Abstract
Clinical question:
What is the best treatment for venous ulcers?
Results:
Compression aids ulcer healing. Pentoxifylline can aid ulcer healing. Artificial skin grafts are more effective than other skin grafts in helping ulcer healing. Correction of underlying venous incompetence reduces ulcer recurrence.
Implementation:
Potential pitfalls to avoid are:
Failure to exclude underlying arterial disease before application of compression.
Unusual-looking ulcers or those slow to heal should be biopsied to exclude malignant transformation.
Keywords: venous ulceration, ulcer healing
Venous ulceration
Definition: A skin defect in a limb with a venous abnormality.
Incidence: A 0.15% point prevalence with women outnumbering men 2.8:1.1
Economics: An unhealed leg ulcer costs approximately £1300 per year to treat.2
Levels of evidence used in this summary: Systematic reviews, meta-analyses, and randomized controlled trials.
Search sources: PubMed, Cochrane Library, clinical evidence, and Google Scholar.
Outcomes: Ulcer healing, time to ulcer healing, pain relief during treatment, and prevention of ulcer recurrence.
Consumer summary: A venous ulcer is a complication of varicose veins. Venous ulcers can be slow to heal and impact on patients’ quality of life. There is good evidence that compression helps heal ulcers. In patients who do not tolerate continuous compression, intermittent compression may help healing. In slow-healing ulcers, the use of pentoxifylline and bilayer artificial skin in conjunction with compression may aid healing. Surgery to incompetent veins reduces the risk of recurrence and endovenous surgery can speed ulcer healing.
The evidence
Does compression aid ulcer healing?
The following were analyzed:
| Systematic reviews: | 2 |
| Meta-analysis: | 0 |
| Randomized controlled trials: | 26 |
One systematic review3 concluded that ‘compression increases ulcer healing rates compared with no compression. Multicomponent systems are more effective than single component systems. Multicomponent systems containing an elastic bandage appear more effective than those composed mainly of inelastic constituents’.
The second systematic review4 concluded that ‘… patients with venous leg ulcers treated with four-layer bandages experience faster healing than those treated with short-stretch bandages’.
The randomized trials show a benefit of compression over no compression. They also tend to favor multilayer, long-stretch compression over short-stretch compression (Table 1).
Table 1.
Randomized controlled trials showing the effect of compression on ulcer healing
| Author | Number randomized | Interventions | Outcome measures | Results |
|---|---|---|---|---|
| Hendricks and Swallow5 | 21 | Gp1: Unna’s boot Gp2: below-knee elastic compression stocking |
Healing at 78 weeks | Gp1: 70% healed Gp2: 71% healed |
| Eriksson6 | 34 | Gp1: inner stocking plus outer elastic bandage Gp2: hydrocolloid dressing plus elastic bandage | Healing at 12 weeks | Gp1: 41% healed Gp2: 53% healed |
| Kikta et al7 | 87 | Gp1: Unna’s boot Gp2: no compression |
Healing at 6 months | Gp1: 70% healed Gp2: 38% healed |
| Rubin et al8 | 36 | Gp1: Unna’s boot Gp2: polyurethane foam dressing |
Healing at 12 months | Gp1: 95% healed Gp2: 41% healed |
| Charles9 | 53 | Gp1: short-stretch compression Gp2: usual care (no compression) |
Healing at 3 months | Gp1: 71% healed Gp2: 25% healed |
| Cordts et al10 | 43 | Gp1: hydrocolloid dressing plus cohesive elastic bandage Gp2: Unna’s boot |
Healing at 12 weeks | Gp1: 50% healed Gp2: 43% healed |
| Travers et al11 | 27 | Gp1: single-layer elastic cohesive bandage Gp2: 3-layer compression | Mean percentage change at 7 weeks | Gp1: −90% Gp2: −83% |
| Danielsen et al12 | 43 | Gp1: long-stretch, nonadhesive compression bandage Gp2: short-stretch, nonadhesive compression bandage | Healing at 6 and 12 months | Gp1: 39% healed at 6 months and 52% at 12 months Gp2: 25% healed at 6 months and 15% at 12 months |
| Gould et al13 | 46 | Gp1: 3-component, long-stretch compression Gp2: 3-component, short-stretch compression | Healing at 15 weeks | Gp1: 58% healed Gp2: 35% healed |
| Morrell et al14,15 | 233 | Gp1: 4-layer compression Gp2: standard community care |
Healing at 12 months | Gp1: 65% healed Gp2: 55% healed |
| Scriven et al16 | 64 | Gp1: 4-layer compression Gp2: short-stretch compression |
Healing at 12 months | Gp1: 55% healed Gp2: 57% healed |
| Taylor et al17 | 36 | Gp1: 4-layer compression Gp2: standard community care |
Healing at 12 weeks | Gp1: 67% healed Gp2: 17% healed |
| Moody18 | 52 | Gp1: short-stretch compression Gp2: long-stretch compression |
Healing at 12 weeks | Gp1: 31% healed Gp2: 31% healed |
| Vowden et al19 | 149 | Gp1: Charing Cross 4-layer compression Gp2: modified 4-layer compression Gp3: 4-layer compression bandage kit | Healing at 12 weeks | Gp1: 60% healed Gp2: 76% healed Gp3: 60% healed |
| Partsch et al20 | 112 | Gp1: 4-layer compression Gp2: short-stretch compression |
Healing at 16 weeks | Gp1: 62% healed Gp2: 73% healed |
| Moffatt et al21 | 112 | Gp1: 4-layer compression Gp2: 2-layer compression |
Healing at 12 weeks | Gp1: 70% healed Gp2: 58% healed |
| O’Brien et al22 | 200 | Gp1: 4-layer compression Gp2: standard community care |
Healing at 12 weeks | Gp1: 54% healed Gp2: 34% healed |
| Ukat et al23 | 89 | Gp1: 4-layer compression Gp2: short-stretch compression |
Healing at 12 weeks | Gp1: 30% healed Gp2: 22% healed |
| Franks et al24 | 159 | Gp1: 4-layer compression Gp2: short-stretch compression |
Healing at 24 weeks | Gp1: 69% healed Gp2: 73% healed |
| Nelson et al25 | 387 | Gp1: 4-layer compression Gp2: short-stretch bandage |
Healing at 4 and 12 months | Gp1: 55% healed at 4 months and 78% healed at 12 months Gp2: 45% healed at 4 months and 72% at 12 months |
| Jünger et al26 | 134 | Gp1: U-stocking consisting of two stockings Gp2: short-stretch bandages |
Healing at 12 weeks | Gp1: 48% healed Gp2: 32% healed |
| Nelson27 | 133 | Gp1: 3-layer compression Gp2: 4-layer compression |
Healing at 52 weeks | Gp1: 80% healed Gp2: 65% healed |
| Polignano et al28 | 68 | Gp1: 4-layer compression Gp2: Unna’s boot |
Healing at 24 weeks | Gp1: 74% healed Gp2: 66% healed |
| Polignano et al29 | 56 | Gp1: short-stretch compression Gp2: multilayer high compression system |
Healing at 12 weeks | Gp1: 17% healed Gp2: 44% healed |
| Blecken et al30 | 12 | Gp1: adjustable compression boot system Gp2: 4-layer compression | Healing at 12 weeks | Gp1: 93% healed Gp2: 51% healed |
| Milic et al31 | 150 | Gp1: tubular compression device (35–40 mm Hg) Gp2: 2medium-stretch compression bandages (20–25 mm Hg) | Healing at 500 days | Gp1: 33% healed Gp2: 33% healed |
Abbreviations: Gp1, group 1; Gp2, group 2; Gp3, group 3.
Conclusions
Compression aids ulcer healing.
Does intermittent pneumatic compression aid ulcer healing?
The following were analyzed:
| Systematic reviews: | 1 |
| Meta-analysis: | 0 |
| Randomized controlled trials: | 5 |
The systematic review32 concluded that ‘IPC may increase healing compared to no compression, but it is not clear whether it increases healing when added to treatment with bandages or if it can be used instead of compression bandages’.
Randomized trials
Two trials have shown a benefit for intermittent pneumatic compression (IPC) with a benefit for fast IPC over slow IPC in one trial. The other two trials didn’t show a benefit for IPC (Table 2).
Table 2.
Randomized controlled trials showing the effects of intermittent pneumatic compression on ulcer healing
| Author | Number randomized | Interventions | Outcome measures | Results |
|---|---|---|---|---|
| Smith et al33 | 45 | Both groups had same dressings and stockings. Sequential IPC for up to 4h in one group | Healing | 48% healed in IPC group and 4% in control group |
| McCulloch et al34 | 22 | Both groups had the same dressings and Unna’s boots. IPC for 60 min twice weekly in one group | Healing | 100% healed in IPC group and 80% in control group |
| Schuler et al35 | 53 | Unna’s boots versus elasticated stockings plus IPC for 60 min in the morning and 120 min in the evening | Healing | 71% healed in IPC group and 75% in Unna’s boot group |
| Rowland36 | 16 | Crossover trial of dressing alone with dressing and IPC for 60 min twice daily for 2–3 months | Healing | No ulcers healed in either arm before crossover |
| Kumar et al37 | 47 | Both groups had 4-layer bandaging IPC for 60 min twice daily for 4 months in one group | Healing | 87% healed in IPC group and 92% in control group |
| Nikolovska et al38 | 104 | Both groups had same dressings Fast IPC for one group and slow IPC in the other group | Healing at 6 months | 86% healed with fast IPC and 61% with slow IPC |
Abbreviation: IPC, intermittent pneumatic compression.
Conclusions
IPC may help healing when continuous compression cannot be tolerated.
Does pentoxifylline aid the healing of venous ulcers?
The following were analyzed:
| Systematic reviews: | 1 |
| Meta-analysis: | 0 |
| Randomized controlled trials: | 6 |
The systematic review concluded that ‘pentoxifylline is an effective adjunct to compression bandaging for treating venous ulcers and may be effective in the absence of compression’.39
Randomized trials
All trials showed increased healing in the pentoxifylline group with no benefit shown for higher doses (Table 3).
Table 3.
Randomized controlled trials showing the effect of pentoxifylline on ulcer healing
| Author | Number randomized | Interventions | Outcome measures | Results |
|---|---|---|---|---|
| Colgan et al40 | 80 | All had 2-layer compression Gp1: 400 mg tds pentoxifylline Gp2: placebo |
Healing at 24 weeks | Gp1: 60% healed Gp2: 29% healed |
| Barbarino41 | 12 | All had 2-layer compression Gp1: 400 mg tds pentoxifylline Gp2: placebo |
Healing | Gp1: 66% healed Gp2: 17% healed |
| Dale et al42 | 200 | All had compression Gp1:400 mg tds pentoxifylline Gp2: placebo |
Healing at 24 weeks | Gp1: 64% healed Gp2: 52% healed |
| Falanga et al43 | 129 | All had compression Gp1: 800 mg tds pentoxifylline Gp2: 400 mg tds pentoxifylline Gp3: placebo |
Healing at 24 weeks | Gp1: 73% healed Gp2: 75% healed Gp3: 63% healed |
| Belcaro et al44 | 172 | All had 2-layer compression Gp1: 400 mg tds pentoxifylline Gp2: placebo |
Healing and reduction in ulcer size | Gp1: 65% healed, 87% size reduction Gp2: 27% healed, 47% size reduction |
| Nikolovska et al45 | 80 | All had hydrocolloid dressing One group had 400 mg tds pentoxifylline | Healing at 24 weeks | 58% healed in pentoxifylline group and 28% in no tablet group |
Abbreviations: Gp1, group 1; Gp2, group 2; Gp3, group 3.
Conclusions
Pentoxifylline 400 mg tds has a role in aiding the healing of venous ulcers.
Does skin grafting aid ulcer healing?
The following were analyzed:
| Systematic reviews: | 1 |
| Meta-analysis: | 0 |
| Randomized controlled trials: | 11 |
The systematic review46 concluded that ‘bilayer artificial skin, used in conjunction with compression bandaging, increases venous ulcer healing compared with a simple dressing plus compression. Further research is needed to assess whether other forms of skin grafts increase ulcer healing’.
Randomized trials
Increased healing was seen compared to no grafting with the greatest difference seen with artificial skin grafts (Table 4).
Table 4.
Randomized controlled trials showing the effect of different types of skin grafting on ulcer healing
| Author | Number randomized | Interventions | Outcome measures | Results |
|---|---|---|---|---|
| Poskitt et al47 | 53 | Both groups received compression Gp1: pinch skin grafts Gp2: porcine dermis |
Healing at 6 and 12 weeks | Gp1: 64% healed at 6 weeks and 72% at 12 weeks Gp2: 29% healed at 6 weeks and 46% healed at 12 weeks |
| Mol et al48 | 11 | Gp1: human skin equivalents Gp2: punch grafts |
Healing at 20 days | Gp1: 80% healed Gp2: 71% healed |
| Teepe et al49 | 47 | Both groups received short-stretch bandages Gp1: cryopreserved allografts Gp2: controls |
Healing at 6 weeks | Gp1: 25% healed Gp2: 22% healed |
| Warburg et al50 | 31 | Both groups received compression Gp1: meshed split-skin graft Gp2: surgery for incompetent perforators | Healing at 12 months | Gp1: 33% healed Gp2: 38% healed |
| Falanga et al51 | 309 | All received compression Gp1: human skin equivalent Gp2: dressing |
Healing at 6 months | Gp1: 63% healed Gp2: 49% healed |
| Lindgren et al52 | 27 | Both groups received compression Gp1: cryopreserved allografts Gp2: no graft |
Healing at 8 weeks | Gp1: 13% healed Gp2: 17% healed |
| Tausche et al53 | 92 | Gp1: autologous epidermal equivalents derived from hair follicles Gp2: meshed skin autograft | Healing at 6 months | Gp1: 42% healed Gp2: 34% healed |
| Krishnamoorthy et al54 | 53 | All received 4-layer compression Gp1: Dermagraft, weekly for 12 applications Gp2: Dermagraft at 0, 1, 4, and 8 weeks Gp3: Dermagraft at 0 weeks Gp4: No Dermagraft |
Healing at 12 weeks | Gp1: 38% healed Gp2: 38% healed Gp3: 7% healed Gp4: 15% healed |
| Liu et al55 | 10 | Both groups had ulcers debrided and multilayer compression bandaging Gp1: keratinocytes cultured on porcine gelatin microbeads Gp2: keratinocytes cultured on porcine collagen pads |
Healing at 12 weeks | 25% healed in both groups |
| Navrátilová et al56 | 50 | Gp1: cryopreserved cultured epidermal keratinocytes Gp2: lyophilized cultured epidermal keratinocytes |
Healing at 90 days | Gp1: 84% healed Gp2: 80% healed |
| Omar et al57 | 18 | Both groups received 4-layer bandaging Gp1: Dermagraft Gp2: no graft | Healing at 12 weeks | Gp1: 50% healed Gp2: 13% healed |
Abbreviations: Gp1, group 1; Gp2, group 2; Gp3, group 3; Gp4, group 4.
Conclusions
Artificial skin helps a greater proportion of ulcers heal than other skin grafts.
Does surgery or endovenous therapy aid ulcer healing and prevent recurrence?
The following were analyzed:
| Systematic review: | 1 |
| Meta-analysis: | 0 |
| Randomized controlled trials: | 5 |
The systematic review58 concluded that ‘… superficial venous surgery is associated with similar rates of ulcer healing to compression alone, but with less recurrence’.
Randomized trials
Only endovenous surgery seems to aid ulcer healing, but all forms of surgery reduce ulcer recurrence (Table 5).
Table 5.
Randomized controlled trials showing the effect of different types of surgery and endovenous therapy on ulcer healing and recurrence
| Author | Number randomized | Interventions | Outcome measures | Results |
|---|---|---|---|---|
| Guest et al59 | 76 | Gp1: compression alone Gp2: compression and superficial venous surgery ± perforator surgery |
Healing | Gp1: 64% healed Gp2: 68% healed |
| Zamboni et al60 | 45 | Gp1: compression alone Gp2: compression and minimally invasive surgical hemodynamic correction of reflux |
Healing and recurrence | Gp1: 96% healed, 38% recurrence Gp2: 100% healed, 9% recurrence |
| Van Gent et al61 | 200 | Gp1: compression alone Gp2: compression and subfascial endoscopic perforating vein surgery |
Healing and recurrence | Gp1: 73% healed, 23% recurrence Gp2: 83% healed, 22% recurrence |
| Gohel et al62 | 500 | Gp1: compression alone Gp2: compression and superficial venous surgery |
Ulcer healing and ulcer recurrence at 3 years | Gp1: 89% healed, 56% recurrence Gp2: 93% healed, 31% recurrence |
| Viarengo et al63 | 52 | Gp1: compression alone Gp2: endovenous laser therapy and compression |
Healing at 12 months | Gp1: 24% healed Gp2: 82% healed |
Abbreviations: Gp1, group 1; Gp2, group 2.
Conclusions
Correction of venous incompetence is important to reduce the incidence of ulcer recurrence after healing.
The practice
Potential pitfalls
There is a small rate of malignant transformation in ulcers (4.4%), 75% basal cell carcinoma, and 25% squamous cell carcinoma.64 Ulcers in unusual locations, with irregular edges, those with islands of epithelium that do not persist, or those slow to heal should be biopsied.64
Management
Venous leg ulceration can often be managed in the community or in nurse-led venous ulcer clinics. Indications for specialist referral are detailed below.
Assessment
Nutritional status of patients should be assessed.
There may be a history of varicose veins.
Any history of intravenous injection should be elicited.
Any medication or medical condition potentially affecting healing should be assessed.
Concomitant arterial disease should be excluded using ankle brachial pressure indices before the application of any compression.
Patients should be examined for evidence of superficial venous incompetence.
Any history of deep vein thrombosis should be elicited.
Treatment
A 4-layer compression, if tolerated.
Short-stretch compression or intermittent compression if 4-layer not tolerated.
Pentoxifylline (400 mg three times daily) and skin grafting should be considered if ulcers are slow to heal.
Incompetent veins should be treated to reduce the risk of ulcer recurrence.
Indications for specialist referral
Worsening despite treatment or slow healing.
Unusual appearance of ulcer.
Footnotes
Date of preparation: 3 February 2011
Conflict of interest: None declared.
References
- 1.Callam MJ, Ruckley CV, Harper DR, Dale JJ. Chronic ulceration of the leg: extent of the problem and provision of care. Br Med J (Clin Res Ed) 1985;290(6485):1855–1856. doi: 10.1136/bmj.290.6485.1855. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 2.Iglesias CP, Nelson EA, Cullum N, Torgerson DJ, VenUS I collaborators Economic analysis of VenUS I, a randomized trial of two bandages for treating venous leg ulcers. Br J Surg. 2004;91(10):1300–1306. doi: 10.1002/bjs.4755. [DOI] [PubMed] [Google Scholar]
- 3.O’Meara S, Cullum NA, Nelson EA. Compression for venous leg ulcers. Cochrane Database Syst Rev. 2009;(1):CD000265. doi: 10.1002/14651858.CD000265.pub2. [DOI] [PubMed] [Google Scholar]
- 4.O’Meara S, Tierney J, Cullum N, et al. Four layer bandage compared with short stretch bandage for venous leg ulcers: systematic review and meta-analysis of randomised controlled trials with data from individual patients. BMJ. 2009;338:b1344. doi: 10.1136/bmj.b1344. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 5.Hendricks WM, Swallow RT. Management of stasis leg ulcers with Unna’s boots versus elastic support stockings. J Am Acad Dermatol. 1985;12(1 Pt 1):90–98. doi: 10.1016/s0190-9622(85)70015-1. [DOI] [PubMed] [Google Scholar]
- 6.Eriksson G. Comparison of two occlusive bandages in the treatment of venous leg ulcers. Br J Dermatol. 1986;114(2):227–230. doi: 10.1111/j.1365-2133.1986.tb02801.x. [DOI] [PubMed] [Google Scholar]
- 7.Kikta MJ, Schuler JJ, Meyer JP, et al. A prospective, randomized trial of Unna’s boots versus hydroactive dressing in the treatment of venous stasis ulcers. J Vasc Surg. 1988;7(3):478–483. [PubMed] [Google Scholar]
- 8.Rubin JR, Alexander J, Plecha EJ, Marman C. Unna’s boot vs polyurethane foam dressings for the treatment of venous ulceration. A randomized prospective study. Arch Surg. 1990;125(4):489–490. doi: 10.1001/archsurg.1990.01410160075016. [DOI] [PubMed] [Google Scholar]
- 9.Charles H. Compression healing of ulcers. J Dist Nurs. 1991;10(3):4–8. [Google Scholar]
- 10.Cordts PR, Hanrahan LM, Rodriguez AA, Woodson J, LaMorte WW, Menzoian JO. 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):480–486. [PubMed] [Google Scholar]
- 11.Travers JP, Dalziel KL, Makin GS. Assessment of a new one-layer adhesive bandaging method in maintaining prolonged limb compression and effects on venous ulcer healing. Phlebology. 1992;7:59–63. [Google Scholar]
- 12.Danielsen L, Madsen SM, Henriksen L. Venous leg ulcer healing. A randomised prospective study of long-stretch versus short-stretch compression bandages. Phlebology. 1998;13:59–63. [PubMed] [Google Scholar]
- 13.Gould DJ, Campbell S, Newton H, Duffelen P, Griffin M, Harding EF. Setopress vs Elastocrepe in chronic venous ulceration. Br J Nurs. 1998;7(2):66–70. doi: 10.12968/bjon.1998.7.2.66. [DOI] [PubMed] [Google Scholar]
- 14.Morrell CJ, King B, Brereton L. Community-based leg ulcer clinics: organisation and cost-effectiveness. Nurs Times. 1998;94(9):51–54. [PubMed] [Google Scholar]
- 15.Morrell CJ, Walters SJ, Dixon S, et al. Cost effectiveness of com munity leg ulcer clinics: randomised controlled trial. BMJ. 1998;316(7143):1487–1491. doi: 10.1136/bmj.316.7143.1487. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 16.Scriven JM, Taylor LE, Wood AJ, Bell PR, Naylor AR, London NJ. A prospective randomised trial of four-layer versus short stretch compression bandages for the treatment of venous leg ulcers. Ann R Coll Surg Engl. 1998;80(3):215–220. [PMC free article] [PubMed] [Google Scholar]
- 17.Taylor AD, Taylor RJ, Marcuson RW. Prospective comparison of healing rates and therapy costs for conventional and four-layer high compression bandaging treatments of venous leg ulcers. Phlebology. 1998;13:20–24. [Google Scholar]
- 18.Moody M. Comparison of Rosidal K and SurePress in the treatment of venous leg ulcers. Br J Nurs. 1999;8(6):345–355. doi: 10.12968/bjon.1999.8.6.6660. [DOI] [PubMed] [Google Scholar]
- 19.Vowden KR, Mason A, Wilkinson D, Vowden P. Comparison of the healing rates and complications of three four-layer bandage regimens. J Wound Care. 2000;9(6):269–272. doi: 10.12968/jowc.2000.9.6.25992. [DOI] [PubMed] [Google Scholar]
- 20.Partsch H, Damstra RJ, Tazelaar DJ, et al. Multicentre, randomised controlled trial of four-layer bandaging versus short-stretch bandaging in the treatment of venous leg ulcers. Vasa. 2001;30(2):108–113. doi: 10.1024/0301-1526.30.2.108. [DOI] [PubMed] [Google Scholar]
- 21.Moffatt CJ, McCullagh L, O’Connor T, et al. Randomized trial of four-layer and two-layer bandage systems in the management of chronic venous ulceration. Wound Repair Regen. 2003;11(3):166–171. doi: 10.1046/j.1524-475x.2003.11303.x. [DOI] [PubMed] [Google Scholar]
- 22.O’Brien JF, Grace PA, Perry IJ, Hannigan A, Clarke Moloney M, Burke PE. Randomized clinical trial and economic analysis of four-layer compression bandaging for venous ulcers. Br J Surg. 2003;90(7):794–798. doi: 10.1002/bjs.4167. [DOI] [PubMed] [Google Scholar]
- 23.Ukat A, Konig M, Vanscheidt W, Münter KC. Short-stretch versus multilayer compression for venous leg ulcers: a comparison of healing rates. J Wound Care. 2003;12(4):139–143. doi: 10.12968/jowc.2003.12.4.26490. [DOI] [PubMed] [Google Scholar]
- 24.Franks PJ, Moody M, Moffatt CJ, et al. Wound Healing Nursing Research Group Randomized trial of cohesive short-stretch versus four-layer bandaging in the management of venous ulceration. Wound Repair Regen. 2004;12(2):157–162. doi: 10.1111/j.1067-1927.2004.012206.x. [DOI] [PubMed] [Google Scholar]
- 25.Nelson EA, Iglesias CP, Cullum N, Torgerson DJ, VenUS I collaborators Randomized clinical trial of four-layer and short-stretch compression bandages for venous leg ulcers (VenUS I) Br J Surg. 2004;91(10):1292–1299. doi: 10.1002/bjs.4754. [DOI] [PubMed] [Google Scholar]
- 26.Jünger M, Wollina U, Kohnen R, Rabe E. Efficacy and tolerability of an ulcer compression stocking for therapy of chronic venous ulcer compared with a below-knee compression bandage: results from a prospective, randomized, multicentre trial. Curr Med Res Opin. 2004;20(10):1613–1623. doi: 10.1185/030079904X4086. [DOI] [PubMed] [Google Scholar]
- 27.Nelson EA. 3 layer paste bandages were more effective than 4 layer bandages for healing venous leg ulcers. Evid Based Nurs. 2004;7(1):21. doi: 10.1136/ebn.7.1.21. [DOI] [PubMed] [Google Scholar]
- 28.Polignano R, Bonadeo P, Gasbarro S, Allegra C. A randomised controlled study of four-layer compression versus Unna’s boot for venous ulcers. J Wound Care. 2004;13(1):21–24. doi: 10.12968/jowc.2004.13.1.26563. [DOI] [PubMed] [Google Scholar]
- 29.Polignano R, Guarnera G, Bonadeo P. Evaluation of SurePress Comfort: a new compression system for the management of venous leg ulcers. J Wound Care. 2004;13(9):387–391. doi: 10.12968/jowc.2004.13.9.26703. [DOI] [PubMed] [Google Scholar]
- 30.Blecken SR, Villavicencio JL, Kao TC. Comparison of elastic versus nonelastic compression in bilateral venous ulcers: a randomized trial. J Vasc Surg. 2005;42(6):1150–1155. doi: 10.1016/j.jvs.2005.08.015. [DOI] [PubMed] [Google Scholar]
- 31.Milic DJ, Zivic SS, Bogdanovic DC, et al. A randomized trial of the Tubulcus multilayer bandaging system in the treatment of extensive venous ulcers. J Vasc Surg. 2007;46(4):750–755. doi: 10.1016/j.jvs.2007.04.062. [DOI] [PubMed] [Google Scholar]
- 32.Nelson EA, Mani R, Vowden K. Intermittent pneumatic compression for treating venous leg ulcers. Cochrane Database Syst Rev. 2008;2:CD001899. doi: 10.1002/14651858.CD001899.pub2. [DOI] [PubMed] [Google Scholar]
- 33.Smith PC, Sarin S, Hasty J, Scurr JH. Sequential gradient pneumatic compression enhances venous ulcer healing: a randomized trial. Surgery. 1990;108(5):871–875. [PubMed] [Google Scholar]
- 34.McCulloch JM, Marler KC, Neal MB, Phifer TJ. Intermittent pneumatic compression improves venous ulcer healing. Adv Wound Care. 1994;7(4):22–24. 26. [PubMed] [Google Scholar]
- 35.Schuler JJ, Maibenco T, Megerman J, Ware M, Montalvo J. Treatment of chronic venous ulcers using sequential gradient intermittent pneumatic compression. Phlebology. 1996;11(3):111–116. [Google Scholar]
- 36.Rowland J. Intermittent pump versus compression bandages in the treatment of venous leg ulcers. Aust N Z J Surg. 2000;70(2):110–113. doi: 10.1046/j.1440-1622.2000.01766.x. [DOI] [PubMed] [Google Scholar]
- 37.Kumar S, Samraj K, Nirujogi V, Budnik J, Walker MA. Intermittent pneumatic compression as an adjuvant therapy in venous ulcer disease. J Tissue Viability. 2002;12(2):42–44. doi: 10.1016/s0965-206x(02)80013-4. 46, 48 passim. [DOI] [PubMed] [Google Scholar]
- 38.Nikolovska S, Arsovski A, Damevska K, Gocev G, Pavlova L. Evaluation of two different intermittent pneumatic compression cycle settings in the healing of venous ulcers: a randomized trial. Med Sci Monit. 2005;11(7):CR337–343. [PubMed] [Google Scholar]
- 39.Jull A, Arroll B, Parag V, Waters J. Pentoxifylline for treating venous leg ulcers. Cochrane Database Syst Rev. 2007;(3):CD001733. doi: 10.1002/14651858.CD001733.pub2. [DOI] [PubMed] [Google Scholar]
- 40.Colgan MP, Dormandy JA, Jones PW, Schraibman IG, Shanik DG, Young RA. Oxpentifylline treatment of venous ulcers of the leg. BMJ. 1990;300(6730):972–975. doi: 10.1136/bmj.300.6730.972. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 41.Barbarino C. Pentoxifylline in the treatment of venous leg ulcers. Curr Med Res Opin. 1992;12(9):547–551. doi: 10.1185/03007999209111520. [DOI] [PubMed] [Google Scholar]
- 42.Dale JJ, Ruckley CV, Harper DR, Gibson B, Nelson EA, Prescott RJ. Randomised, double blind placebo controlled trial of pentoxifylline in the treatment of venous leg ulcers. BMJ. 1999;319(7214):875–878. doi: 10.1136/bmj.319.7214.875. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 43.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 Repair Regen. 1999;7(4):208–213. doi: 10.1046/j.1524-475x.1999.00208.x. [DOI] [PubMed] [Google Scholar]
- 44.Belcaro G, Cesarone MR, Nicolaides AN, De Sanctis MT, Incandela L, Geroulakos G. Treatment of venous ulcers with pentoxifylline: a 6-month randomized, double-blind, placebo controlled trial. Angiology. 2002;53(Suppl 1):S45–S47. [PubMed] [Google Scholar]
- 45.Nikolovska S, Pavlova L, Petrova N, Gocev G, Ivanovski M. Pentoxifylline – efficient in the treatment of venous ulcers in the absence of compression? Acta Dermatovenerol Croat. 2002;10(1):9–13. [PubMed] [Google Scholar]
- 46.Jones JE, Nelson EA. Skin grafting for venous leg ulcers. Cochrane Database Syst Rev. 2007;2:CD001737. doi: 10.1002/14651858.CD001737.pub3. [DOI] [PubMed] [Google Scholar]
- 47.Poskitt KR, James AH, Lloyd-Davies ER, Walton J, McCollum C. Pinch skin grafting or porcine dermis in venous ulcers: a randomised clinical trial. Br Med J (Clin Res Ed) 1987;294(6573):674–676. doi: 10.1136/bmj.294.6573.674. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 48.Mol MA, Nanninga PB, van Eendenburg JP, Westerhof W, Mekkes JR, van Ginkel CJ. Grafting of venous leg ulcers. An intraindividual comparison between cultured skin equivalents and full-thickness skin punch grafts. J Am Acad Dermatol. 1991;24(1):77–82. doi: 10.1016/0190-9622(91)70015-t. [DOI] [PubMed] [Google Scholar]
- 49.Teepe RG, Roseeuw DI, Hermans J, et al. Randomized trial comparing cryopreserved cultured epidermal allografts with hydrocolloid dressings in healing chronic venous ulcers. J Am Acad Dermatol. 1993;29(6):982–988. doi: 10.1016/0190-9622(93)70278-2. [DOI] [PubMed] [Google Scholar]
- 50.Warburg FE, Danielsen L, Madsen SM, et al. Vein surgery with or without skin grafting versus conservative treatment for leg ulcers. A randomized prospective study. Acta Derm Venereol. 1994;74(4):307–309. doi: 10.2340/0001555574307309. [DOI] [PubMed] [Google Scholar]
- 51.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. Human Skin Equivalent Investigators Group. Arch Dermatol. 1998;134(3):293–300. doi: 10.1001/archderm.134.3.293. [DOI] [PubMed] [Google Scholar]
- 52.Lindgren C, Marcusson JA, Toftgård R. Treatment of venous leg ulcers with cryopreserved cultured allogeneic keratinocytes: a prospective open controlled study. Br J Dermatol. 1998;139(2):271–275. doi: 10.1046/j.1365-2133.1998.02364.x. [DOI] [PubMed] [Google Scholar]
- 53.Tausche AK, Skaria M, Böhlen L, et al. An autologous epidermal equivalent tissue-engineered from follicular outer root sheath keratinocytes is as effective as split-thickness skin autograft in recalcitrant vascular leg ulcers. Wound Repair Regen. 2003;11(4):248–252. doi: 10.1046/j.1524-475x.2003.11403.x. [DOI] [PubMed] [Google Scholar]
- 54.Krishnamoorthy L, Harding KG, Griffiths D, et al. The clinical and histological effects of Dermagraft in the healing of chronic venous leg ulcers. Phlebology. 2003;18(1):12–22. [Google Scholar]
- 55.Liu JY, Hafner J, Dragieva G, Seifert B, Burg G. Autologous cultured keratinocytes on porcine gelatin microbeads effectively heal chronic venous leg ulcers. Wound Repair Regen. 2004;12(2):148–156. doi: 10.1111/j.1067-1927.2004.012205.x. [DOI] [PubMed] [Google Scholar]
- 56.Navrátilová Z, Slonková V, Semrádová V, Adler J. Cryopreserved and lyophilized cultured epidermal allografts in the treatment of leg ulcers: a pilot study. J Eur Acad Dermatol Venereol. 2004;18(2):173–179. doi: 10.1111/j.1468-3083.2004.00873.x. [DOI] [PubMed] [Google Scholar]
- 57.Omar AA, Mavor AI, Jones AM, Homer-Vanniasinkam S. Treatment of venous leg ulcers with Dermagraft. Eur J Vasc Endovasc Surg. 2004;27(6):666–672. doi: 10.1016/j.ejvs.2004.03.001. [DOI] [PubMed] [Google Scholar]
- 58.Howard DP, Howard A, Kothari A, Wales L, Guest M, Davies AH. The role of superficial venous surgery in the management of venous ulcers: a systematic review. Eur J Vasc Endovasc Surg. 2008;36(4):458–465. doi: 10.1016/j.ejvs.2008.06.013. [DOI] [PubMed] [Google Scholar]
- 59.Guest M, Smith JJ, Tripuraneni G, et al. Randomized clinical trial of varicose vein surgery with compression versus compression alone for the treatment of venous ulceration. Phlebology. 2003;18(3):130–136. [Google Scholar]
- 60.Zamboni P, Cisno C, Marchetti F, et al. Minimally invasive surgical management of primary venous ulcers vs. compression treatment: a randomized clinical trial. Eur J Vasc Endovasc Surg. 2003;25(4):313–318. doi: 10.1053/ejvs.2002.1871. [DOI] [PubMed] [Google Scholar]
- 61.van Gent WB, Hop WC, van Praag MC, Mackaay AJ, de Boer EM, Wittens CH. Conservative versus surgical treatment of venous leg ulcers: a prospective, randomized, multicenter trial. J Vasc Surg. 2006;44(3):563–571. doi: 10.1016/j.jvs.2006.04.053. [DOI] [PubMed] [Google Scholar]
- 62.Gohel MS, Barwell JR, Taylor M, et al. Long term results of compression therapy alone versus compression plus surgery in chronic venous ulceration (ESCHAR): randomised controlled trial. BMJ. 2007;335(7610):83. doi: 10.1136/bmj.39216.542442.BE. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 63.Viarengo LM, Potério-Filho J, Potério GM, Menezes FH, Meirelles GV. Endovenous laser treatment for varicose veins in patients with active ulcers: measurement of intravenous and perivenous temperatures during the procedure. Dermatol Surg. 2007;33(10):1234–1242. 1241–1242. doi: 10.1111/j.1524-4725.2007.33259.x. discussion. [DOI] [PubMed] [Google Scholar]
- 64.Yang D, Morrison BD, Vandongen YK, Singh A, Stacey MC. Malignancy in chronic leg ulcers. Med J Aust. 1996;164(12):718–720. doi: 10.5694/j.1326-5377.1996.tb122269.x. [DOI] [PubMed] [Google Scholar]