Tools
Venous Leg Ulcer
Introduction
Venous leg ulcers (VLUs) are late indicators of chronic venous insufficiency (CVI) and venous hypertension.[1][2][3][4] Calf muscle contraction and intraluminal valves promote prograde flow while preventing blood reflux in normal conditions.[5] However, when retrograde flow, obstruction, or both exist, chronic venous hypertension is responsible for the dermatologic and vascular complications that form a VLU (See Image. Venous Leg Ulcer).[6]
VLUs are a costly medical condition that greatly affects worldwide healthcare systems.[7][8][9] In the United States (US), the annual cost of Medicare and commercial insurance for caring for patients with VLU is $18,986 and $13,653, respectively.[10] Together, these represent an annual burden of $14.9 billion for the US payers, a considerable increase from a previous $1 billion estimate.[11] The situation may worsen as the aging, obese, and sedentary population increases globally, with an expected rise in the incidence of CVI and VLUs.[12]
Etiology
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Etiology
Although CVI is a well-known precipitant for VLU development, ulceration occurs rarely (5.1%) for unclear reasons.[13] CVI may develop due to blood reflux, obstruction, or both mechanisms, causing macro- and micro-circulatory dysfunction.[5] The increased intraluminal pressure causes protein extravasation and fibrin cuff formation, which impedes the diffusion of oxygen and growth factors and activates the inflammatory response.[14][15]
At a cellular level, mast cell degranulation, leukocyte recruitment, increased matrix metalloproteinase inhibitors, and prostacyclin, the acquisition of a non-contractile secretory phenotype by smooth muscle cells, and fibroblast differentiation into myofibroblasts participate in vein wall remodeling and varix formation. The proinflammatory microenvironment is maintained by M1 macrophages, mainly by releasing interleukin-1α, interferon-gamma, and transforming growth factor-beta 1. Chronic inflammation and incompetent blood flow favor thrombus formation, causing further fibrosis and valvular destruction.[16] Together, this inflammatory cascade of events impairs healing processes, which results in ulcer formation upon wounding.
Most risk factors for the development of VLUs are non-modifiable, and patients often present with more than 1. These involve a family history of CVI, advanced age, female sex, previous thrombosis or pulmonary embolism, multiparity, lipodermatosclerosis, and musculoskeletal and joint disease.[5][1] Modifiable risk factors such as obesity and sedentarism are also associated with venous disease.[17][18][19] Genetic traits may be an additional predisposing factor, presenting as an autosomal dominant trait with variable penetrance.[1][14] However, a specific gene or gene set has not been determined. Forkhead box C2, located on chromosome 16q24, is a candidate marker in subjects with varicose veins.[20]
Compared with healing VLUs, the gene expression profile of non-healing VLUs showed upregulation of secreted frizzled-related protein 4, branched-chain aminotransferase 1, dermatopontin, cytochrome P450, and 17 B hydroxysteroid dehydrogenase genes, which are involved in inflammation control, Wnt signaling, cell growth, extracellular matrix assembly, and steroidogenesis.[21][22][23][24] Conversely, collagen differentiation and epidermal repair genes such as collagen type 13α1, collagen 27α1, keratin 14, keratin 16, and heparin-binding epidermal growth factor were notoriously downregulated. Besides these, single nucleotide polymorphisms of high iron, ferroportin 1, and matrix metalloproteinase 12 indicate venous ulcer development susceptibility.[22][25][26] A gene expression study's results showed that VLUs treated with a bioengineered bilayered living cellular construct skin substitute displayed a shift from a chronic non-healing inflammatory profile to acute healing inflammation, highlighting the negative effects of chronic inflammation in wound healing.[27]
Epidemiology
VLUs are the most common type of chronic wound in the lower extremity.[28] There is an estimation that 1% to 3% of the older adult population is affected in the US and Europe.[29] An epidemiological survey from Asia, Eastern Europe, Latin America, and Western Europe showed that 2.21% of 99,359 patients with CVI had an active or healed VLU when visiting their primary care clinician for various reasons. Individual regional rates were reported at 1.27%, 2.87%, 3.97%, and 1.67%, respectively.[30] The overall incidence is higher for women than men, although the exact number is hard to establish as it depends on the cohort and place of study.[29][31] The average time from CVI diagnosis to ulceration is 5 years, according to the results from a 25-year population study.[32] Another study's results demonstrated that the 3-year risk for the first ulceration in people with CVI was 4.49%, ascending to 4.93% at the 5-year follow-up.[13]
Histopathology
Unless another diagnosis is suspected, a biopsy is not warranted.[33][34] If performed, specimens should be obtained from the wound edge and the base of the ulcer.
History and Physical
Identifying risk factors based on clinical history helps distinguish VLUs from other causes of non-healing wounds in the lower extremities. Patients with CVI and VLUs often refer to pruritus with or without a rash, aching pain in the gaiter area, evening pedal edema, and night cramps.[35][36] Early CVI physical findings must be identified on examination. The initial manifestations are telangiectases and reticular veins.[5] Varicose veins, brown-orange hyperpigmentation, chronic leg edema, stasis dermatitis, atrophie blanche, and lipodermatosclerosis are late indicators of venous insufficiency. VLUs typically affect the distal end of the legs over the medial aspect, appearing as shallow, irregular, well-defined ulcers with fibrinous material on the base.[37][38] The clinical, etiological, anatomical, and pathophysiological classification documents these findings for therapeutic and research purposes.[39] Other less-used instruments are the venous clinical severity score and the Widmer classification.[40][41]
Evaluation
Clinical assessment should describe the ulcer area, depth, edges, wound base, signs of infection, and peripheral skin changes.[33][42][34][42][34] Palpation of distal pulses and ankle-brachial pressure index (ABPI) are used to evaluate adequate arterial blood flow since approximately 20% of patients with VLU have coincident arterial disease. ABPI is obtained by dividing the systolic ankle pressure by the systolic arm pressure in the supine position. An ABPI greater than 1 to 1.3 is considered normal. Below this, cut-off values are used to classify disease severity and guide the appropriateness of compression therapy (see Table. Ankle-Brachial Pressure Index).[43] Paradoxically, an ABPI greater than 1.3 appears in patients with significant vascular calcification, indicating the need for urgent referral to a vascular specialist.[43]
Table. Ankle-Brachial Pressure Index
|
Ankle-brachial pressure index |
Arterial circulation |
Compression treatment |
|
Greater than 1-1.3 |
Normal |
Apply compression |
|
Equal to 0.8-1.0 |
Mild peripheral disease |
Apply compression with caution |
|
Less than or equal to 0.8-0.6 |
Significant arterial disease |
Use modified compression with caution and refer to a vascular specialist |
|
Less than 0.5 |
Critical ischemia |
Do not compress and urgently refer to a vascular specialist |
Color-flow duplex ultrasound is another inexpensive, non-invasive, and highly informative diagnostic test useful for superficial vein assessment.[34][44] The technique can identify thrombi presence and valve incompetence, declared when reflux time exceeds 0.5 seconds.[45] Computed tomography and magnetic resonance imaging are preferred for deeper vessels since they are often harder or impossible to evaluate with ultrasound. Phlebography, plethysmography, and phlebodynamometry are less used due to inferior accuracy and associated risks.[46][47]
Treatment / Management
The standard of care for VLUs relies on 2 strategies: compression therapy and direct wound management.[36] Reducing leg edema is crucial for the effectiveness of wound closure.[33] There are numerous conservative alternatives aimed at improving venous hypertension, such as medical compression, intermittent pneumatic compression (IPC), manual lymphatic drainage, and extracorporeal shockwave therapy. Compression therapy is the most practical, effective, and cost-conscious intervention for the treatment of VLUs.[6][34] This involves using various types of hosiery or bandages, which can be elastic, inelastic, single- or multi-layered.[48] Unlike inelastic wraps, elastic materials provide moldable compression during rest and physical activity.[49] According to a Cochrane review, multi-component, stretchy systems provide superior venous ulcer healing rates compared with single-layered systems.[50] Compression strength can be light (14 to 17 mm Hg), moderate (18 to 24 mm Hg), high (23 to 35 mm Hg), or extra-high (up to 60 mm Hg). High compression is the preferred strength and should reach the knee or higher.[34] Light, cautious compression can be used in mild or significant peripheral vascular disease cases, as the ABPI indicates.[43] Absolute contraindications for compression therapy include arterial occlusive disease, ABPI less than 0.5, serious uncontrolled high blood pressure, heart failure, suspected or documented thrombosis, extensive thrombophlebitis, and erysipelas.(A1)
IPC can be used in addition to compression therapy or in patients who are unable to tolerate the latter.[34] According to a systematic review, normal IPC and rapid IPC were superior to dressings and slow IPC delivery, respectively.[51] Lymphatic drainage and extracorporeal shockwave therapy have very low evidence in VLU treatment.[52][53] As an adjunct to compression therapy, treatment with pentoxifylline or micronized purified flavonoids is an effective ancillary measure.[54] Both drugs have shown improved healing in various systematic reviews and meta-analyses.[55][56][57][58] There is insufficient evidence to recommend other systemic treatments, namely aspirin, zinc, doxycycline, calcium dobesilate, stanozolol, and cilostazol.[54][59](A1)
Direct ulcer interventions involve cleansing, debridement, infection control, and applying dressings and topical substances.[38] Cleansing should be performed with a non-toxic substance to minimize damage to the viable tissue.[34] Debridement can be achieved by surgically removing non-viable tissue, which is strongly recommended.[49] Topical or injected anesthesia can be used to minimize discomfort; autolytic dressings, larval therapy, and enzymatic agents are painless debridement options, albeit results may take longer.[34][38] (A1)
Although VLUs are often colonized, frank infections are less common. Systemic antibiotic therapy should be considered if the infection is suspected to be a new-onset painful ulcer with erythema, tenderness, warmth, and systemic signs (eg, fever, chills). Tissue culture (as opposed to a swab) must be performed in fetid, purulent, or non-healing wounds to guide antimicrobial therapy. Dressings maintain adequate moisture, offer physical protection, and promote granulation and reepithelization. There are numerous absorptive (eg, alginates), moisture-retaining (eg, hydrocolloids), and antiseptic materials (eg, silver) that can be applied to dry, exudative, and infected wounds, respectively. Topical treatments are typically used as antiseptics (eg, cadexomer-iodine), antimicrobials (eg, silver sulfadiazine), and debriding agents such as collagenase or hydrogels).
In a Cochrane meta-analysis, sucralfate and silver dressings were the most highly ranked treatments. Interestingly, using silver dressings increased the probability of healing (risk ratio 2.43, 95% confidence interval 1.58 to 3.74) compared with nonadherent dressings.[60] However, this arose from low-certainty evidence, and the authors could not establish specific treatment recommendations. The benefit-cost balance must be considered since these are often more expensive materials. Adjunctive therapies are recommended for non-improving ulcers after 4 to 6 weeks of standard treatment.[34] Tissue-based products may be useful for these complicated scenarios. According to a systematic review, cultured bilayered skin grafting is more effective than conventional dressings when both were used with compression therapy; there is insufficient evidence to determine if other skin substitutes can effectively improve the healing of VLUs.[61](A1)
Invasive management intends to eliminate incompetent veins through various techniques, such as sclerotherapy, open vascular surgery, radiofrequency, and endovenous procedures. These are often reserved for advanced cases when standard therapies are insufficient.[5][62] In a multicenter study of 450 patients with venous leg ulcers, early endovenous ablation was associated with faster healing and a longer ulcer-free period compared to patients who had the procedure delayed until their ulcer healed or until 6 months if it remained unhealed.[63] (A1)
Differential Diagnosis
Other causes of lower extremity ulceration may be distinguished from VLUs based on the history and physical examination.[1] Arterial ulcers, caused by tissue ischemia, normally appear as deep, dry wounds affecting the toes, foot dorsum, and the anterior aspect of the leg, with abnormal distal pulses, ABPI, and cold extremities. Neuropathic or diabetic ulcers occur due to peripheral neuropathy and arterial disease, presenting as deep wounds surrounded by callous, mainly over the osseous prominences of the plantar surface.
Pressure ulcers arise in limited mobility, usually on the sacrum, coccyx, heels, hips, or anywhere else affected by prolonged pressure and high shear forces. Non-vascular diagnoses should be considered when ulcers show excessive granulation tissue, elevated borders, and failure to improve after standard treatment.[64] These include various types of skin cancers and pyoderma gangrenosum, for which a biopsy is essential.[65][66] Lower extremity ulceration may also occur in calciphylaxis, vasculitis, sickle-cell disease, and other infectious and connective-tissue diseases.
Staging
There is no specific staging instrument for VLUs, but the clinical, etiology, anatomy, pathophysiology (CEAP) classification is often used in patients with CVI patients. See Table. CEAP Classification.[39]
Table. CEAP Classification
|
Clinical |
|
|
C0 |
No visible or palpable signs of venous disease |
|
C1 |
Telangiectases or reticular veins |
|
C2 |
Varicose veins |
|
C3 |
Edema |
|
C4a |
Pigmentation or eczema |
|
C4b |
Lipodermatosclerosis or atrophie blanche |
|
C5 |
Healed venous ulcer |
|
C6 |
Active venous ulcer |
|
Etiological |
|
|
Ec |
Congenital |
|
Ep |
Primary |
|
Es |
Secondary (post-thrombotic) |
|
En |
No venous cause is identified. |
|
Anatomical |
|
|
As |
Superficial veins |
|
Ap |
Perforator veins |
|
Ad |
Deep veins |
|
An |
No venous location was identified. |
|
Pathophysiological |
|
|
Pr |
Reflux |
|
Po |
Obstruction |
|
Pr, o |
Reflux and obstruction |
|
Pn |
No venous pathophysiology identifiable |
Prognosis
Based on a prognostic model, wound area and chronicity are raw determinants for healing.[67] VLUs less than 1 year old and smaller than 10 cm2 at the first visit had a 29% chance of closure failure by the sixth month. The probability increased to 78% for wounds older than 1 year and larger than 10 cm2. Other reported risk factors associated with poor healing are advanced age, non-white race, high body mass index, calf muscle pump impairment, venous reflux, thrombosis, deep vein involvement, and lack of high compression.[68][69]
Results from a multicenter study found that VLUs with a greater than or equal to 3% increase within the first month of treatment had a 68% healing failure probability by the sixth month.[70] In another cohort, a reduction of less than 30% in size by the first month of treatment was associated with a low probability of healing by the third month.[71] Yet, healing predictions based on area or percentage reduction remain under scrutiny.[72][73] Healed ulcers have high recurrence rates, which considerably decrease with sustained compression therapy and vascular surgery.[6][74]
Complications
As with any chronic wound, the most common complications of VLUs include infection and pain, both of which should be controlled to improve healing outcomes and patient adherence.[36][75] Less frequently, skin cancer may develop in wounds that fail to improve over long periods of time.[65]
Deterrence and Patient Education
Individuals affected with VLUs can have an impaired quality of life, mainly related to disability.[76] Plus, heavy exudates can cause malodor, social isolation, and emotional disturbances that severely impact life quality.[76] Compliance is essential to achieve a successful outcome.[36] Patients should be educated because VLUs are chronic processes that require lifelong evaluation and care, even after wound closure. Additionally, conformity to diet and lifestyle modifications may reduce the risk of recurrence, but evidence is lacking.[77]
Enhancing Healthcare Team Outcomes
VLUs remain an unmet clinical need. Numerous guidelines showcase that a consensus between different specialties from various countries has not been reached. Despite this, there have been some attempts at analyzing the quality and consistency of the published literature.[78][79][80] These efforts also demonstrate that an interprofessional team approach is fundamental for a thorough evaluation and treatment strategy. Primary prevention is one crucial strategy in which clinicians should actively participate.[33][81][82]
Patients with limb-threatening diseases and severe infections who are unable to care for themselves should be immediately admitted to the hospital for advanced management and vascular surgery consultation. Mild to moderate cases can be treated in ambulatory wound care facilities.[38] Physiotherapists should also participate in the treatment plan, as a systematic review and meta-analysis demonstrated improved healing with both aerobic and anaerobic activity.[83] Finally, nutrition specialists can help malnourished and overweight patients with specific guidance on improving their overall health, although weight management outcomes remain unclear for VLU healing.[34][84]
Media
(Click Image to Enlarge)
Venous Leg Ulcer. The base of the ulcer, affecting the gaiter area, shows considerable slough and scarce granulation tissue. The borders are irregular but well-defined. The surrounding skin shows hyperpigmentation, and there is notable leg edema.
Contributed by ADC Rodriguez-Mena, MD
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