Chronic Leg Ulcers and Eczema

............................ Management of Leg Ulcers

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Current Problems in Dermatology Vol. 27

Series Editor

G. Burg, Zu¨rich

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Management of Leg Ulcers

Volume Editors

J. Hafner, Zu¨rich A.-A. Ramelet, Lausanne W. Schmeller, Lu¨beck U.V. Brunner, Zu¨rich

78 figures, 23 in color, and 41 tables, 1999

............................ J. Hafner

A.-A. Ramelet

Department of Dermatology University Hospital of Zu¨rich Gloriastrasse 31 CH–8091 Zu¨rich (Switzerland)

2, place Benjamin-Constant CH–1003 Lausanne (Switzerland)

W. Schmeller

U.V. Brunner

Wesloer Landstr. 3k D–23566 Lu¨beck (Germany)

Department of Surgery University Hospital of Zu¨rich Ra¨mistrasse 100 CH–8091 Zu¨rich (Switzerland)

Library of Congress Cataloging-in-Publication Data Management of leg ulcers / volume editors, J. Hafner ... [et al.]. (Current problems in dermatology: vol. 27) Includes bibliographical references and indexes. 1. Leg – Ulcers. I. Hafner, J. (Ju¨rg). II. Series. [DNLM: 1. Leg Ulcer – therapy. 2. Leg Ulcer – diagnosis. 3. Leg ulcer – physiopathology. W1 CU804L v.27 1999] RC951.M315 1999 616.545––dc21 ISSN 0070–2064 ISBN 3–8055–6654–9 (hardcover: alk. paper)

Bibliographic Indices. This publication is listed in bibliographic services, including Current ContentsÔ and Index Medicus. Drug Dosage. The authors and the publisher have exerted every effort to ensure that drug selection and dosage set forth in this text are in accord with current recommendations and practice at the time of publication. However, in view of ongoing research, changes in government regulations, and the constant flow of information relating to drug therapy and drug reactions, the reader is urged to check the package insert for each drug for any change in indications and dosage and for added warnings and precautions. This is particularly important when the recommended agent is a new and/or infrequently employed drug. All rights reserved. No part of this publication may be translated into other languages, reproduced or utilized in any form or by any means electronic or mechanical, including photocopying, recording, microcopying, or by any information storage and retrieval system, without permission in writing from the publisher. Ó Copyright 1999 by S. Karger AG, P.O. Box, CH–4009 Basel (Switzerland) www.karger.com Printed in Switzerland on acid-free paper by Reinhardt Druck, Basel ISBN 3–8055–6654–9

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Contents

1 Editors’ Portraits 3 Acknowledgment

Introduction 4 Management of Leg Ulcers Hafner, J. (Zu¨rich); Ramelet, A.-A. (Lausanne); Schmeller, W. (Lu¨beck); Brunner, U.V. (Zu¨rich)

Part I. Wound Healing 8 Molecular Biology of Chronic Wounds Ko¨nig, M.; Peschen, M. (Freiburg), Vanscheidt, W. (Ho¨chenschwand) 13 Cytokines in Progessing Stages of Chronic Venous Insufficiency Peschen, M (Freiburg) 20 Bacteriology of Leg Ulcers Ramelet, A.-A.; Perrenoud, D. (Lausanne) 26 Synthetic Dressings Aubo¨ck, J. (Linz) 49 Therapy with Growth Factors Limat, A.; French, L.E. (Geneva) 57 Cultured Keratinocyte Grafts Hunziker, T. (Bern); Limat, A. (Geneva)

Part II. Venous Leg Ulcers 65 Epidemiology of Leg Ulcers Wienert, V. (Aachen) 70 Postthrombotic Syndrome Eichlisberger, R. (Zurzach) 81 Classification of Chronic Venous Insufficiency Mayer, W.; Partsch, H. (Vienna) 89 Venous Mapping with Doppler and Duplex Sonography Rabe, E.; Pannier-Fischer, F. (Bonn) 96 Duplex Ultrasound for the Assessment of Venous Reflux Jeanneret, C.; Aschwanden, M.; Labs, K.H.; Ja¨ger, K. (Basel) 102 Phlebography Meents, H.; Hach-Wunderle, V. (Bad Nauheim) 109 Magnetic Resonance Imaging and Computed Tomography in

Advanced Chronic Venous Insufficiency List-Hellwig, E.; Meents, H. (Bad Nauheim)

114 Plethysmography Neumann, H.A.M.; Maessen-Visch, M.B. (Maastricht) 124 Microangiopathy in the Pathogenesis of Chronic Venous Insufficiency Ju¨nger, M.; Hahn, M.; Klyscz, T.; Steins, A. (Tu¨bingen) 130 Compression Therapy of Venous Ulcers Partsch, H. (Wien) 141 Physical Therapy of the Ankle Joint in Patients with Chronic Venous

Incompetence and Arthrogenic Congestive Syndrome Klyscz, T. (Neukirchen); Ju¨nger, M.; Rassner, G. (Tu¨bingen)

148 Manual Lymph Drainage Stahel, H.U. (Zu¨rich) 153 Adjuvant Systemic Drug Therapy in Venous Leg Ulcers Gallenkemper, G.; Schultz-Ehrenburg, U. (Berlin-Pankow) 161 Controversies on Emerging and Obsolete Therapies in Venous Leg Ulcers Ramelet, A.-A. (Lausanne) 165 Chronic Leg Ulcers and Eczema Perrenoud, D.; Ramelet, A.-A. (Lausanne) 170 Complications in the Treatment of Leg Ulcers Kiehlmann, I.; Lechner, W. (Norderney)

Contents

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174 Surgical Management of Varicose Veins in Advanced Chronic Venous

Insufficiency Cassina, P.C.; Brunner, U.V. (Zu¨rich); Kessler, W. (Altsta¨tten)

182 Paratibial Fasciotomy and Crural Fasciectomy Schwahn-Schreiber, C. (Otterndorf) 190 Subfascial Endoscopic Perforator Surgery Sattler, G. (Darmstadt) 195 Shave Therapy for Recalcitrant Venous Ulcers Schmeller, W. (Lu¨beck)

Part III. Arterial Leg Ulcers 203 Assessment of Peripheral Arterial Occlusive Disease Wu¨tschert, R.; Bounameaux, H. (Geneva) 211 Management of Arterial Leg Ulcers and of Combined (Mixed)

Venous-Arterial Leg Ulcers Hafner, J. (Zu¨rich)

220 Percutaneous Transluminal Angioplasty in the Management of

Arterial Leg Ulcers Schneider, E.; Hafner, J. (Zu¨rich)

226 Reconstructive Arterial Surgery Cassina, P.C. (Zu¨rich)

Part IV. Diabetic Ulcers 235 Conservative Therapy of Diabetic Foot Zinnagl, N. (Salzburg) 242 Orthopedic Aspects in Diabetic Neuropathic Osteoarthropathy Wetz, H.H. (Mu¨nster) 252 Diabetic Foot Infection Brunner, U.V.; Hafner, J. (Zu¨rich)

Part V. Leg Ulcers of Different Origin 259 Differential Diagnosis of Leg Ulcers Lautenschlager, S.; Eichmann, A. (Zu¨rich) 271 Management of Leg Ulcers in Rheumatoid Arthritis and in

Systemic Sclerosis Hafner, J.; Truëb, R.M. (Zu¨rich)

Contents

VII

277 Management of Vasculitic Leg Ulcers and Pyoderma gangrenosum Hafner, J.; Truëb. R.M. (Zu¨rich) 286 Conclusions Ramelet, A.-A. (Lausanne); Hafner, J. (Zu¨rich); Schmeller, W. (Lu¨beck); Brunner, U.V. (Zu¨rich) 289 Author Index 290 Subject Index

Contents

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Editors’ Portraits

Ju¨rg Hafner, MD Zu¨rich Medical studies and residency in Zu¨rich and Geneva. Senior staff member at the Department of Dermatology, University Hospital of Zu¨rich. Board-certified dermatologist and angiologist. Special fields of interest: dermatology, phlebology, dermatologic surgery (Mohs’ micrographic surgery of skin cancer). Board member of the Swiss Societies of Phlebology and of Dermatologic Surgery, Vice-President of the Swiss Association of Wound Healing.

Albert-Adrien Ramelet, MD Lausanne Medical studies and residency in Lausanne, Basel and Paris. Board-certified dermatologist and angiologist. Special fields of interest: dermatology, phlebology. Former president of the Swiss Society of Dermatology and Venereology (1987– 1990). President of the Swiss Society of Phlebology. First Vice-President of the French-speaking Association of Dermatologists.

Wilfried Schmeller, MD Lu¨beck Medical studies in Cologne, Du¨sseldorf and Vienna. Residency in Arnsberg, Eschweiler and Lu¨beck. Board-certified dermatologist. Since 1992 senior staff member and professor at the Department of Dermatology, University of Lu¨beck. Special fields of interest: dermatology, phlebology, dermatologic surgery, tropical dermatology. Cooperation with the UNICEF, Chairman of the organization ‘Physicians Help African Children with Skin Disease’. Chairman of the working group ‘Dermatologic Angiology’ of the Germanspeaking Society of Dermatologists. Member of the Advisory Counsil of the German Society of Phlebology.

Urs V. Brunner, MD, Professor emeritus Zu¨rich Medical studies and residency in Zu¨rich. Board-certified surgeon. Head of the Peripheral Vascular Surgery Unit, Department of Surgery, University Hospital of Zu¨rich (1970–1998). Consultant for chronic wounds at the Department of Surgery, University Hospital of Zu¨rich (since 1998). Special fields of interest: reconstructive vascular surgery, phlebological surgery, lymphology, diabetic foot, medicine in modern art. President of the Swiss Association for Wound Healing.

Text Editor: E. Paul Scheidegger, MD Zu¨rich Medical studies and residency in Vienna and Zu¨rich. Postdoctoral research fellow in Ann Arbor, Michigan at the Howard Hughes Medical Research Institute. Currently resident at the Department of Dermatology, University Hospital of Zu¨rich. Special field of interest: the glycobiology of selectin ligands.

Editors’ Portraits

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Acknowledgment

We greatly acknowledge Mr. Franco Lotto, Director (ConvaTec Division, Bristol-Myers Squibb, Baar, Switzerland) and Mr. Philip van Muylders, Director (Servier (Suisse) SA, Meyrin, Switzerland) for the generous financial support of this volume.

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Introduction Hafner J, Ramelet A-A, Schmeller W, Brunner UV (eds): Management of Leg Ulcers. Curr Probl Dermatol. Basel, Karger, 1999, vol 27, pp 4–7

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Management of Leg Ulcers Ju¨rg Hafner a, Albert-Adrien Ramelet c, Wilfried Schmeller d, Urs V. Brunner b Departments of Dermatology and b Surgery, University Hospital of Zu¨rich, Switzerland; c Specialist in Dermatology and Angiology, Lausanne, Switzerland, and d Department of Dermatology, University Hospital of Lu¨beck, Germany a

Management of leg ulcers must encompass two major aspects: treatment of the underlying disease and local wound care. One without the other is only half the solution to the problem and if unaddressed, management often fails (fig. 1). It has been estimated from epidemiological studies that the lifetime risk of having chronic leg ulceration approximates 1%. The course of disease is known to be chronic and recurrent in many patients. This represents a tremendous socioeconomic impact of chronic leg ulcers on the health care systems in Western countries. The total costs (direct and indirect) were calculated to exceed DEM 1 billion a year in Germany and the direct costs of leg ulcers in Great Britain were calculated at GBP 300 million a year. The first part of this book addresses the biology of wound healing as well as standards and recent advances in local wound care. Biology of chronic wounds represents a chronic inflammatory process. This constitutes the simultaneous regeneration and breakdown of wound matrix resulting in disturbed tissue repair. The rapidly evolving insights into physiological and pathological wound healing may finally allow for the rational use of topical or systemic drugs, such as growth factors. Bacterial contamination of chronic wounds is considered normal and must be distiguished from infection. The biosynthetic dressings as they are now widely used for local therapy of chronic wounds do not increase, but rather reduce the occurrence of local infection. Bio-occlusive dressings stimulate tissue repair by creating a physiological, moist environment for the healing of tissues. Bioengineered skin equivalents are a specially exciting

Fig. 1. The ‘leg ulcer columns’ symbolize the two principles of management: treatment of underlying disease and local wound care.

field of development that may greatly influence local treatment of chronic wounds in the future. However, their production is expensive and rigorous safety measures are required to prevent transmission of infectious diseases. Several commercial skin equivalents are currently under evaluation to assess their clinical effectiveness as well as their cost-effectiveness in randomized controlled trials. The second part of the book focuses on venous ulcers that represent the largest group amongst patients with leg ulcers (approx. 70%). About half of the patients presenting with venous ulceration suffer from the sequelae of deep-vein thrombosis. Clinical signs, etiology, anatomy and pathology can be assessed by the CEAP classification of venous disease. For both anatomical and functional examination of the venous system of the lower limbs, duplex sonography has replaced phlebography as the diagnostic golden standard. However, phlebography still has its place in the examination of more complex vascular anomalies, such as angiodysplasias. A phlebogram has the advantage of giving a complete depiction of the vascular system and of being a transportable document that can easily be mounted and read anywhere. Computerassisted tomography and magnetic resonance imaging are experimental in the assessment of venous disease. However, these methods give an interesting


5

insight into trophic changes around the ankle joint as they are found in advanced stages of chronic venous insufficiency. The different plethysmography techniques for the lower limb allow for noninvasive functional examination of the venous ankle pump. Especially photoplethysmography is widely used in phlebologic practice to predict if venous hemodynamics would improve after saphenectomy. Ultimately, venous ulceration is thought to occur because of an impaired cutaneous microcirculation. Fluorescence videomicroscopy has given interesting experimental insight into cutaneous microcirculation in chronic venous insufficiency. Compression therapy remains the mainstay of conservative treatment of venous disease. Multilayer bandaging has been shown to be especially effective in providing sustained compression resulting in healing rates of 70% within 3–6 months. Physical therapy definitely can contribute to the effect of compression. Mobilization of the ankle joint restores an adequate function of the venous ankle pump and in cases of secondary lymphostasis, manual lymph drainage represents a very efficient method to reduce lower leg edema. Several surgical procedures are available to cure recalcitrant venous ulcers, among which paratibial fasciotomy, fasciectomy, perforator vein ligature and shave therapy represent the most important ones. Primary incompetence of the greater saphenous vein in the absence of a postthrombotic syndrome is the cause of about about one third of all venous leg ulcers. Even though long-standing insufficiency of the greater saphenous vein is often accompanied by deep venous incompetence, saphenectomy markedly improves the symptoms in these patients and deep venous incompetence may even regress in the absence of superficial reflux. It is mandatory that before saphenectomy is performed in leg ulcer patients, deep venous obstruction is excluded. Contact eczema to topical agents is very common in leg ulcer patients and should be avoided by using hypoallergic local therapies. Malignant transformation of the ulcer border is an infrequent, but important complication of chronic ulcers that should be ruled out by a biopsy in all cases of nonhealing wounds. Moreover, there are a lot of further adjuvant treatment modalities for chronic leg ulcers, that often are not proven to be effective, but contribute to a tremendous polypragmasy as is typical for chronic medical disorders. Most of the treatments cited above, rational as well as ‘obscure’ ones, are not established by randomized controlled clinical trials or at least by prospective large-scale trials with a sufficient follow-up. This will remain a task for the coming years. Chronic venous disease is so frequent that more clinical investigations are certainly justified. The third part of this book deals with the assessment and management of leg ulcers in peripheral arterial occlusive disease. About 20% of leg ulcer patients do have relevant arterial disease and this group accounts for the most difficult to treat cases and probably also for the most common mistakes in the

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management of leg ulcers. Interventional vascular treatment, i.e. percutaneous transluminal angioplasty and bypass surgery, has considerably improved the outcome of these patients. The diabetic foot and its specific orthopedic, podological and surgical management is subject of the fourth part of the book. Diabetic feet have a very high socioeconomic impact in their own right, accounting for about 20% of diabetes-related hospital admissions and often requiring long hospital stays. Fifty percent of nontrauma-related lower-limb amputations occur in people with diabetes. The fifth part of the book presents the large differential diagnosis of leg ulcers. Special emphasis is given to the management of leg ulcers in rheumatoid arthritis and systemic sclerosis, as well as in cutaneous vasculitis and in pyoderma gangrenosum, since these conditions are not so infrequent and require specialized treatment. In summary, this book aims at giving a practical orientation on the management of leg ulcers. It addresses primarily clinicians who are involved in the care for these patients. We hope that this first-hand information from experts in their fields will help us increase our skills and knowledge in dealing with leg ulcers and ultimately healing our patients.

Ju¨rg Hafner, MD, Department of Dermatology, University Hospital of Zu¨rich, CH–8091 Zu¨rich (Switzerland) Tel. +41 1 255 11 11, Fax +41 1 255 44 03, E-Mail [email protected]


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Part I. Wound Healing Hafner J, Ramelet A-A, Schmeller W, Brunner UV (eds): Management of Leg Ulcers. Curr Probl Dermatol. Basel, Karger, 1999, vol 27, pp 8–12

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Molecular Biology of Chronic Wounds Myriam Ko¨nig a, Manfred Peschen a, Wolfgang Vanscheidt a, b a b

Department of Dermatology, University of Freiburg and Clinic for Wound Biology, Ho¨chenschwand, Germany

Until recently the pathogenesis of chronic wounds was attributed to a lack of essential factors in the healing process. Now there is increasing evidence that chronic wounds cannot heal normally because of an ongoing vicious circle of chronic inflammation. As a matter of fact, chronic wounds do not lack essential substrates known to be involved in wound healing. Instead, proinflammatory cytokines, proteinases, cellular adhesion molecules, growth factors and growth factor receptors [1–3] seem to be increased in chronic wounds which supports the chronic inflammation hypothesis.

Chronic Inflammation Neutrophils and macrophages secrete proinflammatory cytokines, such as tumor necrosis factor-a (TNF-a), interleukin (IL)-1 and IL-8 during the early inflammatory phase of wound healing [4–7]. TNF-a is a strong initiator of a proinflammatory cascade and induces IL-1b synthesis during wound healing. It has been shown that the proinflammatory cytokines TNF-a and IL-1b were about 100-fold higher in wound fluid from chronic wounds than in mastectomy fluid [5]. TNF-a and IL-1b upregulate cellular adhesion molecules [8]. In venous ulcers the cellular adhesion molecules ICAM-1 and VCAM are upregulated. This promotes the migration of inflammatory cells into the wound, as can be demonstrated histochemically by a perivascular accumulation of LFA-1- and VLA-4-positive inflammatory cells in leg ulcers [9]. Neutrophils and macrophages secrete large amounts of elastase into the chronic wound which might lead to constant breakdown of newly formed granulation tissue [10, 11]. The elastase activity is about 10- to 40-fold increased in chronic wounds compared to acute wounds [12].

Perpetual Degradation of Wound Matrix by the Lack of Metalloprotease Inhibitors In any acute or chronic wound, series of matrix metalloproteases (MMPs) are found [13–15]. A number of these zinc-dependent proteases as well as their inhibitors (TIMPs) have been isolated and characterized [16]. Some of the members include collagenases, stromelysins, gelatinases, matrilysins, metalloelastases and membrane-type matrix metalloproteases [17, 18]. Chronic wounds are characterized by a higher enzymatic activity of MMP-1, while the inhibitor TIMP-1 is decreased [19]. Furthermore, the matrix metalloproteases MMP-2 and MMP-9 are 10-fold increased in chronic wounds compared to acute wounds [20], but in earlier stages of chronic venous insufficiency, excessive MMP activity has been observed [21]. Interstitial collagenases such as MMP-1 and MMP-2 catalyze collagen degradation of type I and III collagen, which represent the most important component of extracellular matrix in the dermis [22]. TIMPs-1 and -2 are responsible for the inhibition of MMPs-1 and -2, respectively [23]. In chronic wounds, TIMPs were found to be complex-bound and therefore largely inactivated in their MMP inhibition [13]. The initial wound matrix contains glycosaminoglycans and fibronectin. Fibronectin is an adhesive glycoprotein that promotes cell adhesion, migration, differentiation and proliferation, e.g. of macrophages and fibroblasts [24, 25]. Fibronectin is very susceptible to proteolysis [26]. As a matter of fact, diabetic ulcers and venous ulcers have been shown to contain decreased levels of fibronectin and, instead, its degradation products could be demonstrated [27, 28]. The same has been shown for vitronectin, another adhesive glycoprotein involved in cell migration in the first stages of wound healing [29, 30]. To summarize, there seems to be an imbalance of proteases that are able to continuously break down the newly formed wound matrix and their inhibitors. Increased protease activity in chronic wounds is probably a direct result of the presence of neutrophils and macrophages that are attracted to the ulcer by proinflammatory cytokines. The protease inhibitors that could prevent the damage to the extracellular matrix seem to be largely complexbound and inactivated [20].

Chronic Wounds Are Not Deficient of Growth Factors As of yet a local lack of growth factors could never be demonstrated in chronic wounds. The platelet-derived growth factor (PDGF) receptor-a and -b chains are markedly expressed in venous ulcers. Vascular endothelial growth factor (VEGF) receptors are upregulated in the endothelial and perivascular

Molecular Biology of Chronic Wounds

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mononuclear cells in the wound bed of venous ulcers [31]. The edge of venous ulcers was found to be hypoxic. Hypoxia induces upregulation of VEGF expression in vitro [32] and VEGF increases vascular permeability [33]. This could be a plausible explanation for the papillary edema, leukocyte and platelet sequestration and fibrin deposition in the wound bed and wound edge of venous ulcers [34, 35]. Finally, the expression of other growth factors, such as basic fibroblast growth factor (bFGF) [36] and transforming growth factor-b (TGF-b), is also elevated in chronic wounds. Interestingly, TGF-b is upregulated both in acute and chronic wounds [5]. Insulin-like growth factor-1 (IGF-1) [2] is upregulated in chronic wounds as well [5]. One growth factor receptor, however, namely endothelial growth factor receptor (EGF-R), is downregulated in the wound bed of venous ulcers, whereas it is upregulated in the wound edge [37]. EGF induces the proliferation of epidermal basal cells, endothelial cells and fibroblasts [7] To summarize, chronic wounds do not lack growth factors, but growth factors may be inactivated by enzymatic degradation or bound as complexes.

Conclusion In contrast to the traditional hypothesis that chronic wounds represent inactive tissue, recent research brought to light that chronic wounds are hyperactive tissues that do not heal due to a perpetuated inflammatory process. Tissue hypoxia and consecutive inflammation might be the common pathway in chronic wounds in the setting of venous or arterial ulcers, as well as in diabetic foot ulcers and pressure sores. The understanding of the molecular biology in chronic wounds might eventually lead to rational therapeutic strategies in the treatment of chronic wounds.

References 1 2 3 4 5 6

Bennett NT, Schultz GS: Growth factors and wound healing. II. Role in normal and chronic wound healing. Am J Surg 1993;166:74–81. Bennett NT, Schultz GS: Growth factors and wound healing: Biochemical properties of growth factors and their receptors. Am J Surg 1993;165:728–737. Harris IR, Yee KC, Walters CE, Cunliffe WJ, Kearney JN, Wood EJ, Ingham E: Cytokine and protease levels in healing and non-healing chronic venous leg ulcers. Exp Dermatol 1995;4:342–349. Chedid M, Rubin JS, Csaky KG, Aaronson SA: Regulation of keratinocyte growth factor gene expression by interleukin-1. J Biol Chem 1994;269:10753–10757. Mast BA, Schultz GS: Interactions of cytokines, growth factors, and proteinases in acute and chronic wounds. Wound Rep Reg 1996;4:411–420. Ono I, Gunji H, Suda K, Iwatsuki K, Kaneko F: Evaluation of cytokines in donor site wound fluids. Scand J Plast Reconstr Surg Hand Surg 1994;28:269–273.

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Steenfos HH: Growth factors and wound healing. Scand J Plast Reconstr Hand Surg 1994;28: 95–105. Veraart JC, Verhaegh ME, Neumann HA, Hulsmans RF, Arends JW: Adhesion molecule expression in venous leg ulcers. Vasa 1993;22:213–218. Weyl A, Vanscheidt W, Weiss JM, Peschen M, Scho¨pf E, Simon J: Expression of the adhesion molecules ICAM-1, VCAM-1, and E-selectin and their ligands VLA-4 and LFA-1 in chronic venous leg ulcers. J Am Acad Dermatol 1996;34:418–423. Heiden M, Seitz R, Egbring R: The role of inflammatory cells and their proteases in extravascular fibrinolysis. Semin Thromb Hemost 1996;22:497–501. Herrick S, Ashcroft G, Ireland G, Horan M, McCollum C, Ferguson M: Up-regulation of elastase in acute wounds of healthy aged humans and chronic leg ulcers are associated with matrix degeneration. Lab Invest 1997;77:281–288. Rao CN, Ladin DA, Liu YY, Chilukuri K, Hou ZZ, Woodley DT: Alpha 1-antitrypsin is degraded and non-functional in chronic wounds but intact and functional in acute wounds: The inhibitor protects fibronectin from degradation by chronic wound fluid enzymes. J Invest Dermatol 1995; 105:572–578. Bullen EC, Longaker MT, Updike DL, Benton R, Ladin D, Hou Z, Howard EW: Tissue inhibitor of metalloproteinases-1 is decreased and activated gelatinases are increased in chronic wounds. J Invest Dermatol 1995;104:236–240. Moses MA, Marikovsky M, Harper JW, Vogt P, Eriksson E, Klagsbrun M, Langer R: Temporal study of the activity of matrix metalloproteinases and their endogenous inhibitors during wound healing. J Cell Biochem 1996;60:379–386. Saarialho-Kere UK, Pentland AP, Birkedal-Hansen H, Parks WC, Welgus, HG: Distinct populations of basal keratinocytes express stromelysin-1 and stromelysin-2 in chronic wounds. J Clin Invest 1994;94:79–88. Shapiro SD: Matrix metalloproteinases degradation of extracellular matrix: Biological consequences. Curr Opin Cell Biol 1998;10:602–608. Chu CT, Pizzo SV: Alpha-2-macroglobulin, complement, and biologic defense: Antigens, growth factors, microbial proteases, and receptor ligation. Lab Invest 1994;71:792–812. Weckroth M, Vaheri A, Lauharanta J, Sorsa T, Konttinen YT: Matrix metalloproteinases, gelatinase and collagenase, in chronic leg ulcers. J Invest Dermatol 1996;106:1119–1124. Vaalamo M, Weckroth M, Puolakkainen P, Kere J, Saarinen P, Lauharanta J, Saarialho-Kere UK: Patterns of matrix metalloproteinase and TIMP-1 expression in chronic and normally healing human cutaneous wounds. Br J Dermatol 1996;135:52–59. Wysocki AB, Staiano-Coico L, Grinnell F: Wound fluid from chronic leg ulcers contains elevated levels of metalloproteinases MMP-2 and MMP-9. J Invest Dermatol 1993;101:64–68. Herouy Y, May AE, Pornschlegel G, Stetter C, Preissner KT, Scho¨pf E, Norgauer J, Vanscheidt W: Lipodermatosclerosis is characterized by elevated expression and activation of matrix metalloproteinases: Implications for venous ulcer formation. J Invest Dermatol 1998;111:822–827. Vaalamo M, Mattila L, Johansson N, Kariniemi AL, Karjalainen-Lindsberg ML, Kahari VM, Saarialho-Kere U: Distinct populations of stromal cells express collagenase-3 (MMP-13) and collagenase-1 (MMP-1) in chronic ulcers but not in normally healing wounds. J Invest Dermatol 1997; 109:96–101. Howard EW, Bullen EC, Banda MJ: Preferential inhibition of 72- and 92-kDa gelatinases by tissue inhibitor of metalloproteinase-2. J Biol Chem 1991;266:13070–13075. Romberger DJ: Fibronectin. Int J Biochem Cell Biol 1997;29:939–943. Wysocki AB: Wound fluids in the pathogenesis of chronic wounds. J Wound Ostomy Continence Nurs 1996;23:283–290. Wysocki AB, Grinnell F: Fibronectin profiles in normal and chronic wound fluid. Lab Invest 1990; 63:825–831. Grinnell F, Zhu M: Fibronectin degradation in chronic wounds depends on the relative levels of elastase, a1-proteinase inhibitor, and a2-macroglobulin. J Invest Dermatol 1996;106:335–341. Palolahti M, Lauharanta J, Stephens RW, Kuusela P, Vaheri A: Proteolytic activity in leg ulcer exudate. Exp Dermatol 1993;2:29–37.

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Grinnell F, Ho CH, Wysocki AB: Degradation of fibronectin and vitronectin in chronic wound fluid. Analysis by cell blotting, immunoblotting, and cell adhesion assays. J Invest Dermatol 1992; 98:410–416. Kost C, Benner K, Stockmann A, Linder D, Preissner KT: Limited plasmin proteolysis of vitronectin. Characterization of the adhesion protein as morpho-regulatory angiostatin-binding factor. Eur J Biochem 1996;236:682–688. Peschen M, Grenz H, Brand-Saberi B, Bunaes M, Simon JC, Scho¨pf E, Vanscheidt W: Increased expression of platelet-derived growth factor receptor-a and -b and vascular endothelial growth factor in the skin of patients with chronic venous insufficiency. Arch Dermatol Res 1998;290: 291–297. Brown LF, Harrist TJ, Yeo KT, Stahle-Backdahl M, Jackman RW, Berse B, Tognazzi K, Dvarak HF, Detmar M: Increased expression of vascular permeability factor (vascular endothelial growth factor) in bullous pemphigoid, dermatitis herpetiformis, and erythema multiforme. J Invest Dermatol 1995;104:744–749. Brown LF, Olbricht SM, Berse B, Jackman RW, Matsueda G, Tognazzi K, Manseau EJ, Dvarak HF, Van de Water L: Overexpression of vascular permeability factor (VPF/VEGF) and its endothelial cell receptors in delayed hypersensivity skin reactions. J Immunol 1995;154:2801–2807. Higley HR, Ksander GA, Gerhardt CO, Falanga V: Extravasation of macromolecules and possible trapping of transforming growth factor-b in venous ulceration. Br J Dermatol 1995;132:79–85. Michel CC: Microvascular permeability, venous stasis and oedema. Int Angiol 1989;8:9–13. Peschen M, Grenz H, Grothe C, Schoepf E, Vanscheidt W: Patterns of epidermal growth factor, basic fibroblast growth factor and transforming growth factor-b3 expression in the skin with chronic venous insufficiency. Eur J Dermatol 1998;8:334–338. Falanga V, Grinnell F, Gilchrest B, Maddox YT, Moshell A: Experimental approaches to chronic wounds. Wound Rep Reg 1995;3:132–140.

Prof. Dr. med. Wolfgang Vanscheidt, Leitender Oberarzt der Klinik, Universita¨ts-Hautklinik, Hauptstrasse 7, D–79104 Freiburg (Germany) Tel. +49 761 270 67 89/67 90, Fax +49 761 270 68 18, E-Mail [email protected]

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Hafner J, Ramelet A-A, Schmeller W, Brunner UV (eds): Management of Leg Ulcers. Curr Probl Dermatol. Basel, Karger, 1999, vol 27, pp 13–19

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Cytokines in Progressing Stages of Chronic Venous Insufficiency Manfred Peschen Department of Dermatology, Albert-Ludwigs-Universita¨t Freiburg, Germany

In the chronic wound, the normal cascade of inflammation, granulation and reconstruction phases of healing is interrupted [1]. Chronic venous insufficiency (CVI) is characterized by a steady progession of skin inflammatory response with the clinical signs of telangiectases, venous eczema, pigmentation, lipodermatosclerosis and finally cumulating in poor healing skin ulceration [2]. The aim of this chapter is to summarize recent findings on the complex interaction of a variety of different cell types, such as cytokines, adhesion molecules, growth factors, proteins of the extracellular matrix and various proteases which take place in the various stages of CVI, and which are necessary for cell migration, proliferation and differentiation.

Cytokines Cytokines are produced by most nucleated cells in the body, including epithelial cells, keratinocytes, Langerhans’ cells and macrophages in the skin. Keratinocytes are the major source of cytokines in the epidermis and have been reported to secrete interleukin (IL)-1, IL-3, IL-6, IL-8, CSF, tumor necrosis factor (TNF)-a, transforming growth factor (TGF)-a, TGF-b and platelet-derived growth factor (PDGF) if they are modulated by various agents, including cytokines themselves [3]. It has been observed that skin keratinocytes produced IL-1a, but not IL-6, constitutively. TNF-a stimulation increased IL-1a production by skin keratinocytes and exhibited synergy with interferon (IFN)-c, although the latter had no effect by itself. In contrast, skin keratinocytes produced IL-6 in response to TNF-a, IFN-c or IL-4, and IFN-c and IL-4 exhibited synergy with TNF-a [4].

Recently it has been shown that cells like fibroblasts and myofibroblasts which play an important role in normal wound healing show modulated responses to TGF-b1 and IFN-c, two cytokines known to modulate fibroblast morphology, according to their stage of differentiation [5]. It has been described that all interferons (IFN-a, -b and -c), especially IFN-c were found to inhibit collagen synthesis, whereas the fibronectin production was induced by this cytokine [6]. The importance of these observations for the pathophysiological processes in CVI is still not clear. Overall, research on the abovementioned cytokines led in the past few years to a wealth of information on the multifaceted biology of cytokines which is documented in countless publications.

Adhesion Molecules A central mechanism in the progression of uncontrolled inflammation in CVI is the dysregulation of leukocyte extravasation across the vascular endothelium infiltrating adjacent tissue [7, 8]. The adhesion of the leukocytes to the endothelium is mediated by ICAM-1 and VCAM-1 on endothelial cells and their corresponding ligands LFA-1 and VLA-4 on activated leukocytes which is a direct prerequisite for the transmigration of the leukocytes to the neighboring tissue [9, 10]. Recently we have shown that the expression pattern and mRNA levels of ICAM-1, LFA-1, VCAM-1 and VLA-4 are highly overexpressed in venous eczema, but downmodulated only slightly in lipodermatosclerosis followed by high expression in leg ulcers [11, 12]. These findings suggest that CAM dysregulation on endothelial cells might play an important role in continuous leukocyte migration into dermis, ultimately inducing a nonhealing leg ulceration [8]. In addition to high vascular pressure, the reduced oxygen pressure found in late stages of CVI may induce the expression of ICAM-1 and VCAM-1 on vascular endothelial cells [13–15]. Hypoxia in the capillaries and venules has been demonstrated to induce the release of endothelium-derived cytokines, such as IL-1, that subsequently induce endothelial cell CAM expression [16–18]. Moreover, inflammatory cytokines, i.e. IFN-c (IFN-c) produced by infiltrating leukocytes, are likely to be involved in expression of ICAM-1 on keratinocytes [19]. Described findings propose that a central mechanism in the progression of CVI to nonhealing skin ulceration seems to be a persistent upregulation of endothelial CAMs responsible for a persistent inflammatory process in CVI.

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Growth Factors Growth factors may play a significant role in the process of wound repair by stimulating growth and proliferation by paracrine or autocrine mechanisms [20]. Macromolecules extravasated from the vasculature possibly bind growth factors, such as TGF-b and matrix proteins [21], providing the matrix for migrating fibroblasts and endothelial cells [22]. Previous investigations of our group suggested that the immunohistochemical expression of PDGF-a and b, vascular endothelial growth factor (VEGF), epidermal growth factor receptor (EGFR), basic fibroblast growth factor (bFGF) and TGF-b3 in the skin at various stages of CVI is first increased in endothelial cells of capillaries, pericapillary cells, and connective tissue cells in the stroma of venous eczema and partly with venous leg ulcer skin, and to a smaller extent in the dermis with lipodermatosclerosis, compared to normal skin [23, 24]. Recently, it has been shown that the reduced growth of dermal fibroblasts from chronic venous ulcers can be stimulated by growth factors, such as bFGF, EGF and by IL-1b [25]. Since growth factors stimulate a variety of functions depending on cell type and CVI stage and since the stage of leg ulcer represents a complex of different wound-healing phases, it seems to be very difficult to decide whether a mixed combination of growth factors would be predicted to be more effective than a single factor in the treatment of CVI [26–28].

Metalloproteinases and Plasminogen Activators Recent observations on the protein and mRNA level of late CVI stages, such as lipodermatosclerosis and leg ulcer, described an imbalance of matrix metalloproteinases (MMPs) and their tissue inhibitors (TIMPs) possibly contributing to a breakdown of the extracellular matrix and ulcer formation [29, 30]. Moreover, the well-known altered fibrinolytic activity in CVI patients contributes to an increased activation of the plasminogen activator/plasmin system, which has been implicated in such diverse processes as angiogenesis, inflammatory reaction, wound healing and the control and activation of MMPs [31]. Recently we examined the changes in the enzymatic activity and spatial localization of urokinase-type plasminogen activator (uPA) and tissue-type plasminogen activator (tPA) by in situ zymography during the progression of CVI. We demonstrated that (a) there are profound changes in the activity and spatial localization of both uPA and tPA during the progression of CVI; (b) these changes begin early in CVI (e.g. venous eczema) and (c) the most striking changes in uPA and tPA activity occur in the later stages of CVI, namely lipodermatosclerosis and leg ulceration [unpubl. data].

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In vitro experiments showed that proinflammatory cytokines, such as TNF-a and IL-1b induce a coordinated increase in uPA expression in keratinocytes with an increased pericellular plasmin-mediated proteolysis [32]. Similar to previous studies we describe in venous leg ulcers elevated uPA activity and reduced levels of tPA [33]. Reduced endothelial cell tPA activity is suggested as a major cause of decreased fibrinolytic activity in impaired wound healing [33], and our results clearly show a reduction in blood vessel associated tPA activity. The expression of uPA is confined to the proliferative population of keratinocytes during epidermal wound healing, e.g in venous ulcers, rather than to keratinocytes of the normal epidermis [29, 32, 34], suggesting that the change in uPA activity at the dermo-epidermal junction in leg ulcer patients may stimulate the proliferation of the overlying keratinocytes [35]. Additionally, the enzymatic effect of uPA and the activation of plasmin may provide an environment that is more migratory for keratinocytes, thus inducing reepithelialization [36]. We hypothesize that the imbalance of the protease activity in the later stages of CVI is another important pathogenic factor for the development of venous leg ulcer. Normalization of this imbalance by systemic or topical treatment may be a further step to increase the healing of a chronic wound.

Extracellular Matrix Immunostaining of biopsies from margins of venous leg ulcers demonstrated highly organized perivascular structures composed of laminin, fibronectin, tenascin and collagen as well as trapped leukocytes and fibrin [37, 38]. Our previous investigations demonstrated that the immunostaining of the extracellular matrix proteins laminin, fibronectin and tenascin is also modulated in a stage-dependent fashion in CVI. A first peak of expression is found in venous eczema combined with a degradation of these molecules corresponding to the physiological early reaction on skin wounding [39], in which fibroblasts are stimulated through TGF-b, IL-4 or TNF-a to increase the expression of these extracellular matrix proteins [40, 41]. Degradation processes, especially of fibronectin, which are an essential feature of repair and remodeling [42, 43], are in accordance with elevated levels of plasminogen activators and metalloproteinases [43–45]. In pigmentation, extracellular matrix expression is diminished and increased again in lipodermatosclerosis and leg ulcer specimens, as compared to the faint and inhomogeneous extracellular matrix expression in healthy skin and patients with telangiectases resulting in a disturbed environment of extracellular matrix proteins which are essential for cell migration and differentiation [unpubl. data].

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In summary it has been shown that cellular mechanisms modulating progressing stages of CVI involve a complex interplay of cytoskeletal reorganization, cell-cell adhesion, and cell-extracellular matrix interactions which is modulated by several cytokines. We are just beginning to understand the molecular mechanisms underlying the production, regulation, and precise role of cytokines in progressing stages of CVI. It is highly likely that the cytokine network will be the focus of further investigative activity in CVI research for the nearer future.

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Nath C, Gulati SC: Role of cytokines in healing chronic skin wounds. Acta Haematol 1998;99: 175–179. Anonymous: Classification and grading of chronic venous disease in the lower limbs. A consensus statement. Ad Hoc Committee, American Venous Forum. J Cardiovasc Surg (Torino) 1997;38:437–441. Ansel J, Perry P, Brown J, Damm D, Phan T, Hart C, Luger T, Hefeneider S: Cytokine modulation of keratinocyte cytokines. J Invest Dermatol 1990;94:101S–107S. Li J, Farthing PM, Ireland GW, Thornhill MH: IL-1-alpha and IL-6 production by oral and skin keratinocytes: Similarities and differences in response to cytokine treatment in vitro. J Oral Pathol Med 1996;25:157–162. Moulin V, Castilloux G, Auger FA, Garrel D, O’Connor-McCourt MD, Germain L: Modulated response to cytokines of human wound healing myofibroblasts compared to dermal fibroblasts. Exp Cell Res 1998;238:283–293. Mauch C, Oono T, Eckes B, Krieg T: Cytokines and wound healing; in Luger TA, Schwarz T (eds): Epidermal Growth Factors and Cytokines. New York, Dekker, 1994, pp 325–344. Martin P: Wound healing – Aiming for perfect skin regeneration. Science 1997;276:75–81. Coleridge Smith PD: The microcirculation in venous hypertension. Vasc Med 1997;2:203–213. Cavender DE: Lymphocyte adhesion to endothelial cells in vitro: Models for the study of normal lymphocyte recirculation and lymphocyte emigration into chronic inflammatory lesions. J Invest Dermatol 1989;93:88S–95S. Shimizu Y, Newman W, Tanaka Y, Shaw S: Lymphocyte interactions with endothelial cells. Immunol Today 1992;13:106–112. Weyl A, Vanscheidt W, Weiss JM, Peschen M, Schoepf E, Simon J: Expression of the adhesion molecules ICAM-1, VCAM-1, and E-selectin and their ligands VLA-4 and LFA-1 in chronic venous leg ulcers. J Am Acad Dermatol 1996;34:418–423. Peschen M, Lahaye T, Hennig B, Weyl A, Simon JC, Vanscheidt W: The expression of the adhesion molecules ICAM-1, VCAM-1, LFA-1 and VLA-4 in the skin is modulated in progressing stages of chronic venous insufficiency. Acta Derm Venereol (Stockh) 1999;79:27–32. Vanscheidt W, Peschen M, Kreitinger J, Schoepf E: Paratibial fasciotomy: A new approach for treatment of therapy-resistant venous leg ulcers. Phlebology 1994;23:45–48 Scurr JH, Coleridge-Smith PD: The microcirculation in venous disease. Angiology 1994;45:537–541. Swerlick RA, Lawley TJ: Role of microvascular endothelial cells in inflammation. J Invest Dermatol 1993;100:111S–115S. Michiels C, Arnould T, Remacle J: Hypoxia-induced activation of endothelial cells as a possible cause of venous diseases: Hypothesis. Angiology 1993;44:639–646. Arnould T, Michiels C, Remacle J: Hypoxic human umbilical vein endothelial cells induce activation of adherent polymorphonuclear leukocytes. Blood 1994;83:3705–3716. Detmar M, Tenorio S, Hettmannsperger U, Ruszczak Z, Orfanos CE: Cytokine regulation of proliferation and ICAM-1 expression of human dermal microvascular endothelial cells in vitro. J Invest Dermatol 1992;98:147–153.


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Pastore S, Corinti S, La Placa M, Didona B, Girolomoni G: Interferon-gamma promotes exaggerated cytokine production in keratinocytes cultured from patients with atopic dermatitis. J Allergy Clin Immunol 1998;101:538–544. Steenfos HH: Growth factors and wound healing. Scand J Plast Reconstr 1994;28:95–105. Higley HR, Ksander GA, Gerhardt CO, Falanga V: Extravasation of macromolecules and possible trapping of transforming growth factor-beta in venous ulceration. Br J Dermatol 1995;132:79–85. Dvorak HF: Tumors: Wounds that do not heal. Similarities between tumor stroma generation and wound healing. N Engl J Med 1986;315:1650–1659. Peschen M, Grenz H, Brand-Saberi B, Bunaes M, Simon JC, Schoepf E, Vanscheidt W: Increased expression of platelet-derived growth factor receptor alpha and beta and vascular endothelial growth factor in the skin with chronic venous insufficiency. Arch Dermatol Res 1998;290:291–297. Peschen M, Grenz H, Grothe C, Schoepf E, Vanscheidt W: Patterns of epidermal growth factor receptor, basic fibroblast growth factor and transforming growth factor beta 3 expression in the skin with chronic venous insufficiency. Eur J Dermatol 1998;8:334–338. Stanley AC, Park HY, Phillips TJ, Russakovsky V, Menzoian JO: Reduced growth of dermal fibroblasts from chronic venous ulcers can be stimulated with growth factors. J Vasc Surg 1997;26: 994–1000. Peschen M, Weiss JM, Weyl A, Schoepf E, Vanscheidt W: Autologe thrombozyta¨re Wachstumsfaktoren bei Ulcus cruris; in Tebbe B, Goerdt S, Orfanos CE (eds): Dermatologie – Heutiger Stand. Stuttgart, Thieme, 1995, pp 94–95. Borbolla-Escoboza JR, Maria-Aceves R, Lopez-Hernandez MA, Collados-Larumbe MT: Recombinant human granulocyte-macrophage colony-stimulating factor as treatment for chronic leg ulcers. Rev Invest Clin 1997;49:449–451. Wood F, Griffiths TA, Stoner M: Epidermal-derived factors in the treatment of a chronic leg ulcer. J Wound Care 1997;6:256–258. Vaalamo M, Weckroth M, Puolakkainen P, Kere J, Saarinen P, Lauharanta J, Saarialho-Kere UK: Patterns of matrix metalloproteinase and TIMP-1 expression in chronic and normally healing human cutaneous wounds. Br J Dermatol 1996;135:52–59. Weckroth M, Vaheri A, Lauharanta J, Sorsa T, Konttinen YT: Matrix metalloproteinases, gelatinase and collagenase, in chronic leg ulcers. J Invest Dermatol 1996;106:1119–1124. Chapman HA: Plasminogen activators, integrins, and the coordinated regulation of cell adhesion and migration. Curr Opin Cell Biol 1997;9:714–724. Bechtel MJ, Reinartz J, Rox JM, Inndorf S, Schaefer BM, Kramer MD: Upregulation of cellsurface-associated plasminogen activation in cultured keratinocytes by interleukin-1 beta and tumor necrosis factor-alpha. Exp Cell Res 1996;223:395–404. Stacey MC, Burnand KG, Mahmoud-Alexandroni M, Gaffney PJ, Bhogal BS: Tissue and urokinase plasminogen activators in the environs of venous and ischaemic leg ulcers. Br J Surg 1993;80: 596–599. Jensen PJ, Lavker RM: Modulation of the plasminogen activator cascade during enhanced epidermal proliferation in vivo. Cell Growth Differ 1996;7:1793–1804. Peschen M, Grenz H, Lahaye T, Brand-Saberi B, Simon JC, Schoepf E, Vanscheidt W: Changes of cytokeratin expression in the epidermis with chronic venous insufficiency. VASA 1997;26: 76–80. Lotti T, Benci M: Plasminogen activators, venous leg ulcers and reepithelialization. Int J Dermatol 1995;34:696–699. Herrick SE, Sloan P, McGurk M, Freak L, McCollum CN, Ferguson MW: Sequential changes in histologic pattern and extracellular matrix deposition during the healing of chronic venous ulcers. Am J Pathol 1992;141:1085–1095. Peschen M, Zeiske D, Laaff H, Weiss JM, Schoepf E, Vanscheidt W: Clinical histochemical and immunohistochemical investigation of the capillary basal membrane in chronic venous insufficiency. Acta Derm Venereol 1996;76:433–436. Juhasz I, Murphy GF, Yan HC, Herlyn M, Albelda SM: Regulation of extracellular matrix proteins and integrin cell substratum adhesion receptors on epithelium during cutaneous human wound healing in vivo. Am J Pathol 1993;143:1458–1469.

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Clark RA: Potential roles of fibronectin in cutaneous wound repair. Arch Dermatol 1988;124: 201–206. Vollberg TM Sr, George MD, Jetten AM: Induction of extracellular matrix gene expression in normal human keratinocytes by transforming growth factor beta is altered by cellular differentiation. Exp Cell Res 1991;193:93–100. Herrmann G, Wlaschek M, Bolsen K, Prenzel K, Goerz G, Scharffetter-Kochanek K: Photosensitization of uroporphyrin augments the ultraviolet A-induced synthesis of matrix metalloproteinases in human dermal fibroblasts. J Invest Dermatol 1996;107:398–403. Kahari VM, Saarialho-Kere U: Matrix metalloproteinases in skin. Exp Dermatol 1997;6:199–213. Gailit J, Clark RA: Wound repair in the context of extracellular matrix. Curr Opin Cell Biol 1994; 6:717–725. Lagattolla NR, Stacey MC, Burnand KG, Gaffney PG: Growth factors, tissue and urokinase-type plasminogen activators in venous ulcers. Ann Cardiol Angeiol (Paris) 1995;44:299–303.

M. Peschen, MD, Department of Dermatology, Albert-Ludwigs-Universita¨t Freiburg, Hauptstrasse 7, D–79104 Freiburg (Germany) Tel. +49 761 270 67 01, Fax +49 761 270 68 18, E-Mail [email protected]


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Bacteriology of Leg Ulcers Albert-Adrien Ramelet a, Daniel Perrenoud a b

b

Specialist in Dermatology and Angiology, Lausanne, and Department of Dermatology, CHUV, Lausanne, Switzerland

Introduction Cutaneous wounds, independent of the underlying pathogenesis, are rapidly colonized by bacteria and yeast, either as saprophytes or pathogens. The bacterial flora in leg ulcers is different from the one found in wounds of other origins as well as from normal skin flora [1, 2]. This obviously determines the management of these wounds.

Collection of Bacterial Specimens from Leg Ulcers Microbiological sampling from leg ulcers entails the use of several qualitative or quantitative methods. Cotton-tipped swabs are the commonest and easiest way to obtain a qualitative sample. Anaerobes require a special transport container and culture medium. More subtle methods include culture from biopsy material, irrigation followed by aspiration and sampling with an absorbing pad. Needle aspiration of deep tissues yields quantitatively fewer colonies than swab specimens but allows for a better evaluation of relevant pathogens because superficial contaminants are kept to a minimum [3, 4]. These techniques are suitable for a qualitative and semiquantitative bacteriology [2, 3, 5]. The bacterial count per gram of tissue varies considerably. Therefore, several samplings should be obtained for an average assessment [5]. The use of selective culture media yields a better detection of specific bacterial strains [6]. Red fluorescence under the Wood lamp (a UV-A light source) provides an indication for the presence of Bacteroides melaninogenicus and demonstrates the presence of anaerobes [7].

Some odors are characteristic for certain bacterial infections. A foulsmelling or putrid odor suggests the presence of anaerobes [3, 7, 8]. Olfactory sensors, such as the Multi-Element Odor Detection (MEOD), might be useful for immediate detection of b-hemolytic streptococcal infection [9].

Interpretation of Bacteriology Derived from Leg Ulcers Our personal observations on microbiological findings in leg ulcers [5] are comparable to previously published observations. Staphylococcus aureus (up to 88%) [2], Enterococcus (up to 74%) [2], Pseudomonas (up to 60%) [5], Enterobacteriaceae (up to 40%) [5], Streptococcus and skin flora are the most common bacteria that can be cultured from leg ulcers. A number of ulcers are culture-negative for several weeks [5, 10–12]. However, a culture-negative swab might be due to the use of a nonselective culture media for the implicated strains. Selective culture media might yield more positive results for the bacteria in question [6]. In contrast, Hanson et al. [2] found all ulcers to be colonized in their study. In 70% of patients, more than one strain can be identified [2, 8, 10]. Bacteria will disappear spontaneously with ongoing wound healing. The make-up of the ulcer flora differs from that of the normal skin [2]. This pertains to the bacterial load and to the diversity of bacterial species. Prevalence of anaerobes varies widely in published literature (4.4–60%) [2, 6, 8, 12, 13] and may be higher in diabetics [12]. Yeast (mainly Candida) is found in 2.5–24% of leg ulcers [2, 5]. The bacterial species present on a wound basically remain unchanged during the whole wound healing process, irrespective of treatment [5, 12, 13]. Pseudomonas, however, may disappear, especially under semiocclusive dressings [8]. Parasites are found on chronic leg ulcers only in exceptional cases. Maggots may grow in chronic wounds and have even been used for the cleansing of ulcers [14].

Infection versus Colonization The answer to this issue is determined by clinical findings and not by microbiology. A bacterial count of ?105 microbial cells per mm2 of surface or per gram of tissue correlates well with the threshold for a clinically relevant infection. This method, however, is of little practical value since it cannot be routinely performed in everyday management of leg ulcers. Clinical signs for local infection that calls for treatment are cellulitis, pain, exudation and pus, adenopathy, sepsis and necrotizing fasciitis.

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Clinical Relevance of Isolated Strains Derived from Ulcers Microbiological results derived from venous leg ulcers obviously have no relevance for the etiology of the ulcer. Ulcers resistant to therapy may be more colonized by bacteria than well-healing ulcers. Most authors claim that aerobic, anaerobic bacteria and yeast do not influence the healing process of leg ulcers [2, 5, 6, 8, 13, 15]. Nor does the amount of microorganisms as determined by quantitative bacteriology affect the healing process [2, 13]. In contrast, the presence of anaerobes in a diabetic foot may be detrimental [3]. Four and more bacterial species on the same wound may be associated with impaired wound healing [6]. S. aureus, Pseudomonas and b-hemolytic streptococci were suspected to be a detrimental influence for wound healing [16–18]. S. aureus and Pseudomonas might impair the take of split skin grafts [16, 19]. Pseudomonas and Enterococcus faecalis are encountered more frequently on large ulcerations [2, 12, 17]. It is not clear if the healing process can be complicated by these strains. Halbert et al. [12] believe that bacterial colonization is associated with delayed healing, longer duration of ulceration and a larger wound size. On the other hand, bacterial colonization may facilitate the wound debridement due to their enzymatic activity. Semiocclusive hydrocolloid dressings do not facilitate bacterial proliferation. On the contrary, infections occur less frequently under semiocclusive dressings, than under nonocclusive ones. The composition of bacterial flora does not change under semiocclusive dressings [15] and Pseudomonas even tends to disappear from the wound [8]. A low pH due to high CO2-tension, and the activation of macrophages and neutrophils under semiocclusive conditions are probably responsible for the positive effect of occlusive hydrocolloid dressings on bacterial colonization [8]. In the case of relevant clinical infection, the use of semiocclusive dressings is contraindicated.

The Use of Antiseptics and Antibiotics in Leg Ulcers Long-term antibiotic treatment is useless in uncomplicated leg ulcers. It will just select for resistant flora and is expensive [20, 21]. Local antiseptics may be potent sensitizers and inhibitors of wound healing [1]. The same is true for topical antibiotics [5, 11, 19]. Therefore, an uncomplicated chronic leg ulcer that does not show signs of infection, does not require antimicrobial treatment. In the case of relevant clinical infection, systemic antibiotherapy according to an antibiogram is required. If S. aureus is suspected to be the leading strain, penicillinase-resistant b-lactam antibiotics are recommended. Chinolones, such as ciprofloxacin are the antibiotics of choice to start a treatment when

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Pseudomonas infection is suspected. Systemic metronidazole is not very effective against anaerobes in leg ulcers [7]. The use of topical antibiotics in the treatment of wound infection is controversial. At the very least, they should be used according to the suspected strains and to the antibiogram [11, 19]. Aminoglycosides are potent sensitizers. Their use should be carefully weighed against the possibility of contact eczema, the risk of inhibiting wound healing and the more general problem of inducing resistant strains. At any rate, the long-term use of topical antibiotics and antibiotic gauzes does not represent a standard local therapy for chronic leg ulcers and therefore should be avoided. Topical metronidazole might be more effective to eradicate the odor of putrid smelling wounds [7]. The use of topical antiseptics and dyes in the treatment of chronic wounds is controversial, as well [5]. Many of them are irritants, sensitizers or potent inhibitors of wound healing [1]. Dakin is also a popular and economical antiseptic, but its inhibiting effect on wound healing must be kept in mind. Moreover, the antimicrobial activity of antiseptics is compromised in vivo due to their inactivation by debris and pus. Some well-tolerated substances, such as triclocarban, disodium undecylenamide, triclosan, povidone-iodine and silver sulfadiazine, can be recommended in the local treatment of infected chronic leg ulcers. In contrast to antibiotics, antiseptics do not induce antibiotherapy resistance. Thorough rinsing and cleansing of the wound is more important than local antiseptics or antibiotics

Leg Ulcer and Tetanus Most patients suffering from leg ulcers have obtained a previous vaccination again tetanus. Their immunity may however be too low. Immigrants are frequently not immune against tetanus. The status of vaccination must always be checked and repeated if necessary.

Control of Group A b-Hemolytic Streptococci and of Methicillin-Resistant S. aureus In the hospital setting, certain pathogens represent a risk for other patients and for the medical staff. Group A b-hemolytic streptococci have to be eradicated, in first line with phenoxymethylpenicillin or, in the case of penicillin allergy, with a macrolide antibiotic, such as clarithromycin. Methicillin-resistant S. aureus (MRSA) represents a special nosocomial threat. These strains that are resistant to most major antibiotics [22], such as


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to penicillinase-resistant b-lactam antibiotics, often originate and spread from septic wounds. Therefore, all leg ulcers in inpatients have to be checked for the presence of MRSA. Strict containment measures have to be adopted for MRSA carriers. Usually, it is almost impossible to eradicate MRSA from chronic wounds. The germ does not affect wound healing and therefore does not represent a major risk for its carrier. Therefore, it is useless to try to eliminate MRSA with systemic antibiotherapy. On the contrary, such an attempt will even select for more resistant germs, such as resistance to vancomycin [22]. MRSA may disappear with complete healing of a wound. Until this aim has been achieved, locations of contamination (the wound, and eventually nostrils, axillary and inguinal folds and perineum) can be treated with local antiseptics, in first line with mupirocin, povidone-iodine or silver sulfadiazine [23]. After complete wound healing, containment measures in inpatients can be discontinued after two complete bacteriological examinations from the nostrils, axilla, groin and perineum have proven to be negative. If carriers require antibiotherapy against MRSA, e.g. for surgical procedures on the wound, vancomycin is the drug of choice [24].

Conclusions Most leg ulcers are colonized with bacteria and/or yeast. The presence of microorganisms generally does not impede wound healing. They will disappear spontaneously with ongoing wound healing, when their microenvironment is controlled. Bacteriology from uncomplicated chronic leg ulcers is of little interest, since it has no prognostic relevance on wound healing, nor does it warrant aggressive antibacterial treatment. Thorough rinsing and cleansing of the wound is more important than local antiseptics or antibiotics. However, leg ulcers are a potential source of cross-contamination and cross-infection for other patients, as well as for medical staff. For this reason, bacteriology should be performed routinely in inpatients with leg ulcers to rule out the presence of MRSA. Patients with clinical signs of relevant infection, such as cellulitis, require a systemic antibiotherapy that is adapted to an antibiogram.

References 1 2 3

Niedner R, Scho¨pf E: Wound infections and antibacterial therapy; in Westerhof W (ed): Leg Ulcers, Diagnosis and Treatment. Amsterdam, Elsevier, 1993, pp 293–303. Hanson C, Hoborn J, Mo¨ller A, Swanbeck G: The microbial flora in venous leg ulcers without clinical signs of infection. Acta Derm Venereol 1995;75:24–30. Gerding DN: Foot infections in diabetic patients, the role of anaerobes. Clin Infect Dis 1995; 20(suppl 2):283–288.

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Thivolet J, Fleurette J: Etude de la flore bacte´rienne ae´robie des ulce`res de jambe. Ann Dermatol Syph 1965;92:481–488. Ramelet AA: Bacte´riologie de l’ulce`re de jambe. Phlebologie 1992;21:177–182. Trengove NJ, Stacey MC, McGechie DF, Stingemore NF, Mata S: Qualitative bacteriology and leg ulcer healing. J Wound Care 1996;5:277–280. Witkowski JA, Parish LC: Topical metronidazole gel. The bacteriology of decubitus ulcer. Int J Dermatol 1991;30:660–661. Gilchrist B, Reed C: The bacteriology of chronic venous ulcers treated with occlusive hydrocolloid dressings. Br J Dermatol 1989;121:337–344. Parry AD, Chadwick PR, Simon D, Openheim B, McCollum CN: Leg ulcer odour detection identifies b-haemolytic streptococcal infection. J Wound Care 1995;4:404–406. Kontiainen S, Rinne E: Bacteria in ulcera crurum. Acta Derm Venerol (Stockh) 1988;68:240–244. Pardes JB, Carson PA, Eaglstein VH, Falanga V: Mupirocin treatment of exudative venous ulcers. J Am Acad Dermatol 1993;29:497–498. Halbert AR, Stacey MC, Rohr JB, Jopp-McKay A: The effect of bacterial colonization on venous ulcer healing. Australas J Dermatol 1992;33:75–80. Eriksson G, Eklund AE, Kallings LO: The clinical significance of bacterial growth in venous leg ulcers. Scand J Infect Dis 1984;16:175–180. Sherman RA, My-Tien Tran J, Sullivan R: Maggot therapy for venous stasis ulcers. Arch Dermatol 1996;132:254–256. Annoni F, Rosina M, Pezzoni F, Pisani F, Montorosi W, Marincola FM: Bacterial growth in venous ulcers of the lower extremity and its sensitivity to antibiotics. J Vasc Surg 1989;23:161–167. Gilliland EL, Nathwani N, Dore CJ, Lewis JD: Bacterial colonisation of leg ulcers and its effect on the success rate of skin grafting. Ann R Coll Surg 1988;70:105–108. Madsen SM, Westh H, Danielsen L, Rosdahl VT: Bacterial colonization and healing of venous leg ulcers. APMIS 1996;104:895–899. Schraibman I: The significance of beta-haemolytic streptococci in chronic leg ulcers. Ann R Coll Surg 1990;72:123–124. Lehmann L, Becker A, Gloor M: Lokalantibiotika in der Ulkustherapie. Phlebologie 1998;27: 25–31. Alinovi A, Bassissi P, Pini M: Systemic administration of antibiotics in the management of venous ulcers. J Am Acad Dermatol 1986;15:186–191. Huovinen S, Kotilainen P, Ja¨rvinen H, Malanin K, Sarna S, Helander I, Huovinen P: Comparison of ciprofloxacin or trimethoprim therapy for venous leg ulcers. J Am Acad Dermatol 1994;31: 279–281. Tabaqchali S: Vancomycin-resistant Staphylococcus aureus: Apocalypse now? Lancet 1997;350: 1644–1645. Yoshida T, Ohura T, Sugihara T, Ishikawa T, Homma K, Kouraba S, Kimura C, Murazumi M: Clinical efficacy of silver sulfadiazine for ulcerative lesions infected with MRSA. Jpn J Antibiot 1997;50:39–44. Ploy MC, Gre´laud C, Martin C, de Lumley L, Denis F: First clinical isolate of vancomycinintermediate resistant Staphylococcus aureus in a French hospital. Lancet 1998;351:1212.

Albert-Adrien Ramelet, MD, Specialist in Dermatology and Angiology, 2, place Benjamin-Constant, CH–1003 Lausanne (Switzerland) Tel. +41 21 312 60 60, Fax +41 21 320 40 90, E-Mail [email protected]


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Synthetic Dressings Josef Aubo¨ck Department of Dermatology and Venerology, General Public Hospital, Linz, Austria

Introduction Common experience that blisters heal faster when their roof is left intact was experimentally confirmed four decades ago [1]. Subsequently, it was substantiated that occlusive dressing can significantly accelerate wound healing by secondary intention [2, 3]. These findings promoted the development of modern dressing materials, which have in common the ability to create and maintain a moist environment for healing [4–12]. Moisture retention was originally obtained with completely occlusive materials, which frequently caused excessive accumulation of exudate. To date, many dressings are semiocclusive; they are semipermeable, inhibit permeation of liquids including exudate but allow transmission of water vapour and gases. Moisture vapour transmission rate (MVTR) [13] and water vapour permeance [14] give an exact measure of permeability. Although there may be some variance, MVTR of =35 g/m2/h has been associated with faster healing [13]. In comparison, water vapour loss from uncovered wounds is 4–6 times greater and ranges from 140 to 220 g/m2/h [11]. Another approach to achieving moist wound healing is the use of absorbing materials including polyurethane foams, salts of alginic acid and other gelable polysaccharides. From these components, dressing types as diverse as films, hydrocolloids, foams, hydrogels, as well as fibrous and particulate products are manufactured. Wound dressings are ready for use in a confusingly wide array of types and brands. Selection is often bewildering and requires consideration of the basics of wound healing, condition of the wound and properties of the dressing products [15–19]. This article describes the principles of moist wound healing, summarizes the scientific evidence for the rational use of moisture-retentive dressings, gives

an overview on the different dressing categories and attempts to provide advice on the selection process.

Moist Wound Healing The essential effects of synthetic dressings result from their ability to keep wounds moist. A moist environment provided by occlusive dressings is more conducive to wound healing than a drying environment beneath conventional dressings [4–12, 20–23]. This advantage has been demonstrated in acute [24–31] and chronic wounds, including leg ulcers [32–36] and pressure ulcers [37–41]. Moist wound environment stimulates dermal repair and accelerates epithelialization [27]. Synthetic dressings improve wound healing by several mechanisms. While air exposure causes desiccation of the wound and increases surface necrosis depth by 0.2–0.3 mm/2–3 h, a moist wound environment prevents scab formation [42]. Scab impedes keratinocyte migration and delays wound resurfacing. Compared with drying conditions, moist environment speeds up epithelialization by 30–50% and collagen synthesis by 20–60% [13]. Furthermore, regeneration of epithelia is expected to start 3 days earlier and wounds will heal 2–6 times faster [43]. Moreover, thermal insulation effects of wound dressings should be taken into consideration. For example, raising wound temperature to core temperature may stimulate mitotic activity and epithelialization more than twice [44]. On the other hand, lowering temperature below 28 ºC may substantially retard healing [45]. It has been shown that low oxygen tension (=5 mm Hg) and acidic pH (6–7) found under occlusive dressings [23] do not impair wound healing but rather promote fibroblast proliferation, angiogenesis and keratinocyte migration [5]. Another important aspect of many synthetic dressings is their ability to alleviate pain [28, 46].

Autolytic Debridement In addition, moist environment fosters wound healing by autolytic debridement, which is defined as spontaneous disintegration of tissue by the action of the body’s own enzymes or serum [47]. Thus, the wound is cleansed by wound fluid components, which rehydrate, soften and liquefy both necrotic tissue and slough. The process of autolytic debridement may initially lead to visible worsening in the appearance of the wound. This is normal and should not give rise for concern. Polymorphonuclear leukocytes and macrophages contained in

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the wound fluid promote autolytic debridement and supply the enzymes required. Moist environment favours the activation of local enzymes, which digest fibrin [48–50] and necrotic tissue [51, 52] delaying the healing process. Autolytic debridement is selective and practically painless. It can be accomplished by all sorts of dressings, which are capable of keeping wounds moist. In addition to autolytic debridement, most synthetic dressings also exert significant mechanical cleansing action of variable degree. Bacteria, debris and odour molecules together with the wound fluid are incorporated into the dressing material and regularly removed when the dressing is changed. In contrast, drying dressings provide mechanical debridement and displace tissue from the wound surface indiscriminately [53] and traumatically [27, 54]. In general, moisture-retentive dressings are not likely to re-injure healing tissue when taken off the wound [41, 55, 56].

Properties of Wound Fluid The composition of wound fluid accumulating under synthetic dressings may reflect the microenvironment of the wound and the adjacent tissue fluid [57]. Analysis by sodium dodexyl sulphate-polyacrylamide gel electrophoresis established clear similarities of wound exudate to serum [58]. Exudate obtained from acute wounds has been shown to stimulate proliferation of keratinocytes [24], fibroblasts [57–61], endothelial cells [61, 62] and smooth muscle cells [63] in vitro. Numerous cytokines and growth factors have been shown to be present in animal and human wound fluid: e.g. platelet-derived growth factor [57, 61, 64–66], transforming growth factor-a [65, 67], transforming growth factor-b [65, 66], basic fibroblast growth factor [57, 66, 68, 69], tumour necrosis factor-a [69, 70], epidermal growth factor [69], insulinlike growth factor I [71, 72], interleukin-1a [69], interleukin-6 [65] and somatomedins [73]. While wound fluid obtained from acute wounds usually stimulates cell growth in vitro [74], exudate taken from chronic wounds has been demonstrated to inhibit cell proliferation of cultured fibroblasts, endothelial cells and keratinocytes [75, 76]. Chronic wound fluid contains markedly increased levels of metalloproteinases leading to uncontrolled degradation of the adhesion proteins fibronectin and vitronectin and presumably growth factors, which may explain retardation and inhibition of the healing process [77–79]. Reconciling these findings with clinical experience on moist wound healing, one may argue that the inhibitory effects of chronic wound fluid demonstrated under in vitro conditions might be compensated – at least in part – by the use of moisture-retentive dressings.

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Synthetic Dressings and the Risk of Infection Initial concerns that microbial growth under synthetic dressings might increase infection rates [80] have been disproved. Even though enhanced bacterial growth and a shift in bacterial flora to gram-negative microorganisms under occlusive conditions has been documented [81–83], this is not associated with an increased risk for wound infections [33, 84]. An extensive retrospective analysis comparing conventional with occlusive dressings (including hydrocolloids, films, foams and hydrogels) revealed that use of occlusive dressings may reduce clinical infection rate from 5.37 to 2.05% [85]. Hydrocolloids were associated with the lowest infection rates [85]. Fewer infections with synthetic dressings have also been reported on prospective studies in burns [24] and skin donor sites [31]. Moist wounds heal well despite the presence of dense colonization by aerobic and anaerobic bacteria [85, 86]. Reasons for this might include fewer dressing changes resulting in reduced trauma to the healing tissue and foregoing the use of topical antimicrobials known to retard cell growth [87]. Another possible explanation is enhancement of the host’s defence mechanisms, since wound fluid underneath occlusive dressings has been shown to contain viable neutrophils, macrophages, lymphocytes and monocytes [88, 89]. Phagocytosis and bactericidal activity mediated by neutrophils and an active complement system can be observed in moist environment [23, 85, 90]. Moreover, occlusion promotes autolytic removal of necrotic tissue which is susceptible to wound infection [13, 52]. Finally, occlusive dressings may protect wounds from exogenous contamination with bacteria [84] and viruses [91]. They are effective in preventing the spread of methicillin-resistant Staphylococcus aureus (MRSA) [92] and reduce the risk of distribution of bacteria and airborne contamination [93].

Types of Synthetic Dressings Most synthetic wound dressings share the ability to create and maintain a moist wound environment for enhanced healing and the capacity to promote autolysis of necrotic tissue by retaining moisture at the wound surface. They differ widely in composition, hydrating ability, absorbent capacity, vapour permeability, flexibility, conformability, adhesive properties, indication and handling as well as their distinctive benefits, limitations and drawbacks. Synthetic dressings can be categorized into: (1) films; (2) hydrocolloids; (3) foams; (4) hydrogels; (5) alginates; (6) hydrofibres, and (7) fibrous products and beads.

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Nomenclature Sometimes nomenclature of dressings may give rise to confusion. ‘Semiocclusive’ or ‘semipermeable’ dressings are impermeable to fluid but allow transmission of vapour and gases (i.e. category 1–2, some products of category 3–4). The term ‘occlusive’ is most often applied to products that retain moisture at the wound site (i.e. category 1–6), even though in a strict sense occlusive means impermeable. Similarly, the designation ‘interactive’ has been coined for ‘moisture-retentive’ dressings (i.e. category 1–6) [52]. It emphasizes their ability to interact with tissue to promote the wound healing process in contrast to conventional ‘passive’ dressings. Thus, the terms synthetic, occlusive, interactive and moisture-retentive in conjunction with wound dressings are frequently used interchangeably. Synthetic dressings may be used both as primary and secondary dressings. ‘Primary’ dressings are placed directly onto the wound bed, ‘secondary’ dressings serve to cover and attach a primary dressing. ‘Island’ dressings are made up of a central absorbent part surrounded by a peripheral adhesive border. ‘Composite’ dressings are island dressings defined both by specific construction and by the type of material involved. They consist of a semipermeable bacterial barrier (e.g. polymer film), an absorbent, nonadherent textile layer (e.g. cellulose, polyester) and an adhesive border. Compound dressings, in which the absorbent layer is a hydrocolloid, a hydrogel, foam or an alginate, should therefore not be referred to as composite dressings. It should be borne in mind that not every island dressing is a composite dressing.

Transparent Films [4–12, 94–98] Characteristics/Function Films consist of a thin, transparent polymer sheet (e.g. polyurethane) that is coated with an adhesive layer (e.g. acrylate). Film dressings are typically semipermeable showing MVTRs in the range of 18–36 g/m2/h. It is important to distinguish them from newer high permeability films with several times greater MVTRs. The latter are targeted for use as catheter dressings. Dressing of wounds with high permeability films may lead to drying of tissue and delay of the healing process. While the performance of most brands of film dressings is very similar, they differ in their ease of application. In order to improve handling, some polymer films are equipped with a frame or window delivery system. The film suspended on a frame can be easily and precisely placed without wrinkling and sticking to itself; following attachment the frame is lifted and the film is slightly smoothed into position. Film dressings stick only to intact epithelium.

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Products BioclusiveTM, EpiviewTM, OpraflexTM, OpsiteTM, TegadermTM, etc. Best Uses Film dressings are most appropriate for treating superficial partial-thickness wounds (e.g. blisters, erosions, shallow ulcers, donor sites) and wounds with only little exudate. They are in use for covering intravenous and other catheter sites. Furthermore, films are employed as retention dressings over topical products or various primary dressings and are of great benefit in the prevention of friction damage to skin in susceptible areas of bedridden patients. Advantages/Benefits Films are semipermeable, flexible and transparent permitting continuous evaluation of the wound without removal of the dressing. Furthermore, they provide an effective barrier to external contamination and allow patients to bathe or shower with the dressings in position. Disadvantages/Shortcomings Transparent films have no absorbent capacity, which is why accumulation and leakage of excess wound fluid may occur and lead to maceration and dermatitis of surrounding skin. Removal of film dressings may be painful to the patient especially on hairy skin. Due to their adhesive properties, film polymers have the potential of causing skin tears if removed improperly. They may also cause stripping of newly formed epithelium resulting in a delay of wound healing. In order to break the seal of the adhesive in a gentle manner, it is recommended to stretch the film dressing parallel to the wound rather than to tear it off in an upwards direction.

Hydrocolloids [4–12, 99–104] Characteristics/Function Hydrocolloids are among the most widely used modern dressings and represent absorbent, self-adhesive, waterproof and flexible wafer compounds. They consist of a semipermeable coating (e.g. polyurethane foam or film) that is bonded to a layer that contains hydrophilic colloidal gel-forming particles (e.g. carboxymethylcellulose, gelatine, pectin) dispersed into a hydrophobic adhesive mass or cross-linked matrix (mostly polyisobutylene). When a hydrocolloid dressing comes into contact with wound exudate, it absorbs liquid and swells to form a gel, which covers the wound bed and maintains a moist environment. Some hydrocolloid dressings produce a cohesive gel, which re-

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mains contained within the polymer matrix, while others result in a more mobile, less viscous gel that is not withheld in the dressing structure. The volume of exudate that can be handled by a hydrocolloid dressing depends upon the quality and quantity of hydrocolloid particles incorporated and the moisture vapour permeability of the backing layer. In the dry state most hydrocolloid dressings are virtually impermeable to water vapour, but as they take up fluid and the gelling proceeds, the permeability increases until a steady state is reached. Water vapour transmission through the dressing enhances the ability of the product to cope with exudate production. Hydrocolloids differ significantly in absorbency, structure, design, composition, flexibility, dimensions and other performance parameters. Products BiofilmTM, ComfeelTM, CutinovaTM, DuoDERMTM, GranuflexTM, HydrocollTM, RestoreTM, TegasorbTM, VarihesiveTM, etc. Several products are available in multiple presentations (e.g. thin, extra thin, bordered, oval, square or triangular shape). Some products (e.g. BiofilmTM, ComfeelTM, GranuflexTM) are at hand in the form of a paste, for the treatment of cavity wounds, or as a powder to provide enhanced fluid handling properties in the management of heavily exuding wounds. Also a hydrofibre dressing (AquacelTM) in the form of a hydrophilic nonwoven sheet composed entirely of hydrocolloid fibres (sodium carboxymethylcellulose) is available for the management of exuding wounds. Paste, powder and the hydrofibre dressing should be covered with a moisture-retentive dressing such as a hydrocolloid sheet or a semipermeable film. Best Uses Hydrocolloids are used as primary dressings in the treatment of granulating superficial to flat as well as light to moderately exuding wounds (e.g. leg ulcers, pressure sores). Hydrocolloids are also indicated for second-degree burns and for the promotion of re-epithelialization at skin donor sites. Thin or extra thin versions of hydrocolloid dressings may be used in the management of superficial skin defects (e.g. erosions, abrasions) or as secondary dressings over different dressing products (e.g. hydrogels, alginates). They may also be employed prophylactically to help prevent friction damage to the skin of patients who are at risk of developing pressure sores. Advantages/Benefits Hydrocolloids are self-adhesive and flexible and allow for easy application even to areas subject to movement such as elbows and ankles. They help in reducing pain and are comfortable to wear. On patients with venous leg ulcers

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they can be applied beneath compression bandages or stockings. However, care has to be taken keeping secondary dressing to a minimum, as it may decrease the permeability of the hydrocolloid and critically inhibit transmission of water vapour. Unlike most wound dressings, hydrocolloids can adhere to a moist and dry site as well. Hydrocolloids facilitate control of wound exudate by absorption and water vapour transmission. Moreover, firmly applied over leg ulcers they may effectively diminish production of wound fluid, because the pressure gradient created by accumulation of wound fluid beneath the dressing may inhibit further exudation [102]. Most hydrocolloid dressings are waterproof and provide an effective barrier against contamination from external sources. Hydrocolloids have been successfully employed to prevent the spread of MRSA from the wound bed to the external enviromnent [92]. The impermeable nature of hydrocolloids enables patients to bathe or shower with the dressings in place; also for bedridden patients daily hygiene is made much more comfortable. Hydrocolloid dressings are very gentle to the wound. Upon gel formation, adhesion over the wound decreases, so that the dressing remains attached only to the intact skin. Removal does not injure the healing tissue and is painless to the patient. Disadvantages/Shortcomings Gel residues from hydrocolloid dressings may cause inflammatory reaction in the wound. However, the clinical relevance of this finding has yet to be proved. Allergic contact dermatitis from hydrocolloid dressings has been reported [105–107]. Heavily exuding wounds may exhaust the resorptive capacity of the hydrocolloid dressing within a few days. With some products, upon removal of the dressing a viscous gel with a characteristic odour may be found on the surface of the wound. This is due to breakdown of the hydrocolloid and must not be confused with purulent discharge or interpreted as an indication for the presence of infection. It may be removed by cleansing with saline before the application of the next dressing.

Foam Dressings [4–12, 108–114] Characteristics/Functions Foam dressings in their basic form represent sheets of foamed hydrophilic polymers (e.g. polyurethane) of variable thickness, cell size and structure. Composition of modern foam dressings is generally more complex. Most of them are coated with a semipermeable film layer (e.g. polyurethane, polyester, or silicone), which provides an effective barrier to water and wound exudate

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and also prevents the passage of microorganisms through the exterior barrier of the dressing. Some foam dressings are supplied with an adhesive coating on the wound contact side or an adhesive border at the margin (island configuration). When applied to an exuding wound, the dressing will absorb excess fluid but maintain the wound surface in a moist condition. Due to their cellular structure, foams absorb wound exudate and keep it off the wound bed minimizing the risk of maceration to the peripheral skin. The aqueous component of the absorbed fluid is lost by evaporation through the semipermeable outer layer of the dressing. Cellular debris and protein material remains trapped in the pores of the wound contact surface, which rapidly become occluded if the wound is dirty or produces large volumes of exudate. Products AllevynTM, Cavi-CareTM, CombiDermTM, CutinovaTM, EpigardTM, LyofoamTM, TielleTM, etc. Most foams are available in sheet form, but ‘cavity’ versions are also available. Silastic foam, which is made by adding a stannous octoate catalyst to a silicone mixture, can be applied and moulded exactly to the shape of the cavity. Best Uses Foams (except for thin products) represent the most absorbent wound dressing materials. They are the appropriate choice for treating moderate to heavily exuding wounds (e.g. venous ulcers, pressure ulcers, burns and donor sites). Cavity versions (e.g. chopped foam pieces encapsulated within a thin perforated low-adherent polymeric pouch) work well in deep cavity wounds preventing premature closure while absorbing exudate and maintaining a moist environment. Extra thin foams exert only modest absorbency and are best suited for superficial wounds (e.g. erosions); their resilience makes them an ideal dressing for fingers and toes. Advantages/Benefits Foams are highly absorbent and are able to cope with significant volumes of exudate. They do not shed residues such as fibres or particles, are conformable, can be easily cut, provide thermal insulation and are comfortable to wear. Some manufacturers promote polyurethane foams as an alternative to hydrocolloids. However, a study involving 100 patients with leg ulcers and 99 patients with pressure sores did not reveal any statistically significant difference between a hydropolymer and a hydrocolloid dressing with respect to healing although the hydropolymer performed better with respect to dressing leakage and odour production [115].

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Disadvantages/Shortcomings Foams are opaque and do not permit inspection of the wound. They can exert a drying effect on the wound if there is not enough exudation. Nonadherent foams require a secondary dressing layer to keep them in place.

Hydrogels [4–12, 116–120] Characteristics/Function Two basic types of hydrogel dressings are currently used in wound management, the sheet (or wafer) and the amorphous (or shapeless) variant. Sheet hydrogels are composed of a small quantity (usually 4–10%) of a three-dimensional network of hydrophilic synthetic or semisynthetic crosslinked polymer (e.g. polyacrylamide, polyethylene oxide, and agar) that incorporates water to form a solid sheet of gel. Some brands of hydrogel dressings are covered with a semipermeable germ- and waterproof top layer (e.g. polyurethane film) and may be equipped with an adhesive border. Depending on water content, the sheets may feel moist and slippery. However, squeezing the hydrogel sheet will not set free any of the water trapped within the polymer network. Despite their high water content, hydrogels are able to bind additional fluid due to the presence of hydrophilic residues. However, absorption is slow and delayed as compared with textile materials, alginates, hydrocolloids or foams. Amorphous hydrogels are of similar composition as sheets but are devoid of a fixed three-dimensional cross-linked structure and therefore do not take on a fixed shape. Most amorphous hydrogels consist of about 2–3% of a gelforming polymer, such as carboxymethylcellulose, modified starch or alginate, together with 20% propylene glycol as a humectant and preservative. The balance, about 80%, consists of water. Amorphous hydrogels preimpregnated into gauze dressings are also available. Products Hydrogel sheets: GelipermTM, HydrosorbTM, OpragelTM, TegagelTM, Spenco nd 2 skinTM, VigilonTM, etc. Amorphous hydrogels: DuodermTM, GelipermTM, IntrasiteTM, NormlgelTM, NugelTM, RestoreTM, Varihesive hydrogelTM, etc. Best Uses Hydrogel sheets are of great benefit in superficial, partial-thickness skin defects, particularly in painful wounds with minimal or no exudation (e.g. erosions, ulcers, pressure ulcers, first- and second-degree burns, donor sites for split skin grafts). By immediately increasing moisture content, hydrogels

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foster debridement of necrotic tissue in dry wounds. Amorphous hydrogels are best covered and secured by semipermeable films or thin hydrocolloid dressings. Cavity wounds should not be filled entirely but only covered with an appropriate layer of amorphous gel and then packed up loosely with an alginate or hydrofibre gauze (preimpregnated with gel). Advantages/Benefits Hydrogel sheets are excellent for creating and maintaining a moist environment and are very effective in hydrating and liquefying necrotic tissue on the wound surface, as far as a semipermeable secondary dressing prevents desiccation. Unlike hydrocolloids, foams or alginates, hydrogels do not require exudation to attain gelatinous consistence. Most hydrogel dressings are transparent allowing for easy inspection of the wound. Patients appreciate their cooling and soothing effect especially in the treatment of painful wounds. Provided that they are not allowed to dry out, hydrogel dressings do not adhere to the wound and can be gently removed painlessly without damage to the fragile granulation tissue or newly formed epithelia. Disadvantages/Shortcomings Some products are very poor barriers to microorganisms. Nonadherent hydrogel sheets require secondary dressing; slipperiness of some products may make fixation difficult. Especially on dry wounds, hydrogel dressings have a tendency to dry out. Because of limited absorptive capacity they are inappropriate for heavily exuding wounds, where they can cause maceration. Unlike hydrogel sheets, amorphous hydrogels do not exert cooling effects. They will decrease viscosity as they warm up to body temperature and may be difficult to retain in the wound bed. Improper use will cause maceration of the skin around the wound.

Alginates [4–12, 121–126] Characteristics/Function Alginates are highly absorbent, biodegradable fibre products derived from brown seaweed. For wound dressings, calcium alginate (calcium salt of alginic acid) is most widely used. Alginates possess a complex structure and are composed of mannuronic and guluronic acid forming linear polymers. Alginate dressings conform easily to the wound bed and are available in the format of a flat nonwoven pad for application to open wounds, a loose rope for packing of cavities and a ribbon for narrow wounds or sinuses. In contact with wound exudate or fluids containing sodium ions, the insoluble calcium alginate is partially converted to the soluble and gelable sodium

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salt. Thus, with uptake of exudate, alginates form a nonadherent gel covering the wound and create a moist environment. Alginates possess enormous absorptive capacity exceeding their own weight many times. The handling properties of the resulting alginate gels may greatly differ. Thus, dressings rich in guluronic acid retain their basic structure and can be removed from the wound bed in one piece, while those rich in mannuronic acid form soft amorphous gels leaving significant residues on the wound surface that have to be rinsed off with saline. A comparative study on four alginate dressings did not reveal a significant difference in their effect on epithelialization [124]. Products AlgosterilTM, KaltostatTM, SorbalgonTM, SorbsanTM, TegagenTM, etc. Best Uses Alginates are very useful for moderate to heavily exuding wounds (e.g. split skin graft donor sites, leg ulcers, pressure ulcers, diabetic and trophic foot ulcers, and cavities). Since they require moisture to work correctly, alginates are not indicated for dry wounds. For shallow, heavily exuding wounds, alginate sheets may be chosen, while cavity wounds are preferably dressed with alginate fibre in the form of ribbon or rope. Advantages/Benefits Alginates are highly absorbent; they are particularly useful for packing exuding wounds and do not inhibit wound contraction like gauze. It is widely believed that alginates possess haemostatic activity. However, the value of alginates in this area has been challenged recently [127]. Disadvantages/Shortcomings Alginates must be attached by secondary dressings; film, hydrocolloid or foam dressings are adequate and prevent the gel from desiccation. The use of alginates on wounds with low exudation should be discouraged, because they tend to dry out under these conditions. Dried alginate material may irritate and be quite difficult to remove from the wound bed. Like hydrocolloids, alginate gels may produce an offensive odour and develop a purulent appearance that may be mistaken for a wound infection. Hydrofibres [128] Characteristics/Function Hydrofibre dressings are highly absorptive and entirely composed of hydrocolloid (sodium carboxymethylcellulose) fibres. They absorb exudate imme-

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diately and undergo rapid conversion to a soft coherent gel. Exudate is taken up into the dressing merely in a vertical way and remains incorporated in the sectors of primary contact. Since hydrofibre dressings can retain exudate within the structure of the fibres even under compression and do not allow horizontal spreading of fluid, they provide excellent protection from maceration of the surrounding skin. Products AquacelTM. Hydrofibre products are available as nonwoven sheets or ribbons. Best Uses Hydrofibres are particularly useful in the treatment of heavily exuding wounds (e.g. leg ulcers, pressure sores, diabetic ulcers, donor sites, wounds left to heal by secondary intention). Hydrofibres should be placed onto the wound overlapping the peripheral skin by at least 1 cm. The ribbon is intended for use in cavity wounds and should be loosely applied but not packed in tightly. Hydrofibre dressings need to be covered with a secondary dressing such as a semipermeable film or a hydrocolloid sheet. In addition, hydrofibre dressings used to cover particularly skin areas prone to maceration (e.g. border of fistula or ulcer, periphery of various oozing skin conditions) have proven very effective in preventing impending damage of skin surface [pers. observ.]. Advantages/Benefits Hydrofibre dressings are highly absorbent and may incorporate exudate up to 30 times their weight. (In comparison, alginates absorb up to 20 times their weight.) Even in the presence of heavy exudation, their exquisite absorptive capacity essentially eliminates the risk of maceration to the peripheral skin. It has been shown that in the treatment of leg ulcers, hydrofibre dressings can remain in place up to 7 days [128]. Disadvantages/Shortcomings Hydrofibre dressings do not form an effective barrier to moisture vapour loss from the skin and must be kept in place by secondary semipermeable dressings. Because of their exceptional absorbency, hydrofibre dressings are very suitable for the management of exuding wounds but not for the management of dry skin defects.

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Guidelines for Use of Synthetic Dressings [4–12, 15–19, 129] The choice of the right wound dressing may be puzzling and requires more than following a simple cookbook recipe. It depends very much on experience, practical skills and personal commitment. Finally, it calls for interdisciplinary acceptance and for cooperation between all professions involved in wound management [130]. At any time of treatment it is important to make sure of patients’ compliance. In particular, they should be carefully instructed about the specific features of the dressings in use. For example they should be prepared that an initial enlargement of the wound area and a partly unpleasant odour accompanying dressing removal is normal and may be indicative for successful debridement. The selection of a wound dressing involves knowledge and consideration of the: (1) Principles of wound healing (2) State of the wound Configuration: superficial – deep – cavity; undermined edges Localization: uneven area – hairy skin – mobile region (e.g. over joint or flexure) Bacterial involvement: sterile – colonized – infected Dimensions: size, shape (e.g. oval, round, regular, irregular) Exudate: absent – minimal – moderate – heavy Wound bed: necrotic (black) – sloughy (yellow) – granulating (red) – epithelializing (pink) Condition of peripheral skin: dermatitic – macerated – normal Other characteristics: malodorous, painful (3) Performance parameters of wound dressings Fluid-handling properties (e.g. absorbent capacity, water vapour transmission, hydrating activity to dry wounds) Promotion of moist environment and autolytic debridement Barrier function (e.g. to microorganisms, water, exogenous agents) Adherence Shape, size, ease of application Flexibility (e.g. over joints) and conformability (e.g. to wound contours) Pain reduction Odour-eliminating properties Side effects (e.g. irritation, sensitization) Other: haemostatic activity, thermal insulation, cushion effect (4) Patient characteristics Condition: mobile, chair-bound, bedridden

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Demands: specified interval until next dressing change, showering or bathing (without disturbing wound dressing) Compliance (5) Economic aspects The general principles of wound care include cleansing, debridement, protection and providing a moist wound environment. The type of moistureretentive dressing to use depends mainly on the condition of the wound bed. Therefore, careful assessment of the wound is a fundamental prerequisite. Necrotic wounds covered with black devitalized tissue as well as wounds covered by thick yellow slough (composed of fibrin, nucleoproteins, serous exudate, leukocytes and bacteria), should be thoroughly cleaned by surgical or mechanical debridement, before synthetic dressings are applied. Although it is accepted to exclusively rely on autolytic debridement in the management of sloughy and necrotic wounds, in my opinion surgical or mechanical debridement is preferable, because it cleans the wound instantly. This may both notably shorten healing time and significantly minimize the risk of infection [131]. In dry wounds, hydrogel dressings can be used to provide moisture and rehydrate devitalized tissue for promotion of autolytic debridement. In cavity wounds, conformable dressings (e.g. alginates, hydrofibre dressing, and ‘cavity’ foams) are employed to fill the void space or quickly absorb copious amounts of exudate. Sinuses and other lesions with a narrow opening into a flask-shaped cavity under the skin may be lightly packed with an alginate ribbon to ensure that the orifice does not close before the main part of the wound is healed. Heavily exuding wounds (e.g. granulating wounds) require dressings with high absorbent capacity (e.g. alginates, foams, hydrocolloids, paste and powders). For wounds with minimal exudation (e.g. epithelializing wounds) thin hydrocolloids, thin foam dressings, hydrogels or even transparent films may be appropriate. Contraindications of Synthetic Dressings Colonization of chronic wounds is common and is not a contraindication to the use of synthetic dressings. In contrast, synthetic dressings are not recommended on wounds that show evidence of clinical infection. Whenever infection develops, systemic antibiotic therapy should be initiated. If the use of synthetic dressings is continued, progress of the wound should be monitored carefully. This may mean changing the dressing for the purpose of inspection more frequently than would otherwise be the case. The use in the presence of anaerobic infection should be avoided. Moreover, products with semiperme-

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able properties should not be applied over cavity wounds, undermining wounds and exposed structures such as bones, muscles or tendons. Synthetic dressings should not be fixed to dermatitic skin. Contact allergy against a dressing component precludes the use of the offending product. General Handling Instructions In order to ensure secure attachment, adhesive dressings (especially films, hydrocolloids, some foams) should be allowed a minimum overlap of 2–4 cm from the margin of the wound onto the surrounding skin. The edges are smoothed down with gentle pressure to ensure good adhesion. Adhesive dressings should be applied neither too loosely nor under tension; the first might facilitate wrinkling of the dressing and allow leakage of exudate and entry of exogenous bacteria, the second might cause blister formation as well as ischaemia and necrosis at the periphery of the wound. Similarly, excessive accumulation of fluid beneath the dressing may break up the adhesive seal, allow leakage of fluid onto the patients’ clothes and bedding with consecutive spreading of microorganisms. On heavily exuding wounds, large quantities of fluid sometimes accumulate beneath an adhesive dressing. Saturation of the dressing is indicated by the formation of a ‘blister’ over the wound, making it easy to recognize the proper time for a dressing change. To avoid frequent dressing changes, accumulated fluid may even be aspirated with a syringe using an aseptic technique. A small patch of transparent film can be applied over the puncture to prevent leakage or contamination. For some basic notes with regard to handling nonadhesive dressings, the reader may refer to the corresponding categories’ sections above. Frequency of Dressing Change Inappropriate use or too frequent dressing change may result in skin irritation or stripping. The frequency of dressing change depends on the amount of exudate produced by the wound and the absorptive capacity of the dressing. No consistent recommendation in terms of a definite number of days can be given how long a particular type of dressing might be left in position. However, if the drainage contained in the dressing matches or exceeds its absorptive capacity, the dressing has to be changed. Another important determinant is the integrity of the dressing with respect to structure and attachment. A loosely adherent dressing compromises the optimal wound environment by potentially allowing the wound to dry out or become contaminated by exogenous bacteria or foreign material. Also contamination of the dressing (e.g. with urine, faeces) and clinical signs of infection in the wound area warrant immediate dressing change.

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During the early stages of wound treatment, particularly if slough is present and the exudation is heavy, dressings may require changing on a daily basis or every 2–3 days. When the wound becomes clean and granulation takes place, the frequency of dressing change may be reduced parallel to the decline of exudation. Finally, in the epithelialization stage of healing with only light exudation, some dressings (especially hydrocolloids) may be left undisturbed for up to 7 days. Alginates and hydrogels, particularly if they are used as wound fillers, should be changed once daily. Economic Aspects Since many of the modern wound dressings are substantially more expensive than traditional gauze dressings, there is often resistance against their use. However, addressing ‘per unit cost’ only does not reflect the true cost of care. The latter includes the frequency of dressing changes, cost of alternative materials, treatment efficacy (e.g. time to healing, complications) as well as the cost of caregiver time [132]. Comparisons made upon a basis of treatment but not on unit costs have demonstrated that dressing the wound with moistureretentive materials such as films [39], hydrocolloids [133–136], alginates [137], hydrogel [138] and foam elastomer [139] may be less expensive than using traditional dressings (e.g. saline gauze).

Conclusions It is commonly accepted that a moist environment accelerates healing of wounds. Modern synthetic dressings retain moisture at the surface of the wound by either occlusive or absorptive properties and permit variable degrees of water vapour transmission and gas exchange. Because they maintain a moist environment these dressings promote autolytic debridement, which in contrast to other methods of wound cleansing is highly selective and does not damage the healing tissue. Several categories of wound dressings are available for the wound care practitioner. Documentation from controlled studies on the relative effectiveness of these dressings is scarce. Selection is often based on personal preference and anecdotal evidence. Understanding the characteristics of the dressing materials will help in making the right choice on a rational basis. No single category or brand fulfil the needs for all wound types and all stages of healing. Regular reassessment of wounds is essential and should guide product selection. Frequency of dressing change is variable and depends mainly on dressing products and wound characteristics. Proper wound management concepts and objectives should be defined. Even though some chronic wounds may never heal, optimal wound care at least can significantly improve quality

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of life: it may reduce pain, minimize odour, decrease frequency of dressing changes, preclude leakage of exudate through dressing material onto clothing, ease personal hygiene and allow for greater mobility.

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Schliz M, Rauterberg A, Weiss J: Allergic contact dermatitis from hydrocolloid dressings. Contact Dermatitis 1996;34:146–147. Sasseville D, Tennstedt D, Lachapelle JM: Allergic contact dermatitis from hydrocolloid dressings. Am J Contact Dermatitis 1997;8:236–238. Wood RAB: Foam elastomer dressing in the management of open granulating wounds: Experience with 250 patients. Br J Surg 1977;64:554–557. Thomas S: Foam dressings: A guide to the properties and uses of the main foam dressings available in the UK. J Wound Care 1993;2:153–156. Callam MJ: Lothian and Forth Valley Leg Ulcer Healing Trial. 2. Knitted viscose primary dressing versus a hydrocellular dressing in the treatment of chronic leg ulceration. Phlebology 1992;7:142– 145. Bale S, Harding KG: Foams still find favour. Wound management using foam dressings. Prof Nurse 1991;6:510–518. ¨ rztl Fortbild (Jena) Sedlarik KM: Modern wound dressings. 5. Foam dressings (in German). Z A 1994;88:141–143. Williams C: Allevyn. Br J Nurs 1995;4:107–108. Williams C: Lyofoam. Br J Nurs 1996;5:757–759. Thomas S, Banks V, Bale S: A comparison of two dressings in the management of chronic wounds. J Wound Care 1997;6:383–386. Corkhill PH, Hamilton CJ, Tighe BJ: Synthetic hydrogels. VI. Hydrogel composites as wound dressings and implant materials. Biomaterials 1989;10:3–10. Thomas S, Hay P: Fluid handling properties of hydrogel dressings. Ostomy Wound Manage 1995; 41:54–56. Sedlarik KM, Vacik J, Wichterle O, Berg D: Modern wound dressings. 3. Hydrogels (in German). ¨ rztl Fortbild (Jena) 1993;87:431–436. ZA Bale S, Banks V, Haglestein S, Harding KG: A comparison of two amorphous hydrogels in the debridement of pressure sores. J Wound Care 1998;7:65–68. Agren MS: An amorphous hydrogel enhances epithelialisation of wounds. Acta Derm Venereol 1998;78:119–122. Motta GJ: Calcium alginate topical wound dressings: A new dimension in the cost-effective treatment for exudating dermal wounds and pressure sores. Ostomy Wound Manage 1989;25:52–56. Gensheimer D: A review of calcium alginates. Ostomy Wound Manage 1993;39:34–38. Thomas S: Alginates. A guide to the properties and uses of different alginate dressings available today. J Wound Care 1992;1:29–32. Agren MS: Four alginate dressings in the treatment of partial thickness wounds: A comparative experimental study. Br J Plast Surg 1996;49:129–134. Piacquadio D, Nelson DB: Alginates. A new dressing alternative. J Dermatol Surg Oncol 1992;18: 990–998. Sayag J, Meaume S, Bohbot S: Healing properties of calcium alginate dressings. J Wound Care 1996;5:357–362. Henderson NJ, Crawford PJ, Reeves BC: A randomised trial of calcium alginate swabs to control blood loss in 3–5-year-old children. Br Dent J 1998;184:187–190. Armstrong SH, Ruckley CV: Use of a fibrous dressing in exuding leg ulcers. J Wound Care 1997; 6:322–324. Thomas S: A structured approach to the selection of dressings. World Wide Wounds, July 1997 (http://www.smtl.co.uk/World-Wide-Wounds/1997/july/Thomas-Guide/Dress-Select.html). Baranoski S: Collaborative roles lead to success in wound healing. Decubitus 1992;5:66–68. Fowler E, van Rijswijk L: Using wound debridement to help achieve the goals of care. Ostomy Wound Manage 1995;41(7A suppl):23–35. Hermans MH, Bolton LL: The influence of dressings on the cost of wound treatment. Dermatol Nurs 1996;8:93–94. Ohlsson P, Larsson K, Lindholm C, Moller M: A cost-effectiveness study of leg ulcer treatment in primary care. Comparison of saline-gauze and hydrocolloid treatment in a prospective, randomized study. Scand J Prim Health Care 1994;12:295–299.

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Prof. Dr. Josef Aubo¨ck, Department of Dermatology and Venerology, General Public Hospital, Krankenhausstrasse 9, A–4020 Linz (Austria) Tel. +43 732 7806 3732, Fax +43 732 7806 3701, E-Mail [email protected]

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Therapy with Growth Factors Alain Limat, Lars E. French Department of Dermatology (DHURDV), University Hospital, Geneva, Switzerland

Healing of cutaneous wounds is a tightly controlled process that combines inflammation, cell migration, cell growth, angiogenesis, extracellular matrix synthesis and remodeling, and re-epithelialization. The recent identification of growth factors as key mediators of the cellular and molecular processes required for optimal wound healing has promoted investigations of their potential use in the treatment of impaired wound healing [1, 2]. Growth factors (cytokines) are signaling peptides or proteins that are normally synthesized and secreted in an orderly manner by a variety of cell types involved in the process of wound healing. By signaling through specific cell surface receptors, they regulate a wide range of cellular functions including inflammation, proteolysis, migration, proliferation and differentiation. They are abundant in readily healing wounds, and deficiencies or experimental disruption of their function have been shown to impair healing [3–6]. Based on this encouraging experimental data, certain of these growth factors or combinations thereof have been further investigated as candidate therapeutic agents for the treatment of chronic wounds in humans. Most of this work is very recent, and although many clinical trials are currently underway, definitive results are available for only a few. Here we will briefly review the current knowledge and clinical status of the growth factors and formulations thereof that show promise for the treatment of chronic wounds.

Growth Factors Platelet-Derived Growth Factor (PDGF ) PDGF, a 30-kDa dimeric glycoprotein, is a potent mitogen for fibroblasts, endothelial cells and smooth muscle cells, that exists in 3 isoforms (AA, BB

and AB; BB being the most active), and although present in the serum, is released predominantly by platelets (a-granules) upon activation. PDGF is an important mediator of wound healing that promotes cell recruitment (inflammatory cells and fibroblasts), proliferation (fibroblasts, endothelial cells, smooth muscle cells), extracellular matrix formation and remodeling, all of which contribute to the formation of granulation tissue. Recombinant human PDGF (BB isoform) has been shown accelerate the formation of granulation tissue and wound healing in experimental animal models [7–9]. Controlled clinical trials with recombinant PDGF have been performed in pressure and diabetic ulcers (table 1), and have shown statistically significant reductions in ulcer size and increased incidence of complete healing (table 1). Consequently, a gel containing recombinant human PDGF (100 lg/g), named RegranexÔ (Johnson & Johnson), has recently been commercialized in the United States for the treatment of diabetic ulcers. Larger clinical trials in diabetic ulcers and trials in other types of wounds (venous leg ulcers) are currently underway. Fibroblast Growth Factor (FGF ) The FGF family consists of more than nine isoforms of a homologous protein, all of which stimulate fibroblast growth. The best characterized member of this family is basic FGF (bFGF/FGF-2), which is essentially extracellular matrix bound, and induces fibroblast and endothelial cell recruitment as well as fibroblast and keratinocyte proliferation [10]. In animal wound models, bFGF has been shown to induce angiogenesis, granulation tissue and epithelialization [11–13]. In constrast to PDGF, however, bFGF only appeared to be effective in nonischemic wound models. Despite these encouraging experimental results, published clinical studies are scarce and less encouraging (table 1). In a small (17 patients) randomized, double-blind, placebo-controlled study of diabetic foot ulcers, topical application of bFGF (0.25–0.75 lg/cm2) did not show any healing advantage over placebo [14]. In a small phase I randomized, blinded, and placebo-controlled trial of topical bFGF application to pressure sores, patients receiving high doses (10 lg/cm2) showed a slightly greater but significant healing effect [15]. No confirmation of this study has been reported since its initial publication in 1992. Epidermal Growth Factor (EGF ) EGF is a 6-kDa protein that is released by platelets and keratinocytes in the wound. It stimulates keratinocyte growth, fibroblast growth and extracellular matrix (collagen, fibronectin) production. In vivo, EGF accelerates wound healing in porcine partial thickness thermal wounds [16]. In acute partial

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Table 1. Growth factors under clinical evaluation Growth factor

Function

Clinical activity

Ref.

wound type

patients clinical n outcome

PDGF-BB

Connective tissue formation Stimulation of angiogenesis Chemotaxis and activation of macrophages Mitogen for fibroblasts and smooth muscle cells

Pressure ulcers Pressure ulcers Diabetic neuropathic ulcers Diabetic neuropathic ulcers

20 41 118 382

+ + + +

25 26 27 34

bFGF

Granulation tissue formation Stimulation of angiogenesis Re-epithelialization

Pressure ulcers Diabetic neuropathic ulcers

50 17

+ Ö

15 14

EGF (TGF-a)

Connective tissue formation Re-epithelialization

Partial thickness skin wounds Chronic venous leg ulcers

17 35

Ö Ö

30 17

TGF-b2

Chemotaxis and activation of macrophages and fibroblasts Connective tissue formation and remodeling Stimulation of angiogenesis Keratinocyte growth inhibition

Chronic venous leg ulcers

36

Ö

18

Granulocytemacrophage colonystimulating factor

Stimulation of migration and proliferation of endothelial cells Stimulation of keratinocyte growth

Chronic leg ulcers Acute wounds Chronic leg ulcers

10 10 16

+* Ö +

29 33 35

Granulocyte colonystimulating factor

Stimulation of migration and proliferation of endothelial cells Activator of neutrophils

Diabetic neuropathic ulcers

40

+ **

32

Calcitonin generelated peptide and vasoactive intestinal polypeptide

Vasodilation Immunomodulation

Chronic venous leg ulcers

66

+

28

Prostaglandin E1

Vasodilation Antiplatelet agent

Diabetic neuropathic and chronic leg ulcers

364

+

31

For reasons of space, only major functions and selected studies are listed. +>Significant improvement; Ö>no clinically significant improvement; *>no control wounds; **>reduction of infection rate only.

thickness human wounds, EGF has also shown efficacy (table 1), but unfortu-

Therapy with Growth Factors

51

Table 2. Growth factor formulations under clinical evaluation Formulation

Wound type

Patients, n

Clinical Ref. outcome

Platelet-derived wound healing factors

Diabetic neurotrophic ulcers Chronic leg ulcers Chronic leg ulcers of different etiology

13

+

20

32 18

+ Ö

19 22

Autologous topical hemotherapy

Chronic leg ulcers

15

+*

23

Autologous activated mononuclear cells

Chronic leg ulcers

33

+

24

+>Significant improvement; Ö>no clinically significant improvement; *>no control wounds.

nately in the more relevant situation of chronic wounds, no significant effect has been demonstrated to date [17]. Transforming Growth Factor-b (TGF-b) TGF-b is a glycoprotein that exists in at least three isoforms (TGF-b1, -b2, and -b3), all of which potently stimulate extracellular matrix synthesis (collagen, fibronectin). TGF-b is also chemotactic for macrophages, promotes fibroblast proliferation and migration, inhibits keratinocyte proliferation and inhibits net proteolysis via modulation of collagenase and metalloproteinase activity. In animal trials, TGF-b1 has been shown to accelerate healing of rat incisional wounds, and all TGF isoforms have the capacity to reduce scar formation. Only one human clinical trial using TGF-b2 has been reported in the literature to date. It was a short-course, low-dose treatment study performed in venous leg ulcers (table 1), and showed no statistically significant improvement over placebo controls [18]. Despite encouraging experimental data in vitro and in animal models, only one of the growth factors described above or in table 1, namely PDGF, has proven to be consistently effective in human clinical trials to date. Further investigations will be needed to determine if the inconsistent or poor results obtained with the other growth factors is due to inadequate dosage, inadequate delivery (choice of vehicle), or the fact that combinations of these growth factors are necessary for optimal function in vivo.

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A

B Fig. 1. An illustrative chronic leg ulcer before (A) and after (B) eight applications of autologous topical hemotherapy.

Formulations of Growth Factors (table 2) Platelet-Derived Wound Healing Factors Platelets are early mediators of the natural wound healing process, and are present in the initial clot. They provide a number of growth factors in vivo (including PDGF, TGF-b, EGF, bFGF), and therefore platelet supernatants have been used for the treament of chronic wounds. Three small controlled studies using platelet-derived wound healing factors, essentially in chronic leg wounds related to diabetes, have been reported. Three studies provided encouraging results [19–21], but no benefit could be demonstrated in a fourth study [22]. Although platelet releasates appear to have some beneficial effect, further controlled studies in selected patient populations are needed before drawing definite conclusions on the efficacy of platelet-derived wound healing factors. Autologous Topical Hemotherapy With the concern that an interplay and possibly a synergism between several growth factors and proteolytic enzymes contained within platelets, leukocytes and plasma may be an advantage over single growth factors enhancing the development of granulation tissue, the use of topically applied heparinized autologous blood was assessed in a small open noncontrolled study of 15 patients with chronic leg ulcers of diverse etiologies, that did not improve with other therapies including occlusive dressings. However, topical application


53

every 2 days of heparinized blood covered by an occlusive dressing, rapidly induced the formation of granulation tissue in all cases, with new granulation tissue covering 75% of the ulcer surface within a mean of 9 applications (fig. 1) [23]. A double-blind controlled study of autologous topical hemotherapy in a larger series of patients is now underway to determine if this treatment has an advantage over occlusive therapy alone, versus occlusive therapy and heparin individually. Autologous Activated Mononuclear Cells The capacity of cultured autologous mononuclear cells to induce granulation and re-epithelialization was studied in chronic skin ulcers of arterial (21 patients) or venous (12 patients) origin. Autologous mononuclear cells were shown to be more effective than tissue culture medium alone (control), both in inducing complete closure of ulcers and in reducing pain [24]. Taken together, although the results obtained in animal wound healing models with individual growth factors have been very encouraging, equivalent effects have only rarely been obtained in the human studies performed to date. As has been shown for PDGF however, selected growth factors will certainly prove to be useful in the management of chronic wounds. Further investigations are required to determine the optimal growth factor or combination of growth factors, the optimal dosage, and the best vehicle required for improvement of chronic wound healing. Furthermore, cost-benefit studies will have to be undertaken to determine if treatment with costly recombinant growth factors can be cost-effective. References 1 2 3 4 5

6 7

8

Choucair MM, Phillips TJ: What is new in clinical research in wound healing. Dermatol Clin 1997; 15:45–58. Martin P: Wound healing – Aiming for perfect skin regeneration. Science 1997;276:75–81. McKay IA, Leigh IM: Epidermal cytokines and their roles in cutaneous wound healing. Br J Dermatol 1991;124:513–518. Cooper DM, Yu EZ, Hennessey P, Ko F, Robson MC: Determination of endogenous cytokines in chronic wounds. Ann Surg 1994;219:688–691. Pierce GF, Tarpley JE, Tseng J, Bready J, Chang D, Kenney WC, Rudolph R, Robson MC, Van de Berg J, Reid P: Detection of platelet-derived growth factor (PDGF)-AA in actively healing human wounds treated with recombinant PDGF-BB and absence of PDGF in chronic nonhealing wounds. J Clin Invest 1995;96:1336–1350. Beer HD, Longaker MT, Werner S: Reduced expression of PDGF and PDGF receptors during impaired wound healing. J Invest Dermatol 1997;109:132–138. Grotendorst GR, Martin GR, Pencev D, Sodek J, Harvey AK: Stimulation of granulation tissue formation by platelet-derived growth factor in normal and diabetic rats. J Clin Invest 1985;76: 2323–2329. Mustoe TA, Purdy J, Gramates P, Deuel TF, Thomason A, Pierce GF: Reversal of impaired wound healing in irradiated rats by platelet-derived growth factor-BB. Am J Surg 1989;158:345–350.

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9 10 11

12

13 14

15

16 17 18

19

20

21

22

23 24

25 26

27 28

Pierce GF, Mustoe TA: Pharmacologic enhancement of wound healing. Annu Rev Med 1995;46: 467–481. Rifkin DB, Moscatelli D: Recent developments in the cell biology of basic fibroblast growth factor. J Cell Biol 1989;109:1–6. Davidson JM, Klagsbrun M, Hill KE, Buckley A, Sullivan R, Brewer PS, Woodward SC: Accelerated wound repair, cell proliferation, and collagen accumulation are produced by a cartilage-derived growth factor. J Cell Biol 1985;100:1219–1227. Pierce GF, Tarpley JE, Yanagihara D, Mustoe TA, Fox GM, Thomason A: Platelet-derived growth factor (BB homodimer), transforming growth factor-beta-1, and basic fibroblast growth factor in dermal wound healing. Neovessel and matrix formation and cessation of repair. Am J Pathol 1992; 140:1375–1388. Ortega S, Ittmann M, Tsang SH, Ehrlich M, Basilico C: Neuronal defects and delayed wound healing in mice lacking fibroblast growth factor 2. Proc Natl Acad Sci USA 1998;95:5672–5677. Richard JL, Parer-Richard C, Daures JP, Clouet S, Vannereau D, Bringer J, Rodier M, Jacob C, Comte-Bardonnet M: Effect of topical basic fibroblast growth factor on the healing of chronic diabetic neuropathic ulcer of the foot. A pilot, randomized, double-blind, placebo-controlled study. Diabetes Care 1995;18:64–69. Robson MC, Phillips LG, Lawrence WT, Bishop JB, Youngerman JS, Hayward PG, Broemeling LD, Heggers JP: The safety and effect of topically applied recombinant basic fibroblast growth factor on the healing of chronic pressure sores. Ann Surg 1992;216:401–406. Hebda PA: Stimulatory effects of transforming growth factor-beta and epidermal growth factor on epidermal cell outgrowth for porcine skin explant cultures. J Invest Dermatol 1988;91:440–445. Falanga V, Eaglstein WH, Bucalo B, Katz MH, Harris B, Carson P: Topical use of human recombinant epidermal growth factor (h-EGF) in venous ulcers. J Dermatol Surg Oncol 1992;18:604–606. Robson MC, Phillip LG, Cooper DM, Lyle WG, Robson LE, Odom L, Hill DP, Hanham AF, Ksander GA: Safety and effect of transforming growth factor-b2 for treatment of venous stasis ulcers. Wound Rep Reg 1995;3:157–167. Knighton DR, Ciresi K, Fiegel VD, Schumerth S, Butler E, Cerra F: Stimulation of repair in chronic, nonhealing, cutaneous ulcers using platelet-derived wound healing formula. Surg Gynecol Obstet 1990;170:56–60. Steed DL, Goslen JB, Holloway GA, Malone JM, Bunt TJ, Webster MW: Randomized prospective double-blind trial in healing chronic diabetic foot ulcers. CT-102 activated platelet supernatant, topical versus placebo. Diabetes Care 1992;15:1598–1604. Holloway GA, Steed DL, DeMarco MJ, Masumoto T, Moosa HH, Webster MW, Bunt TJ, Polansky M: A randomized controlled dose-response trial of activated platelet supernatant topical CT-102 (APST) in chronic nonhealing wounds in patients with diabetes mellitus. Wounds 1993;5:198–206. Krupski WC, Reilly LM, Perez S, Moss KM, Crombleholme PA, Rapp JH: A prospective randomized trial of autologous platelet-derived wound healing factors for treatment of chronic nonhealing wounds: A preliminary report. J Vasc Surg 1991;14:526–532. Triquet B, Ruffieux P, Mainetti C, Salomon D, Saurat JH: Topical haemotherapy for leg ulcers. Dermatology 1994;189:418–420. Holzinger C, Zuckermann A, Kopp C, Schollhammer A, Imhof M, Zwolfer W, Baumgartner I, Magometschnigg H, Weissinger E, Wolner E: Treatment of non-healing skin ulcers with autologous activated mononuclear cells. Eur J Vasc Surg 1994;8:351–356. Robson MC, Phillips LG, Thomason A, Robson LE, Pierce GF: Platelet-derived growth factor BB for the treatment of chronic pressure ulcers. Lancet 1992;339:23–25. Mustoe TA, Cutler NR, Allman RM, Goode PS, Deuel TF, Prause JA, Bear M, Serdar CM, Pierce GF: A phase II study to evaluate recombinant platelet-derived growth factor-BB in the treatment of stage 3 and 4 pressure ulcers. Arch Surg 1994;129:213–219. Steed DL: Clinical evaluation of recombinant human platelet-derived growth factor for the treatment of lower extremity diabetic ulcers. Diabetic Ulcer Study Group. J Vasc Surg 1995;21:71–78. Gherardini G, Gurlek A, Evans GR, Milner SM, Matarasso A, Wassler M, Jernbeck J, Lundeberg T: Venous ulcers: Improved healing by iontophoretic administration of calcitonin gene-related peptide and vasoactive intestinal polypeptide. Plast Reconstr Surg 1998;101:90–93.


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29

30

31

32

33

Borbolla-Escoboza JR, Maria-Aceves R, Lopez-Hernandez MA, Collados-Larumbe MT: Recombinant human granulocyte-macrophage colony-stimulating factor as treatment for chronic leg ulcers. Rev Invest Clin 1997;49:449–451. Cohen IK, Crossland MC, Garrett A, Diegelmann RF: Topical application of epidermal growth factor onto partial-thickness wounds in human volunteers does not enhance reepithelialization. Plast Reconstr Surg 1995;96:251–254. Toyota T, Hirata Y, Ikeda Y, Matsuoka K, Sakuma A, Mizushima Y: Lipo-PGE1, a new lipidencapsulated preparation of prostaglandin E1: Placebo- and prostaglandin E1-controlled multicenter trials in patients with diabetic neuropathy and leg ulcers. Prostaglandins 1993;46:453–468. Gough A, Clapperton M, Rolando N, Foster AV, Philpott-Howard J, Edmonds ME: Randomised placebo-controlled trial of granulocyte colony-stimulating factor in diabetic foot infection. Lancet 1997;350:855–859. Ure I, Partsch B, Wolff K, Petzelbauer P: Granulocyte/macrophage colony-stimulating factor increases wound-fluid interleukin-8 in normal subjects but does not accelerate wound healing. Br J Dermatol 1998;138:277–282.

Lars E. French, Department of Dermatology (DHURDV), University Hospital, CH–1211 Geneva 14 (Switzerland) Tel. 41-22-372 94 55, Fax 41-22-372 94 70, E-Mail [email protected]

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............................

Cultured Keratinocyte Grafts Thomas Hunziker a, Alain Limat b Departments of Dermatology, Universities of a Bern and b Geneva (DHURDV), Switzerland

Introduction A major breakthrough in the culture of human keratinocytes was achieved in 1975 by Rheinwald and Green [1]. By serial cultivation of strains of human epidermal keratinocytes, their technology allowed to obtain keratinocyte sheets 1000- to 10,000-fold the surface area of an initial skin biopsy within 3–4 weeks [2]. The first report of autologous keratinocyte grafting in acute wounds, i.e. in burn patients, appeared in 1981 [3], and since that time large burn injuries remained the principal clinical indication for cultured keratinocyte grafts [reviewed in 4–6]. In 1983 was published the first report of allogeneic keratinocyte grafting in burns, which raised a controversy concerning rejection [reviewed in 7]. In chronic wounds, i.e. venous leg ulcers, autologous keratinocyte grafting was reported for the first time in 1986 [8, 9], allogeneic in 1987 [10]. The initial results in chronic wounds were less spectacular than those in acute wounds, adding to the discussions on the requirement for a dermal substitute. To improve take rates and prevent major wound contraction, the need for an additional dermal substitute is now accepted for keratinocyte grafting of acute wounds [reviewed in 6], while in chronic wounds the debate on optimal grafting modalities is still open. Today, development in tissue engineering of the skin focuses on improving the delivery systems for cultured keratinocytes, possibly combined with further cell types, components of dermal matrix and growth factors, which would result in complex biotechnological approaches of cutaneous wound management [reviewed in 4–6]. Leaving the era of pilot trials, several commercial applications are forthcoming, which will have to prove their cost-effectiveness in large-scale trials in the near future. In view of a market covering over 10 million patients worldwide, financial as well as ethical considerations might result in official regulations

differentiating between life-threatening acute wounds such as extensive burns and circumscribed chronic wounds such as leg ulcers, even if the latter may have relevant adverse impact on quality of life. Despite restrictive actual health care policies, it can be anticipated that bioengineered skin products will eventually play an important role in the treatment of both acute and chronic wounds.

Keratinocyte Culture Interfollicular epidermal keratinocytes are usually isolated from adult skin biopsy specimens or neonatal foreskins by enzymatic dissociation. Isolated cells are plated for primary culture in appropriate, growth factor-containing media in the presence of either feeder cells (murine mesenchymal 3T3 cells [1] or human dermal fibroblasts [11]) and fetal calf serum or low Ca concentration and bovine pituitary extract [12]. With such media, expansion of keratinocytes can be performed in a limited number of subcultures. Alternatively, keratinocytes can be isolated from the outer root sheath (ORS) of plucked anagen scalp hair follicles [13]. The ORS represents a source of easily and repeatedly available keratinocytes with high proliferative capacity even in old donors and a similar potential for differentiation as interfollicular keratinocytes [13]. Recent studies suggest that stem cells for the epithelial cell population of the skin are located in the ORS [14, 15]. Culture conditions that mimick the physiological environment of the epidermis give rise to multilayered, stratified epidermal equivalents with a well-developed horny layer [13, 16]. Differentiated keratinocyte cultures may be combined with a dermal equivalent, resulting in a reconstructed skin equivalent. Living dermal equivalents can be established by including fibroblasts into collagen (mainly bovine) gels [17] or into synthetic meshes, e.g. of nylon or polyglactin acid [reviewed in 4]. Nonliving dermal equivalents include deepidermized human dermis [18] and e.g. collagen sponges supplemented by various biological matrix substances [reviewed in 4].

Clinical Application The currently commercialized wound coverage products containing living cells are listed in table 1. The keratinocytes as well as the fibroblasts used for grafting may be autologous or allogeneic. Autologous keratinocytes are considered safe in terms of microorganism transmission (mainly viral such as HIV [19] or hepatitis [20]) and immunological reactions, and they bear the potential of a definite take. Allogeneic keratinocytes do not allow for a perman-

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Table 1. 1998 commercialized wound coverage products containing living cells Trademark

Culture and cell types

Origin

Matrix

Epicel [reviewed in 4]

Sheets of interfollicular keratinocytes

Autologous

None

Epigraft [13, 39]

Epidermal equivalents of ORS keratinocytes

Autologous

None

Apligraf [40]

Composite grafts of interfollicular keratinocytes and fibroblasts

Allogeneic

Bovine collagen

Dermal equivalents of fibroblasts

Allogeneic

Nylon mesh

Dermagraft [reviewed in 4]

ent take [7], while allogeneic fibroblasts are generally considered to be of low immunogenicity [21]. Bovine collagen is thought to induce immunogenic reactions and even autoimmune disease [22]. A further risk of transmitting infectious agents might reside in not defined culture media ingredients such as fetal calf serum and bovine pituitary extract. Acute Wounds The major unresolved problem with extensively burned patients is to achieve a rapid and permanent replacement of skin. Any delay increases the risk of infection. Such replacement should form new dermis as well as epidermis and by this prevent wound contraction and hypertrophic scarring. The first approach, based on the culture technology developed by Rheinwald and Green [1], consisted of applying autologous keratinocyte sheets attached to a Vaseline gauze [3]. This procedure is still routinely used in burn centers in several countries, and in experienced hands it can significantly reduce mortality [reviewed in 4–6]. A more recent approach to apply cultured keratinocytes is the use of carrier materials such as laser-perforated biopolymers based on hyaluronic acid [23] or Teflon membranes enabling culture in a bioreactor [24]. A prerequisite is tissue compatibility of the materials used. Since in burns grafting of autologous keratinocyte cultures in the absence of a dermal substitute is known to result in blistering and ulceration for several months, with the cosmetic and functional skin properties being inferior to those obtained by conventional grafting, cultured epithelial sheets are now often grafted on a previously applied living or nonliving dermal equivalent [reviewed in 4]. To avoid two-step surgery, dermal-epidermal reconstructed skin is a future goal.

Cultured Keratinocyte Grafts

59

Table 2. Autologous keratinocyte grafting of chronic wounds, modalities, outcome Patient/ulcer number

Outcome1

Group (first author)

Modality

Hefton [8]


5

Mean

Leigh [9]


12

Poor?

Stadler [38]


4

Good

Giannotti [30]


3

Poor?

Phillips [36]


3

?

Harris [31]


7

Poor

Scho¨nfeld [37]


3

Poor?

Limova [33]


24

Mean?

Hafner [24]

Interfollicular keratinocytes on a Teflon membrane

10

Mean?

Brysk [29]

Interfollicular keratinocytes attached to collagen-coated dressing

6

Mean?

Mol [34]

Skin equivalents of interfollicular keratinocytes on a collagen gel with allogeneic fibroblasts

7

Mean

Hunyadi [32]

Interfollicular keratinocytes fixed by fibrin glue

15

Mean?

Moll [35]

ORS keratinocytes fixed by fibrin glue

21

Poor?

Limat [13]

Epidermal equivalents of ORS keratinocytes

7

Good

1

Percentage of patients/ulcers completely healed within 8 weeks: poor>=50; mean> 50–80, good>?80. ?>Evaluation hampered by insufficient reporting of the results.

Since autologous keratinocyte sheets are only available within about 3 weeks, allogeneic cultured epithelial sheet grafts, which offer the possibility of banking in a cryopreserved state, are used on partial thickness burns and on donor sites [reviewed in 5, 6]. Although they are ultimately rejected, they accelerate wound healing probably by interactive secretion of growth factors [reviewed in 5–7]. Similar therapeutic approaches seem feasible in other types of acute skin defects including large excision wounds [25, 26] and ulcerating disorders of

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a

b

c

d Fig. 1. Grafting of epidermal equivalents generated from cultured autologous ORS keratinocytes in a chronic leg ulcer. a Highly differentiated epidermal equivalent of 6-mm diameter on a polyester transfer membrane. b Placing of epidermal equivalents of 6-mm diameter on the cleaned, well-granulating surface of a chronic leg ulcer with 6/2-cm maximal diameters in an 85-year-old female. c Immediately after grafting, about 90% of the ulcer surface is covered with 18 epidermal equivalents. d Six weeks after grafting, the former ulcer area is completely reepithelialized, exhibiting slight scarring.

genetic origin such as epidermolysis bullosa [27]. First trials are also reported for reepithelialization of mucous membranes [28]. This opens a broad field of further applications. Chronic Wounds The literature on autologous keratinocyte grafting in chronic wounds mainly deals with chronic leg ulcers of vascular origin. Most of the various modalities hitherto reported for small groups of altogether about 120 patients were moderately effective in terms of definite take rates and rapid total reepithelialization [29–38] (table 2), while stimulation of granulation tissue and prompt pain relief were commonly observed. Results comparable to conventional grafting techniques have been achieved by transplantation of highly differenti-


61

ated epidermal equivalents prepared with autologous ORS keratinocytes [13, 39] (fig. 1). This indicates that in well-granulating chronic wounds there is no need for a dermal substitute, a full stratification of the keratinocyte graft enabling its survival in the proteolytic milieu of the chronic wound. Use of biocompatible or biodegradable delivery systems may improve the handling of the grafts. Reports on keratinocyte grafting in diabetic ulcers and pressure sores are sparse. As for acute wounds, grafting of allogeneic keratinocytes to chronic venous ulcers stimulates granulation tissue formation and reepithelialization from the wound edges (‘edge effect’) [10, reviewed in 5, 37]. A large series of patients is also reported for an allogeneic composite graft [40]. However, if a definite take is the aim, autologous keratinocyte grafts are indispensable. The delay until they are available is rarely critical in chronic wounds.

Future Prospects Actually, much work is devoted to improve the delivery systems for cultured keratinocytes. Furthermore, there are preliminary reports on gene transfection of cultured cells resulting in enhanced production of relevant growth factors, which aims at accelerated in vitro keratinocyte propagation. As an alternative to shorten the delay until grafting in case of burns, the use of mixed allogeneic- or even xenogeneic-autologous cultured epithelia is suggested [41, 42]. To produce a nonimmunogenic in vitro reconstructed skin, it could finally be tried to knock-out the histocompatibility genes from allogeneic or even xenogeneic keratinocytes and fibroblasts – a very complex approach especially when multiple genes are concerned. Another potential approach would consist in identifying and expanding keratinocyte stem cells for grafting purposes.

References 1 2 3 4 5

Rheinwald JG, Green H: Serial cultivation of strains of human epidermal keratinocytes: The formation of keratinizing colonies from single cells. Cell 1975;6:331–344. Green H, Kehinde O, Thomas J: Growth of cultured human epidermal cells into multiple epithelia suitable for grafting. Proc Natl Acad Sci USA 1979;76:5665–5668. O’ Connor NE, Mulliken JB, Banks-Schlegel S, Kehinde O, Green H: Grafting of burns with cultured epithelium prepared from autologous epidermal cells. Lancet 1981;1:75–78. Berthod F, Damour O: In vitro reconstructed skin models for wound coverage in deep burns. Br J Dermatol 1997;136:809–816. Choucair MM, Phillips TJ: What is new in clinical research in wound healing. Dermatol Clin 1997; 15:45–58.

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6 7 8 9 10 11 12 13 14 15 16

17

18 19

20 21 22

23

24 25 26 27 28 29 30

Myers S, Navsaria H, Sanders R, Green C, Leigh I: Transplantation of keratinocytes in the treatment of wounds. Am J Surg 1995;170:75–83. Fabre JW: Epidermal allografts. Immunol Lett 1991;29:161–166. Hefton JM, Caldwell D, Biozes DG, Balin AK, Carter MD: Grafting of skin ulcers with cultured autologous epidermal cells. J Am Acad Dermatol 1986;14:399–405. Leigh IM, Purkis PE: Culture grafted leg ulcers. Clin Exp Dermatol 1986;11:650–652. Leigh IM, Purkis PE, Navsaria HA, Phillips TJ: Treatment of chronic venous ulcers with sheets of cultured allogeneic keratinocytes. Br J Dermatol 1987;117:591–597. Limat A, Hunziker T, Boillat C, Bayreuther K, Noser F: Post-mitotic human dermal fibroblasts efficiently support the growth of human follicular keratinocytes. J Invest Dermatol 1989;92:758–762. Shipley GD, Pittelkow MR: Control of growth and differentiation in vitro of human keratinocytes cultured in serum-free medium. Arch Dermatol 1987;123:1541A–1544A. Limat A, Mauri D, Hunziker T: Successful treatment of chronic leg ulcers with epidermal equivalents generated from cultured autologous outer root sheath cells. J Invest Dermatol 1996;107:128–135. Rochat A, Kobayashi K, Barrandon Y: Location of stem cells of human hair follicles by clonal analysis. Cell 1994;76:1063–1073. Yang JS, Lavker RM, Sun TT: Upper human hair follicle contains a subpopulation of keratinocytes with superior in vitro proliferative potential. J Invest Dermatol 1993;101:652–659. Rosdy M, Clauss L-C: Terminal epidermal differentiation of human keratinocytes grown in chemically defined medium on inert filter substrates at the air-liquid interface. J Invest Dermatol 1990;95: 409–414. Bell E, Ivarsson B, Merril C: Production of a tissue-like structure by contraction of collagen lattices by human fibroblasts of different proliferative potential in vitro. Proc Natl Acad Sci USA 1979;76: 1274–1278. Prunie´ras M, Re´gnier M, Woodley D: Methods for cultivation of keratinocytes with an air-liquid interface. J Invest Dermatol 1983;81:28–33s. Ramarli D, Giri A, Reina S, Poffe O, Cancedda R, Varnier O, Tridente G, De Luca M: HIV-1 spreads from lymphocytes to normal human keratinocytes suitable for autologous and allogeneic transplantation. J Invest Dermatol 1995;105:644–647. Mason A, Wick M, White H, Perrillo R: Hepatitis B virus replication in diverse cell types during chronic hepatitis B virus infection. Hepatology 1993;18:781–789. Sher SE, Hull BE, Rosen S, Church D, Friedman L, Bell E: Acceptance of allogeneic fibroblasts in skin equivalent transplants. Transplantation 1983;36:552–557. Bonnet C, Charrie`re G, Vaquier J, Bertin P, Vergne P, Treves R: Bovine collagen induced systemic symptoms: Antibody formation against bovine and human collagen. J Rheumatol 1996;23:545– 547. Andreassi L, Casini L, Trabucchi E, Diamantini S, Rastrelli A, Donati L, Tenchini ML, Malcovati M: Human keratinocytes cultured on membranes composed of benzyl ester of hyaluronic acid suitable for grafting. Wounds 1991;3:116–126. Hafner J, Kinooka M, Villeneuve PE, Prenosil JE, Senti G, Burg G: Autologous pancellular skin culture in the treatment of leg ulcers: Preliminary report (abstract). Dermatology 1997;195:199. Gallico G III, O’ Connor NE, Compton CC, Kehinde O, Green H: Cultured epithelial autografts for giant congenital nevi. J Plast Reconstr Surg 1989;84:1–9. Higgins CR, Navsaria HA, Stringer M, Spitz L, Leigh IM: Use of two stage keratinocyte-dermal grafting to treat the separation site in conjoined twins. J R Soc Med 1994;87:108–109. Carter DM, Lin AN, Varghese MC, Caldwell D, Pratt LA, Eisinger M: Treatment of junctional epidermolysis bullosa with epidermal autografts. J Am Acad Dermatol 1987;17:246–250. Bo¨hm K, Gerhardt HJ, Kaschke O, Winter H, Bo¨hm F, So¨nnichsen N, Neumann S: Wundverschluss mit Zellsuspension im Haut- und Schleimhautbereich. Dermatol Monatsschr 1992;178:22–26. Brysk MM, Raimer SS, Pupo R, Bell T, Rajaraman S: Grafting of leg ulcers with undifferentiated keratinocytes. J Am Acad Dermatol 1991;25:238–244. Giannotti V, Pimpinelli N, Mariotti V, Borgognoni L, Reali UM: L’epidermide espansa in coltura nel trattamento dell’ulcus cruris: ‘Effetto bordo’ e correlazione con l’indice di proliferazione dei cheratinociti. G Ital Dermatol Venereol 1990;125:161–167.


63

31 32 33 34

35 36 37 38 39

40

41 42

Harris IR, Bottomley W, Wood EJ, Cunliffe WJ: Use of autografts for the treatment of leg ulcers in elderly patients. Clin Exp Dermatol 1993;18:417–420. Hunyadi J, Farkas B, Bertenyi C, Olah J, Dobozy A: Keratinocyte grafting: A new means of transplantation for full-thickness wounds. J Dermatol Surg Oncol 1988;14:75–78. Limova M, Mauro T: Treatment of leg ulcers with cultured epithelial autografts: Treatment protocol and five year experience. Wounds 1995;7:170–180. Mol MAE, Nanninga PB, van Eedenburg JP, Westerhof W, Mekkes JR, van Ginkel CJW: Grafting of venous leg ulcers. An intraindividual comparison between cultured skin equivalents and fullthickness skin punch grafts. J Am Acad Dermatol 1991;24:77–82. Moll I, Scho¨nfeld M, Jung EG: Applikation von Keratinozyten in der Therapie von Ulcera crurum. Hautarzt 1995;46:548–552. Phillips TJ, Bhawan J, Leigh IM, Baum HJ, Gilchrest BA: Cultured epidermal autografts and allografts: A study of differentiation and allograft survival. J Am Acad Dermatol 1990;23:189–198. Scho¨nfeld M, Moll I, Maier K, Jung EG: Keratinozyten aus der Zellkultur zur Therapie von Hautdefekten. Hautarzt 1993;44:281–289. Stadler R, Detmar M, Orfanos CE: Autologe Keratinozytenkulturen als Hautersatz bei langja¨hrig bestehenden Ulcera cruris venosa. Aktuel Dermatol 1989;15:91–95. Limat A, Salomon D, French L, Saurat J-H, Hunziker T: Closure of chronic wounds with epidermal equivalents generated from cultured autologous outer root sheath cells (abstract). J Invest Dermatol 1998;110:677. Falanga V, Margolis D, Alvarez O, Auletta M, Maggiacomo F, Altman M, Jensen J, Sabolinski M, Hardin-Young J: Rapid healing of venous ulcers and lack of clinical rejection with an allogeneic cultured human skin equivalent. Arch Dermatol 1998;134:293–300. Rouabhia M, Germain L, Bergeron J, Auger FA: Allogeneic-syngeneic cultured epithelia: A successful therapeutic option for skin regeneration. Transplantation 1995;59:1229–1235. Rouabhia M: Permanent skin replacement using chimeric epithelial cultured sheets comprising xenogeneic and syngeneic keratinocytes. Transplantation 1996;9:1290–1300.

Prof. Dr. med. Th. Hunziker, Department of Dermatology, Inselspital, CH–3010 Bern (Switzerland)

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Part II. Venous Leg Ulcers Hafner J, Ramelet A-A, Schmeller W, Brunner UV (eds): Management of Leg Ulcers. Curr Probl Dermatol. Basel, Karger, 1999, vol 27, pp 65–69

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Epidemiology of Leg Ulcers Volker Wienert Department of Phlebology, University Hospital, Aachen, Germany

Ulcers on the lower leg and foot are a common diagnosis in surgical and medicine wards. However, little is known about the prevalence of this syndrome. Prevalence is defined as the epidemiological extent to characterize the development of a disease in a population, i.e. the number and frequency of a certain illness – in this case leg ulcers – or certain features – in this case for example age, sex – are recorded and documented at a certain time (point prevalence) or over a certain period (period prevalence). The prevalence rate is the ratio of the number of affected patients to the number of persons interviewed or examined in the study. Some prevalence studies employ simple questionnaires which are completed by the addressees themselves, a member of the household or the interviewer. This type of data collection obviously entails a high error rate, though it does enable prevalence determination in a large population. The alternative for a differentiated recording of data is the performance of clinical and apparative investigations. These various possibilities were also employed to determine the prevalence of leg ulcers. The various studies also defined leg ulcers in different ways: certain authors included all types of ulcer on the lower leg, forefoot and toes, others only accepted ulcers with a venous genesis. Assessments also varied in terms of the acuteness; whereas in some cases only the currently active ulcers were taken into account, others included the complete ulcer history in their study. In this present study all available prevalence studies are evaluated irrespective of the aforementioned problems.

Epidemiology of Leg Ulcers Epidemiological investigations have only been performed in England, Sweden and Australia, and all have taken place in the past 10 years. The

0.7 0.62

0.63 > 50

0.6

0.4 0.32

> 40

> 45

Nelzen et al. [9] n = 12,000 1996, Sw eden

0.19

Baker et al. [8] n = 238,000 1991, Australia

0.18

Lees et al. [6] n = 240,000 1992, UK

0.12 Ebbeskog et al. [3] n = 241,804 1996, Sw eden

0

0.12 Lindholm et al. [1] n = 232,908 1992, Sw eden

0.1

0.16

Cornw all et al. [5] n = 92,100 1986, UK

0.2

Andersson et al. [7] n = 434,699 1984, Sw eden

0.3

Nelzen et al. [4] n = 270,800 1994, Sw eden

Prevalence (%)

0.5

Fig. 1. Studies on leg and foot ulcer prevalence.

respective populations vary from 12,000 to 434,699 persons; the average prevalence rate for all 8 studies is 0.29% (fig. 1) [1–9]. The length of time for which the patient has had the ulcer is also important for the therapy with respect to the healing rate since the earlier treatment starts, the better the chances of a recovery. Two studies have been reported whereby 50% of the patients had suffered with an ulcer for up to 1 year, and the other half had had an ulcer for over a year [4, 10]. The relapse rate for an ulcer provides information on the effectiveness of the therapy and the compliance of the patients. On average, around one third of the patients have 1 relapse, a further third 2–3 times and the final third suffer over 4 relapses [4, 8, 10]. As for the etiology of the ulcer, it is noticeable that over two thirds of the ulcers in all studies are of a venous origin [4, 5, 8, 10].

Risk Factors The prevalence of the ulcer depends largely on the age of the patient. Persons up to the age of 40 rarely suffer from an ulcer. The prevalence increases

Wienert

66

100

s

s

s

s

s

s

21.1 13.0

4.85

6.5

2.35

3.0

1.05

0.8

0.30

0.20

0.08

0.15

0.002

0.015

8.7

13.6

3.6

7.3

1.4

1.9

0.42

1.2

0.07

0.3

20

0.022

0.0

Nelzen et al. [4] 1994, Sw eden

0.05

Baker et al. [8] 1991, Australia

40

19.7

Nelzen et al. [11] 1991, Sw eden

Age (years)

60

8.35

Callam et al. [10] 1987, UK

33.8 80

47.1

28.1

3.6

10.0 5.2 3.2 2.5 1.0 0.9 0.8 0.7 0.2 0.5 0.3

21 7.0 3.0 0.8 0.4

Cornw all [5] 1986, UK

Lindholm et al. [2] 1992, Sw eden

Henry [12] 1986, Ireland

0

Fig. 2. Number of ulcer patients per 1,000 inhabitants according to age.

strongly in older age. For example, over the age of 80 it lies between 8.7 and 33.8 per 1,000 persons (>0.87 and 3.38%) depending on the study (fig. 2) [1, 2, 4, 5, 8, 10, 11]. Apart from age, sex is also a another risk factor. The ratio of women to men varies between 1.5:1 and 3:1 depending on the study [1, 2, 5, 7, 8, 10–13]. Results of various studies as regards the two risk factors age and sex have been published [4, 8, 10–12]. Three studies investigated in which part of the leg the ulcers occurred. The preferred localization is clearly the distal lower leg, followed by the forefoot and proximal lower leg (fig. 3) [4, 8, 10].

The Cost of Leg Ulcers The costs incurred during the course of ulcer treatment are extremely high. Only a few detailed calculations are available, the majority are rough estimates. Thus, the costs of bandages for a patient in England over a period

Epidemiology of Leg Ulcers

67

Baker et al. [8] 1991, Australia n = 153

Nelzen et al. [4] 1994, Sw eden n = 213 nonvenous

n = 250 venous

Callam et al. [10] 1987, UK n = 827

Calf

18

19

14

154

Gaiter

142

103

242

731

Foot

8

118

22

51

Fig. 3. Site of leg ulcers.

of 4 months amount to between GBP 250 and 2,500 [14] and the annual costs of regular treatment for longer than 2 years is GBP 1,067. O’Donnell et al. [15] quote the costs of a ulcer treatment – including doctor’s visits – at around USD 40,000 per year. The Lothian and Forth Valley study names sums of up to GBP 193,000 for the treatment of 200 ulcer patients over a period of 24 weeks, i.e. each patient costs GBP 1,641 [16].

Quality of Life An ulcer has significant effects on the quality of life for patients. Callam et al. [17] showed that 42% of their patients were hindered in their private and professional life, among whom 11% were handicapped in their mobility. Seventy-three patients with chronic ulcers of the lower leg were interviewed by Phillips et al. [18], 83% of whom claimed that their mobility was reduced and a significant number complained primarily of pain. In a further study, over one third of the patients said that they felt handicapped by ulcer pain [19]. Obviously, the treatment also has an effect on the quality of life. Franks et al. [20] asked 185 ulcer patients about their quality of life 12 weeks before and then after a compression therapy. There was a significant reduction in the number of depressions and worries amongst patients after therapy. The share of patients suffering pain dropped from 78 to 22%. 42% of the patients with a healed ulcer reported greater mobility. 10% said that they were sleeping better.

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

20

Lindholm C, Bjellerup M, Christensen OB, Zederfeldt B: Leg and foot ulcers. Acta Derm Venereol (Stockh) 1992;72:224–226. Lindholm C, Bjellerup M, Christensen OB, Zederfeldt B: A dermographic survey of leg and foot ulcer patients in a defined population. Acta Derm Venereol (Stockh) 1992;72:227–230. Ebbeskog B, Lindholm C, Ohman S: Leg and foot ulcer patients. Epidemiology and nursing care in an urban population in south Stockholm, Sweden. Scand J Prim Health Care 1996;14:238–243. Nelzeń O, Bergqvist D, Lindhagen A: Venous and non-venous leg ulcers: Clinical history and appearance in a population study. Br J Med 1994;81:182–187. Cornwall JV, Dore´ CJ, Lewis JD: Leg ulcers: Epidemiology and aetiology. Br J Surg 1986;73: 693–696. Lees TA, Lambert D: Prevalence of lower limb ulceration in an urban health district. Br J Med 1992;79:1032–1034. Andersson E, Hansson C, Swanbeck G: Leg and foot ulcers. Acta Derm Venereol (Stockh) 1984; 64:227–232. Baker SR, Stacey MC, Jopp-McKay AG, Hoskin SE, Thompson PJ: Epidemiology of chronic venous ulcers. Br J Surg 1991;78:864–867. Nelzeń O, Bergqvist D, Lindhagen A: The prevalence of chronic low-limb ulceration has been underestimated. Results of a validated population questionnaire. Br J Surg 1996;83:255–258. Callam MJ, Harper DR, Dale JJ, Ruckley CV: Chronic ulcer of the leg: Clinical history. Br Med J 1987;294:1389–1391. Nelzeń O, Bergqvist D, Lindhagen A, Hallbrook T: Chronic leg ulcers: An underestimated problem in the primary health care among elderly patients. J Epidemiol Community Health 1991;45:184–187. Henry M: Incidence of varicose ulcer in Ireland. Ir Med J 1986;79:65–67. Bobek K, Cajzl L, Cepelak V, Slaisova V, Opatzny K, Bareal R: Etude de la fre´quence des maladies phle´bologiques et de l’influence de quelques facteurs e´tiologiques. Phle´bologie 1966;19:217–230. Harkiss KJ: Cost analysis of dressing material used in venous leg ulcers. Pharm J 1985;31:268–270. O’Donnell TJ, Browse NL, Burnand KG: The socioeconomic effects of an iliofemoral venous thrombosis. J Surg Res 1977;22:483–488. Franks PJ, Bonsanquet N, Brown D: Perceived health in a randomized trial of single and multilayer bandaging for chronic venous ulceration. Phlebology 1995(suppl 1):17–19. Callam MJ, Harper DR, Dale JJ, Ruckley CV: Chronic leg ulceration: Socioeconomic aspects. Scott Med 1988;33:358–360. Phillips T, Stanton B, Provan A: Study of the impact of leg ulcers on quality of life: Financial social and psychological implications. J Am Acad Dermatol 1994;31:49–53. Hamer C, Cullum NA, Roe BH: Patients’ perceptions of chronic leg ulceration; in Harding KG (ed): Proceedings of the 2nd European Conference on Advances in Wound Management, Harrogate. London, Macmillian Magazins, 1992, pp 178–180. Franks PJ, Moffatt CJ, Connolly MJ, Bosanquet N, Oldroyd M, Greenhalgh RM, McCollum CN: Community leg ulcers: Effect on quality of life. Phlebology 1994;9:83–86.

Prof. Dr. V. Wienert, Department of Phlebology, University Hospital Aachen, Pauwelsstrasse 30, D–52057 Aachen (Germany)

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Postthrombotic Syndrome Rene´ Eichlisberger Division of Angiology, Clinic of Rheumatology and Rehabilitation, Zurzach, Switzerland

Introduction The main goal in the treatment of deep-vein thrombosis (DVT) is the prevention of potentially lethal pulmonary embolism (PE). Rapid initiation of parenteral heparin (currently low molecular weight heparins) followed by oral anticoagulation (OAC) markedly reduces the risk of PE [1–3] as well as that of recurrent DVT [4, 5]. The second goal is to prevent late sequelae of DVT or the so-called postthrombotic syndrome (PTS). Despite the fact that PTS, in contrast to chronic arterial occlusive disease, is not a limb-threatening condition, it may considerably affect a patient’s quality of life. PTS may be the cause of frequent medical consultations, long-term treatment and inability to work. The considerable morbidity that can be caused by PTS is well established [6–9], but the actual socioeconomic and sociomedical impact can only be estimated [10]. Precise epidemiological data on the incidence of DVT, PTS after DVT and the prevalence of PTS in the general population are scanty. The benefits and risks of a more aggressive treatment of DVT, such as fibrinolysis and thrombectomy, with the aim to prevent PTS, are still ill defined, as well as the value of valvular reconstruction in the deep veins. Even the benefit of compression therapy should be studied more in depth.

Epidemiology of PTS Incidence of DVT The epidemiology of PTS begins with the epidemiology of DVT. It is difficult to obtain representative results on the incidence of DVT in the general population. Reliable investigations should consider several conditions. All

patients with a suspected diagnosis of DVT, even oligosymptomatic cases, should be referred to a single reference center, where a highly sensitive and a specific method (duplex ultrasound or phlebography) should be used to confirm or to rule out the diagnosis. During the study period, all mortalities should undergo postmortem examination to detect DVT or PE. Nordstro¨m and coworkers [11, 12] investigated the incidence of DVT and PE during 1 year in Malmo¨, Sweden. All patients with a suspected DVT underwent phlebography at one hospital. The incidence of DVT, which included postmortem diagnosis by autopsy, was 650 cases per 236,000 habitants per annum (0.28%). This seems to be a representative result for a population which benefits from modern DVT prevention [13, 14]. The incidence of DVT is correlated to age (¶2 for females ?46 years; ¶5 for males ?46 years) [15]. PTS Incidence after DVT To investigate the incidence of PTS after DVT, the precise anatomic location and extent, the age of the DVT at the time of detection, the treatment used and a sufficient follow-up period with assessment of trophical skin changes, recurrences and mortalities should be studied on a large population. Our own study (Basel 13 years’ follow-up) comprised 223 consecutive patients who where controled 13.1×1.4 years after phlebographically proven unilateral DVT [10, 16]. This study was performed before the CEAP classification became available and therefore, the Widmer classification of chronic venous insufficiency (CVI) was used [10, 16]. In 29 patients the DVT was limited to the calf (C, 1 level), in 45 patients it extended to the poplitea (CP, 2 levels), in 72 patients to the superficial femoral vein (CPF, 3 levels) and in 62 patients to the iliac veins (CPFI, 4 levels). The remaining 15 patients had DVT of special location (SP), e.g. limited to the popliteal or the iliac vein. All patients initially received heparin in therapeutical dosis and subsequent OAC for 6 months. Compression therapy consisted in short stretch bandages in the beginning to reduce edema and a class 3 (compression of 36–46 mm Hg) medical calf stockings thereafter. Additional systemic fibrinolysis was performed in 144 of the 223 patients. A control phlebography was performed on days 5–14, showing that fibrinolysis was completely or partially successful in 100 of the 144 patients. The 44 nonresponders and the 79 only heparinized patients showed no recanalization at that time. The natural course of DVT could be studied in these 123 patients. The 13-year global PTS incidence in these 123 patients was 39%, among whom 10% with venous ulceration and another 29% with advanced trophic skin changes. In 24%, less severe sequelae such as swelling and cyanosis were seen. Only 37% of patients had no sequelae of DVT. The incidence of PTS depends also on the initial extension (C: 3.5%, among 0% ulceration; CP:

Postthrombotic Syndrome

71

% 60 50 40 30 20 10 0

C (n = 28)

CP (n = 26)

CPF (n = 36)

CPFI (n = 29)

Fig. 1. Incidence of PTS after DVT (Basel 13 years’ follow-up). The black part of each column represents the incidence of leg ulcer, the white part the incidence of PTS without ulcer. The PTS incidence depends on the initial extent of DVT: 0–5% after isolated calf vein thrombosis (C), 50–60% (10–15% ulcer) after 3 and 4 level thrombosis (CPF and CPFI).

31%, among 11% ulcerations; CPF: 58%, among 11% ulcerations; CPFI: 55%, among 17% ulcerations) (fig. 1). In the 15 patients with limited thrombosis in a special location (SP) no PTS was observed. ‘Venous complaints’, such as swelling, heaviness and pain were also correlated with the extension of DVT. Recurrences of DVT were seen in 22% of patients during the 13-year followup and extensive thrombosis was associated with a 2.5 times higher recurrence rate compared to calf vein thrombosis. Table 1 shows a comparison of the literature on the incidence of PTS [17–22]. Our study with the longest follow-up revealed one of the highest incidences of PTS. Only 8% of patients developed a PTS in the study of Franzeck et al. [20]. However, these patients had less extensive DVT at the beginning and were regularly encouraged to use compression stockings. The discrepancies between the different studies may be explained by differences in location and extension and by nonstandardized reporting of chronic venous disease. Prandoni et al. [22] emphasized the correlation of repeated DVT with PTS, whereas they could not show any correlation between the original extension of DVT and PTS incidence. Prevalence of PTS Epidemiologic data on the prevalence of CVI are relatively precise. A relevant CVI with trophic skin changes can be found in 2–7% of the adult

Eichlisberger

72

Table 1. Incidence of PTS after DVT treated with anticoagulation and compression therapy Group (first author)

Strandness [17] Widmer [18] Norris [19] Franzeck [20] Monreal [21] Eichlisberger [16] Prandoni [22]

n

65 194 77 39 84 123 148

Interval years

PTS, % without ulcer

with ulcer

3.3 6 2.1 12 3 13 8

23 16 ? 5 14 29 20

5 8 6.5 3 6 10 9

population. Venous ulceration is found in 0.1–1.3% of the male and in 0.3–1.9% of the female population [10]. The prevalence of CVI progresses with age. A major drawback of all epidemiological studies on the prevalence of CVI is the lack of pathophysiologic and functional data. No distinction is made between deep venous insufficiency and superficial vein insufficiency or between postthrombotic and primary vein insufficiency. The CEAP system of reporting venous disease would be ideal to address this lack of information in forthcoming studies [23]. In the meantime, the global prevalence of PTS may be assumed at 0.5–3% in the general population [10].

Pathophysiology and Clinical Presentation of PTS Chronic ambulatory venous hypertension is the main cause of CVI. Postthrombotic recanalization and valve destruction represent the most important cause of deep venous incompetence. However, secondary or preexisting superficial venous incompetence, e.g. of the greater saphenous vein or of perforating veins, may contribute considerably to the development of PTS. In some cases, DVT does not recanalize. Recanalization depends on the individual’s fibrinolytic potential, the extent and location of the thrombus and the development of sufficient collaterals. Duplex scanning is not only highly accurate in detecting fresh DVT [24, 25], but also represents the ideal method of investigating both the morphologic and functional development of acute DVT. The time of recanalization and the intensity of reflux can be detected by repeated follow-up examinations. For example, the superficial femoral vein remains occluded in 20% of cases of extended 3–4 level DVT [26–28].


73

Interestingly, PTS is rather associated with postthrombotic deep venous reflux than with chronic occlusion [27–29]. Delayed recanalization is associated with greater reflux [30, 31]. The combination of recanalized sections with those with chronic occlusion, however, is most deleterious for the development of PTS [26–29]. Distal reflux (popliteal vein and posterior tibial vein) [21, 28, 32], a long section of incompetence and the combination of deep vein and superficial incompetence [32] also favor the development of PTS. Incompetent perforating veins (especially Cockett’s perforating veins) direct the venous reflux towards the subcutaneous and subpapillary plexus of the skin at the distal medial calf. Clinically, perforating veins that are located underneath trophically damaged skin are often missed, although they are readily detectable by duplex scan. Ligation of such perforating veins often results in a dramatic improvement of the skin changes [33, 34]. The peripheral venous pressure, which can be measured by venipuncture on the dorsum of the foot, normally ranges from 90 to 110 mm Hg in the upright position. This pressure is reduced to 20–25 mm Hg when walking. Patients with PTS suffer from ‘ambulatory peripheral venous hypertension’ as a result of an ineffective ankle muscle pump due to valve incompetence. Peripheral venous pressure remains high or even rises at the start of exercise referred to a ‘retrograde pressure wave’ [35]. As a result, venous reflux induces localized cutaneous microangiopathy (‘venous hypertensive microangiopathy’) [36; cf. chapter of M. Ju¨nger et al.]. Until the CEAP system of reporting venous disease [cf. chapter of W. Mayer et al.] was available, the clinical classification of CVI according to Widmer was widely used in the German-speaking countries. Widmer stage I is defined by paraplantar teleangiectasias (‘corona phlebectatica paraplantaris’), stage II by trophical skin changes, such as pigmentation (‘purpura jaune d’ocre’) or depigmentation (‘atrophie blanche’), dermatoliposclerosis and stasis dermatitis. Widmer stage III of CVI encompasses florid venous ulceration, as well as healed venous ulceration [37]. Edema and cyanosis may be present in all stages. Trophical skin changes are typically located around or behind the medial ankle. Secondary lymphostasis [cf. chapter of U. Stahel] is commonly seen in progressing CVI. The CEAP system of classification accounts for the clinical picture and also describes the etiology and pathophysiology of CVI. For instance, [C6/Es/Ad11–15/Pr] means: Clinically: active venous ulceration/Etiology: secondary (postthrombotic)/ Anatomy: deep veins insufficient, ‘11–15’ means calf, popliteal and femoral section/Pathophysiology: reflux. As mentioned before, this refined system of reporting venous disease should represent the standard for future clinical studies on CVI.

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Prevention and Treatment of PTS Prevention and Routine Medical Treatment of DVT Prevention of DVT, as primary prevention of PTS, has considerably improved during the last years. This was principally achieved by the consequent use of low-dose heparins and antithrombosis stockings in risk situations. If DVT occurs, early detection and treatment with heparin in therapeutical doses followed by oral anticoagulation for 3–6 months does not only prevent pulmonary embolism but also further extension of thrombus and recurrent DVT. By that way anticoagulation also represents an effective secondary prevention of PTS [1–5]. Before oral anticoagulation was routinely available to treat DVT, PTS occurred practically in 100% of patients who survived the acute thromboembolic episode [6]. Fibrinolysis Fibrinolysis with streptokinase or urokinase, as adjunct to anticoagulation, results in 30–40% of patients in complete and in 40–50% of patients in partial recanalization [38]. The success rate declines with advancing age of the DVT. In our follow-up study (Basel 13-years’ follow-up) patients who successfully underwent thrombolysis did significantly better after 13 years, especially the patients with extended DVT [10, 16]. Several small randomized trials confirmed the positive effect of thrombolysis compared to anticoagulation alone concerning the development of PTS after extended DVT (table 2) [39–42]. But fibrinolytic treatment is not a harmless device. Major bleeding is the most severe risk of this treatment. In a meta-analysis of Goldhaber et al. [43], major bleeding was 2.9 times more frequent under fibrinolysis than with standard heparin therapy. Jacobsen [44] found that major bleeding occurred practically only in patients over 50 years old. As of yet, no randomized controlled trial on the bleeding risk under streptokinase/urokinase versus heparin is available. PTS is practically never a life- or limb-threatening condition, but fibrinolysis, on contrast, represents a potentially life-threatening treatment. Therefore, the use of fibrinolysis in the treatment of DVT is controversial. Whereas in some centers of German-speaking countries fibrinolysis is almost routinely used to treat acute DVT, it is rarely used in the UK and USA. Thrombectomy There are great differences in the judgment on the value of thrombectomy in acute DVT for the prevention of PTS. The available long-term studies are very inhomogeneous in respect to patient selection, location and extension of the DVT, the number of patients included, dropouts and the period of follow-


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Table 2. Randomized follow-up studies after DVT: comparison of streptokinase with heparin Group (first author)

Therapy Patients at Patients at Time to Asymptomatic patients entrance follow-up follow-up n % n n years

Common [39]

SK H SK H SK H SK H

22 26 9 7 26 25 21 21

15 12 8 6 23 21 17 18

0.6 0.6 11.2 8.8 1.6 1.6 6.3 6.4

10 6 4 2 15 2 13 6

67 50 50 33 65 10 76 33

SK H

78 79

63 57

4.9 4.3

42 16

64 31

Johansson [40] Elliot [41] Arnesen [42]

SK>Streptokinase; H>heparin.

up. Some authors report good long-term results [45–53], however, rethrombosis and PE are frequent in the perioperative phase [54–56]. Thrombectomy of iliofemoral DVT yields the best results in comparison to more distally extended DVT. Unfortunately, precisely these more extended forms of DVT often result in progressing PTS [16]. In conclusion, thrombectomy of acute DVT should be used very carefully. The limb-threatening situation of phlegmasia coerulea dolens is currently the only established indication for thrombectomy in acute DVT. Compression Therapy Compression therapy represents both an effective primary prevention of DVT, as well as the actual mainstay in the secondary prevention of PTS after DVT. A phase of decongestion by elastic short stretch bandages is followed by long-term maintenance with medical calf stockings [57, 58]. Several clinical effects of compression therapy can be distinguished [57–60]. For many years it was generally accepted by clinical experience that compression therapy helps prevent PTS. However, it was only recently that Brandjes et al. [59] reported on a randomized controlled trial on compression therapy after DVT. Among the 80 patients who did not wear medical stockings, 23% developed severe and 47% moderate PTS after 6 years of follow-up. This incidence was about half as high (11% severe, 20% moderate PTS) among

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the patients who used medical calf stockings exerting a compression of about 40 mm Hg (class 3 compression). After this trial, the individual PTS risk and the individual indication for and the duration of compression therapy for each DVT patient is still unknown. Further studies should aim at defining this individual risk more precisely, ideally by regular follow-up visits and regular duplex controls.

Reconstructive Surgery of the Deep Veins in Established PTS In contrast to the great benefit of certain surgical procedures on the superficial venous system [cf. chapters of Cassina et al., Schwahn-Schreiber and Sattler], the reconstructive valvular surgery of the deep venous system still has many drawbacks. Theoretically, bypass surgery is appealing for control of chronic occlusion, valvulorhaphy in primary deep venous incompetence and vein transposition or valve transplantation in the case of postthrombotic valve destruction. Bypass surgery for occlusion of the superficial femoral vein (May and Husni) or of the iliac vein (Palma) tends to result in stenosis at the anastomotic sites and rethrombosis. Therefore, these techniques are hardly used [61]. Valvular reconstructions are highly specialized procedures which are only performed by a few specialists worldwide. Long-term results after valvulorhaphy for primary deep venous incompetence or congenital valvulodysplasia are good (73% success after 10 years), whereas valvular transplantation and vein transposition for postthrombotic deep venous incompetence often is complicated by rethrombosis [62, 63], and should be avoided in this condition.

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Barritt DW, Jordan SC: Anticoagulant drugs in the treatment of pulmonary embolism. A controlled trial. Lancet 1960;18:1309–1312. Lagerstedt CJ, Olsson CG, Fagher BO, Oeqvist BO, Albrechtsson U: Need for long-term anticoagulant treatment in symptomatic calf-vein thrombosis. Lancet 1985;2:515–518. Brandjes DPM, Heijboer H, Bu¨ller HR, de Rjik M, Jagt H, ten Cate JW: Acenocoumarol and heparin compared with acenocoumarol alone in the initial treatment of proximal-vein thrombosis. N Engl J Med 1992;327:1485–1489. Schulman S, Rhedin AS, Lindmarker P, et al, and the Duration of Anticoagulation Trial Study Group: A comparison of six weeks with six months of oral anticoagulant therapy after a first episode of venous thromboembolism. N Engl J Med 1995;332:1661–1665. Bounameaux H, de Moerloose P, Sarasin FP: Optimal duration of oral anticoagulant therapy following deep vein thrombosis of lower limbs. Blood Coagul Fibrinolysis 1996;7:507–514. Bauer G: A roentgenologic and clinical study of the sequelae of thrombosis. Acta Chir Scand 1942; 86(suppl 76).


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Zilliakus H: On specific treatment of thrombosis and pulmonary embolism with anticoagulants with particular reference to postthrombotic sequelae: Results of 5 years’ treatment of thrombosis and pulmonary embolism at a series of Swedish hospitals during years 1940–1945. Acta Med Scand 1946;suppl 171. Halse T: Das postthrombotische Syndrom – Pathogenese, Diagnostik, Behandlung und Verhu¨tung von akuter Beinvenenthrombose. Darmstadt, Steinkopff, 1954. Gjo¨res JE: The incidence of venous thrombosis and its sequelae in certain districts of Sweden. Acta Chir Scand 1956;suppl 206. Eichlisberger R, Widmer MT, Frauchiger B, Widmer LK, Ja¨ger K: The incidence of post-thrombotic syndrome. Wien Med Wochenschr 1994;144:192–195. Nordstro¨m M, Lindblad B, Bergqvist D, Kjellstrom T: A prospective study of the incidence of deep-vein thrombosis within a defined urban population. J Intern Med 1992;232:155–160. Bergqvist D, Lindblad B: Incidence of DVT/PE in medical and surgical patients. European Workshop on the Prevention of Thromboembolism, Windsor UK, 1991. Kierkegaard A: Incidence of acute deep vein thrombosis in two districts: A phlebographic study. Acta Chir Scand 1980;146:267–269. Van Beek EJR, Bu¨ller HR, ten Cate JW: Epidemiology of venous thromboembolism; in Took JE, Lowe GD (eds): A Textbook of Vascular Medicine. London, Arnold, 1996, pp 471–488. Coon WW, Willis PW, Keller JB: Venous thromboembolism and other venous diseases in the Tecumseh Community Health Study. Circulation 1973;48:839. Eichlisberger R, Frauchiger B, Widmer MT, Widmer LK, Ja¨ger K: Spa¨tfolgen der tiefen Venenthrombose: Ein 13-Jahres Follow-up von 223 Patienten. Vasa 1994;23:234–243. Strandness DE, Langlois Y, Cramer M, Randlett A, Thiele BL: Long-term sequelae of acute venous thrombosis. JAMA 1983;250:1289–1292. Widmer LK, Zemp E, Widmer MT, et al: Late results in deep vein thrombosis of the lower extremity. Vasa 1985;14:264–268. Norris CS, Darrow JM: Hemodynamic indicators of postthrombotic sequelae. Arch Surg 1986;121: 765–768. Franzcek UK, Schalch I, Ja¨ger K, Schneider E, Grimm I, Bollinger A: Prospective 12-year followup study of clinical and hemodynamic sequelae after deep vein thrombosis in low risk patients. Circulation 1996;93:74–79. Monreal M, Martorell A, et al: Venographic assessment of deep vein thrombosis and risk of developing post-thrombotic syndrome: A prospective study. J Intern Med 1993;233:233–238. Prandoni P, et al: The long-term clinical course of acute deep venous thrombosis. Ann Internal Med 1996;125:1–7. Partsch H: Klassifizierung und Bewertung von chronischen Venenerkrankungen der unteren Extremita¨ten. Phlebologie 1995;24:125–129. Eichlisberger R, Frauchiger B, Ja¨ger K: Abkla¨rung der Beinvenen mit Duplexultraschall. Ther Umschau 1991;48:697–707. Ja¨ger K, Eichlisberger R, Frauchiger B: Stellenwert der bildgebenden Sonographie und DuplexSonographie fu¨r die Diagnostik der Venenthrombose. Haemostaseologie 1993;13:116–124. Franzcek UK, Schalch I, Bollinger A: On the relationship between changes in the deep veins evaluated by duplex sonography and the postthrombotic syndrome 12 years after deep vein thrombosis. Thromb Haemost 1997;77:1109–1112. Johnson BF, Manzo RA, Bergelin RO, Strandness DE: Relationship between changes in the deep venous system and the development of the postthrombotic syndrome after an acute episode of lower limb deep vein thrombosis: A one- to six-year follow-up. J Vasc Surg 1995;21:307–312. Johnson BF, Manzo RA, Bergelin RO, Strandness DE: The site of residual abnormalities in the leg veins in long-term follow-up after deep vein thrombosis and their relationship to the development of the post-thrombotic syndrome. Int Angiol 1996;15:14–19. Guex JJ: Physiopathology of the post-thrombotic venous syndrome. Update 1994. J Mal Vasc 1994; 19:12–16. Meissner MH, Manzo RA, Bergelin RO, Markel A, Strandness DE: Deep venous insufficiency: The relationship between lysis and subsequent reflux. J Vasc Surg 1993;18:596–605.

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Markel A, Manzo RA, Bergelin RO, Strandness DE: Valvular reflux after deep vein thrombosis: Incidence and time of occurrence. J Vasc Surg 1992;15:377–382. Labropoulos N, Leon M, Nicolaides AN, et al: Venous reflux in patients with previous deep venous thrombosis: Correlation with ulceration and other symptoms. J Vasc Surg 1994;20:20–26. Becker F: Post-thrombotic venous disease of the legs. Current data. J Mal Vasc 1992;17(suppl B): 77–83. Toscano F, Juliano GP, Grassia M, Bordascino L: Post-phlebothrombotic venous insufficiency of the lower limbs. Echo-guided targetted surgery. Minerva Chir 1997;52:683–686. Janssen M, Wollersheim H, van Asten W, de Rooij M, Nova´kova´ I, Thien TH: The post-thrombotic syndrome: A review. Phlebology 1996;11:86–94. Belcaro GV, Hoffmann U, Bollinger A, et al: Laser Doppler. London, Med-Orion, 1994. Widmer LK, Sta¨helin HB, Nissen C, Da Silva (eds): Venen-, Arterien-Krankheiten, koronare Herzkrankheit bei Berufsta¨tigen (Basler Studie I bis III). Bern, Huber, 1981. Martin M (ed): Phleko-Phlefi-Studien. Vasa 1997;suppl 49. Common HH, Seaman AJ, Ro¨sch J, Porter JM, Dotter CT: Deep vein thrombosis treated with streptokinase or heparin: Follow-up of a randomized study. Angiology 1976;27:645–654. Johansson L, Nylander G, Hedner U, Nilsson IM: Comparison of streptokinase with heparin: Late results in the treatment of deep venous thrombosis. Acta Med Scand 1982;206:93–98. Elliot MS, Immelman EJ, Jeffery 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;66:838–843. 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;211:65–68. Goldhaber SZ, Buring JE, Lipnick RJ, et al: Pooled analyses of randomized trials of streptokinase and heparin in phlebographically documented acute deep venous thrombosis. Am J Med 1984;76: 393–397. Jacobsen BO: Thrombolytic treatment in venous thromboembolism; in Eklo¨f B, Gjo¨res JE, Thulesius O, Bergqvist D (eds): Controversies in the Management of Venous Disorders. London, Butterworths, 1989, pp 116–126. Juhan CM, Alimi YS, Barthelemy PJ, Fabre DF, Riviere CS: Late results of iliofemoral venous thrombectomy. J Vasc Surg 1997;25:417–422. Shionoya S, Yamada I, Sakurai T: Thrombectomy for acute deep vein thrombosis: Prevention of post-thrombotic syndrome. J Cardiovasc Surg 1989;30:484–489. De Araujo-Bessa J: Femoral and iliofemoral thrombectomy to prevent chronic venous insufficiency; follow-up of 18 patients. J Cardiovasc Surg 1986;27:443–446. Swedenborg J, Hagglof R, Jacobsson H: Results of surgical treatment for iliofemoral venous thrombosis. Br J Surg 1986;73:87187–4. Ganger KH, Nachur BH, Ris HB, Zurbrugg H: Surgical thrombectomy versus conservative treatment for deep venous thrombosis; functional comparison of long-term results. Eur J Vasc Surg 1989;3:529–538. Kniemeyer HW, Torsello G, Grabitz K, et al: Fru¨h- und Spa¨tergebnisse nach veno¨ser Thrombektomie mit AV-Fistel zur Behandlung der akuten tiefen Beinvenenthrombose. 9. Jahrestagung der dtsch. Ges fu¨r Gefa¨sschirurgie 1993; Abstract: 59. Partsch H, Weidinger P, Mostbeck A, et al: Funktionelle Spa¨tergebnisse nach Thrombektomie, Fibrinolyse und konservativer Therapie von Becken-Beinvenen-thrombosen. Vasa 1980;9: 53–61. Minar E, Ehringer H, Marosi L, et al: Klinische, funktionelle und morphologische Spa¨tergebnisse nach veno¨ser Thrombektomie. Vasa 1983;12:346–351. Hutschenreither S, Loeprecht H, Heyden B: Spa¨tergebnisse nach transfemoraler veno¨ser Thrombektomie bei akuten Ileofemoralvenenthrombosen; in Breddin K (ed): Thrombose und Atherogenese, Pathophysiologie und Therapie der arteriellen Verschlusskrankheit; Bein-Beckenvenenthrombose. Baden-Baden, Ko¨ln, New York: Witzstrock 1981:221–223. Young AE, Thomas ML, Browse NL: Comparison between sequelae of surgical and medical treatment of venous thromboembolism. Br Med J 1974;4:127–130.


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Hold M, Bull PG, Raynoschek H, Denck H: Deep venous thrombosis: Results of thrombectomy versus medical therapy. Vasa 1992;21:181–187. Johansson E, Nordlander S, Zetterquist S: Venous thrombectomy in the lower extremity – Clinical, phlebographic and plethysmographic evaluation of early and late results. Acta Chir Scand 1973; 139:511–516. Sto¨berl C, Gabler S, Partsch H: Indikationsgerechte Bestrumpfung – Messung der veno¨sen Pumpfunktion. Vasa 1989;18:35–39. Stoberl C: Compression therapy in post-thrombotic syndrome. Wien Med Wochenschr 1994;144: 233–237. Brandjes D, Bu¨ller H, et al: Randomized trial of effect of compression stockings in patients with symptomatic proximal vein thrombosis. Lancet 1997;349:759–762. Brakkee A, Kuiper J: The influence of compressive stockings on the haemodynamics in the lower extremities. Phlebology 1988;3:147–153. May R: Chirurgie der Bein- und Beckenvenen. Thieme, Stuttgart 1974. Cheatle TR, Perrin M: Venous valve repair, early results in 52 cases. J Vasc Surg 1994;19:404–413. Masuda E, Kistner R: Long-term results of venous valve reconstruction: A four- to twenty-oneyear follow-up. J Vasc Surg 1994;19:391–403.

Re´my Eichlisberger, MD, Division of Angiology, Clinic of Rheumatology and Rehabilitation, CH–5330 Zurzach (Switzerland) Tel. +41 56 269 51 51, Fax +41 56 269 51 70, E-Mail [email protected]

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Classification of Chronic Venous Insufficiency Wolfgang Mayer, Hugo Partsch Dermatological Department, Wilhelminenspital, Vienna, Austria

Introduction Chronic venous insufficiency (CVI) is worldwide one of the most prevalent medical conditions limiting quality of life for the patient and incurring extraordinary health expenses for the community. About 1% of the adult population of Western countries will develop a venous leg ulcer during their lifetime. The nomenclature of chronic disorders of the lower extremity is quite confusing. CVI, or ‘chronic venolymphatic insufficiency’ are basically functional terms meaning a disturbance of the venous (lymphatic) return. In everyday practice, however, CVI is mainly defined by clinical criteria and the underlying anatomical and functional deficiency is only rarely demonstrated by objective testing.

Widmer’s Classification (1976) In German-speaking countries the so-called Widmer Classification [1] is still widely in use. ‘Uncomplicated’ varicose veins are clearly differentiated from CVI (table 1). Skin changes around the inner ankle are used to assess the functional impairment with three degrees of severity. This simple division may still be useful for everyday practice but especially for scientific clinical trials a more detailed classification is desirable which is not only based on the clinical signs alone, but which also encompasses etiology, venous anatomy and pathophysiology.

Table 1. Widmer’s classification Varicose veins 1. Teleangiectatic veins 2. Reticular varicose veins 3. Truncular varicosities: long or short saphenous vein and their branches Chronic venous insufficiency

Grade I Teleangiectasias beyond the inner ankle, ‘corona phlebectatica’ Grade II Indurated edema, eczema, dermatoliposclerosis, hyperpigmentation Grade III Active or healed ulcer

Table 2. Porter’s classification

Class Class Class Class

0 1 2 3

Asymptomatic Mild swelling and discomfort; superficial veins involved Hyperpigmentation in the gaiter area, subcutaneous fibrosis Ulcerative or preulcerative skin changes, eczema

Table 3. CEAP classification C

Clinical signs (0–6) supplemented by (A) for asymptomatic and (S) for symptomatic patients Etiologic classification: congenital (C), primary (P), secondary (S) Anatomic distribution: superficial (S), deep (D), or perforating veins (P), or combinations Pathophysiologic dysfunction: reflux (R) or obstruction (O), alone or in combination

E A P

Table 4. Clinical classification (C0–C6)

Class Class Class Class Class

0 1 2 3 4

Class 5 Class 6

No visible or palpable signs of venous disease Teleangiectasias or reticular veins Truncal varicose veins and their branches Edema Skin changes ascribed to venous disease (e.g. pigmentation, stasis eczema, dermatoliposclerosis) Skin changes as defined above with healed ulceration Skin changes as defined above with active ulceration

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Porter’s Classification (1988) This classification was published as part of a document on reporting standards in venous diseases [2, 3] and is similar to Widmer’s classification (table 2).

CEAP Classification (1995) Based on the reporting standards of the North American Chapter of the Society for Vascular Surgery in 1988 [2] a consensus was mainly organized by the members of the American Venous Forum at the sixth annual meeting at Maui, Hawaii, in 1994. The consensus was published in 19 journals and books in several languages [e.g. 4–8]. The aim of these publications was to propose a uniform classification of chronic venous dysfunction simple enough to be accepted by many physicians. The acronym CEAP was born, contending the following items (table 3). Clinical Classification (C0–C6) Objective clinical signs of chronic venous diseases (C0–C6) are the base of the clinical classification. ‘A’ indicates asymptomatic and ‘S’ symptomatic changes. The symptoms include feeling of congestion, itching, muscle cramps and skin irritation. The severity of the clinical signs of CVI are classified in an ascending order from 0 to 6 (table 4). Clinical signs and symptoms, as well as reflux patterns may improve after treatment, making it necessary to reclassify the patients. Small varicose veins (C1) are differentiated from large varicosities (C2) since the latter group may cause trophic skin changes and ulceration while reticular veins and teleangiectasias do not lead to functional impairment. C3 corresponds to Widmer stage I of CVI and C4 to stage II. The subdivision of Widmer stage III of CVI into healed ulcers (C5) and active ulcers (C6) is reasonable and relevant. Etiological Classification (EC , EP , ES ) Three etiologic categories are defined (table 5). Congenital changes are present at birth, but sometimes become apparent only later in childhood or early adult life. Secondary pathologies encompass defined causes of venous disease, such as deep venous thrombosis or trauma. Anatomic Classification (AS , AD , AP ) The anatomic changes are subdivided in pathologies of superficial (AS), deep (AD) and perforating veins (AP). It is also possible that one, two or all

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Table 5. Etiologic classification Congenital (EC) Present at birth, but not always recognizable With undetermined cause Primary (EP) Secondary (ES) With known cause Postthrombotic Posttraumatic Other

Table 6. Anatomic classification

Segment

1 2 3 4 5

Superficial Veins (AS ) Teleangiectases/reticular veins Greater (long) saphenous vein (GSV), above knee Greater (long) saphenous vein (GSV), below knee Lesser (short) saphenous vein (LSV) Nonsaphenous

6 7 8 9 10 11 12 13 14 15 16

Deep veins (AD ) Inferior vena cava Common iliac Internal iliac External iliac Pelvic: gonadal, broad ligament, other Common femoral Deep femoral Superficial femoral Popliteal Crural: anterior tibial, posterior tibial, peroneal (all paired) Muscular: gastrocnemial, soleal, other

17 18

Perforating veins (AP ) Thigh Calf

Table 7. Pathophysiological classification

Reflux (PR) Obstruction (PO) Reflux and obstruction (PR, O)

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Table 8. Clinical score Pain Edema Venous claudication Pigmentation Lipodermatosclerosis Ulcer size Ulcer duration Ulcer recurrence Ulcer number

0>none; 1>moderate, not requiring analgetics; 2>severe, requiring analgetics 0>none; 1>mild/moderate; 2>severe 0>none; 1>mild/moderate; 2>severe 0>none; 1>localized; 2>extensive 0>none; 1>localized; 2>extensive 0>none; 1>=2 cm diameter; 2>?2 cm diameter 0>none; 1>=3 months; 2>?3 month 0>none; 1>once; 2> more than once 0>none; 1>single; 2>multiple

three systems are involved. The anatomic and pathophysiologic classification are specially relevant in scientific clinical trials (table 6). Pathophysiological Classification (PR,O ) Reflux (PR) and obstruction (PO) are the main causes of venous dysfunction (table 7). The pathophysiological features can be ascribed to the anatomic segments of concern. Obviously, the CEAP system is based on color-coded duplex scanning as the method of choice to localize reflux or obstruction in each vein segment. Scoring of Venous Insufficiency For scientific comparison and for the evaluation of therapeutic results, a numerical score system has been proposed. The three elements are: Anatomic Score: number of the involved anatomic segments; Clinical Score: the grading of symptoms and signs, and Disability Score. Anatomic Score This is the sum of the anatomic segments, each scored as one point (table 6). Clinical Score This is the sum of values assigned to the signs and symptoms listed in table 8. Disability Score This scoring system considers the working capability of the patient (table 9).


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Diagnostic Tools Medical history and physical examination are the basis to classify a patient with chronic venous disease. The simple continuous-wave (CW)-Doppler is the primary diagnostic tool to screen for pathologic refluxes during the Vasalva maneuver and after manual compression and decompression. Color-coded duplex scanning is the noninvasive method of choice to confirm or exclude the presence of venous obstruction or pathological reflux. Strain-gauge plethysmography, air plethysmography and photoplethysmography may also be useful for different questions, especially regarding the indication for venous surgery. Ascending and descending phlebography can be helpful, specifically when noninvasive methods are inconclusive. In general, the investigative procedures in question will depend on the clinical stage of CVI. For the stages C0–C2, medical history, inspection, palpation and a hand-held CW-Doppler investigation will be sufficient in most instances. For the stages C3–C6, duplex and plethysmographic examinations should be performed. Phlebography and measurement of peripheral venous pressure (phlebodynamometry) can be reserved for special questions. CEAP Classification and Venous Ulceration To confirm the venous origin of a leg ulcer the criteria of the CEAP classification should be fulfilled. The etiology can be congenital in the rare cases of avalvulia, primary in superficial and/or deep valvular incompetence or secondary in postthrombotic syndrome. Patient’s history is crucial. It has to be stressed that ‘congenital’, ‘primary’ and ‘secondary’ are mutually exclusive. The anatomic site and extent of the involvement of superficial veins (AS), deep veins (AD), perforating veins (AP) or any combination should be assigned. This differentiation is preferably made by using duplex ultrasound. In experienced hands, a hand-held CW-Doppler may provide sufficient information, as well. These methods are also able to give clear information on the pathophysiology concerning the presence of refluxes (PR) and/or obstructions (PO, PR, O). Several clinical studies have confirmed that venous reflux mainly drives ambulatory venous hypertension, thereby leading to hypertensive cutaneous microangiopathy and venous ulceration. Therefore, it is mandatory to demonstrate major refluxes in long vein segments to confirm the venous origin of a leg ulcer. The diagnosis of venous ulceration remains doubtful if no refluxes can be detected. When truncal varicosities and/or perforating veins represent the main sites of reflux, surgical treatment should be considered. The function of the venous ankle pump before and after surgery can be estimated by plethysmography

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Table 9. Disability score 0 1 2 3

Asymptomatic Symptomatic, can function with support device Can work 8-hour day only with support device Unable to work even with support device

Table 10. Proposed algorithm for varicose vein surgery based on the CEAP system

C(5, 6) E(P) A(S, P) P(R) B Consider varicose vein surgery

C(5, 6) E(S) A(D) P(R, O) B No varicose vein surgery

Table 11. Scoring system based on severity of symptoms

Class

Signs and symptoms

Weight

0/1 2 3 4 5 6

Symptoms and/or teleangiectasia Varicose veins Edema (venous) Skin changes Healed venous ulcer Active venous ulcer

1 5 10 20 50 100

or venous pressure measurement (phlebodynamometry) applying a tourniquet or digital occlusion of the saphenous vein and/or perforating veins. The CEAP system classifies a venous ulcer as follows: C(5 or 6) E(C or P or S) A(D, S, P or combined) P(R, R+O) . The following algorithm can be recommended to decide wether or not to operate on insufficient truncal veins or perforating veins (table 10). Additional functional information can be obtained by PPG, APG, foot volumetry and phlebodynamometry without and with occlusion tests which simulates a possible postoperative result. The clinical score is useful for comparisons regarding the severity of the ulceration, while the disability score provides rough information on the social implications for the patient.


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Scoring System of the Venous Task Force (1998) In an attempt to evaluate treatment strategies in terms of cost-effectiveness, a scoring system was proposed by a group of experts [9] which tries to weigh the individual symptoms according to their probability to develop an ulcer (table 11). The weights are not additive but the most advanced symptom is crucial for classification.

References 1 2 3 4

5

6

7

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Widmer LK, Sta¨helin HB, Nissen C, Da Silva A (eds): Venen-, Arterien-Krankheiten, koronare Herzkrankheit bei Berufsta¨tigen (Basler Studie I–III). Bern, Huber, 1981. Porter JM, Rutherford RB, Clagett GP, Raju S, et al: Reporting standards in venous disease. J Vasc Surg 1988;8:172–181. Porter JM, Moneta GL: Reporting standards in venous disease: An update. J Vasc Surg 1995;21: 635–645. Beebe HG, Bergan JJ, Bergqvist D, Eklof B, Erikkson I, Goldman MP, Greenfield LJ, Hobson RW II, Juhan C, Kistner RL, Labropoulos N, Malouf GM, Menzoian JO, Moneta GL, Myers KA, Neglen P, Nicolaides AN, O’Donnel TF, Partsch H, Perrin M, Porter JM, Raju S, Rich NM, Richardson G, Schanzer H, Coleridge Smith PH, Strandness DE, Sumner DS: Classification and grading of chronic venous disease in the lower limbs – A consensus statement. Phlebology 1995;10:42–45. Beebe HG, Bergan JJ, Bergqvist D, Eklof B, Erikkson I, Goldman MP, Greenfield LJ, Hobson RW II, Juhan C, Kistner RL, Labropoulos N, Malouf GM, Menzoian JO, Moneta GL, Myers KA, Neglen P,Nicolaides AN, O’Donnel TF, Partsch H, Perrin M, Porter JM, Raju S, Rich NM, Richardson G, Schanzer H, Coleridge Smith Ph, Strandness DE, Sumner DS: Classification and grading of chronic venous disease in the lower limbs – A consensus statement. Int Angiol 1995;14:197–201. Beebe HG, Bergan JJ, Bergqvist D, Eklof B, Erikkson I, Goldman MP, Greenfield LJ, Hobson RW II, Juhan C, Kistner RL, Labropoulos N, Malouf GM, Menzoian JO, Moneta GL, Myers KA, Neglen P, Nicolaides AN, O’Donnel TF, Partsch H, Perrin M, Porter JM, Raju S, Rich NM, Richardson G, Schanzer H, Coleridge Smith Ph, Strandness DE, Sumner DS: Classification and grading of chronic venous disease in the lower limbs – A consensus statement. Vasa, 1995;24:313–318. Beebe HG, Bergan JJ, Bergqvist D, Eklof B, Erikkson I, Goldman MP, Greenfield LJ, Hobson RW II, Juhan C, Kistner RL, Labropoulos N, Malouf GM, Menzoian JO, Moneta GL, Myers KA, Neglen P, Nicolaides AN, O’Donnel TF, Partsch H, Perrin M, Porter JM, Raju S, Rich NM, Richardson G, Schanzer H, Coleridge Smith Ph, Strandness DE, Sumner DS: Classification et stades de severite´ dans les maladies veineuses chroniques des membres inferieurs. Phle´bologie 1995;48:275–281. Beebe HG, Bergan JJ, Bergqvist D, Eklof B, Erikkson I, Goldman MP, Greenfield LJ, Hobson RW II, Juhan C, Kistner RL, Labropoulos N, Malouf GM, Menzoian JO, Moneta GL, Myers KA, Neglen P, Nicolaides AN, O’Donnel TF, Partsch H, Perrin M, Porter JM, Raju S, Rich NM, Richardson G, Schanzer H, Coleridge Smith Ph, Strandness DE, Sumner DS: Klassifizierung und Bewertung von chronischen Venenerkrankungen der unteren Extremita¨ten. Phlebologie 1995;24:125–129. Abenhaim L, Kurz X, Norgren L, Cle´ment D, Veines Task Force. The management of chronic venous disorders of the leg (CVDL). Phlebology 1998; in print.

Dr. W. Mayer, Dermatological Department, Wilhelminenspital, Montleartstrasse 37, A–1171 Wien (Austria)

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Venous Mapping with Doppler and Duplex Sonography Eberhard Rabe, Felicitas Pannier-Fischer Department of Dermatology, University Hospital, Bonn, Germany

Doppler and duplex sonography in venous leg ulcers enables the objective assessment of the superficial and deep venous system as well as extent of concomitant peripheral arterial occlusive disease. Uni- as well as bidirectional Doppler sonography is suitable as a screening examination to detect venous incompetence or occlusion as well as to rule out relevant arterial pathology. Morphological diagnostics, however, are not possible with Doppler sonography. In the specific situation of a venous leg ulcer, duplex sonography or venography are required to rule out deep venous occlusion prior to any vein surgery.

Physical Principle of Doppler and Duplex Sonography Doppler and duplex sonography are based on the Doppler effect. In 1842, Christian Doppler described the phenomenon that acoustic signals change wavelength when reflected from a moving object. In the examination of blood vessels the change of frequency is proportional to the velocity of blood flow and to the cosinus alpha of the angle between the blood vessel and the Doppler probe. Continuous wave Doppler sonography, which is applied in routine vascular diagnostics, is able to detect and reproduce the sum of reflected signals within a given range of penetration that depends on the emitted wavelength (e.g. 3–4 cm with an 8-MHz probe or 6–8 cm with a 4-MHz probe). The 8-MHz probe is most suitable for routine vascular examination in the groin or poplitea, whereas the 4-MHz probe may be required to explore the deep vessels (e.g., the superficial femoral or iliac vessels) or to examine adipose patients. In contrast to unidirectional

Doppler sonography, which cannot differentiate the direction of blood flow, bidirectional Doppler sonography is able to take a bearing of the flow direction, i.e. towards or away from the Doppler probe. Most unidirectional devices transform the registered blood flow into an audible sound without the possibility of registration, whereas most birectional devices also have a possibility for print out [1–4]. Duplex sonography combines B-mode sonography with a Doppler probe. The transsectional B-mode image displays the anatomy of the explored region. Duplex sonography uses a pulsed Doppler signal which allows for the examination within an exactly defined depth. The pulsed Doppler signal is directed into a vascular sample volume that is displayed on the B-mode image. Moreover, the velocity and volume of flow can be calculated using the angle of the Doppler probe and the vessel diameter. Color-encoded duplex sonography is a further development that is able to encode moving particles according to their velocity (color velocity imaging). Flow direction and velocity are displayed on the screen in different colors, e.g., the examinator can chose to display arterial blood flow in shades of red and venous blood flow in shades of blue [5–7].

Lower Extremity Examination with Continuous Wave Doppler Sonography In continuous wave Doppler sonography the probe is positioned above the vessels to examine and hold like a pen in a 45º angle using a little contact gel on the skin. It is important not to compress the vessels to be examined. Arterial signals are synchronous with the heart beat and can be interrupted by proximal compression. In a recumbent position venous signals of the proximal veins (i.e. common femoral, superficial femoral and popliteal vein) are synchronic with the inspiration and expiration. Venous flow stops during inspiration (higher intra-abdominal pressure) and continues with expiration. Distal manual compression accelerates venous flow [1, 4]. Deep venous thrombosis (DVT) is characterized by the absence of a physiologically breath-dependent venous blood flow in the proximal deep veins and spontaneous flow in collateral vessels, e.g. the greater saphenous vein. Continuous wave Doppler sonography is of limited sensitivity and specifity in the detection of DVT. In high clinical pretest probability of proximal DVT (i.e. common femoral, superficial femoral or popliteal vein DVT) it is a valuable tool to confirm the suspected diagnosis and in low pretest probability it is a valuable tool to exclude proximal DVT. In less clear-cut situations as well as to exclude distal DVT, continuous wave Doppler

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ultrasound is unsuitable for accurate diagnosis of DVT. B-mode sonography, duplex sonography or venography are the diagnostic tests of choice in such situations [5]. Chronic venous insufficiency is characterized by superficial, deep or combined superficial and deep venous reflux [8] and/or chronic deep venous obstruction [4]. Physiologically, competent vein valves prevent venous reflux. Both the destruction of the vein valves after DVT as well as venous dilation, e.g. in the course of overload of the deep-venous system in the presence of varicose veins, may lead to valvular incompetence and reflux [8]. A standardized examination of the deep and superficial venous system is advisable. Venous reflux is best diagnosed on the patient in a standing position, with the leg in a slight outer rotation and the knee slightly flexed [4]. The common femoral vein is found just beneath the inguinal ligament and medial to the well audible common femoral artery. It is usually competent. Reflux may be due to incompetence of the greater saphenous vein or incompetence of the superficial femoral vein (e.g. as a sequelae of recanalized DVT). A very short reflux (0.5 s) may be due to a physiologically incompetent distal valve in the external iliac vein [4, 5]. The crosse of the greater saphenous vein (GSV) is found approximately 2 cm medial and distal to the common femoral vein. The correct position of the Doppler probe can be checked by manual compression at the inner thigh or calf. Reflux during the Valsalva maneuver is pathognomonic for an incompetence of the GSV. It can be followed along the course of the GSV at the inner thigh dorsal to the femoral condylus and the proximal and distal calf where the GSV reaches the dorsum of the foot just ventral to the medial ankle. For eventual surgery it is relevant to find the most distal site of GSV incompetence which is often located in the region of Boyd’s perforating vein at the proximal calf [1, 2, 8]. The superficial femoral vein (SFV) is investigated a few centimeters below the groin. It can be identified by the arterial sound of the neighboring superficial femoral artery. Reflux in the SFV can be a hint to a postthrombotic valvular incompetence or to a secondary venous overload in the presence of a large varicose GSV. Rarely it can be the expression of primary valvular dysplasia [4]. The calf veins can be found along the arterial signal of the according arteries. Reflux is best examined by manual compression and decompression at a distal point, e.g. the sole of the foot. It is important to identify an arterial signal next to the investigated vein. Otherwise, superficial incompetent veins may easily be mistaken for deep veins. For the examination of the poplitea the patient is asked to turn around, to shift his weight on one leg and to bend slightly the knee of the other leg

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Fig. 1. Doppler examination of the LSV.

Fig. 2. Venous aneurysm of the LSV.


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to be examined (‘Greek statue position’). In this region, the popliteal vein(s), the lesser saphenous vein (LSV), the muscular veins and the femoro-popliteal (Giacomini) vein are in close anatomical relation and it may be impossible to discriminate among all these structures with the continuous wave Doppler sonography. We suggest to find the LSV 3 cm below the popliteal skin fold (fig. 1). It is located exactly on the median line of the calf and can be well identified by distal compression and decompression. In the case of a reflux, the crosse of the LSV can again be examined in the popliteal skin fold. However, Doppler ultrasound does not allow for localizing the confluence of the LSV with the popliteal vein for preoperative planning. If the reflux in the LSV reveals positive under the Valsalva maneuver this is usually due to deep-venous incompetence. Rarely it may be due a reflux along the GSV that leads through a femoro-popliteal (Giacomini) vein directely to the lesser saphenous vein territories. The popliteal vein(s) are examined at the height of the popliteal skin fold. They lie next to the popliteal artery and are best examined by manual compression and decompression of the calf. It is difficult to examine the perforating veins of the calf with continuous wave Doppler sonography. A tourniquet is placed above the point to be examined. If a reflux can be detected on manual compression and decompression distal to this point, this is a hint to an incompetence of this perforating vein [1, 2, 8]. Several studies have compared the sensitivity and specificity of this examination with that of duplex sonography or venography and found that continuous wave Doppler sonography is hardly accurate in the diagnosis of perforating vein incompetence [9, 10]. It is mandatory that all leg ulcer patients are also screened for peripheral arterial occlusive disease. Continuous wave Doppler sonography is used to examine the systolic ankle pressure which allows for a good clinical judgment on the healing potential of a chronic wound at the distal leg. Assessment of peripheral arterial occlusive disease is discussed in depth in the chapter of R.Wu¨tschert et al. [see below].

Lower Extremity Examination with Duplex Sonography Duplex sonography has proven especially useful in preoperative examination for saphenectomy of the greater and lesser saphenous vein [5, 11]. The region of confluence with the deep venous system can be shown with an excellent resolution of the confluent vein branches, detecting as well eventual doubling of the incompetent vein trunk or an aneurysmatic dilation (fig. 2) at the site of confluence. In the poplitea the confluence of the LSV into the


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deep venous system which may be quite variable, can be seen and confluent muscle veins and the femoro-popliteal vein (Giacomini) can be well identified prior to surgery. Furthermore, duplex sonography is highly sensitive and specific in the identification of incompetent perforating calf veins [9, 10]. Postthrombotic changes can be detected both in the form of deep venous reflux and morphological changes, such as increased echogenicity of the vein wall and luminal irregularities. Persistent occlusion may be seen directly, as well as on the basis of collateral circuits, e.g. by the femoro-popliteal (Giacomini) vein or prepubic collaterals.

Accuracy of Doppler and Duplex Sonography Continuous wave Doppler sonography is highly accurate and suitable in the examination of primary varicosis, such as of the greater and lesser saphenous vein. In the hand of an experienced examiner it also represents an accurate screening test to examine an extremity with advanced vascular pathology. However, the complete examination of a leg with venous or mixed venousarterial leg ulceration ideally requires one of the ‘gold standard’ examinations, i.e. duplex sonography or venography. Duplex sonography is able to identify postthrombotic changes, to confirm patency of the deep venous system, to identify incompetent perforating veins at the calf with a sensitivity of about 90% [10] and to give exact preoperative information on the groin and/or the poplitea [11].


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Partsch H: Doppler-Ultraschalluntersuchung der Extremita¨tenvenen; in Weber J, May R (eds): Funktionelle Phlebologie. Stuttgart, Thieme, 1990, pp 197–201. Straub H, Ludwig M: Der Doppler-Kurs. Mu¨nchen, Zuckschwerdt, 1992. Baldt M, Korn M, Schoder M, Schuller-Petrovic S, Bo¨hler K, Mostbeck GH: Bildgebende Verfahren bei Varikose. Radiologe 1994;33:484–490. Rabe E: Grundlagen der Phlebologie. Bonn, Kagerer, 1994. Rabe E, Fratila A, Stanzenbach W, Bertlich R, Kreysel HW: Wertigkeit der farbkodierten Duplexsonographie in der Diagnostik der chronischen veno¨sen Insuffizienz. Phlebologie 1992;21:130–133. Masuda E, Kistner B, Eklof E: Prospective study of duplex scanning for venous reflux: Comparison of Valsalva and pneumatic cuff techniques in the reverse Trendelenburg and standing positions. J Vasc Surg 1994;20:711–720. Strauss AL: Farbduplex-Sonographie der Arterien und Venen. Leitfaden und Atlas. Berlin, Springer, 1995. Schultz-Ehrenburg U, Hu¨bner HJ: Refluxdiagnostik mit Doppler-Ultraschall. Stuttgart, Schattauer, 1987. Rabe E: Beurteilung der insuffizienten Venae perforantes mit der farbkodierten Duplexsonographie. Phlebologie 1994;23:146–148.


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Stiegler H, Rotter G, Standl R, Mosavi S, von Kooten HJ, Weichenhain B, Baumann G: Wertigkeit der Farbduplex-Sonographie in der Diagnose insuffizienter Vv. perforantes. Vasa 1994;23:109– 120. Yamaki T, Nozaki M, Saski K: Color duplex ultrasound in the assessment of primary venous leg ulcers. Dermatol Surg 1998;24:1124–1128.

Eberhard Rabe, MD, Department of Dermatology, University Hospital of Bonn, Sigmund-Freud-Strasse 25, D–53105 Bonn (Germany) Tel. +49 228 287 5370, Fax +49 228 287 4333


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Duplex Ultrasound for the Assessment of Venous Reflux Christina Jeanneret, Markus Aschwanden, Karl Heinz Labs, Kurt Ja¨ger Division of Angiology, University of Basel Medical School, Basel, Switzerland

Background The most common feature of chronic venous insufficiency is valvular incompetence, possibly related to abnormal distensibility of the venous wall in varicose vein disease or valvular incompetence after valve destruction by venous thrombosis [1–3]. Valvular incompetence can be assessed by measuring venous reflux, defined as flow opposite to antegrade venous flow. Zamboni et al. [4] found a correlation between increasing venous diameter and venous pressure. Elevated venous pressure is known to result in marked disturbance of microcirculation [5]. As shown by Payne et al. [6], ambulatory venous pressure of 70 mm Hg is associated with skin lesions. Venous pressure and severity of clinical signs of venous insufficiency as investigated by Neglen and Raju [7] do correlate with the presence of venous reflux.

Clinical Significance of Venous Reflux Venous reflux of the distal deep veins is seen in 86% of patients with venous ulcer [8]. Labropoulos et al. [9] found no consistent pattern of venous reflux, which means that prediction of ulcer occurrence remains an unsolved problem. On the other hand, they found pain, ankle edema and skin changes predominantly in limbs with reflux in the superficial veins below the knee. Payne et al. [10] tested valvular function in relation to clinical conditions. Venous reflux in the superficial femoral vein (SFV), profunda femoral vein (PFV) and the lesser saphenous vein (LSV) did not correlate to the clinical findings, whereas venous reflux in the common femoral vein (CFV), the popliteal vein (PV) and the greater saphenous vein (GSV) did. Some authors suggest to use total limb reflux time,

as venous ulceration seems to be associated with reflux in multiple vein segments [11]. As described by Weingarten et al. [12], mean total limb reflux time in the CFV, PV, PTV, GSV and the LSV amounted to 9.66 (×5.6) s and was significantly longer in patients with venous ulcer compared to those without.

Duplex Ultrasound Compared to Phlebography Baker et al. [13] found that the presence of venous reflux diagnosed by duplex sonography correlated better with the half volume refilling time measured by plethysmography than the findings in descending phlebography. They concluded that venous reflux is underestimated by phlebography compared with duplex ultrasound. The same investigations were done by Valentin et al. [14], who found twice as many times significant reflux by duplex ultrasound than by phlebography. The positive predictive value of duplex ultrasound to diagnose venous reflux in patients with clinical symptoms was 77% compared to 35–44% for descending phlebography [15].

Methods to Assess Venous Reflux by Duplex Ultrasound The techniques used to measure venous reflux include the Valsalva maneuver, as well as the compression-decompression maneuver, either done manually or by pneumatic cuff compression. The most striking common feature is the variety of examining modalities and the lack of standardization. The position of the subject being examined varies according to the literature from lying to 15º reverse Trendelenburg to standing. The parameters for reflux measurements vary as well, with reflux time being the most commonly used parameter. Van Bemmelen et al. [16] in 1990 showed that valve closure is achieved only if a flow velocity of 30 cm/s persists. Manual compression is not the method of choice to fulfil this condition. We introduce two standardized methods of reflux testing both evaluated in standing healthy subjects and patients.

Standardized Valsalva Maneuver Procedure: The most common test for valvular incompetence in clinical practice is the Valsalva maneuver. In order to have reproducible measurements with acceptable variability, we suggest the following standardized procedure: forceful expiration into a tube system. The airway pressure is measured by means of a pressure transducer (Trantel Model 60-800; American Edward’s

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Fig. 1. B-mode and Doppler curve of the venous reflux in the SFV using the Valsalva method. The Valsalva maneuver is displayed as the expiratory pressure over time.

Laboratories, USA). To avoid false-positive prolonged reflux from a lack of transvalvular pressure gradients, an expiratory pressure of 30 mm Hg has to be established within 0.5 s and is to be held at least for 3 s [17]. The parameters routinely assessed in our studies include venous diameter at rest, venous diameter during Valsalva maneuver, as well as the reflux time and the retrograde peak velocity. A pronounced increase in diameter (30%) is seen in the CFV, both in healthy controls and in patients with varicose veins. Larger diameters are found in the deep venous system in patients with superficial venous disorders. The duration of reflux is significantly longer in patients with varicose veins. This applies not only for the GSV, where the result is expected, but also for the deep venous system (CFV and SFV). In controls, reflux time in the SFV and the GSV is significantly shorter than in the CFV. Normal values for reflux time are 0.8 s for the CFV, 0.4 s for the SFV and 0.3 s for the GSV [18]. The standardized procedure is highly reproducible with coefficients of variation ranging for the venous diameter at rest from 3.8 to 5%, for the venous diameter under Valsalva from 3.3 to 3.7%, for the reflux time from 10.4 to 13% and for the peak velocity from 11.5 to 16.4% [18].

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Fig. 2. B-mode and Doppler curve of the venous reflux in the SFV using the cuff deflation method. Cuff pressure over time is displayed.

The Valsalva maneuver, although most commonly used in routine clinical investigation of venous disorders, is reliable only in the proximal lower limb veins; distal of competent valves, Valsalva pressure cannot be used as a testing method. In addition, this procedure can only be used if patients and subjects have normal lung function and are able to cooperate (fig. 1).

Standardized Cuff Inflation-Deflation Method Procedure: An automatic cuff inflator (Hokanson, Bellevue, Wash., USA) is used for rapid inflation and deflation of cuffs placed at different levels of the limb [19]. Van Bemmelen uses different pressure levels depending on the vein segment under investigation. In standing position pneumatic pressure has to exceed hydrostatic pressure; the following pressure values are chosen: on the thigh a pressure of 80 mm Hg, on the calf 100 mm Hg and on the foot 120 mm Hg is used, respectively. The cuff widths are 24 cm on the thigh, 12 cm on the calf and 7 cm on the foot level. The cuffs are automatically inflated,


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the pressure is held for 3 s, then deflation occurs passively over large tubes within 0.3 s. Variation coefficients for venous diameter vary between 0.6 and 4.4%, mean flow velocity between 13 and 18% and mean flow volume from 12 to 22% as described by Vasdekis et al. [20]. Normal values (i.e. 95th percentile) for reflux time are 0.88 s for the CFV, 0.8 s for the SFV, 0.28 s for the PV, and 0.2 s for the posterior tibial vein [1] (fig. 2).

Discussion The results of the cuff deflation method in standing patients have been compared with results of a nonstandardized Valsalva maneuver and the manual compression technique in supine patients. If the cuff deflation technique is considered the gold standard, the specificity of Valsalva and manual compression alone or in combination is very high (86–100%), but sensitivities are considerably lower. A nonstandardized Valsalva maneuver is more sensitive in the proximal segments (75–83%). Manual compression has a sensitivity of 73% in the PV, whereas it is very low for proximal segments (20–40%). The combination of the two techniques markedly improves sensitivities [21].

Conclusion Venous reflux is an important parameter for the pathophysiological understanding and assessment of the degree of venous insufficiency. There are two different means of measurement: the Valsalva maneuver and the compression method. For research purposes it is mandatory to standardize the methods. Standardization of the technique allows: (1) reliable assessment of valvular function; (2) long-term follow-up in longitudinal studies; (3) comparison of results between different centers and trials, and (4) further insight into the pathophysiology of venous disorders.

References 1

2 3

Van Ramshorst B, van Bemmelen P, Hoeneveld H, Eikelboom B: The development of valvular incompetence after deep vein thrombosis: A follow-up study with duplex scanning. J Vasc Surg 1994;19:1059–1066. Goldman M, Fronek A: Anatomy and pathophysiology of varicose veins. J Dermatol Surg Oncol 1989;15:138–145. Clarke H, Smith S, Vasdekis S, Hobbs J, Nicolaides A: Role of venous elasticity in the development of varicose veins. Br J Surg 1989;76:577–580.

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Zamboni P, Portaluppi F, Marcellino MG, Manfredini R, Pisano L, Liboni A: Ultrasonographic assessment of ambulatory venous pressure in superficial venous incompetence. J Vasc Surg 1997; 26:796–802. Thulesius O: The venous wall and valvular function in chronic venous insufficiency. Int Angiol 1996;15:114–118. Payne S, London N, Newland C, Thrush A, Barrie W, Bell P: Ambulatory venous pressure: Correlation with skin condition and role in identifying surgically correctible disease. Eur J Vasc Endovasc Surg 1996;11:195–200. Neglen P, Raju S: A rational approach to detection of significant reflux with duplex Doppler scanning and air plethysmography. J Vasc Surg 1993;17:590–595. Labropoulos N, Leon M, Geroulakos G, Volteas N, Chan P, Nicolaides A: Venous hemodynamic abnormalities in patients with leg ulceration. Am J Surg 1995;169:572–574. Labropoulos N, Leon M, Nicolaides A, Giannoukas A, Volteas N, Chan P: Superficial venous insufficiency: Correlation of anatomic extent of reflux with clinical symptoms and signs. J Vasc Surg 1994;20:953–958. Payne S, London N, Jagger C, Newland C, Barrie W, Bell P: Clinical significance of venous reflux detected by duplex scanning. Br J Surg 1994;81:39–41. Welch H, Faliakou E, McLaughlin R, Umphrey SE, Blekin M, O’Donnell Th: Comparison of descending phlebography with quantitative photoplethysmography, air plethysmography and duplex, quantitative valve closure time in assessing deep venous reflux. J Vasc Surg 1992;16:913–920. Weingarten M, Branas C, Czeredarczuk M, Schmidt J: Distribution and quantification of venous reflux in lower extremity chronic venous stasis disease with duplex scanning. J Vasc Surg 1993;18: 753–759. Baker S, Burnand K, Sommerville K, Thomas M, Wilson N, Browse N: Comparison of venous reflux assessed by duplex scanning and descending phlebography in chronic venous disease. Lancet 1993;341:400–403. Valentin L, Valentin W, Mercado S, Rosado C: Venous reflux localization: Comparative study of venography and duplex scanning. Phlebology 1993;8:124–127. Neglen P, Raju S: A comparison between descending phlebography and duplex Doppler investigation in the evaluation of reflux in chronic venous insufficiency: A challenge to phlebography as the ‘gold standard’. J Vasc Surg 1992;16:687–693. Van Bemmelen P, Beach K, Bedford G, Strandness DJ: The mechanism of venous valve closure. Its relationship to the velocity of reverse flow. Arch Surg 1990;125:617–619. Jeanneret Ch, Germann-Emers E, Bollinger A, Hoffmann U: Venous diameter and venous reflux in the proximal veins of the lower limb in healthy subjects during standardised Valsalva manoeuvre. Int Angiol 1996;15:52. Jeanneret Ch, Labs KH, Aschwanden M, Bollinger A, Hoffmann U, Ja¨ger K: Physiologic reflux and venous diameter change in the proximal lower limb veins during a standardised Valsalva manoeuvre. Eur J Vasc Endovasc Surg 1999, in press. Van Bemmelen P, Bedford G, Beach K, Strandness D: Quantitative segmental evaluation of venous valvular reflux with duplex ultrasound scanning. J Vasc Surg 1989;10:425–431. Vasdekis S, Clarke G, Nicolaides A: Quantification of venous reflux by means of duplex scanning. J Vasc Surg 1989;10:670–677. Masuda E, Kistner R, Eklof B: Prospective study of duplex scanning for venous reflux: Comparison of Valsalva and pneumatic cuff techniques in the reverse Trendelenburg and standing positions. J Vasc Surg 1994;20:711–720.

Dr. Ch. Jeanneret, Division of Angiology, University of Basel Medical School, Petersgraben 4, CH–4031 Basel (Switzerland) Tel. +41 61 265 51 57, Fax +41 61 265 53 56, E-Mail [email protected]


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Phlebography Heino Meents, Viola Hach-Wunderle Radiology Unit, William Harvey Clinic, Bad Nauheim, Germany

Phlebography (venography) is the classical golden standard in diagnosis of venous disease [1–5] . Even though duplex ultrasound has become widely accessible as an alternative golden standard, thereby reducing the need for contrast phlebography, both methods are highly accurate and therefore currently can be regarded as equivalent [6]. Phlebography requires a venipuncture on the dorsum of the foot, but this is a minor disadvantage that shoud not be overemphasized. The event of low osmolar nonionic contrast media made phlebography a safe routine examination [2].

Techniques of Phlebography (table 1) The ascending pressure phlebography according to Hach [3–5] represents the mainstay of phlebographic examination. It allows for a highly accurate diagnostic distinction between different underlying causes of chronic venous insufficiency, e.g. namely between (1) postthrombotic syndrome (which can be combined with secondary varicosis), (2) decompensated venous recirculation circuits with a primary truncal incompetence of the greater saphenous vein inducing non-postthrombotic secondary valvular incompetence of the deep venous system and (3) venous malformations or valvular dysplasia. The ascending phlebography both displays morphological as well as functional information by identifying incompetent perforating (communicating) veins, primary truncal varicosis that ultimately may lead to recirculation circuits and secondary truncal varicosis due to postthrombotic syndrome. For ascending phlebography the patient is positioned in a ‘relaxed upright position’ corresponding to a 15–30º foot-down position on a tilting table with fluoroscope. A rubber tourniquet is applied above the ankle to direct the

Table 1. Indications, advantages and disadvantages of phlebography Indications of phlebography Preoperative planning in chronic venous insufficiency Identification of extent and points of incompetence in postthrombotic syndrome Identification of points of incompetence in primary truncal varicosis and decompensated venous recirculation circuits Exclusion of chronic obstruction or recurrent thrombosis Preoperative planning in recurrent varicose veins Identification of perforating veins under the venous ulceration (hardly accessible for duplex scanning) Advantages of phlebography (with regard to duplex scanning) Little investigator dependency Phlebograms are comparably easy to read and understand; they give a clear overview Highly sensitive and specific in the identification of a postthrombotic syndrome Highly sensitive and specific in the detection of perforating veins Disadvantages of phlebography (with regard to duplex scanning) Cannot be repeated several times as easily as duplex scanning Venipuncture, low radiation exposure, low risk of urticaria or anaphlactic reaction to contrast medium Does not assess soft tissue pathologies, such as dermatolipofasciosclerosis Does not detect vessel wall thickening

contrast medium into the deep venous system. Under local anesthesia (Meaverin) a small (21- or 23-gauge) needle is introduced into a vein on the dorsum of the foot or on the medial aspect of the great toe. The examinator follows the rapid filling of the veins continuously by fluoroscopy and exposes the film when the filling of each segment is optimal. Within about 30 s, six exposures are made, two from the foot and calf (inner and outer rotation), two from the knee (inner and outer rotation), and each one from the distal and proximal thigh. The pelvis and inferior vena cava are documented if fluoroscopy shows relevant findings. Digital subtraction phlebography reduces background from osseus structures which can be of special value in the documentation of the iliac veins, e.g. a pelvic vein spur at the site, where the right common iliac artery crosses the left common iliac vein [3–5] . Incompetent epifascial veins with atypical deep communications may be traced very exactly by direct venipuncture and contrast injection into the incompetent vein (varicography) [6–8]. In retrograde (descending) pressure phlebography the common femoral vein is punctured in the groin and the contrast medium is injected under a Valsalva maneuver. Retrograde pressure phlebography identifies deep venous reflux and

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Fig. 1. A Compensated recirculation circuit; B decompensated recirculation circuit with secondary deep venous insufficiency, and C postthrombotic syndrome with extrafascial collateralisation.

can distinguish non-postthrombotic valvular incompetence from postthrombotic changes [9, 10] . Based on retrograde pressure phlebography, Kistner [1] graded deep venous incompetence into four degrees: (I) reflux to the proximal thigh; (II) reflux to the distal thigh; (III) reflux to below the knee, and (IV) reflux to below the ankle. Duplex scanning, however, has largely replaced retrograde phlebography in everyday practice [9–12].

Phlebographic Findings in Postthrombotic Syndrome Recanalized veins show an irregular diameter, partial filling defects and sometimes obstructions. Collateral circuits remain visible after recanalization. The valves are deformed to remnants or completely missing. Large Cockett’s perforating veins are a characteristic finding in postthrombotic syndrome, above which venous ulceration typically can be found [2, 5, 7].

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Fig. 2. Postthrombotic syndrome. Chronic occlusion of the superficial and common femoral vein with collateralization. Acute recurrent deep-vein thrombosis of the peroneal, posterior tibial and popliteal vein (arrows).

Phlebographic Findings in Primary Varicosis In primary truncal incompetence of the greater or the lesser saphenous vein, phlebography identifies the incompetent orificial valve (proximal point of incompetence) and the incompetent perforating vein (distal point of incompetence). Over the years, this decompensated venous recirculation circuit overfills the deep venous system resulting in a non-postthrombotic valvular incompetence. Again, venous ulceration typically occurs over the incompetent Cockett’s perforating veins, which is frequently the distal point of incompetence (fig. 1, 2).

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Table 2. Grading of truncal vein incompetence of the greater and lesser saphenous vein according to Hach Greater saphenous vein Grade I Reflux until Grade II Reflux until Grade III Reflux until Grade IV Reflux until Lesser Grade Grade Grade

the the the the

proximal thigh distal thigh proximal calf distal calf

saphenous vein I Reflux until the proximal calf II Reflux until the mid-height of the calf III Reflux until the distal calf

The exact identification of the venous recirculation circuit allows for an accurate staging of primary truncal incompetence according to Hach (table 2) [5–8, 13].

Phlebographic Findings in Primary Deep Venous Incompetence Primary deep venous insufficiency is caused by dilatation of the deep veins leading to insufficient valve closure, whereas secondary postthrombotic deep venous insufficiency is caused by the lack of competent valves after recanalization. Deep venous reflux may also result from a recirculation circuit in extensive truncular varicosis. Pronounced epifascial reflux can overfill the deep venous circulation which in turn leads to deep venous dilatation and secondary valvular incompetence (fig. 1, 3). In these situations deep venous incompetence improves after the epifascial reflux is corrected by ligation and saphenectomy [3]. In deep venous incompetence the diameter increases and the femoropoliteal angle increases as a result of an elongation of these venous segments. Deep venous reflux lasts over more than 4 s after decompression of the calf or under Valsalva’s maneuver [5].

Correlation of Phlebographic Findings and Clinical Pathology Unfortunately, clinical findings of chronic venous insufficiency are only ill correlated with phlebographic findings. More particularly, phlebography does not allow for a quantification of the impairment of the venous ankle pump (or quantification of chronic ambulatory venous hypertension, respectively). The advantage of phlebography rather lies in the exact morphological


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Fig. 3. Primary truncular insufficiency of the greater saphenous vein with decompensated recirculation circuit and severe secondary deep venous insufficiency.

identification of the proximal and distal point of incompetence thereby supplying very accurate information for preoperative planning [3].

Advantages of Phlebography with Regard to Duplex Scanning Both phlebography and duplex scanning allow for a highly sensitive and specific morphological and functional identification of venous pathology in both the deep as well as the superficial venous system.

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Duplex scanning may be repeated as many times as requested. Preoperative mapping can be marked directly on the skin. Unlike phlebography, duplex scanning allows for calculation and quantification of blood flow. Phlebography gives more accurate information on valvular morphology. Therefore, it is highly accurate in the identification of postthrombotic changes in the deep veins. It is specially useful in the detection of incompetent perforating veins, when they underlie venous ulceration. Phlebography is practically investigator-independent. Phlebograms are comparably easy to read, because they display large sections of the venous system on one picture. In summary, phlebography represents a highly accurate and safe diagnostic method in the documentation of venous pathologies. Competetion by duplex scanning should not be overemphasized, since both methods can be combined with a great benefit, especially in challenging cases.


7 8 9 10

11

12 13

Kistner RL: Diagnosis of chronic venous insufficiency. J Vasc Surg 1986;3:185–188. Lea Thomas M: Techniques of phlebography: A review. Eur J Radiol 1990;11:125–130. Hach W, Hach-Wunderle V: Die Rezirkulationskreise der prima¨ren Varikose – pathophysiologische Grundlagen zur chirurgischen Therapie. Berlin, Springer, 1994, pp 27–53. Hach W, Hach-Wunderle V: Phlebography and sonography of the veins. Berlin, Springer, 1997, pp 51–75. Hach-Wunderle V, Meents H, Hach W: Phlebographie; in Rieger H, Schoop W (eds): Klinische Angiologie. Berlin, Springer, 1998, pp 932–966. Baldt MM, Bo¨hler K, Zontsich T, Bankier AA, Breitenseher M, Schneider B, Mostbeck GH: Preoperative imaging of lower extremity varicose veins: Color-coded duplex sonography or venography? J Ultrasound Med 1996;15:143–154. Kistner RL, Kamida CB: 1994 update on phlebography and varicography. Dermatol Surg 1995; 21:71–76. Stonebridge PA, Chalmers N, Beggs I, Bradbury AW, Ruckley CV: Recurrent varicose veins: A varicographic analysis leading to a new practical classification. Br J Surg 1995;82:60–62. Rosfors S, Bygdeman S, Nordstro¨m E: Assessment of deep venous incompetence: A prospective study comparing duplex scanning with descending phlebography. Angiology 1990;41:463–468. Neglen P, Raju S: A comparison between descending phlebography and duplex Doppler investigation in the evaluation of reflux in chronic venous insufficiency: A challenge to phlebography as the ‘gold standard’. J Vasc Surg 1992;16:687–693. Welch HJ, Faliakou EC, McLaughlin RL, Umphrey SE, Belkin M, O’Donnell TF Jr: Comparison of descending phlebography with quantitative photoplethysmography, air plethysmography, and duplex quantitative valve closure time in assessing deep venous reflux. J Vasc Surg 1992;16:913–920. White RH, McGahan JP, Daschbach MM, Harting RP: Diagnosis of deep-vein thrombosis using duplex ultrasound. Ann Intern Med 1989;111:297–304. Stacey MC, Burnand KG, Pattison M, Lea Thomas M, Layer GT: Changes in apparently normal limb in unilateral ulceration. Br J Surg 1987;74:936–939.

H. Meents, MD, Radiology Unit, William Harvey Clinic, Am Kaiserberg 6, D–61231 Bad Nauheim (Germany) Tel. +49 6032 707 660, Fax +49 6032 707 680


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Magnetic Resonance Imaging and Computed Tomography in Advanced Chronic Venous Insufficiency Elisabeth List-Hellwig, Heino Meents Radiology Unit, William Harvey Clinic, Bad Nauheim, Germany

While angiomorphological diagnostic procedures such as phlebography, angiography and color duplex sonography deal with changes of the vascular system, magnetic resonance imaging (MRI) and computed tomography (CT) can detect changes of skin, subcutaneous fat, muscles, tendons, periosteum and bones. These methods contribute important information to assess the grade of chronic venous insufficiency (CVI). Therapeutic management (conservative therapy or surgical treatment such as paratibial fasciotomy and crural fasciectomy) is based on the exact definition of the range of sclerosis (with or without involvement of superficial and deep fascias). In selected cases, follow-up studies after conservative therapy or surgical treatment may be helpful. Schmeller et al. [1] first described CT changes of the lower legs in patients with CVI and arthrogenic stasis syndrome. In the same year, Gmelin et al. [2] presented comparative changes of CVI in CT and MRI. They found both examination methods useful in demonstrating subcutaneous fibrosis, infiltration of the extrafascial space and degeneration of the Achilles tendon. Pre- and postoperative changes in CVI treated with paratibial fasciotomy were described by Peschen et al. [3] who categorized CT and MRI of equal value. MRI provides multiplanar imaging, high soft tissue contrast and high spatial resolution for visualization of soft tissue changes such as subcutaneous edema, dermatolipofasciosclerosis, fatty muscle transformation, and periosteal ossification. CT examinations are superior in detecting changes to the bone and soft tissue calcifications in advanced CVI.

Table 1. Clinical grading of CVI Grade Grade Grade Grade

I II III IV

No sclerosis of cutaneous tissues Sclerosis limited to cutis and subcutis (no involvement of fascia) Segmental dermatolipofasciosclerosis (involvement of fascia) Circular dermatolipofasciosclerosis

Table 2. Changes of soft tissue and bone of the lower leg in CVI

Soft tissue Cutis Subcutaneous fat Fascia Muscles Tendon

Edema, ulcer extension, fibrosis Edema, fibrosis Thickening, involvement with ulceration Edema, fatty degeneration, atrophy Fatty degeneration

Bones Periosteal reaction Osteodystrophy Bone marrow edema

Classification of CVI Clinical classification of CVI can be performed according to the classification of Widmer (1974) which is based on skin changes only. Hach [4, 5] introduced a revised classification with regard to the extent of sclerosis. This classification is presented in table 1. The involvement of the fascia is especially important, because treatment schedules are different in cases with or without fasciosclerosis. Table 2 shows the changes of soft tissue and bone of the lower leg that can be detected and graded in patients with CVI by MRI and CT.

Techniques Our investigations were performed with a 1.5-Tesla MR system (Magnetom Vision, Siemens), and a CT system (Somatom DR, Siemens). Usually both distal calves (including the ankles) are examined to compare both legs including the ankle joint and the preachillary adipoid. In addition to axial slices, coronal and sagittal slices were acquired with MRI.

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a

b Fig. 1. Changes of the calf in axial T1-weighted SE sequence (a) and fat-suppressed T2-weighted TSE sequence (b) in CVI stage II. Edema (long arrows) and fibrosis (short arrows) of dermis and subcutaneous fat and muscle edema of musculus soleus and deep compartment (box).

In MRI, the following two-dimensional sequences are performed: (1) T1weighted axial spin-echo sequences (TR 660 ms, TE 17 ms, 6-mm slice thickness, 256 matrix); (2) D- and T2-weighted axial turbo-spin-echo sequences (TR 3,400 ms, TE 16/98 ms, 6-mm slice thickness, 256 matrix); (3) PD- and T2-weighted axial turbo-spin-echo sequences (TR 3,800 ms, TE 16/98 ms, 6-mm slice thickness, 512 matrix) with fat saturation, and (4) PD- and T2-weighted coronal turbo-spin-echo sequences (TR 3,500 ms, TE 16/98 ms, 4-mm slice thickness, 512 matrix). The axial CT images were acquired with 8-mm slice thickness and 10-mm interslice gap. Contrast media (gadolinium DTPA) can be applied in special indications like inflammatory pathologies.

Evaluation Evaluation of MRI and CT scans were done layer by layer from surface to deep layers. Cutis/Subcutis In CVI, the affected lower extremity shows an ‘inversion of signal intensity’ in comparison to normal tissue. This is the result of: (1) the increase of signal intensity of the cutaneous edema by the high amount of protons (T2 weighting)

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Fig. 2. Coronal T2-weighted TSE sequence in CVI stage III. Ulcer with dermatolipofasciofibrosis with loss of subcutaneous fat (thick arrow). Extended periosteal reactions of fibula (thin arrows).

(fig. 1b) and (2) the decrease of signal intensity in the subcutaneous fat caused by fibrosis (T1 weighting). Occasionally, metaplastic calcifications of the subcutaneous fat can be found. Fibrosis of dermis and subcutaneous field of the lower legs can also be visualized as hyperdense condensation in CT. Fascias and Muscles The evaluation of fasciosclerosis is of great importance for the classification of CVI. Area and extent of fasciosclerosis should thoroughly be evaluated for surgical treatment planning. The grading of edema or fatty degeneration of muscles is important in postoperative follow-up studies. All these changes are most pronounced in the posterior crural compartments containing the flexor muscles. Bones and Joints In advanced CVI the ankle joint and the preachillary adipoid are surrounded by fibrous tissue. The Achilles tendon shows degenerative changes as a result of fat interposition. The extent of both phenomena correlates with the degree of venous insufficiency and is best seen in patients with arthrogenic stasis syndrome [6]. Periosteal reactions of the distal tibia and fibula with partially extensive periosteal calcifications can be seen (fig. 2). Postoperative Findings Pre- and postoperative comparisons are difficult when the affected tissues (ulcer, fibrosis of the subcutaneous fat, sclerotic fascia and sometimes even

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tendons) have been removed. Following fasciotomy, a gap between the fascia edges can be seen in most patients. Figures 1 and 2 present CVI in different stages and various extent.

Conclusion MRI and CT are well-standardized, reproducible and noninvasive methods for grading soft tissue changes in CVI. MRI is a sensitive method in detecting fibrosis, fasciosclerosis and degenerative changes of muscles. Periosteal hyperostosis is well presented on T1-weighted images and edema is shown on T2-weighted images. Osseous changes and calcifications can be demonstrated better by CT.

References 1

2 3

4 5 6

Schmeller W, Rosenthal N, Gmelin E, Tichy P, Busch D: Computertomographische Untersuchungen der Unterschenkel bei Patienten mit chronischer Veneninsuffizienz und arthrogenem Stauungssyndrom. Hautarzt 1989;40:281–289. Gmelin E, Rosenthal M, Schmeller W, Tichy P, Busch D: CT and MRI of the calf in chronic venous insufficiency. Fortschr Ro¨ntgenstr 1989;151:50–56. Peschen M, Vanscheidt W, Sigmund G, Behrens JO, Scho¨pf E: Computertomographische und magnetresonanztomographische Untersuchungen vor und nach paratibialer Fasziotomie. Hautarzt 1996;47:521–525. Hach W, Langer Ch, Schirmers U: Das arthrogene Stauungssyndrom. Vasa 1983;12:109–116. Hach-Wunderle V: Veno¨ser Gefa¨ssstatus. Internist 1995;36:525–543. Schmeller W, Gmelin E, Rosenthal N: Vera¨nderungen des Retromalleolarraums bei chronisch veno¨sem und arthrogenem Stauungssyndrom. Phlebologie Proktol 1989;55:175–181.

Dr. H. Meents, MD, Radiology Unit, William Harvey Clinic, Am Kaiserberg 6, D–61231 Bad Nauheim (Germany) Tel. +49 6032 707 660, Fax +49 6032 707 680

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Plethysmography H.A. Martino Neumann, M. Birgite Maessen-Visch Academisch Ziekenhuis Maastricht, Afdeling Dermatologie, Maastricht, The Netherlands

Introduction There are several methods to evaluate the severity of chronic venous insufficiency. Basically, these methods can be divided into two groups: (1) morphological and (2) functional. Duplex scanning and phlebography are the best known morphological techniques. Duplex with color Doppler has the advantage to add flow direction in the vessels so that reflux can be detected easily. However, reflux will not always be associated with a functional disturbance. Functional disturbances are defined by compromised (calf) muscle pump capacity which is unable to return the (increased) amount of blood in order to diminish the venous pressure. It is the ambulatory venous pressure that correlates directely to the severity of chronic venous insufficiency. There are a variety of tests available for the evaluation of the calf muscle pump function and thus for venous insufficiency. For choosing the right method, several aspects have to be taken in account. Several plethysmographic techniques are available for functional testing of the venous system.

Plethysmography Literally, this term means measuring the volume changes of an organ. In 1905, Brodie and Russel [1] were the first to describe the technique, using water as a medium to measure the volume changes.

Fig. 1. Maximum venous outflow and 2-second outflow calculation.

Strain Gauge Plethysmography (SGP) Whitney [2] introduced the well-known SGP in 1953. Brakkee and Vendrik [3] refined this technique. SGP is based on variations in the circumference of the limb causing variations in the length of mercury-filled rubber tubes – the strain gauge – that are placed around the limb. By varying the length of the strain gauge, the electrical resistance of this gauge will also change. The result can be converted into the percentage of limb volume changes. The ideal gauge length should be 90% of the limb circumference, and the gauge should be stretched 10% when it is applied in a manner completely surrounding the limb. The patient lies in supine position with the limb elevated above heart level, preferably at an angle of 25º [4–6]. A large pneumatic tourniquet at least 20 cm wide is placed around the thigh. The cuff is inflated until a certain pressure is reached (10–80 mm Hg – usually 60 mm Hg). The cuff will occlude the veins, but not the arteries. Leg volume will increase until intravenous pressure is equal to the pressure of the cuff. A new, stable condition is reached at this point. The increase of volume is defined as the venous volume. After this plateau – which will constantly increase slowly due to the formation of tissue edema by the pressure-induced increased capillary filtration rate [7] – the cuff is deflated rapidly. The maximum venous outflow and the related 2-second outflow can be calculated from the decrease of leg volume (fig. 1). Besides the classical SGP, there are several methods widely used in phlebology. Among them photoplethysmography and air plethysmography, which will both be discussed.

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Photoplethysmography (PPG) PPG is a noninvasive optical technique for measuring tissue blood perfusion. In 1938 it was Hertzman [8] who described for the first time a photoelectric plethysmographic method for measuring skin circulation by correlating the intensity of the light reflection of the skin to its blood content. Several PPG methods have since then been described and tested for their practical use [9]. The most important parameter for practical use is the venous refilling time after finishing a standardized exercise of the calf muscles. Several tiptoe movements have to be made to measure the change in skin circulation. This venous refilling time has been shown to be reasonably reproducible and to correlate well with foot vein pressure recovery time [10, 11]. Despite this, it is not a generally accepted method [12, 13]. Light reflection rheography (LRR) is a technique based on the principle of PPG. Wienert and Blazek [14] developed the technique in the early 1980s. Digital photoplethysmography (DPPG) represents a further development of LRR (second-generation LRR) [15]. Measurements comparing the DPPG and the LRR devices have shown a close correlation, which was closer in subjects with venous disorders than in those with healthy veins [16, 17]. PPG is different from all other forms of plethysmography because of the lack of a volume/pressure correlation. The word photoplethysmography is somewhat misleading. PPG differs fundamentally from other plethysmographic techniques like SGP and foot volumetry [18, 19]. This is especially true for the electronic calibration. In contrast to air plethysmography in which calibration takes place by known volume changes, DPPG defines the Rmax. Rmax is the difference between the baseline (R0) and the maximum amplitude obtained after the tiptoe movements. The display will then indicate relative values of the Rmax. Therefore, results of the DPPG should only be compared with other DPPG measurements, such as measuring at different times performed on the same patient or between different patients. This is not only true for the venous refilling time (T0), which is the major parameter, but also for the venous drainage (V0). Air Plethysmography (APG) The technique of APG has been described by Christopoulos and Nicolaides [20]. Briefly, it consists of a 5-liter polyvinyl air chamber that surrounds the lower leg from the ankle to the knee, and is connected to a pressure transducer and a computer. The patient is in supine position with the foot on an elevation of 15 cm. The leg is slightly flexed and in exorotation. The air chamber is inflated with air to a pressure of 6 mm Hg, and after a period of equilibration (room temperature 22–24 ºC), the device is calibrated by measuring the pressure change induced by infusing an air volume of 100 ml.

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The plunger is withdrawn to its original position. During the schedule of the test, all subsequent changes in system pressure, which are caused by limb volume (i.e. venous changes), are registered by a pressure transducer. This transducer is directly linked to a personal computer, which calculates the different tests. All measurements can be expressed in milliliters. First, a pneumatic tourniquet is applied above the knee, and inflated to 80 mm Hg pressure. As a result, the volume of the leg increases, and when a certain level is reached, the tourniquet is suddenly deflated. The decrease of volume during the first second is calculated to an outflow fraction (OF). Next, the patient, still in supine position, is guided off the table. The subject then stands erect with the weight on the opposite limb. The veins of the leg fill and the volume of the calf increases. This increase in volume is called the venous volume (VV, fig. 1), and the time it takes for 90% filling is called the 90% venous filling time (VFT90). From this the venous filling index (VFI) is calculated as follows: VFI>90%¶VV/VFT90. The VFI is a parameter for venous reflux (normally =2 ml/s). Then, the subject performs one heelraise maneuver. The volume change from this movement is defined as ejected volume (EV), reflecting the muscle pump function. From this the ejection fraction (EF) is calculated: EF>EV/VV¶100 (normally ?60%). This is followed by ten heel-raise maneuvers to reach a residual volume (RV) plateau. From this the residual volume fraction (RVF) is calculated: RVF>RV/ VV¶100. Christopoulos and Nicolaides [20] empirically calculated a formula for determining the ambulant venous pressure: AVP>(RVF Ö1.5)/0.98.

Muscle Pump Function A normal muscle pump function is of great importance. Its efficiency depends on the function of the valves in the deep, perforating, and superficial veins of the leg as well as on the muscular power. The muscle pump can only be functional in ambulant condition. The function of the calf muscle pump can be measured by the amount of blood expelled from the calf during exercise (as in APG) [21], or indirectly by the volume expelled from the foot (as in foot volumetry) [22, 23].

Outflow Obstruction The outflow obstruction can be measured with different devices. SGP and APG are mostly used. The maximum venous outflow and the 2-second

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Fig. 2. A normal impedance plethysmograph trace and a trace from a patient with femoral vein thrombosis (obstruction). In the abnormal leg the venous capacitance and the venous outflow in 2 s are both reduced.

outflow values are a measure for the outflow obstructions in the venous system. An obstruction in veins will block the outflow, leading to significant differences in outflow (fig. 2). As duplex scanning is the new golden standard for diagnosing deep venous thrombosis, the outflow measurement is important for evaluating the final result after deep venous thrombosis. Brakkee and Kuiper [24] introduced the measurement of venous flow resistance by measuring the maximum venous outflow at different occlusion pressures. The maximum volume change (DV/V) is determined for each venous occlusion from the difference between the stable volume levels just after completion of the emptying process. The determination of the venous flow resistance is as follows. Following the release of each congestion, venous emptying rates (VER, expressed in %/min) are derived from the tangents, drawn at the emptying curves at 0.5 s after pressure release (fig. 3, VER(.5)). Subsequently, with the use of the Pv-V relation, the volume levels at 0.5 s after each pressure release DV/V(.5) (fig. 3) are converted into the corresponding pressure levels Pv(.5) (fig. 4). Brakkee and Kuiper [24] give more details in the original paper. The venous flow resistance (Rv) proximal to the site of the strain gauges is calculated from the slope of the linearly approximated initial part of the relationship between pressure (Pv(.5)) and flow (VER(.5)) (fig. 5). Rv is expressed in mm Hg·min/%, which – for practical reasons – will be abbreviated to ru (resitance unit). In


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Fig. 3. Schematic drawing of the plethysmographic record in two successive periods of venous congestion. From each record, DV/V (a) is determined as well as DV/V(.5) (b) and VER(.5) at 0.5 s after release of venous congestion.

4

5

Fig. 4. Example of the use of the Pv-V relation for the conversion of DV/V(.5) into the corresponding pressure Pv(.5). Fig. 5. Venous resistance (Rv) is calculated from the slope of the linearly approximated initial part of the relationship between pressure Pv(.5) and flow VER(.5).

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calf and foot measurements, Rv is referred to as Rv-prox and Rv-dist, respectively. Apart from the acclimatization of the subjects, the overall determination of both Rvs at one site of measurement takes about 20 min (i.e. 15 min for the measurement procedure and about 5 min for the computerized calculation procedure) [25]. This venous resistance is a sensitive measure for evaluation of deep venous thrombosis. After deep venous thrombosis, sooner or later the venous resistance will become stable. A further improvement of the venous hemodynamics cannot be suspected. Increase of the venous resistance is a strong indication: re-thrombosis [24].

Ambulatory Venous Pressure Measurements This important parameter can also be measured with plethysmographic techniques. Measurement of foot vein pressure is well established as a reference method for the overall evaluation of the venous calf pump function of the lower limb. The pressure in a dorsal foot vein is measured in standing position and after performing standard exercises. If the pressure does not decrease sufficiently after exercise the subject has an ‘ambulatory venous hypertension’. The test is highly reproducible and shows a high positive correlation with the incidence of venous ulceration. The test is still accepted as the golden standard of the venous calf muscle pump assessment. All new noninvasive tests should be validated with it. However, because the measurement is invasive, it cannot be repeated frequently nor can it be used as a screening test. So noninvasive techniques that are easy to perform, pleasant for the patient, economical and which have a good accuracy and reproducibility are strongly needed nowadays in phlebology [26]. Veraart and Neumann [27] conclude that APG is not suitable for supine venous pump function tests. Further studies are needed to establish whether the venous pump function test of the whole calf can be determined in a supine manner.

Reflux Measurements Quantification of reflux is possible with APG. It was concluded in a study of Bossuyt and Neumann [28] that the venous filling index (VFI) represents the volume change during the time it takes for the venous system to refill when the subject changes from supine to standing position. In supine position, with the examined limb elevated to 45º, the veins are empty. Then the patient is asked to stand up and the observed increase in volume is a result of venous


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filling. This functional venous volume (VV) ranges from 100 to 150 ml in normal limbs and can reach 350 ml in limbs with venous insufficiency [29, 30]. The ratio of 90% of VV divided by the time it takes for 90% filling (VFT90) is defined as the venous filling index: VFI>90% VV/VFT90. This is a measure of the average filling rate of veins, expressed in ml/s. Christopoulos et al. [31] stated a normal subject will have a VFI of =2 ml/s. Under normal conditions the VFI is mainly determined by the arterial inflow. In case of venous insufficiency the VFI increases, due to reflux in the superficial and/or the deep venous system. Our results show that VFI was abnormal in 82% of severe cases of venous insufficiency (Widmer stage II and III). In Widmer stage III there was even a more pronounced correlation of 96%. This is in accordance with the findings of Christopoulos et al. [30], who found that the incidence of ulceration (Widmer stage III) increases with increasing values of VFI.

Discussion Plethysmographic methods reflect the total outflow from the limb both through large and collateral veins. Plethysmographic methods are, however, unable to detect small nonoccluding obstructions unless the flow past the obstruction is compromised. In patients with large superficial veins the outflow from these veins may obscure deep vein obstruction, just as large collateral veins may give normal outflow despite deep venous occlusion [32]. PPG is most appropriately used as a screening test. A normal venous refill time has a high predictive value. However, a short venous refill time is not conclusive. In these cases, a venous pressure measurement (horizontal pressure measurement technique) is indicated. Refill can be quantified with APG outflow, while venous capacity can be measured with APG and SGP. The venous resistance test is mandatory for a secure follow-up of deep venous thrombosis patients. An ambulatory pressure measurement will quantify the severity of the remaining venous insufficiency after stabilization of the venous resistance. No further therapy is necessary in case a normal pressure is found. In a recent study [33] APG, PPG and duplex were evaluated. APG is a sensitive method for the identification of venous reflux, while PPG and duplex are sensitive techniques to detect reflux, though specification is poor. The authors concluded that the combination of APG and duplex is the best for evaluating venous insufficiency. Despite the popularity of duplex scanning, functional tests are still needed for evaluation of patients with a complicated venous insufficiency. Unfortunately, several plethysmographic devices are necessary to perform those tests so they fit best for each individual patient.

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References 1 2 3 4 5 6 7 8 9

10 11 12 13 14 15 16 17 18 19 20 21

22 23 24 25

Brodie TG, Russel AE: On the determination of the rate of blood flow through an organ. J Physiol 1905;32:47. Whitney RJ: The measurement of volume changes in human limbs. J Physiol 1953;121:1–27. Brakkee A, Vendrik A: Strain gauge plethysmography, theoretical and practical notes on a new design. J Appl Physiol 1966;21:701–704. Bygdeman S, Aschberg S, Hindmarsch T: Venous plethysmography in the diagnosis of chronic venous insufficiency. Acta Chir Scand 1971;137:423. Dahn I, Eiriksson E: Plethysmographic diagnosis of deep venous thrombosis of the leg. Acta Chir Scand 1968;398:33. Nicolaides AN, Fernandes JF, Schull K, Miles C: Calf volume plethysmography; in Nicolaides AN, Yao JST (eds): Investigation of Vascular Disorders. New York, Churchill Livingstone, 1981. Geest A van, Veraart JCJM, Neumann HAM: Capillaire filtratiefractie bij oedeem, gemeten met luchtplethysmografie. Scripta Phlebol 1997;5:13–15. Hertzman AB: The blood supply of various skin areas as estimated by the photoelectric plethysmograph. Am J Physiol 1938;124:328–340. Abramowitz HB, Queral LA, Flinn WR, Nova PF Jr, Peterson LK, Bergan JJ, Yao JS: The use of photoplethysmograph in the assessment of venous insufficiency. A comparison to venous pressure measurements. Surgery 1979;86:434–441. Nicolaides AN, Miles C: Photoplethysmography in the assessment of venous insufficiency. J Vasc Surg 1987;5:405–412. Rosfors S: Venous photoplethysmography: Relationship between transducer position and regional distribution of venous insufficiency. J Vasc Surg 1990;11:436–440. Rutgers PH, Kitslaar PJEM, Ermers EJM: Photoplethysmography in the diagnosis of superficial venous valvular incompetence. Br J Surg 1993;80:351–353. Bemmelen PS van, Ramshorst B van, Eikelboom BC: Photoplethysmography reexamined: Lack of correlation with duplex scanning. Surgery 1992;112:544–548. Wienert V, Blazek V: Eine neue Methode zur unblutigen dynamischen Venendruckmessung. Hautarzt 1982;33:498–499. Blazek V, Schmitt HJ, Schultz-Ehrenburg U: Digitale Photoplethysmographie: Ein neues mikroprozessorgesteuertes Messsystem fu¨r die Beinvenendiagnostik. Biomed Tech 1988;33:307–308. Kerner J, Schultz-Ehrenburg U, Blazek V: Digitale Photoplethysmographie (D-PPG) – klinische Eignung der neuen Messmethode zur veno¨sen Funktionsdiagnostik. Phlebol Proktol 1989;18:98–103. Veraart JCJM, Kley AMJ van der, Neumann HAM: Digital photoplethysmography and light reflection rheography. J Dermatol Surg Oncol 1994;20:470–473. Brakkee AJM, Kuiper JP: Grundlagen der unblutigen Venendruckmessung; in May R, Kriessmann A (eds): Periphere Venendruckmessung. Stuttgart, Thieme, 1978, p 86. Thulesius O, Norgren L, Gjoeres JE: Foot-volumetry, a new method for objective assessment of edema and venous function. Vasa 1973;2:325–329. Christopoulos D, Nicolaides AN: Non-invasive diagnosis and quantification of popliteal reflux in the swollen and ulcerated. J Cardiovasc Surg 1988;29:535–539. Christopoulos D, Nicolaides AN, Szendro G, Irvine A, Muilan B, Eastcott HNG: Air-plethysmography and the effect of elastic compression on venous haemodynamics of the leg. J Vasc Surg 1987; 5:148–159. Thulesius O, Norgren L, Gjo¨res JE: Foot volumetry, a new method of objective assessment of edema and venous function. Vasa 1973;2:325–329. Norgren L, Thulesius O, Gjo¨res JE, So¨derlundh S: Foot volumetry and simultaneous venous pressure measurements for evaluation of venous insufficiency. Vasa 1974;3:140–147. Brakkee AJM, Kuiper JP: Plethysmographic measurement of venous flow resistance in man. Vasa 1982;11:166–173. Klein Rouweler BJF: Plethysmographic Measurement of Venous Flow Resistance and Venous Capacity in the Human Leg. Methodical and Clinical Aspects. Enschede, Quick Service Drukkerijen Nederland BV, 1989.


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Veraart JCJM: Clinical Aspects of Compression Therapy. Maastricht, Unigraphic, 1997, pp 9–29. Veraart JCJM, Neumann HAM: Supine venous pump function test performed with air-plethysmography. Phlebologie 1996;25:127–130. Bossuyt LEG, Neumann HAM: Air plethysmography: A critical evaluation of the technique in patients with CVI. Phlebologie 1999;28:7–12. Allen J: Volume changes in the lower limb in response to postural alterations and muscular exercise. South Afr J Surg 1964;2:75–90. Christopoulos D, Nicolaides AN, Szendro G: Venous reflux quantification and correlation with the clinical severity of chronic venous disease. Br J Surg 1988;75:352–356. Christopoulos D, Nicolaides AN, Belcaro G: Airplethysmography. Phlebol Dig 1992;4:4–10. Browse NL, Burnand KG, Lea Thomas M: Disease of the Vein. London, Arnold, 1988. Bays RA, Healy DA, Atnip RG, et al: Validation of air plethysmography, photoplethysmography, and duplex ultrasonography in the evaluation of severe venous stasis. J Vasc Surg 1994;20:721–727.

Prof. A.M. Neumann, MD, PhD, Academisch Ziekenhuis Maastricht, Afdeling Dermatologie, Postbus 5800, NL–6202 AZ Maastricht (The Netherlands) Tel. +31 43 387 5290, Fax +31 43 387 7293

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Microangiopathy in the Pathogenesis of Chronic Venous Insufficiency Michael Ju¨nger, Martin Hahn, Thomas Klyscz, Anke Steins Department of Dermatology, University Hospital, Tu¨bingen, Germany

Introduction Disturbed venous hemodynamics usually results either from primary varicosis or from deep-vein thrombosis. Retrograde pressure waves occur with each calf muscle contraction and extend as far as the cutaneous venules and capillaries of the lower leg. It was hypothesized that increased ambulatory venous pressure causes cutaneous microangiopathy in chronic venous insufficiency (CVI) [1]. However, the propagation of ambulatory venous pressure waves into the nutritive capillaries of the skin could only be demonstrated very recently in vivo.

Ambulatory Capillary Hypertension in CVI Until recently it was very difficult to accurately measure capillary blood pressure [2–6]. The development of micropipettes with a tip of approximately 5 lm in diameter that can be inserted into skin capillaries by the aid of a micromanipulator made cutaneous microcirculation accessible for the first time for direct pressure measurements. By means of a servo nulling pressure system Model 5A (IPM, San Diego, Calif., USA), the pressure can be recorded dynamically [7]. We studied the capillary pressure at the nailfold of the great toe in patients with chronic venous insufficiency during rest and simulated exercise. Muscle contraction was simulated by rhythmic contractions of a cuff that was placed at the mid-calf and inflated to 60 mm Hg. The patients were in supine position with the knee bent at 90º. We could show that the mean capillary pressure

under resting conditions tended to be higher in CVI patients than in healthy controls (trend). Under simulated exercise, however, capillary pressure increased significantly faster in CVI patients than in controls. For the first time these results support the commonly accepted hypothesis that ambulatory venous hypertension is actually propagated into the nutritive capillaries of the skin.

Nutritive Cutaneous Circulation Nutritive cutaneous capillaries change their morphology as a consequence of increased capillary pressure. These capillaries can be visualized by intravital capillaroscopy (Bollinger microscope, Wild+Leitz, Stuttgart, Germany) [8] and oxygen supply can be assessed by transcutaneous oxygen tension (tcPO2) measurement [9]. Cutaneous microangiopathy in CVI patients precedes clinical skin changes. Capillary dilatation (14×1.6 capillaries/mm2) is found in clinically apparently healthy skin of CVI patients when compared to healthy controls (9.5×1.3 capillaries/mm2, p?0.05). With progression of CVI, the capillaries start to lengthen and branch out. They become contorted and show a glomerular appearance on intravital capillaroscopy. Only 1–5 capillaries/mm2 can be found in the edge of venous ulcers which represents an extreme rarefaction of the nutritive circulation. In some of these rarefied capillaries the erythrocytes seemingly stand still, which has been interpreted as ‘microthrombosis’ or ‘persistent blood flow stop’ (fig. 1) [10]. The clinical degree of trophic skin changes is closely correlated with the severity of cutaneous microangiopathy. tcPO2 can come close to zero at the edge of venous ulcers (ulcer edge: 2.6×3.0 mm Hg; atrophy blanche field: 2.2×1.7 mm Hg).

Capillary Leakage Reports about the transcapillary and interstitial leakage of a small molecular dye (Na-fluorescein) are inconsistent. Whereas in slight CVI increased leakage was measured [11], some authors could not confirm this finding in progressive stages of CVI [12]. In our own studies [13] advanced CVI (Widmer’s stage 3) was accompanied by increased transcapillary leakage of Na-fluorescein into the interstitium. Fluorescence videomicroscopy was performed with the lower limb at heart level (recumbent patient). Therefore, increased transcapillary and interstitial diffusion of the dye is thought rather to be related to

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Fig. 1. The capillaries in the ulcer are rarefied (1–5 capillaries/mm2), dilated and look arcade-like. In some capillary segments, which are filled with blood cells (white arrow), no blood flow can be observed (‘microthrombosis’ or ‘long-lasting flow stop’).

pathological diffusion properties of the capillary wall rather than to venous hypertension alone.

Influence of Cutaneous Microcirculation on the Healing of Venous Ulcers In our experiences the healing process of venous ulcers is accompanied by the formation of new capillaries (angiogenesis). We investigated the microcirculation at the edge and in the center of ten venous ulcers (10 patients, ulcer size 8.7×11.6 cm2) by means of capillaroscopy and tcPO2 measurement. The patients were examined at the beginning of treatment and after complete wound healing, on average 8.6×4.3 weeks later. Capillary density increased significantly from 5 to 21 capillaries in the ulcer bed and from 34 to 42 capillaries at the ulcer border. This was accompanied by an increase of tcPO2 from 23 to 30 mm Hg. A rapid increase of capillary density correlated well with wound healing (fig. 2) [14].

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Fig. 2. The capillary density was observed during the healing of venous leg ulcers in 10 patients. In 5 patients, ulcers healed within 6 weeks (‘fast healing’). In this fast healing group, the capillary density increased within the first 2 weeks of therapy, whereas in the ulcers of the group with delayed healing (?6 weeks) only a weak capillarization was observed within this time. U1 is examination before therapy, U2 examination after the first 2 weeks of therapy, U3 final examination after healing of the ulcer.

Discussion Some of the pathological findings in cutaneous microcirculation of CVI patients have been known for a long time [12, 15–20]. For the first time our systematic studies of the relationship between clinical symptoms and microvascular hemodynamics [21] provided conclusive evidence that impaired cutaneous microcirculation represents the link between chronic ambulatory venous hypertension and congestive dermatoses or trophic skin changes, respectively. The key event can be circumscribed as ‘ambulatory capillary hypertension’. This means that, at least in patients with trophic skin changes, venous refluxes are propagated into the nutritive capillaries of the skin. Pressure waves reach the cutaneous capillaries with every contraction of the calf muscles and take their toll. Initial capillary dilatation is followed by gradual rarefaction. Chronic inflammatory processes leading to ‘leukocyte trapping’ may also play a role in the development of CVI. According to our own unpublished data, 45 min of venous congestion during an orthostatic stress test lead to downregulation of lymphocytic L-selectin expression in venous blood from the dorsum of the foot in healthy persons. Venous congestion might upregulate the expression of leukocytic adhesion molecules [22, 23]. However, experimental proof of leukocyte activation in CVI has yet to be provided. Biopsies from the edge


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of venous ulcers showed an increased expression of adhesion molecules on endothelial cells. In the earlier stages of CVI, however, adhesion molecules were not upregulated [24]. To summarize, venous congestion leads to disturbed cutaneous microcirculation, such as capillary rarefaction, cutaneous hypoxia and to the lack of cutaneous vascular reserve, which seems to play the key role in the development of trophic skin changes in CVI [25, 26]. Interestingly, a similar pattern of microangiopathy has been described in chronic critical limb ischemia. Chronic critical limb ischemia leads to rarefaction of capillaries, capillary dilatation, increased permeability of the capillaries, cutaneous hypoxia and lack of vascular reserve with dysregulation of skin flux [27–29]. In conclusion, severe disturbances of blood supply on the one hand and blood drainage on the other can lead to quite similar consequences at the level of cutaneous blood flow. As in chronic critical limb ischemia, pathological hemorheology compromises cutaneous microcirculation in advanced CVI. Plasma viscosity and erythrocyte aggregation and plasticity are altered, as can be demonstrated in venous blood samples from the dorsum of the foot. Experimental orthostatic load can even worsen these impaired blood flow characteristics [30]. On the other hand, effective treatment, such as compression therapy, is able to reverse at least in part the aforementioned pathophysiological steps. The number of nutritive capillaries in the perimalleolar area increases, capillaries normalize in shape and size and interstitial edema disappears which can be shown by a welldelineated pericapillary halo in fluorescence videomicroscopy.

References 1 2 3 4 5 6 7 8 9 10

Partsch H: Das offene Bein. Klinische Pathophysiologie. Ther Umsch 1984;41:825–833. Mahler F, Muheim MH, Intaglietta M, Bollinger A, Anliker M: Blood pressure fluctuations in human nailfold capillaries. Am J Physiol 1979;236:888–893. Tooke JE: A capillary pressure disturbance in young diabetics. Diabetes 1980;29:815–819. Williams SA, Wassermann S, Rawlinson DW, Kitney RI, Smaje LH, Tooke JE: Dynamic measurement of human capillary blood pressure. Clin Sci 1988;74:507–512. Williams SA, Boolell M, MacGregor GA, Smaje LH, Wassermann S, Tooke JE: Capillary hypertension and abnormal pressure dynamics in patients with essential hypertension. Clin Sci 1990;79:5–8. Tooke JE: Capillary pressure in non-insulin-dependent diabetes. Int Angiol 1983;2:167–171. Hahn M, Shore AC: The effect of rapid local cooling on human finger nailfold capillary blood pressure and blood cell velocity. J Physiol 1994;478:109–114. Mahler F, Bollinger A: Die Kapillarmikroskopie als Untersuchungsmethode in der klinischen Angiologie. Dtsch Med Wochenschr 1978;103:523–527. Franzeck UK: Transkutaner Sauerstoffpartialdruck in der klinischen Mikrozirkulation. Bern, Huber, 1991. Ju¨nger M, Hahn M, Patheiger U, Rahmel B, Rassner G: Morphologische und funktionelle Mikroangiopathie im Ulcus cruris venosum; in Wuppermann T, Richter H (eds): Thrombose und Thrombosefolgen. Konstanz, Schnetztor, 1991, pp 121–125.

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Speiser D: Mikroangiopathie bei leichter chronisch-veno¨ser Insuffizienz (CVI), beurteilt durch die Fluoreszenz-Videomikroskopie; Diss, Zu¨rich, 1986. Haselbach P, Vollenweider U, Moneta G, Bollinger A: Microangiopathy in severe chronic venous insufficiency evaluated by fluorescence video-microscopy. Phlebology 1986;1:159–169. Ju¨nger M, Bort S, Hahn U, Klyscz T, Geiger H, May B, Schiek A: In-vivo-Nachweis erho¨hter Durchla¨ssigkeit der Hautkapillaren bei fortgeschrittener chronischer Veneninsuffizienz (CVI). Zentralbl Haut 1993;162(suppl):153–154. Steins A, Ju¨nger M, Klyscz T, Schiek A, Galler S, Jung MF, Hahn M: In vivo investigations of the microcirculation in venous ulcers in view of therapeutic possibilities. Phlebology 1995;(suppl 1): 119–121. Neumann HAM, Van Leeuwen M, Van den Broek MJ, Berretty PJM: Transcutaneous oxygen tension in chronic venous insufficiency syndrome. Vasa 1984;13:213–219. Moosa HH, Falanga V, Steed DL, Makaroun MS, Peitzman AB, Eaglstein WH, Webster MW: Oxygen diffusion in chronic venous ulceration. J Cardiovasc Surg 1987;28:464–467. Franzeck UK, Bollinger A, Huch R, Huch A: Transcutaneous oxygen tension and capillary morphologic characteristics and density in patients with chronic venous incompetence. Circulation 1984; 70:806–811. Fagrell B: Microcirculatory disturbances – The final cause for venous leg ulcers? Vasa 1982;11: 101–103. Leu AJ, Yanar A, Pfister G, Geiger M, Franzeck UK, Bollinger A: Mikroangiopathie bei chronischer veno¨ser Insuffizienz. Dtsch Med Wochenschr 1991;116:447–453. Speiser DE, Bollinger A: Microangiopathy in mild chronic venous incompetence (CVI): Morphological alterations and increased transcapillary diffusion detected by fluorescence videomicroscopy. Int J Microcirc Clin Exp 1991;10:55–66. Ju¨nger M, Hahn U, Bort S, Klyscz T, Hahn M, Rassner G: Bedeutung der kutanen Mikroangiopathie fu¨r die Entstehung von Stauungsdermatosen bei chronischer Veneninsuffizienz (CVI). Wien Med Wochenschr 1994;144:206–210. Coleridge Smith PD, Thomas PRS, Scurr JH, Dormandy JA: Causes of venous ulceration: A new hypothesis. BMJ 1988;296:1726–1727. Scott HJ, Coleridge Smith PD, Scurr JH: Histological study of white blood cells and their association with lipodermatosclerosis and venous ulceration. Br J Surg 1991;78:210–211. Hahn J, Ju¨nger M, Friedrich B, Zuder D, Steins A, Hahn M, Klyscz T: Cutaneous inflammation limited to the region of ulcer in chronic venous insufficiency. Vasa 1997;26:277–281. Ju¨nger M, Klyscz T, Hahn M, Jung MF, Rassner G: Disturbed blood flow regulation in venous leg ulcers. Int J Microcirc Clin Exp 1996;16:259–265. Ju¨nger M, Hahn M, Klyscz T, Rassner G: Influence of healing on the disturbed blood flow regulation in venous ulcers. Vasa 1996;25:341–348. Ju¨nger M, Frey-Schnewlin G, Bollinger A: Microvascular flow distribution and transcapillary diffusion at the forefoot in patients with peripheral ischemia. Int J Microcirc Clin Exp 1989;8:3–24. Fagrell B: Vital capillaroscopy – A clinical method for studying changes of skin microcirculation in patients suffering from vascular disorders of the leg. Angiology 1972;23:284–298. Bollinger A, Hoffmann U, Seifert H: Flux motion in peripheral ischemia; in Intaglietta M (ed): Vasomotion and Flow Modulation in the Microcirculation. Basel, Karger, 1989, pp 87–92. Kiesewetter H, Jung F, Ju¨nger M, Marx U, Koscielny J: Chronic venous insufficiency: Only a macroor also a microangiopathy? Clin Hemorheol 1994;14:65–78.

Michael Ju¨nger, MD, PhD, Department of Dermatology, University Hospital, Liebermeisterstrasse 25, D–72076 Tu¨bingen (Germany) Tel. +49 7071 298 5124, Fax +49 7071 550 134, E-Mail [email protected]


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Compression Therapy of Venous Ulcers Hugo Partsch Dermatological Department, Wilhelminenspital, Wien, Austria

Compression therapy is the basic and most important kind of management for venous ulcers [1]. Although this fact has not changed for centuries, it was only during the last decades that some mechanisms of action of external compression could be elucidated and that the efficacy of this therapy in venous ulcers has been proved in clinical trials.

Mechanisms of Action Various effects of compression have been demonstrated [2] (table 1). Decrease of Edema Short stretch bandages and Unna’s boots are able to reduce the circumference of a swollen leg up to several centimeters per week. This reduction of edema is the cause for the drop of the bandage pressure already after 24 h so that the bandage has to be renewed [3]. Walking exercises exert a kind of massage. Similar effects may be obtained also by four-layer bandages and by intermittent pneumatic compression. In order to prevent recurrence of edema, continued compression is essential. To maintain the edema-free condition, elastic stockings may be sufficient while they are not able to reduce edema in a swollen limb in most instances. Softening of Lipodermatosclerosis Structural skin changes have been reported after intermittent pneumatic compression using CT and ultrasound [4].

Table 1. Compression effects proved by different methods Compression effect

Investigative method

1. Decrease of edema 2. Softening of lipodermatosclerosis 3. Decrease of venous volume (narrowing of veins) 4. Increase of venous velocity 5. Blood shift into central compartments 6. Reduction of venous refluxes 7. Improvement of venous pumping 8. Influence on arterial flow 9. Improvement of microcirculation 10. Increase of lymph drainage

Volumetry, measuring tape, isotopes Ultrasound, CT, Durometer Phlebography, blood pool scintigraphy, APG Circulation time (isotopes), Duplex Blood pool scintigraphy, cardiac output Duplex, APG Foot volumetry, APG, venous pressure Duplex, xenon clearance, laser Doppler Capillaroscopy, tcPO2, laser Doppler Isotopic and indirect lymphography

Decrease of Venous Volume (Narrowing of Veins) Phlebography reveals that firm compression is able to reduce the diameter of superficial and deep veins to the dimension of a thin cord [2]. Radioactivity measurements of labelled red blood cells shows decrease of blood volume with increasing external pressure up to 40 mm Hg in the horizontal position [5]. Blood volume reduction may also be demonstrated by air plethysmography (APG) for the upright position. Inelastic material applied with the same pressure leads to a more intense volume reduction [6, 7]. Acceleration of Venous Flow Due to the narrowing of the venous diameter, blood flow velocity increases if the arterial inflow remains unchanged. This may be demonstrated by calculating circulation times after injection of a radioactive tracer into a dorsal foot vein with and without leg compression [8]. Blood Shift into Central Compartments Compression of both legs leads to a shift of blood into central vascular compartments, to an increase of the preload of the heart and to an increase of cardiac output. Therefore, compression therapy must be performed with caution in patients with severe cardiac failure [5]. Diuresis may be improved by mobilizing fluid from the extravascular compartment. Reduction of Venous Refluxes Venous refluxes due to valvular incompetence play a central role for the pathophysiology of chronic venous insufficiency. They may be measured

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Fig. 1. Mean ambulatory venous pressure [>(2 diastolic+systolic pressure)/3] is lowered by external compression. Inelastic material leads to a more intense pressure reduction than elastic material, even when the exerted pressure is lower (one short stretch bandage versus two GEC stockings). Two layers of short stretch bandages exerting a resting pressure of 53.6 mm Hg achieve a statistically significant reduction of ambulatory venous hypertension. (Measurement of pressure in a dorsal foot vein in 13 patients with chronic venous insufficiency I–II (Widmer) , x×SD, normal values in right column [10].) GEC>Graduated compression stocking used for thromboprophylaxis as a model for elastic material, short stretch bandages (RosidalÔ ) as a model for ‘inelastic’ material.

by Duplex ultrasound and by plethysmography, preferably by APG. Compression decreases reflux in the upright position [7]. Again, at the same pressure, inelastic material is more effective than elastic [6]. Reduction of venous refluxes by external compression is observed also in completely avalvular segments and can therefore not be explained by an approximation of valve leaflets [9]. Improvement of Venous Pump Function Using foot volumetry, expelled volume reflects the amount of venous blood which is pumped up from the foot during standardized knee-bending exercises. This parameter, which is reduced depending on the degree of venous incompetence, shows a steady improvement with increasing external compression pressure [10]. Simultaneous foot volumetry and peripheral venous pressure measurement showed that a decrease of ambulatory venous hypertension can be achieved only with inelastic but not with elastic compression [10] (fig. 1).

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This fact may be explained by the more intense narrowing of deep veins by inelastic material as demonstrated by APG. Influence on Arterial Flow The immediate effect of a firm static compression is a reduction of arterial inflow which can be proved by different methods. In patients with arterial occlusive disease, severe skin damage may be caused by external compression. However, intermittent pressure waves with low pressure peaks adjusted to the systolic ankle pressure have been shown to increase blood flow in the large arteries and in the skin [11, 12]. Inelastic bandages applied with an extremely low pressure may exert similar effects when the ankle pump is moved, actively or passively. Especially edema impedes the oxygenation of the skin in a leg with arterial occlusive disease, a reduction of swelling by a careful intermittent compression regime may improve the condition. These facts are of considerable practical importance in patients with ulcers of mixed (venous-arterial) etiology and in postreconstructive edema or in dependency syndrome. Improvement of Microcirculation Compression therapy accelerates blood flow in the dilated capillary loops, reduces filtration and enhanced tissue pressure improves reabsorption. Effects on mediators involved in the local inflammatory response may explain the immediate pain relief that occurs with good compression as well as ulcer healing [13]. Improvement of Lymph Drainage Intermittent pneumatic compression enhances prefascial lymph drainage [14]. Unna boots are able to increase subfascial lymph transport which is reduced in postthrombotic syndrome [15]. Compression leads to a morphological improvement of pathological initial lymphatics in patients with lipodermatosclerosis which can be demonstrated by indirect x-ray lymphography [2].

Clinical Trials In comparison to local therapy alone, compression leads to significantly faster healing rates of venous ulcers [16]. Additional sequential pneumatic compression promotes ulcer healing [17]. After the ulcers are healed, noncompliance of the patient to wear compression stockings is followed by a higher recurrence rate [18]. Recurrence after healing of leg ulcers could be shown to be significantly lower if compression at a higher pressure was performed [19].


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Table 2. Types of compression devices Graduated compression stockings Custom made Standard size Bandages Inelastic Short stretch Medium stretch Long stretch Intermittent pneumatic compression Single chamber Sequential chambers Intermittent static pressure ‘Mercury bath’

Table 3. Categories of compression material

Stretch Application Stays on the leg

Inelastic

Short stretch

Medium stretch

Long stretch

0 Trained staff Day and night

=70% Trained staff Day and night

70–140% Trained patient Daytime

?140% Every patient Daytime

Compression Material Various modalities of compression are summarized in table 2. There are four main categories of compression material, as shown in table 3. Inelastic bandages, like zinc plaster (Unna boot) and rigid gaiters consisting of multiple adjustable Velco straps around the leg (Circ-AidÔ ) are examples of completely nonelastic material which may remain on the leg for several days. Elastic devices, like elastic bandages or compression stockings, are applied in the morning, preferably before getting up and are removed before going to bed at night. Several layers of different material (wool, crepe, elastic and selfcohesive) are used for the so-called four-layer bandage which may be worn for day and night.

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Table 4. CEN (Commission Europeénne Class de Normalisation) classification for compression stockings I II III IV

Pressure, mm Hg Mild Moderate Strong Very strong

15–21 23–32 34–46 ?49

Medical Compression Stockings Depending on the pressure exerted at the ankle, there are four compression classes [20] (table 4). Nylon or silk socks help to slide the stocking over the foot. Usually knee stockings are prescribed. Pelottes and Pads Venous ulcers are frequently localized behind the inner malleolus or on the flat areas of the medial lower leg. The pressure of a bandage will be low in these areas due to the law of Laplace which states that the pressure is indirect proportional to the radius. A local increase of pressure can be achieved by applying rubber foam pads over the ulcer region, whereby the radius of the leg segment is decreased.

Compression Pressure The range of pressure applied for compression therapy covers a very broad spectrum between 15 mm Hg as exerted by thromboprophylactic stockings and suprasystolic pressure peaks produced by intermittent compression machines like the ‘mercury bath’ for treating patients with lymphedema. The pressure which can be measured by different devices changes with the measuring site (radius of the leg segment), body position (lying, sitting, standing), the consistency of the underlying tissue and with the elastic properties of compression material. A pressure level of 60 mm Hg measured in the standing position will immediately fall to =40 mm Hg in the horizontal position using inelastic material but only to 50 mm Hg if elastic bandages are applied [2] (fig. 2). This latter pressure level may be too high to be tolerated by the patient, which explains that elastic material should be removed during nighttime. On average there is a pressure drop of 10 mm Hg after 24 h with completely inelastic zinc plaster bandages but only of 5 mm Hg with four-layer bandages [3] (fig. 3).


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Fig. 2. Bandage pressure (mm Hg) of elastic and inelastic material. The pressures with elastic bandages are too high to be tolerated during long sitting or lying.

The concept of using higher compression pressure in severe forms of chronic venous insufficiency than in mild stages is based on experience rather than on evidence derived from clinical studies [21, 22]. Recurrence after healing of leg ulcers could be shown to be significantly lower if compression with higher pressure was performed [19]. In patients with arterial occlusive disease the resting pressure of a bandage should come close to zero. Only inelastic material can be used for this purpose. During walking or passive ankle movement the massage waves with every muscle contraction will decrease edema and increase arterial flow in a similar way as shown with intermittent pneumatic compression [16, 17].

Compression Techniques Management of leg ulcers consists of two phases: (1) the healing phase until epithelialization is obtained and (2) the maintenance phase after ulcer healing in which frequently occurring recurrences should be prevented. Because of the superior hemodynamic and clinical efficacy [23] of inelastic material, we prefer zinc plaster bandages for the healing phase. Four-layer bandages which exert equally positive effects may be a good alternative. An international randomized multicenter trial comparing two-layer short stretch and four-layer bandages is under way (PADS>Profore Austrian Dutch Study). It has been shown that medical compression stockings (one ThromboÔ for keeping the local ulcer dressing in place and one Sigvaris 503Ô applied on top) can be quite effective for the treatment of ulcers which are not too large

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a

b

Fig. 3. Bandage pressure in different body positions measured immediately after bandaging and 24 hours later leaving the pressure transducer in situ with Unna’s boot (a) and four-layer bandage (b).

and not too long standing in patients who are able to put on the stockings [24]. To keep the ulcer healed, continuous compression is essential (‘maintenance phase’). Medical compression below-knee stockings, class II and III, are the preferred method of choice [25]. Patients who are unable to put on the stockings may take elastic bandages instead.


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Table 5. Reported ulcer healing rate in the literature Group (first author)

Year

Therapy

Healing rate after 12 weeks

Blair [26] Moffat [27] Mayer [28] Callam [29]

1988 1992 1994 1992

Horakova [24]

1994

Coleridge-Smith [17]

1990

Colgan [30]

1990

Guilhou [31]

1997

Four layer Four layer Unna boot Elastic Inelastic Elastic stockings Inelastic Stockings + Pneumatic compression Bandages + oxpentifylline Bandages + placebo Bandages + Diosmin Bandages + placebo

74% 69% 66% 54% 28% 94% 52% 5% 50% 60.5% 28.6% 32% (8 weeks) 13% (8 weeks)

Many different techniques have been described. Some general rules are outlined in the following: (1) Elastic bandages are easier to handle than inelastic bandages and may also be applied by not specifically trained staff and by the patients themselves. This is also true for compression stockings. (2) Inelastic material like zinc paste should be applied with much higher resting pressure in a kind of modelling work. To obtain a homogeneous pressure distribution without constricting bands it is advisable to cut the zinc bandage when it does not exactly follow the cone-shaped leg surface. A 10-m bandage is recommended for one lower leg. After the lower leg is covered with several layers, a short stretch bandage is wrapped over and the patient is encouraged to walk around immediately for at least 30 min. (3) The bandage should be applied in the morning. Elastic bandages are to be removed during night while inelastic bandages may stay for several days and are renewed when they become loose. (4) Bandaging should start on the foot, preferably at the basis of the toes (although this is not essential in mobile patients in which edema developing distal to the bandage will disappear shortly after walking). The ankle joint is bandaged with maximal dorsal extension of the foot. (5) Graduated compression is achieved by exerting higher pressure to the distal part of the lower leg. Local pressure over ulcers or firm lipodermatosclerotic areas should be increased by pads and pelottes, tendons and the shin can be protected by cotton wool.

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(6) There should be an overlapping of the layers between 30 and 50%. (7) The proximal end of the bandage should cover the capitulum fibulae. (8) Bandaging of the lower leg is sufficient for the majority of patients. Only in cases with extensive swelling or phlebitis of the thigh are compression bandages reaching up to the inguinal fold advisable. Thigh bandages can best be done using adhesive material starting from the proximal lower leg and going up to the proximal thigh. The flexor tendons in the poplitea are protected by cotton wool. (9) Highly exudative ulcers may need frequent dressing changes in the initial phase. However, exudation will subside after several days of firm compression. (10) Walking exercises are essential to optimize the effect of compression therapy.

Criteria for Adequate Compression With adequate compression therapy, 70% of venous ulcers should be healed after 12 weeks. Reports with healing rates =50% raise the suspicion that the technique used was insufficient. This is also true for randomized studies comparing different compression regimes or trying to demonstrate the supplementary effect of drugs. Table 5 shows some examples.

References 1 2 3

4

5 6 7 8 9 10

Alexander House Group: Consensus paper on venous leg ulcers. Phlebology 1992;7:48–58. Partsch H: Compression therapy of the legs. Dermatol Surg Oncol 1991;17:799–805. Partsch H, Menzinger G, Blazek V: Static and dynamic measurement of compression pressure; in Blazek V, Schultz-Ehrenburg U (eds): Frontiers in Computer-Aided Visualization of Vascular Functions. Aachen, Fortschrittberichte VDI, 1997, Ser 20, No 263, pp 145–152. Gniadecka M: Dermal oedema in lipodermatosclerosis: Distribution, effects of posture and compressive therapy evaluated by high frequency ultrasonography. Acta Derm Venereol 1995;75: 120–124. ¨ nderungen der Blutvolumenverteilung im Ganzko¨rper unter Mostbeck A, Partsch H, Peschl L: A physikalischen und pharmakologischen Massnahmen; Vasa 1977;6:137–141. Menzinger G, Horakowa M, Mayer W, Partsch H: Reduction of venous reflux by compression: A comparison between short and long stretch material. Phlebology 1995(suppl 1):888–891. Spence RK, Cahall E: Inelastic versus elastic leg compression in chronic venous insufficiency. A comparison of limb size and venous hemodynamics. J Vasc Surg 1996;24:783–787. Partsch H, Kahn P: Veno¨se Stro¨mungsbeschleunigung in Bein und Becken durch ‘Antithrombosestru¨mpfe’. Klinikarzt 1982;11:609–615. Partsch B, Mayer W, Partsch H: Improvement of ambulatory venous hypertension by narrowing of the femoral vein in congenital absence of venous valves. Phlebology 1992;7:101–104. Partsch H: Improvement of venous pumping function in chronic venous insufficiency by compression depending on pressure and material. Vasa 1984;13:58–64.


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Eze AR, Comerota AJ, Cisek PL, Holland BS, Kerr RP, Veeramasuneni R, Comerota AJ Jr: Intermittent calf and foot compression increases lower extremity blood flow. Am J Surg 1996;172: 130–134. Mayrowitz HN, Larsen PB: Effects of compression bandaging on the leg pulsatile blood flow. Clin Physiol 1997;17:105–117. Abu-Own A, Shami SK, Chittenden SJ, Farrah J, Scurr JH, Smith PD: Microangiopathy of the skin and the effect of leg compression in patients with chronic venous insufficiency. J Vasc Surg 1994;19:1074–1083. Partsch H, Mostbeck A, Leitner G: Experimentelle Untersuchungen zur Wirkung einer Druckwellenmassage (Lymphapress) beim Lympho¨dem. Phlebol Proktol 1980;9:65–66. Haid H, Lofferer O, Mostbeck A, Partsch H: Die Lymphkinetik beim postthrombotischen Syndrom unter Kompressionsverba¨nden. Med Klin 1968;63:754–757. Fletcher A, Cullum N, Sheldon TA: A systematic review of compression treatment for venous leg ulcers. Br Med J 1997;315:576–580. Coleridge-Smith P, Sarin S, Hasty J, Scurr JH: Sequential gradient pneumatic compression enhances venous ulcer healing: A randomized trial. Surgery 1990;108:971–975. Wright DDI, Franks PJ, Blair SD, Backhouse CM, Moffat C, McCollum CN: Oxerutins in the prevention of recurrence in chronic venous ulceration: Randomized controlled trial. Br J Surg 1991; 78:1269–1270. Harper DR, Ruckley CV, Dale JJ, Callam MJ, Allan P, Brown D, Gibson B, Nelson A, Prescott RJ: Prevention of recurrence of chronic leg ulcer – A randomised trial of different degrees of compression; in Raymond-Martinbeau P, Prescott R, Zummo M (eds): Phlebology. London, Libbey, 1992, pp 902–903. Veraart JCJM: Clinical aspects of compression therapy; Thesis, Maastricht 1997. Struckmann J: Compression stockings and their effect on the venous pump – A comparative study. Phlebology 1986;1:37–45. Sto¨berl C, Gabler S, Partsch H: Indikationsgerechte Bestrumpfung – Messung der veno¨sen Pumpfunktion. Vasa 1989;18:35–39. Hendricks WM, Swallow RT, Asheboro BA: Management of stasis leg ulcers with Unna’s boots versus elastic support stockings. J Am Acad Dermatol 1985;12:90–98. Horakova MA, Partsch H: Ulce`res de jambe d‘origine veineuse: Indications pour les bas de compression? Phle´bologie 1994;47:53–57. Samson RH, Showalter DP: Stockings and the prevention of recurrent venous ulcers. Dermatol Surg 1996;22:373–376. Blair SD, Wright DDI, Backhouse CM, Riddle E, McCollum CN: Sustained compression and healing of chronic venous ulcers. BMJ 1988;297:1159–1161. Moffat CJ, Franks PJ, Oldroyd M, Bonsaquet N, Brown P, Greenhalgh RM, McCollum CN: Community clinics for leg ulcers and impact of healing. BMJ 1992;305:1389–1392. Mayer W, Jochmann W, Partsch H: Ulcus cruris: Abheilung unter konservativer Therapie – Eine Prospektive Studie. Wien Med Wochenschr 1994;144:250–252. Callam MJ, Harper DR, Dale JJ, Brown D, Gibson B, Prescott RJ, Ruckley CV: Lothian and Fourth Valley Leg Ulcer Healing Trial. 1. Elastic versus non-elastic bandaging in the treatment of chronic leg ulceration. Phlebology 1992;7:136–141. Colgan MP, Dormandy JA, Jones PW, Schraibman IG, Shanik DG, Young RA: Oxpentifylline treatment of venous ulcers in the leg. BMJ 1990;300:972–975. Guilhou JJ, Dereure O, Marzin L, Ouvry P, Zuccarelli F, Debure C, Van Landuyt H, Gillet-Terver MN, Guillot B, Levesque H, Mignot J, Pillion G, Fe´vrier B, Dubeaux D: Efficacy of Daflon 500 mg in venous leg ulcer healing: A double-blind, randomized, controlled versus placebo trial in 107 patients. Angiology 1997;48:77–85.

Prof. Dr. H. Partsch, Dermatological Department, Wilhelminenspital, Montleartstrasse 37, A–1171 Wien (Austria)

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Physical Therapy of the Ankle Joint in Patients with Chronic Venous Incompetence and Arthrogenic Congestive Syndrome Thomas Klyscz a, Michael Ju¨nger b, Gernot Rassner b a b

Spezialklinik Neukirchen, Neukirchen; Department of Dermatology, University Hospital, Tu¨bingen, Germany

Introduction Primary varicosis and postthrombotic syndrome cause macro- and microcirculatory disturbances that may induce trophic changes of the skin, especially at the inner ankle region. Venous congestion is thought to be the pathogenic mechanism for both trophic skin changes and alterations of tendino-osseus structures, especially of the upper and the lower ankle joint. Schmeller and coworkers [1, 2] have shown that mobility of the upper ankle joint is generally reduced in elderly people and even more so in patients with chronic venous insufficiency (CVI). In these patients, venous drainage of the legs usually worsens as disease progresses. Chronic venous congestion does not only afflict the skin itself, but also the subcutaneous tissue, the Achilles tendon, the joint capsules of the talocrural and talocalcaneal joints. Reduced venous drainage capacity and consecutive congestion in the tissues may lead to both temporary and longlasting restriction of ankle flexibility. Mobility may be become extremely reduced, resulting in an equinus position of the foot. This impairs the function of the calf muscle-ankle joint pump, thereby closing the vicious cycle of CVI [3]. Sufficient dorsal extension in the upper ankle joint, however, is one of the most important mechanisms for venous drainage of the legs, since it is closely linked to the activity of the calf muscle pump. Restriction of mobility in the ankle joint exacerbates venous congestion in patients with CVI. Microan-

giopathy develops in the skin of the distal calf which in turn induces a deficit in skin oxygenation [4]. Even though patients with CVI commonly claim to perform sufficient exercise, they always have a severely compromised walking pattern. Put simply, their unnaturally cautious gait is hemodynamically insufficient. Physical therapy has to focus on the improvement of upper ankle joint mobility by use of active and passive mobilization [5].

Medically Supervised Physical Exercise Training Medically supervised physical exercise training and optimized compression therapy are basic therapeutic approaches in conservative treatment of CVI [6]. According to our experience, several sessions of individual physiotherapy may be required if mobility is extremly reduced. In addition, patients should join physical exercise training in groups at least twice a week. A stress electrocardiogram is required before training participation in order to rule out severe coronary heart disease. Patients are requested to wear compression bandages or stockings during training [6]. A typical 1-hour session of the indoor training program is divided into four parts with different therapeutical aspects. Training starts with a 15-min warm-up period which is especially designed to improve the mobility in the upper ankle joint by games and walking exercises. The following 15 min of the session are used to strengthen calf muscles. For this purpose, we designed a multipurpose pedal ergometer [7]. Patients are asked to lift weights by pressing pedals with their legs, preferably from a lying position. By an inverse block and pulley mechanism, weights are lifted against gravitation forces by the patient’s leg muscle. The axis of the pedal construction can be individually set to the same horizontal level and direction as the axis of the upper ankle joint of the patients. Walking exercises are preferably performed on a staircase which is more effective for calf muscle pump than walking horizontally. The remaining 15 min of the hour are spent on games and relaxation exercises. After the exhausting parts of the session, patients have to elevate their legs to faciliate venous drainage. The 7 years’ experience we have with this therapeutic concept is very good and promising. We have had no complications at all and no worsening of clinical symptoms or subjective complaints. The patients who were enrolled in this training program experienced reduction in swelling and pain of the lower leg and nearly all ulcers healed completely. Improved venous drainage and increased transcutaneous oxygen tension were noted [6, 7]. Physical training was accompanied by regular lessons on compression therapy and pathophysiology of the underlying disease. The social atmosphere

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and the presence of sportsmen and physicans during these sessions was especially appreciated by the patients and an important key to the success of the outpatient training group. The improvement of the venous hemodynamics and skin microcirculation is closely correlated with a reduction of subjective complaints. Improvement in plantar flexion, dorsal extension and transcutaneous oxygen tension could be shown after a 6-week intensified training program, whereas there was no improvement in the control group [6, 13]. Isokinetic exercise performance increased significantly during the training period, which reflects an improvement in calf muscle strength and activity. There was a therapetic benefit in all the patients entering the training program. Costs for the participants are covered by the patients’ health insurance companies under the German ‘Behindertensportabkommen’ which was last revised in 1993. Physical exercise training should become an integral part of therapy for chronic venous incompetence. The formation of outpatient training groups should be supported by phlebologists.

Physiotherapy Management of the arthrogenic congestive syndrome due to CVI must focus on surgical correction of epifascial reflux, accurate compression therapy, and activation of the calf muscle-ankle pump [8]. The currently available measures directed against arthrogenic congestive syndrome encompass venous exercise therapy, individually tailored physiotherapy programs [8], and includes special methods such as Maitland’s physiotherapy [9] or Kabat’s (‘proprioceptive facilitation technique’) (PNF) [10]. PNF therapy is a mobilization program with so-called complex movements specifically designed to stimulate agonist and antagonist muscles. It is used especially in the treatment in paraplegics. In patients with severe trophic changes or ulceration there might be a need for analgetics at the beginning before performing physical therapy. All of these methods are targeted to reverse the pathological restriction of mobility in the talocrural and talocalcaneal joint. All the therapeutic methods listed above have proven their efficacy, although best results are achieved when patients still have residual mobility [1–3, 5, 6, 8, 9]. The situation is different if the arthrogenic congestive syndrome has been present for many years and an almost immobile talipes equinus is present. In such instances, an improvement of only a few degrees in flexibility must be regarded as a success, since a long-lasting arthrogenic congestive syndrome does not respond well to any type of treatment.

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1

2 Fig. 1. Patient being treated by physiotherapist using the BMS apparatus. The height of the machine can be adjusted hydraulically and can be swivelled by up to 120º to create optimal treatment conditions. Passive mobilization of the ankle joint by the therapist and simultaneous exposure of the lower extremity to vibrations from the BMS unit. The foot is resting on the vibrating head of the unit. Fig. 2. The Tu¨bingen angle meter makes it possible to determine joint flexibility and force exerted in the ankle joint without examiner bias. The rotating axis of the pedal, onto which the foot is strapped, can be individually adjusted to the ankle joint axis of the patient so that the examiner can accurately determine ankle joint flexibility. In the background the two little monitors are visible displaying functional values, which are relayed to a computer via a special interface.

Biomechanical Stimulation Method Biomechanical stimulation therapy (BMS) was first tried by us to assist elderly patients with arthrogenic congestive syndrome to improve their gait [11]. BMS has been used for several years in the former Soviet Union in the area of competitive sports [12]. We used the original ‘Grizzly’ BMS unit (Ramax, Minsk, Ukraine) for therapeutic purposes (fig. 1). Patients were treated on the BMS equipment by an experienced physiotherapist. The heel or sole was placed gently on the vibrating head of the


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Fig. 3. Change in upper ankle joint mobility achieved with BMS therapy for arthrogenic congestive syndrome. On average, ankle joint flexibility in 19 treated legs of the 14 patients increased by 15.5º degrees within only ten therapy sessions (p=0.05).

machine and the ankle joint was stretched by mechanically engaging the vibrations – either actively by the patient or passively by the therapist. The therapy sessions lasted 15 min including a number of interruptions. The therapeutic vibrations had an adjustable frequency between 18 and 33 Hz. Ankle joint flexibility was assessed with a specially developed electronic device [13] which measured and digitally displayed the angular range of movement in 1º increments, thereby eliminating investigator bias (fig. 2). No side effects or increase in pain were observed during BMS treatment. The measurable significant gain in ankle joint flexibility was accompanied by a noticeable improvement in gait and general mobility of the patients. Several patients reported that the pain in the ankle area had dissipated for several hours after treatment [15, 16]. On average, ankle joint flexibility in 19 treated legs of 14 patients increased by 15.5º within only 10 therapy sessions (p=0.05). Transcutaneous oxygen tension in the border around venous leg ulcers increased significantly, which was clinically noticeable as improved wound healing (fig. 3). In contrast to conventional physical therapy methods, biomechanical stimulation therapy is able to passively mobilize the foot at the ankle joint by defined longitudinal vibrations with a fixed amplitude and an adjustable frequency [17]. The BMS equipment causes the leg and bone structures to vibrate visibly along the longitudinal axis at frequencies between 18 and 33 Hz.


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The vibrations radiate from the heel toward the center of the body as far as the thigh and even higher, while the amplitude at the vibrating head of the machine is only 4 mm [11, 14, 15]. Unlike the mechanical vibrations all too familiar to us as a side effect of motor-driven equipment, the BMS-type vibration is characterized by an ellipsoid motion of the vibrating head. This vibration profile generates a palpable and visible radiation of the peripherally transmitted vibration from the extremity where it is applied over the entire limb toward the center of the body [11, 12, 14, 15, 17–19]. By choosing different frequencies, we can obtain different therapeutic effects. The lower frequencies from 18 to 23 Hz ‘warm’ the muscles and have a pronounced antiedematous effect. From a frequency of about 23 Hz upwards, stretching of the muscle and joint structures is achieved, and at the maximum frequency around 33 Hz there is an analgesic effect [16]. The results achieved with BMS surpass by far all the methods described to date in the literature, both with regard to the measurable improvement in joint flexibility as in the frame time that is required to reach a noticeable therapeutic effect [18, 19]. Since bone and muscle are not the only components that determine joint flexibility, the tendons, ligaments and joint capsules affected by the underlying disease also benefit from muscle relaxation. This relaxation of the muscle structures is probably accompanied by improved perfusion of the muscles, as several investigators have observed [11, 14, 15, 17–19]. It seems that muscle relaxation induces stretching of capsule structures, tendons and ligaments, presumably by dissolving fibrous adhesions and thereby expanding the anatomical range of motion.

Conclusion Based on our experience we feel that physical exercise training, physiotherapy and BMS therapy are important methods that contribute to a lasting benefit in patients with CVI. Especially BMS could offer new therapeutic options for patients with extremely chronic forms of arthrogenic congestive syndrome that otherwise would be refractory to conventional physical therapy.

Acknowledgment Supported by a grant of the Swiss Society of Phlebology, 1997.


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References 1 2

3 4 5 6

7 8

9 10 11 12 13 14

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16 17 18 19

Schmeller W: Das arthrogene Stauungssyndrom. Sprunggelenksvera¨nderungen bei chronischer Veneninsuffizienz. Berlin, Diesbach, 1990. ¨ ber den Bewegungsumfang im oberen Sprunggelenk bei Schmeller W, Steidel G, Borgis KJ: U Venengesunden und Venenkranken – ein Beitrag zum arthrogenen Stauungssyndrom. Phlebol Proktol 1990;19:100–110. Langer C, Schmidbauer U: Das prima¨re arthrogene Stauungssyndrom. Phlebologie 1993;22:280–281. Gaylarge PM, Dodd HJ, Sarkany I: Venous leg ulcers and arthropathy. Br J Rheumatol 1990;29: 142–144. ¨ ber die Wirkung aktiver und passiver Bewegungen im Staubesand J, Heisterkamp T, Stege H: U oberen Sprunggelenk fu¨r den veno¨sen Ru¨ckstrom. Phlebologie 1994;29:264–271. Klyscz T, Ju¨nger M, Ju¨nger I, Hahn M, Steins A, Zuder D, Rassner G: Gefa¨sssport zur ambulanten Therapie veno¨ser Durchblutungssto¨rungen der Beine. Diagnostische, therapeutische und prognostische Aspekte. Hautarzt 1997;48:384–390. Klyscz T, Ju¨nger I, Stracke F, Schiebel O, Ju¨nger M: Neuartiges Pedalergometriegera¨t. Phlebologie 1995;24:1–8. Lentner A, Wittkopf-Baumann C, Wrobel K, Grifka J, Wienert V: Beweglichkeit im oberen Sprunggelenk bei fortgeschrittener chronischer Veneninsuffizienz. Verbesserung durch gezielte Krankengymnastik. Phlebologie 1994;23:149–155. Maitland GD: Peripheral Manipulation. London, Butterworth, 1977. Knott M, Voss D: Komplexbewegungen. Bewegungungsbahnung nach Dr. Kabat. Stuttgart, Fischer, 1981. Klyscz T, Ritter-Schempp C, Ju¨nger M, Rassner G: Biomechanische Stimulationstherapie zur physikalischen Behandlung des arthrogenen Stauungssyndroms. Hautarzt 1997;48:318–322. Nazarov V, Spivak G: Development of athlete’s strength abilities by means of biomechanical stimulation method. Theory Pract Phys Cult (Moscow) 1987;12:37–39. lyscz T, Ju¨nger M: Entwicklung eines neuartigen Messgera¨tes zur Beurteilung der Beweglichkeit und Kraftentwicklung im oberen Sprunggelenk. Biomed Tech 1995;40(suppl):355–356. Klyscz T: Pathologische und therapeutische Einflu¨sse mechanischer Schwingungen auf das Hautorgan – Neue Aspekte fu¨r die Lymphologie; in Lymphologie: State of the Art. Bonn, Kagerer, 1998, pp 17–26. Klyscz T, Bussmann J, Ju¨nger M, Blazek V, Michael K, Rassner G: Klinische Relevanz mechanischer Schwingungen in der Dermatologie – diagnostische und therapeutische Aspekte; in Garbe C, Rassner G (eds): Dermatologie. Leitlinien und Qualita¨tssicherung fu¨r Diagnostik und Therapie. Heidelberg, Springer, 1988, pp 27–32. Lundeberg T, Nordemar R, Ottoson D: Pain alleviation by vibratory stimulation. Pain 1984;20: 25–44. Homma S, Kabayashi H, Watanabe S: Vibratory stimulation of muscle and stretch reflex. Jpn J Physiol 1970;20:309–319. Issurin VB, Liebermann DG, Tenenbaum G: Effect of vibratory stimulation training on maximal force and flexibility. J Sports Sci 1994;12:561–566. Samuelson B, Jorfieldt L, Ahlborg B: Influence of vibration on endurance of maximal isometric contraction. Clin Physiol 1989;9:21–25.

¨ rztlicher Direktor/Hautarzt, Spezialklinik Neukirchen, Priv. Doz. Dr. med. Thomas Klyscz, A Allergologie/Umweltmedizin/Phlebologie, Krankenhausstrasse 9, D–93453 Neukirchen (Germany) Tel. 0049 9947 280, Fax 0049 9947 28-109, E-Mail [email protected]


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Manual Lymph Drainage Hans Ulrich Stahel Angiology Centre, Zu¨rich, Switzerland

Most venous ulcers heal within a relatively short time, if adequate compression therapy and local care is properly maintained. Therefore, a venous ulcer which does not respond to standard therapy within 3 months is referred to as ‘therapy-resistant’ or ‘complicated’. Most commonly, other underlying conditions than uniquely venous disease are responsible for treatment failure. Before surgical options are considered, however, conservative treatment should be supplemented in conjunction with manual lymph drainage [1]. As a result of progressing dermatoliposclerosis, the lymphatic network as well as the lymph collectors at the medial gaiter area may become severely damaged and consequently become obliterated [2]. Clinically these legs present the classical signs of lymphedema, such as Stemmer’s sign (a highly characteristic indurated edema on the dorsum of the second toe), edema of the dorsum of the foot, and ultimately lymphostatic papillomatosis that is frequently found around venous ulcers [3]. These patients obviously benefit from therapy with manual lymph drainage. Lymphostasis may be underestimated due to the dermatoliposclerotic ‘armoring’ around the distal calf. Therefore, patients with recalcitrant venous ulceration and dermatoliposclerosis often benefit from manual lymph drainage, even though the classical signs of lymphostasis may be absent.

History In 1892 the German angiologist A. von Winiwarter described the treatment of elephantiasis with a combined therapy. His treatment, still valid today, consisted of surface massage, bandages and elevation of the affected limb. The Danish physical therapist Vodder [4] emphasized the importance of massage in lymphedema as early as 1936.

Fig. 1. Scoop grip.

The Technique of Manual Lymph Drainage Manual lymph drainage differs from classic massage in the grip technique, as well as in the amount and rhythm of pressure applied. Vodder [4] differentiated four basic grips: (1) standing circles; (2) pump; (3) scoop and (4) twist (fig. 1, 2). These grips are to be applied on a large area of skin by alternating contraction by relaxation phases. Lymph drainage promotes lymphatic flow by stimulating vegetative noci- and mechanoreceptors. The massage is started on skin areas proximal to the affected zone, e.g. on the lower abdomen and proximal thigh. Massage of the edema itself proceeds along the course of the lymph collectors.

Combined Physical Decongestion Therapy Brunner and Klaüs [5] and Fo¨ldi and Casley-Smith [6] revised the principles put forward by von Winiwarter and Vodder. The modified technique was called combined physical decongestion therapy. This comprised manual

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Fig. 2. Twist grip.

lymph drainage, compression dressings, skin care and exercise therapy. The importance of combining manual lymph drainage with compression therapy is obvious. Compression therapy increases interstitial pressure, thereby reducing lymphatic filtration and it preserves elasticity of the skin, which rapidly is lost in lymphedema. Compression therapy of lymphedema consists in specialized padding and a tight multilayer bandage system. It is applied from proximal to distal (feetKlegsKthighs) and usually includes the toes. Additional exercise therapy increases lymphatic flow and the decongestional effect.

Manual Lymph Drainage in the Presence for Recalcitrant Venous Ulcers Manual lymph drainage for recalcitrant venous ulcers starts with the cleansing of the wound, with a patient who is in recumbent position [7]. One finger moves under gentle pressure radially from the edge to the center of the wound. The surrounding skin is then treated with gentle rotational movements (fig. 3a, b). The actual manual lymph drainage is commonly started on the

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a

Fig. 3. a Massage of the venous ulcer: From the edge to centre. b Standing circles [adapted from 1].

b

neck to allow the patient to attune to the procedure. Second, the area above the leg is treated, i.e. the lower abdomen and the proximal thigh. Then manual lymph drainage moves from the foot to the leg and thigh. The whole procedure may be repeated two or more times. Local wound care is adjusted to the stage of wound healing and thereafter the padded and tight multilayer compression bandage is applied. The session concludes with exercises aiming especially at mobilizing the ankle joint. In the outpatient treatment of a difficult ulcer, the number of therapy sessions depends on the wound size and the mobility of the patient. In most cases 2–3 sessions per week are sufficient. If necessary the treatment can be given daily. The patient is advised to walk every day and to repeat the exercises for the ankle joint at home. In everyday pratice, the care of a leg ulcer patient can be provided by one person or by two therapists, one taking care of the wound and the other applying manual lymph drainage. In cases of persistent therapy resistance (no response after 3 weeks of manual lymph drainage), the diagnosis must be worked up again and additional tests, such as skin biopsy, carried out [cf. chapter of Lautenschlager et al.].

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Contraindications Three contraindications of manual lymph drainage are to be mentioned: (1) acute or recurrent deep venous thrombosis in the previous 3 months; (2) acute infection, such as cellulitis or erysipelas, and (3) malignant disease of the treated leg.

Conclusion Manual lymph drainage for recalcitrant venous ulcers is a time-consuming therapy requiring a high motivation of both the patient and the therapist. The therapist has to undergo specialized training in wound care of chronic ulcers as well as in the technique of manual lymph drainage. Since manual lymph drainage can be conducted as an outpatient procedure, it can be very costeffective, if hospitalization can be circumvented.

References 1 2 3 4 5 6 7

Fo¨ldi M, Kubik S (eds): Lehrbuch der Lymphologie. Stuttgart, Fischer, 1993. Partsch H: Lymphangiopathie bei chronischer Veneninsuffizienz. Phlebol Proktol 1985;15:85–89. el-Gammal S, Schultz-Ehrenburg U, Panz B, Tiedjen KU: Vera¨nderungen der peripheren Lymphstrombahn bei Papillomatosis cutis lymphostatica. Phlebol 1993;22:148–155. Vodder E: Le drainage lymphatique, une nouvelle me´thode the´rapeutique. Paris, Sante´ pour tous, 1936. Brunner U, Klaüi E: Manuelle Entstauung des prima¨ren Lymphoedems der Beine; in Brunner U (ed): Physikalische Therapie in Phlebologie und Lymphologie. Bern, Huber, 1976. Fo¨ldi M, Casley-Smith JR (eds): Lymphangiology. Stuttgart, Schattauer, 1983. Stro¨ssenreuther R, Gu¨ltig O, Knauer A, Pritschow H, Seffers A, Stro¨ssenreuther R: Praktische Hinweise fu¨r Physiotherapeuten; in Fo¨ldi M, Kubis S (eds): Lehrbuch der Lymphologie. Stuttgart, Fischer, 1993.

H.U. Stahel, MD, Angiology Centre (Private Practice), Stadelhoferstrasse 8, CH–8001 Zu¨rich (Switzerland) Tel. +41 1 269 80 10, Fax +41 1 269 80 11, E-Mail [email protected]

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Adjuvant Systemic Drug Therapy in Venous Leg Ulcers G. Gallenkemper, U. Schultz-Ehrenburg Department of Dermatology, Klinikum Buch, Berlin-Pankow, Germany

Conservative (essentially physiotherapeutic) measures combined with surgical measures are the basic methods to treat chronic venous insufficiency and venous ulceration [1]. Nevertheless, there is clearly a role for adjuvant drug treatment. Better understanding of venous hypertensive microangiopathy and several randomized controlled trials with reproducible investigative techniques recently underlined the interest of this field which has been underestimated too long and neglected by many physicians. Yet, many questions on the pathophysiology of chronic venous insufficiency and on the choice of drugs with an optimal profile remain to be answered [2, 3].

Classification of Adjuvant Drugs in the Treatment of Chronic Venous Insufficiency Adjuvant drugs for chronic venous insufficiency and venous ulceration can be classified as (1) edema-protective (so-called phlebotropic drugs), (2) hemorheologic and (3) fibrinolytic agents (table 1) [4]. Most edema-protective agents are derived from plants. Amongst the many commercially available preparations are combinations of several generics and in some products the exact composition is unknown. Coumarin (5,6a-benzopyrone, not to be confounded with the oral anticoagulants) has an established edema-preventive effect, especially in primary and secondary lymphedema [5]. This seems to be the result of lipoxygenase and leukotriene biosynthesis inhibition [6]. Drug-induced hepatitis occurs in as many as 1 of 300 patients, with geographical differences [7, 8]. Therefore, the liver enzymes must be controlled monthly as long as the drug is prescribed. Fatigue, nausea, pruritus

Table 1. Classification of adjuvant drugs in the treatment of chronic venous insufficiency (modified after Ramelet [4]) Edema-preventive drugs (‘phlebotropic drugs’) Benzopyrones a-Benzopyrones Coumarin (5,6a-benzopyrone) Esculetin (6,7-dihydroxycoumarin) Umbelliferone (7-hydroxycoumarin) c-Benzopyrones (flavonoids) Flavone and flavonols Diosmin Diosmetin Kaempferol Oxerutins, such as troxerutin (O-(b-hydroxyethyl)rutoside) Quercetin Rutin Flavanes and flavanones Hesperetin Hesperidin Pycnogenol Saponins Centella asiatica extracts Escin, horse-chestnut extracts (protoescigenin, barringtogenol, a- and b-escin, cryptoescin) Ruscus extracts Other plant extracts Anthocyanosides (blueberry extract) Ginkgo biloba Proanthocyanidols (grape seed extract) Synthetic products Benzarone Calcium dobesilate Naftazone Tribenoside Hemorheologic modifiers Acetylsalicylic acid (aspirin) Iloprost Pentoxifyllin Prostaglandin E1 Fibrinolytic drugs Defibrotide Stanozolol Sulodexide

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and jaundice are clinical signs that should alert the patient to see his physician. Although lethal hepatotoxic reactions to coumarin are very rare [7, 8] and the drug-induced hepatitis usually is completely reversible [8, 9], some European countries have withdrawn the substance from the market. The a-benzopyrones seem to act by stimulation of macrophage activity and by direct enhancement of lymphatic flow [2, 5]. Flavonoids (c-benzopyrones), such as diosmin and the rutosides, have shown to be effective in edema prevention both in animal experiments [10, 11] as well as in clinical trials [12]. They seem to reduce the capillary filtration rate and they have a moderate vasoconstrictive and anti-inflammatory effect [2, 10, 11]. Pharmacologically, flavonoids interact with the arachidonic acid cascade and with adenosine receptors which in part can explain their edemaprotective and anti-inflammatory action [6]. Escin, which is composed of about 30 triterpene glycosides and triterpene saponins and the synthetic substance calcium dobesilate have also both experimentally as well as clinically a pronounced edema-protective effect [13]. They seem to act by an inhibiting effect on the permeability of capillaries. Dobesilate has platelet antiaggregant properties and stimulates nitric oxid release in endothelium in animal experiments [6]. Besides coumarin, two other edema-protective agents have to be mentioned for their side effects. Tribenoside is associated with cutaneous toxicity in as many as 7.2% of patients [4]. More severely, benzarone was associated with lethal hepatotoxicity and therefore must be avoided [14]. Acetylsalicylic acid is a potent inhibitor of platelet aggregation and an anti-inflammatory drug. It acts by irreversible cyclooxygenase inhibition. Cyclooxygenase is a key enzyme in both the formation of the proaggregant and vasoconstrictive thromboxane A2 which is generated in the platelet and of the antiaggregant and vasodilative prostacyclin (PGI2), which is generated in the endothelial cell. In clinical practice the antiaggregant properties of aspirin predominate [2, 15]. Pentoxifylline originally was introduced into vascular medicine because of its positive effect on the deformability of red cells, thereby improving oxygen supply to ischemic tissues. Recent research indicates that pentoxifylline is also a potent inhibitor of neutrophil activation and therefore should prove useful in the treatment of venous hypertension microangiopathy [2, 14, 15]. Prostaglandin E1 (PGE1) increases capillary blood flow and nutritional oxygen supply to ischemic tissues. It also has distinct anti-inflammatory properties [2, 16]. Iloprost, a stable prostacyclin analogue, increases capillary blood flow, inhibits platelet aggregation and has profibrinolytic and anti-inflammatory effects [2, 17]. Moreover, several oral agents with a moderate fibrinolytic activity have been used in the treatment of chronic venous insufficiency and

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of venous ulceration. Stanozolol is a modified anabolic steroid, which enhances deficient fibrinolysis. The main side effects, such as symptoms of virilization in female users, headache and nausea can be attributed to its weak androgen effect and fluid retention [18]. Sulodexide is a natural glycosaminoglycan that enhances fibrinolysis [19].

Adjuvant Drug Therapy in Venous Leg Ulceration Several adjuvant agents have been assessed in the treatment of venous leg ulcers. The randomized controlled trials (RCT) that we could identify by a Medline search and the screening of secondary literature is shown in table 2. In all of these trials both the verum group as well as the placebo group received standardized compression therapy. Among the edema-preventive drugs, micronized diosmin is the only member which has been shown to modify ulcer healing as of yet. Guilhou et al. [20] reported on a RCT (105 patients) with 450 mg micronized diosmin (in a combination with 50 mg hesperidine) twice a day versus placebo. Among 91 patients with an ulcer diameter =10 cm, 14/44 (32%) receiving diosmin healed their ulcer within 8 weeks compared to 6/47 (13%) under placebo (p>0.028). The results of RCTs using oxerutins are less consistent. Schultz-Ehrenburg and Mu¨ller [21] reported on two RCTs using two different dosages of troxerutin versus placebo for 12 weeks. In the group which received 2¶500 mg/day, the healing rate was 12/23 (52%) compared to 7/25 (28%) (p>0.087) with the lower dosage. In the second trial, 57 patients were enrolled to receive either troxerutide 2¶1000 mg/day or placebo. The outcome of the two trial groups was not different (NS). Wright et al. [22] reported on a RCT to assess the possible prevention of recurrent venous ulceration in 138 patients with healed leg ulcers by the administration of troxerutin 2¶500 mg/day or placebo for 18 months. The recurrence rates in the two groups were virtually the same (at 12 months: 23 vs. 22%; at 18 months: 34 vs. 32%; NS). There are two RCTs on the use of aspirin 300 mg/day versus placebo in the treatment of venous leg ulceration. Layton et al. [15] reported on a RCT that enrolled 20 patients. Some patients had several ulcers, all of which were evaluated. After 4 months, 38% of the ulcers under aspirin had healed compared to none under placebo (p=0.007). Reduction in wound size was also significantly better under aspirin. This trial, although interesting, is too small to allow for a reliable judgment on the effect of aspirin on the healing of venous ulceration. Ibbotson et al. [23] repeated the trial enrolling 40 patients. They, however, focused more on abnormalities in the coagulation status. Ulcer size reduction was 69 vs. 47% in favor of aspirin (p>0.002). As recognized


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Table 2. Randomized clinical trials on adjuvant drug treatment for venous ulceration (standardized compression therapy was warranted in all studies) Substance

Patients

Healing rates

Reference

Aspirin 1¶300 mg/day vs. placebo, for 4 months Aspirin 1¶300 mg/day vs. placebo, for 4 months

20 Mean ulcer area about 15 cm2 40 Mean ulcer area about 15 cm2

38 vs. 0% (p=0.007) (several ulcers/patient)

Layton

Ulcer size reduction: 69 vs. 47% (p>0.002) Healing rate: not done

Ibbotson

Diosmin 2¶500 mg/day vs. placebo, for 2 months

105 91 ulcers =10 cm 14 ulcers ?10 cm

Diameter =10 cm: Guilhou 14/44 vs. 6/47 (p>0.028) Diameter ?10 cm: 0/9 vs. 0/5 (NS)

Troxerutin 2¶500 mg/day vs. placebo, for 12 weeks Troxerutin 2¶1000 mg/day vs. placebo, for 12 weeks Troxerutin 2¶500 mg/day vs. placebo, for 18 months

48

12/23 vs. 7/25 (p>0.087)

SchultzEhrenburg

57

NS

SchultzEhrenburg

138 Recurrences: Wright Trial on prevention 12 months: 23 vs. 22% (NS) of ulcer recurrence 18 months: 34 vs. 32% (NS)

Iloprost topical application 5 vs. 20 lg/ml vs. placebo, 2¶/week, 8 weeks

148 Mean ulcer area 26–35 cm2

Pentoxifyllin 3¶400 mg/day vs. placebo, for 6 months Pentoxifyllin 3¶400 mg/day vs. placebo

80 23/38 vs. 12/42 (p>0.03) Mean ulcer area about 5 cm2 200 NS Complex multifactorial trial (cf. text)

Prostaglandin E1 60 lg i.v. during 3 h/day vs. placebo, for 6 weeks

44 Mean ulcer area about 6–10 cm2

8/20 vs. 2/22 (p=0.001)

Rudofsky

Stanozolol 2¶5 mg/day vs. placebo, for 60 weeks

75 (84 ulcers) Ulcer area (range) 0.025–100 cm2

26/40 vs. 27/44 (NS) (healed ulcers)

Layer

Defibrotide 2¶400 mg/day vs. placebo (for 2¶3 months, crossover)

32 Ulcer size reduction: 18 A (start with 96 vs. 31% (p=0.005) defibr.) Healing rate: not done 14 B (start with plac.)

5 lg/ml: 2/49 (NS) 20 lg/ml: 5/49 (NS) Placebo: 2/50


WernerSchlenzka

Colgan

Cheatle

Belcaro

157

by the Alexander House Consensus Paper [24], ulcer healing should be the primary endpoint in clinical studies on leg ulceration. Ulcer size reduction may be used as a secondary endpoint. Therefore, more clinical studies with a sufficient statistical power are required to assess the effect of aspirin as an adjuvant treatment of venous ulceration. Pentoxifylline is one of the orally administered hemorheologic agents that might have a moderate benefit on the healing of venous ulceration. Colgan et al. [25] enrolled 80 patients in a RCT on pentoxifylline 3¶400 mg/day versus placebo during a period of 6 months. The healing rate under pentoxifylline was 23/38 (60.5%) compared to 12/42 (28.5%) under placebo (p=0.03). In a complex multifactorial trial [2] (pentoxifylline vs. placebo; hydrocolloid dressing vs. viscose dressing; single-layer vs. four-layer bandage) with 200 patients, there was only a trend in favor of a more rapid ulcer healing under pentoxifylline. Perhaps the effect of other factors that were studied, especially that of compression therapy, concealed the effect of pentoxifylline [2]. Rudofsky [16] reported on an RCT with intravenous PGE1 60 lg during 3 h daily, versus placebo i.v., in the treatment of venous leg ulceration. Healing rates after 6 weeks were 8/20 (40%) vs. 2/22 (9%) (p=0.001). Although such an intense and expensive treatment may not seem attractive prima vista, it would be interesting to calculate cost-effectiveness and assess against the resources spent on outpatient treatment for unhealed ulcers. There is only one RCT on iloprost as adjuvant treatment in venous ulceration. Werner-Schlenska and Kleine Kuhlmann [17] used a topical formulation of iloprost at two different concentrations that was applied twice weekly to the ulcer border and surrounding skin. After 8 weeks of treatment no significant difference was found between the agent in comparison to placebo, nor among the two different dosages. Although both the fibrinolytic agents stanozolol [18] and defibrotide [26] have been reported to reduce the area of dermatoliposclerosis, the effect on healing of venous ulceration is probably only moderate. After some promising first reports on the benefit of stanozolol in advanced stages of chronic venous insufficiency, Layer et al. [27] published an RCT with 75 patients who received either 2¶5 mg stanozolol or placebo. After 60 weeks of treatment 26/40 ulcers (65%) were healed compared to 27/44 (61%) under placebo (NS). Belcaro and Marelli [26] reported on an RCT investigating defibrotide versus placebo during a period of twice 3 months, with a crossover between active agent and placebo at half-time. The ulcer size reduction in the first half of the trial was 96% in the defibrotide group compared to 31% under placebo (p=0.005). In conclusion, adjuvant systemic drug therapy of venous leg ulceration might be of much greater clinical value than commonly assumed. Further research on venous hypertensive microangiopathy might open new perspectives


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for the application of adjuvant drugs with an optimal profile. Controlled clinical trials in phlebology should be designed to ensure comparability of the groups of patients included in the studies [3]. Venous etiology of the underlying condition should be confirmed. Ideally the CEAP criteria of classification should be applied [cf. chapter of Mayer et al.]. Peripheral arterial occlusive disease should be ruled out by exclusion of patients with an ankle-arm index =0.8 [cf. chapter of Wu¨tschert et al.]. Size (e.g. =10 cm2 ) and age (e.g. =6 months) should be similar. Standardized compression therapy must be ensured [cf. chapter of Partsch]. Only one reference ulcer should be included per patient, because it is unlikely that two ulcers in the same patient or even the same leg will develop in an independent fashion. Despite such difficulties, controlled clinical studies are a requirement for modern phlebology [cf. chapter of Vanscheidt].

References 1 2

3 4 5 6 7 8 9 10

11

12 13

14

Gallenkemper G, Bulling BJ, Kahle B, Klu¨ken N, Lehnert W, Rabe E, Schwahn-Schreiber C: Leitlinien zur Diagnostik und Therapie des Ulcus cruris venosum. Phlebologie 1996;25:254–258. Cheatle T, McMullin G, Watkin GT: The drug treatment of chronic venous insufficiency and venous ulceration; in Coleridge Smith PD (ed): Microcirculation in Venous Disease. Austin, Landes Bioscience, 1998, pp 205–223. Lok C: Ulce`res de jambe d’origine veineuse. Ann Dermatol Veńe´reól 1997;124:112–121. Ramelet AA: Therapeutic strategy in venous disease: Value of phlebotropic drugs. Phlebolymphology 1998;19:3–7. Casley-Smith JR, Gwyn Morgan R, Piller NB: Treatment of lymphedema of the arms and legs with 5,6-benzo-[alpha]-pyrone. N Engl J Med 1993;329:1158–1163. Zaragoza´-Garcıá F, Domıńgues-Rodrı´gues JC: Mechanism of action of the venotonic drugs. Scope Phlebol Lymphol 1998;5/3:16–19. Pharmakovigilance-Zentrum I: Medikamento¨se Hepatitis unter dem Wirkstoff Cumarin. Schweiz Arzteztg 1996;77:1348. Casley-Smith JR, Casley-Smith JR: Frequency of coumarin hepatotoxicity. Med J Aust 1995;162: 391. Loprinzi CL, Sloan J, Kugler J: Coumarin-induced hepatotoxicity. J Clin Oncol 1997;15:3167– 3168. Nolte D, Pickelman S, Schu¨tze E, Mo¨llmann M, Messmer K: Effects of DaflonÔ 500 mg on postischemic macromolecular leak syndrome in striated skin muscle of the hamster. Int J Microcirc 1997; 17(suppl 1):6–10. Bouksela E, Svensjo¨ E, Cyrino FZGA, Lerond L: Oxidant-induced increase in vascular permeability is inhibited by oral administration of S-5682 (DaflonÔ 500 mg) and alpha-tocopherol. Microcirculation 1997;17(suppl 1):18–20. Laurent R, Gilly R, Frileux C: Clinical evaluation of a venotropic drug in man. Int Angiol 1988; 7(suppl 2):39–43. Diehm C, Trampisch HJ, Lange S, Schmidt C: Comparison of leg compression stocking and oral horse-chestnut seed extract therapy in patients with chronic venous insufficiency. Lancet 1996;347: 292–294. Hautekeete ML, Henrion J, Naegels S, De Neve A, Adler M, Deprez C, Devis G, Klo¨ppel G: Severe hepatotoxicity related to benzarone: A report of three cases with two fatalities. Liver 1995; 15:25–29.


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15 16 17 18 19

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Layton AM, Ibbotson SH, Davies JA, Goodfield MJD: Randomised trial of oral aspirin for chronic venous leg ulcers. Lancet 1994;344:164–165. Rudofsky G: Intravenous prostaglandin E1 in the treatment of venous ulcers – A double-blind, placebo-controlled trial. Vasa 1989;28:39–43. Werner-Schlenska H, Kleine Kuhlmann R: Treatment of venous leg ulcers with topical iloprost: A placebo-controlled study. Vasa 1994;23:145–149. Browse NL, Jarrett PEM, Morland M, Burnand K: Treatment of liposclerosis of the leg by fibrinolytic enhancement: A preliminary report. Br J Med 1977;ii:434–435. Saviano M, Maleti O, Liguori L: Double-blind, double-dummy, randomized, multi-centre clinical assessment of the efficacy, tolerability and dose-effect relationship of sulodexide in chronic venous insufficiency. Curr Med Res Opin 1993;13:96–108. Guilhou JJ, Dereure O, Marzin L, Ouvry P, Zuccarelli F, Debure C, Van Landuyt H, Gillet-Terver MN, Guillot B, Levesque H, Mignot J, Pillion G, Fe´vrier B, Dubeaux D: Efficacy of DaflonÔ 500 mg on venous leg ulcer healing: A double-blind, randomized, controlled versus placebo trial in 107 patients. Angiology 1997;48:77–85. Schultz-Ehrenburg U, Mu¨ller B: Two multicentre clinical trials of two different dosages of O-(b-hydroxy)rutosides in the treatment of leg ulcers. Phlebology 1993;8(suppl 1):29–30. Wright DDI, Franks PJ, Blair SD, Backhouse CM, Moffatt C, McCollum CN: Oxerutins in the prevention of recurrence in chronic venous ulceration: Randomized controlled trial. Br J Surg 1991; 78:1269–1270. Ibbotson SH, Layton AM, Davies JA, Goodfield MJD: The effect of aspirin on haemostatic activity in the treatment of chronic venous leg ulceration. Br J Dermatol 1995;132:422–426. The Alexander House Group: Consensus paper on venous leg ulcer. J Dermatol Surg Oncol 1992; 18:592–602. Colgan MP, Dormandy JA, Jones PW, Schraibman IG, Shanik DG, Young RAL: Oxpentifylline treatment of venous ulcers of the leg. BMJ 1990;300:972–975. Belcaro G, Marelli C: Treatment of venous lipodermatosclerosis and ulceration in venous hypertension by elastic compression and fibrinolytic enhancement with defibrotide. Phlebology 1989;4: 91–106. Layer GT, Stacey MC, Burnand KG: Stanozolol and the treatment of venous ulceration — An interim report. Phlebology 1986;1:197–203.

G. Gallenkemper, MD, Department of Dermatology, Klinikum Buch, Wiltbergstrasse 50, D–13122 Berlin-Pankow (Germany) Tel. +49 30 9401 2582, Fax +49–30 9401 4581, E-Mail [email protected]


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Controversies on Emerging and Obsolete Therapies in Venous Leg Ulcers Albert-Adrien Ramelet Specialist in Dematology and Angiology, Lausanne, Switzerland

Since the treatment of leg ulcers may be challenging, a great number of therapies have been developed and proposed. In this chapter an array of emerging therapies on the one and obsolete modalities on the other hand are reviewed. Only a few of them have been studied in controlled trials. CO2 laser, water-jet scalpel, vacuum sealing and maggots are ‘alternative’ approaches to wound debridement. Wound healing may be stimulated by ultrasound, electrical stimulation with direct current or with hyperbaric oxygen, but the results are inconsistent. Low-level lasers, infrared light and ultraviolet radiation have failed to demonstrate any beneficial effect on wound healing, so far. Topical application of sugar has a potent antibacterial effect, whereas honey bears the risk of sensitization to propolys. Zinc and vitamin supplementation has never been shown to enhance wound healing, except obviously in malnourished patients.

Debridement The vacuum sealing technique is a promising novel concept for the treatment of infected wounds in traumatology [1]. A polyvinylalcohol sponge is placed on the wound, sealed with an airtight foil and connected with a vacuum pump that maintains a vacuum of about –50 mm Hg. The first generation of vacuum pumps were criticized of being too large. This shortcoming has been improved by smaller pumps that can be worn by ambulating patients around the waist. Initial experience with vacuum sealing in the phlebologic field have recently been reported [2, 3], but controlled clinical trials are mandatory to evaluate the potential of the method in the treatment of leg ulcers.

Debridement with the CO2 laser is easy to perform and has been reported to have a profound antibacterial and hemostatic effect [4]. Adequate anesthesia can pose a problem in CO2 laser debridement. Common techniques of local anesthesia that usually work well in scalpel debridement (such as, e.g. local anesthetic creams), are hardly sufficient to prevent the patient from the burning sensation of CO2 laser debridement. The proof of an enhanced wound healing following the procedure is also lacking. Jet-stream debridement with a water jet (Aquatom NTS-1000Ô) is a careful and effective procedure in traumatology as well as in the treatment of chronic wounds that preserves the vial tissue [5]. However, considerable amounts of water and debris are sprayed in the air, which may pose hygienic problems. Maggot infestation of open wounds that heal by secondary intention is known for centuries to enhance debridement and wound healing. Recently, the use of maggots from sterile cultures (biosurgery) has experienced a revival in the treatment of chronic wounds [6]. Still, their effectiveness should be demonstrated in a controlled trial.

Stimulation of Wound Healing Hyperbaric oxygen therapy has been discussed as a treatment of chronic wounds since decades, but its interest is still highly debatable. Hyperbaric oxygen therapy can be administered in pressure chambers (as they are used in decompression traumatism in divers) or it can be delivered locally by the means of a disposable polyethylene bag [7]. Experimentally, hyperbaric oxygen increases tissue oxygenation and stimulates angiogenesis, fibroblast proliferation and epithelization [7–9]. However, evidence of benefit in the treatment of chronic wounds (arterial wounds in first line, but actually in any kind of chronic wound) is still lacking as of yet. Hyperbaric treatment in pressure chambers is potentially dangerous (barotraumatism, pulmonary and central nervous system toxicity) and must be carried out under rigid precautions. Several studies have shown a certain benefit of low-frequency ultrasound (intensity =0.5 W/cm2; frequency =100 kHz) in the treatment of recalcitrant wounds. It has been found to stimulate debridement, angiogenesis and fibroblast proliferation and was found to have a bactericidal effect. The applications differs considerably between studies. Peschen et al. [10] applied 30 kHz continuous ultrasound at a density of 0.1 W/cm2 three times a week in a footbath, whereas Callam et al. [11] reported a tuning of 1 kHz at 0.5 W/cm2 once a week. Lundeberg et al. [12], however, failed to detect any benefit under the same conditions.

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Electrostimulation of chronic leg ulcers with direct current has been reported to be safe and effective in a small, uncontrolled clinical trial [13]. These authors stated also an improvement of microcirculation in and around the ulcer under the treatment. This observation should be confirmed by larger controlled trials. Low-level lasers (soft lasers), water-filtered infrared radiation and ultraviolet radiation are frequently used especially in paramedical settings to enhance healing of otherwise recalcitrant wounds. However, scientific assessment of these methods is still lacking as of yet [14]. Both sugar and honey have been used in popular medicine to treat chronic wounds. The rationale is their potent antibacterial effect due to high osmolarity [15]. To the best of our knowlegde, the effect of sugar on healing of chronic wounds has not been investigated by a controlled trial as of today. The use of honey as local wound care was already popular in ancient Egypt and meets modern ecological trends. However, topical use of honey should be discouraged for allergological reasons, since it contains sensitizers, as propolys.

Supplementation with Zinc and Vitamins Ensuring an adequate diet is a sine qua non for any healing process. For a number of years, special attention was given to zinc supplementation in leg ulcer patients. Zinc is essential in the function of several enzymes and it seems to be involved in early stages of wound healing [16]. In 1970, Greaves and Skillen [17] reported complete healing of 13/18 recalcitrant leg ulcers after a 4-month course of 220 mg zinc sulfate 3 times/day. However, these results could not be confirmed in later controlled trials, among others by the same authors [18–20]. Schraibman and Stratton [21] have compared the nutritional status of venous ulcer patients with that of age- and sex-matched controls. Of 11 indices thought to represent nutritional deficiency, only hemoglobin was significantly lower in patients with venous ulcers. Therefore, zinc and vitamin supplements to the diet are unlikely to be of much benefit to the majority of leg ulcer patients, except those with severe nutritional problems.

References 1 2 3

Fleischmann W, Lang E, Russ M: Infektbehandlung durch Vakuum-Versiegelung. Unfallchirurgie 1997;100:301–304. Mu¨ller G: Der Vakuumverband in der septischen Wundbehandlung. Langenbecks Arch Chir 1997(suppl II):537–541. Stu¨cker M, Herde M, Hoffmann K, Altmeyer P: Die Therapie chronischer Ulcera mittels Vakuumversiegelungstechnik. Phlebologie 1998;27:206–209.

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4 5 6 7 8 9 10 11 12 13

14 15 16 17 18 19 20 21

Dommann S, Serbes B, Dommann-Scherrer C, Ku¨ng EE: Wundreinigung von Ulcera cruris mit Hilfe des CO2-Lasers. Akt Dermatol 1995;21:232–236. Rausis C, El Assaooui A, Bianco S: Hydrodynamique ultra-pressuriseé en chirurgie. Helv Chir Acta 1990;57:951–955. Sherman RA, My-Tien Tran J, Sullivan R: Maggot therapy for venous stasis ulcers. Arch Dermatol 1996;132:246–254. Heng MCY, Pilgrim JP, Beck FWJ: A simplified hyperbaric oxygen technique for leg ulcers. Arch Dermatol 1984;120:640–645. Beer A, Fritz T, de Pay A: Die hyperbare Oxygenation in der Behandlung von chronischen Wunden. Akt Dermatol 1996;22:226–229. Lefebvre F, Dossa J, Serre L, Joyeux R, du Cailar J: Re´sultats the´rapeutiques de l’oxyge`ne hyperbare dans les ulce`res variqueux. Semaine Hoˆp Paris 1970;46:127–129. Peschen M, Weichental M, Scho¨pf E, Vanscheidt W: Low-frequency ultrasound treatment of chronic venous leg ulcers in an outpatient therapy. Acta Dermatol Venereol 1997;77:311–314. Callam MJ, Harper DR, Dale JJ, Ruckley CV, Prescott RJ: A controlled trial of weekly ultrasound therapy in chronic leg ulceration. Lancet 1987;ii:204–206. Lundeberg T, Nordstrom F, Broda-Jansen G, Erikson SV: Pulsed ultrasound does not improve healing of venous ulcers. Scand J Rehabil Med 1990;22:195–197. Ju¨nger M, Zuder D, Steins A, Hahn M, Klyscz T: Behandlung von veno¨sen Ulzera mit niedrigfrequentem gepulstem Strom (Dermapulse): Effekte auf die kutane Mikrozirkulation. Hautarzt 1997; 48:897–903. Pierschalla P, Anders A, Tronnier H: Klinische Untersuchung zum Einfluss von Laserlicht niedgriger Leistungsdichte auf die Wundheilung beim Ulcus cruris. Aktuel Dermatol 1986;12:174–176. Greenwood D: Honey for superficial wounds and ulcers. Lancet 1993;341:90–91. Dreno B, Vandermeeren MA, Rigou V: Le zinc et la peau. Ann Dermatol Veńe´reól 1988;115: 741–746. Greaves MW, Skillen AW: Effects of long-continued ingestion of zinc sulfate in patients with venous leg ulceration. Lancet 1970;ii:889–891. Greaves MW, Ive FA: Double-blind trial of zinc-sulfate in the treatment of chronic venous leg ulceration. Br J Dermatol 1972;87:632–634. Myers MB, Cherry G: Zinc and the healing of chronic leg ulcers. Am J Surg 1970;120:77–81. Phillips A, Davidson M, Greaves MW: Venous leg ulceration: Evaluation of zinc treatment, serum zinc and rate of healing. Clin Exp Dermatol 1977;2:395–399. Schraibman IG, Stratton FJ: Nutritional status of patients with leg ulcers. J R Soc Med 1985;78: 39–42.


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Chronic Leg Ulcers and Eczema Daniel Perrenoud a, Albert-Adrien Ramelet b a

b

Department of Dermatology, University Hospitals (DHURDV) Lausanne and Geneva; Specialist in Dermatology and Angiology, Lausanne, Switzerland

Introduction Chronic leg ulcer patients are a high-risk population for contact sensitization. We know that about two-thirds of all patients in this group are sensitized – i.e. allergic. Therefore, the prudent course of action is to start by finding what culprit(s) might be present, i.e. to consider every single leg ulcer patient as potentially sensitized. The number of implicated substances tends to increase with duration of the disease [1]. The typical substances can be categorized into four groups: lanolins and derivatives, Peru balsam and/or colophony and/or fragrances, neomycin and related antibiotics, and finally preservatives. These can be identified by using standardized patch tests. Although these tests are simple to administer, they require special expertise for their interpretation. One note of caution: Patients who do not have dermatitis can and do have contact sensitization. In a 1996 study, as many as 30% of patients suffering from leg ulcers were shown to be sensitized in spite of having neither periulcerous dermatitis nor vesicular eczema [2]. More recently, it has been shown that 50% of leg ulcer patients without a past or present history of eczema also had sensitization [3, 4]. As stated above, at least two-thirds of leg ulcer patients are sensitized, but what about the other third? Here we must remember the adage ‘do no harm’; in other words, avoid using anything that can induce contact sensitization. Fortunately, modern wound management is based on two simple principles regarding dressings: (1) control of the wound environment, and (2) the use of a small number of simple ingredients which are for the most part nonallergenic.

Sensitization, Allergic Contact Dermatitis and Stasis Eczema Allergic contact sensitization is not an ‘inborn’ condition but an active process. The risk of becoming sensitized to a topically applied substance depends on: (a) the intrinsic allergenic properties of the applied substance itself; (b) the duration of use (expressed in years), and (c) the skin condition where the substance is applied, in particular in terms of permeability and inflammation (increased risk when both permeability and inflammation are increased). Therefore, the daily application of pharmaceutical preparations over a number of years on a chronic leg ulcer and/or its surroundings is the perfect way to induce contact sensitization. One should remember that allergic contact is a two-step event: (1) The sensitization phase, which is clinically inapparent and highly specific. It represents a lifelong reaction characterized by the production of clonal memory T cells against a specific substance. (2) Elicitation, which occurs when a substance which a person is sensitized to is applied on the skin. The hallmark of the elicitation phase of allergic contact dermatitis is acute eczema, i.e. vesicular, frequently oozing, erythematous and pruritic condition on the site of application of the allergen. Leukocyte trapping as seen in stasis eczema may increase the risk of sensitization [5]. As stasis eczema/leg ulcers evolves over a number of years, the number of substances a patient becomes sensitized to tends to increase [1, 2, 6]. However, as long as these substances are not used, sensitization remains asymptomatic. Remember, if you use a substance you are sensitized to, you will suffer acute contact dermatitis, even many years after you have been sensitized. Chronic leg ulcer patients are usually over 60 and therefore: (a) can be sensitized to many different substances (the first many years ago and at present); (b) have been treated by many persons both medical and otherwise, and (c) liable to forget earlier episodes of contact dermatitis. Healthcare people should consider every single chronic leg ulcer patient as potentially sensitized. Allergic contact dermatitis can exhibit various morphologies: it can be mainly erythematomacular, vesicular, bullous, edematous, purpuric, hyperkeratotic, etc. Due to the usual skin alterations accompanying chronic venous leg insufficiency, the clinical signs of allergic contact dermatitis are not very specific. It can be very difficult or even impossible to distinguish morphologically allergic contact dermatitis from the skin manifestations of venous leg insufficiency. Stasis dermatitis is an expression of the capillary inflammation which follows chronic venous hypertension and of its trophic consequences to the adjacent skin. Its peculiar pattern – like ‘sprinkled cinnamon’ – is due to the leakage of red blood cells into the dermis. When stasis dermatitis shows eczematous signs and tends to spread to the rest of the body, it is supposed that

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Table 1. Allergens with a specific association to the presence of chronic leg ulcers in a population of 2,185 consecutive patients patch tested from January 1995 to December 1997 in Western Switzerland (DHURDV): the median age in the leg ulcer patients group is 78 years, and 48 years in the control group Allergens

Amerchol L101 Fragrance mix Lanolins Peru balsam Neomycin Stearyl alcohol Colophony Benzalkonium chloride Cetostearyl alcohol Chloracetamide

Leg ulcer patients

Patients without leg ulcer

tested, n

positive, %

tested, n

positive, %

126 140 149 146 153 55 150 147 148 152

34 31 30 25 18 14 13 11 11 5

413 1,708 1,778 1,743 1,791 243 1,806 1,528 943 1,588

7 18 5 8 4 1 3 3 1 1

it might represent an autosensitization phenomenon to autologous proteins produced on the site of the venous insufficiency [5]. Stasis dermatitis and allergic contact dermatitis are sometimes morphologically identical and are often associated; therefore, always consider the possibility of allergic contact dermatitis when diagnosing stasis dermatitis. The average frequency of sensitized patients over the last 30 years in published studies on stasis dermatitis/chronic leg ulcer patients in Europe has remained unchanged over the years around 66% [1–3, 8–10].

Principal Allergens Allergen exposure varies over space and time with local customs and habits. The most frequently implicated allergens, however, are quite steady over the past 20 years in Europe in chronic leg ulcer patients [1, 2, 6–10]. Unfortunately, control groups frequently do not exist in the published literature so it is difficult to know precisely which of the allergens are specifically associated with chronic leg ulcers. We have recently analyzed the data of 2,185 consecutive patients, including 167 suffering from chronic leg ulcers, who were patch tested at the University Dermatology Clinics of Lausanne and Geneva (DHURDV) between January 1, 1995 and December 31, 1997. The main results are shown in table 1.

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Table 2. The four top allergen groups in chronic venous leg ulcers in order of frequency (Western Switzerland, January 1995 – December 1997) 1

2

3

4

Lanolins and derivatives (adeps lanae, wool alcohols, cetostearyl alcohol, stearyl alcohols, Amerchol L01) Widely used in pharmaceuticals and cosmetics as base substances (excipients) and as emulsifiers Peru balsam – colophony – fragrances Plant origin Were present in many wound healing products Often cross-react with fragrances, which are present in most skin care products, not only in perfumes and toilet waters Neomycin and related antibiotics (gentamycin, kanamycin, framycetin, tobramycin, and bacitracin) Usually not found in wound dressings, but are still largely present in otorhino-, ophthalmo-, gyneco- and proctological preparations All neomycin-sensitized patients should be informed about the possibility of crossreaction Preservatives Benzalkonium chloride and chloracetamide

If the allergens are grouped according to their cross-reactivity and to their similarity, the list of the main allergens associated with chronic leg ulcers can be summarized in four groups (table 2). Allergies to compression bandages are very rare, but may include reactions to adhesive substances, to additives in zinc paste bandages and to rubber additives in the elastic [11].

Patch Testing, Prevention and Treatment Patch testing should be routinely administered to each patient who is suffering from chronic leg ulcer. We must not hesitate to repeat this examination as often as necessary over the years. Correct interpretation of patch tests requires special training. It is important to give the patient written information on the results of the tests – and not only the patient, but also all healthcare workers who might be treating him/her. Modern wound dressing materials – such as hydrogels, hydrofibers, hydrocolloids and polyurethane foams – have a remarkably low allergenicity, although few cases have been reported [12]. For the treatment of surrounding skin, we recommend very simple nonperfumed ointment – since they contain far fewer ingredients than creams.

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The cornerstone of contact dermatitis treatment is identification and avoidance of the causative allergens. It goes without saying that if inflammation and edema are severe, bed rest and bandages are a necessary aspect of the treatment regimen.

References 1

2 3 4 5 6 7

8 9

10 11 12

Paramsothy Y, Collins M, Smith AG: Contact dermatitis in patients with leg ulcers. The prevalence of late positive reactions and evidence against systemic ampliative allergy. Contact Dermatitis 1988; 18:30–36. Emmenegger V: Sensibilisations de contact chez 61 patients souffrant d’ulce`res chroniques des membres infe´rieurs; thesis, Lausanne, 1996. Le Coz CJ, Scrivener Y, Santinelli F, Heid E: Contact sensitization in leg ulcers. Ann Dermatol Veńe´reól 1998;125:694–699. Zortea-Calflisch C, Hanser-Conza M: Kontaktallergie bei chronisch-veno¨ser Insuffizienz. Ther Umsch 1984;41:863–868. Coleridge Smith PD: Microcirculation in Venous Disease, ed 2. Austin, Landes Bioscience, 1998. Hogan DJ, Hill M, Lane PR: Results of routine patch testing of 542 patients in Saskatoon, Canada. Contact Dermatitis 1988;19:120–124. Storrs FJ, Rosenthal LE, Adams RM, Clendenning W, Emmett EA, Fisher AA, Larsen WG, Maibach HI, Rietschel RL, Schorr WF, et al: Prevalence and relevance of allergic reactions in patients patch tested in North America – 1984 to 1985. J Am Acad Dermatol 1989;20:1038–1045. Enders F, Przybilla B, Ring J, Gollhausen R: Patch test results in 1987 compared to trends from the period 1977–1983. Contact Dermatitis 1989;20:230–232. Schnuch A, Geier J, Uter W, Frosch PJ, Lehmacher W, Aberer W, Agathos M, Arnold R, Fuchs T, Laubstein B, Lischka G, Pietrzyk PM, Rakoski J, Richter G, Rueff F: National rates and regional differences in sensitization to allergens of the standard series. Population-adjusted frequencies of sensitization (PAFS) in 40,000 patients from a multicenter study (IVDK). Contact Dermatitis 1997; 37:200–209. Bangha E, Elsner P: Sensitizations to allergens of the European standard series at the Department of Dermatology in Zu¨rich 1990–1994. Dermatology 1996;193:17–21. Perrenoud D: Allergies to compression bandages; in Gardon-Mollard C, Ramelet A-A (eds): La contention me´dicale. Paris, Masson, 1999. Sasseville D, Tennstedt D, Lachapelle JM: Allergic contact dermatitis from hydrocolloid dressings. Am J Contact Dermatitis 1997;8:236–238.

Dr. Daniel Perrenoud, Department of Dermatology, Universital Hospital (DHURDV), CH–1011 Lausanne (Switzerland). E-Mail [email protected]

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Complications in the Treatment of Leg Ulcers Ingomar Kiehlmann, Walter Lechner Allergologic and Dermatologic Clinic, Norderney, Germany

Careful and thorough vascular and dermatological examination can reduce the number of complications that may occur in the treatment of leg ulcers. Especially arterial insufficiency, infection and malignant disease should not be overlooked. Sclerotherapy requires foremost proper training and special care during the actual injection.

Every Leg Ulcer Patient Has to Undergo Arterial Examination Peripheral arterial occlusive disease (PAOD) is a commonly underestimated cause of leg ulcers [1]. Roughly 10% of leg ulcers have a combined venous and arterial background. Clinically, these legs show the signs of chronic venous insufficiency. However, PAOD compromises the potential of wound healing. Another 10% of leg ulcers are purely arterial in origin [2]. An anklearm index =0.8 is indicative of a clinically relevant arterial stenosis. Spontaneous wound healing is impaired below a systolic ankle pressure of 80 mm Hg and chronic critical leg ischemia starts at 50 mm Hg [3, 4]. Compression therapy for mixed venous and arterial leg ulcers should be reduced when systolic ankle pressure is =90 mm Hg [3]. Otherwise, iatrogenic damage, such as friction blisters and pressure sores, may occur at the most exposed points, i.e. at the heel and Achilles tendon as well as at the dorsum of the foot. Diabetics require specially careful control for pressure points underneath their compression bandages, because sensory neuropathy may mask the pain that usually would alert the patient. Callam et al. [5] sent a questionnaire to all 154 consultants in general surgery in Scotland. Forty-nine (32%) reported at least one case of necrosis that was specifically induced by compression bandages, elastic stockings or antithromboembolism stockings over an observation period of 5 years.

Arterial leg ulcers generally will not improve with compression therapy, except under certain circumstances, such as postischemic edema. Edema after revascularization procedures may be treated with an Unna paste boot using nonelastic zinc bandages. This type of compression exerts a very low pressure at rest, whereas it becomes highly effective when the patient starts to walk. Unna’s paste boot can be regarded a safe and established treatment for edema in the presence of PAOD [6; cf. the chapter of Partsch, above in this book].

Necrotizing Fasciitis Necrotizing fasciitis is a rapidly spreading, life-threatening soft-tissue infection with subsequent necrosis of the muscle fascia and subcutaneous fat. Signs of necrotizing fasciitis versus cellulitis are: (1) rapidly spreading swelling and inflammation; (2) severe pain that sometimes is followed by anesthesia; (3) blisters and later skin necrosis; (4) streptococcal toxic shock syndrome, and (5) elevated creatine kinase level [7, 8]. Rapid recognition, immediate antimicrobial therapy and aggressive surgical management are crucial to reduce mortality [9]. Two types of patients are commonly distinguished: type I have polymicrobial mixed aerobic and anaerobic infection. Streptococcus pyogenes is the predominant pathogen in type II. Empiric antimicrobial therapy should start with a combination of a b-lactam with a b-lactam inhibitor (e.g. piperacillin-tazobactam of ticarcillin-clavulanate) plus clindamycin [7]. Clindamycin suppresses bacterial toxin synthesis and is effective against anaerobic pathogens.

Venous Leg Ulcers and Malignancy Malignant leg ulcers may occur in three clinical settings: (1) de novo malignancy with ulceration that may mimic a venous ulcer [10–12]; (2) secondary squamous cell carcinoma [13] or basal cell carcinoma arising from a chronic venous ulcer [14] or (3) secondary squamous cell carcinoma arising from a burn scar [15] or from chronic osteomyelitis [16] (Marjolin’s ulcer). Leg ulcers that fail to show any healing under appropriate conservative treatment within 3 months should be biopsied [12]. In a Swedish leg ulcer clinic the prevalence of de novo malignant skin lesions (ulcerating tumors as well as independent malignancies next to vascular ulcers) has been reported to be 3% (20/705). Seventeen of these patients had basal and/ or squamous cell carcinoma and in half of the cases the lesions were ulcerated. Prior to biopsy, some of these lesions had been mistaken for venous ulcers. Several authors emphasized that ulcerating skin tumors of the lower limbs may look

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inocuous and easily be misdiagnosed as venous ulcers [11, 12]. The tumors may have the appearance of healthy granulation tissue, sometimes of a specially translucent aspect and protrude over the margins of the ulcer [11]. Secondary squamous cell carcinoma that arises from venous ulcers has been reported to occur at a cumulative lifetime risk of 0.21% (17/10,913 patients, population-based cohort study) [13]. The median duration of a venous leg ulcer to the occurrence and diagnosis of cancer was 25 years. The clinical appearance of cancer formation is usually that of exophytic growth at the margin of the ulcer or an irregularity in the ulcer base. The incidence of basal cell carcinoma arising in venous ulcers is currently not defined, but it is estimated to be equal to that of squamous cell carcinoma [10, 14]. Basal cell carcinomas found in chronic venous ulcers tend to be multifocal and of the sclerosing type. The patients may be managed by excision and skin grafting [14]. Ulcerating neoplasm in scar tissue has been defined as Marjolin’s ulcer. Burn scars [16] or chronic osteomyelitis [15] are typical conditions in which Marjolin’s ulcers may occur, however, malignancy has been reported in chronic scars of diverse origin, such as lupus vulgaris or sinus tracts of various etiology. Complete evaluation for metastatic disease and Mohs’ micrographic surgery or amputation, if indicated, are required to control the disease [16].

Severe Complications of Sclerotherapy Sclerotherapy of feeder veins is still largely used in the management of venous ulcers. Intra-arterial injection is the most deleterious complication of sclerotherapy. Oesch et al. [17] reported on 4 cases where intra-arterial injection into the posterior tibial artery precipitated severe foot ischemia, which led to major amputation in one instance. All of these cases occurred during sclerotherapy of feeding veins in leg ulcer patients. Natali and Farman [18] reviewed the files of the French medical liability insurance from 1972 to 1992 and identified 40 cases of intra-arterial injection that had medico-legal implications. This is a relatively small number, bearing in mind that sclerotherapy is very common in France. Some precautions help to obviate this feared complication. Sigg inserted a bare large needle into the vein while the patient was standing. Then the patient laid back into a recumbent position for the actual injection. With this technique intra-arterial injection becomes practically impossible [17]. Other authors suggested to inject the sclerosant in small volumes of 0.1–0.2 ml. During accidental intra-arterial injection the patient experiences an immediate excrutiating pain in his foot. Since the damage seems to depend on the amount of sclerosant, fractionated injection might limit the sequelae of accidental intra-arterial injection [18].

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Most complications in the treatment of leg ulcers can be avoided, as long as a standardized vascular screening procedure is followed. Signs and symptoms of infection and malignancy should always be controlled for. Sclerotherapy of feeder veins carries the risk of intra-arterial injection. Therefore it requires appropriate training and standard precautions during injection that help avoid severe complications.

References 1 2 3 4 5 6 7 8 9

10 11 12 13 14 15 16 17 18

Callam MJ, Harper DR, Dale JJ, Ruckley CV: Arterial disease in chronic leg ulceration: An underestimated hazard? Lothian and Forth Valley Leg Ulcer Study. Br Med J 1987;294:929–931. Baker SR, Stacey MC, Singh G, Hoskin SE, Thompson PJ: Aetiology of chronic leg ulcers. Eur J Vasc Surg 1992;6:245–251. Wu¨tschert R, Bounameaux H: Predicting healing of arterial leg ulcers by means of segmental systolic pressure measurements. Vasa 1998;27:224–228. Hafner J: Management des arteriellen Ulcus cruris. Z Hautkr 1998;73:430. Callam MJ, Ruckley CV, Dale JJ, Harper DR: Hazards of compression treatment of the leg: An estimate from Scottish surgeons. Br Med J 1987;295:1382. Partsch H: Compression therapy of the legs. J Dermatol Surg Oncol 1991;17:799–805. File TM, Tan JS, Dipersio JR: Diagnosing and treating the ‘flesh-eating bacteria syndrome’. Cleve Clin J Med 1998;65:241–249. Chelsom J, Halstensen A, Haga T, Høiby EA: Necrotising fasciitis due to group A streptococci in western Norway: Incidence and clinical features. Lancet 1994;344:1111–1115. Bilton BD, Zibari GB, McMillan RW, Aultman DF, Dunn G, McDonald JC: Aggressive surgical management of necrotizing fasciitis serves to decrease mortality: A retrospective study. Am Surg 1998;64:397–400. Hansson C, Andersson E: Malignant skin lesions on the legs and feet at a dermatological leg ulcer clinic during five years. Acta Dermatol Venereol (Stockh) 1997;78:147–148. Harris B, Eaglstein WH, Falanga V: Basal cell carcinoma arising in venous ulcers and mimicking granulation tissue. J Dermatol Surg Oncol 1993;19:150–152. Phillips TJ, Salman SM, Rogers GS: Nonhealing leg ulcers: A manifestation of basal cell carcinoma. J Am Acad Dermatol 1991;25:47–49. Baldursson B, Sigurgeirsson B, Lindelo¨f B: Venous leg ulcers and squamous cell carcinoma: A largescale epidemiological study. Br J Dermatol 1995;133:571–574. Gosain A, Sanger JR, Yousif NJ, Matloub HS: Basal cell carcinoma of the lower leg occurring in association with chronic venous stasis. Ann Plast Surg 1991;26:279–283. Fishman JRA, Parker MG: Malignancy and chronic wounds: Marjolin’s ulcer. J Burn Care Rehabil 1991;12:218–223. Kirsner RS, Garland LD: Squamous cell carcinoma arising from chronic osteomyelitis treated by Mohs’ micrographic surgery. J Dermatol Surg Oncol 1994;20:141–143. Oesch A, Stirnemann P, Mahler F: Das akute Ischa¨miesyndrom des Fusses nach Varizenvero¨dung. Schweiz Med Wochenschr 1984;114:1155–1158. Natali J, Farman T: Implications me´dico-le´gales au cours du traitement scle´rosant des varices. J Mal Vasc (Paris) 1996;21:227–232.

Prof. Dr. Walter Lechner, Allergologic and Dermatologic Clinic, Lippestrasse 9–11, D–26548 Norderney (Germany) Tel. +49 4932 8050, Fax +49 4932 805200

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Surgical Management of Varicose Veins in Advanced Chronic Venous Insufficiency Paolo C. Cassina a, Urs Brunner a, Wolfgang Kessler b a b

Department of Surgery, Division of Vascular Surgery, University Hospital, Zu¨rich Division of Surgery, Spital Altsta¨tten, Switzerland

Historical Notes The value of surgery of superficial veins in the management of chronic venous insufficiency remains controversial ever since the days when Hippocrates observed a correlation between varicose veins and leg ulceration. Venous ulceration and chronic venous insufficiency is thought to be caused exclusively by a dysfunction of the deep venous system. Some authors even postulated that obstruction of the deep venous system was the critical factor, while valve incompetence played a minor role [1]. An editorial in the Lancet [2] stated that primary varicose veins never give rise to venous ulcers, and the patient presenting with a swollen foot, browny edema, lipodermatosclerosis and ulceration was described as having a ‘postphlebitic leg’. Dodd and Cockett [3] first demonstrated an association between venous ulcers and incompetent perforating veins at the calf, thus lending credence to the 2,000-year old observations of Hippocrates. Initially ligation of incompetent calf and ankle perforating veins in the treatment of venous ulceration was reported to generate good results in carefully conducted studies [4, 5]. But a series of disappointing results in patients with postthrombotic deep vein incompetence [6] led to a change of mind with avoidance of all surgery in these patients. Postthrombotic ulcers were described as being ‘resistant to all present forms of treatment’ [7]. This concept resulted in surgical indifference regarding chronic venous insufficiency.

Patient Selection The development and application of modern vascular laboratory techniques like duplex ultrasound scanning improved the assessment of reflux in the deep and superficial system as well as the examination of perforator veins. The findings achieved with the B-mode real-time ultrasound combined with pulsed Doppler ultrasonography correlate well with ascending and descending venography. In contrast to venography, however, duplex scanning allows the repeated assessment of single veins under physiological conditions. As with venography, the quantification of reflux is difficult and the information remains limited to a qualitative detection of reflux in the deep and superficial system. This information, however, is crucial to identifying patients who will ultimately benefit from an intervention on the superficial veins. In the last 10 years several studies were published where patients with chronic venous ulcers were assessed prospectively with regard to incompetence of the venous system by duplex scanning, venography or both [8–12]. An isolated incompetence of the deep venous system was present in 8–54% of the patients, in 15–80% of them the incompetence was described to be combined deep and superficial and, surprisingly, isolated superficial venous incompetence was present in up to 53% of examined cases [13]. In 1997, we evaluated 79 consecutive patients with leg ulcers, among whom half of the patients (n>38) had a purely venous ulcer. Half of these patients (47%, n>18) showed a postthrombotic deep venous reflux, in 32% of the cases (n>12) there was a combined superficial and deep incompetence, and finally eight patients (21%) suffered from an isolated superficial venous reflux while the deep system was competent. On the basis of these reports and our observations, we could affirm that superficial venous reflux may be a major single cause of chronic venous insufficiency (fig. 1). For patients with isolated incompetence of the great or lesser saphenous vein and a normal deep venous system, saphenectomy should prove sufficient and effective in healing the venous ulcer. In a series of 69 patients with 96 leg ulcers, Negus and Friedgood [14] reported complete healing after stripping of the incompetent saphenous vein and subfascial ligation of incompetent perforator veins in 92% of the cases without recurrence after 3 years of follow-up.

The Overload Theory The next question addresses the management of patients with a combined superficial and deep venous incompetence. There is skepticism among surgeons about the indication to remove superficial veins in patients with deep venous

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Fig. 1. Etiopathology of chronic venous insufficiency.

insufficiency and a history of deep venous thrombosis. Many surgeons believe that the main hemodynamic problem in chronic venous insufficiency is related to the deep venous system, suggesting that this one should be corrected first. Moreover, removal of the superficial veins could worsen the venous outflow obstruction and consequently impair venous insufficiency. There are two good reasons why these two theories are incorrect. First, in only 5–10% of patients is chronic deep venous insufficiency caused by venous outflow obstruction, whereas valvular incompetence represents the main cause (90–95% of patients) [15]. Second, incompetent varicose veins are useless in reducing outflow obstruction of the deep veins. Flow in the incompetent superficial veins is directed distally leading to an overload of the deep system. For this reason, patients with combined insufficiency should undergo surgery of the superficial veins and as required combined with ligation of the calf perforators. In a recent study, Padberg et al. [16] could demonstrate in 10 patients with primary combined deep and superficial venous insufficiency and venous ulceration that superficial vein ablation reduced deep venous reflux significantly and improved calf pump function. Walsh et al. [17] reported that preoperative femoral reflux was abolished by greater saphenous stripping in 27 of 29 limbs. In patients with popliteal reflux, both femoral and popliteal reflux were abolished. Van Bemmelen and Bergan [17, 18] suggested the ‘overload theory’ to explain this

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Fig. 2. Venous surgery in advanced chronic venous insufficiency.

phenomenon. They hypothesize that superficial incompetence produces an overload of venous return through perforating veins which elongate and kink femoral and popliteal veins as well as the femoropopliteal junction leading to incompetence of the deep venous valvular apparatus. Almost 10 years earlier, Hach and coworkers [19, 20] postulated the recirculation theory by means of venography. They observed that the mean popliteal diameter in limbs with superficial vein incompetence was 17 mm compared to 12 mm in control limbs.

Lesser Saphenous Vein: An Underestimated Etiology Special attention should be given to ulcers affecting the lateral side of the ankle. The role of the short saphenous system reflux in causing chronic venous insufficiency and ulceration is still underestimated. Recent publications demonstrated that venous incompetence of the lesser saphenous vein may cause venous insufficiency at the lateral aspect of the ankle and foot similar to that seen with the greater saphenous vein on the medial aspect [21]. Therefore, if a patient presents with an isolated lateral ulcer of the ankle, he should be assessed at least by continuous-wave Doppler for a reflux of the saphenopopliteal junction. Recently our attention was directed to the possible causes for the high rate of recurrent varicosis after removal of the lesser saphenous vein despite


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3a

3c Fig. 3. a Chronic venous ulcer affecting the right medial ankle. b Preoperative anterograde venography discloses an incompetent great saphenous vein. The deep venous system does not present abnormalities, i.e. normal valves and no postthrombotic signs. c Two months after surgical intervention the leg ulcer is closed.

established surgical therapy. In a previously reported series on 160 incompetent lesser saphenous veins, we observed small- to medium-size recurrences in about 10% of cases [22]. In a prospective study including 94 consecutive patients and 98 legs with varicosis of the lesser saphenous vein, we preoperatively examined patients by means of venography and duplex sonography which allows direct assessment of valvular morphology [23]. Seventy percent of cases were found to be associated with deep venous incompetence, usually due to primary valvular dysplasia. We postulate that the saphenopopliteal junction is subjected to considerable venous stasis and increased pressure leading to incompetency of the junction and to variceal degeneration of the lesser saphenous vein. In this case the associated deep venous insufficiency rather than


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3b

the short saphenous varicoses explains why signs of chronic venous insufficiency are usually found in these patients. The causal therapy should therefore rather address valvular reconstruction of the deep femoropopliteal axis, but this type of surgery is still experimental. The ligation of the lesser saphenous vein has to be performed ‘a` niveau’ with the popliteal vein and the stump must be shortened to a few millimeters. Nevertheless, recurrent varices can already be demonstrated a few months postoperatively and therefore patients with deep valvular dysplasia should be thoroughly informed about the risk of relapse before they undergo surgery.

Conclusions The development of the modern vascular laboratory has allowed precise assessment of the distribution of the venous reflux between the deep and the superficial venous system. This represents a significant aid to the surgeon in deciding which patients with chronic venous leg ulcer could benefit from surgery of superficial veins (fig. 2). Patients with an isolated superficial reflux will show good results after surgery and ulcer relapse will be low. If the


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superficial reflux is combined with incompetence of one or more calf perforators, these should be ligated during the same intervention, preferably by videoendoscopy [cf. chapter of Sattler]. A similar surgical approach is indicated for patients with combined superficial and deep venous reflux, although the success rate will be less predictable. These patients should be carefully assessed preoperatively for incompetent perforator veins, usually located under the ulcer. An endoscopical approach is mandatory in such cases and it can be easily combined with a short stripping of the greater saphenous vein below the knee. Ulcers located more distally in the malleolar region cannot be reached through a subfascial endoscopical approach. In this case, ulcer excision combined with a paratibial fasciotomy is a valuable surgical therapy in our hands. Long-term external compression is strongly recommended. The surgical management of patients with isolated deep venous incompetence is still experimental and results are not uniformly encouraging. Functional results after deep venous reconstruction depend upon the origin of venous insufficiency. They are poor in postthrombotic syndrome but more promising in primary deep venous insufficiency. It is unclear why results after valvuloplasty are much better than after valve transposition. The question whether valves should be reconstructed at the popliteal or at the femoral level is unresolved. Moreover, there is controversy whether the reconstruction of one single valve is sufficient. Additional experimental and clinical studies are necessary in the future to define more precisely the role of this demanding surgery.

References 1 2 3 4 5 6 7 8 9 10

Ludbrook J: Disorders of veins; in Sabiston DC Jr (ed): Textbook of Surgery, ed 10. London, Saunders, 1972, p 1617. Editorial: Venous ulcers. Lancet 1977;i:522. Dodd H, Cockett FB: The Pathology and Surgery of the Veins of the Lower Limb, ed 2. London, Churchill Livingstone, 1976, p 248. Bertelsen S, Gammelgaard A: Surgical treatment of postthrombotic leg ulcers. J Cardiovasc Surg 1965;6:452–458. Silver D, Gleysteen J, Rhodes GR, Georginde GR, Anlyan WG: Surgical treatment of the refractory postphlebitic ulcer. Arch Surg 1971;103:554–560. Burnand KG, Lea Thomas M, O’Donnel E, Browse NL: Relation between postphlebitic changes in the deep veins and results of surgical treatment of venous ulcers. Lancet 1976;i:936–938. Browse NL, Burnand KG: The cause of venous ulceration. Lancet 1982;ii:243–245. Darke SG, Penfold C: Venous ulceration and saphenous ligation. Eur J Vasc Surg 1992;6:4–9. Van Bemmelen PS, Bedford G, Beach K, Strandness DE: Status of the valves in the superficial and deep venous system in chronic venous disease. Surgery 1991;109:730–734. Sethia KK, Darke SG: Long saphenous incompetence as a cause of venous ulceration. Br J Surg 1984;71:754–755.


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17 18 19

20 21 22 23

Hoare MC, Nicolaides AN, Miles CR, Shull K, Jury RP, Needham T, Dudley HAF: The role of primary varicose veins in venous ulceration. Surgery 1982;92:450–453. Grabs AJ, Wakely MC, Nyamekye I, Ghavri AS, Poskitt KR: Colour duplex ultrasonography in the rational management of chronic venous leg ulcers. Br J Surg 1996;83:1380–1382. Shami SK, Sarin S, Cheatle TR, Scurr JH, Coleridge Smith PD: Venous ulcers and the superficial venous system. J Vasc Surg 1993;17:487–490. Negus D, Friedgood A: The effective management of venous ulceration. Br J Surg 1983;70:623–627. McEnroe CS, O’Donnel ThF, Mackey W: Correlation of clinical findings with venous hemodynamics in 386 patients with chronic venous insufficiency. Am J Surg 1988;156:148–152. Padberg FT, Pappas PJ, Araki CT, Back TL, Hobson RW: Hemodynamic and clinical improvement after superficial vein ablation in primary combined venous insufficiency with ulceration. J Vasc Surg 1996;24:711–718. Walsh JC, Bergan JJ, Beeman S, Comer TP: Femoral venous reflux abolished by greater saphenous vein stripping. Ann Vasc Surg 1994;8:566–570. Van Bemmelen PS, Bedford G, Beach K, Strandness DE: Quantitative segmental evaluation of venous valvular reflux with duplex ultrasound scanning. J Vasc Surg 1989;10:425–431. Hach W, Schirmers U, Becker L: Vera¨nderungen der tiefen Leitvenen bei einer Stammvarikose der Vena saphena magna; in Mu¨ller-Wiefel H (ed): Mikrozirkulation und Blutrheologie. Baden-Baden, Witzstrock, 1980. Hach-Wunderle V: Die sekunda¨re Popliteal und Femoralveneninsuffizienz. Phlebologie 1992;21: 52–58. Bass A, Chayen D, Weinmann E, Ziss M: Lateral venous ulcer and short saphenous vein insufficiency. J Vasc Surg 1997;25:654–657. Hauser M, Brunner U: Neue pathophysiologische und funktionelle Gesichtspunkte zur Insuffizienz der Vena saphena parva. Vasa 1993;22:338–341. Brunner U, Lachat M, Hauser M: Petite veine saphe`ne et insuffisance veineuse profonde primitive. Phle´bologie 1997(suppl):517–521.

Paolo Cassina, MD, Department of Surgery, Division of Vascular Surgery, University Hospital, CH–8091 Zu¨rich (Switzerland)


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Paratibial Fasciotomy and Crural Fasciectomy Christine Schwahn-Schreiber Gefa¨sschirurgische Klinik, Otterndorf, Germany

Introduction Advanced chronic venous stasis syndrome (CVSS) is characterized by irreversible and self-perpetuating morphological alterations in the lower leg. A chronic inflammatory process results in sclerosis which, according to Leu [1] and Schmeller et al. [2], progresses from the superficial epidermis layers of the skin to the subcutaneous tissue, and ultimately the fascia. Fascia sclerosis is a result of interfibrillar edema followed by fascial necrosis (initially disseminated ultimately extensive) and finally resulting in granulation and scar tissue [3]. This fibrosis results in disturbed microcirculation with reduced oxygen pressure in the affected area [4]. Clinically extensive hard thickening due to granulation tissue and severe fibrosis can be found. In 1994, Hach suggested to classify chronic venous stasis syndrome into four stages according to the degree of sclerosis. Stage I is defined as lack of sclerosis. In stage II sclerosis involves skin and subcutaneous tissue which corresponds to dermatoliposclerosis. If the fascia in circumscribed areas is involved in the sclerotic process, it is referred to as regional dermatolipofasciosclerosis (stage III). In the case of circular crural ulcer, there is circular dermatolipofasciosclerosis, which represents stage IV. If the fascia is involved in the sclerotic process, the disease will evolve independent of the underlying etiology (i.e. postthrombotic syndrome or decompensated recirculation circuit). By electron microscopic studies, Staubesand [5] showed that fascial sclerosis is associated with alterations of the fascial texture. The scissor-like configuration of the fascia is lost and there is a tight disorderly network of abnormal collagenous fibrils, instead. These are no longer able to adapt to the intrafascial variations of pressure.

According to Pflug [6], Langer et al. [7] and to our own studies [8], dermatolipofasciosclerosis leads to increased pressure in the muscular compartments in the upright position resulting in an orthostatic compartment syndrome. Compartment pressure of healthy volunteers in supine position is about 13 mm Hg in the superficial lower leg compartment, and about 15 mm Hg in the deep compartment. In the upright position, pressure increases markedly to average values of 25 mm Hg (superficial) and 29 mm Hg (deep), respectively. In the stages III and IV of CVSS, pressure increases up to 21 mm Hg in the supine patient. Thus, progressive fascial sclerosis is associated with a permanent increase of pressure on the muscles. In the standing patient, the compartment pressure increases from 29 mm Hg to an average of 62 mm Hg, i.e. by more than 100% in stages III–IV. The difference in pressure between stage III and IV is not relevant. High subfascial pressure leads to chronic damage of the muscles which consecutively undergo fatty degeneration and partial sclerosis. This impairs the muscular pump function and worsens chronic ambulatory venous hypertension. If the ankle joint is involved in the sclerotic process, arthrogenous stasis syndrome results as a severe complication. The morphological alterations in muscles, tendons and fascia can be demonstrated by magnetic resonance imaging. Thus, decompression of the compartments by incision or resection of the fascia should prove to be beneficial for chronic venous stasis syndrome. By this procedure, the pathological pressure in the deep lower leg compartment will return close to normal values (fig. 1).

Paratibial Fasciotomy Indication Paratibial fasciotomy is indicated in cases of regional dermatolipofasciosclerosis at the medial malleolus. The diagnosis is based on increased compartment pressure or clinical findings of fascial sclerosis as skin and subcutaneos tissue cannot be moved across fascia and are fixed to each other. Prior to surgery, presence of arterial occlusive disease and coagulation disorder should be ruled out. Acute bacterial inflammation within the operating area has to be controlled adequately. However, complete healing of an ulcer is not required. The ulcer should be cleansed thoroughly. Afterwards, the operation should be performed under single-shot antibiotic prophylaxis [9]. Surgical Technique The therapeutic principle of paratibial fasciotomy comprises two parts: fasciotomy and dissection of the insufficient perforating veins to improve the

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60 50

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40 30 20 10 0

LP

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Preoperatively (n = 10) (LP 19.6; SP 52.5)

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Fig. 1. Compartment pressure in the deep dorsal compartment in lying position (LP) and standing position (SP) in patients with CVSS stage III pre- and postoperatively.

macrocirculation. The main advantage of the method compared to other procedures, is skin incision proximal to the area of dermatolipofasciosclerosis, thereby reducing problems of wound healing. Two methods are available: conventional paratibial fasciotomy and the endoscopic procedure. With both methods, skin incision and fascial incision are made in a medial-paratibial direction in a distance of 2–3 cm at the proximal lower leg. Endoscopic dissection of the insufficient perforating veins is selectively performed subfascially and the fascia is separated by means of endoscopic scissors or a fasciotome. Using the conventional method, the perforating veins are nonselectively disrupted by a spatula which is pushed forward in a proximal-distal direction to the medial malleolus. Then, the fascia is separated by a fasciotome along the ridge of the tibia (fig. 2). Fasciotomy should be performed in a paratibial direction to ensure opening of the deep dorsal compartment and inclusion of the important anterior perforating veins, located below the ridge of the tibia. To achieve wide opening of the fascia and decompression of the compartments, fasciotomy should extend from the proximal part of the lower leg to the medial malleolus. This provides decompression of the posterior tibial nerve and reduces pain [6]. Since Staubesand and Li [10] demonstrated nerves in the fascia, the mechanism of pain relief could be the decompression of the fascia itself. When fasciotomy includes the fibrotic ligaments of the ankle joint, motility of the ankle joint

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Fig. 2. Paratibial fasciotomy: entering with fasciotoma.

can be significantly improved. This helps to interrupt a vicious circle of impaired muscle pumping function which perpetuates ambulatory hypertension and may promote inflammation. Complications Due to the paratibial type of incision, the risk of injury to the tibial nerve and artery is low. Among about 5,000 operations performed in our patients, injury to the tibial artery occurred in 0.1%. Injury to the tibial nerve was reported in 1 patient. Injury to the saphenous nerve in approximately 10% is acceptable when paratibial fasciotomy is performed. Both superficial infections and hematomas occurred in 3–4.5%. One case of necrotic fasciitis has been reported in the literature [11]. The infection rate can be reduced significantly by perioperative single-shot antibiotic prophylaxis with a cephalosporin or gyrase inhibitor [8]. Prolonged postoperative pain was observed in about 11%. Results Since 1983, paratibial fasciotomy was performed in more than 5,000 limbs. As we could show by PaFas study [12], 90% of the ulcers could be cured after 1 year, 100% after 4 years. The venous macrocirculation is only improved if saphenous vein is resected at once, but not by the paratibial procedure itself, as could be observed by phlebodynamometry. Percutaneous oxygen pressure showed an improved microcirculation of the skin marginal to the ulcer.


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Fig. 3. The crural fasciectomy; removal of skin, sclerosis and fascia.

a

b Fig. 4. a, b Recalcitrant venous ulcer pre- and postoperative after crural fasciectomy.

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Crural Fasciectomy Indication Crural fasciectomy is indicated in patients suffering from extensive or circular stasis ulcer with dermatolipofasciosclerosis and chronic fascial compression syndrome. As the fascia is fixed by sclerosis and fails to divaricate by fasciotomy, the compartment pressure cannot be reduced. Surgical Technique By means of crural fasciectomy, all necrotic and sclerotic tissue of the lower leg is removed together with all perforating veins in the affected area. The compartments are abolished and the muscles are decompressed. The muscles provide a sufficient basis for extensive skin grafts. Lo¨fqvist’s rolls are used to achieve bloodlessness. The ulcer is circumcised together with the sclerotic periphery, until healthy tissue is reached (fig. 3, 4). After circular incision the fascia is opened along the entire length of the ulcer. The skin-fascia flap is removed circularly from crural muscles, tibia and fibula. It must be removed from the ligaments of the ankle joint and from tibia and fibula. Care should be taken to avoid injury to the periosteum or the tendon sheath. Necrotic tendons, sometimes even the Achilles tendon, have to be resected. In the presence of a rigid ankle joint, they have no use anyway. The extensive skin lesions are covered with mesh grafts which are applied to muscles, periosteum and tendons. The thigh is usually chosen as donor site. Dressing consists of a greasy gauze and foam material as well as padded compression bandages. Postoperative healing takes 6–15 weeks. In many patients, minor skin lesions require repeated transplantations. In cases of pre- or postoperative lymphedema, intermittent pressure massage is an essential part of the postoperative treatment. Afterwards continued compression therapy seems to be helpful. Complications Rejection of the graft may be caused by wound infection or heavy exudation, sometimes as a result of impaired lymphatic drainage or lymphatic fistulas. Results Between March 1994 and September 1997, crural fasciectomy was performed in 36 limbs. There were 23 postthrombotic ulcers, 4 limbs had isolated arthrogenic stasis syndrome without venous refluxes, 3 showed combined


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Fig. 5. Compartment pressure in the deep dorsal compartment in lying position (LP) and standing position (SP) in patients with CVSS stage IV pre- and postoperatively.

postthrombotic syndrome and epifascial truncular varicosis, and decompensated recirculation could be demonstrated in 6 limbs. Often, there is no correlation between the clinical picture and the status of the deep veins. The high coincidence of coxarthrosis and gonarthrosis in 33% of our limbs indicates that impaired mobility leads to loss of muscular function. This is an important pathogenetic factor for the persistence of ulcers in arthrogenic stasis syndrome. Among 36 limbs, complete healing was achieved in 80% allowing the patients to resume all activities of daily life. Superficial sensitivity often is reduced after operation while deep sensitivity remains. 20% of patients experienced remarkable reduction in ulcer size, some had minor recurrences. Postoperatively, the compartment pressure decreased significantly (66?40 mm Hg). In 8 patients who were followed up for 1–2 years, the pressure remained low. Though venous hemodynamics was poor both before and after surgery, as assessed by phlebodynamometry, all extended ulcerations showed satisfactory healing (fig. 5). Repair of the extrafascial macrocirculation is a prerequisite to all operations on the crural fascia.

References 1 2

Leu HJ: Morphology of chronic venous insufficiency – Light and electron microscopic examinations. Vasa 1991;20:330–342. Schmeller W, Gimelin E, Rosenthal N: Vera¨nderungen des Retromalleolarraumes bei chronisch veno¨sem und arthrogenem Stauungssyndrom. Phlebol Proktol 1989;18:175–181.

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9 10 11 12

Paulini K: Histologische Untersuchungen der Faszie und der subfaszialen Muskulatur beim chronischen Faszienkompressionssyndrom. Vortrag Workshop Neue Operationsmethoden beim chronisch veno¨sen Stauungssyndrom, Frankfurt am Main 1993. Dru¨cke M: Prospektive Untersuchungen der peripheren veno¨sen Ha¨modynamik zur Beurteilung des Effekts der paratibialen Fasziotomie bei Patienten mit chronisch-veno¨sem Stauungssyndrom; Diss, Frankfurt 1995, pp 57–58. Staubesand J, Li Y: Begriff und Substrat der Fasziensklerose bei chronisch-veno¨ser Insuffizienz. Phlebologie 1997;26:72–79. Pflug JJ: Operative Behandlung des supramalleola¨ren medialen Konstriktionssyndroms bei nicht oder schlecht heilenden Ulcera cruris venosa. Phlebologie 1995;24:36–43. Langer C, Fuhrmann J, Grimm H, Vohrpal U: Orthostatische Kompartmentdruckmessung nach endoskopischer Fasziotomie. Phlebologie 1996;24:163–167. Hach W, Schwahn-Schreiber C, Kirschner P, Nestle HW: Die crurale Fasziektomie zur Behandlung des inkurablen Gamaschenulkus (chronisches Faszienkompressionssyndrom). Gefa¨sschirurgie 1997; 2:101–107. Salzmann G, Kirschner P, Hoffmann O, Vanderpuye R: Perioperative Antibiotikaprophylaxe bei der paratibialen Fasziotomie. Phlebologie 1995;24:44–47. Staubesand J, Li Y: Zum Feinbau der Fascia cruris mit besonderer Beru¨cksichtigung epi- und intrafaszialer Nerven. Manuelle Med 1996;34:196–200. Schmeller W, Muhl E, Gatermann S: Nekrotisierende Fasziitis nach paratibialer Fasziotomie, Phlebologie 1992;21:278–282. Vanderpuye R: Die paratibiale Fasziotomie. WMW1994;10/11:262–263.

Christine Schwahn-Schreiber, Gefa¨sschirurgische Klinik, D–21762 Otterndorf (Germany)


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Subfascial Endoscopic Perforator Surgery Gerhard Sattler Klinikum Darmstadt-Hautklinik, Darmstadt, Germany

The importance of incompetent perforators of the lower leg for the development of lipodermatosclerosis and leg ulcers has been discussed for more than half a century. In 1949, Linton [11, 12] described his technique of dissecting incompetent perforators under direct control of the procedure by a long paratibial incision. However, Linton’s operation never became popular due to problems in wound healing associated with trophic skin changes in advanced chronic venous insufficiency [2]. More than 40 years later, Fischer [4] explored the subfascial space with spatulas and small rectoscopes. In 1987, Hauer [9] introduced a set of instruments for subfascial endoscopic perforator surgery (SEPS) and since the early 1990s several kinds of SEPS instruments have been promoted [14]. It is well known that incompetent perforator veins are present in advanced stem vein varicosities. They play an important role in the development of stasis, eczema, hyperpigmentation, lipodermatosclerosis and venous ulcers. These perforators can be removed from a remote incision in normal skin by endoscopic surgery [1–3, 5–10, 13–17].

Instruments Due to lipodermatosclerosis of the lower leg, working conditions in this area may be difficult. Instruments have to be stable, ergometric and must be long enough. All instrument producers offer good quality endoscopes which are robust and most of them are autoclavable. They have a length from 20–30 cm with a diameter of 12 mm, due to the narrow retromalleolar area in the subfascial space. Beside the endoscope itself, the instruments for dissection

usually include a pair of endoscopic scissors, a bipolar clamp and, optionally, specially designed clipping clamps. The videocamera hooked on the endoscope is connected to a camera unit and to a monitor [13].

Indications The main indications for SEPS are [5–7]: (1) multiple incompetent perforators accompanied by stem vein varicosis; (2) multiple incompetent peforators accompanied by a postthrombotic syndrome; (3) multiple incompetent perforators accompanied with lipodermatosclerosis or concurrent venous leg ulcers, and (4) an individual and localized posttraumatic insufficiency.

Methods SEPS can be done in tumescent local anesthesia but it is performed mostly in general anesthesia. A bloodless field will provide best endoscopic vision. The longitudinal skin incision is made on the medial area of the calf about 3–5 cm dorsal of the medial edge of the tibia. The size of the incision varies between 1.5 and 4 cm according to the size of the endoscope. After exposure of the fascia an incision of the fascia is performed and the endoscope is inserted (fig. 1). The subfascial space is mobilized with the endoscope by a pendular motion. The skin is either elevated percutaneously with a strong needle or the subcutaneous space is inflated with carbon dioxide gas to create space for endoscopic inspection. The area reaches longitudinally from the medial malleolus to the proximal part of the medial tibia and horizontally from the fascia cruris at the medial edge of the tibia to the deeper parts of the dorsal calf. Once an incompetent perforator is identified, it is coagulated by bipolar current or clipped using metal or resorbable clips before being dissected by endoscopic scissors. Advanced cases of chronic venous insufficiency show at least one, on average about three incompetent perforators. They are located in the area with the most severe trophic skin changes. Preoperatively color duplex scanning and/or phlebography should be performed. Incompetent perforators are diagnosed endoscopically by their corkscrew appearance, their fibrous tissue sheathing, a different diameter of the twin vessels or by a wide diameter of more than 2.5 mm. The dissection can also be carried out by a CO2 laser. Especially for large perforators, the clipping technique shows superior performance. After wound closure a compression bandage is applied and – in general anesthesia – the compression sleeve is removed [13, 14].

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b

a

c

Fig. 1. a SEPS – case performance in the operation room. b Subfascially located incompetent perforator after preparation. c Incompetent perforator after clipping. d Incompetent perforator after dissection.

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Table 1. Complications of subfascial endoscopic perforator surgery (Department of Dermatology Darmstadt, Germany; study of 1,254 cases, 3/91–8/96) Complication

%

Reversible dysesthesia Persisting incompetent perforators Postoperative subfascial hematoma Wound infection Damage of branch of posterior tibial nerve Damage of arteries

19.8 5.8 3.5 0.4 0.1 0

Results The process of ulcer healing is significantly shortened. Hyperpigmentation and lipodermatosclerosis will be improved or even disappear.

Complications Table 1 shows the complications following SEPS. The data has been compiled from the cases of SEPS procedures performed in the Department of Dermatology, Darmstadt, Germany, during the time from March 1991 to August 1996. Postoperative dysesthesia distal of the exposed area occurs in about 20% of the cases and usually resolves within 6–10 weeks. Subfascial damage can be extensive after ‘aggressive’ surgery. Before the clipping technique was available the risk was about 3%; currently, complications are less frequent. The incidence of wound infection is at 0.4%, considerably lower compared with the percutaneous approaches with an infection rate of about 50%. The incidence of deep venous thrombosis following the endoscopic procedure is at 0.6% and therefore comparable with ‘normal’ surgery. Damage to the posterior tibial nerve, whose ramus plantaris innervates the planta, is the most unwanted complication [6, 7, 14, 15, 17].

Future Perspectives Endoscopic dissection of perforators has improved the treatment of advanced chronic venous insufficiency. Long-term results have demonstrated a

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low rate of recurrence of stasis-related problems of the skin. Since resorbable clips for SEPS surgery are available, the possibility for outpatient treatment concepts can be envisioned.

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

14 15 16

17

Bergan JJ, Muray J, Greason K: Subfascial endoscopic perforator vein surgery: A preliminary report. Ann Vasc Surg 1996;10:211–219. Cockett F: Techniques of Operations on the Perforating Veins. Perforating Veins. Munich, Urban & Schwarzenberg, 1981, pp 203–207. Conrad P: Endoscopic exploration of the subfascial space of the lower leg with perforator vein interruption using laparoscopic equipment: A preliminary report. Phlebology 1994;9:154–157. Fischer R: Erfahrungen mit der endoskopischen Perforantensanierung. Phlebologie 1992;21:224– 229. Fischer R, Sattler G: Die Indikation zur subfaszialen Endoskopie der Cockettschen Venae perforantes. Phlebologie 1994;23:174–179. Fischer R, Schwahn-Schreiber C, Sattler G: Conclusions of a consensus conference on subfascial endoscopy of perforating veins in the medial lower leg. Vasc Surg 1998;32:4339–4347. Fischer R, Schwahn-Schreiber C, Sattler G: Ergebnisse der Konsensuskonferenz u¨ber die subfasziale Endoskopie der Vv. Perforantes des medialen Unterschenkels. Phlebologie 1997;26:60–65. Gloviczki P: Endoscopic perforator vein surgery: Does it work? Vasc Surg 1998;32:303–305. Hauer G: Operationstechnik der endoskopischen Diszision der Perforansvenen. Chirurgie 1987;58: 172–175. Iafrati MD, Welch HJ, O’Donell TF Jr: Subfascial endoscopic perforator ligation: An analysis of early clinical outcomes and cost. J Vasc Surg 1997;25:995–1000. Linton RR: Surgery of veins of lower extremities. Minn Med 1949;32:38–46. Ruckley CV: Surgery for Varicose Veins. Berlin, de Gruyter, 1984. Sattler G, Mo¨ssler K, Hagedorn M: Prophylaxe und Therapie des Ulcus cruris: Endoskopische Perforansvenendiszision und antegrade paratibiale Fasziotomie; in Mahrle G, Schulze HJ, Krieg T (eds): Fortschritte der operativen und onkologischen Dermatologie, vol 8: Wundheilung – Wundverschluss. Berlin, Springer, 1994, pp 225–229.. Sattler G, Mo¨ssler K, Hagedorn M: Endoscopic perforating vein dissection and paratibial fasciotomy for the treatment of the venous ulcer. Phlebology 1992;7:1089–1091. Sparks SR, Ballard JL, Bergan JJ, Killeen JD: Early benefits of subfascial endoscopic perforator surgery in healing venous ulcers. Ann Vasc Surg 1997;11:367–373. Stuart WP, Adam DJ, Bradbury AW, Ruckley CV: Subfascial endoscopic perforator surgery is associated with significantly less morbidity and shorter hospital stay than open operation (Linton’s procedure). Br J Surg 1997;84:1364–1365. Whitely MS, Smith JJ, Galland RB. Subfascial endoscopic perforator vein surgery: Current practice among British surgeons. Ann R Coll Surg Engl 1998;80:104–107.

Dr. med. G. Sattler, Klinikum Darmstadt-Hautklinik, Heidelberger Landstrasse 379, D–64297 Darmstadt (Germany)

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Shave Therapy for Recalcitrant Venous Ulcers Wilfried Schmeller Department of Dermatology and Venereology, Medical University, Lu¨beck, Germany

Introduction For leg ulcers caused by insufficiency of epifascial veins, a number of standardized surgical procedures with good short-term and long-term results are used worldwide. However, for ulcers associated with deep venous insufficiency – due to either primary varicosis or postthrombotic syndrome – no causative surgical treatment is available and therapy results are often quite unfavorable. Replacement of insufficient vein segments by vein valve transplants, valvuloplasties and venous transposition operations are still under development [1]. If there is no contraindication because of peripheral occlusive arterial disease, compression therapy is the treatment of choice [2, 3]. But it is only successful in about 80% of all venous leg ulcers; in additon to this, recurrence rates of 30% within 1 year have been reported [4]. To improve these results, several surgical procedures have been advocated. Conventional skin grafting shows success rates between 50 and 90% with recurrence rates of about 50% within the following years [5, 6]. Paratibial fasciotomy has generated favorable results, but can only be employed for ulcers of the inner ankle [7, 8]. The effect of endoscopic perforator dissection on ulcer healing is still discussed controversially [9]. Ulcers of the outer ankle, ulcers covering the whole gaiter area and ulcers which recur after the abovementioned procedures have been performed, still represent an enormous therapeutic challenge. The common feature of these recalcitrant or ‘therapy-resistant’ ulcers are extensive trophic changes in the form of acute or chronic dermatosclerosis or lipodermatosclerosis [10–13]. Because the nonhealing ulcer does not only depend on incompetent

veins but also on structural changes of the supramalleolar tissue coat, a radical removal of all fibrotic changes of skin, subcutaneous tissue and fascial sheets enclosing the muscular compartments has been advocated [8, 14, 15]. However, removal of ulcer and lipodermatosclerosis without the underlying fascia had proved to be beneficial as well [16]. Therefore, in patients with so-called therapy-resistant ulcers we propose the use of a surgical procedure called shave therapy.

Patients Within a period of 4 years (January 1994 to December 1997) 81 patients with 107 nonhealing venous leg ulcers were treated by shave therapy at the Department of Dermatology and Venereology of the Medical University of Lu¨beck, Germany. Ten patients were operated on in 1994, 8 in 1995, 30 in 1996 and 33 in 1997. Most of the patients were older than 65 years (range 42–87); the mean duration of the ulcers was 22 years (range 2–46). All ulcers had proved to be resistant to conservative (local, systemic and compression therapy) and to surgical procedures (fasciotomy, fasciectomy, dissection of perforator veins and/or stripping of superficial veins). In some patients, limb amputations had already been discussed because of recurrent cellulitis and extreme pain. In nearly all of them a reduced ankle movement could be found, often with a fixed talipes equinus. Doppler ultrasound and duplex sonography revealed deep venous refluxes in all patients, sometimes combined with refluxes of the superficial and/or the perforator veins. In nearly 50% of the patients, refluxes were a result of postthrombotic syndrome. The classification of venous disease according to CEAP [17] was employed: C6, S (clinical signs: active ulceration with symptoms), ES or EP (etiology: due to thrombosis or primary varicosis), AD and AS or AD and AP (anatomy: deep and superficial veins affected or deep and perforator veins affected; segments affected were Nos 2 and 3 in the long saphenous veins, 11–15 in the deep veins and 18 in the perforator veins), PR (pathophysiology: reflux). The disability scores in our patients were 2 (can work 8 h daily only with support device) or 3 (unable to work even with support device). Fig. 1. Shave therapy operative procedure. a Appearance after removal of the ulcer and most of the surrounding lipodermatosclerosis with the Schink grafting knife. b Split skin graft at the end of the operation. Fig. 2. 78-year-old female patient with deep venous insufficiency; ulcer of 15 years’ duration. a Preoperative. b 2.5 years after shave therapy.

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In 10 legs ‘mixed ulcers’ were present; ankle-brachial index =1 indicated arterial occlusive disease in combination with venous insufficiency. The lowest values of arterial pressure found in the foot arteries were 50 mm Hg in normotensive patients.

Shave Therapy Operative Procedure Using a Schink skin grafting knife (Aesculap, Tuttlingen, Germany) the ulcers and the surrounding lipodermatosclerosis were removed under general or spinal anesthesia. The indurated areas, next to and underneath the ulcers and above the fascia, were excised in flat, horizontal layers (fig. 1a), until palpation indicated a less indurated tissue and until an improved bleeding pattern was noted. In order to evaluate the improvement of this bleeding pattern, during surgery no arterial occlusion of the affected leg was used in most patients. The fascia itself was not removed. Following this procedure, a meshed split skin graft of 0.4–0.6 mm thickness from the thigh was placed on the wound area (fig. 1b). In patients with ulcers covering the whole gaiter area (fig. 2, 3), the complete circumference of the lower leg was treated. In some patients, shave therapy was combined with saphenectomy and/or with dissection and ligation of insufficient perforator veins.

Results One week postoperatively in 98 of 107 operated ulcers, more than 75% of the wound areas were healed. Two patients had an increase of body temperature postoperatively; transfusions had to be administered to 4 patients in 1994. Perioperative antibiotics were given in the first 6 patients only. Since 1995, no peri- or postoperative antibiotics and no blood transfusions were required. After 3 months in 79% of the ulcers the grafts were taken completely. Initial long-term follow up after 2 years showed that 88% of the patients had no recurrences [18].

Discussion Chronic leg ulcers associated with deep venous insufficiency – especially with postthrombotic syndrome – are surrounded by extensive trophic changes with hyperpigmentation and induration. These areas of lipodermatosclerosis show abnormal morphologic and functional phenomena. Histomorphology

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Fig. 3. 55-year-old male patient with postthrombotic syndrome; ulcer of 10 years’ duration. a Preoperative. b 3 years after shave therapy.

reveals clusters of small vessels with prominent endothelial cells and thickened walls, surrounded by several basement membranes and amorphous material like fibrinogen, laminin and type IV collagen [19]. Microcirculation shows an increase of laser Doppler flow and a decrease of transcutaneous and intracutaneous oxygen tension [12, 20–22]. There is a close correlation between the extent of morphological and functional abnormalities and the amount of lipodermatosclerosis [10, 12, 13]. Examinations with 20-MHz ultrasound reveal that sclerosis in chronic venous insufficiency starts in the upper dermis and proceeds to the lower dermis; in more severe forms it can also be found both in the upper and in the lower subcutaneous fat [23, 24]. This is expressed by the German term ‘dermatoliposclerosis’, which seems more appropriate than ‘lipodermatosclerosis’, which is used in the international literature. In patients with pronounced induration, like in postthrombotic syndrome, the fascia may be involved as well (dermatolipofasciosclerosis). Computed tomography and magnetic resonance imaging have shown that induration of


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dermis and subcutaneous fat is the prerequisite for the development of ulceration; venous leg ulcers without lipodermatosclerosis have never been observed [12, 13]. The reduced ankle movement is a common feature in recalcitrant venous leg ulcers [25]. It is associated with dermatoliposclerosis in the ankle region and around the Achilles tendon [13]. The diminished efficiency of the venous pump (e.g. calf muscles) aggravates the chronic venous hypertension. Therefore, ulcer recurrences are a common feature in patients with ankle stiffness; this was observed after shave therapy as well. In our own studies, extensive changes in fascia, tendons, muscles, periost and bones could be demonstrated by computed tomographic scanning and magnetic resonance imaging [12, 13, 18]. However, the severity and therapy resistance of venous ulcers seem to be dependent on the extent of trophic changes in dermis and subcutaneous fat (lipodermatosclerosis). Therefore, only the tissue with the most extensive induration above the fascia is removed by shave therapy. Although an increase of induration in the transplanted areas could be noticed after surgery, morphological examinations with 20 MHz ultrasound 2 weeks and 3 months postoperatively showed no increase of dermatoliposclerosis within this period [26]. Functional examinations of the microcirculation at the ulcer edge before shave therapy and of the skin graft at identical locations 3 months after surgery revealed decreased laser Doppler flow and increased transcutaneous and intracutaneous oxygen tension with significant differences [27]. We therefore hypothesize that the better vascularization and oxygenation in deeper layers of the subcutaneous tissue improve wound healing. Compared to other surgical procedures such as ulcer excision, fasciectomy and paratibial fasciotomy, shave therapy is a relatively simple surgical method with very good functional and cosmetic short-term and long-term results [18, 27]. It can be used in all ulcers caused by deep venous insufficiency, whether they are at the inner or the outer ankle. It has also proved to be enormously effective in ulcers covering the whole circumference of the lower leg and also in patients with venous ulcers in combination with peripheral occlusive arterial disease. Shave therapy can be combined with operations of insufficient superficial or perforating veins. However, continuous compression with elastic bandages or stockings is necessary, because shave therapy is only a symptomatic treatment which does not reduce the pathological refluxes in the deep veins. Therefore, long-term results are very much dependent on the patients’ compliance after successful operation as well. In conclusion, shave therapy is considered a considerable improvement in the treatment of recalcitrant or so-called therapyresistant venous leg ulcers.

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Alexander House Group: Consensus paper on venous leg ulcers. Phlebology 1992;7:48–58. Douglas WS, Simpson NB: Guidelines for the management of chronic venous leg ulceration. Report of a multidisciplinary workshop. Br J Dermatol 1995;132:446–452. Falanga V: Venous ulceration. J Dermatol Surg Oncol 1993;19:764–771. Mayer W, Jochmann W, Partsch H: Ulcus cruris: Abheilung unter konservativer Therapie. Wien Med Wochenschr 1994;144:192–195. Kirsner RS, Mata SM, Falanga V, Kerdel FA: Split-thickness skin grafting of leg ulcers. The University of Miami Department of Dermatology’s experience (1990–1993). Dermatol Surg 1995; 21:701–703. Sebastian G: Die Rolle der Hauttransplantation im Behandlungsplan veno¨ser (postthrombotischer) Ulzera cruris. Wien Med Wochenschr 1994;144:269–272. Vanscheidt W, Peschen M, Kreitlinger J, Scho¨pf E: Paratibial fasciotomy. A new approach for treatment of therapy-resistant venous leg ulcers. Phlebologie 1994;23:45–48. Pflug JJ: Operative Behandlung des supramalleola¨ren medialen Konstriktionssyndroms bei nicht oder schlecht heilenden Ulcera cruris venosa. Phlebologie 1995;24:36–43. Coleridge Smith P: Calf perforating veins – Time for an objective appraisal? Editorial. Phlebology 1996;11:135–136. Kirsner RS, Pardes JB, Eaglstein WH, Falanga V: The clinical spectrum of lipodermatosclerosis. J Am Acad Dermatol 1993;28:623–627. Greenberg AS, Hasan A, Montalvo BM, Falabella A, Falanga V: Acute lipodermatosclerosis is associated with venous insufficiency. J Am Acad Dermatol 1996;35:566–568. Schmeller W, Roszinski S, Tronnier M, Gmelin E: Combined morphological and physiological examinations in lipodermatosclerosis; in Raymond-Martimbeau P, Prescott R, Zummo M (eds): Phlebology 1992. Paris, Libbey, 1992, pp 172–174. Schmeller W, Rosenthal N, Gmelin E, Tichy P, Busch D: Computertomographische Untersuchungen der Unterschenkel bei Patienten mit chronischer Veneninsuffizienz und arthrogenem Stauungssyndrom. Hautarzt 1989;40:281–289. Dunn RM, Fudem GM, Walton RL, Anderson FA, Malhotra R: Free flap valvular transplantation for refractory venous ulceration. J Vasc Surg 1994;19:525–531. Langer Ch, Fuhrmann J, Grimm H, Vorpahl U: Orthostatische Kompartmentdruckmessung nach endoskopischer Fasziotomie. Phlebologie 1995;24:163–167. Galli KH, Wolf H, Paul E: Therapie des Ulcus cruris venosum unter Beru¨cksichtigung neuerer pathogenetischer Gesichtspunkte. Phlebologie 1992;21:183–187. Classification and grading of chronic venous disease in the lower limbs: A consensus statement. Phlebology 1995;10:42–45. Schmeller W, Gaber Y, Gehl HB: Shave therapy is a simple, effective surgical treatment for persistent venous leg ulcers. J Am Acad Dermatol 1998;39:232–238. Tronnier M, Schmeller W, Wolff HH: Morphological changes in lipodermatosclerosis and venous ulcers: Light microscopy, immunohistochemistry and electron microscopy. Phlebology 1994;9: 48–54. Roszinski S, Schmeller W: Influence of erythema and sclerosis on skin oxygenation and microcirculation around venous ulcers; in Negus D, Jantet G, Coleridge Smith PD (eds): Phlebology ’95. Berlin, Springer, 1995 pp 781–783. Roszinski S, Schmeller W: Differences between intracutaneous and transcutaneous skin oxygen tension in chronic venous insufficiency. J Cardiosvasc Surg 1995;36:407–413. Schmeller W, Maack A: Multilokula¨re Sauerstoffpartialdruckmessung (‘oxygen mapping’) an den unteren Extremita¨ten Venengesunder und Venenkranker. Aktuel Dermatol 1990;16:181–186. Schmeller W, Welzel J, Plettenberg A: Lokalisation und Auspra¨gungsgrad der Dermatoliposklerose lassen sich mittels 20 MHz-Sonographie gut beurteilen. Vasa 1993;3:219–226. Welzel J, Schmeller W, Plettenberg A: A 20-MHz ultrasound examination of lipodermatosclerosis; in Altmeyer P, Hoffmann K, el Gammal S, Hutchinson J (eds): Wound Healing and Skin Physiology. Berlin, Springer, 1995, pp 945–948.


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Helliwell PS, Cheesbrough MJ: Arthopathica ulcerosa: A study of reduced ankle movement in association with chronic leg ulceration. J Rheumatol 1994;21:1412–1414. Schmeller W, Wunderle U, Welzel J: 20 MHz-Sonographie zur Verlaufskontrolle nach Shave-Therapie veno¨ser Ulzera. Phlebologie 1998;27:7–14. Schmeller W, Roszinski S: Shave-Therapie zur operativen Behandlung persistierender veno¨ser Ulzera mit grossfla¨chiger Dermatoliposklerose. Hautarzt 1996;47:676–681.

Prof. Dr. med. Wilfried Schmeller, private: Wesloer Landstr. 3k, D–23566 Lu¨beck (Germany) Tel. +49 451 65611, E-Mail wilfried.schmeller@t-online-de

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Part III. Arterial Leg Ulcers Hafner J, Ramelet A-A, Schmeller W, Brunner UV (eds): Management of Leg Ulcers. Curr Probl Dermatol. Basel, Karger, 1999, vol 27, pp 203–210

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Assessment of Peripheral Arterial Occlusive Disease Robert Wu¨tschert, Henri Bounameaux Division of Angiology and Hemostasis, Department of Internal Medicine, University Hospital, Geneva, Switzerland

Introduction Chronic skin ulceration of the lower limbs results often from several concomitant etiopathogenic factors, even though venous insufficiency is certainly the most common cause. However, the importance of peripheral arterial occlusive disease (PAOD) seems to be underestimated in this situation [1]. Indeed, patients with leg ulcers are old (70 years or more), and the prevalence of diabetes (between 20 and 30%) in this population is high [2, 3]. It is, therefore, not surprising that a prevalence of about 20% of chronic arterial insufficiency has been reported in such patients. Significant arteriopathy is usually defined as an ankle/arm systolic pressure index =0.9 but there is still some confusion in the literature between the definitions of arterial insufficiency and ischemic ulcer [4]. Critical limb ischemia is only present in a minority of patients with PAOD [5]. It is a serious condition in which the viability of the leg is jeopardized due to the impaired blood flow. It was defined in the Second European Consensus Document as a persistent ischemic rest pain lasting for more than 2 weeks and/or ulceration of the leg, associated with an ankle systolic pressure p50 mm Hg and/or a toe systolic pressure of p30 mm Hg [6]. Without an adequate management, the prognosis of the limb is poor. Thus, it is important to recognize and diagnose this condition early on. In the present review, we intend to discuss the clinical findings and the noninvasive vascular tests that allow to diagnose severe PAOD which may be responsible of ischemic skin ulcers.

Clinical Findings Presence of risk factors such as atherosclerosis, history of stroke, myocardial infarction, intermittent claudication and ischemic rest pain should be looked for in order to predict the presence of PAOD. Prevalence of intermittent claudication may be as high as 19% in a population with leg ulcers [4], but symptoms can be masked by the absence of walking in these old populations or by a polyneuropathy secondary to diabetes. It is estimated that approximately 15–20% of patients with intermittent claudication will progress to critical ischemia [5]. Ischemic rest pain is typically a nocturnal pain of disturbing severity that involves the foot distal to the metatarsals, although it may be sharply localized to the vicinity of an ischemic ulcer or a gangrenous toe. Horizontally sleeping patients are usually awakened by this pain, and forced to get up. Clinical signs such as calf muscles atrophy, loss of hair growth over the dorsum of the toes and foot, thickening of the toenails, atrophy of the skin and delayed return of the capillary blush after pressure to the pulp of the digit are suggestive of severe arterial insufficiency, but all these signs are rarely present together. Ischemic ulcers are usually quite painful with irregular edges at first, but when chronic they are more likely to have a ‘punched out’ appearance. They are commonly located distally over the dorsum of the foot or toes, but may occasionally be pretibial. The ulcer base usually consists of poorly developed, grayish granulation tissue. These characteristics are not always present and often do not permit the distinction of ischemic ulcers from other types of ulcers (venous, neurotrophic, vasculitic, ...). Pedal pulses should always be palpated in limbs with ulcers. However, dorsalis pedis pulse may be absent in about 10% of normal patients, and palpation of the posterior tibial pulse is sometimes difficult in patients with chronic venous insufficiency because of the swollen leg or the location of the ulcer. The presence of a pedal pulse implies that the ankle systolic pressure is ?100 mm Hg [7], which should allow arterial ulcers to heal [8]. If pedal pulses are not present, noninvasive vascular testing should always be performed.

Noninvasive Vascular Tests Noninvasive tests provide a valuable, objective, and reproducible means to diagnose and quantify the severity of PAOD and to define the prognosis of skin lesions. In the following, the most commonly used and generally accepted techniques will be discussed.

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Measurement of Ankle Systolic Pressure The measurement of ankle systolic pressure became simple in the late sixties with the development of instruments that could detect flow in vessels distal to a pneumatic cuff. The cheapest, easiest and widely available technique consists of applying a Doppler probe (8–10 MHz for distal arteries) on the tibial posterior and dorsalis pedis arteries. This measurement can easily be performed by a trained general practitioner or a nurse. During this test the patient is resting in supine position, the room and if possible the extremities should be comfortably warm. The cuff width is generally ?12 cm. It is usually accepted to consider the highest pressure measured on the ankle arteries, because this will reflect the true foot perfusion. One major limitation of this test is the presence of a mediocalcinosis, as it is often the case in diabetics, which may overestimate the true ankle pressure value. If the pressure is below the level of critical limb ischemia (ankle systolic pressure =50 mm Hg) [6], leg ulcers will heal only in 20% [9] and aggressive revascularization therapy should be performed to save the limb. We have suggested in a thorough review of the literature that an ankle systolic pressure threshold of 80 mm Hg provides a good prognosis for an ulcer to heal, with a positive predictive value ?80% [9]. In such cases, arterial insufficiency as the etiology of a leg ulcer can be reasonably excluded. Between 50 and 80 mm Hg, additional vascular tests such as systolic toe pressure or transcutaneous oxygen (tcPO2) measurement should be performed. When the ankle arteries are not compressible, or when the ankle-to-arm blood pressure index is ?1.3, or when the difference between the pressure measured at ankle level and arm exceeds 75 mm Hg, then calcifications are almost always seen on X-rays [10]. In these cases, ankle systolic pressure is no longer a good predictor of leg ulcer healing and a toe systolic pressure or a tcPO2 should be measured. When Mo¨nckeberg mediocalcinosis is suspected, the ‘pole test technique’ can be applied: using an 8-MHz probe applied on ankle arteries, the patient is lying in supine position, and the test leg is elevated [11]. If the Doppler signal disappears before 80 cm above the bed surface, ankle systolic pressure is =50 mm Hg, and critical limb ischemia is likely to be present. This test can easily be performed by a trained general practitioner, but there is too little experience in the literature to recommend it routinely in the assessment of leg ulcers. The ankle/arm systolic pressure index is useful to identify peripheral arterial insufficiency. However, this method is of no recognized help in defining critical ischemia, even though some authors use the threshold of 0.5 to define severe arterial insufficiency. Elastic compression stockings are widely used in the treatment of venous ulcers. Pressure of a newly applied bandage is around 30 mm Hg at ankle level

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and is not evenly distributed around the circumference of limb but, according to the Laplace formula, is much greater over bony or tendinous prominences, where convexity is greater. If there is a concomitant arterial insufficiency, this external pressure may induce new ischemic ulcers or even precipitate amputation [12]. Actually, there is no established consensus on the minimal ankle systolic pressure necessary to allow sufficient perfusion on hyperpression area, but this threshold value is probably around 90–100 mm Hg [13]. Measurement of Toe Systolic Pressure The measurement of digital pressure in the lower limbs is generally performed on the great or the second toe with a 25-mm wide cuff fixed on the proximal phalanx (20 mm for the other toes). The accepted gold standard to perform this test is the mercury strain gauge technique, the results of which correlate well with intra-arterial measurements [14]. A fine-bore silicone rubber tube filled with mercury is wrapped around the distal phalanx with just enough tension to ensure good contact. The pneumatic cuff is inflated above toe systolic pressure and then slowly deflated. Once the cuff pressure is just below the systolic toe pressure, arterial blood flow causes a volume increase of the toe which in turn increases the length of the gauge. This increase induces a variation of resistance that is accurately recorded with a variety of bridge circuits. This method requires fragile gauges and relatively expensive material. Thus, other techniques such as photoplethysmography are more widely used to measure digital pressure. Their performances and reproducibility is, however, less well studied. Critical ischemia is defined by a toe pressure =30 mm Hg and this cut-off is now generally accepted [6]. When the pressure is above this cut-off, it has been suggested that healing of leg ulcers occurs in about 90% of cases. Mediocalcinosis of digital arteries is rare, therefore the measurements are generally representative of PAOD in diabetics [9]. Unfortunately, ulcers located on the toes in diabetics may sometimes compromise the assessment of digital pressure. Mercury-in-silicone elastomer gauges are very sensitive and have high frequency response, and allow for the measurement of pulsatile phenomenon. The digital pulses are often severely reduced or entirely absent in critical ischemia, so that the residual toe pressure is often too low to be measured accurately. One major limitation of this test is the extreme sensitivity of digital blood flow to temperature variations, and recordings should only be performed on warm or warmed feet, which also applies to digital pressure measurements. Measurement of Transcutaneous Oxygen Pressure The principle of tcPO2 measurement is based on a polarographic method with a modified Clark-type electrode. The probe contains a platinum cathode


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and a silver anode. Oxygen is reduced on the surface of the cathode, and an electric current is generated proportionally to the amount of oxygen. The probe consists of a ring with a 20-mm diameter, tightly fitted to the skin by a self-adhesive tape. At normal skin temperature, oxygen diffusion through the skin is poor (3–4 mm Hg) so that the skin has to be heated at 44 ºC by an integrated heating system. At this standardized temperature, there is an important local vasodilatation and the ratio of transcutaneous to arterial PO2 remains constant and close to one [15]. This is also explained by a better oxygen diffusion through the skin and a deviation to the right of the oxyhemoglobin curve [16]. Steady state is obtained only after 15–20 min. Localization of the probe must be standardized because there is a linear relation between tcPO2 and capillary density [17], which can vary from 30 for the leg to 150/mm2 for the face. To evaluate the peripheral arterial perfusion, the patient must lie in supine position, breathe ambient air, and the electrode is placed on the dorsum of the foot, between the first and the second metatarsial. In vitro variability of tcPO2 is very low (3 mm Hg) but is greater when applied on the skin (11 mm Hg) [18]. TcPO2 may be underestimated by (i) local factors such edema or skin thickness of various skin layers and (ii) factors which induce systemic hypoxemia or increased local consumption (inflammation or infection). Overestimation of tcPO2 is generally due to methodological factors, usually due to a leak of the adhesive tape. TcPO2 remains normal (normal range 40–80 mm Hg) when the systolic toe pressure is ?80 mm Hg, so that this technique is not useful to detect moderate peripheral arterial insufficiency. On the other hand, tcPO2 is widely used to predict ulcer healing and to determine amputation level. This technique has been put forward by the Second European Consensus Meeting on Chronic Critical Leg Ischemia as an aid in defining jeopardized extremities [6]. Indeed, it has been shown that a tcPO2=10 mm Hg without significant increase after pure oxygen breathing predicts an unfavorable outcome of leg ulcers with major amputation if vascular revascularization is not successful [19]. TcPO2 is particularly helpful for predicting stump healing after major amputation. A pooled analysis of published series from the literature totaling more than 600 patients recently demonstrated that the optimal cut-off to discriminate patients who will heal their stump or not was 20 mm Hg [20]. Even though the contribution of tcPO2 for predicting healing of leg ulcers has not be studied in large series, the same cut-off can probably be used, at least to exclude a severe underlying arterial insufficiency. Indeed, in vitro studies have shown that a minimum of 20 mm Hg oxygen pressure is necessary to permit optimal cellular fibroblast division and collagen synthesis [21]. Pecoraro et al. [22] have also reported with a probe placed close to the ulcer, that a tcPO2=20 mm Hg increases the risk of nonhealing by a factor of 40 [22].


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However, tcPO2 measurement can be influenced by several factors and its performance is probably poorer than that of toe systolic pressure for predicting healing of leg ulcers. To improve them, it has been proposed to combine the basic technique with systematic measurement following pure oxygen inhalation by the patient, or by measurement in both supine and sitting position or with chest/limb indices. These refinements may be promising but the populations studied so far are too small to suggest their widespread use. A tcPO2 =10 mm Hg or a tcPO2 between 10 and 20 mm Hg with poor clinical outcome should lead to further evaluation with an aim toward achieving revascularization of the limb. In patients with a tcPO2 ?20 mm Hg, a severe underlying arterial insufficiency should be considered unlikely. Other Tests Other tests like skin thermography, laser Doppler flux studies, skin arterial blood pressure measurements, or epicutaneous 133Xe clearance studies have also been used to determine skin perfusion but their use in predicting healing of skin ulcers is still experimental and the cost-effectiveness of some of them is highly questionable. Ultrasonic duplex scanning or arteriography are mandatory to provide exact localization of arterial lesions but they cannot be used as an index of severity of arterial disease or to predict healing of leg ulcers [10]. Angiography remains the ‘gold standard’ to investigate PAOD when invasive revascularization is planned, especially in cases of crural peripheral bypass operation and the vascular surgeon needs exact information about morphologic features of tibial and peroneal arteries in case of femoropoliteal occlusion [23, 24]. However, angiography is invasive, expensive, with possible complications so that ultrasonic duplex scanning can be used as a first-step screening in order to evaluate the necessity of a radiological percutaneous procedure or in patients with severely impaired kidney function or with a history of allergy to contrast media. Duplex scanning can define the degree of stenosis in the iliac and femoropoliteal areas but this exam is probably not sufficient (even in experienced hands) to replace a preoperative angiogram for evaluating tibioperoneal arteries [24]. Lastly, duplex imaging can be repeatedly used in surveillance programs following a radiological or surgical procedure, but these programs are time-consuming and the proof of their cost-effectiveness is still lacking.

Conclusion In the management of leg ulcers, peripheral arterial insufficiency should always be considered as a potential cause (table 1). Indeed, severe arteriopathy


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Table 1. Use of noninvasive vascular tests to predict the presence of underlying severe arteriopathy Noninvasive vascular testing

Findings

Severe arteriopathy

Pedal pulses

Present Absent

Unlikely Possible1

Ankle systolic pressure

?80 mm Hg 80–50 mm Hg p50 mm Hg

Unlikely Possible1 Likely

Toe systolic pressure

?30 mm Hg p30 mm Hg

Unlikely Likely

tcPO2

?20 mm Hg 10–20 mm Hg =10 mm Hg

Unlikely Possible1 Likely

1 Proceed with further, noninvasive vascular tests to confirm or rule out severe arteriopathy especially if clinical evolution is poor.

may induce ischemic ulcers, leading to amputation if not adequately diagnosed and treated. The clinician should first assess the pedal pulses; if present, pedal pulses rule out severe arteriopathy with sufficient likelihood. Therefore, other noninvasive vascular tests are not necessary in this situation. If pedal pulses are absent, ankle systolic pressure or, in some cases, toe systolic pressure should be measured. If the criteria of critical limb ischemia are met [6], limb revascularization is the best therapeutic option. In cases of chronic limb ulcers without a favorable evolution, an ankle systolic pressure q80 mm Hg, a toe systolic pressure ?30 mm Hg, or a tcPO2?20 mm Hg can rule out the presence of underlying severe arteriopathy.

References 1

2

3 4

Callam MJ, Harper DR, Dale JJ, Ruckley CV: Arterial disease in chronic leg ulceration: An underestimated hazard? Lothian and Forth Valley Leg Ulcer Study. Br Med J 1987;294:929– 931. Baccaglini U, Giraldi E, Spreafico G, Castoro C, Sorentino P, Baggio E, Lipari G, Maleti O, Pinataro M: Etude multicentrique sur les ulce`res veineux en Italie: les ulce`res rebelles. Phle´bologie 1997;50:371–378. Nelzen O, Bergqvist D, Lindhagen A: High prevalence of diabetes in chronic leg ulcer patients: A cross-sectional population study. Diabet Med 1993;10:345–350. Cornwall JV, Dore´ CJ, Lewis JD: Leg ulcers: Epidemiology and aetiology. Br J Surg 1986;73: 693–696.


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Weitz JI, Byrne J, Clagett P, Clagett GP, Farhouh ME, Porter JM, Sachett DL, Strandness DE Jr, Taylor LM: Diagnosis and treatment of chronic arterial insufficiency of the lower extremities: A critical review. Circulation 1996;94:3026–3049. European Working Group on Critical Leg Ischemia: Second consensus document on chronic critical leg ischemia. Circulation 1991;84(suppl IV):1–25. Wu¨tschert R, Kern P, Bounameaux H: Quantification de l’insuffisance arte´rielle des membres infe´rieurs: me´thodes et applications. Me´d Hyg 1998;56:137–140. Christensen JH, Freundlich M, Jacobsen BA, Faltie-Jensen N: Clinical relevance of pedal pulse palpation in patients suspected of peripheral arterial insufficiency. J Int Med 1989;226:95–99. Wu¨tschert R, Bounameaux H: Predicting healing of arterial leg ulcers by means of segmental systolic pressure measurements. Vasa 1998;27:224–228. Orchard TJ, Strandness E Jr: Assessment of peripheral vascular disease in diabetes. Report and recommendations of an international workshop sponsored by the American Diabetes Association and the American Heart Association. Circulation 1993;88:818–828. Smith FCT, Shearman CP, Simms MH, Gwynn BR: Falsely elevated ankle pressure in severe leg ischaemia: The pole test, an alternative approach. Eur J Vasc Surg 1994;8:408–412. Callam MJ, Ruckley CV: Hazards of compression treatment of the leg: An estimate from Scottish surgeons. Br Med J 1987;295:1382. Ramelet AA, Monti M: Contention e´lastique dans les affections veineuses des membres infe´rieurs; in Phle´bologie, ed 2. Paris, Masson, 1994, pp 282–292. Gundersen J: Comparison of indirectly measured blood pressure in the thumb and simultaneous direct recording of the pressure in the radial artery. Acta Chir Scand 1972(suppl 426):43–49. Huch R, Huch A, Lubbers HU: Transcutaneous measurement of blood PO2 (tcPO2). Method and application in perinatal medicine. J Perinat Med 1973;1:183–191. Bongard O, Bounameaux H: Oxyme´trie percutaneé; in Vayssairat M, Carpentier P (eds): Microcirculation clinique. Paris, Masson, 1996, pp 109–117. Franzeck UK: Transkutaner Sauerstoffpartialdruck (tcPO2): Messungen mit neuen electrodentypen; in Mahler F, Messmer K, Hammersen F (eds): Methoden der klinischen Kapillarmikroskopie. Basel, Karger 1986, vol 11, pp 107–123. Wyss CR, Frederick A, Matsen A, Simmons CW, Burgess EM: Transcutaneous oxygen tension measurements on limbs of diabetic and nondiabetic patients with peripheral vascular disease. Surgery 1984;95:339–346. Bongard O, Krahenbuhl B: Predicting amputation in severe ischemia: The value of transcutaneous PO2 measurement. J Bone Joint Surg [Br] 1988;70:465–467. Wu¨tschert R, Bounameaux H: Determination of amputation level in ischemic limbs. Diab Care 1997;20:1315–1318. Bauer P, Larcan A: Oxygeńothe´rapie hyperbare dans le traitement des ulce`res ische´miques. Sang Thromb Vaiss 1997;9:497–503. Pecoraro RE, Ahroni JH, Boyko EJ, Stensel VL: Chronology and determinants of tissue repair in diabetic lower-extremity ulcers. Diabetes 1991;40:1305–1313. Androulakis AE, Giannoukas AD, Labropoulos N, Katsamouris A, Nicolaides AN: The impact of duplex scanning on vascular practice. Int Angiol 1996;15:283–290. Larch E, Minar E, Ahmadi R, Schnurer G, Schneider B, Stumpfen A, Ehringer H: Value of color duplex sonography for evaluation of tibioperoneal arteries in patients with femoropopliteal obstruction: A prospective comparison with anterograde intraarterial digital substraction angiography. J Vasc Surg 1997;25:629–636.

Robert Wu¨tschert, Division of Angiology and Hemostasis, Department of Internal Medicine, University Hospital of Geneva, CH–1211 Geneva 14 (Switzerland)


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Management of Arterial Leg Ulcers and of Combined (Mixed) Venous-Arterial Leg Ulcers Ju¨rg Hafner Department of Dermatology, University Hospital, Zu¨rich, Switzerland

The degree of peripheral arterial occlusive disease (PAOD) in leg ulcer patients is largely underestimated and might account for the most common mistakes in the management of leg ulcers [1–4] . The prevalence of symptomatic PAOD is between 1% (at 40 years) and 5% (at 60–65 years). The prevalence of asymptomatic (Fontaine stage I) PAOD is 5 times higher [5]. Among leg ulcer patients, 10% have a combined venous-arterial etiology and another 10% are uniquely of arterial origin [3, 6, 7]. Chronic venous insufficiency, which is accompanied by relevant (ABI=0.8) PAOD, represents the pathogenesis in so-called combined venous-arterial leg ulcers. On clinical presentation, combined venous-arterial leg ulcers usually cannot be distinguished from venous leg ulcers. Advanced PAOD (usually Fontaine stage IIb) alone represents the underlying pathology in arterial leg ulcers. Arterial leg ulcers typically occur in the lateral or pretibial aspect of the calf, on the heel or on the dorsum of the foot [3, 4, 8, 9]. Primarily, management of combined venous-arterial and arterial leg ulcers is determined by the Fontaine stage of PAOD (table 1).

General Measures in Fontaine Stage II PAOD General measures in PAOD encompass secondary prevention, as well as walking exercise, except for chronic critical leg ischemia, where bed rest may be mandatory. So-called vasoactive substances, such as buflomedil, naftidrofuryl or pentoxifylline, lead to a significant increase in pain-free walking distance, although this effect is not very pronounced [10].

Table 1. Fontaine stage of POAD Secondary Walking Interventional Prostaglandin Bier’s arterial arrest for infected foot ulcers; G-CSF prevention of exercise vascular E1 , iloprost arteriosclerosis procedures for diabetic foot infection Early PAOD stages PAOD stage I + PAOD stage IIa +

+ +

Handicapping claudication PAOD stage IIb +

+

Chronic critical leg ischemia and/or PAOD stage III + PAOD stage IV +

+ + +

+ +

+ +

Walking exercise represents the principle measure in Fontaine stage II PAOD. Patients are encouraged to walk 1 h/day (1¶60 or 2¶30 min). Exercise induces hyperemia in the poststenotic muscles. This lowers the poststenotic blood pressure, thereby increasing the pressure gradient and blood flow. Walking exercises should be performed at intervals. The patient is advised to ambulate rather rapidly until the typical cramp-like muscle pain sets in. A short break will allow the muscle to recover from ischemia and the walking exercise can be continued. Alternating exercise with recovery is accompanied by reactive hyperemia and represents the strongest stimulus for the formation of collaterals and for metabolic adaptation of the affected muscles. Patients should be discouraged from exaggerated exercise under pain, because this may have an adverse effect on the damaged tissues. Walking exercise substantially improves the free walking distance. The typical result achieved by intensive vascular training is on the order of 50–100% improvement in walking distance [11–13]. Interventional treatment of PAOD is only required when the patient is limited in his/her everyday activities (corresponding to Fontaine stage IIb PAOD). Moreover, certain exercises can aim at improving the oxygenation of specific muscle groups, such as foot exercises for PAOD of the calf arteries, tiptoes for PAOD of the superficial femoral artery and knee bends for PAOD of the iliac arteries [14]. Some general advice can be helpful for all PAOD patients. Footwear should be warm and fitted to avoid pressure. Tailored orthopedic footwear may be necessary. Patients should not sit with their legs crossed. Moisture and exposure to cold temperatures should be avoided as far as possible. Footcare

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comprises regular washing with temperate water (diabetic polyneuropathy!), dry skin should be moisturized with hypoallergenic creams and the toenails should be cut with great care and not too short, in order to avoid ingrown toenails. Patients who feel insecure in footcare should better see a podologist. Hot-water bottles and electric heat pads can have deleterious effects in PAOD patients and are to be avoided.

General Measures in Fontaine Stage III and IV PAOD Pain can be a major problem in chronic critical leg ischemia. Elevation of the head and putting the bed into a declive position may alleviate considerably ischemic rest pain. The foot has to be protected from the weight of the sheets. Protection from cold, e.g. by using cotton-wool boots, is important. Necrosis has to be kept dry and moist wounds should be dried out as far as possible. Therefore, moist tissue necrosis (gangrene) can be removed surgically by conserving as much viable tissue as possible. Infection must be treated vigorously. Surgical debridement and intravenous broad-spectrum antibiotics that cover gram-positive, gram-negative and anaerobe strains are necessary in the case of rapidly spreading infection in gangrene. Very high antibiotic concentrations in peripheral tissues can be achieved under retrograde transvenous pressure injection (Bier’s arterial arrest, see below). Only when healthy granulation tissue starts to form, moist wound dressings may be started [cf. chapter of Aubo¨ck]. Under these circumstances, hydroactive synthetic dressings develop analgesic properties and stimulate the formation of granulation tissue. Leg edema in PAOD can result from the slanted positioning of the bed, from dependency syndrome, or from reperfusion syndrome after interventional therapy. Unna’s paste boot [cf. chapter of Partsch] represents a safe and effective type of unelastic compression therapy for these patients. These bandages exert a very low compression at rest and a relatively high compression under exercise, thereby safely reducing peripheral edema in legs with low arterial perfusion. When chronic critical leg ischemia is successfully treated, PAOD usually returns to Fontaine stage II, allowing again for taking up walking exercise.

Secondary Prevention in PAOD Secondary prevention in PAOD aims at inhibiting the progression of clinically manifest arteriosclerosis [15]. Secondary prevention is based on the modification of the classical cardiovascular risk factors such as hypercholester-

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olemia, hypertension, smoking and diabetes, as well as on antithrombotic therapy [16–19]. Arteriosclerosis must be seen as a generalized disease. For instance, the ARIC Study revealed that individuals with a resting ankle-brachial index =0.9 had a 2-fold risk of coronary heart disease (95% Cl 1.0–5.1) and a 4-fold risk to experience stroke or transient ischemic attack (TIA) (95% Cl 1.8–9.5) [20]. The coincidence of several risk factors potentiates the total cardiovascular risk [15]. Cigarette smoking is considered the most important risk factor for PAOD. Smoking is correlated with a 6-fold risk for PAOD [21] and a 70% increase of coronary artery disease [22] . The combination of smoking, diabetes and dyslipidemia is especially deleterious for PAOD patients. Cessation of smoking is one of the most relevant measures in secondary prevention of arteriosclerosis. Cessation of smoking prevents progression of PAOD [23] and within 5 years after cessation the coronary risk approaches that of a nonsmoker [24]. The pathogenesis of diabetic macroangiopathy is multifactorial, since diabetics also tend to have dyslipidemia and hypertension. The risk of developing PAOD is 6-fold higher in diabetics and the risk of undergoing lower extremity amputation is even 15 times higher than in nondiabetic controls [25]. Hypercholesterolemia is correlated with coronary mortality [26]. The Scandinavian Simvastatin Study showed that a cholesterol-lowering treatment (essentially by diet and statins) decreased the coronary mortality by 42% in persons at risk [27]. A correlation of LDL-cholesterol and triglycerides with the presence of PAOD as well as an inverse correlation with HDL-cholesterol has been shown [28]. Treatment of high cholesterol in PAOD essentially aims at reducing the coronary risk. Treatment of high cholesterol in PAOD patients essentially aims at reducing the coronary risk. Hypertension is closely correlated with coronary artery disease and with stroke/TIA. The Framingham Study revealed a 5-fold risk for myocardial infarction and a 5-fold risk for stroke/TIA in middle-aged men with hypertension [26]. Hypertension is also an independent predictor of PAOD presence [28]. Of course, treatment of hypertension in PAOD patients primarily aims at the reduction of the coronary and cerebrovascular risk. Aspirin is the best investigated and most widely used antithrombotic agent in the secondary prevention of arteriosclerosis [16, 17]. Aspirin inhibits the synthesis of the platelet-aggregating thromboxane A2, whilst it does not influence the synthesis of the endogenous antiaggregant prostacyclin. Large clinical studies could demonstrate the effectiveness of low-dose aspirin (75–160 mg) in the secondary prevention of coronary artery disease and of cerebrovascular disease [16, 17]. Thus far, the effectiveness of aspirin in the secondary preven-

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tion of PAOD has only been shown in a study that used high doses (990 mg) [29]. The antiplatelet trialists’ meta-analysis shows that low-dose aspirin also has a secondary preventive effect on PAOD, although this still should be confirmed by clinical trials designed for the investigation of PAOD. In summary, low-dose aspirin is probably effective in the secondary prevention of PAOD. However, it is definitely effective in the secondary prevention of coronary and cerebrovascular morbidity and mortality in PAOD patients, since arteriosclerosis must be regarded as a generalized pathology.

Interventional Vascular Procedures Interventional vascular procedures are indicated in Fontaine stage IIb and in chronic critical leg ischemia. These patients require preinterventional vascular assessment by angiography or duplex sonography in order to determine if their atherosclerotic lesions are amenable to percutaneous transluminal angioplasty (PTA), bypass surgery or if no interventional treatment is suitable at all [30, 31]. Advances in PTA and vascular surgery have resulted in limb salvage rates [32] that may reach 80% at 6 months after intervention [33].

Complicated Fontaine Stage IIb PAOD and Arterial Leg Ulcers Advanced PAOD remains often undiagnosed in leg ulcer patients. Claudication is only rarely reported because these patients do not walk sufficiently to experience muscle ischemia. On vascular examination, they do not meet the criteria of chronic critical leg ischemia. If these patients could ambulate normally, most of them would enter a Fontaine stage IIb PAOD and therefore qualify for an interventional vascular procedure. Bollinger coined the term complicated Fontaine stage IIb PAOD for this condition [3, 8, 34]. In a preliminary analysis of 73 inpatients with chronic leg ulcers, 10 were found to have arterial leg ulcers. Arterial leg ulcers were defined as presenting with advanced PAOD, without demonstrable venous insufficiency as assessed by duplex ultrasound. The mean ABI in these patients was 0.57 (0.4–0.7) and the mean ankle systolic blood pressure was 68.4 mm Hg (50–90 mm Hg) [34]. These findings are in accordance with a recent meta-analysis published by Wu¨tschert and Bounameaux [35]: In three clinical studies totalling 220 patients, an ankle pressure of ?80 mm Hg predicted spontaneous wound healing in more than 80% of patients. Therefore, until larger clinical studies are available, we suggest to use an ankle systolic blood pressure of 80 mm Hg or an ABI of 0.5 as a


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cut-off level, below which leg ulcer patients should be referred for interventional vascular procedures, even in the absence of claudication or rest pain. In ambulating patients, these values would be in good accordance with Fontaine stage IIb PAOD [8]. Moreover, compression therapy for mixed venous-arterial ulcers becomes hazardous and painful at =80 mm Hg systolic ankle pressure [8]. Diabetics with mixed venous-arterial leg ulcers are specially prone to develop complications of compression therapy, because diabetic polyneuropathy may conceal painful pressure points [2].

Additional Options for Chronic Critical Leg Ischemia Several alternative options are available when vascular procedures are considered impossible. Prostaglandin E1 (PGE1) and iloprost (a prostacyclin analogue) are the best investigated medical treatment for advanced PAOD. In Fontaine stage III and IV PAOD unsuitable for vascular reconstruction, a meta-analysis on six randomized controlled trials showed a significant (p=0.05) beneficial effect of iloprost over placebo in ulcer healing, pain relief and the probability of being alive with both legs at 6 months’ follow up [36]. Breuer and Abri [37] investigated the additional effect of iloprost in patients with Fontaine stage IV PAOD undergoing minor surgery (intravenous iloprost at an individual tolerable dose, mean dose 1.7 ng/kg/min, during 6 h/day). In this open-labeled, randomized controlled study, primary postoperative wound healing and long-term postoperative response after 1 year were significantly in favor of iloprost. An increase in tcPO2 on the dorsum of the foot correlated well with good clinical response. Best surgical results were obtained when the procedure was scheduled in the middle of the iloprost treatment phase. Spinal cord stimulation (SCS) results in an improved nutritive skin perfusion as can be shown by tcPO2 measurement, whereas the systolic ankle/ brachial blood pressure index remains unchanged [38, 39]. A quadripolar lead is placed into the epidural space by percutaneous lumbar puncture between L3 and L4. If the patient experiences significant pain relief, an implantable pulse generator is placed in an abdominal subcutaneous pocket. Several uncontrolled clinical studies found significant pain relief and limb salvage rates of approximately 70% with SCS-treatment. However, a recent randomized controlled trial did not find that SCS was of benefit above that of best medical treatment. Amputation-free survival was not improved (67% vs 68%) nor was the risk of major amputation significantly reduced (42% vs 48%) [40].

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Infected Foot Ulcers For infected foot ulcers in chronic critical leg ischemia Bier’s arterial arrest represents an interesting treatment modality that allows for very high antibiotic tissue levels, such as they never can be achieved by intravenous or intra-arterial antibiotherapy. This procedure consists in transvenous pressure injection of antibiotics into a dorsal foot vein, after the venous system has been emptied by elevating the leg and a tourniquet at the thigh is inflated to 300 mm Hg to achieve arterial arrest [40, 41]. Burgmann et al. [42] compared tissue concentrations of antibiotics in skin biopsies after intravenous, intra-arterial application and Bier’s arterial arrest. Thirty-two patients received either clindamycin (16 patients) or gentamycin (16 patients) intravenously, intra-arterially or in Bier’s arterial arrest, in a randomized order. Tissue concentrations of clindamycin were 18 times (14 times) higher and tissue concentrations of gentamycin were 9.4 times (9.7 times) higher 80 min after application with Bier’s arterial arrest than with intravenous (intra-arterial) application. Granulocyte-colony stimulating factor, an endogenous hematopoietic growth factor, has been shown to stimulate wound healing in diabetic foot infection by improving granulocyte chemotaxis and function [43; cf. chapter of Brunner].


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Callam MJ, Harper DR, Dale JJ, Ruckley CV: Arterial disease in chronic leg ulceration: An underestimated hazard? Lothian and Forth Valley Leg Ulcer Study. Br Med J 1987;294:929–931. Callam MJ, Ruckley CV, Dale JJ, Harper DR: Hazards of compression treatment of the leg: An estimate from Scottish surgeons. Br Med J 1987;295:1382. Hafner J, Bounameaux H, Burg G, Brunner U: Management of venous leg ulcers. Vasa 1996;25: 161–167. Hafner J, Cassina P, Brunner U, Burg G: Ulcus cruris: Behandlung der schwierigen Fa¨lle. Geriatr Prax 1997;8:29–34. Boccalon H, Lehert P: Diagnostic prećoce de l’arte´riopathie des membres infe´rieurs a` l’aide de mesures adapteés a` la pratique geńe´raliste: l’index systolique et la perception des pouls. J Mal Vasc 1995;20:28–37. Baker SR, Stacey MC, Singh G, Hoskin SE, Thompson PJ: Aetiology of chronic leg ulcers. Eur J Vasc Surg 1992;6:245–251. Konradsen L, Wounlund J, Holstein P: Chronic critical leg ischemia must include leg ulcers. Eur J Vasc Endovasc Surg 1996;11:74–77. Bollinger A: Arterielle Verschlusskrankheiten; in Bollinger A (ed): Funktionelle Angiologie. Stuttgart, Thieme, 1979, p 80. Hansson C, Andersson E, Swanbeck G: Location of ulcers on the lower limb in relation to distal systolic blood pressure indices. Acta Derm Venereol (Stockh) 1990;71:502–505. Spitzer S, Bach R, Schieffer H: Walk training and drug treatment in patients with peripheral arterial occlusive disease stage II. A review. Int Angiol 1992;11:204–210. Skinner JS, Strandness DE: Exercise and intermittent claudication. II. Effect of physical training. Circulation 1967;36:23–29.


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Klyscz T, Ju¨nger M, Ju¨nger I, Hahn M, Rassner G: Success of an outpatient claudication group training program for patients with peripheral arterial occlusive disease (PAOD): The Tu¨bingen model. Cent Eur J Public Health 1997;5:13–20. Creasy TS, McMillan PJ, Fletcher EWL, Collin J, Morris PJ: Is percutaneous transluminal angioplasty better than exercise for claudication? Preliminary results from a prospective randomised trial. Eur J Vasc Surg 1990;4:135–140. Kappert A: Lehrbuch und Atlas der Angiologie, ed 12. Bern, Huber, 1987, pp 323–329. Hoffmann U, Leu AJ: Sekunda¨rpra¨vention der Arteriosklerose. Schweiz Rundsch Med Prax 1996; 85:1201–1205. Antiplatelet Trialists’ Collaboration: Secondary prevention of vascular disease by prolonged antiplatelet treatment. Br Med J 1988;296:320–331. Antiplatelet Trialists’ Collaboration: Collaborative overview of randomized trials of antiplatelet therapy. II. Maintenance of vascular graft or arterial patency by antiplatelet therapy. BMJ 1994; 308:159–168. Ranke C, Creutzig A, Alexander K: Acetylsalicylsaüre bei arteriellen Durchblutungssto¨rungen. Dtsch Med Wochenschr 1994;119:815–821. Wu¨schert R, Bounameaux H: Utilisation des antithrombotiques en pathologie arterielle pe´riphe´rique. Arch Mal Coeur 1996;89(suppl):1551–1555. Zheng ZJ, Sharett AR, Chambless LE, Rosamond WD, Nieto FJ, Sheps DS, Dobs A, Evas GW, Heiss G: Associations of ankle-brachial index with clinical coronary heart disease, stroke and preclinical carotid and popliteal atherosclerosis: The Atherosclerosis Risk in Communities (ARIC) study. Atherosclerosis 1997;131:115–125. Fielding JE: Smoking – Health effects and control. N Engl J Med 1985;313:491–495. Stammler J: Established coronary risk factors; in Marmot M, Elliot P (eds): Coronary Heart Disease Epidemiology – From Etiology to Public Health. New York, Oxford University Press, 1992, pp 35–66. Jonason T, Bergstro¨m R: Cessation of smoking in patients with intermittent claudication. Acta Med Scand 1987;221:253–260. Rosenberg L, Kaufman DW, Helmrich SP, Shapiro S: The risk of myocardial infarction after quitting smoking in men under 55 years of age. N Engl J Med 1985;313:1511–1514. Brand FN, Abbott RD, Kannel WB: Diabetes, intermittent claudication and risk of cardiovascular events. Diabetes 1989;38:504–509. Wilson PW, Castelli WP, Kannell WB: Coronary risk prediction in adults. The Framingham Study. Am J Cardiol 1987;59:91G–94G. The Scandinavian Simvastatin Survival Study: Randomized trial of cholesterol-lowering in 4,444 patients with coronary heart disease. Lancet 1994;344:1383–1389. Drexel H, Steurer J, Muntwyler J, Meienberg S, Schmid HR, Schneider E, Gro¨chenig E, Amann FW: Predictors of the presence and extent of peripheral arterial occlusive disease. Circulation 1996; 94(suppl II):199–205. Hess H, Mietaschk A, Deichsel G: Drug-induced inhibition of platelet function delays progression of peripheral occlusive arterial disease. Lancet 1985;i:415–419. Zinnagl N: Periphere arterielle Verschlusskrankheit. Diagnostik und moderne konservative Therapie. Hautarzt 1996;47:70–78. Pemberton M, London NJ: Colour flow duplex imaging of occlusive arterial disease of the lower limb. Br J Surg 1997;84:912–919. Mattes E, Norman PE, Jamrozik K: Falling incidence of amputations for peripheral occlusive arterial disease in Western Australia between 1980 and 1992. Eur J Vasc Endovasc Surg 1997;13:14–22. Schneider E, Gru¨ntzig A, Bollinger A: Die perkutane transluminale Angioplastie in den Stadien III und IV der peripheren arteriellen Verschlusskrankheit. Vasa 1982;11:336–339. Hafner J: Klinik und Management der arteriellen Beinulzera. Z Hautkr 1998;73:430. Wu¨tschert R, Bounameaux H: Predicting healing of arterial leg ulcers by means of segmental systolic pressure measurements. Vasa 1998;27:224–228. Loosemore TM, Chalmers TC, Dormandy JA: A meta-analysis of randomized placebo control trials in Fontaine stages III and IV peripheral occlusive arterial disease. Int Angiol 1994;13:133–142.

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Breuer C, Abri O: Prostazyklin (Iloprost) als Adjuvans bei lokalchirurgischer Therapie im Stadium IV der arteriellen Verschlusskrankheit. Ist mit tcPO2-Messung eine Quantifizierung des Therapieeffekts mo¨glich? Vasa 1995;24:62–71. Horsch S, Claeys L: Epidural spinal cord stimulation in the treatment of severe peripheral arterial occlusive disease. Ann Vasc Surg 1994;8:468–474. Claeys LG, Horsch S: Transcutaneous oxygen pressure as predictive parameter for ulcer healing in endstage vascular patients treated with spinal cord stimulation. Int Angiol 1996;15:344–349. Klomp HM, Spincemaille GHJJ, Steyerberg EW, Habbema JDF, van Urk H: Spinal-cord stimulation in critical limb ischemia: A randomised controlled trial. Lancet 1999;353:1040–1044. Pohlmann G, Reinhardt D, Grohmann G, Eidner G, Muller S: Retrograde intraveno¨se Perfusion als ultima ratio bei amputationsgefa¨hrdeten Patienten mit einer peripheren arteriellen Verschlusskrankheit. Vasa 1995;24:275–281. Burgmann H, Georgopoulos A, Graninger W, Koppensteiner R, Maca T, Minar E, Schneider B, Stumpflen A, Ehringer H: Tissue concentration of clindamycin and gentamycin near ischaemic ulcers with transvenous injection in Bier’s arterial arrest. Lancet 1996;348:781–783. Gough A, Clapperton M, Rolando N, Foster AVM, Philpott-Howard J, Edmonds ME: Randomised placebo-controlled trial of granulocyte-colony stimulating factor in diabetic foot infection. Lancet 1997;350:855–859.



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Percutaneous Transluminal Angioplasty in the Management of Arterial Leg Ulcers Ernst L. Schneider a, Ju¨rg Hafner b a b

Angiology Unit, Department of Internal Medicine and Department of Dermatology, University Hospital, Zu¨rich, Switzerland

Over 30 years ago, Dotter and Judkins [1] developed catheter-delivered balloon dilatation in peripheral arterial occlusive disease (PAOD). The procedure was later refined by the invention of the double-lumen catheter by Gru¨ntzig [2]. Solitary short stenosis responds best to percutaneous transluminal angioplasty (PTA), whereas diffuse stenosis and longer occlusions frequently reocclude, even after an initial technical success. In the following we summarize the techniques, indications and outcome of PTA in PAOD.

Endovascular Techniques in PAOD The common access for PTA is in the groin. A delivery sheath is placed into the direction of the occlusion and a guide wire is advanced to the site of the stenosis. The double-lumen balloon catheter advances along the guide wire. Distal procedures reach until the calf arteries [3, 4]. The outcome of advanced stages of PAOD with skin lesions and menacing amputation has considerably improved since the development and refinement of peripheral vascular procedures [5, 6]. Technical success rates over all stages of PAOD are reported to be around 90% [4, 5]. In advanced PAOD (Fontaine stages III and IV), Schneider et al. [5] reported an early success of around 80% and secondary patency rates after 6 months of around 75%. This is an excellent result when taking into consideration that half of the 173 patients in this series were diabetics, among whom many inoperable. Faglia et al. [4] reported that among 80 consecutive patients with diabetic foot ulcers, 26 qualified for PTA. Technical success was 85% (22/26) and patency at 12 months 95% (21/22).

a

b Fig. 1. a, b Arterial ulcer on the dorsum of the left foot. Ankle pressure 65 mm Hg, ABI 0.45. Split skin graft after successful PTA (fig. 2a, b).

Subacute thrombosis of a stenotic lesion is the main reason for a sudden clinical deterioration of PAOD. Arterial thrombi remain at least partially lysable for about 2–8 months. This makes subacute arterial thrombosis accessible for catheter-deliverable local thrombolysis (LTL) and percutaneous thromboembolectomy (PTEE) [7]. In 1989, Schneider [3] reported on a series of 255 interventions using local thrombolysis. Technical success rate was 88% and patency after 1 year was as high as 73%. Results are even improved when local thrombolysis and thromboembolectomy are combined with balloon angioplasty.

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a

b Fig. 2. a, b Successful percutaneous transluminal angioplasty of a short occlusion of the left superficial femoral artery (same patient as fig. 1a, b).

In the past few years, several devices for catheter-deliverable endarterectomy have been developed, such as the Auth Rotablator, the Trac-Wright Catheter, the Transluminal Extraction Catheter (TEC), the Simpson AtheroCath and the OminCath [8]. These devices allow for the percutaneous transluminal treatment of complex lesions, such as long occlusions. However, the intervention has a relatively high rate of complications, such as arterial thrombosis (11%), dissection (6%), perforation (4%), peripheral embolization (10%), arterial spasm, groin hematoma (5%) and hemoglobinuria (13%) [8, 9]. Early (in-hospital) clinical success is reported to be around 75–80%, whereas the cumulative primary patency rate is 47% after 6 months and 20% after 24 months [9]. In one study, 0/33 patients were found to have a patent femoral or popliteal artery 5 years after successful catheter atherectomy with the TEC device [10]. Therefore, percutaneous endarterectomy has limited applications for treatment of PAOD, until the problems with immediate complications and late restenosis are solved.

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Catheter-deliverable endovascular prosthesis (stents) improved the possibilities for the nonsurgical treatment of arterial aneurysm, of arterial dissection after interventional procedures and of fragile (‘soft’) atherosclerotic lesions that otherwise would represent a high risk of peri-interventional embolization. The stent framework consists of a steel alloy or nitinol. Nitinol is an alloy that can be folded around the catheter tip in the cold and that autoexpands in the warmth. Stents that are covered with Dacron or Polytetrafluoroethylene (PTFE) can be used for the treatment of aneurysms or arteriovenous fistulas. The iliac arteries give the best results after treatment with expandable stent grafts. Technical success reaches almost 100% in iliac occlusions and secondary patency rate is still around 95% at 18 months. However, stent grafts are less effective in femoro-popliteal occlusions, with about 55% technical success and 80% secondary patency [10]. These results are comparable to those of balloon angioplasty.

Indications for PTA in PAOD The indications for interventional peripheral vascular procedures are the following ones: severe claudication of a handicapping extent and chronic critical leg ischemia [cf chapters of Wu¨tschert et al. and Hafner]. The choice for PTA or bypass surgery depends on the morphology of the obstruction and on the general state of the patient. Short solitary stenosis and occlusions are best suitable for PTA, whereas bypass surgery results in better long-term patency rates in long obstructions (defined ?10 cm) [5, 7, 11, 12]. Technically, PTA is often also feasible in longer occlusions of the superficial femoral artery. In elderly multimorbid patients an improved arterial perfusion of limited duration (e.g. several months) may help achieve healing of skin lesions and improve mobilization. Even though reocclusion may occur during follow-up, the reduction of a Fontaine stage IIb–IV PAOD to a stage I–IIb may help avoid surgery in these patients.

Indications for PTA in Arterial Leg Ulcers For the specific situation of recalcitrant leg ulceration in patients with PAOD (arterial leg ulcers and mixed venous-arterial leg ulcers), we suggest not to base the indication for an interventional procedure on claudication or the criteria of chronic critical leg ischemia alone [13]. PAOD is largely underestimated in leg ulcer patients and may account for the most common mistakes in their management [13–17]. Due to poor mobility,


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most leg ulcer patients will not report intermittent claudication, even though their arterial perfusion may already be severely compromised. Recently, Wu¨tschert and Bounameaux [18] published a meta-analysis on the healing rate of chronic leg ulcers: In three clinical studies totalizing 220 patients, an ankle pressure of ?80 mm Hg predicted spontaneous wound healing in ?80% of patients. From January 1996 to June 1998, we treated 198 leg ulcer patients at the Department of Dermatology, University Hospital of Zu¨rich, among whom 16 patients had an arterial leg ulcer without chronic venous insufficiency. The systolic ankle pressure was 71×28 mm Hg (0–110 mm Hg) and the ABI was 0.48×0.18 (0.0–0.70). PTA was performed in 11 patients and bypass surgery in one. Healing was achieved in 10 patients, improvement in 5 and one patient with osteomyelitis underwent below-knee amputation. Currently we are investigating the long-term outcome and trying to draw more consistent conclusions on the indication for interventional vascular procedures in leg ulcer patients [13].

Conclusions PTA and the related catheter-delivered procedures, such as local thrombolysis and percutaneous thromboembolectomy, rotational endarterectomy and stent implantation on the one hand and advances in vascular surgery on the other, have greatly improved the prognosis of patients with severe PAOD. In multimorbid patients, catheter interventions are less invasive and better tolerated than surgical procedures. As a rule, proximal circumscribed lesions are best to treat with PTA, whereas bypass surgery achieves better patency rates in long (?10 cm) obstructions. PTA and bypass surgery must not be understood as competing methods, but many patients benefit at the same time of PTA and bypass surgery. For the special situation of recalcitrant arterial leg ulcers of over 6 months’ duration, Bollinger coined the term ‘complicated Fontaine stage IIb’ PAOD. As otherwise in Fontaine stage IIb, such patients should be evaluated with regard to an interventional vascular procedure. Due to poor mobility, advanced PAOD is often underestimated and masked, since these persons do not complain about intermittent claudication. We observed that leg ulcer patients (both arterial and combined venous-arterial) with an ankle-arm index =0.5 or a systolic ankle pressure =80 mm Hg often benefit from an interventional vascular procedure, despite the fact that most of these patients do not meet the strict criteria of chronic critical leg ischemia. More studies addressing this issue are required.

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References 1 2 3

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5 6

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Dotter CT, Judkins MP: Transluminal treatment of arteriosclerotic obstruction. Circulation 1964; 30:654–670. Gru¨ntzig A: Die perkutane Rekanalisation chronisch arterieller Verschlu¨sse (Dotter Prinzip) mit einem neuen doppellumigen Dilatationskatheter. Fortsch Ro¨ntgenstr 1976;124:80–86. Schneider E: Die perkutane transluminale Angioplastie, lokale Thrombolyse und perkutane Thrombenextraktion in der Behandlung von Extremita¨tenarterienverschlu¨ssen. Internist (Berl) 1989;30: 440–446. Faglia E, Favales F, Quarantiello A, Calia P, Brambilla G, Rampoldi A, Morabito A: Feasibility and effectiveness of peripheral percutaneous transluminal balloon angioplasty in diabetic subjects with foot ulcers. Diabetes Care 1996;19:1261–1264. Schneider E, Gru¨ntzig A, Bollinger A: Die perkutane transluminale Angioplastie in den Stadien III und IV der peripheren arteriellen Verschlusskrankheit. Vasa 1982;11:336–339. Mattes E, Norman PE, Jamrozik K: Falling incidence of amputations for peripheral occlusive arterial disease in Western Australia between 1980 and 1992. Eur J Vasc Endovasc Surg 1997;13: 14–22. Schneider E, Hoffmann U: Perkutane lokale Lysetherapie und Thrombenextraktion bei Verschlu¨ssen der Extremita¨tenarterien. Internist (Berl) 1996;37:607–612. Ahn SS, Concepcion B: Current status of atherectomy for peripheral arterial occlusive disease. Word J Surg 1996;20:635–643. The Collaborative Rotablator Atherectomy Group CRAG: Peripheral atherectomy with the rotablator: A multicenter report. J Vasc Surg 1994;19:509–515. Kolvenbach R, Strosche H: Long-term results after rotation angioplasty and catheter atherectomy. A retrospective analysis. J Cardiovasc Surg (Torino) 1998;39:15–18. Gray BH, Olin JW: Limitations of percutaneous transluminal angioplasty with stenting for femoropopliteal arterial occlusive disease. Semin Vasc Surg 1997;10:8–16. Hunink MGM, Wong JB, Donaldson MC, Meyerovitz MF, de Vries J, Harrington DP: Revascularization for femoropopliteal disease. A decision and cost-effectiveness analysis. J Am Med Assoc 1995;274:165–171. Hafner J: Klinik und Management der arteriellen Beinulzera. Z Hautkr 1998;73:430. Callam MJ, Harper DR, Dale JJ, Ruckley CV: Arterial disease in chronic leg ulceration: An underestimated hazard? Lothian and Forth Valley Leg Ulcer Study. Br Med J 1987;294:929–931. Callam MJ, Ruckley CV, Dale JJ, Harper DR: Hazards of compression treatment of the leg: An estimate from Scottish surgeons. Br Med J 1987;295:1382. Konradsen L, Wounlund J, Holstein P: Chronic critical leg ischemia must include leg ulcers. Eur J Vasc Endovasc Surg 1996;11:74–77. Hafner J, Cassina P, Brunner U, Burg G: Ulcus cruris: Behandlung der schwierigen Fa¨lle. Geriatr Prax 1997;8:29–34. Wu¨tschert R, Bounameaux H: Predicting healing of arterial leg ulcers by means of segmental systolic pressure measurements. Vasa 1998;27:224–228.

E. Schneider, MD, Angiology Unit, Department of Internal Medicine, University Hospital of Zu¨rich, CH–8091 Zu¨rich (Switzerland) Tel. +41 1 255 27 66, Fax +41 1 255 45 10


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Reconstructive Arterial Surgery Paolo C. Cassina Department of Surgery, Division of Vascular Surgery, University Hospital, Zu¨rich, Switzerland

Introduction Chronic ulceration of the leg is a common disease, especially among the elderly, affecting up to 1% of the population. Up until recently, management of ulcers was rarely based upon scientific principles but rather marketing pressures which determined the choice of dressing irrespective of its efficacy. In the past 10 years several studies have revealed that most ulcers are the results of several etiological factors operating together. Although the majority of ulcers result from venous insufficiency, simultaneous arterial disease has been underestimated in the past [1]. Recent advances in duplex Doppler ultrasonography allows for the rapid, noninvasive fuctional and anatomical assessment of both the venous and arterial systems of the lower limb. Subsequently, coexisting severe arterial disease was found in up to 35% of patients with so-called ‘venous limb ulcer’ [2]. Furthermore, up to 9% of these cases were purely arterial [3]. It is necessary to identify the ulcers with an arterial component, not only because many of them will heal after improvement of the circulation but also because inappropriate compression bandaging of these legs may have deleterious consequences even leading to critical ischemia. In a recent study [4] it was shown that foot ulcerations were predominantly caused by arterial disease (74% of the cases). Therefore it is necessary to distinguish ulcerations confined to the leg from those involving the foot. In the following section, general principles of vascular reconstruction in chronic ischemic lower extremity ischemia are discussed.

General Considerations Atherosclerosis is primarily a disease of the arterial intima that extends into the media but usually spares the outer media and adventitia. Atheroscle

rosis is a systemic disease with a remarkable segmental distribution. It develops at major arterial bifurcations and in areas of posterior fixation or acute angulation. The distal arterial segment of the superficial femoral artery in the adductor canal is the site most commonly involved in atherosclerosis of the lower extremity. The common femoral artery represents another frequent location for plaques that extend into the proximal superficial femoral and deep femoral arteries. Other sites for atherosclerosis are the common iliac arterial bifurcation, the popliteal artery and the popliteal trifurcation. As the true extent of atherosclerotic involvement of the posterior arterial wall may be difficult to appreciate on routine arteriograms, it is only careful palpation during surgery that reveals the exact extension of the problem and permits appropriate modification of the proposed reconstructive procedure. Limb ischemia can be classified as functional or critical. Functional ischemia occurs when blood flow is adequate for the resting extremity but cannot be increased in response to exercise. Clinically, claudication (derived from Latin ‘to limp’) is the leading symptom. It consists of three essential features: the pain is always felt in a functional muscle unit; it worsens with increasing exercise, and it is promptly relieved by stopping exercise. Critical limb ischemia (CLI) is defined by (1) recurring ischemic rest pain that persists for more than 2 weeks and requires analgesics, with an ankle systolic pressure of 50 mm Hg or less, or (2) ulceration or gangrene of the foot or toes with similar hemodynamic parameters. Unlike claudication, ischemic rest pain is not felt in a muscle group but in the foot, especially the toes and metatarsal heads. At this stage, the pain is usually relieved by dangling the leg over the side of the bed or ambulation. This nocturnal pain should be distinguished from the more severe rest pain that is constant and present even with dependency. Such limbs are incapacitated by chronic pain, paresthesia, and paresis. Because patients keep such limbs dependent there is often a concomitant edema which in itself compromises tissue perfusion. In such cases imaging procedures always demonstrate serial obstructions of the arterial vasculature, in contrast to patients with claudication who usually have only one or two segments involved. A clear distinction between the two categories (i.e. functional ischemia and CLI) is not always possible since they represent two forms of the same disease that may overlap. The diagnosis of ischemic rest pain can be particularly difficult to make in patients with diabetes mellitus, because atherosclerosis with loss of peripehral pulses is commonly associated with peripheral neuropathy which can mimic rest pain. In these cases the noninvasive vascular laboratory can be very helpful. Although atherosclerosis is not qualitatively different in diabetic patients, it appears at an earlier age and progresses more rapidly. The distribution of atherosclerotic lesions differs as the vessels of the lower extremities are more

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diffusely and severely involved whereas the aorta and the iliac arteries may remain unaffected. The vascular lesions in both diabetic and nondiabetic subjects are qualitatively similar but in diabetics atherosclerosis is more frequent, severe and occurs in more distal location (calf vessels).

Indications for Surgery The choice of surgical management of peripheral arterial disease will be determined by following clinical settings: (1) functional ischemia and (2) CLI. Patients with functional ischemia face little risk of limb loss if they manage to eliminate risk factors, especially tobacco. However, if claudication imposes an unacceptable alteration in lifestyle, surgical revascularization should be considered. Because the determination of disability resulting from functional limb ischemia is relative, it should be the patient’s prerogative to request revascularization, provided he understands the risks involved and the benefits of the more conservative, nonoperative approach. Critical limb ischemia represents a definite indication for arterial reconstruction. Surgical procedures encompass either endarterectomy or bypass grafting. Obviously location of disease and the patient’s general status will determine the amenability of these techniques. As a result of advances in anesthesiology and postoperative management as well as the development of a variety of percutaneous endovascular techniques for surgical revascularization, currently reported operative mortality rates for most vascular procedures are actually lower than those for amputation of an extremity. Furthermore, even temporary graft patency may be sufficient to permit healing of an ischemic ulcer or toe amputation. Subsequently, failure of vascular repair will not inevitably threaten survival of the limb. Patients whose graft became occluded 6 months to 1 year postoperatively frequently experience pain relief allowing for a more efficient rehabilitation than amputation and a prosthesis would allow for [5]. Similar to other areas in medicine, success in vascular surgery depends on rigorous patient selection, meticulous attention to technical details, and choice of the correct operative procedure based on certain important principles. Among these, the most important is the assurance of a relatively unobstructed inflow and a patent distal run-off if both early and late patency are to be achieved (fig. 1). For example, if a femoropopliteal bypass is being planned, it is essential that there is no significant obstruction in the aorta or iliac arteries. Furthermore, a patent segment of popliteal artery with sufficient runoff to sustain a graft must be present. The importance of ensuring adequate inflow cannot be overemphasized. In an experimental canine model, graft occlusion regularly occurred if an

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1

100

Patency (%)

Secondary vein patency Prim ary vein patency 50 Secontary PTFE patency Prim ary PTFE patency

10

20

30

40

50

M onths

2 Fig. 1. Postoperative iv-DSA of a 73-year-old female patient with chronic limb ischemia and leg ulcer (ABI>0.45). Three weeks after femorotruncal bypass with autologous saphenous vein, the wound was completely closed. Fig. 2. Lifetable analysis of femorocrural reconstructions using autologous vein and PTFE grafts with distal vein collar. The dotted line represents standard error of the mean in excess of 10%. Redrawn after Cheshire et al. [5].


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3a

3b Fig. 3. a Ulcer and mummification of the left foot after acute occlusion of the left iliac artery and chronic occlusion of the superficial femoral artery. b Reconstruction with an iliacofemoral bypass into a widely patent deep femoral artery. c Two weeks after revascularization the wound is covered with mesh graft.

inflow stenosis was induced. The graft remained patent however when an equivalent degree of outflow stenosis was induced [6]. The patency of run-off vessels distal to an obstruction may be difficult to assess. Although a patent common femoral artery with disease-free superficial and deep femoral arteries or a patent popliteal artery with an intact crural run-off is ideal, the deep femoral artery can be an adequate recipient for the entire inflow into the lower extremities. Exellent long-term patency and function can be expected despite superficial artery occlusion. Similarly, extensive disease in the popliteal artery or crural vessels does not preclude revascularization in limb-threatening situations. Bypass into a patent popliteal segment without direct run-off into the

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3c

tibial arteries can be performed with results comparable to those of conventional femoropopliteal grafting [7]. This approach is particularly suitable for the treatment of rest pain or superficial focal gangrene. When the gangrene is more extensive, higher perfusion pressures are needed to achieve healing, and direct bypass onto the crural arteries is usually required. The technical failure rate for these demanding small vessel anastomoses is higher than that for femoropopliteal bypass, and only 50–60% of them will remain patent 2 years after implantation (fig. 2). Limb salvage rates, however, are higher, averaging 75% over the same period for the reasons already given. Most patients selected for vascular reconstruction have arterial obstructions at two or more levels in the same arterial system. The general principles that govern the choice of operation in these cases are (1) if all lesions are of equal severity, correct the most proximal lesion first, and (2) if the lesions are of greatly differing severity, correct the most several occlusion first. The


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importance of correcting ‘inflow’ disease first is worth re-emphasizing. The most common example of this problem is the patient with significant aortoiliac stenosis and an ipsilateral occlusion of the superficial femoral artery. Aortofemoral bypass into a widely patent deep femoral artery will heal ischemic lesions of the foot, relieve rest pain, and markedly reduce claudication, especially if the distal deep femoral artery is disease-free and the popliteal artery and its tibial branches are patent (fig. 3a–c). Management of less severe degrees of proximal disease (i.e. iliac arteries) has been a particularly perplexing problem. The development of percutaneous transluminal angioplastly has provided surgeons with a valid alternative. Before the proposed distal bypass is undertaken, the proximal lesion can be corrected with angioplastly and the hemodynamic improvement of this procedure can be assessed by means of noninvasive tests. If the distal bypass still appears to be necessary, the surgeon can proceed with the assurance that good inflow has now been provided. Since no vascular procedure alters or arrests the underlying atherosclerotic process, the patient remains susceptible to progression of the disease in the vessels contiguous to the bypass or at sites remote from the primary operation. The responsible surgeon must perform continuous long-term follow-up of all patients with symptomatic arterial occlusive disease.

Autologous Vein and Prosthetic Graft The reversed autologous saphenous vein has remained the graft material of choice for femoropopliteal bypass since Kunlin [8] first described this procedure in 1949. However, between 20 and 40% of patients requiring infrainguinal bypass grafting will not have an adequate ipsilateral greater saphenous vein. If the surgeon intends to use arm veins or to construct composite grafts using vein fragments harvested from multiple sites, autologous conduits can be fashioned in a significant percentage of these patients. Such grafts, however, do not have a long-term patency equivalent to a good, greater saphenous vein. Polytetrafluoroethylene (PTFE) grafts were first introduced for clinical use in 1973 and tested in several trials which demonstrated patency and limb salvage rates similar to those with reversed saphenous vein for bypasses to the above-knee popliteal artery. However, superiority of saphenous vein over synthetic material has been consistently demonstrated for infrageniculate grafting [9]. The excellent performance of the saphenous vein in the femoropopliteal position led vascular surgeons to successfully achieve limb salvage with more distal (crural and pedal) reconstructions, thereby expanding the possibility to maintain functional viability of the lower extremity. However, a significant

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failure rate up to 50% at 5 years is inherent to all these reconstructions, eventually leading to additional interventions (fig. 2).

Postoperative Management Comorbid conditions will determine if the patient will need to be admitted to the intensive care unit. Pulses should be assessed frequently, either by palpation or by monitoring with Doppler ultrasound during the first 24 h and several times daily thereafter to ensure sustained patency. In the absence of significant systemic complications, early graft thrombosis should prompt immediate return to the operating room for thrombectomy, angiography, and revision as necessary. Patients without significant tissue necrosis ambulate routinely on the first postoperative day, and those with healing lesions later. Patients with uncomplicated procedures are usually discharged 5–7 days postoperatively, whereas those with systemic complications or cutaneous distal lesions may required longer hospital stays. Following discharge, all grafts require periodic surveillance to identify hemodynamically significant stenoses in time before thrombosis occurs. It has been repeatedly demonstrated that revision of such stenotic lesions results in improved graft patency, whereas revision following graft thrombosis yields poor results [10]. There is still little clinical evidence available to support a routine use of anticoagulant agents (i.e. low-molecular-weight heparin, platelet inhibitors, coumarins) to maintain graft patency, though some studies suggest that anticoagulation may improve the results of infrapopliteal bypass surgery [11, 12]. Patients with unexplained graft thrombosis following thrombectomy and those with hypercoagulability, however, are frequently maintained on oral anticoagulation. Wound healing may be significantly delayed by the inevitable appearance of postischemic edema in the leg after successful revascularization. Edema results from increased interstitial fluid accumulation, lymphatic obstruction and, to some degree, from venous interruption. Patients should be instructed to elevate their legs periodically during early recovery. The edema gradually regresses in most patients over the course of a few weeks, but may occasionally remain for several months. Delayed wound complications have been reported to occur in as many as 50% of these patients.


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References 1 2 3 4 5 6 7 8 9

10 11

12

Callam MJ, Harper DR, Dale JJ, Ruckley CV: Arterial disease in chronic leg ulceration: An understimated hazard? Lothian and Forth Valley Leg Ulcer Study. Br Med J 1987;294:929–931. Cornwall JV, Dore CJ, Lewis JD: Leg ulcers: Epidemiology and aetiology. Br J Surg 1986;73: 693–696. Scriven JM, Hartshorne T, Bell PRF, Naylor AR, London NJ: Single-visit venous ulcer assessment clinic: The first year. Br J Surg 1997;84:334–336. Baker SR, Stacey MC, Singh G, Hostin SE, Thompson PJ: Aetiology of chronic leg ulcer. Eur J Vasc Surg 1992;6:245–251. Chesire NJW, Wolfe JHN: How to select the treatment of choice in critical leg ischemia. Ann Chir Gynaecol 1992;81:146–152. Kirkpatrick JR, Miller DR: Effects of decreased arterial inflow and runoff of vein graft patency. Surgery 1971;69:870–873. Loh A, Chester JF, Taylor RS: PTFE bypass grafting to isolated popliteal segments in critical limb ischemia. Eur J Vasc Surg 1993;7:26–30. Kunlin J: Le traitement de l’arte´rite oblite´rante par la greffe veineuse. Arch Mal Cœur Vaiss 1949; 42:371–372. Veith FJ, Gupta SK, Ascer E, White-Flores S, Samson RH, Scher LA, Towne JB, Bernhard VM, Bonier P, Flinn WR, et al: Six-year prospective multicentre randomized comparison of autologous saphenous vein and expanded polytetrafluoroethylene grafts in infrainguinal arterial reconstruction. J Vasc Surg 1986;3:104–114. Bandyk DF, Bergamini TM, Towne JB, Schmitt DD, Seabrook GR: Durability of vein graft revision: The outcome of secondary procedures. J Vasc Surg 1991;113:200–208. Kretschmer G, Herbst F, Prager M, Sautner T, Wenzl E, Berlakovich GA, Zekert F, Marosi L, Schemper M: A decade of oral anticoagulant treatment to maintain autologous vein graft for femoropopliteal atherosclerosis. Arch Surg 1992;127:1112–1125. Flinn WR, Rohrer MJ, Yao JST, McCarthy WJ, Fabey VA, Bergan JJ: Improved long-term patency of infragenicular polytetrafluoroethylene grafts. J Vasc Surg 1988;7:685–690.

Paolo Cassina, MD, Department of Surgery, Division of Vascular Surgery, University Hospital, CH–8091 Zu¨rich (Switzerland) Tel. +41 1 2555738, Fax +41 1 2554449, E-Mail [email protected]

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Part IV. Diabetic Ulcers Hafner J, Ramelet A-A, Schmeller W, Brunner UV (eds): Management of Leg Ulcers. Curr Probl Dermatol. Basel, Karger, 1999, vol 27, pp 235–241

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Conservative Therapy of Diabetic Foot Norbert Zinnagl Konservative Angiologie, Landeskrankenanstalten, Salzburg, Austria

The syndrome of the diabetic foot is a specific complication of diabetes mellitus. Several pathomechanisms are involved in its pathogenesis. These include: (1) diabetic macro- and microangiopathy; (2) diabetic neuropathy; (3) diabetic osteoarthropathy, and (4) reduced resistance to infection in diabetics. The combined actions of these factors in the development of the diabetic foot are shown in figure 1, and table 1. Lesions of the feet affect an estimated 7% of diabetics at some stage of their disease. The amputation rate is 15-fold higher compared to nondiabetics. Approximately 45% of all lower extremity amputations concern diabetics [1]. However, type I and type II diabetes differs clearly regarding the relative incidence rates. Atherosclerosis is rarely seen in type I diabetics younger than 40 years of age, whereas atherosclerotic pathologies either coincide with the initial diagnosis of a type II diabetes or may even start years before [2]. Up until now it was debated if diabetic angiopathy is primarily caused by diabetes itself or whether it represents an entity of its own. Standl [3] has compiled a variety of cardiovascular risk factors in 274 selected type II diabetics (table 2). Since diabetic microangiopathy can occur years before the manifestation of diabetes, the term ‘late complication’ is debatable. As a consequence, doctors and patients tend to underestimate the risk of vascular changes in the absence of clinical overt diabetes. Management of the diabetic foot requires a complex and interdisciplinary approach and an understanding of the basic pathomechanisms. In the following, we will discuss the essential aspects.

Diabetic Micro- and Macroangiopathy Diabetic macroangiopathy affects all anatomic segments of the vasculature, i.e. cerebral, coronary as well as peripheral arteries, especially of the

Neuropathy

Angiopathy

Osteoarthropathy

Infection

Fig. 1. Combined action of neuropathy, angiopathy, osteoarthropathy and infection in the development of the diabetic foot.

Table 1. Pathomechanisms of diabetic foot Primary causes Polyneuropathy Peripheral arterial occlusive disease Microangiopathy, thickening of basal membranes Osteoarthropathy Secondary causes Locally reduced resistance to infection Poor formation to collateral vessels

lower extremities. Histologically, diabetic macroangiopathy does not differ from nondiabetic atherosclerosis [4]. However, atherosclerotic lesions are distributed differently. Diabetic macroangiopathy primarily affects the distal segments of the lower extremities (calf and foot arteries), as well as the profound femoral artery [5]. Disappearance of a palpable pedal pulse, while the popliteal and inguinal pulse still remains palpable, combined with a pathological great toe pulse curve in oscillography are typical findings in diabetic macroangiopathy. Mo¨nckeberg’s medial calcinosis renders the peripheral arteries rigid and incom-

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Table 2. Cardiovascular risk factors in selected type II diabetics (n>274) Risk factor

%

HbA1c?8% Hypertension (RR?160/95 mm Hg) Hypertriglyceridemia?200 mg/dl Hypercholesterolemia?250 mg/dl Obesity (?Broca weight+10%) Smoker Former smoker

49 65 64 43 51 16 9

pressible. Therefore, measurement of ankle blood pressure with Doppler ultrasound and calculation of an ankle-arm index (ischemic index) is unreliable [cf chapter of Wu¨tschert et al.]. Arterial calcification is readily detectable on plain radiograms of diabetic patients with macroangiopathy. Commonly, angiography reveals little alterations at the level of the aorta and pelvic arteries, but rather at the level of the calf arteries. Oxygen supply is, therefore, critically compromised in the periphery of these extremities [6]. Moreover, gas exchange is compromised by marked thickening of the capillary basal membrane, a common feature in diabetic microangiopathy [7].

Diabetic Neuropathy Diabetic neuropathy affects peripheral sensory and motor nerve fibers as well as C-fibers of the autonomous nerve system. The C-fibers transmit the so-called deep-sensory qualities, i.e. pain and pressure. Initially the deep sensory perception is reduced and finally completely abrogated in later stages, which results in loss of protective reflexes against physical injury. Foreign bodies may penetrate the sole of a diabetic patient without being noticed. Typically, sensory neuropathy manifests itself in a socklike distribution. The neurologist uses a tuning fork to check for neuropathy [8]. Motor neuropathy leads to denervation and atrophy of small foot muscles. Clinically this can be easily observed by the protrusion of the metatarsal heads of the sole. Therefore, the most common type of diabetic neuro-osteoarthopathy results in a so-called malum perforans located over the metatarsal heads.

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Moreover, instability of the transversal foot vault results in a splay foot and ‘clawing’ of the toes, which in turn exposes the pulpits as well as the dorsum of the proximal interphalangeal joint to increased pressure, which can cause ulcerations at the toes. Finally, any type of unnoticed pressure, e.g. from poorly fitting shoes, exposes the diabetic foot to the risk of developing a foot ulcer [cf chapter of Wetz]. Autonomous neuropathy leads to vasodilatation and cessation of sweat secretion (‘auto-sympathectomy’). Therefore, the typical neuropathic foot is warm, rosy, dry, scaly, develops fissures and is visibly deformed. Presumably, infection of the diabetic foot is also related to cracking of the skin at the soles, which facilitates the penetration of infectious pathogens across the impaired skin barrier.

The Diabetic Osteoarthropathy Many diabetics develop the complex picture of the so-called Charcot’s foot. Initially, decalcification can be observed on plain radiograms. Gradually the feet exhibit fallen arches and a flat-splay foot morphology. The vault of the foot skeleton then breaks down leaving the patient with a rocker foot. Ultimately, the skeleton dissolves, leaving only remnants of calcification to be seen on the radiogram.

Increased Infection Rate Diabetic foot ulcers are prone to infections. Skin fissuration of the soles facilitates the penetration of infectious microbes. Polymorphonuclear granulocyte chemotaxis and phagocytosis is impaired in poorly controlled diabetes. Diabetics with a polyneuropathy can acquire a foot infection due to impaired pain sensation. Therefore, deep muscle and soft tissue destruction often develops to a deleterious extent, a clinical picture which is termed diabetic gangrene. Both aerobe and anaerobe bacteria are frequently involved in diabetic foot infection. Therefore, broad-spectrum polychemotherapy is mandatory at the very beginning of treatment. In the German-speaking countries either the six-step classification of diabetic foot lesions according to Wagner or the four-step classification of the malum perforans given by Arlt are in use (tables 3, 4).

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Table 3. Wagner classification [9] Grade Grade Grade Grade Grade Grade

0 1 2 3 4 5

Skin intact, no foot deformity, no hyperkeratosis Superficial ulcer Deep ulcer Deep ulcer with infection Limited necrosis Necrosis of the entire foot

Table 4. Arlt classification of malum perforans [10]

Stage Stage Stage Stage Stage

1 2a 2b 3 4

Necrosis of epidermis Malum perforans extended to the subcutaneous fat Malum perforans extended to bone or joint Malum perforans with destruction of bone or joint Malum perforans with deep infection

Preventive Foot Care in Diabetics Effective preventive foot care is mandatory in all diabetics. Unequivocally an optimal control of blood glucose is crucial. Established neuro-osteoarthropathy is not reversible, but its progression may be controlled. Therefore, local control and early treatment of initial lesions are essential to avoid complications in diabetic feet. For that purpose the soles and interdigital spaces need to be inspected on a regular basis. If a patient is unable to inspect his soles, e.g. due to rheumatism, a mirror should be used. In patients with impaired sight, e.g. because of diabetic retinopathy, other persons should control the feet regularly for developing lesions, callus or pressure sores. In elderly patients, often physically handicapped, nailcare should be performed by a professional chiropodist to avoid additional trauma. Unfortunately, inappropriate nailcare (‘bathroom surgery’) often causes badly healing wounds on the toes of diabetics. Because the diabetic foot often is dry due to neuropathy, regular application of moisturizing cream and proper hygiene, using Syndets, are recommended. However, we do not recommend to soak the foot for more than 5 min and to monitor the temperature of the water, which ideally should be around 32 ºC, with the hands in order to avoid burns. It is also necessary to inform the patient not to walk barefoot and to be aware of dermal injuries, that may remain unnoticed because of neuropathy.


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Last but not least, we must insist on the requirement of optimally fitted footwear in the preventive care of the diabetic foot.

Therapy of the Diabetic Macro- and Microangiopathy Today the therapy of diabetic macroangiopathy follows the therapeutic principles as put forward for peripheral arterial occlusive disease (PAOD). Initial PAOD needs to be diagnosed as early as possible and the patient has to be informed. The doctor must be aware that intermittent claudication may be masked by polyneuropathy. Diabetics often do not consult their physician before developing stage III or IV PAOD. Since the extremity is already at risk in these stages of PAOD, an angiography aids to evaluate for the chance of recanalization by catheter intervention or vascular surgery. Today, bypass surgery in the periphery of the leg (cruropedal bypass) is much more successful than a couple of years ago. Therefore, the chance to save the extremity of diabetic patients has much improved. If vascular procedures are contraindicated or not feasible, especially when the vascular lesions are located in the lower leg and pedal arteries, the wounds need to be treated in a conservative way. Proper dressing technique is essential as well as rational local therapy [cf chapter of Aubo¨ck]. Secondary prevention which entails the use of aspirin lowers the risk of coronary heart disease and probably also is effective in the secondary prevention of PAOD. Among vasoactive substances, prostaglandins are the best investigated [cf chapter of Hafner].

Therapy of Diabetic Polyneuropathy Up until now an effective therapy of diabetic neuropathy has not been found. Clinical experience shows that advanced polyneuropathy does not improve much with drugs like vitamin B and folic acid. A suitable local therapy of the neuropathic ulcer will also enhance healing. Finally, we want to stress once more that fitted footwear is crucial in diabetics.

Therapy of Diabetic Gangrene and Infection When infection occurs in a diabetic foot, it is very important to start an early empirical treatment with broad-spectrum antibiotics, without waiting for the swab result. Since aerobic as well as anaerobic organisms have to be

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considered, a combination of clindamycin and ciprofloxacin has proved effective in our experience. An alternative could be clindamycin and phosphomycin. In uncomplicated soft tissue infections in out-patients, we also use a combination of penicillin and clavulanic acid. The sine qua non of diabetic foot ulcer care is twofold: Debridement of callus and necrotic tissue and off-loading the ulcer site. Short-term application of povidone iodine or local antiseptics like rivanol are suitable local therapies. Nevertheless, minor amputations, e.g. along a demarcation line or a transmetatarsal amputation, cannot always be avoided.

References 1 2 3 4 5 6 7 8

9 10

Most RS, Sinnock P: The epidemiology of lower extremity amputations in diabetic individuals. Diab Care 1983;6:87–91. Alexander K: Mikro- und makroangiopathische Vera¨nderungen bei Diabetes mellitus. Ha¨mostasiologie 1983;4:3–27. Standl E: Klinische Folgen der Hyperinsulina¨mie bei Diabetes mellitus. Klin Wochenschr 1992; 69(suppl 29):63–67. Conrad MC: Large and small artery occlusion in diabetics and nondiabetics with severe vascular disease. Circulation 1967;36:83–91. Lo Gerfo FW, Marcacio EJ: Etiology and assessment of ischemia in the diabetic. Ann Chir Gynaecol 1992;81:122–124. Zeitler E: Angiographische Ro¨ntgendiagnose bei Makroangiopathie; in Alexander K, Cachovan M (eds): Diabetische Angiopathien. Baden-Baden, Witzstrock, 1977. Flynn MD, Tooke JE: Aetiology of diabetic foot ulceration: A role for the microcirculation. Diabet Med 1992;8:320–329. Forst T, Pfu¨tzner A, von Hasselbach Y, Lehnert H, Beyer J: Evaluation of neuropathic involvement by fibre type in patients with either insulin-dependent or non-insulin-dependent diabetes with and without neurotrophic foot ulceration. Diab Nutr Metab 1994;8:292–297. Wagner FW: The dysvascular foot: A system for diagnosis and treatment. Foot Ankle 1981;2: 64–122. Arlt B: Notwendigkeit einer einheitlichen Nomenklatur am ‘Diabetischen Fuss’. Diabetes Stoffwechsel 1993;2:324–325.

Dr. med. N. Zinnagl, Konservative Angiologie, Landeskrankenanstalten, Mu¨llner Hauptstrasse 48, A–5020 Salzburg (Austria) Tel. +43 662 44 830 11


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Orthopedic Aspects in Diabetic Neuropathic Osteoarthropathy Hans Henning Wetz Department of Technical Orthopedic Surgery and Reeducation, Westfalian Wilhelms’ University, Mu¨nster, Germany

Introduction Charcot [1] was the first to report a case of neuropathic osteoarthropathy in a patient with tabes dorsalis (fig. 1). It was only after insulin became available (discovered in 1921 by Sir Frederick Grant Bantig [2], an orthopedic surgeon) that this type of osteoarthropathy was observed in long-standing diabetes. A multidisciplinary approach to the diabetic foot by internists, orthopedic surgeons, vascular surgeons, neurologists and dermatologists is relatively new and only came to its own right in the 1940s [3–5]. Our modern understanding on the pathogenesis of the diabetic foot is the result of ongoing biochemical and biomechanical research.

The Metabolic Theory ‘Autosympathectomy’ is one of the currently accepted hypotheses on the pathogenesis of diabetic neuropathic osteoarthropathy (DNOAP). Sorbitol is a product of an increased aldose-reductase metabolism and is toxic on the myosin metabolism of the peripheral and autonomous nerves. Consecutive vasodilation leads to bone resorption and destabilization of the foot skeleton. Ultimately, minor trauma may result in the sintering of the forefoot and/or backfoot [6, 7]. Noteworthy, this process is a consequence of diabetes and, therefore, has to be covered by the health insurance and not by the accident insurance.

Fig. 1. Copperplate engraving of Charcot’s original report on neuropathic osteoarthropathy in tabes dorsalis. [Courtesy of Prof. Dr. R. Baumgartner].

Classification of DNOAP Sander’s classification of DNOAP encompasses five main types according to location on the foot [8]. Modifications of Sander’s classification are under way; however, we recommend the use of the original five-stage classification in order to compare results among investigators [6]. DNOAP type I, II and III are most common, accounting for about 70% [8] to 80% [own results] of patients. DNOAP Type I (fig. 2a, b) The hallmark of DNOAP type I is necrosis of the metatarsophalangeal joints, eventually ending in the so-called candystick deformity. The point of the metatarsals may actually perforate the skin of the sole, resulting in a so-called central malum perforans (fig. 2a, b). Moreover, an atrophy of the subcutaneous fat pad of the sole favors skin ulceration of the sole at the forefoot. Resection of the distal metatarsals while conserving the toes (operation according to Velpeau, modified after Baumgartner) represents an established approach to this type of deformity [9–17].

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a

b Fig. 2. a, b DNOAP type I. Malum perforans over the head of metatarsal I and IV. Osteolysis of metatarsal II. Candystick deformity of metatarsal III.

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a

b Fig. 3. a, b DNOAP type II. Sintering of the foot vault and destruction of Lisfranc’s articulation exposes the sole of the middlefoot to pressure. Ulceration over the os cuneiforme I.

DNOAP Type II (fig. 3a, b) In DNOAP type II the tarsometatarsal joints (Lisfranc’s joint) are affected. Neuropathic osteoarthropathy essentially affects the cuneiforms, which basically results in a destabilized backfoot. Luxation of the naviculare leads to a clubfoot with abduction of the forefoot and rocking foot deformity. In case of insufficient orthopedic shoe supports, exposure of the cuneiform-naviculare joint may lead to ulceration at this location (fig. 3a, b). DNOAP Type III (fig. 4a, b) DNOAP type III involves the Chopart’s joint, i.e. essentially the area between the talus and naviculare. An entire breakdown of the foot vault leads to the classical rocking foot deformitiy where the middle of the sole becomes exposed to pressure. A soft tissue radiography shows the ulceration lying directly beneath the verticalized talus (fig. 4a, b). Cystic demineralization of the backfoot is another characteristic feature. Further orthopedic pathology encompasses broadening of the backfoot, abduction of the forefoot and talonavicular luxation with involvement of the deep plantar ligament, as can be demonstrated on CT scan.


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a

b Fig. 4. a, b DNOAP type III. Destruction of Chopart’s articulation, talonaviculare luxation and verticulization of the talus exposes the middlefoot to pressure. Ulceration over the os naviculare.

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a

b Fig. 5. a, b DNOAP type IV. Destruction of the upper ankle joint (tibiotalare joint).

DNOAP Type IV (fig. 5a, b) DNOAP type IV involves the upper ankle joint (tibiotalare joint) (fig. 5a). Painless osseous breakdown in the ankle region develops during normal walking (fig. 5b). DNOAP Type V (fig. 6a, b) DNOAP type V involves the back part of the lower ankle joint, i.e. the talocalcanear joint. The breakdown of this section of the ankle joint results unavoidably in a clump backfoot with the bayonet type of deformity (fig. 6a, b). Lateral ulceration of the trophically damaged skin may lead to infection of soft tissue and eventually of the joint. Prevalence and Management of DNOAP in an Outpatient Setting We screened the patient files of the Technical Orthopedics Unit (Department of Orthopedics Surgery, Balgrist, University Hospital of Zu¨rich) and


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b

Fig. 6. a, b DNOAP type V. Destruction of the lower ankle joint (talocalcanear joint) leading to ‘bayonet’ deformity and dangerous lateral skin ulceration.

a

recalled all the patients with DNOAP for a clinical follow-up. All patients were classified according to Sanders [8].

Results From 1989 through 1994, we identified 136 diabetic patients (diabetes type I and II) who were treated for a specific foot problem. Among this group, 59 patients had DNOAP, 30 men and 29 women. The mean age was 64 years (range 29–85). Twenty-four patients (40%) had DNOAP type I, another 24 patients (40%) DNOAP type II and III, 9 patients (15%) DNOAP type IV and 3 patients (5%) DNOAP type V. Treatment of DNOAP Type I Twenty of 24 patients with clinical and radiological DNOAP type I required surgical treatment for soft tissue infection. In 65% of these patients a resection of two thirds of the metatarsal underneath the malum perforans (according to Baumgartner [13, 15]) was performed. In cases with extensive plantar ulceration, all five metatarsals were completely resected. After the intervention, an ulcer took 4–6 weeks on average to heal. Recurrences were found in 28% after 5 years of follow-up. All the patients with DNOAP type

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Fig. 7. Suspension leg orthesis (ankle foot orthesis) of light carbon fiber-strengthened epoxy resin laminate. This type of orthopedic aid is used in DNOAP type II–V with foot ulceration.

I received an orthopedic shoe support. If no surgical intervention was performed, the patients received orthopedic footwear to offload the forefoot. For this purpose the support consisted of a middlefoot roll (rocker sole), a broad retrocapital platform (at least 2.5 cm divergence) and a heel roll or heel buffer [10]. Patients who underwent the resection of a single metatarsal used the same support system. In case all five metatarsals were resected, an individually tailored orthopedic footwear was designed and included an integrated footpoint, ankel cap, stiff sole and middlefoot roll (rocker sole). Treatment of DNOAP Type II and III Management of DNOAP type II and III is conservative. In 45% of patients the middlefoot ulcer was complicated by soft tissue infection. Management consisted in orthopedic footwear and antibiotherapy. Eleven patients (45%) among the DNOAP type II and III patients who were at risk to develop a further deformation of the middle foot, received a suspension leg orthesis (ankle-foot orthesis) made of light carbon fiber-strengthened epoxy resin laminate (fig. 7). Thirteen patients (55%) among the DNOAP type II and III patients had inactive or burned out osteoarthropathy. They received orthopedic footwear with an integrated footprint, ankle cap, stiff sole and middlefoot roll. Figure 8 shows a transsectional radiogram of this type of orthopedic footwear.


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Fig. 8. Orthopedic footwear with an integrated footprint, ankle cap, stiff sole and middlefoot roll. This type of orthopedic footwear is used in DNOAP type I–V with healed foot ulcers.

Plantar ulceration recurred in 56% within 5 years, usually as a result of ongoing sintering of the vault. Among patients with recurrent ulceration, 84% healed again under conservative management, whereas 16% finally required a backfoot amputation according to Syme. Treatment of DNOAP Type IV and V Twelve patients (20%) had destruction of the upper or lower ankle joint. Management was primarily conservative. Two among twelve (12%) had a heel ulcer and received a suspension leg orthesis (ankle-foot orthesis), as used in DNOAP type II and III and ulcerations (fig. 7). The other 10 patients were supplied by individually tailored orthopedic footwear. In 2 patients with recurrent ulceration and impairment, backfoot amputation according to Syme could not be avoided.

Discussion In our series of 59 patients, surgical management was successful in DNOAP type I. In our experience, the modified resection of the metatarsals according to Velpeau and Baumgartner leads to ulcer healing within 6 weeks [9–17]. A conservative treatment regimen was preferred for DNOAP type II–V.

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If no ulcerations were present, patients were supplied with orthopedic footwear. Suspension leg ortheses (ankle-foot orthesis) were used in the presence of foot ulcers. Prevalence of the different types of DNOAP was comparable with that reported in the literature [18–20]. Our analysis revealed no linkage between recurrence of foot ulcers and orthopedic management. This demonstrates an excellent collaboration between orthopedic surgeons and orthopedic shoemakers. However, efficient prevention of recurrences depended much on a regular clinical follow-up, especially in patients with poor compliance.

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

13 14 15 16 17 18 19 20

Charcot JM, Feret CH: Affections osseuses et articulaires du pied chez les tabe´tiques (pied tabe´tique). Arch Neurol 1883;2:305–319. Bantig FG, Best CH: Pancreatic extracts in the treatment of diabetes mellitus. Can Med Assoc J 1922;12:141–146. Jordan WR: Neuritic manifestations in diabetes. Arch Intern Med 1936;57:307–366. Steindler A: The tabetic arthropathies. JAMA 1935;96:250. Soto-Hall R: The diagnosis of neuropathic joint disease, an analysis of 40 cases. JAMA 1940;114:2076. Levin ME: The Diabetic Foot, ed 5. St. Louis, Mosby, 1993. Frykberg RG: The High Risk Foot in Diabetes mellitus, ed 1. New York, Livingstone, 1991. Sanders LJ, Frykberg RG: Diabetic neuropathic osteoarthropathy: The Charcot foot; in Frykberg RG (ed): The High Risk Foot in Diabetes mellitus. New York, Livingstone, 1991. Wetz HH, Baumgartner R: Diabetische Osteoarthropathie und Malum perforans. Z Allg Med 1990; 66:453–457. Wetz HH, Imhoff A: Der diabetische Fuss. Orthop Tech 1991;11:807–815. Wetz HH: Osteotomien am Fuss bei der Behandlung der diabetischen Osteoarthropathie. Med Orthop Tech 1993;113:288–291. Wetz HH, Stadelmann A, Feldmann U: Der Einfluss der othopa¨dischen Schuhzurichtung auf die Druckverteilung am Fuss – Ergebnisse einer experimentellen Studie. Orthopo¨dieschuhtechnik 1994; 2:36–42. Baumgartner R, Wetz HH: Amputationen am Vorfuss. Operat Orthop Traumatol 1991;3:203–212. Baumgartner R, Wetz HH: Forefoot amputations. Operat Orthop Traumatol 1991;1:68–77. Baumgartner R, Wetz HH: Amputationes des antipie´. Operat Orthop Traumatol 1992;3:197–206. Baumgartner R, Greitemann B: Die Resektion von Mittelfussknochen als Alternative zur Vorfussamputation. Operat Orthop Traumatol 1994;6:119–131. Drescher H, Wetz HH, Baumgartner R: Die Mittelfussknochenresektion zur Therapie des Malum perforans. Med Orthop Tech 1990;110:12–22. Cofield RH, Morrison MJ, Beabout JW: Diabetic neuroarthropathy in the foot: Patient characteristics and patterns of radiographic changes. Foot Ankle 1983;4:15–22. Sinha S, Munichoodappa CS, Kazak GP: Neuroarthropathy (Charcot joints) in diabetes mellitus (clinical study of 101 cases). Medicine (Baltimore) 1972;52:191–210. Miller DS, Lichtman WF: Diabetic neuropathic arthropathy of feet. Arch Surg 1955;70:513.

Prof. Dr. Hans Henning Wetz, Head of Department, Department of Technical Orthopedic Surgery and Reeducation, Westfalian Wilhelms’ University, D–48148 Mu¨nster (Germany) Tel. +49 251 83 56764, Fax +49 251 83 56776, E-Mail [email protected]


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Diabetic Foot Infection Urs V. Brunner a, Ju¨rg Hafner b a b

Departments of Surgery and Dermatology, University Hospital, Zu¨rich, Switzerland

The outcome of a diabetic foot ulcer depends both on the wound depth, the presence of peripheral arterial occlusive disease and infection. Armstrong et al. [1] described a simple and accurate clinical classification system to predict the risk of amputation. In their study, a wound penetrating to a tendon or a joint capsule carried an amputation risk of 28.6% in the presence of infection and a wound penetrating to bone or joint had an amputation risk of 92%, whereas no amputations had to be performed in the absence of both infection and ischemia. Chronic wounds are usually colonized by bacteria. Infection occurs when microorganisms penetrate into underlying tissue. The practical classification after Gibbons and Eliopoulos distinguishes uncomplicated, non limb-threatening from complicated, limb-threatening infection [2, 3]. Non limb-threatening infection is defined as superficial cellulitis of limited extension that can be treated on an outpatient basis with oral antibiotics, local wound care and regular follow-up [4, 5]. Limb-threatening infections are more extended and penetrate to deeper tissues, such as tendons, joint capsules, bone or articulations. Fulminant spread along tendons or the plantar aponeurosis may lead to extensive soft tissue destruction. Limb-threatening infection requires inpatient treatment, immobilization, intravenous broad-spectrum antibiotic treatment combined with surgical de´bridement of necrotic tissue and often resection of infected bone [2, 3]. In our view, it is also important to distinguish ‘mummification’ (dry necrosis) from frank ‘gangrene’ (moist necrosis). Mummification has a low risk of infection and should be kept dry in order to allow for demarcation. Gangrene is always infected and comprises a great risk of infectious spread [6]. Repeated toe infection leads to lymphostatic swelling of single toes initiating a vicious circle. The swollen diabetic toe is a good example of ‘infection-related lymphology’ [7].

Osteomyelitis is present in one- to two-thirds of patients with limbthreatening infection. Because the presence of osteomyelitis usually has therapeutic implications (such as resection of bone or prolonged courses of antibiotherapy), it is important to establish diagnosis accurately [2, 3, 8, 9]. The diagnosis of osteomyelitis is difficult, since plain radiographs are neither sensitive nor specific. Differentiating between aseptic diabetic osteoarthropathy and osteomyelitis is difficult. The ability to reach bone by gently advancing a sterile blunt surgical probe (‘probe to bone’) has a high specifity and positive predictive value in the diagnosis of osteomyelitis, but the sensitivity of this technique is not very high (66%) [10]. More expensive tests, such as technetium99m bone scan, indium-111 leukocyte scan and magnetic resonance imaging do have a higher sensitivity, but these tests are not available in every medical setting [10]. Therefore, combining plain radiography with a probe for bone is a reasonable initial approach to the diagnosis of osteomyelitis [2]. Because occult osteomyelitis may be present, radiography should be repeated after 2 weeks, where bone resorption will have progressed and osteomyelitis become apparent [9].

Microbiology in Diabetic Foot Infection The technique to obtain microbiologic cultures from diabetic foot infections is crucial for the accurate identification of pathogens. Because 36–80% of all diabetic foot infections contain a mixture of aerobic and anaerobic pathogens, both aerobic and anaerobic cultures should be obtained. Bacteriology from superficial swabs differs considerably from that of deep tissue specimens, since they can be collected only during necrosectomy or by bone biopsy. Superficial swabs are more likely to yield multiple organisms, whereas deep specimens rather yield a small number of organisms and will allow for detection of anaerobe infection. Fortunately, the bacteriology of a superficial swab overestimates the relevant pathogens. An inadequate antibiotic treatment due to superficial swab results may occur in about 10%. Therefore, a representative bacteriology from the depth of the wound is always preferable to a swab because it allows for selecting the appropriate antimicrobial treatment [3, 9]. In uncomplicated, previously untreated diabetic foot infections, monomicrobial infection with Staphylococcus aureus is commonly found. In pretreated or hospitalized patients, coinfection due to gram-negative bacilli (Proteus sp., Klebsiella sp., Escherichia coli and Pseudomonas sp.) or to anaerobes (Bacillus fragilis, Peptostreptococcus) occur in about 50%. Infections caused solely by aerobic gram-negative bacilli of anaerobes are uncommon [3, 9].

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Methicillin-resistant staphylococci (MRSA) are resistant to all b-lactam antibiotics, but sensitive to vancomycin, teicoplanin, rifampicin and gentamycin. MRSA do not provoke a more extensive wound infection than other staphylococci. Therefore, they are not actually a specific threat to the carriers of chronic wounds, but rather represent a dangerous source of infection to other inpatients, especially in intensive care units. Chronic wounds represent the most important reservoir of multiresistant pathogens and more specifically of MRSA. These germs are transmitted by contaminated hands of the hospital staff. Eradication of MRSA from an unhealed wound is virtually impossible. Therefore, these patients have to be subjected to strict isolational measures and to leave the hospital as soon as possible [9].

Antimicrobial Therapy Treatment of a diabetic foot infection should not be restricted to the administration of adequate antibiotics. Impaired host defense in poorly controlled diabetes is a very important factor in the development of diabetic foot infection. Polymorphonuclear granulocyte (PMG) chemotaxis, phagocytosis and oxidative killing activity are impaired in poorly controlled diabetes and PMG function recovers under near normoglycemic conditions [11]. Recently, a strong adjuvant effect of G-CSF (granulocyte-colony stimulating factor) could be demonstrated in the antibiotherapy of limb-threatening diabetic foot infection [12]. Orthopedic care for problem zones is indispensable. The majority of uncomplicated diabetic foot infections can be treated on an outpatient basis with oral antibiotics. The clinician should be aware, however, of underestimating the severity of infection and should follow the patient at regular intervals of 2–3 days during the initiation of therapy. A 2-week course of either clindamycin or cephalexin has been studied in this indication, achieving healing rates of 96 and 86%, respectively. Amoxicillin/clavulanic acid is regarded as a valid option by other authors, although this drug has not been studied for this indication as of yet [3, 4, 9]. Ciprofloxacin monotherapy has been used with cure rates of 77%, but there are concerns because of the development of ciprofloxacin resistance among staphylococci. The combination of ciprofloxacin and clindamycin would be expected to provide excellent broad-spectrum activity (including S. aureus, anaerobes and Pseudomonas aeruginosa) and therefore is an attractive therapeutic alternative for multibacterial infections, although there are no published studies of this regimen [3, 9]. In limb-threatening infections, parenteral therapy is usually required. The regimen should be active against staphylococci, streptococci and the commonly

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a

b Fig. 1. a Diabetic foot infection: emergency plantar wedge resection in fulminant plantar abscess formation. b Six months postoperatively a weight-bearing, functionally stable foot is preserved.

encountered gram-negative bacilli and anaerobes. Enterococci should be treated if the infection is severe. Cephalosporins and clindamycin are not active against enterococci. Most enterococci are sensitive to ampicillin, extendedspectrum penicillins, imipenem/cilastatin and vancomycin. P. aeruginosa may also require special consideration. This pathogen is sensitive to ciprofloxacin, extended-spectrum penicillins, ceftazidim, imipenem/cilastatin and the aminoglycosides. Interestingly, empiric therapy that covers all these possible pathogens may not be necessary unless the infection is life-threatening. For example, ampicillin/sulbactam has an antibacterial activity almost identical to that of ampicillin/clavulanic acid, and has excellent activity against most pathogens encountered in diabetic foot infection, except P. aeruginosa and MRSA. Grayson [3] compared the effectiveness of ampicillin/sulbactam with that of imipenem/cilastatin in a randomized double-blind study. Both agents were comparably effective at the end of therapy (cure rate of 81 and 85%, respectively) and at 1 year follow-up (cure rate at 1 year 69 and 80%, respectively).


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Table 1. Surgery in limb-threatening diabetic foot infection: ‘IRAS’ 1. Infection Strict nonweight-bearing regimen, glycemic control, empirical antimicrobial therapy, early surgical intervention (de´bridement, drainage, amputation as indicated) 2. Revascularization Endovascular or vascular surgery 3. Amputation Secondary formal revision of the open amputation stump and stump closure 4. Shoes Orthopedic footwear

Although osteomyelitis is regarded as a limb-threatening form of diabetic foot infection and usually requires in-hospital treatment with parenteral antimicrobial therapy and de´bridement of infected tissue and bone, limited forms of osteomyelitis can be treated with a prolonged course of 8–12 weeks of oral antibiotic therapy on an outpatient basis [4, 5, 8, 13]. Burgmann et al. [14] have reported on the transvenous pressure injection of clindamycin and gentamycin into a vein on the dorsum of the foot in Bier’s arterial arrest. They reached manyfold antibiotic tissue concentrations 20 min and 3 h after the local transvenous pressure injection, as compared to systemic intravenous or intra-arterial injection. This method may offer advantages in peripheral arterial occlusive disease or in advanced osteomyelitis with sequestration of necrotic bone, where tissues are poorly accessible to intravenously or intra-arterially administered antibiotics. Life-threatening infection requires urgent resection or amputation (initial urgent guillotine amputation) as indicated and high-dose, very-broad-spectrum antibiotic therapy that covers all pathogens known to be encountered in this setting. Antibacterial agents should have reliable activity against S. aureus, all common gram-negative bacilli including P. aeruginosa and anaerobes. Aminoglycosides that are especially effective in gram-negative septicemia can be used in combination with broad-spectrum agents. The potential for short-term nephrotoxicity should be minimized by short-term use. If MRSA plays a role in the hospital microbiologic flora, vacomycin should be included in the empiric regimen [3, 9]. Surgery in limb-threatening diabetic foot infection follows four steps that can be abbreviated with the acronym ‘IRAS’ [2, 3, 15] (table 1). Abscess formation underneath infected calluses or even fulminant spread of infection along the tendons may be underestimated because of sensory neuropathy. Therefore, one has to watch out for erythema, edema and lymphan-

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gitis as visible alarm signs of limb-threatening infection. These signs are usually recognizable on the dorsum of the foot, since the tight plantar skin does not swell and inflame so obviously. Abscess formation and/or fulminant infectious spread requires urgent surgical drainage. Urgent surgical drainage should aim at preserving as much viable tissue as possible. If amputation is indicated, this should be performed through the ‘grenzzone’ of necrotic and viable tissue (English: minor amputation; German: Grenzzonen-Amputation). Necrotic tissues within the grenzzone can be expected to recover under an adequate conservative management. Later, secondary interventions may be necessary to remodel a stable stump. Special attention should be given to the preservation of as much plantar full-thickness skin as possible that can be used to cover amputational stumps. Split-thickness skin grafts are not stable in weight-bearing zones of the sole [6]. J. Ochsner [16] raised the question: ‘How much foot is better than none?’ We are convinced that the preservation of as much stable foot tissue as possible must be the goal of surgery in diabetic feet, since preservation of the foot means social independence.


6 7 8 9 10 11 12

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Armstrong DG, Lavery LA, Harkless LB: Validation of a diabetic wound classification system. Diab Care 1998;21:855–859. Caputo G, Cavanagh J, Ulbrecht J: Assessment and management of foot disease in patients with diabetes. N Engl J Med 1994;331:854–860. Grayson M: Diabetic foot infections. Antimicrobial therapy. Infect Dis Clin North Am 1995;9: 143–161. Lipsky BA, Pecoraro RE, Larson SA, Hanley ME, Ahroni JH: Outpatient management of uncomplicated lower-extremity infections in diabetic patients. Arch Intern Med 1990;150:790–797. Eckman MH, Greenfield S, Mackey WC, Wong JB, Kaplan S, Sullivan L, Dukes K, Pauker SG: Foot infections in diabetic patients. Decision and cost-effectiveness analysis. JAMA 1995;273: 712–720. Brunner U: Der diabetische Fuss in chirurgischer Sicht: Allgemeinmedizinische Gesichtspunkte. Ther Umsch 1987;44:677–681. Brunner U, Geroulanos S, Leu HJ: Infektlymphologie und Zugangslymphologie. Zwei neue Begriffe in der peripheren Gefa¨sschirurgie. Vasa 1988;17:275–282. Lew D, Waldvogel F: Osteomyelitis. N Engl J Med 1997;336:999–1007. Reike H: Infektionen beim Syndrom des diabetischen Fusses; in Reike H (ed): Diabetisches FussSyndrom. Berlin, de Gruyter, 1998, pp 95–119. Grayson ML, Gibbons GW, Balogh K, Levin E, Karchmer AW: Probing to bone in infected pedal ulcers. JAMA 1995;273:721–723. Gallacher S: Neutrophil bactericidal function in diabetes mellitus: Evidence for association with blood glucose control. Diabet Med 1995;12:916–920. Gough A, Clapperton M, Rolando N, Foster AVM, Philpott-Howard J, Edmonds ME: Randomised placebo-controlled trial of granulocyte-colony stimulating factor in diabetic foot infection. Lancet 1997;350:855–859. Venkatesan P, Lawn S, Macfarlane R: Conservative management of osteomyelitis in the feet of diabetic patients. Diabet Med 1997;14:487–490.


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Burgmann H, Georgopoulos A, Graninger W, Koppensteiner R, Maca T, Minar E, Schneider B, Stu¨mpflen A, Ehringer H: Tissue concentration of clindamycin and gentamycin near ischaemic ulcers with transvenous injection in Bier’s arterial arrest. Lancet 1996;348:781–783. Vollmar J, Trede M, Laubach K, Forrest H: Principles of reconstructive procedures for chronic femoropopliteal occlusions. Report on 546 operations. Ann Surg 1968;168:215–223. Brunner U, Zollinger H: Wieviel Fuss ist besser als keiner. Langenbecks Arch Chir 1989;(suppl II): 621–622.

Prof. Urs Brunner, MD, Department of Surgery, University Hospital of Zu¨rich Ra¨mistrasse 100, CH–8091 Zu¨rich (Switzerland) Tel. +41 1 255 56 57, Fax +41 1 255 4413

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Part V. Leg Ulcers of Different Origin Hafner J, Ramelet A-A, Schmeller W, Brunner UV (eds): Management of Leg Ulcers. Curr Probl Dermatol. Basel, Karger, 1999, vol 27, pp 259–270

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Differential Diagnosis of Leg Ulcers Stephan Lautenschlager, Alfred Eichmann Outpatient Clinic of Dermatology, Triemli Hospital, Zu¨rich, Switzerland

Chronic ulceration of the leg affects 0.18–2% of European populations [1–5]. In order to properly manage a leg ulcer, the most important step is to determine its etiology [6]. Although 80–90% of all leg ulcers are of venous origin [7], it should always be kept in mind that the remaining ulcers can have many causes (table 1). The second most common cause is peripheral arterial occlusive disease which accounts for another 5–10%. The others are mostly due to neuropathy or combinations of these diseases. More recently a shift in the etiologic spectrum to arterial (12%) and mixed (arteriovenous) ulcers has been shown (22%) [8], which probably reflects the aging of the population and the improvement in the detection of arterial disease. Evaluation of a leg ulcer (table 2) should comprise a detailed general history, a thorough clinical examination, vascular studies and laboratory examinations. In addition, bacterial swabs, biopsy, radiologic examination and patch tests should be performed when indicated.

History The patient’s history provides important information necessary for the differentiation of the types of ulcers that develop in the lower extremity. The general medical history may reveal a deep venous thrombosis, particularly during or after pregnancy or surgery, but the majority of patients have clinically inapparent thromboses [7]. The patient with venous leg ulcer may complain of aching and swelling in the legs that are exacerbated by dependency and relieved by elevation of the limb. For patients with peripheral arterial disease, history may provide clues for intermittent claudication, characterized by pain in the calves or buttocks that occurs on exertion and is relieved by rest. The pain from arterial leg ulceration is usually severe and difficult to control. These

Table 1. Causes of leg ulcers [modified from 7] Vascular diseases Venous Arterial Atherosclerosis Hypertension (Martorell ulcer) Thromboangiitis obliterans Arteriovenous malformation Cholesterol embolism Vasculitis Small vessel Hypersensitivity vasculitis Rheumatoid arthritis Lupus erythematosus Scleroderma Sjo¨gren’s syndrome Behçet’s disease Atrophie blanche Medium and large vessel Polyarteritis nodosa Nodular vasculitis Wegener’s granulomatosis Lymphatics Lymphedema Neuropathic Diabetes Tabes dorsalis Syringomyelia Poliomyelitis Peripheral nerve lesion Metabolic Diabetes Gout Calciphylaxis Prolidase deficiency Gaucher’s disease Hematologic diseases Red blood cell disorders Sickle cell anemia Hereditary spherocytosis Thalassemia Polycythemia rubra vera White blood cell disorders Leukemia Dysproteinemias Cryoglobulinemia Cold agglutinin disease Macroglobulinemia

Lautenschlager/Eichmann

Trauma Pressure Cold injury Radiation dermatitis Burns Factitial Neoplastic Epitheliomas Squamous cell carcinoma Basal cell carcinoma Keratoacanthoma Sarcoma Kaposi sarcoma Lymphoproliferative Lymphoma Cutaneous T-cell lymphoma Metastatic tumors Infectious Bacterial Furuncle Ecthyma Ecthyma gangrenosum Septic emboli Gram-negative infections Anaerobic infections Mycobacterial Spirochetal Fungal Majocchi’s granuloma Deep fungal infections Protozoal Leishmania Infestations and bites Panniculitis Alpha-1-antitrypsin deficiency Weber-Christian disease Pancreatic fat necrosis Crural leg ulcer in dermatoses Necrobiosis lipoidica Necrobiotic xanthogranuloma Pyoderma gangrenosum Sarcoidosis Immunol. mediated blistering dis. Genetic defects Sickle-cell anemia Klinefelter’s syndrome Topical and systemic drugs

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Table 2. Approach to the differential diagnosis of a leg ulcer patient by history and physical examination History Personal medical history (e.g. thrombosis, vascular operations) Family medical history (diabetes) Medications Risk factors (hypertension, diabetes, smoking, trauma) Onset and course Relieving and exacerbating factors of symptoms Complete physical examination, especially Deep tendon reflex factors Evidence of peripheral neuropathy Peripheral pulses (posterior tibial pulse with best predictive value) Ulcer Location Appearance Surrounding skin Bedside examinations (e.g. capillary and venous refilling time, ankle-brachial index)

characteristics of pain and its alleviating or exacerbating factors can be helpful in making a diagnosis [6, 7]. Neuropathic ulcers may be associated with paresthesia, burning sensations, or may be painless which is also the rule for neoplastic ulcers. Neuropathic pain may be relieved by exertion, whereas ischemic pain is exacerbated by exercise [7]. Arterial ulcers tend to develop slowly, whereas venous ulcers and pyoderma gangrenosum progress more rapidly. The presence of other conditions such as diabetes, connective tissue disorders, hypertension or inflammatory bowel disease may provide clues to the etiology of the ulcer. It is important to obtain the patient’s current medications, because systemic and topical drugs can impair wound healing or even cause ulceration as has been shown for hydroxyurea [9]. Common contact sensitizers include lanolin, parabens, and particularly topical antibiotics and emulsifiers [10, 11]. A family history of diabetes or hereditary hematologic disorders can also be helpful. Habits such as smoking can severely impair wound healing and high alcohol consumption is often associated with poor nutritional status which may also be relevant.

Clinical Examination Examination of the ulcer should include location, borders, base, and discharge (table 3). The condition of the surrounding skin and the presence

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Table 3. Diagnostic aspects of the ulcer and the surrounding skin Leg ulcer

Location

Appearance

Surrounding skin

Venous

Malleoli, particularly medial

Irregular ‘shaggy’ border Fibrinous debris Extensive granulations Weeping

Edema Pigmentation Purpura Eczema Sclerosis Cellulitis

Arterial

Acral Bony prominences Lateral malleolus

Sharp, ‘punched-out’ border Gray or black base Dry Scant or absent granulations

Loss of hair Shiny, atrophic

Neuropathic

Weight-bearing sites

Sharp, ‘punched-out’ border Deep Purulent discharge (if osteomyelitis is present)

Thick callus around ulcer Anesthetic/ hyperesthetic

Vasculitis

Dorsum of the foot Pretibial Calf

Sharp, ‘punched-out’ border Deep Multiple, confluent Necrotic debris

Palpable purpura

of edema and diminished or absent peripheral pulses can be helpful in determining the etiology [7, 12]. A palpable or audible bruit over the femoral artery is suggestive of atherosclerotic lesions in the iliac or common femoral arteries. Capillary refilling time is prolonged in patients with arterial disease. It is measured by manual compression of the tip of the great toe for a few seconds until it blanches and then released. Normally, it takes 3–4 s for the toe to return to normal color. The change in color of the limbs with alteration in position is another simple bedside test for ischemia. When elevated at 45 º for 1 min, an ischemic limb will turn pale. On subsequent dependency, filling of the veins will take longer than normal (10–15 s). When the color returns, the limb turns pink or bright red due to reactive hyperemia. In general, the greater the arterial insufficiency, the longer the venous filling time and the greater the intensity and extent of rubor. Another simple test for evaluating the lower extremity circulation is the ankle-brachial index. Neuropathic disease can be detected by testing light touch, pin-prick sensations, and deep tendon reflexes [7]. In all patients with leg ulcers, a general physical examination should be performed to exclude significant underlying medical conditions.


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Investigations A routine blood cell count and blood glucose level are helpful to exclude hematologic disorders or diabetes mellitus. An elevated erythrocyte sedimentation rate may indicate an underlying osteomyelitis or connective tissue disease. Albumin or transferrin and trace elements are important for wound healing and low levels may suggest nutritional deficiencies which should be corrected [13]. Tests for rheumatoid factor, antinuclear antibody or antitreponemal antibodies should be performed when indicated [7, 12]. Biopsy should be performed if there is a diagnostic possibility of vasculitis, granuloma or tumor and, depending on the context, for bacterial, mycobacterial, and fungal cultures. Ideally, a deep wedge biopsy should be performed, including the ulcer margins and bed. Alternatively multiple punch biopsies should be obtained from several areas to avoid sampling error. Indications for histopathologic examination include the following [14]: (a) typical venous, arterial, or pressure ulcer of 3 months’ duration, lack of response to treatment or worsening; (b) atypical ulcer presentations: unusual site, nodularity, induration, raised border with rolled edges, local adenopathy; (c) signs indicative of vasculitis; (d) presence of unexplained systemic manifestations or travel to a tropical country before or at the time of ulcer formation.

Selected Causes of Leg Ulcers As stated above, causes of leg ulcers are multiple. The following will only consider selected, less common causes which have not been discussed in other chapters of this book.

Hematologic Disorders Chronic indolent ulcers above the malleoli have been described in several hemolytic disorders. 5% of patients with thalassemia minor will develop leg ulcers which may be the first sign of the disease [15], whereas this is uncommon in thalassemia major. High oxygen affinity of hemoglobin F, abnormal deformability of red blood cells, and repeated local trauma may be factors responsible for ulcer formation. Clinically, the ulcers are very similar to those occurring in the monozygous form of sickle-cell anemia and are located mostly on the lower leg above the lateral malleoli. They have a ‘punched-out’ appearance with sharply defined edges and a granulating base (fig. 1). Due to population migration we should be aware of these possible underlying conditions especially


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Fig. 1. Eighteen-year-old woman with thalassemia minor and a painless ulcer above the lateral malleolus. Fig. 2. Multiple sharply demarcated ulcers in an 80year-old male with cryoglobulinemia.

2

if ulceration occurs in younger age groups. For more elderly patients, leg ulcers also have been reported with severe forms of hereditary spherocytosis. In addition, a quarter of patients with Felty syndrome are affected by large refractory skin ulcers. The characteristic triad of Felty syndrome comprises rheumatoid arthritis, leukopenia and splenomegaly. Essential thrombocythemia, polycythemia vera, dysglobulinopathies and coagulation disorders may lead to ulceration by varied mechanisms, such as vasculitis or stasis with sludging of blood [14]. Ulcers in myeloproliferative disorders with thrombocythemia may be an initial symptom of this disease. Beside ulcers it is important to recognize livedo reticularis, purpura, erythromelalgia, recurrent superficial thrombophlebitis and ischemic limbs. Knowledge of these cutaneous manifestations and prompt diagnosis is important because treatment of thrombocythemia may prevent severe hemorrhagic or thrombotic events [16]. Additionally it has to be emphasized that hydroxyurea, the commonly used agent to treat myeloproliferative disorders, may induce painful and difficult to treat leg ulcers by itself [9]. During the last decade, inherited deficiencies of anticoagulant proteins of the coagulation system have been discovered and found to be of importance for the evolution of deep venous thrombosis and consecutively for ulcer formation. Deficiencies of the protein C and S, antithrombin III and


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the resistance to activated protein C (APC) are of particular clinical significance. APC resistance is associated with a 5- to 10-fold increased risk of venous thrombosis [17] and was reported to occur in 20–40% of patients with previous symptomatic deep venous thrombosis [17, 18]. If there is a history of thrombophlebitis, evaluation of the patient with leg ulcers should include testing for APC resistance [19]. Leukocytoclastic vasculitis may be responsible for the pathogenesis of leg ulcers as a result of a variety of causes including infection, drugs, dysglobulinemias and connective tissue disease. Especially lupus erythematosus [20], rheumatoid arthritis [21], and polyarteritis nodosa [22] may be accompanied by leg ulcers. In contrast to venous ulcers, these lesions occur in the setting of a systemically ill patient and other signs of the underlying illness. The ulcers are typically deep, well demarcated and painful. The sites of ulceration, such as the dorsum of the foot or the calf, are unusual for routine venous insufficiency [for further reading, c.f. Hafner]. In cryoglobulinemia, immunoglobulins reversibly precipitate in the cold. Cutaneous findings in these patients include purpura, urticaria, livedo reticularis, Raynaud’s disease, and leg ulcers. These signs can be found most commonly in type I cryoglobulinemia (25%) [23]. The ulcers are often atypical and may resemble dermatitis artefacta with irregular, sharply demarcated borders (fig. 2). Cutaneous ulceration also may occur as the first sign of antiphospholipid syndrome [24]. This syndrome is an acquired primary or secondary multisystem disorder of hypercoagulation in which venous and/or arterial thromboses develop. The serologic markers for this syndrome are antiphospholipid antibodies, which are represented by the lupus anticoagulant tests and anticardiolipin antibodies. Clinical features include recurrent thrombotic events, repeated fetal loss, and thrombocytopenia. Skin manifestations include mainly livedo reticularis, necrotizing vasculitis, thrombophlebitis, and ulceration [25]. Ulcers are sharply marginated and painful, usually of the pretibial area and ankle. Awareness of the dermatological signs and the histopathologic features should prompt a serologic investigation and an early diagnosis. Atheroembolism (cholesterol embolism) is a disease of patients with severe atherosclerosis, typically of the aortofemoral system [26]. Fragments from ulcerated atheromatous plaques lead to embolism of peripheral vessels of the skin and organs (kidneys!). The disorder can develop spontaneously or most commonly is caused by invasive vascular procedures. The lesions can develop immediately or weeks to months after the predisposing event. Some authors mention the possible role of anticoagulant drugs and thrombolytic therapy in precipitating atheromatous embolization [27, 28]. The mechanism by which anticoagulation may lead to atheroembolism remains obscure. Clinical pre-


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Fig. 3. Atheroembolism following peripheral percutaneous transluminal balloon angioplasty in a 68-year-old male.

sentation range from tender, violaceous toes and discoloration of the soles (fig. 3) to a diffuse multiorgan systemic disease with a high mortality rate, reflecting the size and number of the atheromatous fragments and the site of origin. Skin ulcers may develop despite palpable distal pulses. Calciphylaxis is a rare condition of rapidly extending ischemic skin necrosis or acral gangrene in chronic renal failure. Skin necrosis is caused by medial calcification and intimal hyperplasia in subcutaneous and/or digital arteries. It may be accompanied by extensive metastatic calcifications of soft tissue. If the lower leg is involved, painful and bizarre ulcers may be seen [29]. The pathogenesis of calciphylaxis is only poorly understood but most patients have hyperparathyroidism and an elevated calcium-phosphate product which is thought to be a major pathogenetic factor. 155 patients with calciphylaxis were reviewed and subjected to statistical meta-analysis very recently by Hafner et al. [30]. Calciphylaxis has also been noted in patients with the acquired immunodeficiency syndrome [31]. Pyoderma gangrenosum (PG) is classically described as a rapidly enlarging, purulent ulceration with undermined bluish borders (fig. 4). Actively advancing lesions often have an intense surrounding erythema. These ulcerations are characteristically extremely painful and have a propensity to appear on the lower limbs or trunk. Approximately 50% of patients have an associated systemic disease such as inflammatory bowel disease or myelodysplastic disease. Although ulcerative PG is typically preceded by a pustule, some ulcerations


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Fig. 4. Active progressive ulcerative pyoderma gangrenosum with prominent violaceous border and purulent base in a 30-year-old female.

5

6 Fig. 5. Ulcerated necrobiosis lipoidica in a 19-year-old diabetic female patient. Fig. 6. Twenty-seven-year-old male returning from Thailand with fast developing multiple tropical ulcerations on the lower extremities.


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Fig. 7. Fifty-year-old male with nonhealing leg ulcer revealing cutaneous T-cell lymphoma.

develop from inflammatory nodules, and others occur after trauma to normal appearing skin [32]. Besides the common neuropathic and ischemic type of leg ulcers in the diabetic patient, necrobiosis lipoidica (NL) and a variety of infections may be sometimes associated with ulceration. The classical lesion occurs over the front of the lower limb and tends to be an oval or irregular reddish brown plaque with central atrophy and translucent telangiectasias (fig. 5). Ulceration after minor trauma is seen in one third of patients with NL. Between 60 and 70% of patients with NL have manifest diabetes but only 0.3% of diabetic patients are affected by NL [33]. It occurs more frequently in women under 40 years. Tropical ulcer is an acute localized necrotic lesion of the skin and subcutaneous tissues seen mainly in tropical and subtropical countries. The ulcer occurs on the legs or feet, mostly affecting children. It has been little studied but is now recognized to have an infectious cause associated with trauma. The circular ulcer is well circumscribed and covered by a foul-smelling yellowish discharge, with elevated indurated margins (fig. 6). It may rapidly extend to involve deeper structures. Early lesions reveal the presence of spirochetes and anaerobes, notably a recently described species, Fusobacterium ulcerans [34, 35]. In patients with indolent leg ulcers returning from the tropics, especially in


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absence of vascular disease, this entity has to be considered. Healing without appropriate antibiotics is unlikely. A prominent and indurated border in a long-standing ulcer is characteristic for ulcerated neoplasms. Ulceration in lymphoma occurs commonly during the tumor stage of cutaneous T-cell lymphoma and occasionally in the plaque stage [36]. In addition, cutaneous B-cell lymphoma may present as ulcerated tumors on the leg [37]. Different subtypes of non-Hodgkin lymphomas may show ulcers which usually occur late in the course of the disease. There are reports of nonhealing leg ulcers revealing the lymphoma [38] as it was in our case (fig. 7). References 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21

Biland L, Widmer LK, Baillod L: Zur Haüfigkeit und Bedeutung des Ulcus cruris. Ther Umsch 1984;41:834–838. Hansson C, Andersson E, Swanbeck G: Leg ulcer epidemiology in Gothenburg. Acta Chir Scand Suppl 1988;544:12–16. Cornwall JV, Dore CJ, Lewis JD: Leg ulcers: Epidemiology and aetiology. Br J Surg 1986;73: 693–696. Hallbook T: Leg ulcer epidemiology. Acta Chir Scand Suppl 1988;544:17–20. Nelzen O, Bergqvist D, Lindhagen A: The prevalence of chronic lower-limb ulceration has been underestimated: Results of a validated population questionnaire. Br J Surg 1996;83:255–258. Nelzen O, Bergqvist D, Lindhagen A: Leg ulcer etiology – A cross-sectional population study. J Vasc Surg 1991;14:557–564. Phillips TJ, Dover JS: Leg ulcers. J Am Acad Dermatol 1991;25:965–987. Nelzen O, Bergqvist D, Lindhagen A, Hallbook T: Chronic leg ulcers: An underestimated problem in primary health care among elderly patients. J Epidemiol Community Health 1991;45:184–187. Best PJ, Daoud MS, Pittelkow MR, Petitt RM: Hydroxyurea-induced leg ulceration in 14 patients. Ann Intern Med 1998;128:29–32. Zaki I, Shall L, Dalziel KL: Bacitracin: A significant sensitizer in leg ulcer patients? Contact Dermatitis 1994;31:92–94. Pasche-Koo F, Piletta PA, Hunziker N, Hauser C: High sensitization rate to emulsifiers in patients with chronic leg ulcers. Contact Dermatitis 1994;31:226–228. Young JR: Differential diagnosis of leg ulcers. Cardiovasc Clin 1983;13:171–193. Pollack SV: Wound healing: A review. III. Nutritional factors affecting wound healing. J Dermatol Surg Oncol 1979;5:615–619. Ouahes N, Phillips TJ: Leg ulcers. Curr Probl Dermatol 1995;7:114–142. Stevens DM, Shupack JL, Javid J, Silber R: Ulcers of the leg in thalassemia. Arch Dermatol 1977; 113:1558–1560. Itin PH, Winkelmann RK: Cutaneous manifestations in patients with essential thrombocythemia. J Am Acad Dermatol 1991;24:59–63. Svensson PJ, Dahlback B: Resistance to activated protein C as a basis for venous thrombosis. N Engl J Med 1994;330:517–522. Munkvad S, Jorgensen M: Resistance to activated protein C: A common anticoagulant deficiency in patients with venous leg ulceration. Br J Dermatol 1996;134:296–298. Grossman D, Heald PW, Wang C, Rinder HM: Activated protein C resistance and anticardiolipin antibodies in patients with venous leg ulcers. J Am Acad Dermatol 1997;37:409–413. Yell JA, Mbuagbaw J, Burge SM: Cutaneous manifestations of systemic lupus erythematosus. Br J Dermatol 1996;135:355–362. Walchner M, Messer G, Meurer M, Konz B, Kind P, Plewig G: Hautulzerationen bei rheumatoider Arthritis. Hautarzt 1995;46:406–412.


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Daoud MS, Hutton KP, Gibson LE: Cutaneous periarteritis nodosa: A clinicopathological study of 79 cases. Br J Dermatol 1997;136:706–713. Cohen SJ, Pittelkow MR, Su WPD: Cutaneous manifestations of cryoglobulinemia: Clinical and histopathologic study of seventy-two patients. J Am Acad Dermatol 1991;25:21–27. Nahass GT: Antiphospholipid antibodies and the antiphospholipid antibody syndrome. J Am Acad Dermatol 1997;36:149–168. Gibson GE, Su WP, Pittelkow MR: Antiphospholipid syndrome and the skin. J Am Acad Dermatol 1997;36:970–982. Kalter DC, Rudolph A, McGavran M: Livedo reticularis due to multiple cholesterol emboli. J Am Acad Dermatol 1985;13:235–242. Bols A, Nevelsteen A, Verhaeghe R: Atheromatous embolization precipitated by oral anticoagulants. Int Angiol 1994;13:271–274. Applebaum RM, Kronzon I: Evaluation and management of cholesterol embolization and the blue toe syndrome. Curr Opin Cardiol 1996;11:533–542. Hafner J, Keusch G, Wahl C, Sauter B, Hu¨rlimann A, van Weizsa¨cker F, Krayenbu¨hl M, Biedermann K, Brunner U, Helfenstein U, Burg G: Uremic small-artery disease with medial calcification and intimal hyperplasia (so-called calciphylaxis): A complication of chronic renal failure and benefit from parathyroidectomy. J Am Acad Dermatol 1995;33:954–962. Hafner J, Keusch G, Wahl C, Burg G: Calciphylaxis: A syndrome of skin necrosis and acral gangrene in chronic renal failure. Vasa 1998;27:137–143. Cockerell CJ, Dolan ET: Widespread cutaneous and systemic calcification (calciphylaxis) in patients with the acquired immunodeficiency syndrome and renal disease. J Am Acad Dermatol 1992;26: 559–562. Powell FC, Su WPD, Perry HO: Pyoderma gangrenosum: Classification and management. J Am Acad Dermatol 1996;34:395–409. Lowitt MH, Dover JS: Necrobiosis lipoidica. J Am Acad Dermatol 1991;25:735–748. Webb J, Murdoch DA: Tropical ulcers after sports injuries. Lancet 1992;339:129–130. Adriaans B, Hay R, Draser B, Robinson DC: The infectious aetiology of tropical ulcer: A study of the role of anaerobic bacteria. Br J Dermatol 1987;116:31–37. Stringer MD, Melcher D, Stachan CJ: The lower limb as a presenting site of malignant lymphoma. Ann R Coll Surg Engl 1987;69:8–11. Burg G, Dummer R, Dommann ST: Other cutaneous lymphomas: B-cell lymphoma, non-mycosis fungoides T-cell lymphoma, and adult T-cell lymphoma/leukemia; in Arndt KA, Leboit PE, Robinson JK, Wintroub BU (eds): Cutaneous Medicine and Surgery: An Integrated Program in Dermatology. Philadelphia, Saunders, 1996, vol 2, pp 1660–1669. Pion IA, Buchness MR, Lim HW: Nonhealing leg ulcer. Arch Dermatol 1996;132:1105–1108.

Stephan Lautenschlager, MD, Outpatient Clinic of Dermatology, Triemli Hospital, Herman Greulich-Strasse 70, CH–8004 Zu¨rich (Switzerland) Tel. +41 1 298 89 00, Fax +41 1 298 89 89, E-Mail [email protected]


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Management of Leg Ulcers in Rheumatoid Arthritis and in Systemic Sclerosis Ju¨rg Hafner, Ralph M. Truëb Department of Dermatology, University Hospital, Zu¨rich, Switzerland

Leg ulcers are common in patients with rheumatoid arthritis [1–3]. Thurtle and Cawley [1] found a prevalence of 9% (20 out of 215 patients) among their rheumatoid arthritis patients to suffer from leg ulcers. This is twice as many as in a control group of patients with degenerative arthrosis. The etiopathogenesis of these ulcers is not always well understood [2, 4] and is often attributed to vasculitis or to cutaneous microangiopathy, even though there is little evidence for this hypothesis [4]. Thurtle and Cawley [1] and Pun et al. [2] subjected their case series to a careful analysis and found relevant chronic venous insufficiency in 45% of the patients [1, 2]. Peripheral arterial occlusive disease (PAOD) was present in 36% of patients [2], but unfortunately the severity of PAOD was not assessed exactly in these series. Corticosteroids are administered to about half of patients with rheumatoid arthritis leg ulcers [1, 2], thereby leading to skin atrophy, which in turn makes the pretibial area specially susceptible to minor shearing trauma (fig. 1). As a matter of fact, minimal trauma initiates the chronic leg ulceration in as many as 45.5%. In summary, the underlying cause of leg ulcers in rheumatoid arthritis seems to be multifactorial in most cases [2] and a rational management should address alleviating all contributing factors as possible. In the last few years we have seen several patients with leg ulcers in rheumatoid arthritis or in systemic sclerosis who greatly improved, as soon as their macrocirculation pathology was treated (e.g. by saphenectomy of an incompetent greater saphenous vein or by revascularization in arterial insufficiency). In the following we discuss these multifactorial aspects in more detail.

a

b Fig. 1. a, b Multiple medial leg ulcers in the presence of an incompetent greater saphenous vein in a patient with systemic sclerosis. Spontaneous and permanent (4 years’ followup) healing after saphenectomy.

Medial Leg Ulcers and Incompetence of Greater Saphenous Vein Thurtle and Cawley [1] and Pun et al. [2] found that leg ulcers in rheumatoid arthritis are associated with venous disease in as many as 45% of their patients. Rabe et al. [5] found chronic venous insufficiency to be a determining factor for the development of leg ulcers in systemic sclerosis. To the best of our knowledge, the effect of saphenectomy on medial leg ulcers in rheumatoid arthritis or in systemic sclerosis has not been reported as of yet. We believe that an incompetent greater saphenous vein can represent a relevant contributing factor in these patients. Among a series of 15 patients with leg ulcers in collagen vascular disease we saw 2 patients with rheumatoid arthritis and 2 patients with systemic sclerosis who presented with a medial

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leg ulcer in supramalleolar location. None of these patients showed classical signs of chronic venous insufficiency, such as dermatoliposclerosis or hemosiderin depositis. One of the patients with rheumatoid arthritis underwent percutaneous transluminal balloon-catheter angioplasty for Fontaine stage IIb peripheral arterial occlusive disease 1 year before, but had no improvement of her leg ulcer despite an almost normalized ankle-arm index. In all of these 4 patients we found a truncular incompetence of the greater saphenous vein from the groin until the distal leg (stage IV according to Hach). Under normal conditions, one would not have expected these epifascial vein incompetences to cause leg ulceration. Nevertheless, all these 4 patients underwent saphenectomy. Postoperatively the 2 patients with systemic sclerosis experienced spontaneous and recurrence-free healing of their ulcers (fig. 1a, b). In the 2 patients with rheumatoid arthritis, a split skin graft was performed together with the saphenectomy procedure. Both of them also experienced recurrence-free healing [unpubl. data]. Another of our leg ulcer patients with systemic sclerosis had postthrombotic syndrome and Fontaine stage IIb peripheral arterial occlusive disease. This patient healed only after a femoropopliteal bypass and shave therapy [6].

Ineffective Venous Pump as a Consequence of Ankle Joint Arthritis Schmeller [7] and Gaylarde et al. [8] studied the interdependence of reduced ankle movement and the venous ankle pump. An ineffective ankle pump increases peripheral venous hypertension in the leg, which in turn aggravates dermatoliposclerosis around the Achilles tendon thereby impairing again the ankle movement. Rheumatoid arthritis can result in a completely immobilized ankle joint and trophic skin changes, which are indistinguishable from those in chronic venous insufficiency (fig. 2). Limb elevation and careful compression using orthopedic wool and short stretch bandages help reduce peripheral edema in such patients [3]. As long as some ankle mobility can be preserved, this should be maintained by physical therapy [9].

PAOD and Leg Ulcers in Rheumatoid Arthritis or Systemic Sclerosis Pun et al. [2] reported 36% of their leg ulcer patients with rheumatoid arthritis to have PAOD. According to the meta-analysis of Wu¨tschert and Bounameaux [10], we believe that an ankle arterial pressure =80 mm Hg (or an ankle-arm index =0.5) compromises the likelihood of spontaneous wound healing, even though no chronic critical leg ischemia is evident [11]. Therefore,

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2

3 Fig. 2. Inefficient venous pump due to complete ankle stiffness in long-standing rheumatoid arthritis may lead to chronic venous hypertension in the leg and trophic skin changes indistinguishable from those in common chronic venous insufficiency. Fig. 3. Pretibial leg ulcer after minor trauma on atrophic skin in a patient with rheumatoid arthritis under long-term corticosteroid medication. These wounds are notoriously difficult to treat and often require repeated split skin grafts in order to heal.

revascularization may be advisable in such situations in order to improve the chance of these chronic wounds to heal.

Pretibial Leg Ulcers in Corticosteroid-Induced Skin Atrophy The pretibial area is another typical location for leg ulcers in rheumatoid arthritis. These wounds usually occur after minor trauma on an atrophic pretibial skin, and can be notoriously difficult to treat (fig. 3). Semiocclusive synthetic dressings can be used in these situations, under the precaution not to tear off the atrophic pretibial skin after dressing changes. If these wounds do not show any trend to heal, split skin grafting may become unavoidable.

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Table 1. Multifactorial etiopathogenesis of leg ulcers in rheumatoid arthritis and in systemic sclerosis Incompetence of the greater saphenous vein as decisive factor for leg ulceration in rheumatoid arthritis or in systemic sclerosis Inffective venous pump as a consequence of ankle joint arthritis PAOD (‘complicated Fontaine stage IIb’) Systolic ankle pressure =80 mm Hg, ankle-arm index =0.5 Pretibial leg ulcres in corticosteroid-induced skin atrophy Rheumatoid vasculitis Pyoderma gangrenosum in rheumatoid arthritis Cutaneous microangiopathy in systemic sclerosis Dystrophic subcutaneous calcification in rheumatoid arthritis or in systemic sclerosis

Pun et al. [2] reported a take rate of 42.9%, which is in good accordance with the experience that these patients often require several subsequent split skin grafts to heal their chronic pretibial wounds [12].

Rheumatoid Vasculitis Small-vessel vasculitis accounts only for 10(–20)% of leg ulcerations in rheumatoid arthritis [1, 2]. Clinically and histologically, rheumatoid vasculitis shows the features of leukocytoclastic vasculitis. These patients often develop systemic small-vessel vasculitis which requires immunosuppressive treatment according to the severity of systemic disease. Prednisone combined with methotrexate or cyclophosphamide as steroid-sparing agents [13] have proven to be effective in the treatment of rheumatoid vasculitis.

Pyoderma gangrenosum in Rheumatoid Arthritis Pyoderma gangrenosum is a rare cause of leg ulcers in rheumatoid arthritis. Clinically it is characterized as a painful inflammatory wound with a progressive pustular and violaceous border. Immunosuppressive treatment is required to control pyoderma gangrenosum [see chapter: Vasculitis and Pyoderma gangrenosum].

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Cutaneous Microangiopathy as a Cause of Delayed Wound Healing in Systemic Sclerosis Cutaneous microangiopathy in systemic sclerosis is only poorly investigated apart from what is known from acral angiopathy and nailfold capillaroscopy. In our view, one should be cautious not to attribute all chronic wounds in systemic sclerosis to microangiopathy alone, but to subject all patients to thorough vascular examination, as described above in this chapter. However, there will be a few remaining patients in whom no pathology in arterial or venous macrocirculation can be found. In these patients, cutaneous microangiopathy may be the main underlying cause for chronic skin ulcerations. In the absence of any hard data from the literature, prostanoids may be a valid therapeutic approach for these patients.

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

Thurtle OA, Cawley ID: The frequency of leg ulceration in rheumatoid arthritis: A survey. J Rheumatol 1983;10:507–509. Pun YLW, Barraclough DRE, Muirden KD: Leg ulcers in rheumatoid arthritis. Med J Aust 1990; 153:585–587. McRorie ER, Jobanputra P, Ruckley CV, Nuki G: Leg ulceration in rheumatoid arthitis. Br J Rheumatol 1994;33:1978–1084. Nishikawa JA: Are leg ulcers in rheumatoid arthritis due to vasculitis? Eur J Rheumatol Inflamm 1983;6:288–290. Rabe E, Elsmann HJ, Kuster W, Kreysel HW: Veno¨se Insuffizienz bei Patienten mit progressiver systemischer Sklerose. Vasa 1991(suppl 33):333–334. Hafner J, Kohler A, Enzler M, Brunner U: Successful treatment of an extended leg ulcer in systemic sclerosis. Vasa 1997;26:302–304. Schmeller W: Das arthrogene Stauungssyndrom. Berlin, Diesbach, 1990. Gaylarde PM, Dodd HJ, Sarkany I: Venous leg ulcers and arthropathy. Br J Rheumatol 1990;29: 142–144. Klyscz T, Ritter-Schempp C, Ju¨nger M, Rassner G: Biomechanische Stimulationstherapie zur physikalischen Behandlung des arthrogenen Stauungssyndroms. Hautarzt 1997;48:318–322. Wu¨tschert R, Bounameaux H: Predicting healing of arterial leg ulcers by means of segmental systolic pressure measurements. Vasa 1998;27:224–228. Hafner J: Management des arteriellen Ulcus cruris. Z Hautkr 1998;73:430. Lo SS, Rangoonan C, Marks J, Hughes LE: Surgical aid for intractable rheumatoid ulcers. Br J Rheumatol 1987;26:235–237. Scott DGI, Bacon PA: Intravenous cyclophosphamide plus methylprednisolone in treatment of systemic rheumatoid vasculitis. Am J Med 1984;76:377–384.


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In spite of substantial efforts by many investigators, classification of systemic vasculitis remains difficult (table 1). In 1990 the American College of Rheumatology (ACR) developed criteria for the classification of vasculitis [1]. These criteria were based on a prospective multicenter study on 1,000 vasculitis patients and allowed to classify seven types of vasculitis with a defined sensitivity and specificity. For some entities, such as Churg-Strauss syndrome, giant cell (temporal) arteritis and Takaysu arteritis sensitivity and specificity of the diagnostic criteria were excellent, whereas small-vessel vasculitis, such as Henoch-Scho¨nlein purpura or hypersensitivity vasculitis, were more difficult to define [2]. The ACR criteria were designed for the classification of groups of patients as they occur in clinical trials and therefore cannot be directly applied for diagnosis in an individual patient, although they are being widely used for this purpose. Subsequently, the Chapel Hill Consensus Conference on the nomenclature of systemic vasculitis suggested a subdivision according to vessel size: Large-vessel vasculitis (aorta and largest branches), mediumsized vessel vasculitis (main visceral arteries, e.g. renal, hepatic, coronary, mesenteric) and small-vessel vasculitis (arterioles, capillaries, venules) [3]. These authors state that the ACR 1990 criteria are not adequate for differentiating among the various clinicopathological expressions of small-vessel vasculitis [4]. They suggest to distinguish cutaneous leukocytoclastic vasculitis, Henoch-Scho¨nlein purpura, cryoglobulinemic vasculitis and ANCA-associated small-vessel vasculitis (encompassing microscopic polyangitis, Wegener’s granulomatosis and Churg-Strauss sydrome). Small-vessel vasculitis typically produces palpable purpura that eventually may necrotize and lead to leg ulcerations. Vasculitic manifestations may remain limited to the skin or involve other organs, such as the musculoskeletal system,

Table 1. Types of vasculitis categorized on the basis of morphologic and proposed pathogenic criteria [modified from 32] A. Infectious vasculitis (direct microbial invasion of vessels) 1. Bacterial vasculitis (e.g. neisserial) 2. Rickettsial vasculitis (e.g. Rocky Mountain spotted fever) 3. Mycobacterial (e.g. tuberculosis) 4. Spirochetal (e.g. syphilis, Borrelia, etc.) 5. Fungal (e.g. Candida) 6. Viral (e.g. herpes) B. Immunologic injury 1. Involving predominantly large vessels: a. Takayasu arteritis b. Granulomatous giant cell arteritis (1) Giant cell temporal arteritis and extracranial giant cell arteritis (2) Disseminated visceral granulomatous arteritis (3) Granulomatous angiitis of the central nervous system c. Arteritis of rheumatic diseases 2. Involving predominantly medium-sized and small vessels: a. Thrombangiitis obliterans (Buerger’s disease) b. Polyarteritis nodosa (PAN) group: (1) Classic PAN (2) Benign cutaneous PAN (3) Microscopic PAN (pANCA-associated) (4) Infantile PAN c. Kawasaki’s disease (possibly mediated by antiendothelial antibodies) d. Pathergic-allergic granulomatoses: (1) Wegener’s granulomatosis (cANCA-associated) (2) Churg-Strauss syndrome (allergic granulomatous angiitis) e. Vasculitis of collagen-vascular disease, including rheumatoid arthritis, systemic lupus erythematosus, dermatomyositis, Sjo¨gren’s syndrome, Behçet’s syndrome, relapsing polychondritis, Cogan’s syndrome 3. Involving predominantly small blood vessels (immune complex mediated, synonym: leukocytoclastic vasculitis) a. Serum sickness vasculitis (induced by whole serum or heterologous proteins) b. Drug-induced vasculitis (e.g. sulfonamides) c. Infection-induced immune complex vasculitis (e.g. Streptococcus) d. Cryoglobulinemic vasculitis e. Rheumatoid and lupus vasculitis f. Paraneoplastic vasculitis (lymphoproliferative disease, solid tumors) g. ‘Clinical syndromes’: (1) Henoch-Scho¨nlein purpura (IgA-related) (2) Idiopathic (non-IgA) cutaneous small-vessel vasculitis (3) Acute hemorrhagic edema of infancy (Finkelstein) (4) (Hypocomplementemic) urticarial vasculitis syndrome (5) Erythema elevatum diutinum C. ‘Vasculitis simulators’ 1. Vasculopathy of antiphospholipid syndrome 2. Livedoid vasculitis/atrophie blanche (segmental hyalinizing vasculopathy) 3. Ko¨hlmeier-Degos disease (malignant atrophic papulosis) 4. Embolic phenomena: atheromatous, cholesterol, endocarditis, left atrial myxoma 5. Coumarin necrosis (in protein C or S deficiency) 6. Disseminated intravascular coagulopathy 7. Chronic ergotism

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the kidneys, respiratory system, nervous system, gastrointestinal tract and heart (coronary arteries). A skin biopsy reveals leukocytoclastic vasculitis of the small cutaneous vessels. Direct immunofluorescence on frozen sections may detect vascular deposits of immune complexes. Vascular deposits of IgA are highly indicative of Henoch-Scho¨nlein purpura and vascular deposits of IgM or IgG are typical of mixed-type cryoglobulinemia [4]. Vasculitis patients should be screened for infectious disease, drugs, autoimmune disease and malignancies. Cutaneous leukocytoclastic vasculitis often follows an upper respiratory infection and drug therapy with antibiotics or nonsteroidal antiinflammatory drugs (NSAID) [5, 6]. Henoch-Scho¨nlein purpura can be associated with b-hemolytic streptococci group A [7]. Therefore, streptococcal pharyngitis should be ruled out by throat swabs and the antistreptolysin titer should be checked. Mixed-type cryoglobulinemia can be associated with hepatitis C [8]. When small-vessel vasculitis occurs in the setting of collagenvascular disease, such as rheumatoid arthritis, systemic lupus erythematosus, Sjo¨gren’s and Behçet’s syndrome, systemic involvement is more likely to occur [5]. As a rule, patients with any type of small-vessel vasculitis have to be monitored for systemic involvement, especially of the kidneys (dysmorphic hematuria, proteinuria, renal insufficiency, hypertension), as long as the disease remains clinically active. In the following chapter we limit our considerations to cutaneous leukocytoclastic vasculitis, cryoglobulinemic vasculitis, cutaneous panarteritis nodosa and pyoderma gangrenosum (PG). PG is not considered to be a form of vasculitis, but requires a management that has much in common with that of vasculitic leg ulcers.

Cutaneous Leukocytoclastic Vasculitis Cutaneous leukocytoclastic vasculitis presents as palpable purpura that sometimes necrotizes leading to leg ulcerations (fig. 1). In about 50% of the patients a possible triggering event can be recognized. Of these patients, 30% have recent drug intake for a coexistent infection, usually an upper respiratory tract infection. b-Lactamic antibiotics and NSAID are the most commonly incriminated drugs [5, 6]. A skin biopsy reveals leukocytoclastic vasculitis of the small cutaneous vessels and the direct immunofluorescence of a fresh lesion typically reveals vascular deposits of complement and immunoglobulin. The overall prognosis of cutaneous leukocytoclastic vasculitis is good. Blanco Alonso et al. [5] performed a large retrospective study on 334 consecutive, unselected patients with cutaneous vasculitis according to the ACR criteria. Among 204 adults, 148 had primary cutaneous vasculitis and 56 had

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secondary cutaneous vasculitis. The 148 adults with primary cutaneous vasculitis were classified as having hypersensitivity vasculitis in 81 cases, HenochScho¨nlein purpura in 43 and cutaneous polyarteritis nodosa in 18 cases. The 81 adults with hypersensitivity vasculitis (ACR 1990 criteria) correspond largely to the entity cutaneous leukocytoclastic vasculitis (Chapel Hill Conference). After a mean follow-up of 15.5×28.9 months, only 2 among these 81 adults had slight renal impairment [6]. With regard to the treatment, this implicates that an aggressive treatment is often not warranted. Among the 81 adult patients reported by the same group [6], 54 received no specific treatment and 26 patients had NSAID. Only 12 patients required systemic steroids and 2 patients received cytotoxic drugs because of renal involvement. When leg ulcers are caused by cutaneous vasculitis, a mild immunosuppressive treatment is usually required. Prednisone 20–40 mg/day should be used initially and tapered as soon as a clinical response is achieved. Since we observed that our patients with vasculitic leg ulcers tend to have more active and recurrent disease, we prefer to continue treatment with colchicine (1.5 mg/day) [9] or with dapsone (100 mg/day) [10] for 3–6 months, before discontinuation of immunosuppressive medication is considered. More severe cases must be carefully monitored for progression to systemic involvement and azathioprine [11] or cyclophosphamide [12] may be required to control disease activity. Usually, smaller ulcers heal spontaneously under immunosuppressive treatment. However, in large ulcers and in ulcers occurring at ‘high-risk’ locations, such as the dorsum of the foot, a split skin graft may be suitable for otherwise recalcitrant vasculitic wounds.

Cryoglobulinemic Vasculitis Cryoglobulins are circulating immune complexes that reversibly precipitate when the serum is cooled. The blood sampling has to be performed at the specialized laboratory at 37 ºC. Brouet et al. [13] described three distinct groups of cryoglobulins. Type I cryoglobulins consist of a single monoclonal immunoglobulin in high titers, normally IgG or IgM, usually associated with multiple myeloma or chronic lymphatic leukemia. Type II (a monoclonal immunoglobulin complexed with polyclonal immunoglobulins) and type III (polyclonal immunoglobulins complexed with polyclonal immunoglobulins or other proteins) represent the so-called mixed types of cryoglobulinemia. They occur in conjunction with infectious diseases, collagen-vascular diseases and lymphoproliferative disorders. Most cases of mixed-type cryoglobulinemia were believed to be idiopathic up until recently. Currently 50–70% of these cases are associated with hepatitis C [8, 14, 15]. About one third of mixed-

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1

2

Fig. 1. Palpable purpura in cutaneous leukocytoclastic vasculitis (53-year-old man with prior upper respiratory tract infection). Fig. 2. Extended ulcerating livedo in type III cryoglobulinemia (29-year-old woman, intravenous drug user with chronic hepatitis C). Fig. 3. PG that showed rapid response to systemic cyclosporine (52-year-old woman, no association to underlying disease, e.g. inflammatory bowel disease, could be found).

3

type cryoglobulinemia remains to be classified as ‘essential mixed-type cryoglobulinemia’. Type I cryoglobulins increase blood viscosity and therefore typically can cause acrocyanosis, Raynaud’s phenomenon, arterial thrombosis and retinal hemorrhage. Type II and III cryogloblins induce immune complex-mediated leukocytoclastic vasculitis of small vessels. Clinically, they are associated with recurrent palpable purpura (80–100%), oligoarthritis (60–80%), renal involvement (50–60%) (purpura-arthralgia-nephritis syndrome [16]), polyneuropathy (40%) and gastrointestinal symptoms (30%) [4, 8]. During the active phases of disease, cutaneous small-vessel vasculitis can lead to marked and ultimately ulcerating livedo (fig. 2). Skin biopsy shows leukocytoclastic vasculitis and direct immunofluorescence typically reveals vascular deposits of IgG and IgM. Elevated immune complexes reflecting disease activity can be measured in the serum. Treatment of cryoglobulinemia is based on the severity of disease. Mild purpura can be treated with topical corticosteroids. Bed rest and compression therapy may help prevent immune complex precipitation in the cutaneous vessels of the lower extremities. Visceral involvement as well as the occurrence of cutaneous ulcerations require systemic corticosteroid therapy in conjunction with cytotoxic drugs [17]. Interferon may offer a new perspective to treat the underlying disease for patients with mixed-type cryoglobulinemia associated with chronic hepatitis C [15].

Cutaneous Polyarteritis nodosa Cutaneous polyarteritis nodosa is a benign variant of polyarteritis nodosa (PAN) that remains limited to the small and medium-sized arteries of the skin. A livedo and multiple nodular skin lesions that are tender on palpation are mainly found on the legs, but also on the arms and trunk [18]. About half of the patients develop painful skin ulcerations. These patients also tend to develop a mild form of polyneuropathy of the legs [18, 19]. Histopathology is identical to that in systemic PAN. The acute phase shows fibrinoid necrosis of the intima and a dense mainly polymorphonuclear infiltrate of the entire arterial wall. In later stages the infiltrate becomes histiocytic leading to vessel fibrosis [19–21]. Elastin stains may be helpful, especially in the presence of severely damaged vessels. Direct immunofluorescence is nonspecific. The etiology of cutaneous PAN is unknown. It has been associated with inflammatory bowel disease, but unlike systemic PAN, not with hepatitis B and C infection. Immunological abnormalities are not found. Progression to systemic disease is very rare. Daoud et al. [21] reported on 79 patients of the Mayo Clinic series among whom 40 patients had a mild form of disease

with nonulcerating skin nodules that essentially were responsive to topical corticosteroids, 39 patients developed skin ulcerations, but none of the patients progressed to systemic PAN after a mean follow-up of 6.9 years (6 months to 30 years). Among the 20 patients studied by Chen [20], 2 (10%) progressed to systemic PAN after more than 18 years of a benign course. Therefore, monitoring is necessary as long as cutaneous PAN remains clinically active. Only the severe cases of cutaneous PAN require systemic immunosuppressive treatment. Prednisone is started at 20–60 mg/day and tapered to 5–10 mg, according to disease activity. Low-dose methotrexate (7.5–15 mg weekly) and NSAID have been used successfully as steroid-sparing agents [18, 20].

Pyoderma gangrenosum PG is a noninfectious destructive inflammatory skin disease that leads to painful and progressively enlarging ulcers with an undermined violaceous pustular border (fig. 3). In 50–60% of the patients, PG is associated with an underlying disease, most commonly Crohn’s disease, colitis ulcerosa, rheumatoid arthritis, myelodysplastic and hematoproliferative disorders, autoimmune hepatitis and Behçet’s disease. In 20% of patients, minor trauma can precipitate new lesions (pathergy phenomenon). These patients are prone to develop PG at sites of a surgical intervention [22]. Therefore, surgical de´bridement of PG should be avoided if possible. When surgical de´bridement is necessary in order to remove large zones of eschar, it should only be attempted after effective immunosuppression has been started. PG is not regarded to be a form of vasculitis but rather thought to be a so-called neutrophilic dermatosis, in which dysregulation of neutrophil chemotaxis plays a major role. Histopathology is not specific or pathognomonic, although some histological features, such as neutrophilic infiltration, thrombosis of the small cutaneous vessels (veins and arteries) and hemorrhage are consistently found within the border of the ulcer. Leukocytoclastic vasculitis is found in about 40% of cases [22]. Direct immunofluorescence is nonspecific. Systemic corticosteroids represent the best documented treatment modality of PG. Initial doses of 100–200 mg of prednisone are required to induce healing and are tapered slowly and discontinued when complete resolution has occurred. Patients with severe PG may require suprapharmacological doses of intravenous methylprednisolone, 1 g/day on 5 consecutive days [23]. Sulfa drugs (especially dapsone), azathioprine, cyclophosphamide and clofazimine can be used as steroid-sparing agents in cases where treatment extends over several months [22, 24]. Cyclosporine is now well documented to be effective in cases which do not respond to systemic corticosteroids [25]. Matis et al. [26] reported a complete


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response in 10 of 11 patients on cyclosporine 5–10 mg/kg/day. Two patients relapsed after cessation of medication. Nephrotoxicity and hypertension as well as an increased risk of malignant disease, such as lymphoma, limit the use of cyclosporine [25]. Nephrotoxicity and hypertension occur in a dosedependent fashion. Zumdick et al. [27] reported a series of 6 patients responsive to low-dose cyclosporine (3 mg/kg/day) and Theissen et al. [28] reported the successful use of topical cyclosporine in a patient where systemic administration was contraindicated. Serum levels under topical administration reached only 50 ng/ml (as assessed by radioimmunoassay), whereas the therapeutic serum level is between 100 and 200 ng/ml. Toxicity must be anticipated above 200 ng/ml. Neoral is the new, ultramicronized formulation of cyclosporine that results in improved bioavailability due to better intestinal resorption [25]. In cases unresponsive to cyclosporine, mycophenolate [29] and systemic [30] as well as topical tacrolimus [31] have been successfully used as further possibilities of immunosuppression. There are only very limited data on the use of split skin grafts in the treatment of PG. Most authors prefer to wait for spontaneous healing, even if this can take several months. In our experience, surgical interventions and especially split skin grafts can be successfully used as soon as the disease is responsive to immunosuppression. However, continued immunosuppression is mandatory until complete healing is achieved. References 1

2

3

4 5

6 7 8

Hunder GG, Arend WP, Bloch DA, Calabrese LH, Fauci AS, Fries JF, Leavitt RY, Lie JT, Lightfoot RW, Masi AT, McShane DJ, Michel BA, Mills JA, Stevens MB, Wallace SL, Zvaifler NJ: The American College of Rheumatology 1990 criteria for the classification of vasculitis. Introduction. Arthritis Rheum 1990;33:1065–1067. Fries JF, Hunder GG, Bloch DA, Michel BA, Arend WP, Calabrese LH, Fauci AS, Leavitt RY, Lie JT, Lightfoot RW, Masi AT, McShane DJ, Mills JA, Stevens MB, Wallace SL, Zvaifler NJ: The American College of Rheumatology 1990 criteria for the classification of vasculitis. Summary. Arthritis Rheum 1990;33:1135–1136. Jennette JC, Falk RJ, Andrassy K, Bacon PA, Churg J, Gross WL, Hagen C, Hoffman GS, Hunder GG, Kallenberg CGM, McCluskey RT, Sinico RA, Rees AJ, van Es LA, Waldherr R, Wiik A: Nomenclature of systemic vasculitides. Proposal of an international consensus conference. Arthritis Rheum 1994;37:187–192. Jennette JC, Falk RJ: Small-vessel vasculitis. N Engl J Med 1997;337:1512–1523. Blanco AR, Martıńez-Taboada VM, Armona J, Fernańdez-Sueiro JL, Sańchez-Andrade A, Rodrı´guez-Valverde V: Disease associations and etiologic factors in 334 patients with cutaneous vasculitis. Arthritis Rheum 1995;38(suppl 9):S391. Martıńez-Taboada VM, Blanco R, Garcıá-Fuentes M, Rodrı´guez-Valverde V: Clinical features and outcome of 95 patients with hypersensitivity vasculitis. Am J Med 1997;102:186–191. Blanco R, Martıńez-Taboada VM, Rodrı´guez-Valverde V, Garcıá-Fuentes M, Gonza´lez-Gay MA: Henoch-Scho¨nlein purpura in adulthood and childhood. Arthritis Rheum 1997;40:859–864. Peche`re-Bertschi A, Schifferli JA: Les cryoglobuline´mies essentielles. Schweiz Rundsch Med (Praxis) 1993;82:163–166.

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Callen JP: Colchicine is effective in controlling chronic cutaneous leukocytoclastic vasculitis. J Am Acad Dermatol 1985;13:193–200. Wozel G: Dapson. Stuttgart, Thieme, 1996. Callen JP, Spencer LV, Bhatnagar Burruss J, Holtman J: Azathioprine. Arch Dermatol 1991;127: 515–522. Fauci AS, Katz P, Haynes BF, Wolff SM: Cyclophosphamide therapy in severe systemic necrotizing vasculitis. N Engl J Med 1979;310:235–238. Brouet JC, Clauvel JP, Danon F, Klein M, Seligmann M: Biologic and clinical significance of cryoglobulins. Am J Med 1974;57:775–788. Agnello V, Chung RT, Kaplan LM: A role for hepatitis C virus infection in type II cryoglobulinemia. N Engl J Med 1992;327:1490–1495. Akriviadis EA, Xanthakis I, Navrozidou C, Papadopoulos A: Prevalence of cryoglobulinemia in chronic hepatitis C virus infection and response to treatment with interferon-alpha. J Clin Gastroenterol 1997;25:612–618. Fontana A, Doll B, Joller H: IgG-IgM-Kryoglobulina¨mie mit Purpura-Arthralgie-Nephritis-Syndrom. Schweiz Med Wochenschr 1982;112:7–13. McMurray RW, Elbourne K: Hepatitis virus infection and autoimmunity. Semin Arthritis Rheum 1997;26:689–701. Truëb R, Hu¨rlimann AF, Burg G: Periarteriitis nodosa cutanea. Hautarzt 1995;46:568–572. Kleeman D, Kempf W, Burg G, Hafner J: Cutaneous polyarteritis nodosa. Vasa 1998;27:54–57. Chen KR: Cutaneous polyarteritis nodosa: A clinical and histopathological study of 20 cases. J Dermatol 1989;16:429–442. Daoud MS, Hutton KP, Gibson LE: Cutaneous periarteritis nodosa: A clinicopathological study of 79 cases. Br J Dermatol 1997;136:706–713. Wolff K, Stingl G: Pyoderma gangrenosum; in Fitzpatrick TB, Eisen AZ, Wolff K, Freedberg IM, Austen KF (eds): Dermatology in General Medicine. New York, McGraw-Hill, Inc, 1993, pp 1171–1182. Prystowsky JH: Present status of pyoderma gangrenosum. Arch Dermatol 1989;125:57. Shelley WB, Shelley ED: Advanced Dermatologic Therapy. Philadelphia, Saunders, 1987, pp 438– 442. Lim KK, Su WPD, Schroeter AL, Sabers CJ, Abraham RT, Pittelkow MR: Cyclosporine in the treatment of dermatologic disease: An update. Mayo Clin Proc 1996;71:1182–1191. Matis WL, Ellis CN, Griffiths CEM, Lazarus GS: Treatment of pyoderma gangrenosum with cyclosporine. Arch Dermatol 1992;128:1060–1064. Zumdick M, Goerz G, Schuppe HC, Milde P, Ruzicka T: Niedrig dosierte Cyclospoirn-A-Therapie bei Pyoderma gangraenosum. Erfahrungen bei 6 Patienten. Hautarzt 1995;46:697–701. Theissen U, Luger TA, Schwarz T: Erfolgreiche topische Anwendung von Cyclosporin A bei Pyoderma gangraenosum. Hautarzt 1996;47:132–135. Hohenleutner U, Landthaler: Mycophenolate mofetil in pyoderma gangrenosum. Lancet 1997;350: 1748. Abu-Elmaged K, Jegasothy BV, Ackerman CD, Thomson AW, Rilo H, Nikolaidis N, van Thiel D, Fung JJ, Todo S, Starzl TE: Efficacy of FK-506 in the treatment of recalcitrant pyoderma gangrenosum. Transpl Proc 1991;23:3328–3329. Schuppe HC, Homey B, Assmann T, Martens R, Ruzicka T: Topical tacrolimus for pyoderma gangrenosum. Lancet 1998;351:832. Callen JP: Cutoneous vasculitis: Relationship to systemic disease and therapy; in Curr Probl Dermatol. Basel, Karger, 1993, vol 5, pp 45–80.



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Conclusions Albert-Adrien Ramelet a, Ju¨rg Hafner b, Wilfried Schmeller d, Urs V. Brunner c a

Specialist in Dematology and Angiology, Lausanne, Switzerland; Departments of Dermatology and c Surgery University Hospital, Zu¨rich, Switzerland, and d Department of Dermatology, University Hospital, Lu¨beck, Germany b

Leg ulcers represent a major health concern in Western countries. They generate substantial costs to the health care systems. The lifetime risk to develop a chronic leg ulcer has been found to reach 1–2% and many patients will never consult a doctor for their problem. It has been clearly shown that chronic leg ulceration severely affects quality of life. For several reasons the incidence of newly diagnosed chronic leg ulcers might decrease in the future. Considerable advances have been achieved in the prevention as well as in the treatment of deep-vein thrombosis. This should help reduce the incidence of venous leg ulcers in the setting of postthrombotic syndrome. It has been shown that postthrombotic complications can be markedly reduced by a consequent long-term use of compression stockings. The wide accessibility of duplex scanning has markedly improved insight into the understanding of chronic venous insufficiency. Surprisingly, postthrombotic changes are found in only 50–60% of patients, the remaining 40–50% of patients exhibit primary valvular incompetence. A majority of the patients with primary valvular incompetence essentially show superficial venous incompetence that may be accompanied by incompetence of the perforating veins. These conditions are amenable to surgical intervention. Effective surgical removal of varicose veins should result in a decrease in morbidity from venous ulcers. Changes in smoking habits and control of the other vascular risk factors might reduce the occurrence of peripheral arterial occlusive disease and of arterial ulcers. At the same time interventional procedures have greatly improved and thus the salvage rates of arterially impaired limbs. Diabetic foot ulcers should diminish as a consequence of improved management of late complications in diabetes.

On the other hand, demographic changes might contribute to a future increase in chronic leg ulcers. An increase in the percentage of older people coincides with an elevated incidence of vascular disease and diabetes. Vascular risk factors that seemed decreasing may increase in following generations, such as cigarette smoking in young women. Growing socio-economic problems in the cities may be accompanied by an increase of chronic diseases. The introduction of new therapies might lead to new nosologic entities, such as hydroxyureainduced leg ulcers. We feel that there is still a wide gap between the high prevalence of chronic leg ulcers in the general population and the medical training concerning these conditions. The increase in research and training activities in the field of wound healing will hopefully help overcome the former lack of interest in this major medical field. Angiology and phlebology in particular should be taught to all medical students and not belittled by medical schools as it occurs frequently. Seminars and publications should regularly direct the attention of physicians and nurses to the subject of wound healing and leg ulcer care. This would be in the interest of our patients and we hope that all the contributions sampled in this book will contribute to this aim.


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Author Index

Aschwanden, M. 96 Aubo¨ck, J. 26 Bounameaux, H. 293 Brunner, U.V. 2, 4, 174, 252, 286 Cassina, P.C. 174, 226 Eichlinsberger, R. 70 Eichmann, A. 259

Ju¨nger, M. 124, 141 Kessler, W. 174 Kiehlmann, I. 170 Klyscz, T. 124, 141 Ko¨nig, M. 8 Labs, K.H. 96 Lautenschlager, S. 259 Lechner, W. 170 Limat, A. 49, 57 List-Hellwig, E. 109

French, L.E. 49 Gallenkemper, G. 153 Hach-Wunderle, V. 102 Hafner, J. 1, 4, 211, 220, 252, 271, 277, 286 Hahn, M. 124 Hunziker, T. 57 Ja¨ger, K. 96 Jeanneret, C. 96

Maessen.Visch, M.B. 114 Mayer, W. 81 Meents, H. 109

Rabe, E. 89 Ramelet, A.-A. 1, 4, 20, 161, 165, 286 Rassner, G. 141 Sattler, . 190 Scheidegger, E.P. 3 Schmeller, W. 2, 4, 195, 286 Schneider, E. 220 Schultz-Ehrenburg, U. 154 Schwahn-Schreiber, C. 182 Stahel, H.U. 148 Steins, A. 124 Truëb, R.M. 271, 277 Vanscheidt, W. 8

Neumann, H.A.M. 114 Pannier-Fischer, F. 89 Partsch, H. 81, 130 Perrenoud, D. 20, 165 Peschen, M. 8, 13

Wetz, H.H. 242 Wienert, V. 65 Wu¨tschert, R. 203 Zinnagl, N. 235

289

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Subject Index

Acetylsalicylic acid, see Aspirin Achilles tendon 112 Adhesion molecules 8, 14 Adjuvant drug treatment 153 Age 67 Air plethysmography 116, 131 Alexander House Consensus Paper 158 Alginates 36 Allergic contact sensitization, allergic contact dermatitis 166 Allogeneic composite graft 62 Allogeneic keratinocytes 58 Ambulatory capillary hypertension 127 Ambulatory venous hypertension 73, 74, 87, 120, 125, 132 Ambulatory venous pressure 114 measurements 120, see also Phlebodynamometry Amputation 252, 256 major 257 minor (Grenzzone) 257 Anaerobes 20, 253 Anatomy congenital insufficiency 83, 86 primary insufficiency 83, 86 secondary insufficiency 83, 86 Angiography (arteriography) 208 Ankle joint 141, 145, 184, 196 systolic pressure 203, 205

Ankle–arm index 22, 237, 252, 254 Ankle-foot orthesis 249 Antibiotic therapy 254 Antibiotic treatment 252 Antibiotics 22 Antiphospholipid syndrome 265 Antiseptics 22 Arterial leg ulcer(s) 211, 215, 262 Arterial reconstruction 228 Arthrogenic congestion (stasis) syndrome 109, 143, 187, 196, 273 Aspirin 156, 214, 240 Atheroembolism (cholesterol embolism) 265 Autologous keratinocyte(s) 58 grafting 57 Autologous topical hemotherapy 53 Bandage(s) elastic 132 four-layer 130, 134, 136 inelastic 132–134, 136 long stretch 134 medium stretch 134 short stretch 130, 134 Basal cell carcinoma 171 Basic fibroblast growth factor 15 Bier’s arterial arrest 216, 256 Biomechanical stimulation therapy 144 Biopsy 263, 279

290

Bypass grafting 228 surgery 215 Calciphylaxis 266 Calf muscle pump 114 venous 117. 141 Candida 21 Capillaroscopy 125, 126 Cavity 34, 38, 40 CEAP classification 74, 82 Cellulitis 21, 252 Chronic critical limb ischemia, see Critical leg ischemia Chronic inflammation 8 Chronic venous insufficiency 13, 81, 141, 174, 191, 195, 271 prevalence 72 circumferential venous ulcer 200 Claudication 211, 227 CO2 laser 162 Cockett’s perforating veins, see Perforating veins Colonization 21, 29, 40 Combined physical decongestion therapy 149 Combined venous-arterial leg ulcer 211, 226, 259 Compartment pressure 183 Complicated Fontaine stage IIb peripheral arterial occlusive disease 215 Complications 170, 185, 187, 193 Compression graduated 138 stockings 72, 130, 134–136 therapy 76, 130, 138, 150 Compression-decompression maneuver 97 Computed tomography 109, 199 Contact sensitization, contact dermatitis 165, 166 Continuous-wave Doppler 86 Costs 67 Coumarin 153 Critical leg ischemia 203, 207, 213, 227, 228 Crural fasciectomy 109, 186

Subject Index

Cryoglobulinemia 265, 280 Cuff inflation-deflation (Hokanson) 99 Cultured keratinocyte grafts 57 Cutaneous lymphoma 269 Cutaneous polyarteritis nodosa 282 Cytokines 13, 28 Debridement 27, 40, 161, 241 Deep venous insufficiency 73, 77, 106, 178, 195 Deep venous obstruction 91 Deep venous thrombosis 70, 90 incidence 70 prevention 75 Dependency syndrome 227 Dermatitis 165 Dermatolipofasciosclerosis 109, 182, 198, 199 Dermatoliposclerosis 198, 199 Diabetic angiopathy 235 Diabetic foot infection 238, 252 limb-threatening 252 non-limb-threatening 252 syndrome 235, 242 Diabetic neuropathic osteoarthropathy 242 Sander’s classification 243 Diabetic neuropathy 237, 262 Diabetic osteoarthropathy 238, 242 Differential diagnosis 259, 260 Diosmin 155, 156 Distal point of incompetence 105 Doppler ultrasound 89, 205 Dorsal extension 141, 143 Drugs 153, 154 Duplex-Doppler ultrasound 85, 86, 89, 97, 175, 208 Eczema 165 Edema 130, 233 Electrostimulation 163 Endoscope 190 Epidemiology 65, 70 Epidermal growth factor 15, 50 Escin 155

291

Exercise 142, 150, 211 Exudate 28, 33, 34, 37, 38, 40 Fascia sclerosis 182 Felty syndrome 264 Femoro-popliteal (Giacomini) vein 93 Fibrinolysis 70, 75 Fibroblast growth factor 50 Fibronectin 9, 16 Film dressing 30 Fluorescence videomicroscopy 125 Foam dressings 33 most absorbent material 34, 37 Foot ulcer 211, 226, 235, 242 volumetry 132 Gangrene 231 Granulocyte-colony stimulating factor 217, 254 Greater saphenous vein 91, 105 Growth factors 9, 15, 49 Healing rate(s) 133, 138, 142, 156, 185, 193, 198 ß-Hemolytic streptococci 21–23 Hokanson 99 Honey 163 Hydrocolloids 31 Hydrofibres 37 Hydrogels 35 Hydroxyurea 264 Hyperbaric oxygen therapy 162 Iatrogenic damage 170 Iloprost 216 Infection 21, 29, 40, 252 Interactive dressings 30 Intercellular adhesion molecule-1 8, 14 Interfollicular epidermal keratinocytes 58 Intermittent claudication 204 Intermittent pneumatic compression 130, 133 Interventional vascular procedures 215, 223, 240 Ischemic rest pain 213, 227

Subject Index

Laminin 16 Lanolins 165, 168 Laplace law 135 Laser, low-level 163 Lesser saphenous vein 93, 105, 177 Leukocytoclastic vasculitis 265, 279 cutaneous 279 Localization 67 Lymph drainage 133 manual 148 Lymphedema 148 Maggot therapy 162 Magnetic resonance imaging 109, 199 Malignant leg ulcers 171, 269 Malum perforans 237, 243 Arlt classification 239 Wagner classification 239 Marjolin’s ulcer 171 Matrix metalloproteases 9, 15 tissue inhibitors 15 Medial calcinosis Mönckeberg 205, 237 Methicillin-resistant staphylococci 254 Microbiology 20, 253 Microcirculation 124, 126 Mixed venous-arterial ulcers 211, 226, 259 Moist wound healing 26 Molecular biology 8 Muscles, fatty degeneration 112 Myeloproliferative disorders 264 Nailcare 213, 239 Necrobiosis lipoidica 268 Necrosis 213 gangrene (moist necrosis) 253 mummification (dry necrosis) 253 Necrotizing fasciitis 171 Neomycin 165, 168 Nutrition 163 Obsolete treatment modalities 161 Occlusive dressing(s) 26, 30, 74 Oral anticoagulation 75 Orthopedic footwear 240, 249 Orthostatic compartment syndrome 183

292

Osteomyelitis 253 Outer root sheath keratinocytes 58 Outflow obstruction 117 Pain 27, 32, 145, 184, 213, 261 Palpable purpura 277 Paratibial fasciotomy 109, 183 Patch test(s) 165, 168 Patency 223, 229 Pedal pulse 204, 236 Pelottes 135, 138 Pentoxifylline 155, 158 Percutaneous transluminal angioplasty 215, 220, 273 Perforating vein(s) 74, 174, 184, 190 Peripheral arterial occlusive disease 89, 133, 170, 198, 209, 211, 220, 226, 240, 252, 259, 271 Peru balsam 165, 168 Phlebodynamometry 87, 120, 132, see also Ambulatory venous pressure measurements Phlebography (venography) 102, 175 antegrate (ascending) 102 retrograde (descending) 103 Photoplethysmography 116 Physiotherapy 143 Plantar flexion 143 Plasminogen activator 15 Platelet-derived growth factor(s) 9, 13–15, 49 Plethysmography 87, 114 Podologist, chiropodist 239 Pole test technique 205 Porter’s classification 82 Postthrombotic syndrome 70, 102, 104, 175, 187, 191, 195 prevalence 72 Preoperative examination 93, 107 Preservatives 165, 168 Prevalence 65, 70 Probe to bone 253 Proinflammatory cytokines 8 Prostaglandin E1 155, 158, 216 Pseudomonas 21, 22, 253 Pulmonary embolism 70 Pyoderma gangrenosum 266, 275, 283

Subject Index

Quality of life 68 Randomized controlled trials 156 Recanalization 104 Recirculation 177 circuits (overload theory) 105, 177 Rest pain 213, 227, 231 Rheumatoid arthritis 271 Rheumatoid vasculitis 275 Risk factors (cardiovascular) 204, 213 Rocker foot 238, 245 Sclerotherapy 172 Secondary prevention 211, 213 Semiocclusive dressings 22, 26, 30 Sex 67 Shave therapy 195 Sickle-cell anemia 263 Small-vessel vasculitis 277 Spinal cord stimulation 216 Squamous cell carcinoma 171 Stanozolol 156, 158 Staphylococcus aureus 21–23, 253 methicillin-resistant 23 Stasis dermatitis 166 Stemmer’s sign 148 Stents 223 Strain gauge plethysmography 115 Subfascial endoscopic perforating vein surgery 180, 190 Sugar 163 Superficial venous insufficiency 73, 175 Surgery, superficial veins 174, 179 Surgical revascularization 228 Synthetic dressings 26, 30, 168 Systemic sclerosis 271 Tenascin 16 Tetanus 23 Thalassemia minor 263 Therapy-resistant (recalcitrant) venous ulcer 200 Thrombectomy 76 Tissue inhibitors of metalloproteases 9 Toe systolic pressure 206 Transcutaneous oxygen pressure 206

293

Transforming growth factor-ß 10, 13, 15, 52 Tropical ulcer 268 Troxerutin 156 Tübingen angle meter 144 Tumor necrosis factor-· 8, 13 Ultrasound 162 Unna’s boots 130, 134, 138, 171 Vacuum sealing technique 161 Valsalva maneuver 91, 97, 98 Valvular incompetence 96 Valvular reconstruction(s) 70, 77, 180 Varicography 103 Vascular cellular adhesion molecule-1 8, 14 Vasculitis 265, 271 classification 277 small-vessel 277

Subject Index

Venography, see Phlebography Venous filling index 117, 120 Venous flow resistance 118 Venous malformations 102 Venous recirculation circuit(s) 177 Venous refilling time 116 Venous reflux 74, 86, 91, 96 Venous ulcer(s) 130, 148, 150, 174, 187, 191, 195, 262 Venous-arterial leg ulcers 211, 226, 259 Vitamin 163 Water jet 162 Widmer classification 74, 81 Wound matrix 9 Zinc 163 Zinc plaster, see Unna’s boots

294