LEG ULCERS

Leg ulcers are common in the population in general. The differential diagnoses and frequencies of various types of leg ulcers vary with the population studied. Vascular pathology is associated with the majority of leg ulcers. Almost 70% of leg ulcers have a venous etiology; approximately 20–25% are due to arterial insufficiency; and some of these have a mixed vascular etiology. The remaining leg ulcers have a variety of less common causes, including infection, malignancy, vasculitis and other conditions. The Canadian Medical Advisory Secretariat reported the prevalence of leg ulcers to be 0.12 – 0.32% of the general population. Other reports indicate a prevalence of 1–2% of adults. The prevalence of leg ulcers increases with age, with most patients at least 65 years of age. Comorbidities are common in this population, and many leg ulcer patients having multiple health problems.

Venous leg ulcers result from venous hypertension due to valve dysfunction, venous obstruction, and/or failure of calf muscle pump function. They often take a prolonged time to heal, frequently months to more than a year, and they commonly recur. Prevention of recurrence is based on definitive surgery or the lifelong use of compression or support stockings. Patients with venous leg ulcers experience increased stress, pain; they may have difficulty coping due to decreased mobility, sleep and social interaction.

Arterial leg ulcers, which are due to arterial insufficiency, are seen most commonly in the elderly, among people with diabetes and in smokers. Inadequate perfusion perpetuates these ulcers; they generally do not heal in the absence of revascularization. As arterial disease is progressive, and sometimes rapidly progressive, early diagnosis and definitive management are necessary to prevent further tissue loss. A bilateral lower leg physical assessment that includes ankle-brachial pressure index (ABPI) measurement helps to determine ulcer cause.

Clearly, complex clinical management challenges can be expected in treating the population with leg ulcers. Leg ulcers are associated with both a significant quality-of-life impact for patients and their families and a substantial economic impact for the healthcare system.

Costs associated with managing leg ulcers are high. A Canadian 4-week costing study estimated the annual nursing costs of managing leg ulcers in 192 patients at approximately $1 million and wound-care supplies at $260,000. Evidence-based care strategies have the potential to reduce these costs by increasing healing. A community-based study found that implementing an evidence-based protocol for leg ulcer management had the following impact, comparing the year before and the year after implementation:

• 3-month healing rates increased from 23% to 56%
• Decrease in median nursing visits per case from 37 to 25
• Decrease in median supply cost ($CDN) per case from $1923 to $406

An aging population will only increase the importance of effective management of leg ulcers. Broader knowledge and implementation of evidence-based strategies for management of leg ulcers can reduce both the economic and personal impact of this significant health problem.

A systematic literature search for clinical practice guidelines on leg ulcer prevention and treatment was completed using the Medline, CINAHL, and Embase databases and 46 guideline clearinghouses. A librarian was involved in identifying the appropriate keywords and search strategies to ensure that all guidelines on the topic were found.

31 leg ulcer prevention and treatment clinical practice guidelines were found in the English literature from 2002 until May 2007. 19 (61.3%) of these published articles were excluded because they were: not specifically addressing leg ulcers (11), supplemental documents of a guideline (3), research studies or studies that were appraisals of the implementation of the guidelines (3), evaluations of guidelines (1) and evaluations of the health care system in general (1).

Of the identified papers, 12 guidelines were appraised by a minimum of three reviewers using the AGREE instrument (http://www.agreecollaboration.org/instrument/). The AGREE instrument has six domains: scope and purpose, stakeholder involvement, rigour of development, clarity and presentation, applicability, and editorial independence. It is not recommended that the scores obtained for the domains be aggregated. Instead the guidelines that received the highest scores for most of the domains and particularly for rigour of development were ranked highest and their recommendations will be reported throughout this diabetic foot ulcer stream.

The most highly ranked guidelines were developed by the Registered Nurses Association of Ontario (RNAO) on assessment and management of leg ulcers (2004); a guideline by Graham et al on adapting national and international leg ulcer practice guidelines for local use (2005); a New Zealand guideline for people with chronic leg ulcers (1999); one by the Wound Ostomy Continence Nurses (WOCN) on the management of wounds in patients with lower-extremity venous disease (2005); one by Association for the Advancement of Wound Care (AAWC) that provides an algorithm for venous ulcer care with annotations of available evidence (2005).

The following figure indicates the AGREE domain scores for these leg ulcer guidelines.

Identify and Treat the Cause		Level of Evidence
1	Take a careful history (venous/ arterial characteristics, other diagnoses, infection, medication, coexisting diseases, factors that may impair wound healing)	5
2	Perform a bilateral lower leg physical assessment including an ankle-brachial pressure index (ABPI).	1a
3	Determine the cause(s) and for possible chronic venous insufficiency based on etiology: abnormal valves (reflux), obstruction, or calf-muscle-pump failure.	5
4	Treat the cause and implement appropriate compression therapy for venous disease in the absence of arterial predominant disease.	1a
5	Implement appropriate medical therapy.	5
6	Consider surgical management (for venous (if significant superficial or perforator vein disease exists in the absence of deep venous disease) or arterial disease (bypass, dilation, or stent).	Not Assessed
7	For nonhealable or maintenance wounds, provide support, pain control and modified local care (conservative debridement, bacterial and moisture reduction)	1a
Address patient-centered Concerns		Level of Evidence
8	Communicate (patients, family, caregivers) to establish a social support system with realistic expectations for healing and to prevent leg ulcer recurrences.	5
9	Assess / Control pain and optimize activities of daily living	Not Assessed
Provide Local Wound Care		Level of Evidence
10	Assess and document the wound at regular intervals.	Not Assessed
11	Optimize local wound care: debridement, inflammation / infection control, and moisture balance. Consider biopsy of appropriate active (including biologicals) & adjunctive therapies if the wound is not healing at the expected rate.	1a
Provide Organizational Support		Level of Evidence
12	Consult appropriate disciplines to maximize healing (e.g. mobility and nutrition).	1a

High Ranking Guidelines
1	Assessment and management of venous leg ulcers	Quality Indicator	Type: CPG (Clinical Practice Guideline)
Registered Nurses Association of Ontario (RNAO). Assessment and management of venous leg ulcers. Toronto (ON): Registered Nurses Association of Ontario (RNAO); 2004 Mar. 115 p.
This is a very well-developed clinical practice guideline that provides clear and succinct recommendations for clinical practice and indicates their supporting evidence. Although this guideline was developed for nurses, its recommendations would be useful to clinicians from other disciplines, e.g., family physicians, physical and occupational therapists, dietitians.
2	Adapting guidelines for local use	Quality Indicator	Type: CPG (Clinical Practice Guideline)
Graham ID, Harrison MB, Lorimer K, Piercianowski T, Friedberg E, Buchanan M, Harris C. Adapting national and international leg ulcer practice guidelines for local use: the Ontario Leg Ulcer Community Care Protocol. Adv Skin Wound Care. 2005 Jul-Aug;18(6):307-18. Review.
This guideline is the result of an adaptation of existing guidelines that employed rigorous methods. The article provides a Protocol Reference Guide (Figure 2) that indicates the levels of evidence for the various recommendations and would be useful to clinicians in community care.
3	General leg ulcer guideline	Quality Indicator	Type: CPG (Clinical Practice Guideline)
Care of People with Chronic Leg Ulcers: An evidence based guideline. New Zealand Guideline Group: December 1999.
This guideline was published nearly 10 years ago but it is still relevant. The information about infection is basic and other sources could be explored. The recommendations are very specific and detailed, and could be implemented easily using the application tools. The presentation style is easy to follow.
4	Management of venous leg ulcers	Quality Indicator	Type: CPG (Clinical Practice Guideline)
Wound, Ostomy, and Continence Nurses Society (WOCN). Guideline for management of wounds in patients with lower-extremity venous disease. Glenview (IL): Wound, Ostomy, and Continence Nurses Society (WOCN); 2005. 42 p. (WOCN clinical practice guideline; no. 4).
This is a recent guideline for which the search strategy for evidence was very thorough.
5	Algorithm for venous ulcer care	Quality Indicator	Type: CPG (Clinical Practice Guideline)
Association for the Advancement of Wound Care (AAWC). Summary algorithm for venous ulcer care with annotations of available evidence. Malvern (PA): Association for the Advancement of Wound Care (AAWC); 2005. 25 p.
This is a recent guidline with the recommendations laid out in an organized manner so it is easy to follow.

Arterial ulcers result from inadequate perfusion of skin and subcutaneous tissue, and they are primarily a complication of peripheral arterial disease (PAD). A punched-out appearance, with a pale, dry poorly perfused base is characteristic of arterial ulcers. The foot and leg may be cold, pale or bluish, with shiny, taut skin and dependent rubor, and possibly gangrenous toes. Pain is commonl, especially after exertion or leg elevation. A decreased ankle-brachial index (ABI) confirms the diangosis. Arterial insufficiency may be slowly or rapidly progressive, and early diagnosis is critical to prevent further tissue death.

Revascularization is an important treatment option for non-healing arterial ulcers or in the presence of gangrene, rest pain or progression of claudication. Referral should be made to a vascular surgeon for possible angiography and surgical management. Not only can revascularization allow arterial ulcers to heal but also it can reduce the high risk of further ischemia, gangrene and limb loss. Candidates for revascularization may have significant systemic atherosclerosis and a high risk of cardiovascular events and surgical morbidity. As a result, modifiable cardiovascular risk factors should ideally be addressed before planning revascularization surgery. Patient factors that may contribute to delayed healing include comorbid conditions, nutrition, edema, and pressure.

Revascularization approaches:

• Aortoiliac system: Aortoiliac reconstruction with aortofemoral bypass remains the gold standard, with an 80–85% 5-year patency. Less invasive approaches, including percutaneous balloon angioplasty, possibly with stenting, may be appropriate for unilateral iliac disease or in critically ill patients. Bypass procedures can now also be performed endovascularly, and laser surgery may be available.
• Femoral-popliteal-tibial system: Femoropopliteal bypass using the saphenous vein achieves 75–85% 5-year patency. Reconstruction of the arteries below the knee using the saphenous vein can achieve 70% 5-year patency. Endovascular interventions in these vessels are not yet as successful as those in the aortoiliac system. New technologies may, however, allow these minimally invasive techniques to heal wounds, salvage limbs, or provide a bridge to reconstructive surgery.

As arterial ulcers tend to be dry, the wound should be kept moist to prevent additional cell death and necrosis. Infection must always be considered, but it is uncommon until perfusion is restored. After successful revascularization, normal wound care approaches generally result in healing of arterial ulcers. Infection can cause rapid deterioration, and treatment may require systemic antibiotic therapy and surgical debridement.

Patient education, lifestyle changes and medical management are critical in addressing atherosclerotic risk factors. Smoking cessation and medical and lifestyle management of dyslipidemia, hypertension and hyperglycemia can substantially reduce cardiovascular risk. It is also important to address patient factors, such as nutrition, that may delay healing.

Identify and Treat the Cause		Level of Evidence
1	Take a careful history and conduct a physical inspection.	Not Assessed
2	Use appropriate vascular investigations to delineate the extent of stenoses and occlusion and provide information for revascularization.	Not Assessed
Address patient-centered Concerns		Level of Evidence
3	Provide patient education about lifestyle modification that may reduce the risk of additional cardiovascular events.	Not Assessed
Provide Local Wound Care		Level of Evidence
4	Implement aggressive risk factor management in patients with arterial ulcers.	Not Assessed
5	Arterial ulcers should be kept dry.	Not Assessed
6	Address patient factors that may be contributing to delayed healing.	Not Assessed
7	After revascularization, use normal wound care strategies for ulcer healing.	Not Assessed
8	Paint wound with low toxicity local anticeptic to dry out the wound and decrease surfact bacteria.	Not Assessed
Provide Organizational Support		Level of Evidence
9	Establish and empower an interprofessional team to maximize healing.	Not Assessed

Essential Publications
1	Outcome measure – complete ulcer healing in patients with critical limb ischemia	Quality Indicator	Type: Systematic review
Hoffmann U, Schulte KL, Heidrich H, Rieger H, Schellong S. Complete Ulcer Healing as Primary Endpoint in Studies on Critical Limb Ischemia? A Critical Reappraisal, 2007, European Journal of Vascular and Endovascular Surgery, 311-316.
This well-designed systematic review of cohort studies was conducted to evaluate the figures for complete healing rates and healing rates in revascularization studies in patients with critical limb ischemia that was assess the value of the endpoint in studies on reconstructive measures. Complete ulcer healing is not a consistently reported criterion for success of revascularization in critical limb ischemia. The study illustrates the importance of using a consistent outcome measure in intervention studies, similar to clinical practice.
2	Low-frequency Ultrasound therapy – Ischemic wounds	Quality Indicator	Type: RCT
Kavros, Steven J. DPM, FAPWCA; Miller, Jenny L. PT; Hanna, Steven W. MPT . Treatment of Ischemic Wounds with Noncontact, Low-Frequency Ultrasound: The Mayo Clinic Experience, 2004-2006. Advances in Skin & Wound Care. 20(4):221-226, April 2007.
In this open-label RCT conducted to evaluate the clinical effectiveness of MIST Therapy in the treatment of ulcers associated with chronic critical limb ischemia, 35 patients received MIST therapy plus standard care, and 35 patients formed a control group that received standard care for 12 weeks or until fully healed. Most patients had a history of smoking, and the mean age was 75 years. 63% of patients who had MIST therapy compared with 29% of the control group achieved more than 50% healing (P
3	Bypasses	Quality Indicator	Type: Narrative Review
Lazarides MK, Giannoukas AD. The role of hemodynamic measurements in the management of venous and ischemic ulcers. Int J Low Extrem Wounds; 2007: 6(4) 254-261.
Contrast arteriography of the abdominal aorta and branches remains the gold standard for the anatomic diagnosis of arterial disease. CFDI quantifies any proximal disease and the degree of involvement of distal vessels that may be possibly used for distal bypass grafting. In a recent study, preoperative Color Flow Doppler Imaging (CFDI) was equally effective as arteriography in selecting the target vessel for distal anastomosis in patients undergoing bypass to the tibial arteries.
4	Bypasses	Quality Indicator	Type: Narrative Review
Natale A, Belcastro M, Palleschi A, Baldi I. The Mid-Distal Deep Femoral Artery: Few Important Centimeters in Vascular Surgery. Ann Vas Surg; 2007: 21 111-116.
The deep femoral artery is an important artery in lower-limb revascularization. This review highlighted the importance of the mid-distal deep femoral artery (MD-DFA) both as an outflow and as an inflow site for peripheral bypasses.
5	Bypasses	Quality Indicator	Type: Retrospective Analysis
Tefera G, Hoch J, Turenipseed WD. Limb-salvage angioplasty in vascular surgery practice. J Vasc Surg 2005; 41: 988-93.
Peripheral arterial angioplasty should be considered as an alternative to primary amputation in selected patients with Critical Limb Ischemia (CLI) who are poor candidates for traditional surgical bypass. Infrainguinal lower extremity bypass surgery for limb salvage is the gold standard treatment for ischemic nonhealing ulcers, gangrenous digits, or rest pain The comparative limb-salvage rates with Percuraneous Transluminal Angioplasty (PTA) and bypass surgery in the treatment of limb-threatening ischemia are 78% vs. 81%, respectively, at 2 years.
6	Bypasses	Quality Indicator	Type: RCT
Jivegard L, Drott C, Gelin J, Groth O, Hensater M, Jensen N, Johansson G, Konrad P, Lindberg B, Lindhagen A, Lundqvist B, Oden A, Smith L, Stenberg B, Thornell E, Wingren U, Ortenwall P. Effects of Three Months of Low Molecular Weight Heparin (dalteparin) Treatment After Bypass Surgery for Lower Limb Ischemia – A Randomised Placebo-controlled Double Blind Multicentre Trial. Eur J Vas Endovasc Surg 2005; 29: 190-198
This RCT evaluated the primary graft patency at 3 and 12 months after Peripheral Arterial Bypass Graft (PABG) surgery in patients receiving 3 months of treatment with subcutaneous injection of dalterparin. There is no difference in graft patency at 3 or 12 months between patients receiving 5000 IU of dalterparin daily for 3 months after bypass surgery versus those receiving placebo injections, so routine long-term Low Molecular Weight Heparins (LMWH) treatment after peripheral arterial bypass graft surgery for lower limb ischemia is not justified.
7	Bypasses	Quality Indicator	Type: Longitudinal study (1 group)
Feiring AJ, Wesolowski, Lade S. Primary Stent-Supported Angioplasty for Treatment of Below-Knee Critical Limb Ischemia and Severe Claudication. Journal of the American College of Cardiology 2004; 44(12): 2307-14.
Below-Knee Stent-Supported Angioplasty (BKSSA) for Critical Limb Ischemia (CLI) and Lifestyle-Limiting Claudication (LLC) improves ankle brachial indexes comparable to tibial bypass, heals amputations, relieves rest pain, and improves ambulation. In patient with CLI, the mean ABI increased from 0.32 ± 0.13 to 0.9 ± 0.14, (p≤0.0001). Those with claudication improved from 0.65 ± 0.09 to 0.95 ± 0.12, (p≤0.0001). Because BKSSA is associated with minimum major adverse events, it may be an alternative therapy for patients with CLI and LLC.
8	Bypasses	Quality Indicator	Type: Retrospective Analysis
Murphy TP, Ariaratnam NS, Carney WI, Marcaccio EJ, Slalby JM, Soares GM, Kim HM. Aortoiliac Insufficiency: Long-term Experience with Stent Placement for Treatment. Radiology 2004; 231(1): 243-249.
Findings from long-term experience with aortoiliac stent placement for treatment of chronic lower-extremity ischemia confirmed the procedure to be a durable, low-risk revascularization option. For patients with arterial stenosis, there was a significant mean reduction in pressure gradient, of 13 mm Hg (P < 0.001).

Leg ulcers are associated with a significant quality-of-life impact for patients and their families and a substantial economic impact for the healthcare system. Vascular pathology is associated with the majority of leg ulcers. Almost 70% of leg ulcers have a venous etiology; approximately 20–25% are due to arterial insufficiency; and some of these have a mixed vascular etiology. The remaining causes include infection, malignancy, vasculitis and other conditions. The prevalence of leg ulcers has been reported to be 0.12 – 0.32% of the general population and 1–2% of adults. Most patients are at least 65 years of age. Comorbidities are common, and serious complications, such as cellulitis, osteomyelitis, gangrene and amputation, may develop.

An interdisciplinary team with the knowledge and skills to assess and manage the problem, integrating the best evidence for practice and educating and involving patients in their care, can improve healing, reduce recurrence and improve quality of life.

Risk factors Risk factors for venous ulcers include sustained venous hypertension associated with chronic venous insufficiency, varicose veins (pregnancy, long hours standing or sitting), deep vein thrombosis (DVT) and risk factors for DVT, congenital venous disease, lack of physical activity, immobility or paralysis; trauma, causing saphenous vein damage; joint disease or surgery of the leg resulting in joint fixation, trauma, obesity, congestive cardiac failure, increasing age, smoking, and female sex. Ischemia due to peripheral arterial disease (PAD) causes arterial ulcers. Associated risk factors include smoking, diabetes, hypertension, dyslipidemia, hyperhomocysteinemia and increasing age.

Differential diagnosis

• Venous ulcers tend to be shallow and moist and situated on the gaiter area of the leg. Edema, eczema, varicose veins, ankle flare, hyperpigmentation, atrophie blanche, and lipodermatosclerosis may be present. Superficial phlebitis may be present, usually affecting the saphenous vein. Associated pain may be aching, especially at the end of the day, and relieved by leg elevation.
• Arterial ulcers usually have a punched-out appearance, with a pale, dry poorly perfused base. The foot and leg may be cold, pale or bluish, with shiny, taut skin and dependent rubor, and possibly gangrenous toes. Arterial ulcers are often painful, especially after exertion or leg elevation.
• Mixed arterial/venous or venous/arterial ulcers demonstrate a range of features of venous and arterial ulcers, depending on the relative contribution of both problems.
• Neuropathic ulcers are generally found at sites of pressure, such as the heels or toes, and are accompanied by numbness and paresthesias. Neuropathic ulcers may involve tendon, fascia, joint capsule or bone and be surrounded by a callus. Sinus tracts may be present.
• Vasculitic ulcers may be multilocular, extremely painful, and surrounded by livedo and petechiae. These ulcers may be associated with a variety of disorders.
• Pyoderma gangrenosum ulcers begin as tender erythematous nodules and progress to painful ulcers, sometimes with undermined borders, surrounded by hemorrhagic sterile pustules.
• Infectious ulcers may develop as a result of bacterial infection at the site of minor trauma. The ulcer may be deep, with sharp margins and a necrotic ulcer bed.
• Malignancy, especially skin cancers, may present as an ulcer, often with an indistinct base and raised, rough or scaly edges with changes in the surrounding skin consistent with chronic sun exposure. These may enlarge rapidly, be associated with pain and bleeding and have a rolled margin.
• Less common causes of ulceration may require specific tests for identification.

Assessment and diagnosis The history should evaluate general health; risk factors for atherosclerosis; signs and symptoms of ischemic vascular disease, such as intermittent claudication; medical conditions affecting the venous system, such as Raynaud’s disease; previous DVT; history of varicose veins, including previous stripping; pregnancies; recurrent leg ulcers; coronary artery bypass grafting (CABG) using saphenous vein grafts; and ulcer pain.

Physical examination of the vasculature should include blood pressure measurement, a check for aortic aneurysm and edema, palpation of peripheral pulses, evaluation of the saphenous vein, identification of elevation pallor and dependent rubor, the Brodie-Trendelenberg test to assess venous reflux and incompetent valves in the perforating and junctional venous system, and examination of nail and skin colour and texture.

Assessment of the venous system of the leg may include the following investigations:

• Hand-held Doppler: This evaluation can detect reflux and venous pulsatility and identify surgically correctable venous disease
• Colour flow duplex ultrasonography: Although highly operator dependent, this test can provide both anatomic and flow data, allowing localization of reflux and detailed assessment of perforator and junctional veins before varicose vein surgery. This test can also detect DVT, including thrombus age, and clot size and mobility.
• Venography: The significant risks associated with venography generally restrict its use to providing detailed information necessary for reconstructive surgery.

Assessment of arterial status may require the following investigations:

• Ankle brachial index (ABI): ABI, the ratio of the systolic ankle pressure and the higher of the systolic pressures in the arms, is calculated for both legs. Most studies consider an ABI between 0.9 and 1.3 to be normal [note: CCS consensus conference on PAD, 2005]. An ABI below 0.9 indicates the presence of PAD, with values below 0.5 denoting severe ischemia. Values above 1.3 are associated with arterial calcification. Gross edema can confound ABI determination. If a falsely elevated ABI is suspected, a toe brachial index may provide a better indication of tissue perfusion.
• Transcutaneous oxygen pressure (TcpO2) measures microvascular perfusion. Values 30 mmHg are associated with adequate healing.
• Duplex ultrasonography: Duplex scanning can identify vascular lesions and determine their hemodynamic impact, differentiate between plaque and thrombus, assess plaque morphology, and identify lesions suitable for angioplasty. Duplex ultrasound does not predict functional impairment and ulcer healability. Calcification, edema and large amounts of subcutaneous fat can reduce visualization.
• Angiography: Due to the potential for significant complications, angiography is reserved primarily for preoperative evaluation and interventional procedures.

The optimal management strategy for an individual patient can only be developed by integrating results of vascular investigations, the history, physical examination, ulcer assessment and other investigations.

Identify and Treat the Cause		Level of Evidence
1	Take a careful history, including risk factors for atherosclerosis and signs and symptoms of venous and arterial disease.	Not Assessed
2	Perform a physical examination, including a complete examination of the arterial and venous systems in all patients with leg ulcers. Evaluate the ulcer to narrow the differential diagnosis.	Not Assessed
3	Perform neurological testing to diagnose or rule out diabetic neuropathy.	Not Assessed
4	Diagnose infection based on a clinical evaluation and supported by microbiologic data.	Not Assessed
5	Investigate suspected vasculitis to determine a specific diagnosis.	Not Assessed
6	Determine the cause(s) and for possible chronic venous insufficiency based on etiology: abnormal valves (reflux), obstruction, or calf-muscle-pump failure.	5
7	Treat the cause and implement appropriate compression therapy for venous disease in the absence of arterial predominant disease.	Not Assessed
8	Implement appropriate medical therapy.	Not Assessed
9	Consider surgical management (for venous (if significant superficial or perforator vein disease exists in the absence of deep venous disease) or arterial disease (bypass, dilation, or stent).	Not Assessed
10	For nonhealable or maintenance wounds, provide support, pain control and modified local care (conservative debridement, bacterial and moisture reduction)	Not Assessed
11	Perform the appropriate vascular investigations to diagnose or rule out arterial disease: at a minimum, an ankle-brachial index.	Not Assessed
12	In patients suspected of having vessel calcification, a toe brachial index or assessment of Doppler arterial waveforms may detect arterial disease.	Not Assessed
13	Perform duplex ultrasonography to identify lesions suitable for angioplasty.	Not Assessed
14	Perform a hand-held Doppler examination to assess reflux in the superficial and deep venous system and to identify surgically correctable lesions.	Not Assessed
15	Perform colour flow duplex ultrasonography to assess deep vein thrombosis and venous structure preoperatively.	Not Assessed
16	Perform a hand-held Doppler examination to assess reflux in the superficial and deep venous system and to identify surgically correctable lesions.	Not Assessed
17	Reserve invasive tests, such as angiography and venography, for preoperative evaluation if additional information, not provided by non-invasive testing, is required.	Not Assessed
Address patient-centered Concerns		Level of Evidence
18	Communicate (patients, family, caregivers) to establish a social support system with realistic expectations for healing and to prevent leg ulcer recurrences.	Not Assessed
19	Assess / Control pain and optimize activities of daily living	Not Assessed
Provide Local Wound Care		Level of Evidence
20	Assess and document the wound at regular intervals.	Not Assessed
21	Optimize local wound care: debridement, inflammation / infection control, and moisture balance. Consider biopsy of appropriate active (including biologicals) & adjunctive therapies if the wound is not healing at the expected rate.	Not Assessed
22	Biopsy ulcers that are not healing despite appropriate care to identify malignancy.	Not Assessed
Provide Organizational Support		Level of Evidence
23	Consult appropriate disciplines to maximize healing (e.g. mobility and nutrition).	Not Assessed

Essential Publications
1	Ankle to brachial pressure – unknown etiology – assessment and diagnosis	Quality Indicator	Type: Validation study
Caruana MF, Bradbury AW, Adam DJ. The Validity, Reliability, Reproducibility and Extended Utility of Ankle to Brachial Pressure Index in Current Vascular Surgical Practice, European Journal of Vascular and Endovascular Surgery 2005;29:443-451.
A systematic search was undertaken to locate articles addressing the validity, reliability, and utility of ankle to brachial pressure index for clinical and research use. This article provides a great deal of information about ABPI suggesting that it is useful in evaluating people with venous leg ulcers, atypical symptoms, and asymptomatic PAD.
2	Wound bed preparation classification system – Chronic wounds	Quality Indicator	Type: Validation study
Falanga V, Saap LJ, Ozonoff A. Wound bed score and its correlation with healing of chronic wounds. Dermatologic Therapy 2006;19:383-390.
This article describes a new wound bed preparation classification system and its predictive validity. Eight parameters: healing edges (wound edge effect), presence of eschar, greatest wound depth/granulation tissue, amount of exudate amount, edema, peri-wound dermatitis, peri-wound callus and or fibrosis, and a pink/red wound bed, are scored from 0 (worst score) to 2 (best score), for a total wound bed score (WBS) of 16. The WBS was found to predict wound closure in this sample of patients with venous leg ulcers. It may be useful in clinical practice and in research.
3	Wound Assessment	Quality Indicator	Type: Prospective Correlation study
Romanelli M, Dini V, Bianchi T, Romanelli P (2007). Wound Assessment by 3-Dimensional Laser Scanning. Arch Dermatol 143 (10): 1333-1334.
15 patients with venous leg ulcers were prospectively examined. The laser scanner system that was used to measure wound size in a patient with venous leg ulcers enables users to accurately acquire 3-dimesional digital models of various types of skin wounds. The mean ± SD time for a full scan acquisition on the wound area and volume was 3.6±1.4 minutes.
4	Special Assessment – Laser Doppler vs. Laser Speckle Imaging	Quality Indicator	Type: Correlation study
Stewart CJ, Forrester FKR, Tulip J, Lindsay R, Bray RC (2005). A comparison of two laser-based methods for determination of burn scar perfusion: Laser Doppler versus laser speckle imaging. Burns 31: 744-752.
Patients were scanned monthly in the 11 months period. Clinical assessment was done on the burn scar and burns were graded according to the standard Vancouver burn scar scale. Both Laser Doppler perfusion imaging (LDI) and Laser Speckle Perfusion Imaging (LSPI) yielded a relative measurement of tissue blood flow and both instruments have a linear response to blood flow over normal physiological ranges. The fast temporal response of the LSPI instrument could be used to monitor vascular response to mechanical or pharmacological interventions to study dynamic vascular changes to burn damaged tissues. It is favoured because of patient comfort.

Many genetic conditions have been associated with skin ulceration and should be considered when leg ulcers, especially recurrent ulcers, are seen in children or young adults. Some of these disorders are described below.

♦ Hypercoagulability A variety of genetic clotting disorders may be associated with a history of recurrent DVT and an increased risk of venous leg ulcers, including Factor V Leiden; prothrombin G20210A mutation; antithrombin, protein C, or protein S deficiency; and hyperhomocysteinemia. Exercise programs, compression hose, smoking cessation, and avoidance of estrogen therapy can reduce the risk of DVT. Long-term anticoagulation may be necessary.

♦ Hematologic disorders Several inherited forms of anemia have been linked to the development of leg ulcers, including thalassemia and sickle cell anemia. In sickle-cell disease, deoxygenation of abnormal hemoglobin causes formation of sickle-shaped cells, which may not be flexible enough to traverse the microcirculation. The resulting vaso-occlusive crisis causes tissue injury and pain. Painful ulcers in anemic young individuals of African descent suggest sickle cell disease, and a blood smear demonstrating sickle-shaped red blood cells confirms the condition. Wound care for patients with this multisystem disease requires a team approach. Management of sickle-cell disease includes patient education, support and genetic counselling; management of pain and, possibly, depression and anxiety; and monitoring and management of organ involvement.

♦ Klinefelter syndrome Leg ulcers in Klinefelter syndrome result from a combination of factors, including chronic venous insufficiency, obesity, arterial dysplasia in the legs, and decreased fibrinolysis due to increased levels of plasminogen activator inhibitor-1 (PAI-1).

♦ Felty syndrome describes the triad of rheumatoid arthritis, splenomegaly and neutropenia. Leg ulcers in patients with this syndrome appear to have a multifactorial etiology, which includes venous insufficiency, vasculitis, arterial insufficiency and diabetes.

♦ TAP 1 mutation Mutations in a subunit of the transporter associated with antigen processing is associated with recurrent bacterial respiratory infections and granulomatous skin lesions that begin as a small pustule or subcutaneous nodule and progressively extend and ulcerate. These lesions are most often distributed asymmetrically over the legs.

♦ Leucocyte adhesion deficiency syndrome type 1: This deficiency is associated with recurrent bacterial and fungal infections and chronic leg ulcers.

♦ Werner’s syndrome, a rare genetic premature aging disorder, is associated with atrophic skin and subcutaneous tissue and the development of chronic foot ulcers.

Identify and Treat the Cause		Level of Evidence
1	Take a careful history (venous/ arterial characteristics, other diagnoses, infection, medication, coexisting diseases, factors that may impair wound healing).	Not Assessed
2	Consider genetic causes when leg ulcers are seen in children and young adults.	Not Assessed
3	For nonhealable or maintenance wounds, provide support, pain control and modified local care (conservative debridement, bacterial and moisture reduction).	Not Assessed
Address Patient-centered Concerns		Level of Evidence
4	Communicate (patients, family, caregivers) to establish a social support system with realistic expectations for healing and to prevent leg ulcer recurrences.	Not Assessed
5	Assess / control pain and optimize activities of daily living	Not Assessed
Provide Local Wound Care		Level of Evidence
6	Assess and document the wound at regular intervals.	Not Assessed
7	Optimize local wound care: debridement, inflammation / infection control, and moisture balance. Consider biopsy of appropriate active (including biologicals) & adjunctive therapies if the wound is not healing at the expected rate.	Not Assessed
Provide Organizational Support		Level of Evidence
8	Consult appropriate disciplines to maximize healing (e.g. mobility and nutrition).	Not Assessed

Essential Publications
1	Klinefelter Syndrome	Quality Indicator	Type: Case-control study (2 groups)
Zollner TM, Veraart JC, Wolter M, Hesse S, Villemur B, Wenke A, Werner RJ, Boehncke WH, Jost SS, Scharrer I, Kaufmann R. Leg ulcers in Klinefelter’s syndrome – further evidence for an involvenment of plasminogen activator inhibitor-1. British journal of dermatology 1997; 136(3): 341-344.
This report found that Plasminogen Activator Inhibitor-1 (PAI-1) activity is not elevated in Klinfelter’s syndrome in general; elevation of PAI-1 activity in patients suffering from Klinefelter’s syndrome does not appear to be secondary to PAI-1 influencing parameters; elevation of PAI-1 activity may play a crucial role in the pathogenesis of leg ulceration in Klinefelter’s syndrome. Overall, a therapy for leg ulceration in Klinefelter’s syndrome that aims to return the elevated PAI-1 activity to normal should be explored.
2	Felty Syndrome	Quality Indicator	Type: Case-control study (2 groups)
Chin-Yee I, Halasi S and Hassan A. Successful Treatment of Perianal Ulcers in a Patient with Felty’s Syndrome Using Granulocyte Colony Stimulating Factor. J Clin Rheumatol 1996; 2: 283-288.
Intermittent use of Granulocyte Colony Stimulating Factor (G-CSF) may be a useful therapy for patients who have Felty’s Syndrome and develop complications from their neutropenia. G-CSF contributed to an increase in neutrophil counts and gradual healing of ulcers. Discontinuation of the G-CSF resulted in a return to the baseline neutropenic site without recurrence of ulceration.

Infection may cause an ulcer or delay its healing. It is critical to identify infection and the causative organism.

Infected chronic ulcers Although high microbe numbers and virulence contribute to tissue invasion, the most important determinant of infection in chronic wounds is reduced host resistance. Local and systemic factors affecting resistance include the following:

• Increasing wound size increases the microbial burden and risk of infection.
• Specific wound locations, such as the plantar surface of the foot, perineum or sacrum, increase the risk of infection.
• Wound age >6 weeks is associated with increased risk of infection and polymicrobial flora.
• Inadequate perfusion favours microbial proliferation and increases the risk of infection.
• The presence of devitalized tissue and foreign bodies predisposes to infection.
• Behavioural determinants, such as depression, poor nutrition, alcohol abuse, smoking and poor hygiene interfere with healing.
• Financial resources may affect healability of wound, such as the ability to purchase offloading devices.
• Various comorbidities can reduce host defences, presdisposing to infection.

Assessment of infection in a chronic wound is based on clinical evaluation and supported by microbiological data. Signs of infection include delayed healing, increased serous drainage and inflammation, increased tenderness, friable or bleeding granulation tissue, foul odour, and increased wound breakdown. Infection must be differentiated from inflammatory processes, such as pyoderma gangrenosum and acute Charcot foot. Moderately severely infected wounds may also have a rim of cellulitis with increased erythema, swelling, and local skin temperature. Severe infection may be associated with systemic signs of sepsis.

Effective management of chronic wounds depends on recognizing critical colonization and infection early, addressing contributing host factors, preparing the wound bed, and instituting appropriate antimicrobial therapy. Topical antibiotic agents are redundant in treating infected wounds when systemic antibiotic therapy is used.

Initial empiric systemic antibiotic therapy should be individualized once detailed culture and sensitivity information is available. Gram-positive organisms usually cause infections in wounds that have been present for less than 1 month. Polymicrobial infection is usually found in wounds that have been present for more than 1 month. Wounds in immunosuppressed individuals should be assumed to have a polymicrobial infection. Broad-spectrum antibiotic therapy is appropriate for suspected infection in patients with diabetes, as diabetic foot infections are polymicrobial. Specific microbiologic data are required to select antibiotic therapy for extensive and longstanding infection. Resistance should be suspected when an infected wound does not respond to appropriate antimicrobial treatment. Repeat culture and sensitivity can identify the resistant organism and treatment options.

Infectious ulcers Ulcers may also be caused by infection, especially in patients with a history of immunodeficiency, tropical travel, trauma, insect bite or surgery. Bacteria, viruses, fungi and protozoa may cause infectious ulcers. ♦ Bacteria ◊ Necrotizing fasciitis may develop at the site of a recent surgical incision or traumatic wound, or it may complicate a chronic wound. Group A β-hemolytic streptococci are usually the cause of this surgical emergency, but other organisms have also been found. Patients are usually unwell with fever and chills. Apparent cellulitis quickly develops into blisters or black necrotic areas. Rapid diagnosis, surgical debridement, broad-spectrum antibiotic therapy, and treatment of shock and septicemia are required. Specific antibiotic therapy is instituted when culture and sensitivity data are available. ◊ Ecthyma, an ulcerative infection caused by Group A β-hemolytic streptococci (Pseudomonas aeruginosa in immunocompromised patients) starts as blood blisters with a red halo and develops into black-crusted ulcers surrounded by erythema. Gram stain, culture and biopsy can confirm the diagnosis. ◊ Cutaneous anthrax: Bacillus anthracis can produce lesions resembling insect bites that develop into necrotic ulcers with a depressed centre. Gram stain and culture confirm the diagnosis. Oral ciprofloxacin is the treatment of choice. ◊ Syphilis: Ulcers (gummas) in tertiary syphilis (Treponema pallidum) may heal spontaneously with scarring, and new lesions continue to develop. Penicillin is the treatment of choice. ◊ Tropical ulcer: This polymicrobial (Fusobacterium, Bacillus fusiformis, Treponema vincentii), rapidly expanding, painful ulcer on the lower leg may develop from minor trauma in individuals living in the tropics. Treatment consists of tetracycline and metronidazole. ◊ Yaws: This condition is similar to tropical ulcer, except for the presence of multiple lesions due to Treponema pertenue. Yaws is most often seen in Central and West Africa in children under 15 years of age. ◊ Mycobacterial ulcers: • Mycobacterium tuberculosis: Tuberculous chancres, lupus vulgaris, erythema induratum of Bazin, scrofuloderma • Mycobacterium leprae: Neuropathic ulcers in lepromatous leprosy • Mycobacterium ulcerans: Buruli ulcer, an indolent ulcer seen in tropical and subtropical areas • Mycobacterium marinum: (an atypical mycobacterium) Fish-tank granuloma, a solitary, slowly growing, largely asymptomatic ulcer developing at the site of minor trauma that occurs while cleaning a fish tank or swimming pool. Doxycycline or minocycline are the usual treatment. ♦ Fungi ◊ Blastomycosis: Inhalation of, or direct skin contact with Blastomyces dermatitidis may lead to a single, slow-growing, asymptomatic ulcer. Biopsy can aid in diagnosis, and chest x-ray is necessary to identify or rule out simultaneous pulmonary disease. ◊ Sporotrichosis: Skin nodules or ulcers, often distributed along lymphatics, are caused by Sporothrix schenkii (present in the soil). Biopsy confirms the diagnosis. ◊ Histoplasmosis: This pulmonary infection, caused by Histoplasma capsulatum (present in the soil) may be accompanied by skin involvement and ulceration in immunocompromised individuals. ◊ Dermatophytes: Tinea capitis, usually due to Trichophyton or Microsporum, may present as superficial pustules, with development of a deep abscess, hair loss and scarring. Systemic antifungal therapy is required. ♦ Viruses ◊ Herpes simplex, herpes varicella zoster and cytomegalovirus may cause ulcerating skin lesions in immunocompromised individuals. ◊ Epstein-Barr virus may cause persistent genital ulcerations. ◊ Orf, a virus of sheep and goats may cause ulcerating skin lesions, especially on the hands of animal handlers. ♦ Protozoa ◊ Leishmaniasis: A sand fly bite can transmit Leishmania, which can produce cutaneous, mucocutaneous, and visceral disease. Skin lesions may be highly variable. Leishmaniasis is seen in South America and the Middle East.

Identify and Treat the Cause		Level of Evidence
1	Implement a regular wound assessment protocol that allows early identification of critical colonization or infection.	Not Assessed
2	Identify critical colonization or infection through clinical evaluation and support the diagnosis with microbiologic data.	Not Assessed
3	Manage infected wounds effectively by addressing host factors, preparing the wound bed and instituting appropriate antimicrobial therapy.	Not Assessed
4	Diagnose infectious ulcers based on history, clinical characteristics, culture and sensitivity, and biopsy.	Not Assessed
5	Treat infected wounds with systemic empiric antibiotic therapy followed by individualized treatment once culture results are available.	Not Assessed
6	Treat suspected infection in diabetic ulcers with broad-spectrum antibiotic therapy.	Not Assessed
Address patient-centered Concerns		Level of Evidence
7	Communicate (patients, family, caregivers) to establish a social support system with realistic expectations for healing and to prevent leg ulcer recurrences.	Not Assessed
8	Assess / control pain and optimize activities of daily living	Not Assessed
Provide Local Wound Care		Level of Evidence
9	Consider the possibility of resistant organisms when wound infection is unresponsive to treatment.	Not Assessed
Provide Organizational Support		Level of Evidence
10	Consult appropriate disciplines to maximize healing (e.g. mobility and nutrition).	Not Assessed

Essential Publications
1	Kaposi’s Sarcoma	Quality Indicator	Type: Case-control study (2 groups)
Newton R, Carpenter L, Casabonne D, Beral V, Babiker A, Darbyshire J, Weller I, Weiss R, Kwan A, Bourboulia D, Munoz F, Lagos D, Boshoff C. A prospective study of Kaposi’s sarcoma-associated herpesvirus and Epstein-Barr virus in adults with human immunodeficiency virus-1. British Journal of Cancer; 2006: 94(10) 1504-9.
This purpose of this study was to investigate using data collected prospectively, the evolution of antibody response to Karposi’s Sarcoma associated herpes virus (KSHV) and to Epstein Bar Virus (EBV) in HIV infected individuals, who subsequently developed Karposi’s Sacroma or non-Hodgkin’s Lymphoma compared to that in HIV infected controls without cancer. No significant association was found between anti-EBV-VCA antibodies and non-Hodgkin’s lymphoma or Kaposi’s sarcoma in HIV seropositive adults. Among HIV infected people, high levels of antibodies against KSHV appear strongly associated with subsequent risk of Kaposi’s sarcoma but not with non-Hodgkin’s lymphoma.
2	Kaposi’s Sarcoma	Quality Indicator	Type: RCT
Cooley T, Henry D, Margaret T, Sun S, O’Connell M, Rackoff W. A randomized, double-blind study of pegylated liposomal doxorubicin for the treatment of AIDS-related Kaposi’s sarcoma. The Oncologist; 2007: 12 114-23.
Pegylated liposomal doxorubicin was found to be safe and effective for the treatment of AIDS-related KS, with most patients experiencing clinical benefit defined as an improvement from baseline in at least one of five AIDS-related KS symptom categories that lasted for 28 days in the absence of disease progression or severe drug-induced toxicity, tumour response or both. Results from this study indicate that even in the era of highly active antiretroviral therapy (HAART). Chemotherapy still plays an important role in the treatment of advanced AIDS-related KS.

Pyoderma gangrenosum (PG) is a primary ulcerating inflammatory skin disease that has a sudden onset and may progress rapidly. A variety of immunologic abnormalities have been identified in people with PG, and these may play a role in pathogenesis. Approximately half of cases are associated with underlying systemic disease, especially inflammatory bowel disease, arthritis and myeloproliferative disorders. Four main types are described: classic, pustular, bullous and vegetative. ♦ Classic PG typically presents on the leg as a deep ulcer with a well defined, blue or purple undermined border. It may begin as one or more papules, which break down to form a cluster of small ulcers that coalesce into a single lesion. Nonspecific systemic symptoms, including fever, malaise, myalgia and arthralgia, may accompany the ulcer. Lesions are usually painful and sometimes severely painful. In up to half of cases, the lesion develops at the site of minor trauma. Ulcers are initially sterile but staphylococci and streptococci may be detected later. ♦ Pustular PG, which occurs in patients with inflammatory bowel disease and does not progress beyond the pustular stage, tends to occur on the trunk or extensor surfaces of the limbs. ♦ Bullous PG, which occurs primarily in patients with hematologic malignancies, is seen on the arms or face more frequently than on the legs. It usually presents as concentric bullae that spread rapidly and may ulcerate, generally forming superficial ulcers with an undermined blue border. ♦ Vegetative PG, a superficial form of disease, appears to be less aggressive than other types. It usually occurs as a single lesion in patients who are otherwise well and may respond to topical treatment.

Rapid diagnosis is important to prevent treatment delays and minimize scarring. Diagnosis is usually based on clinical features, as histology is nonspecific. Biopsy can exclude other conditions. Culture is recommended to rule out infection. Identification of any underlying systemic disease is critical, as effective treatment of the underlying condition may also improve the PD. Conditions that may resemble PG include vasculitis, malignancy, infection, necrotizing ulcers from spider bites, and pustular drug reactions.

Treatment is directed to halting ulcer progression, reducing pain, promoting healing and minimizing scarring. Treatment is empiric, as no guidelines currently exist. A systematic review indicated that the treatment of choice is a corticosteroid plus cyclosporine. Other immunosuppressive agents and dapsone have been used with mixed results. Infliximab has demonstrated benefit compared with placebo. Long-term immunosuppression is often necessary. The best sign of treatment efficacy is a decrease in pain.

When performing local wound care, it is important to minimize trauma, due to the potential for pathergy. As a result, surgical intervention and debridement should be avoided. High-potency topical corticosteroids and tacrolimus may also be useful, especially in conjunction with systemic therapy.

Identify and Treat the Cause		Level of Evidence
1	Diagnose and treat suspected pyoderma gangrenosum rapidly to prevent severe scarring.	Not Assessed
2	Confirm the diagnosis and rule out other causes by clinical examination, a search for underlying conditions, culture and biopsy.	Not Assessed
3	Implement combination therapy with a corticosteroid plus cyclosporine in patients requiring systemic therapy.	Not Assessed
4	Implement aggressive treatment of any underlying condition.	Not Assessed
5	Avoid wound trauma due to the potential for pathergy.	Not Assessed
6	For nonhealable or maintenance wounds, provide support, pain control and modified local care (bacterial and moisture reduction)	Not Assessed
Address patient-centered Concerns		Level of Evidence
7	Communicate (patients, family, caregivers) to establish a social support system with realistic expectations for healing and to prevent leg ulcer recurrences.	Not Assessed
8	Assess / Control pain and optimize activities of daily living.	Not Assessed
Provide Local Wound Care		Level of Evidence
9	Assess and document the wound at regular intervals.	Not Assessed
10	Optimize local wound care: inflammation / infection control, and moisture balance. Consider biopsy, if appropriate, active (including biologicals) & adjunctive therapies if the wound is not healing at the expected rate.	Not Assessed
Provide Organizational Support		Level of Evidence
11	Consult appropriate disciplines to maximize healing (e.g. mobility and nutrition).	Not Assessed

Essential Publications
1	Pyoderma Gangrenosum	Quality Indicator	Type: Narrative Review
Ehling A, Karrer S, Klebl F, Schaffler A, Muller-Ladner U. Therapeutic management of pyoderma gangrenosum. Arthritis and Rheumatism 2004: 50(10) 3076-3084.
Although few controlled trials of interventions have been performed on this topic, the information that has been collected in this review provides treatment options for clinicians to consider, including topical therapy, surgery, adjuvant and complement therapy, established systemic therapy and novel therapies. These therapeutic approaches can later be adapted to the specific problems of the individual patient.
2	Pyoderma Gangrenosum	Quality Indicator	Type: Narrative Review
Patel P and Topilow A (2002). Images in clinical medicine: Atypical pyoderma gangrenosum in a splenectomy. The New England Journal of Medicine 347 (18): 1419-1420.
Atypical pyoderma gangrenosum is a rare, idiopathic inflammatory disease that is easily confused with classic pyoderma gangrenosum. The dermal lesions of atypical pyoderma gangrenosum are more superficial than those of classic pyoderma gangrenosum and are frequently located on the arms rather than on the legs.
3	Pyoderma Gangrenosum	Quality Indicator	Type: Systematic review
Reichrath J, Bens G, Bonowitz A, Tilgen W (2005). Treatment recommendations for pyoderma gangrenosum: An evidence-based review of the literature based on more than 350 patients. J Am Acad Dermatol 53: 273-83.
This systematic review was undertaken to determine the extent and levels of evidence supporting treatment recommendations for Pyoderma Gangrenosum (PG). Therapeutic efficacy of systemic treatment with corticosteroids and cyclosporine is best documented. The mechanism of action of thalidomide in Pyoderma Gangrenosum (PG) is unclear. Anti-inflammatory effects include inhibition of both macrophage phagocytosis and neutrophil chemotaxis. Topical treatment of PG should be primarily directed to avoid secondary wound infection. Antiseptic or occlusive wound dressings are the topical treatment of choice in these patients. Overall, more rigorous comparative trials are urgently needed for definitive conclusions with respect to PG treatment.
4	Pyoderma Gangrenosum	Quality Indicator	Type: Systematic review
Weenig RH, Davis MDP, Dahl PR, Su WPD (2002). Skin ulcers misdiagnosed as pyoderma gangrenosum. The New England Journal of Medicine 347(18): 1412-8.
The charts of 240 patients were reviewed. The objective of this study was to determine the frequency of misdiagnosis of pyoderma gangrenosum and to identify the causes of cutaneous ulceration and the usefulness of biopsy in patients who receive such misdiagnoses. The results show that the misdiagnosis of pyoderma gangrenosum is not uncommon (as high as 10%) and it exposes patients to substantial risks associated with its treatment, since cutaneous ulceration is a common manifestation of several vasculitides. It was found that Wegener’s granulmatosis was the most frequent cause of pyoderma gangrenosum-like ulceration. A thorough workup (including biopsy) is required in all patients suspected of having pyoderma gangrenosum in order to rule out diagnoses that mimic pyoderma gangrenosum.

Vasculitis, or inflammation of the blood vessel wall, often presents with one or more cutaneous signs, such as petechiae, purpura, blisters, deep nodules, ulcers and livedo. Systemic signs and symptoms may or may not accompany the cutaneous manifestations. Demographic factors often point to specific underlying vasculitic syndromes, as many may be more common in specific age or ethnic groups.

Leucocytoclastic vasculitis (LCV) describes palpable purpura, or raised vasculitic purpura on the legs. LCV is a cutaneous small-vessel vasculitis that may be limited to disease of the skin or accompanied by involvement of one or more organ systems. Approximately half of cases are idiopathic, and the remainder are associated with a variety of disorders, including infection, drug reaction, collagen vascular diseases, autoimmune disorders and malignancy. Infectious agents include bacteria (especially β-hemolytic Streptococcus), viruses (especially hepatitis C virus, which may be associated with cryoglobinemia), fungi, and parasites. Severe and disabling pain accompanies most LCV ulcers when cryoglobins are present, and pain management is a treatment priority in this situation. Large-vessel vasculitides are more likely to ulcerate than LCV but are less common. Vasculitis may also be associated with neuropathy, with development of a neuropathic ulcer.

Clinical features may suggest involvement of a specific size of vessel and specific systemic conditions:

• Palpable purpura is usually associated with vasculitis involving postcapillary venules. It may be seen with any vasculitis except giant-cell arteritis and Takayasu’s arteritis.
• Skin ulcers are usually associated with involvement of arterioles and small arteries. Polyarteritis, Churg-Strauss vasculitis, Wegener’s granulomatosis and hypersensitivity vasculitis are the most common causes.
• Gangrene in an extremity is associated with small-to-medium arteries and often related to polyarteritis, Churg-Strauss vasculitis or Wegener’s granulomatosis.
• Neuropathic ulcer usually involves small-artery vasculitis, most often due to polyarteritis, Churg-Strauss vasculitis, Wegener’s granulomatosis or cryoglobinemia.

The clinical approach to suspected vasculitis includes a detailed history and physical examination; biopsy of a new lesion for pathology, Gram staining, immunofluorescence, and culture and sensitivity; and laboratory investigations to determine organ involvement and the presence of other conditions.

Treatment of cutaneous vasculitis depends on the severity of cutaneous disease and any cause identified, the location and size of vessel involved, and the presence and severity of systemic disease. Generally, however, systemic immunosuppression is required to manage cases that are not self-limiting. Management of pain associated with vessel infarction is also an important consideration. Effective treatment of ulcers should recognize the increased fragility of the skin due to the purpura and skin breakdown and the presence of pain.

Identify and Treat the Cause		Level of Evidence
1	Take a careful history (venous/ arterial characteristics, other diagnoses, infection, medication, coexisting diseases, factors that may impair wound healing)	Not Assessed
2	Investigate suspected vasculitis to determine a specific diagnosis.	Not Assessed
3	Perform a basic investigation, which includes a detailed history and physical examination; biopsy of a new lesion for pathology, Gram staining, immunofluorescence, and culture and sensitivity; and laboratory investigations to identify systemic involvement and other conditions.	Not Assessed
4	Manage vasculitic ulcers with cause-specific therapy where possible, systemic immunosuppression, pain management and local wound care.	Not Assessed
5	For nonhealable or maintenance wounds, provide support, pain control and modified local care (conservative debridement, bacterial and moisture reduction)	Not Assessed
Address patient-centered Concerns		Level of Evidence
6	Communicate (patients, family, caregivers) to establish a social support system with realistic expectations for healing and to prevent leg ulcer recurrences.	Not Assessed
7	Assess / Control pain and optimize activities of daily living.	Not Assessed
Provide Local Wound Care		Level of Evidence
8	Assess and document the wound at regular intervals.	Not Assessed
9	Optimize local wound care: debridement, inflammation / infection control, and moisture balance. Consider biopsy, if appropriate, active (including biologicals) & adjunctive therapies if the wound is not healing at the expected rate.	Not Assessed
Provide Organizational Support		Level of Evidence
10	Consult appropriate disciplines to maximize healing (e.g. mobility and nutrition).	Not Assessed

Essential Publications
1	Inflammatory Vasculitis – Iloprost	Quality Indicator	Type:
Veale DJ, Muir AH, Morley KD, Belch JJF. Treatment of Vasculitic Leg Ulcers in Connective Tissue Disease with Iloprost. Clinical Rheumatology 1995; 14(2): 187-190.
This study suggests that iloprost may be used as an adjunctive therapy for vasculitic leg ulcers. The three patients with Rheumatoid Arthritis and one patient with overlap connective tissue disease showed rapid improvement with healing of the vasculitic lesions and leg ulcers on iloprost therapy (all >50% reduction in ulcer diameter). There are many factors which determine the rate of healing of vasculitic leg ulcers including immunosuppressive therapy, concomitant treatment of infection, improved blood flow, bed rest, general health and nutrition.
2	Inflammatory Vasculitis – VAC Therapy	Quality Indicator	Type:
Zutt M, Haas E, Kruger U, Distler M, Neumann C. Successful Use of Vacuum-Assisted Closure Therapy for Leg Ulcers Caused by Occluding Vasculopathy and Inflammatory Vascular Diseases – A Case Series. Dermatology 2007; 214: 319-324.
This study shows that VAC is an excellent and effective alternative in the treatment of therapy-resistant chronic wounds caused by vasculopathy. It results in pain reduction in all of the five cases described.
3	Inflammatory Vasculitis – Hypercoagulability	Quality Indicator	Type:
Mekkes JR, Loots M, Van Der Wal A, Bos JD. Increased incidence of hypercoagulability in patients in leg ulcers caused by leukocytoclastic vasculitis. J Am Acad Dermatol 2004; 50: 104-7.
The purpose of the study was to investigate if patients with vasculitis ulcers have an increased incidence of hypercoagulability. Hypercoagulable disorders were found in 7 of 13(53%) patients with leg ulcers caused by leukocytoclastic vasculitis. The authors recommend that all patients with severe skin necrosis caused by histologically confirmed vasculitis be screened routinely for hypercoagulable disorders.

Lymphedema, or accumulation of protein rich fluid in the interstitial space , usually in one or more limbs, results from congenital or acquired abnormalities in lymphatic outflow. Lymphedema is usually chronic and is classified as either primary or secondary.

Primary lymphedema usually appears spontaneously and is divided into congenital (onset at 35 years of age). ♦ Congenital lymphedema (6-12% of primary lymphedema) may be familial and inherited through autosomal dominant or other types of transmission. Congenital lymphedema is more common in males than females. Sporadic cases are more common than hereditary lymphedema and inherited conditions associated with lymphedema, which are relatively rare. Swelling usually involves only one leg, although both legs, the genitals and even the face may also be affected. Congenital primary lymphedema may result from aplasia or hypoplasia of peripheral lymphatics, abnormalities of the lymph trunks or valvular incompetence. ♦ Lymphedema precox (77-94% of primary lymphedema) may be familial or sporadic. It is 5-10 times more common in females than males, and its frequent appearance at puberty has led to the hypothesis that estrogen may be involved. Edema is usually unilateral and generally restricted to the foot and calf. ♦ Lymphedema tarda (11% of primary lymphedema).

Secondary lymphedema, which is considerably more common than primary lymphedema, develops when lymphatic pathways are obstructed or interrupted by surgery, radiation or a disease process. ♦ Lymphatic obstruction: Therapeutic radiation causes fibrosis and increases the risk of lymphedema. Trauma may also obstruct lymphatics. Infections, such as filariasis or streptococcal lymphangitis or cellulitis, can cause inflammation and secondary lymphedema. Tumour invasion may destroy lymphatic ducts, vessels and lymph nodes. Lymphedema can accompany both rheumatoid and psoriatic arthritis. In addition, different types of chronic edema, such as venous insufficiency and lipedema, may lead to secondary lymphedema. ♦ Lymphatic interruption: Surgery for breast, cervical or prostate cancer with lymph node excision can interrupt lymphatics.

In established disease, history, physical examination, characteristic clinical presentations and ruling out other causes may allow diagnosis. It is important to determine the etiology, as treatment of the cause is an integral part of management. Established lymphedema may involve the entire lower leg with dorsal swelling, leading to an almost uniform diameter of the leg below the knee.Swelling is usually non-pitting. Numerous skin changes may be present, including thickening, woody fibrosis, hyperkeratosis, enhanced skin creases, a positive Stemmer’s sign, a verrucous warty texture, mushroom-like papules and papillomatosis. Lymphedema is rarely associated with ulceration or pain, but recurrent cellulitis is common, and malignancy may develop in the edematous limb.

Early disease and disease with a mixed etiology may require investigation. Lymphoscintigraphy, the best and least invasive diagnostic tool currently available, can differentiate between lymphedema and edema of venous origin, identify lymphatic abnormalities following arterial reconstruction, differentiate between postthrombotic disease and lymphedema, and measure response to treatment. Both early (1-hour) and delayed (2-24-hour) films may be necessary for diagnosis. The sensitivity of lymphoscintigraphy is 73-97%, and the specificity is 100%. Lymphoscintigraphy may be adequate for preoperative assessment, or lymphangiography may also be required. Other potentially useful investigations include ultrasonography, computed tomography and magnetic resonance imaging.

Continuous fluid accumulation in lymphedema can lead to progressive lymphatic damage and further edema, recurrent infection,, impaired limb function, septic or malignant complications, and significant psychologic consequences. Skin tightness, decreased range of motion, and disfigurement are important patient concerns. Patients may also fear complications, such as infection and its consequences, including sepsis, cellulitis, chronic ulceration, necrosis, gangrene, and amputation.

Lymphedema is not curable and requires lifelong treatment to manage symptoms and prevent progression.. Successful management of lymphedema is associated with improved wound healing, decreased infection and improved quality of life. Patient education about the disease and its management is critical to empower the patient to undertake lifelong self-care. No pharmaceutical agents or dietary supplements have been proven effective and safe in the management of lymphedema. The main components of treatment are skin care, compression and support, lymphatic massage and exercise.

Meticulous skin care can reduce the risk of cellulitis and lymphangitis. Good hygiene, use of a low-pH moisturizer, and prompt treatment of conditions such as tinea pedis and minor wounds are important. Antibiotics should be available to the patient for use when signs of infection are seen, and indefinite antibiotic prophylaxis should be provided to patients with recurrent infection.

Complex decongestive physiotherapy enhances lymphatic contractility, stimulates lymph flow and improves lymphatic drainage. This specialized type of massage is the standard of care for lymphedema treatment, and it is the initial therapy, in conjunction with temporary short-stretch compression bandaging. Patients may require higher compression than those with venous disease alone. Routine maintenance is comprised of elevation, exercise and use of a compression garment. Massage is used to treat exacerbations. Thermal therapy (microwave, electromagnetic irradiation or immersion in hot water) reduces leg volume and may be combined with complex decongestive physiotherapy.

Surgery, including debulking procedures, bypass surgery, prophylactic omentoplasty or lymphovenous anastamosis may be considered for individual patients.

Identify and Treat the Cause		Level of Evidence
1	Take a complete history and perform a physical examination to diagnose lymphedema and determine the etiology.	Not Assessed
2	Perform lymphoscintigraphy as the investigation of choice if clinical evaluation does not establish the diagnosis.	Not Assessed
3	Implement complex decongestive physiotherapy plus short-stretch compression bandaging as initial therapy.	Not Assessed
4	Implement appropriate maintenance therapy using elevation, exercise and compression garments.	Not Assessed
5	Manage acute exacerbations with a course of complex decongestive physiotherapy.	Not Assessed
6	Consider heat therapy as a useful adjunct.	Not Assessed
7	Consider surgery for refractory cases.	Not Assessed
Address patient-centered Concerns		Level of Evidence
8	Provide effective patient education to support long-term self-management of lymphedema and prevent complications.	Not Assessed
9	Assess / Control pain and optimize activities of daily living	Not Assessed
Provide Local Wound Care		Level of Evidence
10	Assess and document the wound at regular intervals.	Not Assessed
11	Optimize local wound care: debridement, inflammation / infection control, and moisture balance. Consider biopsy of appropriate active (including biologicals) & adjunctive therapies if the wound is not healing at the expected rate.	Not Assessed
Provide Organizational Support		Level of Evidence
12	Consult appropriate disciplines to maximize healing (e.g. mobility and nutrition).	Not Assessed

Essential Publications
1	Lymphoedema	Quality Indicator	Type: Systematic review
Badger C, Seers K, Preston N, Mortimer P. Antibiotics/anti-inflammatories for reducing acute inflammatory episodes in lymphoedema of the limbs. Cochrane Database Syst Rev 2; 2004: CD003143.
Few RCTs were found addressing the use of antibiotics and anti-inflammatories to reduce acute inflammatory episodes of lymphedema. Only three studies involving 150 patients were included in the review. None used the same intervention, and thus they could not be combined. The authors were however able to conclude that wearing a compression sleeve is beneficial, especially over the long term when compared with no compression. There is a clear need for randomized trials in this area.

Approximately 5 to 10% of individuals with cancer may experience a malignant wound. Ulcer may be the presenting sign of a primary skin cancer, or less commonly, it may represent metastatic disease. Primary skin cancers that most often present as ulcers are basal-cell carcinoma, squamous-cell carcinoma, melanoma, and cutaneous T-cell lymphoma. Angiosarcoma, merkel-cell carcinoma and Kaposi sarcoma may also ulcerate. Metastatic lesions are most commonly associated with primary squamous-cell carcinoma; breast, lung or renal carcinoma; or melanoma arising in the skin or elsewhere.

As long-term immunosuppression in transplant recipients increases the risk of skin cancer, malignancy should be suspected in a transplant recipient presenting with an ulcer. An ulcerating squamous-cell carcinoma (Marjolin’s ulcer) may also develop in chronic wounds, including venous ulcers. It may not be possible to ascertain the length of time the ulcer has been present, but many ulcerated basal-cell or squamous-cell carcinomas have been present for at least several months.

Clinically, the base of an ulcerated skin cancer is indistinct, but the borders may be raised, rough or scaly, with prominent telangiectasia and changes consistent with chronic sun exposure in the surrounding skin. An ulcerated melanoma may or may not have a pigmented border. Features indicating malignancy include rapid lesion enlargement despite appropriate care; pain; bleeding; and often a rolled wound margin. A biopsy should be performed on chronic ulcers that do not respond to appropriate wound care to rule out malignancy. The biopsy should be taken from intact skin demonstrating the features of a skin cancer near the edge of the ulcer.

Surgical excision is the treatment of choice for primary skin cancers. As healing may not be possible for metastatic lesions, palliation may be a more appropriate goal. All treatment options should be explored. Local wound care management challenges include odour, exudate, bleeding and pain. The care plan for metastatic lesions needs to consider patient comfort, the ability of the patient and caregiver to manage wound care, and the availability of home care.

Identify and Treat the Cause		Level of Evidence
1	Suspect malignancy when chronic ulcers that receive appropriate wound care do not heal.	Not Assessed
2	Perform a biopsy of intact skin that demonstrates the features of skin cancer near the edge of the ulcer.	Not Assessed
3	Manage primary skin cancers surgically (treatment of choice).	Not Assessed
4	Explore all treatment options for metastatic lesions and develop a care plan focused on patient comfort.	Not Assessed
5	For nonhealable or maintenance wounds, provide support, pain control and modified local care (conservative debridement, bacterial and moisture reduction)	Not Assessed
Address patient-centered Concerns		Level of Evidence
6	Communicate (patients, family, caregivers) to establish a social support system with realistic expectations for healing and to prevent leg ulcer recurrences.	Not Assessed
7	Assess / Control pain and optimize activities of daily living	Not Assessed
Provide Local Wound Care		Level of Evidence
8	Assess and document the wound at regular intervals.	Not Assessed
9	Optimize local wound care: debridement, inflammation / infection control, and moisture balance. Consider biopsy of appropriate active (including biologicals) & adjunctive therapies if the wound is not healing at the expected rate.	Not Assessed
Provide Organizational Support		Level of Evidence
10	Consult appropriate disciplines to maximize healing (e.g. mobility and nutrition).	Not Assessed

Essential Publications
1	Malignant Melanoma excision margins	Quality Indicator	Type: RCT
Thomas JM, Newton-Bishop J, A’Hern R, Coombes G, Timmons M, Evans J, Cook M, Theaker J, Fallowfield M, O’Neil T, Ruka W, Bliss JM.Excision margins in high-risk malignant melanoma. The New England Journal of Medicine 2004; 350(8): 757-67
In this RCT excision margins of 1 cm were compared with 3 cm margins. It was found a 1 cm margin of excision was associated with a significantly increased risk of locoregional recurrence and a reduced overall survival rate.
2	Malignant Ulcers	Quality Indicator	Type: Narrative Review
De Conno F, Ventafridda V, Saita L. Skin problems in advanced and terminal cancer patients. Journal of Pain and Symptom Management; 1991: 6(4) 247-56.
No recent articles have been found on this important topic of skin problems in this population. The little currently known about the epidemiology and physiopathology of malignant ulcers in the advanced phase of cancer is presented and approaches to management are also provided. However it is clear that controlled studies are needed to provide new information regarding new technologies and drugs for preventing and treating skin lesions in cancer patients.
3	Malignant melanoma – Chemoimmunotherapy	Quality Indicator	Type: Systematic review
Sasse AD, Sasse EC, Clark LGO, Ulloa L, Clark OAC. Chemoimmunotherapy versus chemotherapy for metastatic malignant melanoma. Cochrane Database of Systematic Reviews 2007, Issue 1. Art. No.: CD005413. DOI: 10.1002/14651858.CD005413.pub2.
The purpose of this review was to determine the effect of chemoimmunotherapy (chemotherapy and immunotherapy) compared to chemotherapy alone in metastatic malignant melanoma patients. 18 studies containing 2625 patients were included in this review. Chemoimmunotherapy did not significantly improve survival rate and was associated with increases in both hematological and non-hematological toxicities.
4	Malignant melanoma – Early diagnosis	Quality Indicator	Type: RCT
de Gannes GC, Ip JL, Martinka M, Crawford RI, Rivers JK. Early detection of skin cancer by family physicians: A pilot project. J Cutan Med Surg 2004;8(2):103-109.
The purpose of this study was to determine if education can improve the ability of family physicians’ to diagnose skin cancers. The intervention group was provided with an educational video while the control group was not. Family physicians who received education scored higher on a post-intervention quiz than the control group, but this difference was not statistically significant.
5	Malignant melanoma – Isolated limb perfusion	Quality Indicator	Type: Systematic review
Lens MB, Dawes M. Isolated limb perfusion with melphalan in the treatment of malignant melanoma of the extremities: a systematic review of randomised controlled trials. Lancet Oncol 2003;4(6):359-64.
The efficacy of isolated limb perfusion for treating malignant melanoma of the extremities is evaluated in this review. Isolated limb perfusion is the local surgical delivery of high doses of chemotherapeutic or immunochemotherapeutic agents. The authors found that prophylactic isolated limb perfusion does not significantly impact survival and do not recommend its routine use.
6	Malignant melanoma – Personality	Quality Indicator	Type: Prospective Correlation study
Canada AL, Fawzy NW, Fawzy FI. Personality and disease outcome in malignant melanoma. Journal of Psychosomatic Research 2005;58(1):19-27.
In this study, the role of the patient’s personality on the outcome of early-stage malignant melanoma was evaluated. The researchers found that personality was a poor predictor of disease outcome and disease biology had a significant impact on prognosis.
7	Malignant melanoma – Psychoeducation	Quality Indicator	Type: RCT
Boesen EH, Ross L, Frederiksen K, Thomsen BL, Dahlstrom K, Schmidt G, Noested J, Krag C, Johansen C. Psychoeducational intervention for patients with cutaneous malignant melanoma: A replication study. J Clin Oncol 2005;23(6):1270-77.
The purpose of this study was to evaluate the effect of psychoeducation on malignant melanoma patients’ psychological distress and ability to cope. Psychoeducation consisted of health education, problem-solving skills, stress management, and psychological support. The authors found that psychoeducation can help decrease stress and improve coping ability, but there was no apparent clinical relevance.
8	Malignant melanoma – Quality of life	Quality Indicator	Type: Systematic review
Cashin RP, Lui P, Machado M, Hemels MEH, Corey-Lisle PK, Einarson TR. Advanced cutaneous malignant melanoma: A systematic review of economic and quality-of-life studies. Value Health 2008;11(2):259-71.
In this review, the impact of interventions, consisting of drugs and screening, on quality of life in malignant melanoma patients was evaluated. Treatments and screening for malignant melanoma generally were not cost-effective, and no significant differences or improvements in quality of life were found in any of the various treatments.
9	Malignant melanoma – Sunscreen	Quality Indicator	Type: RCT
Lee TK, Rivers JK, Gallagher RP. Site-specific protective effect of broad spectrum sunscreen on nevus development among white schoolchildren in a randomized trial. J Am Acad Dermatol 2005;52(5):786-92.
The purpose of this study was to determine the effect of sunscreen on nevus development in white schoolchildren. Children who used sunscreen had significantly fewer nevi on the trunk than children who did not use sunscreen. This difference was more noticeable in freckled children compared with children without freckles.
10	Malignant melanoma – Tamoxifen	Quality Indicator	Type: Systematic review
Lens MB, Reiman T, Husain AF. Use of tamoxifen in the treatment of malignant melanoma: Systematic review and metaanalysis of randomized controlled trials. Cancer 2003;98(7):1355-61.
The effect of tamoxifen combined with different chemotherapy regimens was evaluated in this review. Tamoxifen does not significantly improve the patient’s response to treatment or survival rate when used in combination with chemotherapy.

Mixed arterial and venous insufficiency is seen in Patients may present with symptoms that suggest both arterial and venous disease, such as claudication pain accompanying a venous leg ulcer The location of the ulcer may be outside the common area for a venous ulcer or may be deeper. Leg ulcers are associated with numerous patient-centred concerns, including increased stress; pain; and difficulty coping. Decreased mobility, sleep disruption and limited social interaction decrease patient quality of life.

Accurate diagnosis with evaluation of both arterial and venous systems is critical. Mixed venous/arterial ulcers are predominantly venous and generally have an ankle-brachial index (ABI) of 0.6-0.8, whereas mixed arterial/venous ulcers are predominantly arterial, and they have an ABI of Mixed ulcers are difficult to manage. It is important to review the medical and surgical management options to determine if revascularization, vein surgery and compression therapy are appropriate. A combination of treatment approaches may be necessary: ♦ Surgical treatment: Revascularization is indicated if the ABI♦ Compression: The most effective treatment for venous ulcers, high-compression bandaging, is contraindicated in the presence of any arterial insufficiency, and modified compression therapy is contraindicated in the presence of at least moderate arterial disease (♦ Local wound care: Wound assessment establishes a baseline for developing an individualized wound care plan. Local wound care includes debridement; cleansing; identification and treatment of critical colonization and infection; attention to moisture balance; and appropriate dressings. Arterial ulcers tend to be dry, and the wound should be kept dry After revascularization, normal wound care approaches generally result in healing of arterial ulcers. Infection is uncommon until perfusion is restored. If infection is present however it should be treated promptly as it can progress quickly. If infection develops after reperfusion, antibiotic therapy and surgical debridement may be necessary. Autolytic debridement is most commonly used for venous ulcers. Dressings should be selected on an individual basis based on their characteristics and desired action and on patient comfort and cost effectiveness. ♦ Exercise: Exercise therapy may improve healing. ♦ Medical therapy: Pentoxyfilline and micronized purified flavonoid fraction (MPFF) are effective for healing venous ulcers. Stanozolol has been shown significantly to reduce the area affected by chronic lipodermatosclerosis. ♦ Advanced therapies: Topical negative pressure, hyperbaric oxygen, electrical stimulation, therapeutic ultrasound, biologicals and skin substitutes may stimulate healing at the edge of nonhealing wounds (edge effect). ♦ Patient factors: Identified factors that may affect healing, such as poor nutrition and sedentary lifestyle, can be addressed through an exercise prescription and management of nutritional deficiencies. ♦ Adjunctive therapies: Physical therapy may improve restricted ankle mobility. Both therapeutic ultrasound and electrical stimulation may accelerate ulcer healing. Lifelong use of support hose is usually necessary to prevent recurrence, and lifestyle changes are also important to address vascular disease risk factors, including smoking, hypertension, dyslipidemia, sedentary lifestyle and obesity. Lifestyle change can reduce the risk of ulcer recurrence and of cardiovascular events, such as myocardial infarction and stroke. Effective communication and patient, family and caregiver education (especially incorporating self-management components) are critical in obtaining adherence to therapeutic and preventive strategies and achieving optimal long-term outcomes.

 

 

Identify and Treat the Cause		Level of Evidence
1	Assess all patients with leg ulcers for venous and arterial disease.	Not Assessed
2	Take a careful history (venous/ arterial characteristics, other diagnoses, infection, medication, coexisting diseases, factors that may impair wound healing)	Not Assessed
3	Perform a bilateral lower leg physical assessment including an ankle-brachial pressure index (ABPI).	Not Assessed
4	Diagnose mixed venous/arterial ulcer in patients with venous disease and ABI 0.7–0.9.	Not Assessed
5	Diagnose mixed arterial/venous ulcer in patients with venous disease and ABI <0.7.	Not Assessed
6	Refer for revascularization if ABINot Assessed
7	Do not implement high-compression bandaging if arterial disease is present (ABI<0.9).	Not Assessed
8	Modify compression bandaging to treat the venous component if ABI >0.6.	Not Assessed
9	Develop an individual treatment plan for patients with mixed ulcers, addressing the arterial and venous components appropriately.	Not Assessed
10	For nonhealable or maintenance wounds, provide support, pain control and modified local care (conservative debridement, bacterial and moisture reduction)	Not Assessed
Address patient-centered Concerns		Level of Evidence
11	Implement effective patient education and lifestyle changes to prevent ulcer recurrence and reduce the risk of myocardial infarction and stroke.	Not Assessed
12	Educate patients about the need for lifelong compression hose and reinforce adherence frequently.	Not Assessed
13	Communicate (patients, family, caregivers) to establish a social support system with realistic expectations for healing and to prevent leg ulcer recurrences.	Not Assessed
14	Assess / Control pain and optimize activities of daily living	Not Assessed
Provide Local Wound Care		Level of Evidence
15	Assess and document the wound at regular intervals.	Not Assessed
16	Optimize local wound care: debridement, inflammation / infection control, and moisture balance. Consider biopsy of appropriate active (including biologicals) & adjunctive therapies if the wound is not healing at the expected rate.	Not Assessed
Provide Organizational Support		Level of Evidence
17	Consult appropriate disciplines to maximize healing (e.g. mobility and nutrition).	Not Assessed

Essential Publications
1	Mixed Arterial and Venous	Quality Indicator	Type: RCT
Romanelli M, Dini V, Bertone M, Barbanera S and Brilli C. OASIS wound matrix versus Hyaloskin in the treatment of difficult-to-heal wounds of mixed arterial/venous aetiology. Int Wound J 2007; 4:3-7
This study evaluated the effects of OASIS and Hyaloskin in their ability to achieve complete wound healing of mixed arterial/venous ulcers. Complete wound closure was achieved in 82.6% of OASIS-treated ulcers compared with 46.2% of Hyaloskin-treated ulcers (P
2	Mixed Arterial and Venous	Quality Indicator	Type: RCT
Vijayaraghavan KS, Ayyappan MK, Ganesh S, Bhattacharya K. Chronic Nonhealing Ulcer of the Lower Limb With Mixed Arterio-Venous Pathology. The International Journal of Lower Extremity Wounds 2004; 3(1): 47-48.
This study shows that when there is coexistent mixed pathodology, it is mandatory to evaluate arterial flow and, when there is evidence of moderate to significant ischemic disease, treat as deemed fit.
3	Mixed Arterial and Venous	Quality Indicator	Type: Prospective Correlation study
Ghauri ASK, Nyamekye K, Grabs AJ, Farndon JR, Poskitt KR. The Diagnosis and Management of Mixed Arterial/Venous Leg Ulcers in Community-based Clinics. Eur J Vasc Endovasc Surg 1998; 16: 350-355.
In this study, limbs with mixed disease were treated according to the resting ankle-brachial pressure index. Ulcers with venous and a severe arterial component responded slowly despite early aggressive revasculisation. Overall, this study indicated that supervised modified compression bandaging in ulcerated limbs with mixed venous ad moderate arterial disease is safe and effective.

Chronicity and recurrence of venous leg ulcers have an important effect on patient quality of life and societal costs of management. Evidence-based management has the potential to improve patient quality of life and to reduce these costs substantially.

Compression Compression therapy is the gold-standard treatment for venous ulcers. High-compression bandaging is optimal, but this approach may require modification in patients with diabetes, arthritis, infection, or mild arterial disease (ankle-brachial index [ABI] 0.6-0.8). Compression is contraindicated in patients with ABI Local wound care Wound assessment establishes a baseline for developing an individualized wound care plan. Local wound care includes debridement; cleansing; identification and treatment of critical colonization and infection; attention to moisture balance; and appropriate dressings. Debridement and moist wound healing are only appropriate in wounds with an adequate blood supply for healing. Autolytic debridement is most commonly used for venous ulcers. Specific types of dressings have not been shown to improve wound healing or decrease pain. Dressings should be selected based on their characteristics, desired action, patient comfort, and cost effectiveness.

Medical therapy Pentoxyfilline and micronized purified flavonoid fraction (MPFF) are effective for healing venous ulcers. Stanozolol has been shown significantly to reduce the area affected by chronic lipodermatosclerosis. Acetylsalicylic acid (ASA) or other nonsteroidal antiinflammatory drugs (NSAIDs) can treat acute lipodermatosclerosis. Superficial phlebitis may also respond to an NSAID, and low-dose ASA may speed healing of a venous ulcer. Patients with deep vein thrombosis (DVT) require anticoagulation.

Lifestyle management Exercise therapy may improve healing. Lifelong use of support hose is usually necessary to prevent recurrence, and lifestyle changes may also be important. Patients should be educated about warning signs of arterial disease and monitored for development of arterial disease.

Effective communication and patient, family and caregiver education (especially incorporating self-management components) are critical in obtaining adherence to therapeutic and preventive strategies and achieving optimal long-term outcomes.

Patient-centred concerns Venous ulcers are associated with numerous patient-centred concerns, including increased stress; pain; and difficulty coping, both at a psychologic and a functional level. Decreased mobility, sleep disruption and limited social interaction decrease patient quality of life.

Nonhealing ulcers—complementary and advanced therapies, skin substitutes Evidence indicates that wounds whose size has not decreased by 30% within 4 weeks do not heal by 12 weeks. Attention to initial healing rates may allow earlier identification of nonhealing and prompt changes in the care plan. The following factors have a statistically significant association with nonhealing venous leg ulcers: ♦ ABI <0.8 ♦ History of venous ligation or stripping ♦ Hip or knee surgery ♦ Yellow, fibrin-like material >50% of ulcer base ♦ Larger area ♦ Longer duration.

Advanced therapies, including topical negative pressure, hyperbaric oxygen, electrical stimulation, therapeutic ultrasound, biologicals and skin substitutes, may stimulate healing at the edge of nonhealing wounds (edge effect). Cellular and acellular skin substitutes have a role in managing stalled but healable chronic ulcers. Evidence supports the use of Oasis, an acellular skin substitute, in healing venous leg ulcers. The use of composite cellular skin substitutes, such as Apligraf and Dermagraft, is supported by good evidence in healing diabetic foot ulcers. This therapy may be cost effective if ulcers have been present for more than 1 year.

Adjunctive therapy Identified factors that may affect healing, such as poor nutrition and sedentary lifestyle, can be addressed through an exercise prescription and management of nutritional deficiencies. Physical therapy may improve restricted ankle mobility in patients. Both therapeutic ultrasound and electrical stimulation may accelerate ulcer healing.

Surgery Significant superficial or perforator vein disease, without extensive deep valvular disease, may be treated surgically, with subfascial endoscopic perforator surgery (SEPS). SEPS is associated with almost 90% ulcer healing rates and low recurrence. This operation may be accompanied by Linton’s procedure, or removal of the long saphenous vein. Longer follow-up of patients treated surgically is necessary to evaluate the effectiveness of surgery fully. Until then, venous surgery should be reserved for medically fit patients who fail to respond to standard therapy and who adhere to medical therapy. Surgery is unlikely to be helpful in patients with deep venous incompetence.

Identify and Treat the Cause		Level of Evidence
1	Take a careful history (venous/ arterial characteristics, other diagnoses, infection, medication, coexisting diseases, factors that may impair wound healing)	5
2	Perform a bilateral lower leg physical assessment including an ankle-brachial pressure index (ABPI).	1a
3	Determine the cause(s) and for possible chronic venous insufficiency based on etiology: abnormal valves (reflux), obstruction, or calf-muscle-pump failure.	5
4	Treat the cause and implement appropriate compression therapy for venous disease in the absence of arterial predominant disease.	1a
5	Implement appropriate medical therapy.	5
6	Consider the addition of medical therapy to increase wound healing and manage problems such as lipodermatosclerosis and superficial phlebitis.	Not Assessed
7	Address systemic factors that may affect healing, including lifestyle modification.	Not Assessed
8	Consider surgical management for venous (if significant superficial or perforator vein disease exists in the absence of deep venous disease) or arterial disease (bypass, dilation, or stent).	1a
9	For nonhealable or maintenance wounds, provide support, pain control and modified local care (conservative debridement, bacterial and moisture reduction)	1a
Address patient-centered Concerns		Level of Evidence
10	Communicate (patients, family, caregivers) to establish a social support system with realistic expectations for healing and to prevent leg ulcer recurrences.	5
11	Educate patients about the need for lifelong compression hose and reinforce adherence frequently.	5
12	Assess / Control pain and optimize activities of daily living.	Not Assessed
Provide Local Wound Care		Level of Evidence
13	Assess and document the wound at regular intervals.	Not Assessed
14	Optimize local wound care: debridement, inflammation / infection control, and moisture balance. Consider biopsy of appropriate active (including biologicals) & adjunctive therapies if the wound is not healing at the expected rate.	1a
15	Consider surgery for adherent and medically fit patients who have nonhealing ulcers and superficial or perforator disease without deep valvular disease.	1a
Provide Organizational Support		Level of Evidence
16	Consult appropriate disciplines to maximize healing (e.g. mobility and nutrition).	1a

Essential Publications
1	Compression Therapy	Quality Indicator	Type: Systematic review
Cullum N, Nelson EA, Fletcher AW, Sheldon TA. Compression for venous leg ulcers. Cochrane Database of Systematic Reviews 2001, Issue 2. Art. No.: CD000265. DOI: 10.1002/14651858.CD000265.
This well designed systematic review indicates that compression is more effective in treating venous leg ulcers than no compression, high compression is more effective than low compression, elastic is more effective than non-elastic, multi-layered high compression is more effective than single-layered compression.
2	Compression Therapy for prevention of recurrence of venous leg ulcers	Quality Indicator	Type: Systematic review
Nelson EA, Bell-Syer SEM, Cullum NA. Compression for preventing recurrence of venous ulcers. Cochrane Database of Systematic Reviews 2000, Issue 4. Art. No.: CD002303. DOI: 10.1002/14651858.CD002303.
This review that is quite old is important because a gap was identified – that there was no evidence to show if compression prevents venous leg ulcers. This led to the development of a RCT on this topic.
3	Compression for the prevention of recurrence of venous leg ulcers	Quality Indicator	Type: RCT
Nelson EA, Harper, DR, Prescott RJ, Gibson B, Brown D and Ruckley V. Prevention of recurrence of venous ulceration: Randomized controlled trial of class 2 and class 3 elastic compression. J Vasc Surg 2006;44:803-8.
This paper is important because it illustrates the trade-off between clinical effectiveness and reduced compliance in patients assigned to high compression. Thirty-six percent (107/300) of patients had recurrent leg ulceration by 5 years. Recurrence occurred in 59 (39%) of 151 class 2 elastic compression cases and in 48 (32%) of class 3 compression cases. there was no statistically significant difference in recurrence rates, but fewer people experienced recurrence with high compression, although not at the conventional levels of statistical significance. It is important to note that this trial does not demonstrate equivalence in recurrence rates in moderate and high compression. In addition, the two factors most important to leg ulcer recurrence were multiple previous episodes of leg ulceration and less than full ankle range of motion.
4	Compression therapy in venous insufficiency and venous ulcers	Quality Indicator	Type: Systematic review
Berliner et al, A systematic review of pneumatic compression for treatment of chronic venous insufficiency and venous ulcers, 2003, Agency for Healthcare Research and Quality, 1-12.
In this well-designed systematic review of RCTs and cohort studies it was found that compression therapy is an important part of treatment for chronic venous insufficiency (CVI) and venous leg ulcers. Long-term use of pneumatic compression devices in the home environment may be used in addition to or as an alternative to other compression therapies for patients who are unable or refuse to comply with other methods.
5	Compression Therapy – Post-thrombotic Syndrome	Quality Indicator	Type: Systematic review
KolbachDN, SandbrinkMWC, NeumannHAM, PrinsMH.Compression therapy for treating stage I and II (Widmer) post-thrombotic syndrome. Cochrane Database of Systematic Reviews 2003, Issue 4. Art. No.: CD004177. DOI: 10.1002/14651858.CD004177.
This systematic review of RCTs was conducted to determine the relative effectiveness of compression therapy in people with stage I and II post-thrombotic syndrome according to the classification of Widmer. There is some evidence of a beneficial effect of intermittent pneumatic compression units.
6	Dressings – venous and mixed etiology leg ulcers	Quality Indicator	Type: Systematic review
Bouza C, Munoz A, Amate JM. Efficacy of modern dressings in the treatment of leg ulcers: A systematic review. Wound Repair and Regeneration 2005;13:218-229.
This is well-conducted systematic review to determine the benefit of using modern dressings to treat patients with leg ulcers of venous, mixed or poorly differentiated etiology. There were no differences in the proportion of healed ulcers or in the reduction of wound size between modern and conventional dressings or between different dressings. This review illustrates the need for further research on this topic.
7	Dressings – venous leg ulcers	Quality Indicator	Type: Systematic review
Palfreyman SJ, Nelson EA, Lochiel R, Michaels JA. Dressings for healing venous leg ulcers. Cochrane Database of Systematic Reviews 2006, Issue 3. Art. No.: CD001103. DOI: 10.1002/14651858.CD001103.pub2
This is a well-conducted Cochrane systematic review that included 42 RCTs and 3001 subjects indicated that when hydrocolloid was compared with foam dressings, alginate dressings, hydrocolloid and low-adherent dressings, there were no evidence of a statistically significant difference in healing rates. Similarly hydrocolloids are no more effective for healing than low adherent dressings used beneath compression (RR=1.09, 95%CI 0.89 to 1.34). Decisions regarding which dressing to apply should be based on local costs of dressings and patient preferences. More research in this area is required.
8	Dressings – venous leg ulcers	Quality Indicator	Type: Systematic review
Palfreyman SJ, Nelson EA, Michaels JA. Dressings for venous leg ulcers: systematic review and meta-analysis. BMJ 2007;335:244.
This systematic review is a condensed version (12 pages) of the Cochrane review published in 2006 (62 pages) by the same authors. In addition to providing the information in fewer pages, it contains Forest plots that provide a visual illustration that no differences were detected.
9	Silver dressing – venous leg ulcers	Quality Indicator	Type: Systematic review
Chambers H, Dumville JC, Cullum N.Silver treatments for leg ulcers: a systematic review. Wound Repair and Regeneration 2007;15:165-173.
This is a well-conducted systematic review of four RCTs that were included in the meta-analyses. It is important for illustrating lack of evidence to support the use of silver products, as studies provided inconsistent evidence regarding the effects of silver-based dressings and topical agents on leg ulcer healing.
10	Electromagnetic therapy – venous leg ulcers	Quality Indicator	Type: Systematic review
Ravaghi H, Flemming K, Cullum N, Olyaee Manesh A. Electromagnetic therapy for treating venous leg ulcers. Cochrane Database of Systematic Reviews 2006, Issue 2, 1-15.
This is a well-conducted update of a Cochrane review (2005); no new RCTs were found comparing electromagnetic therapy with sham or other therapies. No significant difference was found in the three RCTs in the original review. This study illustrates the need for more individual studies of electromagnetic therapy.
11	Skin grafting – venous leg ulcers	Quality Indicator	Type: Systematic review
Jones JE, Nelson EA. Skin grafting for venous leg ulcers. Cochrane Database of Systematic Reviews 2007, Issue 2. Art. No.: CD001737. DOI: 10.1002/14651858.CD001737.pub3.
Grafts were compared with standard care, with other grafts, and with other agents. Pooling of five trials of fresh or frozen allografts compared with standard care of low-adherent dressing or hydrocolloid showed there were significantly higher healing rates with allografts than dressings (RR 2.00, 95% CI 1.04 to 3.84). Since there were methodological problems, this result should be accepted with some caution and confirmed by large, well-designed and conducted trials. Pooled results of two trials of bilayered human skin equivalent compared with standard care of foam or placebo dressing yielded a relative risk of healing with the artificial skin compared with simple dressings of 1.51 (95%CI 1.22 to 1.88). The increase in healing rate from approximately 40% to 60% represents an NNT of 5 for six months’ treatment, indicating that five people would need to be treated with artificial skin, rather than a simple dressing, in order for one additional ulcer to heal at six months. These two trials provide reasonable evidence that a greater proportion of venous ulcers heal with artificial skin than a simple dressing.
12	Oral treatment with Daflon – venous leg ulcers	Quality Indicator	Type: Systematic review
Coleridge Smith P, Daflon 500 mg and Venous Leg Ulcer: New Results From a Meta-Analysis, 2005, Angiology, S33-S39.
This is a well-conducted systematic review of RCTs to assess the effect of oral treatment with micronized purified flavonoid fraction (MPFF, Daflon 500 mg) on leg ulcer healing. At 6 months based on 616 subjects irrespective of study conditions, 61.3% were completely healed in the Daflon 500 mg group versus 47.7% in the control group. The relative hazard of healing was 38% higher in the Daflon 500 mg group compared with the control group (CI, 11% to 70%). The time to complete healing of ulcers was shorter in the Daflon group (16 weeks vs 21 weeks; hazard ratio = 1.33). A strong trend in favor of Daflon 500 mg began to emerge by week 8 of treatment. Daflon 500 mg might be a useful adjunct to conventional therapy in large and longstanding ulcers that might be expected to heal slowly.
13	Adjunctive therapy – Micronized Purified Flavonoid Fraction (MPFF) – Venous leg ulcers	Quality Indicator	Type: Systematic review
Coleridge-Smith P, Lok C, Ramelet A-A, Venous leg Ulcer: A Meta-analysis of Adjunctive Therapy with Micronized Purified Flavonoid Fraction, 2005, European Journal of Vascular and Endovascular Surgery 30, 198-208.
This well-conducted review of 5 RCTs was undertaken to assess the effect of oral treatment with micronized purified flavonoid fraction (MPFF) on leg ulcer healing. After 6 months, 61.3% of these patients were completely healed in the MPFF group versus 47.7% in the control group (RRR 32% 95%CI 3-70%). At 2 months, the chance for ulcer healing in the MPFF group compared to the controls (N=723) was 44% (CI, 7–94%; P=0.015). The effect was seen particularly in ulcers between 5 and 10 cm2 and present for 6-12 months duration. This review suggests that MPFF may be effective in accelerating venous leg ulcer healing in large ulcers of long duration.
14	Topical agents versus dressings for pain – Venous leg ulcers	Quality Indicator	Type: Systematic review
Briggs M, Nelson EA. Topical agents or dressings for pain in venous leg ulcers. Cochrane Database of Systematic Reviews 2003, Issue 1.Art. No.: CD001177. DOI: 10.1002/14651858.CD001177.
This is a well-conducted systematic review assessing the effectiveness of dressings, local anaesthetics or topical analgesia for pain relief in people with venous leg ulcers. There are six trials indicating that a eutectic mixture of local anaesthetic (EMLA) (5%) provides pain reduction of 20.6 mm (95% CI 29.1 to 12.2) during venous leg ulcer debridement. Further research is required to determine whether debridement of venous leg ulcers aids healing and what impact local anaesthetic has on leg ulcer healing. This review indicates the lack of evidence to answer several of the questions about pain in people with leg ulcers.
15	Ultrasound treatment of venous leg ulcers	Quality Indicator	Type: Systematic review
Flemming K, Cullum N. Therapeutic ultrasound for venous leg ulcers. Cochrane Database of Systematic Reviews 2000, Issue 4. Art. No.: CD001180. DOI: 10.1002/14651858.CD001180.
This well-conducted systematic review of RCTs was undertaken to determine if therapeutic ultrasound stimulates venous leg ulcer healing, and specific details of the optimum treatment regimen. The study methods and outcomes were not homogeneous and the results were not combined. Although no statistical differences in healing rates between any of the therapies were found the direction of effect was consistently in favour of ultrasound. This review illustrates the need for well-designed trials of ultrasound.
16	Laser therapy for venous leg ulcers	Quality Indicator	Type: Systematic review
Flemming K, Cullum N. Laser therapy for venous leg ulcers. Cochrane Database of Systematic Reviews 1999, Issue 1. Art. No.: CD001182. DOI: 10.1002/14651858.CD001182.
This well-conducted systematic review of RCTs was undertaken to determine if low level laser therapy stimulates venous leg ulcer healing, and specific details of the optimum treatment regimen. The four studies included do not demonstrate a statistically significant improvement in venous leg ulcer healing with the use of low level laser therapy. The only suggestion of therapeutic benefit is shown in one small RCT where a combination of laser and infrared light led to an improvement in the healing rates of venous ulcers. This review illustrates the need for well-designed trials of laser therapy.
17	Pentoxifylline for venous leg ulcers	Quality Indicator	Type: Systematic review
Jull AB, Waters J, Arroll B. Pentoxifylline for treating venous leg ulcers. Cochrane Database of Systematic Reviews 2002, Issue 1. Art. No.: CD001733. DOI: 10.1002/14651858.CD001733.
This well-conducted systematic review was undertaken to determine if pentoxifylline improves healing of venous leg ulcers, when compared with placebo, both with or without compression therapy. The relative risk of healing with pentoxifylline versus placebo, with compression, in trials of eight to 12 weeks, pooled using a fixed effects model, was significant (RR 2.36, 95% CI 1.74 to 3.19). Comparison of pentoxifylline with placebo, without compression, also favoured pentoxifylline (RR 2.25, 95% CI 1.49 to 3.39). However, comparison of pentoxifylline versus defibrotide indicated no significant difference in healing at three months. Pentoxifylline appears to be an effective adjunct to compression bandaging for treating venous ulcers and may be effective for treating venous leg ulcers even without compression.
18	Pentoxifylline, compression, dressings – Venous leg ulcers	Quality Indicator	Type: RCT
Nelson EA, Prescott RJ, Harper DR, Gibson B, Brown D, Ruckley CV. A factorial, randomized trial of pentoxifylline or placebo, four-layer or single-layer compression, and knitted viscose or hydrocolloid dressings for venous ulcers. J Vasc Surg 2007;45:134-41.
In this excellent recent factorial design RCT involving 245 patients, the effectiveness of pentoxifylline (1200 mg daily) was compared with placebo, knitted viscose with hydrocolloid dressings, and single-layer with four-layer bandaging for venous ulceration. In unadjusted analyses, only four-layer bandages were associated with significantly higher healing rates than single-layer bandages (67% vs. 49%; P=0.009). In adjusted analysis, the significance of the pentoxifylline effect increased just to significance (relative risk of healing, 1.4; 95% confidence interval, 1.0 to 2.0). This study further indicates the important effect of high-compression bandaging on healing rate, irrespective of dressing, and less strongly suggests that pentoxifylline may increase the chance of healing.
19	Topical pale sulfonated shale oil – Venous leg ulcers	Quality Indicator	Type: RCT
Beckert S, Warnecke J, Zelenkova H, Kovnerystyy O, Cholcha W, Konigsrainer A and Coerper S. Efficacy of topical pale sulfonated shale oil in the treatment of venous leg ulcers: A randomized, controlled, multicenter study. J Vasc Surg 2006;43: 94-100.
This is a well-designed multi-center observer-blind RCT, conducted to determine if Pale Sulfonated Shale Oils (PSSO) are more effective at facilitating venous healing than simple compression therapy in patients with venous leg ulcers. The cumulative wound area was significantly more reduced in the PSSO group compared with the vehicle group (P
20	Pycnogenol® and Daflon® in Treating Chronic Venous Insufficiency	Quality Indicator	Type: RCT
Cesarone MR, Belcaro G, Rohdewald P, Pellegrini L, Ledda A, Vinciguerra G, Ricci A, Gizzi G, Ippolito E, Fano F, Dugall M, Acerbi B, Cacchio M, Di Renzo A, Hosoi M, Stuard S and Corsi M. Comparison of Pycnogenol® and Daflon® in Treating Chronic Venous Insufficiency: A Prospective, Controlled Study. Clin Appl Thrombosis/Hemostasis 12(2):205–212, 2006.
This RCT was conducted to investigate the clinical effectiveness of two doses of Pycnogenol compared to Daflon in a group of 86 patients with severe chronic venous insufficiency (CVI), venous hypertension, ankle swelling and previous history of venous ulcerations. All microcirculatory parameters indicated a significantly larger (p < .05) improvement of CVI produced by Pycnogenol in comparison with the Daflon treatment group both in the lower dose and in the higher dose groups. Edema formation, resting flux, and rate of ankle swelling were reduced about twice as much by Pycnogenol in comparison with Daflon (P
21	Prevalence of venous leg ulcers	Quality Indicator	Type: Systematic review
Graham ID, Harrison MB, Nelson A, Lorimer K, Fisher A. Prevalence of Lower-Limb Ulceration: A Systematic Review of Prevalence Studies, 2003, Advances in Skin & Wound Care, 305-16.
This well-conducted systematic review of cohort studies was undertaken to determine the prevalence of leg ulcers reported in the literature. In the population-based prevalence studies that used clinical validation, the prevalence rate of ulceration was 1.8% with a range of 0.12% to 1.1%. Good quality prevalence studies with large numbers, description of case identification, and definition of ulcers with clinical confirmation, are required. This study provides an estimate of venous leg ulcer prevalence.
22	Ketansein – patients with diabetes with venous insufficiency	Quality Indicator	Type: RCT
Quatresooz P, Kharfi M, Paquet P, Vroome V, Cauwenbergh G and Pierard GE. Healing effect of ketanserin on chronic leg ulcers in patients with diabetes. JEADV 2006, 20, 277–281.
This double blind study suggests that application of topical 2% ketanserin ointment affects the healing rate of chronic leg ulcers present in patients with diabetes with venous insufficiency. Twelve patients with diabetes and at least 2 difficult-to-treat leg ulcers that were randomly allocated to treatment served as their own control. Within subjects, there was significant relative wound area reduction at week 4 (P=0.010) at week 6 (P=0.010) and at week 8 (P=0.004). Weekly reduction was 10.25% for the ketanserin-treated ulcers and 2.5% for the placebo-treated ulcers.
23	Mimosa tenuiflora cortex extract – Venous leg ulcers	Quality Indicator	Type: RCT
Rivera-Arce E, Chavez-Soto MA, Herrera-Arellano A, Arzate S, Aguero J, Feria-Romero IA, Cruz-Guzman A and Lozoya X. Therapeutic effectiveness of a Mimosa tenuiflora cortex extract in venous leg ulceration treatment. Journal of Ethnopharmacology 2007;109:523–528.
This is a well-designed randomized, double-blind clinical trial. For 13 weeks, the treatment group (n=20) received a hydrogel containing 5% of a crude extract standardized in its tannin concentration initially followed by topical application of the corresponding hydrogel and dressing while the control group received placebo hydrogel (n=20). Reduction in wound size was noted in all patients in the extract group with mean reduction by 8 weeks of 92%, while wound size reduced in only in one patient in the control group (p=0.0001). This study shows that the extract obtained from Mimosa tenuiflora bark facilitated skin-ulcer cicatrization when used as a coadjuvant in conventional VLU treatment in ambulatory patients.
24	Larval Therapy – Venous leg ulcers	Quality Indicator	Type: RCT
Petherick ES, O’Meara S, Spilsbury K, Iglesias CP, Nelson EA, Torgerson DJ. Patient acceptability of larval therapy for leg ulcer treatment: a randomised survey to inform the sample size calculation of a randomised trial. BMC Medical Research Methodology 2006;6:43 doi:10.1186/1471-2288-6-43
This randomized survey was undertaken as a precursor to RCT to evaluate patient aversion to larval therapy and preference for loose versus bagged larvae to debride and heal sloughy and necrotic venous leg ulcers. In addition, acceptable time to healing for this method was determined. People aged 18 years and above (n=35) with at least one leg ulcer of venous or mixed (venous and arterial) aetiology completed a survey comparing Loose Larvae and hydrogel, and a survey comparing bagged larvae and hydrogel. 77% of participants would consider the use of larval therapy as an acceptable treatment option, regardless of the method of containment. Half the respondents would be willing to use this therapy even if they were equally able to achieve healing using hydrogel by 20 weeks. Regarding the use of loose larvae, complete healing would have to occur over 17 weeks for patients to choose larvae rather than hydrogel. Patient acceptance of this therapy may be of value to clinicians; specific details will inform research.
25	Vacuum-assisted closure – chronic leg ulcers	Quality Indicator	Type: RCT
Vuerstaek JDD, Vainas T, Wuite J, Nelemans P, Neumann MHA and Veraart JCJM. State-of-the-art treatment of chronic leg ulcers: a randomized controlled trial comparing vacuum-assisted closure (V.A.C.) with modern wound dressings. J Vasc Surg 2006;44:1029-38.
This well-designed RCT was conducted to determine the efficacy of V.A.C. in wound healing compared with standard wound dressings in hospitalized patients with chronic venous, combined venous and arterial, or microangiopathic leg ulcers with durations greater than six months. Median total healing time in the V.A.C. group was 29 days (95% CI 25.5-32.5) compared with 45 days (95% CI 36.2-56.8) in the control group (P=0.0001). Median wound bed preparation time (time from surgical debridement to application of punch skin grafts) was less in the V.A.C. group 7 days (95% CI 5.7-8.3) than in the control group 17 days (95% CI 10-24). There were non-significant differences in recurrence rates, relapse rates, and complications. This study indicates that there may be advantages to using V.A.C. to reduce healing time in these patients.
26	Surgical treatment versus conservative – Venous leg ulcers	Quality Indicator	Type: RCT
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. Journal of Vascular Surgery. 2006; 44:563-71.
This multicentre RCT was conducted to determine if ambulatory compression therapy with venous surgery is better than just ambulatory compression in leg ulcer patients. Subfascial endoscopic perforating vein surgery (SEPS) was provided to patints with 94 ulcers; standard ambulatory compression therapy 102 patients. There was no difference between the groups in the length of the ulcer free period following treatment (P=0.11). Only patients with recurrent ulceration or medially located ulcers remained ulcer-free longer following surgery than patients treated conservatively (P=0.02). Although the findings of this study are biased by the inclusion of 200 ulcers in 170 patients, the findings suggest that patients with recurrent and or/ medial ulceration might benefit from SEPS in addition to compression.
27	Amelogenins (XelmaTM) – Venous leg ulcers	Quality Indicator	Type: RCT
Vowden P, Romanelli M, Peter R, Bostrom A, Josefsson A, Stege H. The effect of amelogenins (XelmaTM) on hard-to-heal venous leg ulcers. Wound Repair and Regeneration 2006; 14: 240-246
This single-blind randomized multicenter study was conductd to examine wound size reduction using amlogenin proteins in patients with hard to heal venous ulcers. Patients were randomly allocated to receive treatment with XelmaTM cream (n=62) or to the control group that received propylene glycol alginate 7% (n=61) for 12 weeks. The group treated with amelogenins experienced greatest healing, especially in large or hard-to-heal wounds.
28	Autologous keratinocytes in fibrin sealant – Recalcitrant venous leg ulcers	Quality Indicator	Type: RCT
Vanscheidt W, Ukat A, Horak V, Bruning H, Hunyadi J, Pavlicek R, Emter M, Hartmann A, Bende J, Zwingers T, Ermuth T, and Eberhardt R. Treatment of recalcitrant venous leg ulcers with autologous keratinocytes in fibrin sealant: A multinational randomized controlled clinical trial. Wound Rep Reg (2007) 15 308–315.
This is a very well-described open-label multicntre RCT to compare wound healing using BioSeed®-S and compression therapy (n=116) with standard care (nonadherent gauze and compression therapy) (n=109) in patients with chronic venous leg ulcers of at least 3 month duration, with areas between 2 and 500 cm^2. Time to healing was less in the BioSeed®-S group than in the standard care group, 176 days versus more than 201 days (P
29	Outcome measures and comparison of hydrogels – Venous leg ulcers	Quality Indicator	Type: RCT
De la Brassinne, M., Thirion, L., Horvat, L. A novel method of comparing the healing properties of two hydrogels in chronic leg ulcers (2005). JEADV, 20, 131-135.
This pilot study was conducted to compare alginate gel Flaminal® (n=10) and hydrocolloid gel Intrasite® as the control (n=10) on the healing of leg ulcers and to describe the use of volume and surface area reduction as outcome measures in trials. Significant difference in wound volume reduction after treatment with Flaminal® was detected at 7 days, while surface area reduction was detected only by 28 days. In this pilot study volume reduction detected greater effect with Flaminol® than Intrasite® at 7, 14, and 28 days. This study suggests that reduction in volume may be a good outcome measure for comparing and measuring different treatment effects.
30	Comparison of two foam dressings – Venous leg ulcers	Quality Indicator	Type: RCT
Franks PJ, Moody M, Moffatt CJ, Hiskett G, Gatto P, Davies C, Furlong WT, Barrow E, Thomas H on behalf of the Wound Healing Nursing Research Group. Randomized trial of two foam dressings in the management of chronic venous ulceration. Wound Rep Reg 2007;15:197-202.
This multicentre RCT was undertaken to compare two foam dressings, Allevyn Hydrocellular (n=81) and Mepilex (n=75) in the management of chronic venous leg ulcers. Propotion of wound closure: Allevyn 61.7%, Mepilex 66.7% closure. The hazard ratio for healing after adjustment for bandage type and trial centre was not significant at 1.48 (95% CI 0.87 to 2.54, P=0.15). The groups had similar Pain scores and similar proportions of bandage related withdrawls. This study is important because it illustrates that the effect of using these two foam dressings is similar. It also illustrates the need for statistically powered studies on this topic.
31	Biatain-Ibu versus Biatain dressings – Venous leg ulcers	Quality Indicator	Type: RCT
Gottrup F, Jorgensen B, Karlsmark T, Sibbald RG, Rimdeika R, Harding K, Price P, Venning v, Vowden P, Junger M, Wortmann S, Sulcaite R, Vilkevicius G, Ahokas T-L, Ettler K, Arenbergerova M. Less pain with Biatain-Ibu: initial findings from a randomised, controlled, double-blind clinical investigation on painful venous leg ulcers. International Wound Journal 2007; 4 (Suppl. 1):24-34.
This is a very well-designed multinational, multicenter, parallel group, double-blind RCT to compare a non adhesive foam dressing with ibuprofen with a non adhesive foam without ibuprofen in 122 patients with painful chronic venous leg ulcer of more than 8-week duration. 74% of 62 patients treated with the Biatain-Ibu non adhesiveexperineced persistent (chronic) pain relief on days 1-5 versus 58% of 60 patients treated with the comparator foam dressing, Biatain non-adhesive (P=0.0003). Persistent pain intensity was reduced in 40% versus 30% of subjects respectively (P=0.0003). Non-significant differences in the adverse events were detected. The study is well described and effectively demonstrates that ibuprofen-foam dressing is beneficial for persistent pain relief and reducing persistent and temporary wound pain intensity. The potential for adverse events related to dressings should be observed.
32	Ibuprofen-foam versus local best practice – Venous leg ulcers	Quality Indicator	Type: RCT
Sibbald RG, Coutts P Fierheller M, Woo K. A pilot (real-life) randomised clinical evaluation of a pain-relieving foam dressing: (Ibuprofen-foam versus local best practice). International Wound Journal, 2007, 4, SUPPL.1, 16-23.
This is a well-conducted pilot RCT to compare a foam dressing with continuous low-level release of Ibuprofen (Biatain-ibu) with local best care involving a variety of dressings. Persons with chronic painful exudating leg ulcers were randomly allocated to receive continuous low-level release of Ibuprofen (Biatain-ibu) (n=12) or local best care (n=12) for one week. Pain intensity (pooled morning and evening scores) was less in the Ibuprofen group (P=0.0217) and ulcer area was significantly reduced (P=0.05). This is a good short-term pilot study that provides numbers to inform a RCT and suggests that Biatain-Ibu may control pain in patients with venous leg ulcers.
34	Dressings – Venous Leg Ulcers	Quality Indicator	Type: RCT
Jørgensen B, Price P, Andersen KE, Gottrup F, Bech-Thomsen N, Scanlon E, Kirsner R, Rheinen H, Roed-Petersen J, Romanelli M, Jemec G, Leaper DJ, Neumann MH, Veraart J, Coerper S, Agerslev RH, Bendz SH, Larsen JR, Sibbald RG. The silver-releasing foam dressing, Contreet Foam, promotes faster healing of critically colonised venous leg ulcers: a randomised, controlled trial. Int Wound J. 2005 Mar; 2(1):64-73.
The RCT provides evidence of the superior performance of the silver-releasing dressing, Contreet Foam, compared with a traditional moist foam wound healing dressing. After 4 weeks of treatment, the median relative reduction in ulcer area are significantly higher in the Contreet Foam group than in the Allevyn Hydrocellular group (P=0.034). The overall estimated wear time for the silver-containing dressing (mean of 5.1 days) was significantly higher than for the foam dressing without added silver (mean of 3.9 days) (P=0.023). These results suggest an important role of sustained silver-releasing dressings in the treatment of critically colonised chronic wounds.
35	Outcomes After Surgical Management of Venous Disease – Subfascial Endoscopic Perforator Surgery	Quality Indicator	Type: Systematic review
TenBrook JA, Iafrati MD, O’Donnell TF, Wolf MP, Hoffman SN, Pauker SG, Lau J, Wong JB. Systematic review of outcomes after surgical management of venous disease incorporating subfascial endoscopic perforator surgery, 2004, Journal of Vascular Surgery, 39:583-9.
The purpose of the systematic review is to quantify the overall rates of surgical outcomes for patients with severe chronic venous insufficiency treated with surgical management that incorporated subfascial endoscopic perforator surgery (SEPS). Surgical management of venous ulcer including SEPS, with or without saphenous ablation, leads to an 88% chance of ulcer healing and a 13% chance of ulcer recurrence over the short term. RCTs are needed to clarify the contributions of compression therapy, superficial venous surgery, and SEPS in the treatment of venous ulcer disease.
36	Comparison of Two Periwound Skin Protectants – Venous Leg Ulcers	Quality Indicator	Type: RCT
Cameron J, Hofman D, Wilson J, Cherry G. Comparison of two periwound skin protectants in venous leg ulcers: a randomised controlled trial. J Wound Care 2005; 14(5): 233-6.
This study was conducted to compare the efficacy and cost-effectiveness of two skin protectants. No Sting Barrier Film (NSBF) is preferred over zinc paste for effective barrier preparations because it is easy to apply and transparent. The benefits of NSBF include reduced treatment time (p
37	Antibiotics and Antiseptics – Venous Leg Ulcers	Quality Indicator	Type: Systematic review
O’Meara S, Al-Kurdi D, Ovington LG. Antibiotics and antiseptics for venous leg ulcers. Cochrane Database of Systematic Reviews 2008, Issue 1. Art. No.: CD003557. DOI: 10.1002/14651858.CD003557.
The objective of the review is to determine the effects of systemic antibiotics, topical antibiotics and antiseptics on the healing of venous ulcers. In terms of topical preparations, there is some evidence to support the use of cadexomer iodine. Due to the increasing problem of bacterial resistance to antibiotics, current prescribing guidelines recommend that antibacterial preparations should only be used in cases of defined infection and not for bacterial colonisation. Further research is required to support the routine use of systemic antibiotics to promote healing in venous leg ulcers.
38	Protein Extracts	Quality Indicator	Type: RCT
Varelias A, Cowin AJ, Harries RHC, Cooter RD, Belford DA, Fitridge RA, Rayner TE. Mitogenic bovine whey extract modulates matrix matalloproteinase-2, – 9 and tissue inhibitor of matrix metalloproteinase-2 levels in chronic leg ulcers. Wound Repair and Regeneration. 2006; 14: 28-37.
In this study, a mitogenic bovine whey extract (MBWE) enriched with growth factors was investigated to determine if it modulated the expression and activity of MMP-2 and -9 and the tissue inhibitor of MMP-2 in chronic leg ulcers. MBWE significantly decreased active MMP-2 levels over all time points compared with placebo (p=0.007) at the 2.5 and 10mg/mL doses but not at the 20 mg/mL dose. Fibroblasts expressing MMP-2 were reduced at biopsy in days 15 and 29 (p
39	Debridement	Quality Indicator	Type: RCT
König M, Vanscheidt W, Augustin M, Kapp H. Enzymatic versus autolytic debridement of chronic leg ulcers: a prospective randomised trial. J Wound Care 2005;14(7):320-3
The efficacy of two debriding approaches for chronic leg ulcers were compared in this study. The two approaches were TenderWet 24, an autolytic degradation treatment (n=15), and Iruxol N (Santyl), an enzymatic approach (n=27). The authors were unable to recruit 29 subjects per group, the sample size required to detect 30% superiority. Therefore, the difference between the two products was not statistically significant. This article illustrates some of the difficulties researchers face in trying to compare the effectiveness of wound care products.
40	Causes for onset of chronic wounds	Quality Indicator	Type: Narrative Review
Chen WY, Rogers AA. Recent insights into the causes of chronic leg ulceration in venous diseases and implications on other types of chronic wounds. Wound Repair Regen. 2007 Jul-Aug;15(4):434-49.
This publication provides an exemplary summary of the cause-effect relationship between venous insufficiency and chronic wounds. It then proceeds to examine the correlation between this relationship and other types of chronic wounds. It is an effective publication in examining the causes of onset of chronic wounds.
41	Surgery in the treatment of venous leg ulceration	Quality Indicator	Type: RCT
Barwell JR, Davies CE, Deacon J, Harvey K, Minor J, Sassano A, Taylor M, Usher J, Wakely C, Earnshaw JJ, Heather BP, Mitchell DC, Whyman MR, Poskitt KR. Comparison of surgery and compression with compression alone in chronic venous ulceration (ESCHAR study): randomised controlled trial. Lancet. 2004; 363(9424):1854-9.
The purpose of this study was to compare surgical and non-surgical treatment strategies, based on the ability to promote ulcer healing and prevent recurrence. Based on the results, healing rates were not affected by the implementation of surgical treatment. Recurrence rates, however, decrease significantly if surgical treatment is employed (p
42	Surgery in the treatment of venous leg ulceration	Quality Indicator	Type: RCT
Gohel MS, Barwell JR, Taylor M, Chant T, Foy C, Earnshaw JJ, Heather BP, Mitchell DC, Whyman MR, Poskitt KR. Long term results of compression therapy alone versus compression plus surgery in chronic venous ulceration (ESCHAR): randomised controlled trial. BMJ. 2007; 335(7610):83.
The purpose of this study was to compare surgical and non-surgical treatment strategies, based on their ability to prevent recurrence of leg ulcers. Through a comparison of compression alone versus compression and saphenous surgery, it was demonstrated that the surgical approach decreases recurrence of leg ulcers and increases ulcer-free time. Therefore, the study suggests that venous surgery can be implemented in most treatment approaches for venous ulcers.
43	Electrical Stimulation	Quality Indicator	Type: RCT
Houghton PE, Kincaid CB, Lovell M, Campbell KE, Keast DH, Woodbury MG, Harris KA. Effect of electrical stimulation on chronic leg ulcer size and appearance. Physical Therapy 2003;83(1):17-28.
High-Voltage Pulsed Current (HVPC) applied to chronic leg ulcers reduced the wound surface area over the 4-week treatment period to approximately one half the initial wound size, which was over 2 times greater than that observed in wounds treated with sham units. The rate of wound closure was appropriately twice that observed in wounds treated identically with sham HVPC.
44	Therapeutic Ultrasound	Quality Indicator	Type: Systematic review
Al-Kurdi D, Bell-Syer SEM, Flemming K. Therapeutic ultrasound for venous leg ulcers. Cochrane Database of Systematic Reviews 2008, Issue 1. Art. No.: CD001180. DOI: 10.1002/14651858.CD001180.pub2.
Ultrasound may increase healing of venous leg ulcers, however due to the poor quality of the studies included in the review these results need to be interpreted with caution.