Evaluation and management of chronic venous insufficiency including venous leg ulcer

INTRODUCTION — Chronic venous disease (CVD) includes all manifestations of venous disease, while the term chronic venous insufficiency (CVI) is used for the advanced stages of CVD, with manifestations that include pitting edema, skin changes, and chronic venous wounds (ie, ulcers). Chronic wounds are characterized as those that are "refractory and do not heal in the projected time frame, often physiologically impaired due to an underlying pathology" as compared with acute wounds that undergo a process of predicted wound healing [1]. Venous leg ulcer (VLU) is the most common chronic wound, accounting for approximately 70 percent of lower extremity wounds [2].

The evaluation and management of CVI, including VLUs, are reviewed. The clinical features and classification of CVD and management of mild-to-moderate CVD including varicose veins are reviewed separately. (See "Clinical manifestations of lower extremity chronic venous disease" and "Classification of lower extremity chronic venous disorders".)

GENERAL CONSIDERATIONS

●Prevalence – The prevalence of VLU is estimated to be about 4 percent of the population [3]. VLUs are associated with prolonged disability, burdened socioeconomic impact, and significant psychosocial morbidity due to recurrence rates as high as 66 percent at five years [4]. (See "Overview of lower extremity chronic venous disease", section on 'Epidemiology and risk factors'.)

●Pathophysiology – CVI is the result of a complex interplay between genetic and environmental factors, causing abnormalities in the venous macrovasculature, microvasculature, skin, and soft tissue, often complicated by chronic infection and inflammation. Venous macrovascular abnormalities (valvular and wall changes) cause venous hypertension, while microvascular abnormalities (capillaries, postcapillary venules, and lymphatics) can trigger local inflammation, causing damage to the interstitial and surrounding skin and soft tissue. Risk factors for venous hypertension include family history, obesity, female sex, history of deep venous thrombosis, increasing age, pregnancy, prolonged standing, and taller stature [5-7]. (See "Overview of lower extremity chronic venous disease", section on 'Epidemiology and risk factors'.)

Venous hypertension, the underlying cause of CVI and VLUs, can be due to intravascular and/or extravascular etiologies [8].

•Intravascular causes – Intravascular causes for venous hypertension are often due to valvular reflux. Reflux can occur due to primary valve damage, or secondary causes such as post-thrombotic syndrome (PTS) following deep vein thrombosis, vascular tumors, or vascular malformations (eg, Klippel-Trenaunay syndrome). The resulting valvular reflux causes venous hypertension in the legs, especially near the ankles, which are the most dependent and most affected area for increased pressure. A venous thrombotic event can also cause damage within the vein walls with scarring that may result in PTS and outflow obstruction, resulting in venous hypertension.

•Extravascular causes – Extravascular causes for venous hypertension include increased central pressures (obesity, right heart failure, pelvic congestion), anatomic compression (May-Thurner syndrome, Nutcracker syndrome), tumor compression, foot and calf muscle pump dysfunction, dependent edema due to motor disorders (sedentary state, arthritis, other immobility), and lymphedema. The mere existence of venous hypertension in these cases does not necessarily cause venous ulcers but is often triggered by inciting factors such as pressure, inflammation (cellulitis), or trauma.

●Ulcer development – As the most distal aspect of the extremity, the gaiter area of the leg, ankle, and foot are the locations where hydrostatic pressure builds up due to column height and gravity. As a result, there is an increase in ambulatory venous pressures, which triggers cytokines expressed by leukocytes, triggering inflammation within the vein wall. The extravasation of inflammatory cells/molecules additionally activates matrix metalloproteinases, leading to extracellular matrix degeneration. Eventually, this cascade of inflammatory responses leads to skin changes, and if the venous hypertension and associated inflammatory response meets a critical threshold, VLUs will result [5,9]. (See "Pathophysiology of chronic venous disease".)

PTS predicts an increased risk for VLUs. The pathophysiology behind PTS is likely due to the resulting venous hypertension from a venous thrombotic event. Venous hypertension results from both the acute obstruction and from the chronic scarring and destruction of the valves and vessel wall leading to pathologic reflux [10]. The presence of VLUs represent the severest form of PTS. Preexisting venous disease, diabetes, and male sex have all been demonstrated to be independent predictors for development of VLUs in PTS [11]. (See "Post-thrombotic (postphlebitic) syndrome".)

CLINICAL EVALUATION — A thorough medical history, history of symptoms, and physical examination must be undertaken to properly identify venous hypertension as a contributing etiology to the patient's symptoms. Symptoms of venous hypertension may include leg heaviness, fatigue, and throbbing, which can be relieved by leg elevation and compression. A comprehensive physical examination should also include assessment of the limb, including the presence and severity of edema (unilateral, bilateral), and evaluation of the condition of the skin, including a specific assessment of VLUs.

The history should include details on venous insufficiency, prior venous thromboembolism, diabetes, peripheral artery disease, chronic kidney disease, autoimmune disorders, connective tissue disease, and medications. It is also essential to note the onset and chronicity of any ulcers, including previously attempted treatment modalities.

The patient's social history should include questions specifically focusing on VLU. Occupation and postural positions throughout the day (eg, prolonged standing or sitting or sleeping with legs in a dependent position worsens leg swelling) are important to note. Ambulatory status, exercise habits, changes in weight, use of compression hosiery and garments, ability to perform dressing changes, and access to care are all important social factors affecting VLU healing. Older adult patients and patients with obesity often have difficulty reaching their lower legs, making self-care and compression therapy routines difficult, which are factors that can affect the treatment plan [12].

Edema — Venous edema can present unilaterally if there is significant venous disease in just one lower extremity (eg, trauma, congenital abnormalities). However, for any patient presenting with bilateral edema, it is important to note their ambulatory status and examine ankle and foot mobility. Weak calf muscle function and limb dependancy contribute to swelling. Dorsal foot swelling and a positive Stemmer sign (inability to pinch the dorsal finger or toe) are indicative of lymphedema, which can also contribute to limb swelling in patients with CVI (ie, phlebolymphedema) [12]. (See "Clinical features and diagnosis of peripheral lymphedema", section on 'Clinical features'.)

Skin changes — Prolonged venous hypertension predisposes to scaly, cracked, oozing, and itchy skin (stasis dermatitis), and this can cause recurrent cellulitis with erythema and induration around the gaiter area. Notable skin changes include brawny skin, hemosiderin staining causing hyperpigmentation, and lipodermatosclerosis, which causes hardening of the skin, often with a bark-like shiny appearance (picture 1). Painful, polyangular, ivory-white depressed atrophic plaques with prominent erythematous dots within the scar are commonly seen in CVI, and are called atrophie blanche (picture 2). Prominent dilated reticular veins around the ankles known as corona phlebectatica (picture 1) are additional signs of advanced venous disease [13].

Skin hardening can cause a stricture around the ankle, causing tapering of legs above the ankles resembling an inverted champagne bottle (picture 3), making adequate compression in this area difficult.

Venous leg ulcer — The Society for Vascular Surgery (SVS) and American Venous Forum (AVF) 2014 consensus statement suggests using a standard definition of a VLU as "an open skin lesion of the leg or foot that occurs in an area affected by venous hypertension" [8].

VLUs most commonly occur on the medial lower half of the leg, above the medial malleolus in the gaiter area, but can occur on the posterior lateral side of the lower leg and on the dorsum of the foot as well.

Wounds vary from small, isolated wounds to multiple wounds or circumferential wounds, and often recur. Wounds are usually limited to full-thickness skin breakdown and do not extend to the muscle or deeper structures. These wounds can drain heavily, leading to further skin irritation and maceration if swelling is not adequately controlled.

Associated cellulitis or wound infection should be identified and treated when present. Routine culture of VLUs is unnecessary and should only be obtained if clinical evidence of infection is present [8]. (See 'Antimicrobial therapy' below and "Acute cellulitis and erysipelas in adults: Treatment".)

DIAGNOSTIC EVALUATION — CVI as the cause for leg ulceration can often be established based on history and clinical features; however, a history and physical exam alone are often insufficient to establish a venous etiology and reliably rule out other potential causes or contributing factors to a leg ulcer.

Clinical Practice Guidelines for the management of VLU from The Society for Vascular Surgery (SVS), in conjunction with the American Venous Forum (AVF; endorsed by the American Venous and Lymphatic Society [AVLS]), specifically recommend as a "best practice" comprehensive evaluation of a patient presenting with a leg wound to identify the presence of venous disease as well as any other medical conditions that might be contributing to the wound and/or affect healing [8].

Appropriate evaluation of any lower extremity wound is essential to identifying potential vascular etiologies, as well as directing the treatment plan to optimize healing. Over 50 percent of all lower extremity ulcers have a vascular source (venous, arterial, or both) [14]. Many patients with ulcers have mixed venous and arterial or other pathology that can contribute to poor wound healing. Mixed-etiology ulcers have a different rate of healing compared with purely venous ulcers, and each etiology must be appropriately evaluated and specifically treated for healing to occur and to limit recurrence. For patients with diminished or nonpalpable pedal (anterior tibial, posterior tibial) pulses, noninvasive arterial studies (ankle-brachial indices [ABIs] and/or duplex ultrasound) should be performed. (See 'Noninvasive arterial examination' below.)

Lymphedema may also contribute to nonhealing ulcerations and should be suspected in patients with nonpitting edema or a positive Stemmer sign. Rarer causes of nonhealing ulcers include medication use (eg, hydroxyurea, coumarin, steroids), infection, vasculitis, pyoderma gangrenosum, calciphylaxis, hematologic disorders (eg, sickle cell anemia, polycythemia vera), rheumatologic diseases (eg, rheumatoid arthritis, lupus), and malignancy. The differential diagnosis of VLU is encompasses a variety of etiologies. These are reviewed separately. (See "Approach to the differential diagnosis of leg ulcers".)

Venous imaging — A comprehensive physiologic venous duplex ultrasound is the preferred first-line imaging in patients with CVI, particularly with a suspected VLU [8]. The SVS has endorsed the Intersocietal Accreditation Commission (IAC) recommendations for noninvasive vascular testing [15]. The IAC guidelines for the performance of peripheral venous testing recommend assessing the patient in the dependent position (standing when possible) [16]. All deep, superficial, and perforator veins in the lower extremity should be assessed for patency and reflux. Attention should be taken to perforating veins in the vicinity of the ulcer bed. When reflux is demonstrated, it can contribute to persistent ulceration and VLU recurrence. Comprehensive evaluation of all pathologic venous disease in the lower extremity is important to determine potential treatment options that not only facilitate healing of the VLU but also prevent recurrence [17,18]. Venous stenosis/obstruction cranial to the inguinal ligament may be suspected based on ultrasound findings. Advanced venous imaging may be needed to identify iliocaval venous pathology that is contributing to venous hypertension in the affected extremity. Up to 40 percent of patients with VLUs will have some degree of proximal obstructive pathology [19]. (See "Diagnostic evaluation of lower extremity chronic venous disease", section on 'Other studies'.)

Noninvasive arterial examination — In addition to a thorough venous evaluation, arterial pulse examination combined with determination of the ABI should be performed on any patient presenting with a lower extremity wound to identify significant arterial disease [8]. Up to 20 percent of patients with lower extremity wounds will have arterial insufficiency [20,21]. Any identified abnormality should prompt a referral to a vascular specialist for further evaluation and possible treatment, as adequate arterial perfusion is necessary for healing. An ABI ≤0.9 at rest is considered the cutoff measurement for a diagnosis of peripheral artery occlusion [22]. (See "Noninvasive diagnosis of upper and lower extremity arterial disease", section on 'Ankle-brachial index'.)

Clinical classification — Chronic venous disease (CVD) should be accurately and comprehensively classified using the CEAP (Clinical-Etiology-Anatomy-Pathophysiology) classification, which is the most widely recognized and used classification for venous disease [23,24]. The clinical signs are categorized into classes from C0 to C6 (table 1). Severe CVD is classified as CVI and includes C4 to C6. (See "Classification of lower extremity chronic venous disorders".)

In addition to the CEAP classification, the venous clinical severity score can be used adjunctively for outcomes assessments (calculator 1) [25-27]. Furthermore, given the high prevalence of post-thrombotic syndrome in patients with VLUs, it is also prudent to use the Villalta score (calculator 2) to aid in diagnosis and prognosis in this high-risk patient population [28,29]. (See "Classification of lower extremity chronic venous disorders", section on 'Measures of clinical severity'.)

MEDICAL MANAGEMENT — Appropriate treatment of patients with CVI including VLU involves compression therapy and other measures to reduce edema, counteract venous hypertension, and increase venous blood return [30], as well as venous interventions to treat the underlying venous pathology, prevent worsening venous hypertension, and reduce ulcer recurrence. In addition to debridement of any nonviable or infected tissue and other local wound care, we recommend compression therapy, which is the standard first-line clinical treatment for patients with CVI and imperative to initiate in patients with VLU [31].

Leg elevation plays an important role in reducing edema, especially for patients who are not ambulatory [32]. Improved muscle tone and calf pump functioning can help decrease venous pressure and edema. As such, supervised exercise programs to increase physical activity focused on foot and calf mobility can be tried, and in some studies, have decreased the duration of venous ulcers by reducing lower extremity edema [33,34].

Many patients with CVI and associated edema present concomitantly with lymphedema. As with CVI, compression therapy continues to be the mainstay of lymphedema, but often the addition of lymphatic massage can help reduce lower extremity swelling that contributes to persistent ulcerations [35]. (See "Clinical staging and conservative management of peripheral lymphedema", section on 'Compression therapy'.)

Diuretics have no role in treating edema due purely to venous insufficiency. Diuretics are often prescribed for lower extremity edema but should only be used as indicated to treat other conditions (eg, heart failure) that may coexist with venous insufficiency.

Compression therapy — Compression therapy continues to be the mainstay of edema reduction, improving hemodynamics to decrease venous hypertension, which improves wound healing and decreases recurrence [36]. Randomized trials and systematic reviews have repeatedly demonstrated the benefits of long-term compression therapy (stockings or bandages) in patients with CVI [37-39]. In a systematic review and meta-analysis among five trials, time to complete healing of VLUs was less for those wearing compression bandages or stockings compared with those not wearing compression (pooled hazard ratio 2.17, 95% CI 1.52 to 3.10) [37]. Among 10 trials, complete ulcer healing within 12 months was increased in patients treated with compression bandages or stockings compared with people with no compression (risk ratio 1.77, 95% CI 1.41-2.21). Among patients who are compliant with therapy, VLU healing rates as high as 97 percent can be achieved [40]. Patients with edema, weeping, or skin changes in the absence of ulceration also benefit. Systematic reviews have also concluded that multicomponent systems are more effective than single component systems, and elastic therapies are favored over nonelastic treatment. While active infections including cellulitis are contraindications to compression therapy, the incidence of recurrent cellulitis may be reduced for those who are compliant with compression therapy [41]. For patients with mixed arterial and venous disease, compression stockings should not be used if the ankle-brachial index is 0.5 or less or if absolute ankle pressure is less than 60 mmHg [8].

●Static compression – Initial compression therapy involves static compression. Static compression is accomplished by creating a pressure gradient or graded compression starting from the foot and moving proximally up the leg.

•Compression hosiery – Compression stockings or compression hosiery are the most standard form of compression therapy and can be obtained over the counter or by prescription. Prescription compression hosiery specifies the level of compression (table 2) and the length of the stocking (knee high, thigh high, pantyhose). These stockings are fitted to the individual, ideally measured early in the day before venous edema worsens. Compression >30 mmHg is typically needed for treatment of VLUs with 30 to 40 mmHg and 40 to 50 mmHg as the most common levels. Compression >50 mmHg is typically reserved for patients with severe lymphedema superimposed on CVI. A typical prescription for medical-grade compression hosiery written for patients with VLU is full foot, knee high, 30 to 40 mmHg. For patients with toe deformities, open toe versions are available. In addition, if a patient does not have the strength or dexterity to pull on a stocking, zippered stockings are available. A disadvantage of compression hosiery for patients with VLU is that the ulcer typically drains a considerable amount of fluid throughout the day, which is often impractical for a reusable stocking. (See "Compression therapy for the treatment of chronic venous insufficiency", section on 'Compression hosiery'.)

•Compression bandaging – Compression bandage systems can provide a similar amount of graduated compression with the added benefit of absorption of drainage. In addition, they are often changed as infrequently as weekly, which can benefit patients with complex wounds. There two types of compression bandages are inelastic and elastic systems. (See "Compression therapy for the treatment of chronic venous insufficiency", section on 'Compression bandages'.)

-Inelastic compression – Inelastic compression works when a patient is ambulatory, as high pressure is applied when the calf muscles contract, augmenting the calf muscle pump. While inelastic compression systems lose pressure over time, these dressings can provide a positive benefit for up to one week [42]. The most common system is the Unna boot, which is an inelastic moist bandage impregnated with zinc oxide (alternatively calamine) that hardens after application. It does not change size as the leg changes in volume throughout the day. Typically, three or four layers are applied. It can be left on up to one week or changed more frequently with increased drainage. (See "Compression therapy for the treatment of chronic venous insufficiency", section on 'Unna boot'.)

-Elastic compression – There are a variety of elastic compression wraps that can be used, including long stretch elastic wraps, self-adherent compression bandages, short stretch bandages, and multilayer bandage systems. The most effective are the multilayered bandage systems. These are typically applied in two or four layers. The inner layer is a cotton wool absorbent layer followed by one to three elastic layers. Compared with the Unna boot, these bandages do conform to the leg size and maintain compression at rest [43]. They can also be left on up to one week, depending on the volume of drainage. (See "Compression therapy for the treatment of chronic venous insufficiency", section on 'Multilayer compression bandages'.)

●Dynamic compression therapy – Dynamic compression therapy, also known as intermittent pneumatic compression (IPC), is an alternative strategy for patients who cannot tolerate static compression [8], but offers limited evidence-based benefit in ulcer healing [44]. IPC uses a plastic air cylinder that is circumferentially wrapped around the leg. These cylinders are periodically inflated to a specific pressure and then rapidly deflated. The most effective systems are those with rapid cycles and multichamber systems with graduated compression up the leg. Typically, patients undergo therapy for a minimum of four hours a day with this strategy. Patients may benefit from IPC if traditional compression is not an option [45]. These patients typically have risk factors including severe obesity, severe edema, lipodermatosclerosis, and superimposed lymphedema. (See "Compression therapy for the treatment of chronic venous insufficiency", section on 'Dynamic compression therapy'.)

Ulcer care — In addition to providing appropriate compression therapy and local treatment using basic wound care techniques (debridement, dressings), adjuvant treatment options to limit bacterial overgrowth, inflammation, and tissue death may improve healing rates and also addresses problems that affect the patient's wellbeing, such as odor, bleeding, itching, excess exudate, and pain [46]. VLUs that do not show improvement after optimization of venous hypertension and maximizing wound care should be re-evaluated for other contributing factors to nonhealing [47].

Debridement and dressings — Wound debridement, which removes necrotic tissue, bacterial burden, and cellular byproducts, is an essential component in the management of VLUs. The presence of devitalized tissue increases the risk for local bacterial infection and reduces wound healing rates. VLUs should undergo initial debridement followed by routine debridement, as needed, at each dressing change. While debridement is well supported for all wounds (not just venous wounds) with few exceptions, for venous wounds, studies have repeatedly shown that debrided wounds heal significantly faster than nondebrided wounds [48-51]. (See "Basic principles of wound management", section on 'Wound debridement'.)

Topical or local injection of an anesthetic agent can be used to minimize pain associated with surgical debridement [8]. In a systematic review of six trials (343 participants), the between-group difference in pain measured on a 100 mm scale significantly favored the EMLA group (mean difference -20.65, 95% CI -29.11 to -12.19) [52].

Providers can choose from a variety of debridement methods, and although more than one debridement method may be appropriate to care for a VLU, surgical debridement (preferably sharp debridement or alternatively using hydrosurgical methods) is often favored over nonsurgical methods, especially at the initial encounter. Biologic debridement (ie, larval therapy) is an alternative to surgical debridement. Enzymatic debridement can generally be reserved for situation when preferred methods are not available [8]. In a systematic review that compared various autolytic agents (three trials) for the debridement of VLUs, hydrogel, Edinburgh University Solution of Lime (EUSOL), and biocellulose, no agent was identified as superior to another [53].

VLUs should be assessed regularly to determine need for repeated debridement. Many wound centers recommend weekly cleansing and debridement, but the interval is often based on the frequency of dressing changes. Wounds should be cleaned with nonirritating and neutral solutions to limit chemical trauma [8,54].

Dressings are an important component of ulcer care. The dressing should maintain fluid balance controlling exudate while maintaining a moist, wound healing environment and protect the periulcer skin [8]. In addition, dressings control odor and help control pain. A moist wound environment accelerates re-epithelialization, promotes angiogenesis, and is essential for wound healing [55]. However, due to the venous hypertension, most venous ulcers produce large amounts of exudate, which in many cases can be problematic. Dressings should thus effectively manage wound exudate and should be prioritized to reduce inflammation and promote expedited wound healing [56]. The surrounding skin of the venous ulcer should also be kept dry to avoid maceration [57]. (See 'Adjacent skin care' below.)

No one dressing type has proven superior over another for the treatment of VLU [58-63]. Dressings are characterized by their composition and properties (eg, adherence, absorbency, conformability) and are tailored to the characteristics of a particular ulcer (eg, wound drainage, infection), frequency of dressing changes, and cost (table 3 and table 4) [64-68]. In practice, several different dressings are used while caring for a VLU. Frequency of dressing changes should be based on absorptive capacity; if the dressing is saturated at any point, replacement is warranted (table 3 and table 4) [69,70]. (See "Basic principles of wound management" and "Overview of treatment of chronic wounds".)

Topical agents — Topical agents are used selectively (eg, hydrogel with or without silver, collagenase [enzyme], honey, topical antibiotics ) to manage bioburden or residual necrotic tissue; however, some topical agents are irritating and can cause contact sensitization, or are cytotoxic (eg, silver sulfadiazine, antiseptics), resulting in delayed healing [53,71-73].

Allergic contact dermatitis can develop from sensitization to a variety of products used in the treatment of stasis dermatitis and venous ulceration; thus, avoidance is the main preventive measure. (See "Irritant contact dermatitis in adults", section on 'Management' and "Management of allergic contact dermatitis in adults".)

Contact sensitization occurs more readily in areas of stasis dermatitis. The routine use of systemic or topical antimicrobials may also increase the incidence of contact dermatitis [74-76]. Contact dermatitis in patients with CVI is common and may be difficult to diagnose without a high index of suspicion since it often mimics stasis dermatitis or cellulitis. Symptoms include redness, pruritus, and vesicle or bullae formation. The patient with contact dermatitis does not typically experience a dramatic clinical worsening, but rather a failure to improve with treatment. Some patients develop an eczematous rash in other areas of the body, a form of "id" or autoeczematous reaction. Contact dermatitis may also be a direct trigger to development of an ulcer in patients with CVI [77]. (See "Stasis dermatitis", section on 'Contact sensitization' and "Stasis dermatitis", section on 'Autosensitization (autoeczematization)'.)

Skin substitutes and skin grafts — Skin substitutes and skin grafts should not be used as a primary therapy in the treatment of VLUs. However, they may play an adjunctive role for managing large venous wounds that have failed to heal after maximizing medical care after a period of four to six weeks [8,12,78-84]. Wounds should be appropriately debrided, exudate should be at a minimum, and bacterial overgrowth under control prior to using a skin substitute. Split-thickness skin grafting is generally not recommended as first line treatment for VLUs but may be considered after standard of care has failed, for large soft tissue defects, or based on the patient's or clinician's preference. (See "Skin substitutes".)

Adjacent skin care — Periulcer skin management is often as important as management of venous ulcer. The venous hypertension surrounding the ulcer causes a significant inflammatory response with cytokines and proteases, making the periulcer skin vulnerable to dermatitis, irritation, etc. Recognizing skin changes around the venous ulcer is necessary to prevent expansion [85,86].

Stasis dermatitis manifests as a combination of pruritus, skin color changes due to hemosiderin deposition, erythema, and scaling and is often seen with advanced venous disease (Clinical-Etiology-Anatomy-Pathophysiology [CEAP] category 4 or higher). Itching may be intense, and sometimes blistering and oozing occurs. For areas of chronic dryness, a petroleum-based emollient can be used. Symptoms of oozing or vesiculation may require treatment of the involved areas with midpotency topical corticosteroids. (See "Clinical manifestations of lower extremity chronic venous disease" and "Stasis dermatitis", section on 'Skin care' and "Topical corticosteroids: Use and adverse effects".)

Systemic therapies

Anti-inflammatory and antithrombotic agents — Several systemic drugs focusing specifically on venous ulcer healing have been tested. Due to the inflammatory consequences of venous hypertension and ulcer formation, many anti-inflammatory drugs have had promising potential in improving venous ulcer healing. Unfortunately, steroids (ie, stanozolol), aspirin, ifetroban, and others have failed to show benefit in ulcer healing compared with placebo [87,88].

●Micronized purified flavonoid fraction – Micronized purified flavonoid fraction (MPFF) interacts with leukocyte activation and has demonstrated a significantly accelerated healing of venous ulcers. MPFF has also improved other venous symptoms outside of venous ulcers, but unfortunately is not available in the United States [36,47].

●Aspirin – Aspirin has been recommended as an inexpensive, universally available therapy for healing of venous ulcers, reduction in healing time, or reduction in ulcer size. However, randomized trials and systematic review have not verified earlier studies [89-92]. As such, there is no support for the use of aspirin with the aim of improving healing of venous ulceration, or at best, there is insufficient evidence to detect either a beneficial effect or even harm associated with aspirin therapy.

●Pentoxifylline – The use of pentoxifylline in venous ulcers has shown promising results, but it is not widely used in clinical practice for VLU unless there is another etiology that may be contributing to compromised microcirculation. The drug's mechanism of action inhibits cytokine-mediated neutrophil activation, oxidative stress, and adhesion to endothelium. Its anti-inflammatory effects, combined with compression, have been reproducibly shown to significantly improve ulcer healing [93-95]. In a meta-analysis that evaluated 11 trials of variable quality, complete or partial ulcer healing was significantly improved for pentoxifylline compared with placebo or no treatment (relative risk 1.7, 95% CI 1.3-2.2) [94]. Pentoxifylline used as an adjunct to compression was more effective than without compression. When used without compression, it was more effective than placebo or no treatment at a dose of 800 mg three times a day [96]. Gastrointestinal side effects (nausea, indigestion, diarrhea) were relatively common in patients treated with pentoxifylline.

Antimicrobial therapy — Clinical signs of infection beyond the wound bed should be treated with systemic antibiotics. However, there is no evidence to support the routine use of systemic antibiotics to promote healing in VLUs [71,72]. In addition, while treatment of colonized bacteria in the wound bed has varied, there is a lack of evidence to suggest any benefit for topical antibiotics for VLUs [38,58,74-76].

The presence of infection may impede VLU healing. The following signs and symptoms suggesting significant infection:

●Local heat and tenderness

●Increasing erythema of the surrounding skin

●Lymphangitis (red streaks traversing up the limb)

●Rapid increase in the size of the ulcer

●Fever

When infection is suspected clinically, a tissue specimen should be sent for gram stain, culture, and sensitivity to confirm infection and to guide selection of antimicrobial therapy. The ulcer is irrigated to remove surface debris, and then a tissue specimen is obtained by biopsy from the base of the ulcer and sent for culture. Some practitioners inject sterile saline (1 to 2 mL) into the dermis surrounding the ulcer and then quickly withdraw the fluid, which is sent for culture. Systemic antibiotics are warranted for patients with >100,000 colonizing forming units (CFU)/g in the wound bed and with clinical evidence of infection. Lower CFU/g thresholds may justified for more virulent bacteria (eg, pseudomonas, beta-hemolytic streptococci) [97].

Cellulitis treatment should be directed at gram-positive bacteria, and if resistant, expanded to broader coverage [98]. The duration of antibiotic therapy for VLU infection should be limited to two weeks unless persistent evidence of wound infection is present [8]. Patients with rapidly progressing infections, particularly if associated with fever and other signs of systemic toxicity, should be hospitalized, and receive intravenous antibiotics with broad coverage. Patients with are more prone to develop rapidly progressive infections. (See "Acute cellulitis and erysipelas in adults: Treatment".)

Ineffective adjuncts — Hyperbaric oxygen is not approved for the treatment of VLUs. A systematic review of hyperbaric oxygen therapy in patients with chronic wounds found only one trial of 16 participants with venous ulcers [99]. A decreased wound size was found at six weeks, but no difference in wound size or number of ulcers healed was apparent at 18 weeks. A subsequent trial analyzed complete ulcer healing of chronic nonhealing venous ulcers characterized by transcutaneous oxygen measurements indicative of a hypoxic wound [100]. Thirty-one patients were randomly assigned to hyperbaric oxygen therapy or sham treatment. At 12 weeks, there was no significant difference between groups in complete ulcer healing. Other tried but ineffective therapies include electrical stimulation, electromagnetic therapy, and therapeutic ultrasound.

VENOUS INTERVENTION

Goals and efficacy — While compression therapy is a critical first step in VLU healing, when indicated, many patients with CVI can be treated using venous ablation therapies, which improves ulcer healing and lowers rates of recurrence [8]. Patients with primary venous etiologies achieve more benefit compared with secondary etiologies (ie, post-thrombotic) [101]. For patients with VLUs who are candidates for intervention, we suggest earlier (within two weeks of ulcer treatment) venous intervention (superficial venous ablation, perforator ablation) rather than later intervention. The United Kingdom Early Venous Reflux Ablation (EVRA) trial provided support for early (within two weeks versus once the ulcer has healed) endovenous ablation of superficial venous reflux in addition to compression therapy and appropriate wound care [102,103]. Early intervention reduced time to ulcer healing and more patients healed their ulcers. Thus, sooner rather than later referral to a venous specialist for patients with a venous ulcer is appropriate. (See "Approach to treating symptomatic superficial venous insufficiency".)

The key to venous intervention is to definitively treat any refluxing axial veins, associated pathologic perforator veins, or associated varicose veins. Typically, in extremities with skin changes or VLUs, there are multiple incompetent veins, so therapy is targeted toward the veins directly contributing to the ulcer as well as those pathologically contributing to overall venous hypertension of the lower extremity.

Often, repeat reflux studies are necessary if healing stagnates despite successful procedural intervention, adequate wound care, and compliance with compression. This may reveal an inadequately treated segment, associated perforator veins, or varicosities associated with the ulcer that require additional interventions.

Superficial axial venous reflux — Superficial axial venous ablation has been evaluated for the treatment of VLUs and for prevention of VLU recurrence. By ablating or removing incompetent superficial veins, treatment is thought to produce beneficial effects by reducing venous reflux from the deep to the superficial veins, thereby modifying the effect of venous hypertension on the cutaneous tissues [104].

Options for superficial axial venous ablation include endovenous and surgical methods. Surgical treatment has largely been replaced by minimally invasive endovenous techniques. Endovenous techniques are classified by their method of vein ablation: thermal or nonthermal. A general comparison of thermal and nonthermal ablation techniques can be found in the table (table 5) and associated topics. (See "Comparison of methods for endovenous ablation for chronic venous disease".)

Thermal ablation techniques are an effective method to close incompetent axial veins. Thermal damage to the vein endothelium is induced by heating the inside of the vein, leading to permanent vein closure [105]. Given the heat that is produced, tumescent anesthesia (saline, lidocaine, epinephrine) is required to prevent unintended thermal damage to the surrounding soft tissue, nerves, and skin. The two common techniques for thermal ablation are radiofrequency ablation and endovenous laser ablation, which produce similar results [106-108]. Techniques are reviewed separately. (See "Techniques for radiofrequency ablation for the treatment of lower extremity chronic venous disease" and "Techniques for endovenous laser ablation for the treatment of lower extremity chronic venous disease".)

For patients with VLU, it can be difficult to administer adequate tumescence around the area of the ulcer due to the quality of the skin. In addition, if reflux is present to the ankle, often a portion of the refluxing vein is left untreated due to risk of thermal nerve injury. Nonthermal, nontumescent techniques provide a minimally invasive option that treats the entire length of the refluxing vein without the risk of thermal nerve or skin injury with a single access site. Techniques include cyanoacrylate adhesive closure (CAC), polidocanol endovenous microfoam (PEM), and endovenous mechanochemical ablation (MOCA). (See "Nonthermal, nontumescent ablation techniques for the treatment of lower extremity superficial venous insufficiency".)

For the treatment of VLUs:

●A multicenter retrospective cohort study demonstrated that CAC had a superior time to wound healing compared with radiofrequency ablation in patients with Clinical-Etiology-Anatomy-Pathophysiology (CEAP) category 6 venous disease [109].

●Retrospective reviews also demonstrated the efficacy of PEM for patients with CEAP 6 disease [110].

●MOCA uses mechanical injury at the saphenofemoral junction to close the vein and then distribute sclerosant distally to induce endothelial damage. MOCA also effectively ablates the vein of interest with low complication rates [111].

Pathologic perforating veins — Refluxing perforator veins delay ulcer healing and directly contribute to ulcer recurrence [18]. To adequately prevent ulcer recurrence, pathologic perforators should also be treated.

Many of the techniques used to treat the axial veins can be used to directly target perforator veins, including radiofrequency ablation and endovenous laser ablation. Foam sclerotherapy, often used to treat varicose veins (1% polidocanol mixed with CO² or air in 1:3 ratio using Tessari method), can also be injected directly into the perforator veins. Additional techniques that are used much less frequently include open ligation and subfascial endoscopic perforator ligation [112].

Iliocaval venous obstruction — For patients with post-thrombotic syndrome, there are limited data on the best treatment. Compression therapy and exercise may provide some benefit, but high-quality data are lacking [10,113]. Iliocaval recanalization with stenting has emerged in as a technically safe and effective method to relieve proximal obstruction and facilitate ulcer healing. (See "Endovenous intervention for iliocaval venous obstruction".)

ULCER RECURRENCE — The continued use of graduated compression hosiery after ulcer healing reduces recurrence, and patients should be offered the strongest compression (up to 40 mmHg) (table 2) with which they can comply [35,114]. In one study with 36-month follow-up, ulcers recurred in 100 percent of patients who were noncompliant versus 16 percent in those who were [40]. A later systematic review identified four trials comparing ulcer recurrence rates for patients treated with compression hosiery versus no compression [115]. One trial suggested that compression reduced venous ulcer recurrence compared with no compression (risk ratio 0.46, 95% CI 0.27-0.76). Two trials compared high compression with moderate compression; one found no difference in ulcer recurrence after five years, while the other found lower recurrence rates at three years using high-compression hosiery.

Patients with recurrent ulcers should undergo repeat venous duplex ultrasound to identify any additional segments with incompetence that may be contributing.

SOCIETY GUIDELINE LINKS — Links to society and government-sponsored guidelines from selected countries and regions around the world are provided separately. (See "Society guideline links: Chronic venous disorders".)

INFORMATION FOR PATIENTS — UpToDate offers two types of patient education materials, "The Basics" and "Beyond the Basics." The Basics patient education pieces are written in plain language, at the 5^th to 6^th grade reading level, and they answer the four or five key questions a patient might have about a given condition. These articles are best for patients who want a general overview and who prefer short, easy-to-read materials. Beyond the Basics patient education pieces are longer, more sophisticated, and more detailed. These articles are written at the 10^th to 12^th grade reading level and are best for patients who want in-depth information and are comfortable with some medical jargon.

Here are the patient education articles that are relevant to this topic. We encourage you to print or e-mail these topics to your patients. (You can also locate patient education articles on a variety of subjects by searching on "patient info" and the keyword(s) of interest.)

●Basics topics (see "Patient education: Varicose veins and other vein disease in the legs (The Basics)")

●Beyond the Basics topics (see "Patient education: Lower extremity chronic venous disease (Beyond the Basics)")

SUMMARY AND RECOMMENDATIONS

●Chronic venous insufficiency – Chronic venous disease (CVD) encompasses all manifestations of venous disease. The term chronic venous insufficiency (CVI) is reserved for advanced stages of CVD with manifestations that includes pitting edema, skin changes, and venous leg ulcers (VLUs). (See 'Introduction' above and 'General considerations' above.)

●Pathophysiology – CVI results from a complex interplay of genetic and environmental factors, causing abnormalities in the venous vasculature, soft tissue, and skin, often complicated by chronic inflammation and infection. Venous macrovascular abnormalities cause venous hypertension, while microvascular abnormalities trigger local inflammation. (See 'General considerations' above.)

●Clinical evaluation – Symptoms of CVI may include leg heaviness, fatigue, and throbbing, relieved by leg elevation. A comprehensive physical examination includes assessment of the limb including the presence and severity of edema (unilateral, bilateral); evaluation of the pulses, condition of the skin, and presence of stasis dermatitis; and assessment of any VLUs. It is essential to note the onset and duration of the ulcer, including previously attempted treatments. (See 'Clinical evaluation' above.)

•Stasis dermatitis – Stasis dermatitis manifests as a combination of pruritus, skin color changes due to hemosiderin deposition, erythema, and scaling, and is often seen in patients with CVI. Itching may be intense. (See 'Skin changes' above.)

•Ulceration – A VLU is defined as "an open skin lesion of the leg or foot that occurs in an area affected by venous hypertension." VLU accounts for approximately 70 percent of all lower extremity wounds. VLUs most commonly occur on the medial lower half of the leg, above the medial malleolus in the gaiter area, but can occur on the posterolateral leg or on the dorsum of the foot. (See 'Venous leg ulcer' above.)

●Diagnostic evaluation – CVI as the likely cause of skin changes or VLU can often be established based on history and clinical features; however, venous duplex ultrasound is necessary to identify venous obstruction and venous valvular incompetence. Advanced venous imaging may be needed to identify iliocaval venous obstruction that is contributing to venous hypertension in the affected extremity. Other studies may be necessary to help identify other pathologies that can contribute to poor wound healing (eg, peripheral artery disease, lymphedema, vasculitis, malignancy). For patients with diminished pedal pulses, we obtain noninvasive arterial studies. (See 'Diagnostic evaluation' above.)

●Management – Management of patients with CVI primarily involves leg elevation (when possible), compression therapy, and local care of VLU (algorithm 1). Contributing etiologies must also be appropriately evaluated and treated for healing to occur and to limit ulcer recurrence. (See 'Medical management' above.)

•Compression therapy – For patients with CVI associated with severe edema, weeping, eczema, recurrent cellulitis, or VLU, we recommend compression therapy (Grade 1B). Compression therapy improves hemodynamics to decrease venous hypertension, which improves VLU healing and decreases recurrence. Compression hosiery or compression bandaging systems (elastic or nonelastic) can be used. (See 'Compression therapy' above.)

•Local wound care – Ulcer treatment uses appropriate wound care and adjuvant treatments to improve healing rates and address problems that affect the patient's wellbeing (eg, odor, itching, excess exudate, pain). Periulcer skin management is also important in the management of VLUs. (See 'Ulcer care' above and 'Adjacent skin care' above.)

●Venous intervention – Thermal and nonthermal venous ablation techniques aim to reduce reflux contributing to venous hypertension. Treatment is targeted to superficial or perforator veins that are pathologically contributing to overall venous hypertension and to veins directly contributing to the skin changes of VLU. For patients with VLU who are candidates for intervention, we suggest earlier (less than two weeks of ulcer treatment) referral and venous intervention (superficial venous ablation, perforator ablation) rather than later referral (Grade 2C). Perforator ablation can be performed simultaneous with superficial venous ablation, particularly for healing VLUs, or following re-evaluation of perforator reflux after superficial venous ablation. (See 'Venous intervention' above.)