Standard, Appropriate, and Advanced Care and Medical-Legal Considerations: Part Two—Venous Ulcerations (B)
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In fact, one European consensus paper recommended utilizing standard care for a full year before considering skin grafting. Seventy-eight percent of ulcers treated with split-thickness skin grafts were healed completely or partially in a retrospective review from an academic dermatology group. Others have reported 20-percent healing rates for venous ulcers treated with skin grafts. Attempts have been made to identify risk factors, which would identify graft success rates. One group has evaluated the use of the immunosuppressive agent, FK506, as a topical to prolong the survival of skin allografts. A novel approach has been proposed using a hyaluronic acid-based topical dressing to prepare the wound bed followed by the application of cultured keratinocytes. The recent explosion of work in the field of bioengineered tissue has given clinicians another option for advanced care for venous ulcers when standard therapy fails or is not appropriate for the individual patient. The Cochrane library has produced a review of seven randomized, controlled trials concerning the use of autologous and bioengineered tissue. The results showed limited evidence supporting bioengineered tissue, but further research would be required to support the use of standard skin grafting at this time based on this meta-analysis.
Bioengineered tissue. The first attempt to develop bioengineered skin tissue was with acellular collagen-chondroitin-6-sulphate lamina as a matrix scaffold to regenerate dermal tissue. Later, an epidermal replacement using cultured autologous epithelium was attempted for burn wounds. Eventually, a bilayered model of skin was developed using a contracted collagen lattice containing live fibroblasts with an overlying lamina of epidermal cells. This living skin equivalent (LSE) (Apligraf®, Novartis Pharmaceuticals Inc., East Hanover, New Jersey) is a Food and Drug Administration (FDA)-approved bilayered construct for the treatment of venous ulcers. The healing response of LSE is a result of its impact as a biological dressing, potential frank take of the graft, and the stimulation of the wound bed through the release of growth factors. Several reports have identified positive clinical outcomes using this technology for hard-to-heal venous ulcers.[160–162]
The decision to use this technology is still left to clinician preference. As stated before, if a patient can be identified as recalcitrant or be classified into a category with known poor outcomes, should this technology be used earlier in the course of care? It has yet to be determined if a more aggressive approach on the front end of the treatment course will achieve cost efficiency.
There are many treatment modality options for the treatment of chronic wounds including venous ulcers. These include but are not limited to ultrasound, electrical stimulation, laser light, warming therapy, radio frequency, pulsed short wave diathermy, and hyperbaric oxygen. These modalities are well described in the literature and textbooks.[163,164] Several ongoing trials may help identify the roles of these treatment options in the near future. Electrical stimulation has been recently shown in a meta-analysis to provide significant benefit for healing chronic wounds of many etiologies including venous ulcers and at this point has the most literature-based support. As described in the section on bioengineered tissue, modalities have a definite role in the treatment of venous ulcers but a question still remains: Which modality, what combination, and when during the course of therapy should they be used? Once again the identification of a recalcitrant patient might lead a clinician to use a modality earlier in the treatment plan.
1. Lazarus GS, Cooper DM, Knighton DR. Definitions and guidelines for assessment of wounds and evaluation of healing. Arch Dermatol 1994;130(4):489–93.
2. Ricotta JJ, Dalsing MC, Ouriel K, et al. Research and clinical issues in chronic venous disease. Cardiovasc Surg 1997;5(4):343–9.
3. McGuckin M, Stineman M, Goin J, Williams S. The road to developing standards for the diagnosis and treatment of venous leg ulcers. Ost/Wound Manag 1996;42(10A):62S–6S.
4. McGuckin M, Stineman M, Goin J, Williams S. Draft guideline: Diagnosis and treatment of venous leg ulcers. Ost/Wound Manag 1996;42(4):48–78.
5. Douglas SW, Simpson NB. Guidelines for the management of chronic venous leg ulceration. Report of a multidisciplinary workshop. Br J Dermatol 1995;132:446–52.
6. Cresswell J. New guidelines on venous leg ulcer management. Nurse Prescr/Comm Nurse 1999:53–5.
7. Nelson EA, Ruckley CV, Dale J, Morison M. The management of leg ulcers. J Wound Care 1996;5(2):73–6.
8. Barr JE, Cuzzell J. Wound care clinical pathway: A conceptual model. Ost/Wound Manag 1996;42(7):18–25.
9. Hess CT. Management of a venous ulcer: A case study approach. Adv Skin Wound Care 2001;14(3):148–9.
10. Zimmet SE. Venous leg ulcers: Modern evaluation and management. Dermatol Surg 1999;25:236–41.
11. Bello YM, Phillips TJ. Management of venous ulcers. J Cut Med Surg 1998;3 (Suppl. 1):S1–12.
12. Negus D, Friedgood A. The effective management of venous ulceration. Br J Surg 1983;70:623–7.
13. Ryan TJ. Management of leg ulcers. Hosp Med 1998;59(11):838–40.
14. Burton CS. Venous ulcers. Am J Surg 1994;(167 Suppl 1A):37S–41S.
15. Kerstein MD. The nonhealing leg ulcer: Peripheral vascular disease, chronic venous insufficiency, and ischemic vasculitis. Ost/Wound Manag 1996;42 (Suppl 10A):19S–35S.
16. Miller OF, Phillips TJ. Leg ulcers. J Am Acad Dermatol 2000;43:91–5.
17. Nelson EA. Understanding compression therapy. J Wound Care 1998;7(7):323.
18. Falanga V. Care of venous leg ulcers. Ost/Wound Manag 1999;45(Suppl 1A):33S–43S.
19. Browse NL, Burnand KG, Irvine AT, Wilson NM. Milestones, pebbles, and grains of sand. In: Browse NL, Burnand KG, Irvine AT, Wilson NM (eds). Diseases of the Veins. London: Arnold Publishers, 1999;1–22.
20. Kerstein MD, Gahtan V. Outcomes of venous ulcer care: Results of a longitudinal study. Ost/Wound Manag 2000;46(6):22–9.
21. Sibbald RG. Venous leg ulcers. Ost/Wound Manag 1998;44(9):52–64.
22. Falanga V, Margolis D, Alvarez O, et al. Rapid healing of venous ulcers and lack of clinical rejection with allogeneic cultured human skin equivalent. Arch Dermatol 1998;134:293–300.
23. Lyon RT, Veith FJ, Bolton L, et al. Clinical benchmark for healing of chronic venous ulcers. Am J Surg 1998;176:172–5.
24. Smith JJ, Guest MG, Greenhalgh RM, Davies AH. Measuring the quality of life in patients with venous ulcers. J Vasc Surg 2000;31:642–9.
25. Phillips T, Stanton B, Provan A, Lew R. A study of the impact of leg ulcers on quality of life: Financial, social, and psychologic implications. J Am Acad Dermatol 1994;31:49–53.
26. Mathias SD, Prebil LA, Boyko L, Fastenau J. Health-related quality of life in venous leg ulcer patients successfully treated with Apligraf: A pilot study. Adv Skin Wound Care 2000;13:76–8.
27. Dalsing MC, Ricotta JJ, Wakefield T, et al. Animal models for the study of lower-extremity chronic venous disease: Lessons learned and future needs. Ann Vasc Surg 1998;12:487–98.
28. Browse NL, Burnand KG, Irvine AT, Wilson NM. Physiology and functional anatomy. In: Browse, Browse NL, Burnand KG, Irvine AT, Wilson NM (eds). Diseases of the Veins, Second Edition. London: Arnold Publisher, 1999; 49-65.
29. Araki CF, Back TL, Padberg FT, et al. The significance of calf muscle pump function in venous ulceration. J Vasc Surg 1994;20:872–9.
30. Yang D, Vandongen YK, Stacey MC. Effect of exercise on calf muscle pump function in patients with chronic venous disease. Br J Surg 1999;86:338–44.
31. Browse NL, Burnand KG, Irvine AT, Wilson NM. Venous ulceration: Pathology. In: Browse NL, Burnand KG, Irvine AT, Wilson NM (eds). Diseases of the Veins, Second Edition. London: Arnold Publisher, 1999;505–29.
32. Bradbury A, Evans C, Allan P, et al. What are the symptoms of varicose veins? Edinburgh vein study cross sectional population survey. Br Med J 1999;318:353–6.
33. DePalma RG. Do primary varicose veins lead to ulceration? Vasc Surg 1996;30(1):1–3.
34. Homans J. The etiology and treatment of varicose ulcer of the leg. Surg Gyne Obstet 1917;24:300–11.
35. Stuart WP, Adam DJ, Allan PL, et al. The relationship between the number, competence, and diameter of medial calf perforating veins and the clinical status in healthy subjects and patients with lower-limb venous disease. J Vasc Surg 2000;32:138–43.
36. Labropoulos N, Delis K, Nicolaides AN, et al. The role of the distribution and anatomic extent of reflux in the development of signs and symptoms in chronic venous insufficiency. J Vasc Surg 1996;23:504–10.
37. 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;20:20–6.
38. Shami SK, Sarin S, Cheatle TR, et al. Venous ulcers and the superficial venous system. J Vasc Surg 1993;17:487–90.
39. Caps MT, Manzo RA, Bergelin RO, et al. Venous valvular reflux in veins not involved at the time of acute deep vein thrombosis. J Vasc Surg 1995;22:524–31.
40. Labropoulos N, Volteas N, Leon M, et al. The role of the venous outflow obstruction in patients with chronic venous dysfunction. Arch Surg 1997;132:46–51.
41. Schwartzberg JB, Kirsner RS. Stasis in venous ulcers: A misnomer that should be abandoned. Dermatol Surg 2000;26:683–4.
42. Dormandy JA. Pathophysiology of venous leg ulceration: An update. Angiology 1997;48(1):71–5.
43. Junger M, Hahn M, Klyscz T, Steins A. Microangiopathy in the pathogenesis of chronic venous insufficiency. Curr Probl Dermatol 1999;27:124-9.
44. Abu-Own A, Shami SK, Chittenden SJ, et al. Microangiopathy of the skin and the effect of leg compression in patients with chronic venous insufficiency. J Vasc Surg 1994;19:1074–83.
45. Christopoulos DC, Nicolaides AN, Belcaro G, Kalodiki E. Venous hypertensive microangiopathy in relation to clinical severity and effect of elastic compression. J Dermatol Surg Oncol 1991;17:809–13.
46. Mayrovitz HN, Larsen PB. Periwound skin microcirculation of venous leg ulcers. Microvasc Res 1994;48:114–23.
47. Bull R, Ansell G, Stanton AWB, et al. Normal cutaneous microcirculation in gaiter zone (ulcer-susceptible skin) versus nearby regions in healthy young adults. Int J Microcirc 1995;15:65–74.
48. Steins A, Jhngen M, Zuder D, Rassner G. Microcirculation in venous leg ulcers during healing: Prognostic impact. Wounds 1999;11(1):6–12.
49. Haimovici H. Role of precapillary arteriovenous shunting in the pathogenesis of varicose veins and its therapeutic implications. Surgery 1987;101(5):515–22.
50. Malanin K, Haapanen A, Kolari PJ, Helander I, et al. The peripheral resistance in arteries of legs is inversely proportional to the severity of chronic venous insufficiency. Acta Derm Venereol (Stockh) 1977;77:22–5.
51. Browse NL, Burnand KG. The cause of venous ulceration. Lancet 1982;2(8292):243–5.
52. Mani R, Whbite JE, Barrett DF, Weaver PW. Tissue oxygenation, venous ulcers, and fibrin cuffs. J Roy Soc Med 1989;82:345–6.
53. Falanga V, McKenzie A, Eaglstein WH. Heterogeneity in oxygen diffusion around venous ulcers. J Dermatol Surg Oncol 1991;17:336–9.
54. Falanga V, Kirsner R, Katz MH, et al. Pericapillary fibrin cuffs in venous ulceration: Persistence with treatment and during ulcer healing. J Dermatol Surg Oncol 1992;18:409–14.
55. Gniadecka M. Localization of dermal edema in lipodermatosclerosis, lymphedema, and cardiac insufficiency. J Am Acad Dermatol 1996;35:37–41.
56. Chant ADB. Hypothesis: Why venous oedema causes ulcers and lymphoedema does not. Eur J Vasc Surg 1992;6:427–49.
57. Kim DI, HuhS, Hwang JH, et al. Venous dynamics in leg lymphedema. Lymphology 1999;32:11–4.
58. Falanga V, Eaglstein WH. The trap hypothesis of venous ulceration. Lancet 1993;341:1006–8.
59. 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.
60. Coleridge-Smith PD, Thomas P, Scurr JH, Dormandy JA. Causes of venous ulcerations: A new hypothesis. Br Med J 1988;296:1726–7.
61. Thomas P, Nash GB, Dormandy JA. White cell accumulation in dependent legs of patients with venous hypertension: A possible mechanism for trophic changes in the skin. Br Med J 1988;296:1693–5.
62. Moyses C, Cederholm-Williams SA, Michel CC. Haemoconcentration and accumulation of white cells in the feet during venous stasis. Int J Microcirc Clin Exp 1987;5:311–20.
63. Salim AS. The role of oxygen-derived free radicals in the management of venous (varicose) ulceration: A new approach. World J Surg 1991;15:264–9.
64. Kaminski MV, Cordts PR. Gut-derived oxidative stress: A pathological factor in leg ulcers with and without chronic venous insufficiency. Wounds 1998;10(1):33–7.
65. Falanga V, Kruskal J, Franks JJ. Fibrin- and fibrinogen-related antigens in patients with venous disease and venous ulceration. Arch Dermatol 1991;127:75–8.
66. Margolis DJ, Kruithof EKO, Barnard M, et al. Fibrinolytic abnormalities in two different cutaneous manifestations of venous disease. J Am Acad Dermatol 1996;34:204–8.
67. Maessen-Visch MB, Hamulyak K, Tazelaar DJ, et al. The prevalence of factor V leiden mutation in patients with leg ulcers and venous insufficiency. Arch Dermatol 1999;135:41–4.
68. Munkvad S, Jorgensen M. Resistance to activated protein C a common anticoagulant deficiency in patients with venous leg ulceration. Br J Dermatol 1996;134:296–8.
69. 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;37:409–13.
70. Hasan A, Murata H, Falabella A, et al. A dermal fibroblasts from venous ulcers are unresponsive to the action of transforming growth factor-b1. J Dermatol Sci 997;16:595–66.
71. Porter JM, Rutherford RB, Clagett GP, et al. Reporting standards in venous disease. J Vasc Surg 1988;8:172–81.
72. Beebe HG, Bergan JJ, Bergqvist D, et al. Classification and grading of chronic venous disease in the lower limbs. Dermatol Surg 1995;21:642–7.
73. Beebe HG, Bergan JJ, Bergqvist D, et al. Classification and grading of chronic venous disease in the lower limbs. Vasc Surg 1996;30(1):5–11.
74. Bergan JJ. Experience with classification of venous disorders. Vasc Surg 1997;31(3):218–21.
75. London NJ, Donnelly R. ABC of arterial and venous disease. Ulcerated lower limb. Br Med J 2000;320:1589–91.
76. London NJ, Nash R. ABC of arterial and venous disease: Varicose veins. Br Med J 2000;320:1391–4.
77. Tumman J, Coggins R. A case of mistaken identity: Primary cutaneous lymphoma presenting as venous ulceration. Hosp Med 1999;60(10):761.
78. DePalma RG. CEAP in clinical practice. Vasc Surg 1997;31(3):223.
79. Kurz X, Kahn SR, Abenhaim L, et al. Chronic venous disorders of the leg: Epidemiology, outcomes, diagnosis, and management. Int Angiol 1999;18:83–102.
80. Rulli F, Muzi M, Giordano A. A new assessment of incompetent perforating veins in patients with leg venous ulceration. Wound Rep Reg 1998;6(5):A-478.
81. Christopoulos DC, Nicolaides AN, Szendro G. Venous reflux: Quantification and correlation with the clinical severity of chronic venous disease. Br J Surg 1988;75:352–6.
82. McDaniel HB, Marston WA, Farber MA, et al. Recurrence of chronic venous ulcers on the basis of clinical, etiologic, anatomic, and pathophysiologic criteria and air plethysmography. J Vasc Surg 2002;35(4):723–8.
83. Weingarten MS, Czeredarczuk M, Scovell S, et al. A correlation of air plethysmography and color flow assisted duplex scanning in the quantification of chronic venous insufficiency. J Vasc Surg 1996;24:750–4.
84. Lynch TG, Dalsing MC, Ouriel K, et al. Developments in diagnosis and classification of venous disorders: Noninvasive diagnosis. Cardiovasc Surg 1999;7(2):160–78.
85. Moffatt CJ, Franks PJ, Oldroyd M, et al. Community clinics for leg ulcers and impact on healing. Br Med J 1987;305:1389–92.
86. Skene AI, Smith JM, Dore CJ, et al. Venous leg ulcers: A prognostic index to predict time to healing. Br Med J 1992;305:1119–21.
87. Margolis DJ, Gross EA, Wood CR, et al. Planimetry rate of healing in venous ulcers of the leg treated with pressure bandage and hydrocolloid dressing. J Am Acad Dermatol 1993;28:418–21.
88. Tallman P, Muscare E, Carson P, et al. Initial rate of healing predicts complete healing of venous ulcers. Arch Dermatol 1997;133:1231–4.
89. van Rijswijk L. Full-thickness leg ulcers: Patient demographics and predictors of healing. J Fam Pract 1993;36:625–32.
90. Noel B. Regarding risk factors associated with the failure of a venous leg ulcer to heal. Arch Dermatol 2000;136:425–6.
91. Hoffman R, Noble J, Eagle M. The use of proteases as prognostic markers for the healing of venous leg ulcers. J Wound Care 1999;8(6):273–6.
92. Kantor J, Margolis DJ. A multicentre study of percentage change in venous leg ulcer area as a prognostic index of healing at 24 weeks. Br J Dermatol 2000;142:960–4.
93. Kantor J, Margolis DJ. Prognostic models: Evidence-based approach to predicting disease outcome. J Cut Med Surg 1999;3(3):157–61.
94. Gorin DR, LaMorte WW, Barry M, Menzoian JO. Is complete wound healing a valid endpoint for clinical trials of venous stasis treatment? Vasc Surg 1997;31(2):163–9.
95. Margolis DJ, Berlin JA, Strom BL. Risk factors associated with the failure of a venous leg ulcer to heal. Arch Dermatol 1999;135:920–6.
96. Wipke-Trevis DD, Rantz MJ, Mehr DR, et al. Prevalence, incidence, management, and predictors of venous ulcers in the long-term-care population using the MDS. Adv Skin Wound Care 2000;13:218–24.
97. Barr DM. The Unna’s Boot as a treatment for venous ulcers. Nurse Pract 1996;21(7):55–73.
98. Partsch H. Compression therapy of the legs. J Dermatol Surg Oncol 1991;17:799–805.
99. Nelson EA. Compression bandaging in the treatment of venous leg ulcers. J Wound Care 1996;5(9):415–8.
100. Charles H. Short-stretch bandaging in the treatment of venous leg ulcers. J Wound Care 1999;8(6):303–4.
101. Duby T, Hoffman D, Cameron J, et al. A randomized trial in the treatment of venous leg ulcers comparing short-stretch bandages, four-layer bandage system, and long stretch-paste bandage system. Wounds 1993;5(6):276–8.
102. Gupta AK, DeKoven J, Lester R, et al. Open-label study to evaluate the healing rate and safety of the Profore extra four layer bandage in patients with venous leg ulceration. J Cutan Med and Surg 2000;4(1):8–11.
103. Cordts PR, Hanrahan LM, Rodriguez AA, et al. A prospective randomized trial of Unna’s boot versus Duoderm CGF hydroactive dressing plus compression in the management of venous leg ulcers. J Vasc Surg 1992;15(3):480–6.
104. Fletcher A, Cullum N, Sheldon TA. A systematic review of compression treatment for venous leg ulcers. Br J Med 1997;315:576–80.
105. Allenby F, Boardman L, Pflug JJ, Calnan JS. Effects of external pneumatic intermittent compression on fibrinolysis in man. Lancet 1973;2(7843):1412–4.
106. Smith PC, Sarin S, Hasty J, Scurr JH. Sequential gradient pneumatic compression enhances venous ulcer healing: A randomized trial. Surgery 1990;108(5):871–5.
107. Rowland J. Intermittent pump versus compression bandages in the treatment of venous leg ulcers. Aust N Z J Surg 2000;70:110–3.
108 McCulloch JM, Marler KC, Neal MB, Phifer TJ. Intermittent pneumatic compression improves venous ulcer healing. Adv Wound Care 1994;7(4):22–5.
109. Pekanmäki K, Kolari PJ, Kiistala U. Intermittent pneumatic compression treatment for post-thrombotic leg ulcers. Clin Exper Dermatol 1987;12:350–3.
110. Margolis DJ, Cohen JH. Management of chronic venous leg ulcers: A literature-guided approach. Clin Dermatol 1994;12:19–26.
111. Arnold TE, Stanley JC, Fellows WP, et al. Prospective, multicenter study of managing lower-extremity venous ulcers. Ann Vasc Surg 1994;8:356–62.
112. Ohlsson P, Larsson K, Lindholm C, et al. A cost-effectiveness study of leg ulcer treatment in primary care. Scand J Prim Health Care 1994;12:295–9.
113. Falanga V. Venous ulceration: Assessment, classification, and management. In: Krasner DL, Kane D (eds). Chronic Wound Care: A Clinical Source Book for Healthcare Professionals, Second Edition. Wayne, PA: Health Management Publication, 1977:165–71.
114. Madsen SM, Westh H, Danielsen L, Rosdahl VT. Bacterial colonization and healing of venous leg ulcers. APMIS 1996;104:895–9.
115. Schmidt K, Debus ES, Jeberger S, et al. Bacterial population of chronic crural ulcers: Is there a difference between the diabetic, the venous, and the arterial ulcer? VASA 2000;29:62–70.
116. Lookingbill DP, Miller SH, Knowles RC. Bacteriology of chronic leg ulcers. Arch Dermatol 1978;114:1765–8.
117. Eriksson G, Eklund AE, Kallings LO. The clinical significance of bacterial growth in venous leg ulcers. Scand J Infect Dis 1984;16:175–80.
118. Alinovi A, Bassissi P, Pini M. Systemic administration of antibiotics in the management of venous ulcers. J Am Acad Dermatol 1986;15:186–91.
119. Hansson C, Hoborn J, Möller A, Swanbeck G. The microbial flora in venous leg ulcers without clinical signs of infection. Acta Derm Venereol (Stockh) 1995;75:24–30.
120. Trengove NJ, Stacey MC, McGechie DF, Mata S. Qualitative bacteriology and leg ulcer healing. J Wound Care 1996;5(6):277–80.
121. Falanga V, Eaglstein WH, Bucalo B, et al. Topical use of human recombinant epidermis growth factor (h-EGF) in venous ulcers. J Dermatol Surg Oncol 1992;18:604–6.
122. Robson MC, Phillip LG, Cooper DM, et al. Safety and effect of transforming growth factor-b2 for treatment of venous stasis ulcers. Wound Rep Reg 1995;3:157–67.
123. Falanga V, Carson P, Greenberg A, et al. Topically applied recombinant tissue plasminogen activactor for the treatment of venous ulcers. Dermatol Surg 1996;22:643–4.
124. Dormandy JA. Pharmacologic treatment of venous leg ulcers. J Cardiovasc Pharmacol 1995;25(Suppl 2):S61–5.
125. Belcaro G, Marelli C. Treatment of venous lipodermatosclerosis and ulceration in venous hypertension by elastic compression and fibrinolytic enhancement with defibrotide. Phlebology 1989;4:97–106.
126. Corbett CRR. Report of the spring meeting of the venous forum on 12 May 1989 at Withington Hospital, Manchester. Phlebology 1989;4:209–12.
127. Layer GT, Stacey MC, Burnand KG. Stanozolol and the treatment of venous ulceration: An interim report. Phlebology 1986;1:197–203.
128. Burnand K, Clemenson G, Morland M, et al. Venous lipodermatosclerosis: Treatment with fibrinolytic enhancement and elastic compression. Br Med J 1980;280(6206):7–11.
129. Belcaro G, Rulo A, Candiani C. Evaluation of the microcirculatory effects of Venoruton (H.R.) in patients with chronic venous hypertension by laser-Doppler flowmetry, transcutaneous pO2 measurements, leg volumetry, and ambulatory venous pressure measurements. Phlebology 1989;4:23–9.
130. Nocker W, Diebschlag W, Lehmacher W. Clinical trials of the dose-related effects of O-(b-hydroxyethyl)-rutosides in patients with chronic venous insufficiency. Phlebology 1990;5(Suppl 1):23–6.
131. DeJongste AB, Jonker JJC, Huisman MV, et al. A double-blind trial on the short-term efficacy of HR in patients with the post-thrombotic syndrome. Phlebology 1990; (Suppl 1):21–2.
132. Diehm C, Trampisch HJ, Lange S, Schmidt C. Comparison of leg compression stocking and oral HCSE therapy in patients with CVI. Lancet 1996;347:292.
133. Beitner H, Hammar H, Olsson AG, Thyresson N. Prostaglandin E1 treatment of leg ulcers caused by venous or arterial incompetence. Acta dermato-venereologica (Stockh) 1980;60:425–30.
134. Layton AM, Ibbotson SH, Davies JA, Goodfield MJD. Randomised trial of oral aspirin for chronic venous leg ulcers. Lancet 1994;344:164–5.
135. Colgan MP, Dormandy JA, Jones PW, et al. Oxpentifylline treatment of venous ulcers of the leg. Br Med J 1990;300:972–5.
136. Weitgaser H. The use of pentoxifylline (Trentall 400) in the treatment of leg ulcers: Results of a double-blind trial. Pharmatherapapy
137. Dale JJ, Ruckley CV, Harper DR, et al. Randomised, double blind placebo controlled trial of pentoxifylline in the treatment of venous leg ulcers. Br Med J 1999;319:875–8.
138. Falanga V, Fujitani RM, Diaz C, et al. Systemic treatment of venous leg ulcers with high doses of pentoxifylline: Efficacy in a randomized, placebo controlled trial. Wound Rep Reg 1999;7:208–13.
139. Schanzer H, Sklandany M. Varicose vein surgery with preservation of the saphenous vein: A comparison between high ligation-avulsion versus saphenofemoral banding valvuloplasty-avulsion. J Vasc Surg 1994;20:684–7.
140. Walsh JC, Bergan JJ, Beeman S, Comer TP. Femoral venous reflux abolished by greater saphenous vein stripping. Ann Vasc Surg 1994;8:566–70.
141. DePalma RG, Kowallek DL. Venous ulceration: A cross-over study from nonoperative to operative treatment. J Vasc Surg 1996;24:788–92.
142. Sottiurai VS. Surgical correction of recurrent venous ulcer. J Cardiovasc Surg 1991;32:104–9.
143. Lees T, Singh S, Beard J, et al. Prospective audit of surgery for varicose veins. Br J Surg 1997;84:44–6.
144. Iafrati MD, Welch HJ, O’Donnell TF. Subfascial endoscopic perforator ligation: An analysis of early clinical outcomes and cost. J Vasc Surg 1997;25:995–1001.
145. Gloviczki P, Cambria RA, Rhee RY, et al. Surgical technique and preliminary results of endoscopic subfascial division of perforating veins. J Vasc Surg 1996;23:517–23.
146. Pierik RG, Van Urk H, Wittens CH. Endoscopic ligation of perforating veins using a mediastinoscope. Surg Laparosc Endosc 1997;7(1):25–8.
147. Gloviczki P, Bergan JJ, Menawat SS, et al. Safety, feasibility, and early efficacy of subfascial endoscopic perforator surgery: A preliminary report from the North American registry. J Vasc Surg 1997;25:94–105.
148. Schmeller W, Gaber Y, Gehl HB. Shave therapy is a simple, effective treatment of persistent venous leg ulcers. J Am Acad Dermatol 1998;39:232–8.
149. Steed DL, Donohoe D, Webster MW, et al. Effect of extensive debridement and treatment on the healing of diabetic foot ulcers. J Am Coll Surg 1996;183:61–4.
150. Kirsner RS, Eaglstein WH, Kerdel FA. Split-thickness skin grafting for lower-extremity ulcerations. Dermatol Surg 1997;23:86–91.
151. Kirsner RS, Mata SM, Falanga V, Kerdel FA. Split-thickness skin grafting of leg ulcers. Dermatol Surg 1995;21:701–3.
152. Wood MK, Davies DM. Use of split-skin grafting in the treatment of chronic leg ulcers. Ann R Coll Surg Engl 1995;77:222–3.
153. Harrison PV. Split-skin grafting of varicose leg ulcers: A survey and the importance of assessment of risk factors in predicting outcome from the procedure. Clin Exp Dermatol 1988;13:4–6.
154. Fujita T, Takahashi S, Yagihashi A, et al. Prolonged survival of rat skin allograft by treatment with FK506 ointment. Transplant 1997;64(6):922–5.
155. Beldon P. Management of chronic venous leg ulcers using a new autologous skin graft system. J Wound Care 1999;8(8):380–2.
156. Jones JE, Nelson EA. Skin grafting for venous leg ulcers. Cochrane Database Syst Rev 2000;(2):CD001737.
157. Yannas IV, Burke IF, Orgill DP, Scrabut EM. Wound tissue can utilize a polymeric template to synthesize a functional extension of skin. Science 1982;215:1174–6.
158. Gallico GG III, O’Connor N, Compton CC, et al. Permanent coverage of large burn wounds with autologous cultured human epithelium. N Engl J Med 1984;311:448–51.
159. Bell E, Ehrlich P, Buttle DJ, Nakatsuji T. Living tissue formed in-vitro and accepted as skin-equivalent of full thickness. Science 1981;221:1052–4.
160. Sabolinski ML, Alvarez O, Auletta M, et al. Cultured skin as ‘smart material’ for healing wounds: Experience in venous ulcers. Biomaterials 1996;17:311–20.
161. Falanga V, Sabolinski M. A bilayered living skin construct (Apligraf®) accelerates complete closure of hard-to-heal venous ulcers. Wound Rep Reg 1999;7:201–7.
162. Falanga V, Margolis D, Alvarez O, et al. Rapid healing of venous ulcers and lack of clinical rejection with an allogeneic cultured human skin equivalent. Arch Dermatol 1998;134:293–300.
163. Gogia PP. Physical therapy modalities for wound management. Ost/Wound Manag 1996;42(1):46–54.
164. Williams RL, Armstrong DG. Wound healing: New modalities for a new millenium. Clin Podiatr Med Surg 1998;15(1):117–28.
165. Gardner SF, Frantz RA, Schmidt FL. Effect of electrical stimulation on chronic wound healing; A meta analysis. Wound Repair Regen 1999;7(6):495–503.
166. Gevers S. Legal issues in the development and use of clinical practice guidelines. Med Law 2001;20(2):183–91.
167. Jacobson PD. Legal and policy considerations in using clinical practice guidelines. Am J Cardiol 1997;80(8B):74H–79H.
168. Tzeel A. Clinical practice guidelines and medical malpractice. Physician Executive 2002;28(2):36–9.