, 614 venous allografts, 612 – 613 Protein C, 277– 278 methods of testing, 278 resistance, activated, 281 – 282 Protein S deficiency, 278 Proteus, aneurysm infection, 674 Pseudoaneurysm aortoiliac inflow, adequacy of, 119 endograft exclusion, development of procedure, 4 iatrogenic, 1096 noninvasive studies, 119 venous, infected, from intravenous drug injection, 1109– 1110 Pseudomonas, aneurysm infection, 674 PTFE grafts (see Polytetrafluoroethylene grafts) Pulmonary angiography, 175 – 177 Pulmonary embolism, prophylactic prevention of, development of procedures, 8 Pulmonary hilum, penetrating wounds of, 1053– 1054 Pulmonary hypertension, angiothrombotic, from intravenous drug injection, 1110– 1111 Pulmonary thromboembolism, 970 – 975 arterial blood gases, 971 central venous pressure, 971 chest radiography, 971 diagnosis, 970 – 972 electrocardiography, 971 lung scan, 971– 972 management, 973 – 974 overview, 970
[Pulmonary thromboembolism] pathophysiology, 972 – 973 pulmonary arteriography, 972 pulmonary embolectomy, 974 – 975 Pulses examination of, 106 – 107 hemodynamics of, 91 – 93 Quality of life instruments, generic, 224 Quality of Well-Being Scale, 224 Quinidine, drug interactions, 289 Racial predisposition, atherosclerosis, 55–56 Radial artery, injury, 1089 Radioactive-labeled fibrinogen, deep vein thrombosis, 966 Radioisotope techniques, venous disease diagnosis, 157 –158 Radiologic studies, infected aneurysms arteriography, 679 computed tomography, 678 – 679 Randomization, clinical trial, 214 Ray amputation of toe, 561 Raynaud’s syndrome, 106, 903 – 914 associated diseases, 906 – 907 clinical evaluation, 908 – 909 angiography, 909 laboratory evaluation, 909 noninvasive vascular laboratory evaluation, 908 diseases associated with, 904 epidemiology, 905 – 906 pathophysiology, 903 – 905 patient presentation, 907 – 908 results of treatment, 912 treatment, 909 –911 digital gangrene, 909 – 910 surgical therapy, 911 vasospasm, 909 Real-time B-mode imaging, 127 Reflex dystrophy, 1124 clinical examination, 105 – 106 of extremities, 1124 Rehabilitation, vascular amputee, 575 –594 amputation levels, 576 amputation prevention, 592 computer-aided design-computerassisted manufacturing, 579 – 580 energy consumption during gait, amputees, 591 – 592 exoskeletal versus endoskeletal, 579 follow-up care, 598 incidence, 575 – 576 phantom pain, 590 – 591 postoperative management, 577 – 578 preprosthetic phase of management, 578
1285
[Rehabilitation, vascular amputee] prognosis, 576 prosthetic components, 580 – 584 articulated foot-ankle assembly, 583 dynamic response, energy-storing feet, 580– 583 foot-ankle assembly, 580 transtibial prosthetic sockets, 584 prosthetic knees, 588 – 590 prosthetic phase of management, 578– 579 prosthetic prescription, 579, 592 – 593 transfemoral amputee, 593 transtibial amputee, 592 – 593 suspension variations transfemoral amputees, 588 transtibial amputee, 585 transfemoral amputees mechanical, 588 suction, 588 transfemoral prosthesis, 584 – 587 transtibial amputee mechanical suspension, 585 suction suspension, 584 treatment, 592 Remote ischemic vascular complications, with aortoiliofemoral occlusive disease, 449– 450 Renal arteriography, 188 – 191, 825– 826 Renal artery atherosclerosis, medical management, 251 Renal artery disease, historical developments in treatment of, 7 Renal artery endarterectomy, development of procedure, 7 Renal artery occlusion historical developments in treatment of, 6 secondary hypertension, establishment of importance of, 7 Renal duplex sonography, 825 Renal tumors, 637 Renal vein renin assays, 826 Renografin-60, as contrast agent, 170 Renografin-76, as contrast agent, 170 Renovascular disease, 823 – 837 diagnostic evaluation, 825 – 826 functional studies, 826 renal arteriography, 825 – 826 renal duplex sonography, 825 renal vein renin assays, 826 screening studies, 825 split renal function studies, 826 hypertension aortorenal bypass, 831 characteristics of, 824 – 825 effect of operation on, 832
1286
Index
[Renovascular disease] medical therapy, 826 – 827 nephrectomy, 831 –832 nephrectomy for, development of procedure, 7 operative techniques, 828 – 832 percutaneous transluminal dilation, 828 postoperative care, 832 preoperative preparation, 828 therapeutic options, 826 – 827 thromboendarterectomy, 831 treatment of, 826 – 832 pathophysiology of, 824 prevalence of, 823 –824 Restenosis, 325 – 340 after endarterectomy, 331 – 332 atherosclerosis, human angioplasty, 330 cellular response to injury, 327 – 328 endothelium, 327 increased response of SMCs to mitogens, 328 inflammation, 328 medial SMC proliferation, 328 platelets, 327 proliferation of SMCs in intima, 328 SMC migration, 328 smooth-muscle cells, 327 –328 embryology, 325 – 326 extracellular matrix, 329 injury response, 326 –329 models, 326– 327 mediators, 328– 329 growth factors, 328 hormonal factors, 328 – 329 mechanical factors, 329 patency after endarterectomy, 332 preventive strategies, 332 – 334 ACE inhibitors, 333 drug delivery methods, 334 heparin, 333 lipid-lowering agents, 333 photodynamic therapy, 333 radiation, 333– 334 prospective agents to inhibit formation of, 332 prosthetic bypass grafts, neointimal hyperplasia in, 331 thrombosis, 329 vein bypass grafts, neointimal hyperplasia in, 330– 331 Results of clinical trial, presentation of, 215– 216 Revascularization, complications of, 409 Reversed autogenous saphenous vein femoral popliteal bypass, development of procedure, 5
Risk factors, atherosclerosis, 56 – 70 age, 56– 57 alcohol consumption, incidence of coronary heart disease, 63 antioxidant vitamins, 68 – 69 behavior patterns, 68 diabetes mellitus, 66 – 67 fish consumption, 66 hyperhomocystinemia, 68 hyperlipidemia, 61 – 66 hypertension, 57 – 58 lipoprotein cholesterol levels according to alcohol consumption, 63 alcohol consumption and, 63 male sex, 57 obesity, 67 – 68 omega-3 fatty acids, 66 physical inactivity, 67 – 68 smoking, 58 – 61 stress, 68 thrombosis, 69 – 70 Roadmapping, digital fluoroscopy, 396 Rob, Charles, 7 Roentgen, Wilhelm, 2 Root of neck, vessels of, injuries of, 1076– 1078 operative management, 1077 – 1078 Running, metabolic equivalent level for, 317 Ruptured aortic aneurysm, 637 – 638 Salicylates, drug interactions, 289 Salmonella infection, 674, 675 Saphenofemoral vein crossover bypass, development of procedure, 8 ligation, development of procedure, 8 Saphenopopliteal vein, bypass, development of procedure, 8 Saphenous vein arterial bypass, in situ, 485– 494 arteriovenous fistulas, 491– 492 history of, 485 preoperative saphenous vein anatomy, 485– 486 results, 494 surgical technique, 486 –489 technical requirements, 489 – 491 venous spasm, 491 Saphenous vein ligation, stripping, 1202– 1203 Savage, Lester, 4 Scalene muscle, 890 abnormalities, 891 – 892 Scanning technique, for venous disease diagnosis, 163 – 164
Schistosomiasis, portal hypertension, 1027– 1028 SCRIP (see Stanford Coronary Risk Intervention Project) Searching for medical date on computer, 231– 234 Septic thrombophlebitis, from intravenous drug injection, 1108– 1109 Sexual function with aortoiliofemoral occlusive disease, 449 impotence noninvasive laboratory testing for, 878 operations specifically for, 882– 883 vascular surgery and, 877 – 888 aortoiliac aneurysm repair, 881 – 882 aortoiliac occlusive disease, operations for, 880 – 881 cavernosometry, cavernosal artery occlusion pressure, 880 duplex Doppler scanning, 879 erection, physiology of, 877 internal iliac endarterectomy, 882– 883 intracavernous injection, 879 medical treatment, 885 nocturnal penile, tumescence monitoring, 880 penile microvascular surgery, 883– 884 physical examination, 878 vascular operations, 880 – 882 vascular testing, 878 – 879 vasculogenic impotence, classification of, 878 venous interruption procedures, 884– 885 vascular testing neurologic testing, 879 penile brachial pressure indices, 878 penile plethysmographic pulse volume recordings, 878 Shaw, R.S., 7 Shear, effect on arterial wall, 97 Sheaths, 343 Short-term vascular access, 1147 – 1153 Shoulder-hand syndrome, 1124 Steinerocher’s, 1124 Sickness Impact Profile, 224 Sigmoid colon ischemia, with aortoiliofemoral occlusive disease, 449 Simpson AtheroTrak, 351 – 355 Simvastatin, 64 Sinusoidal portal hypertension, 1016
Index Skeletal muscle ischemia, microcirculatory dysfunction, 413 – 426 hyperpermeability, mechanisms of signal transduction in, 414 – 415 microvascular dysfunction, mechanisms of, 417– 422 endothelial, vascular wall cells, 417– 418 endothelium-leukocyte interactions, 419– 420 leukocytes, 418 microvascular permeability, 414 – 417 biochemical bases, 414 nitric oxide synthase, 416 – 417 Skin examination of, 108 – 109 perfusion pressures, for amputation, 559 temperature measurement, for amputation, 559 Small artery occlusive disease, upper extremity, 903 – 914 Small bowel retrieval, for transplantation, 1178– 1179 Small bowel transplantation, for transplantation, vascular surgical technique of, 1180– 1181 Smoking, as risk factor for disease, 58– 61, 240 Smooth muscle, in atherosclerosis, 22 –24 lipid metabolism, 23 – 24 smooth-muscle proliferation, 22 – 23 Society for Clinical Vascular Surgery, 232 Southern Association for Vascular Surgery, 232 Splanchnic artery aneurysms, 659 – 667 celiac artery aneurysms, 665 gastric, gastroepiploic aneurysms, 665– 666 gastroduodenal, pancreaticoduodenal aneurysms, 665 hepatic artery aneurysm, 661 – 662 clinical presentation, 661 investigations, 661 – 662 operations, 662 intestinal branch artery aneurysms, 666 splenic artery aneurysms, 659 – 661 clinical presentation, 660 – 661 superior mesenteric artery aneurysms, 662– 665 clinical presentation, 662 – 663 operations, 663 – 665 Splanchnic artery disease, historical developments in treatment of, 6–7 Splenic artery aneurysms, 659 – 661 clinical presentation, 660 – 661
Splenic vein thrombosis, 1028 – 1029 Split renal function studies, 826 Spontaneous dissection, carotid artery, 783– 793 Spreading neuralgia, posttraumatic, 1124 Spreadsheets on computer, 229 St. Thomas’ Atherosclerosis Regression Study, 254 Stabilization, in humans, 251 – 261 Stairs, climbing, metabolic equivalent level for, 317 Stanford Coronary Risk Intervention Project, 254 Staphylococcus, aneurysm infection, 674 Staphylokinase, 299 STARS (see St. Thomas’ Atherosclerosis Regression Study) Stasis dermatitis, dermal fibrosis, pathophysiology of, 941 – 944 Statistical design, clinical trial, 214 – 215 Stellate ganglion block technique, 1127– 1128 Stenosis asymptomatic, efficacy of carotid endarterectomy, clinical trials on, 757– 758 symptomatic, efficacy of carotid endarterectomy, clinical trials, 756 – 757 Stents, 344– 345, 1007– 1011 axillo-subclavian venous stenosis, 1008 background, 1007 Budd-Chiari syndrome, 1010 – 1011 iliac vein stents, 1007 –1008 superior vena cava syndrome, 1010 venous stenosis in hemodialysis patients, 1008– 1010 Strain-gauge plethysmograph, 116 Streptococcus, aneurysm infection, 674 Streptokinase, 298 Stress, as risk factor for atherosclerosis, 68 Stripping, saphenous vein, 1202 – 1203 Stroke, 446 completed, 699 – 700 Progressing, 699 Subclavian artery, injury, 1088 Subclavian vein thrombosis, 970 Subclavian vessels, penetrating wounds of, 1053 Subclavian-carotid artery bypass, development of procedure, 8 Subcutaneous arteriovenous fistulas, 1153– 1155 Subtraction, digital fluoroscopy, 395 – 396 Sudeck’s atrophy, 1124 Sudeck’s osteodystrophy, 1124 Sudeck’s syndrome, 1124 Sulfonamides, drug interactions, 289
1287
Superficial femoral artery injury, 1090 stenosis, 47 Superficial vein thrombosis clinical examination, 110 “puffy hand,” from intravenous drug injection, 1108 Superior mesenteric artery aneurysms, 662 –665 clinical presentation, 662 – 663 operations, 663 – 665 embolectomy, development of procedure, 7 infected aneurysm, 682 thrombosis, acute, 847 – 849 Superior mesenteric venous thrombosis, acute, 849– 851 Superior vena cava syndrome, 1010 venography, 201 – 202 Suprahepatic caval stenosis, 1183 Surgical techniques, 1187 – 1259 aortic aneurysm repair, 1210 –1227 aortofemoral bypass, for occlusive disease, 1228– 1239 arterial dissection, 1188 –1189 arterial incision, 1188– 1189 suture closure of arteriotomy, 1188– 1189 artery, lacerated, repair of, 1194 axillofemoral bypass, 1250 –1255 carotid endarterectomy, 1204 – 1209 end-to-end vascular anastomosis, 1190– 1191 end-to-side vascular anastomosis, 1192– 1193 femoral artery, lacerated, repair of, 1196– 1197 femorofemoral bypass, 1256 – 1259 femoropopliteal bypass, 1240 – 1249 inferior vena cava lacerated, repair of, 1194– 1195 plication, 1198 –1201 saphenous vein ligation, stripping, 1202– 1203 vascular injury, types of, 1194 vein, lacerated, repair of, 1194 Sushruta, contribution of, 1 Swimming, metabolic equivalent level for, 317 Syme amputation, ankle, 561 – 562 Sympathalgia, 1124 posttraumatic, 1124 Sympathectomy, 95 lumbar, 595– 599 chemical sympathectomy, 598 complications, 598
1288
Index
[Sympathectomy] effects of, 595 operative technique, 596 – 598 patient selection, 595 –596 results of, 1130 Sympathetic dysfunction, posttraumatic, 1124 Sympathetic dystrophy neurovascular, 1124 posttraumatic, 1124 Sympathetically maintained pain, vs. sympathetically independent pain, 1125– 1126 Symptomatic extracranial vascular disease, 695– 710 anticoagulant therapy, 700 – 701 antithrombotic therapy, evaluation of, 700– 706 completed, 699 – 700 platelet antiaggregant drugs, clinical trials of, 705– 706 platelet-suppressant therapy, 704 – 705 progressing stroke, 699 thrombolytic therapy, 701 –704 transient ischemic attacks, 695 – 699 atheromatous material, 698 hemodynamic pathogenesis, 698 – 699 natural history, 699 platelet-fibrin emboli, 698 thromboembolic pathogenesis, 698 Synthetic grafts, 614 development of, 6, 8 Systolic pressure, lower extremity, normal values, 115 Taheri, S.A., 8 Takayasu’s arteritis, 915– 917 Temporal arteritis, 917 – 919 Tennis, metabolic equivalent level for, 317 Therapeutic regimens, clinical trial, 213– 214 Thienopyridines, 306 Thoracic aorta descending, blunt rupture of, 1057 – 1058 to femoral artery bypass, 534 – 536 Thoracic aortic aneurysm, homograft replacement, development of procedure, 6 Thoracic aortography, 171 – 172 Thoracic outlet, vascular injuries in, 1071– 1079 Thoracic outlet maneuvers, clinical exam, 109 Thoracic outlet syndrome, 882 – 902 anatomy, 890– 892 normal anatomy, 890 – 891
[Thoracic outlet syndrome] scalene muscle abnormalities, 891– 892 angiography, 896 cervical rib, 889 clinical examination, 105 clinical presentation, 892 – 894 first thoracic rib, 890 medical therapy, 896 –897 noninvasive laboratory evaluation, 894 electrophysiologic blocks, 894 electrophysiologic tests, 894 somatosensory evoked response, 894 vascular tests, 894 physical examination, 895 – 896 scalene muscle, 890 surgical therapy, 897 – 902 combined operations, 898 first rib resection, 898 Paget-Schroetter syndrome, 898 – 901 scalenectomy, 898 venography, 896 Thoracic vascular trauma blunt, 1054– 1058 descending thoracic aorta, blunt rupture of, 1057–1058 diagnosis, 1054– 1056 endovascular stents, for repair of great vessels, 1056 innominate artery, blunt rupture, 1057 nonoperative, delayed operative management, 1056 operative management, 1057 penetrating, 1049– 1054 diagnosis, 1049– 1050 emergency department management, 1051 innominate vessels, penetrating wounds of, 1052 intrathoracic left common carotid artery, penetrating wounds of, 1052– 1053 nonoperative management, 1052 operative management, 1052 pathophysiology, 1049 pulmonary hilum, penetrating wounds of, 1053– 1054 subclavian vessels, penetrating wounds of, 1053 Thoracoabdominal aneurysms, intraluminal graft repair, development of procedure, 6 Thoracoabdominal aortic aneurysms, 641– 651 comorbid conditions, 642 complications, postoperative, 642 – 693 diagnosis, 643– 644
[Thoracoabdominal aortic aneurysms] etiology, 641– 642 natural history, 642 – 643 operative treatment, 645 – 648 postoperative care, 649 preoperative evaluation, 644 – 645 results, 649– 650 survival rate, 642 Thrombin inhibitors, direct, 289 – 290 Thromboangiitis obliterans, 919 – 921 Thromboembolectomy, fluoroscopically assisted, 399– 400 Thromboembolism, pulmonary, 970 – 975 Thrombolytic agents, 297 – 302, 701– 704 clinical application, 299 – 301 acute peripheral arterial occlusion, results of thrombolysis in, 300 –301 arterial thrombolysis, 299 – 300 contraindications to, 301 Desmodus rotundus, plasminogen activator, 299 fibrinolysis, 297 – 298 fibrolase, 299 staphylokinase, 299 streptokinase, 298 thrombolytic agents, 298 – 299 Desmodus rotundus, plasminogen activator, 299 fibrolase, 299 staphylokinase, 299 streptokinase, 298 tissue plasminogen activator, 299 urokinase, 298–299 tissue plasminogen activator, 299 urokinase, 298– 299 Thrombophlebitis, septic, from intravenous drug injection, 1108– 1109 Thrombophlebitis migrans, 970 Thrombosed aortic bifurcation, homograft replacement of, development of procedure, 3 Thrombosis, 69 – 70 from arteriovenous fistulas, 1156– 1158 clinical examination, 110 – 111 deep vein thrombosis, 110 – 114 superficial vein thrombosis, 110 deep vein, 929– 935, 963– 978 abdominal vein thrombosis, 970 anticoagulation, 967 arterial blood gases, 971 central venous pressure, 971 changes in vessel wall, 930 chest radiography, 971 chronic, pulmonary hypertension, 975 clinical resolution of thrombosis, 932 diagnosis, 965 – 966, 970– 972 effect of treatment, 932 – 933
Index [Thrombosis] electrocardiography, 971 fibrin, assay of, 966 fibrinolysis, 967 – 968 future therapeutic possibilities, 933 historical perspective, 963 history, 929 hypercoagulability of blood, 930 impedance plethysmography, 965– 966 lung scan, 971– 972 management, 973 – 974 monocyte in thrombus resolution, 931 operative thrombectomy, 968 organization, natural lysis, 930 – 931 overview, 970 pathogenesis, 929 – 930 pathophysiology, 963 – 964, 972– 973 postthrombotic limb, 932 prophylaxis, 966 – 967 pulmonary arteriography, 972 pulmonary embolectomy, 974 – 975 pulmonary thromboembolism, 970– 975 radioactive-labeled fibrinogen, 966 recanalization, 931 stasis, 930 subclavian vein thrombosis, 970 surgical approaches, 968 – 969 thrombophlebitis migrans, 970 thrombus resolution, 930 – 931 treatment, 967 – 969 ultrasound, 965 vena cava interruption, 968 – 969 venography, 966 physical exam, 111 Thrombotic occlusions, iatrogenic, 1097 Through-knee amputation, 565 – 566 Tibial arterial occlusive disease, historical developments in treatment of, 5 Ticlopidine, 290 Tissue plasminogen activator, 277, 299 Tobacco smoking (see Smoking) Toe, amputation of, 560 – 561 ray amputation of toe, 561 transphalangeal level, 560 Tolbutamides, drug interactions, 289 Total fluid energy, in hemodynamics, 82– 84 Total portosystemic shunts, 1023 TPA (see Tissue plasminogen activator) Transfemoral amputee, 593 Transhepatic variceal sclerosis, 1022 Transhepatic venous access, 182 Transient ischemic attacks, 695 – 699 atheromatous material, 698 hemodynamic pathogenesis, 698 –699
[Transient ischemic attacks] natural history, 699 platelet-fibrin emboli, 698 thromboembolic pathogenesis, 698 Transjugular intrahepatic portal catheterization, 177– 179 Transjugular intrahepatic portosystemic shunt, 1026– 1027 Translumbar aortography, development of procedure, 3 Transluminal extraction catheter, 355 –356 complications associated with, 356 Transmetatarsal amputation of forefoot, 561 Transplantation, 1173– 1186 kidney transplantation, 1184 – 1185 hemorrhage, 1184 multiple donor renal arteries, 1184 renal artery stenosis, 1184 renal artery thrombosis, 1184 renal vein thrombosis, 1184 short renal artery, 1184 short right donor renal vein, 1184– 1185 suboptimal recipient vessels, 1185 liver transplantation, 1185 anomalous donor hepatic arteries, 1185 arcuate ligament syndrome, 1182 hepatic artery pseudoaneurysms, 1183 hepatic artery stenosis, 1182 – 1183 hepatic artery thrombosis, 1182 inadequate recipient hepatic artery, 1185 infrahepatic caval stenosis, 1183 portal vein stenosis, thrombosis, 1183 portal vein thrombosis, 1185 suprahepatic caval stenosis, 1183 organ procurement, 1173– 1181 cardiac, lung procurement, 1173– 1174 kidney retrieval, 1177– 1178 kidney transplantation, vascular surgical technique of, 1180 liver retrieval, 1174– 1176 liver transplantation, vascular surgical technique of, 1179 pancreas retrieval, 1177 pancreas transplantation, vascular surgical technique of, 1179 – 1180 reduced liver donation, 1176 – 1177 small bowel transplantation, vascular surgical technique of, 1180 – 1181 small-bowel retrieval, 1178 – 1179 pancreas transplantation, 1185 unsuitability of donor iliac grafts, 1185
1289
[Transplantation] vascular complications, 1182 – 1184 kidney transplantation, 1184 liver transplantation, 1182 – 1185 pancreas transplantation, 1183 – 1184 Transtibial amputee, 592 – 593 Trapidil, 332 Trash foot, with aortoiliofemoral occlusive disease, 449– 450 Trauma, angiography, 182 – 183 Traumatic arterial disruptions, endograft exclusion, development of procedure, 4 Triglyceride-rich lipoproteins, for atherosclerosis, 261 – 266 Tumor of carotid body, 811 – 821 clinical presentation, 812 – 813 complications, 817 – 819 diagnostic considerations, 813 – 814 pathophysiology, 812 prognosis, 817 surgical technique, 816 – 817 therapeutic considerations, 814 –816 Tumor of lymphatics, benign, 1040 Tumors, angiography, 183 – 185 alimentary tract tumors, 183 – 185 hepatic tumors, 185 pancreatic tumors, 183 Type II Coronary Intervention Study, 252 Ulceration, chronic venous insufficiency, 989 Ulcerative lesions, carotid artery, 729 – 736 angiography, 732 – 733 classification, 731– 732 definitions, 730 historical development, 729 – 730 medical management, 733 natural history, 732 noninvasive testing, 733 pathophysiology, 730 – 731 presentation, 731 stroke rate, by symptom, lesion, 732 surgical management, 733 – 735 Ulnar artery, injury, 1089 Ultrasound techniques, venous disease diagnosis, 160– 162 Unfractionated heparin, 287 Unilateral limb occlusion, with aortoiliofemoral occlusive disease, 448 University of California, San Francisco, Specialized Center of Research, Intervention Trial, 254 Upper extremity arterial injuries, 1088– 1089 Upper extremity arteriography, 200 – 201
1290
Index
Upper extremity compartment syndrome, 1140– 1141 Upper extremity ischemia, 411 Upper extremity small artery occlusive disease, 903– 914 Upper extremity venography, 201 – 202 Ureteric obstruction, with aortoiliofemoral occlusive disease, 449 Urokinase, 298 – 299 Valvular heart disease, perioperative cardiovascular risk, 319 Valvuloplasty, development of procedure, 8 Vanguard Endovascular Aortic Graft, 366 Vapiprost, 332 Variceal banding, 1021 Variceal injection sclerotherapy, banding, 1021 Varices in unusual locations, 1030 Varicose veins, 949 – 962 ankle-to-groin stripping, 955 – 956 clinical classification of, 154 clinical examination, 110 duplex-guided sclerotherapy, 959 etiology, 952 intervention, indications for, 952 intrinsic factors, 950 – 951 ligation, versus stripping, 954 physical exam, 111 physical forces, 951 – 952 prospective studies, 954 – 955 recurrent varicosities, 955 removal of, development of procedures, 8 risk factors, 949– 950 saphenous ablation, 958 saphenous ligation, 955 sclerotherapy, 958 – 959 testing before intervention, 952 – 954 varicose clusters, excision of, 956 varicose vein surgery, 956 – 958 Vascular access neuropathy, from arteriovenous fistulas, 1159 Vascular access surgery, 1145 –1160 arteriovenous fistulas, physiology of, 1145– 1147 complications, arteriovenous fistulas, 1156– 1159 aneurysms, 1159 congestive heart failure, 1158 infection, 1158 thrombosis, 1156– 1158 vascular access neuropathy, 1159 vascular insufficiency, 1158 venous hypertension, 1158 – 1159 long-term vascular access, 1153 – 1156
[Vascular access surgery] bridge fistulas, 1155– 1156 subcutaneous arteriovenous fistulas, 1153– 1155 percutaneous central venous cannulation techniques, 1147– 1153 anatomy, 1147– 1148 approaches, 1148 –1152 complications, 1152– 1153 short-term vascular access, 1147 – 1153 Vascular amputee, rehabilitation, 575 – 594 amputation levels, 576 amputation prevention, 592 computer-aided design-computerassisted manufacturing, 579 – 580 energy consumption during gait, amputees, 591– 592 exoskeletal versus endoskeletal, 579 follow-up care, 598 incidence, 575 –576 phantom pain, 590 – 591 postoperative management, 577 – 578 preprosthetic phase of management, 578 prognosis, 576 prosthetic components, 580 – 584 articulated foot-ankle assembly, 583 dynamic response, energy-storing feet, 580– 583 foot-ankle assembly, 580 transtibial prosthetic sockets, 584 prosthetic knees, 588 – 590 prosthetic phase of management, 578– 579 prosthetic prescription, 579, 592 – 593 transfemoral amputee, 593 transtibial amputee, 592 – 593 suspension variations for transfemoral amputees, 588 transtibial amputee, 585 transfemoral amputees mechanical, 588 suction, 588 transfemoral prosthesis, 584 – 587 transtibial amputee mechanical suspension, 585 suction suspension, 584 treatment, 592 Vascular anastomosis end-to-end, 1190– 1191 end-to-side, 1192– 1193 Vascular anomalies, 1161 – 1171 arterial malformations diagnostic evaluation, 1168 differential diagnosis, 1168 natural history, 1168 options for treatment, 1168 – 1169
[Vascular anomalies] outcome of management, 1169 signs, symptoms, 1168 capillary malformations diagnostic evaluation, 1165 differential diagnosis, 1165 natural history, 1165 options for treatment, 1165 signs, symptoms, 1165 hemangiomas, 1163– 1164 clinical characteristics, 1163 corticosteroids, 1163 cryotherapy, 1164 diagnosis, 1163 embolization, 1164 excision, 1164 interferon-alpha, 1163 – 1164 laser therapy, 1164 ligation of feeder vessels, 1164 radiation therapy, 1164 treatment, 1163– 1164 Klippel-Trenaunay syndrome, 1169– 1170 lymphatic malformations, treatment, 1165– 1166 malformations, 1164– 1165 arterial malformations, 1167 – 1169 capillary malformations, 1165 complex-combined malformations, 1169 lymphatic malformations, 1165 – 1166 venous malformations, 1166 – 1167 venous malformations diagnostic evaluation, 1166 differential diagnosis, 1166 –1167 natural history, 1167 options for treatment, 1167 outcome of management, 1167 signs, symptoms, 1166 Vascular complications from drug abuse, 1107– 1121 arterial infections, 1113 – 1115 arterial injury, extremity gangrene, 1111– 1113 barbiturate crystallization, 1112 chemical endarteritis, 1111 – 1112 particulate embolization, 1112 pathophysiology, 1111 – 1113 vasoconstriction, 1111 cocaine abuse, vascular complications related to, 1113 ergot derivatives, pharmacologic properties of, 1115 intravenous drug injection, 1108 –1111 angiothrombotic pulmonary hypertension, 1110– 1111 deep venous thrombosis, 1108
Index [Vascular complications from drug abuse] infected venous pseudoaneurysms, 1109– 1110 septic thrombophlebitis, 1108 – 1109 superficial venous thrombosis, “puffy hand,” 1108 management, 1113 vasculitis, related to drug abuse, 1115 Vascular conduits, prosthetic materials for, 611– 619 arterial, venous xenografts, 613 –614 arterial allografts, 612 biological grafts, 612 current recommendations, 615 endothelial cell seeding, 615 – 616 expanded polytetrafluoroethylene, 614– 615 graft thromboreactivity, 611 –612 human umbilical cord vein allograft, 613 impregnated grafts, 616 new polymers, 616 photofixation techniques, 616 polyester grafts, 614 synthetic grafts, 614 venous allografts, 612 – 613 Vascular Home Page, 231 – 232 Vascular injury endovascular grafts, 363 – 394 iatrogenic, 1095– 1106 methods of repair, 1194 types of, 1194 Vascular insufficiency, from arteriovenous fistulas, 1158 Vascular pathology of popliteal fossa, noninvasive studies, 119 Vascular societies administrative office, communicating with, on computer, 230 – 231 with linked web pages, 232 Vascular surgical techniques, 1187 – 1259 aortic aneurysm repair, 1210 – 1227 aortofemoral bypass, for occlusive disease, 1228– 1239 arterial dissection, 1188 – 1189 arterial incision, 1188– 1189 suture closure of arteriotomy, 1188– 1189 artery, lacerated, repair of, 1194 axillofemoral bypass, 1250 – 1255 carotid endarterectomy, 1204 – 1209 end-to-end vascular anastomosis, 1190– 1191 end-to-side vascular anastomosis, 1192– 1193 femoral artery, lacerated, repair of, 1196– 1197 femorofemoral bypass, 1256 –1259
[Vascular surgical techniques] femoropopliteal bypass, 1240 – 1249 inferior vena cava, lacerated, repair of, 1194– 1195 inferior vena cava plication, 1198 – 1201 saphenous vein ligation, stripping, 1202– 1203 vascular injury, types of, 1194 vein, lacerated, repair of, 1194 Vasculitis, 915 – 926 Behcet’s disease, 922– 923 clinical examination, 104 fibromuscular dysplasia, 923 – 926 Kawasaki’s disease, 921–922 large-vessel lesions, 915 – 923 related to drug abuse, 1115 small-vessel disease, 923 – 926 Takayasu’s arteritis, 915 – 917 temporal arteritis, 917 – 919 thromboangiitis obliterans, 919 – 921 Vasculogenic impotence, classification of, 878 Vasodilators, 95 Vasomotor disorders, posttraumatic, 1124 Vasopressin analogue, 1020 Vasospasm, traumatic, 1124 Vein, lacerated, repair of, 1194 Vein bypass grafts, neointimal hyperplasia in, 330– 331 Vein-valve transplant, development of procedure, 8 Veith, Frank, 4, 5 Vena cava interruption, deep vein thrombosis, 968 – 969 Venography, deep vein thrombosis, 966 Venous allografts, 612 – 613 Venous disease, historical developments in treatment of, 8 – 9 Venous disease diagnosis, 155 –165 noninvasive techniques, 158 – 165 congenital vascular malformation, 165 duplex scanning, 162 – 163 plethysmography, 158 scanning technique, 163 – 164 ultrasound techniques, 160 – 162 venous outflow obstruction, 158 venous reflux, 158– 160 venous reflux detection, duplex scanning, color flow imaging, 164 phlebography, 157 radioisotope techniques, 157 – 158 venous thrombosis, radiographic signs of, 157 Venous hypertension from arteriovenous fistulas, 1158– 1159 correction of, development of procedures, 8
1291
Venous insufficiency chronic, 937– 947 arteriovenous fistula theory, 937– 938 cytokine regulation, tissue fibrosis, 942– 943 deep veins, 988 dermal fibroblast function, 943 – 944 diffusion block theory, 938 endothelial cell characteristics, 940 extracellular matrix alterations, 941 historical theories, 937 leukocyte activation, 938 – 939 macroscopic alterations, 945 matrix metalloproteinases, inhibitors in venous ulcer healing, 944 –945 natural history, application, 988 – 989 segmental disease, patterns of, 988 stasis dermatitis, dermal fibrosis, pathophysiology of, 941 – 944 types, distribution of leukocytes, 940– 941 ulceration, 989 venous microcirculation, 939 – 941 venous stasis theory, 937 physical exam, 111 Venous interruption procedures, penis, 884– 885 Venous malformations, 1166 – 1167 diagnostic evaluation, 1166 differential diagnosis, 1166 – 1167 natural history, 1167 options for treatment, 1167 outcome of management, 1167 signs, symptoms, 1166 Venous outflow obstruction, noninvasive diagnosis, 158 Venous reflux detection, duplex scanning, color flow imaging, 164 noninvasive diagnosis, 158 – 160 Venous stenosis in hemodialysis patients, 1008– 1010 Venous stenting, 1003– 1014 Venous system examination, 109 – 111 chronic venous insufficiency, 110 history, 110 thrombosis, 110 – 111 deep vein thrombosis, 110 – 114 superficial vein thrombosis, 110 varicose veins, 110 Venous thromboembolism prophylaxis against, 292 –293 therapy, 290– 291 Venous thrombosis conditions associated with, 154 lower extremities, clinical manifestations, 153– 154
1292
Index
[Venous thrombosis] radiographic signs of, 157 Venous xenografts, 613 – 614 Verapamil, 311– 312 Vertebral artery endarterectomy, bypass, development of procedure, 8 injuries, 1074– 1075 postoperative care, 1075 Vertebrobasilar ischemia, 771 – 782 anatomy, 772– 773 arterial pathology, 773 common carotid, to subclavian artery, bypass for, 774– 775 common carotid to distal vertebral artery bypass, 777– 779 distal vertebral artery reconstruction of, 777 transposition of to cervical internal carotid artery, 780 external carotid, transposition of to vertebral artery, 779 – 780 left subclavian artery, transthoracic repair of, 775– 776 occipital artery, transposition of to distal vertebral artery, 780 proximal subclavian artery, surgical reconstruction of, 774 – 776 proximal vertebral artery, transposition of to common carotid artery, 776– 777 subclavian artery, transposition of to common carotid artery, 775 subclavian to vertebral artery bypass, 777
[Vertebrobasilar ischemia] ultrasound, radiologic imaging, 774 vertebral artery reconstruction of, 776 – 780 transposition of to another subclavian site, 777 vertebral/proximal subclavian artery reconstruction, 774 Veterans Administration Cooperative Study Group on Antihypertensive Agents, 58 Veto, R. Mark, 4 Vinyon-N synthetic aortic graft, development of, 6, 8, 703 Viral infection, atherosclerosis and, 242 Visceral ischemia, 411 chronic, 861– 875 anatomic considerations, 861 autogenous antegrade bypass, 864– 865 bypass, 864– 867 clinical presentation, 861 – 862 endarterectomy, 867 –869 nonoperative therapy, 869 – 870 pathophysiology, 862 – 863 prosthetic antegrade bypass, 865– 867 recurrent visceral ischemia, 870– 873 reimplantation, 863 –867 retrograde bypass, 864 revascularization options, 863– 869 Visceral vessels, infected aneurysm, 682– 683
Viscosity, blood, reducing, 95 Vitamin K antagonists, 287 –289 drug interactions, 288 – 289 mode of action, 288 pharmacokinetics of warfarin, 288– 289 physical properties, 287 drug interactions, 289 Voorhees, Arthur, 5 Walking, metabolic equivalent level for, 317 Warfarin, 332 anticoagulation, reversal of, 294 complications of, 293 – 294 monitoring, 289 Web pages, communication with, 229– 234 Western Collaborative Group Study, 58 Western Vascular Society, 232 W.L. Gore and Associates, Excluder, development of, 366 Wordprocessing on computer, 228 Work around house, metabolic equivalent level for, 317 World Medical Manufacturing Corporation, 366 Wylie, Edwin, 4, 6 Xenografts, 613 –614 Yasargil, M. Gazi, 8 Yersinia, aneurysm infection, 674
About the Editors
ROBERT W. HOBSON II is Director of the Division of Vascular Surgery and Professor of Surgery and Physiology, University of Medicine and Dentistry of New Jersey, New Jersey Medical School, and Director of the Department of Surgery, St. Michael’s Medical Center, Newark, New Jersey. The author, coauthor, editor, or coeditor of more than 350 journal articles, book chapters, and books, he serves on the editoral boards of numerous journals, and is the immediate past president of the American Association for Vascular Surgery, as well as a past president of the Association for Academic Surgery (1981), the American Venous Forum (1996), the Eastern Vascular Society (1997), and the Association of Program Directors in Vascular Surgery (1998 – 2000). Dr. Hobson received the B.S. (1959) degree in chemistry and the M.D. (1963) degree from The George Washington University, Washington, D.C. SAMUEL E. WILSON is Professor and Chair of the Department of Surgery, University of California Irvine, Orange, California. The author or coauthor of 400 publications, the editor or coeditor of 15 textbooks, a Fellow and president of the Southern California Chapter of the American College of Surgeons, and a member of the American Surgical Association and the Society for Vascular Surgery, he is past president of the Los Angeles Surgical Society, the Orange County Surgical Society, and the Southern California Vascular Society, as well as president-elect of the Pacific Coast Surgical Association. Dr. Wilson received the B.A. (1963) and M.D. (1965) degrees from Wayne State University, Detroit, Michigan, and is a distinguished alumnus of his alma mater. FRANK J. VEITH is The William J. von Liebig Chair in Vascular Surgery, Montefiore Medical Center, Albert Einstein College of Medicine, New York, New York. Dr. Veith is the author, coauthor, editor, or coeditor of more than 1200 professional publications, including Current Status of Carotid Bifurcation Angioplasty and Stenting and Endoleaks and Endotension (both titles, Marcel Dekker, Inc.). He is a member and past president of the Society for Vascular Surgery and the Eastern Vascular Society and a member of the American Association for Vascular Surgery, as well 15 other professional societies. Dr. Veith is a Fellow of the American Surgical Association, the American Heart Association, and the American College of Surgeons. He received the A.B. (1952) and M.D. (1955) degrees from Cornell University, Ithaca, New York, and his training in surgery at the Peter Brent Brigham Hospital and Harvard Medical School, Boston, Massachusetts.
