Venous Ulcers: Pathophysiology and Treatment Options—Part 1

    A chronic wound, as defined by the Wound Healing Society, is a wound that has not healed in a timely fashion.¹

Factors that affect “timely” include, but are not limited to, patient age, wound location, and wound origin/cause. Many conditions lead to ulcer formation but most wounds are caused by venous disease, arterial disease, prolonged pressure, or complications of diabetes mellitus. Nearly 90% of the estimated 600,000 leg ulcers occurring annually in the US are due to either chronic venous insufficiency or a combination of arterial and venous insufficiency.² Treating venous ulcers represents a therapeutic challenge — the immediate goal is to restore epithelium.³ This article focuses on one specific type of chronic wound — the venous ulcer — and highlights the proposed mechanisms by which venous ulcers occur as well as treatment approaches.

Epidemiology

    Chronic venous ulcers are costly in terms of both economics and quality of life. Economic considerations include direct medical costs as well as indirect costs from reduced productivity.⁴ An estimated 5% to 8% of the world’s population is afflicted with venous disease^5,6; 1% suffers from chronic venous ulcers (CVU) of the lower extremities.⁶ The prevalence of venous ulcers in the US is similar to that of foot ulcers caused by diabetes mellitus⁷ — 5 million people have venous insufficiency and at least 500,000 patients have CVU.^8-11 In the UK, 100,000 patients have CVU.¹²

    While venous disease affects all races, both constitutive and modifiable risk factors exist. Constitutive factors include a family history of venous disease or an inherited coagulopathy. Jobs requiring prolonged standing, smoking, obesity, hypertension, or leg trauma are considered modifiable risk factors, at least in theory.^5-13 One study⁴ estimated the cost of complete healing of the ulcer to be upwards of $1,474 for each primary ulcer and up to $2,200 for each recurrent ulcer. In a recent study¹⁴ performed at the Cleveland Clinic, the direct cost of caring for a venous ulcer until complete healing was more than $9,000. In the UK, France, and Germany, the cost of venous ulcers is estimated to be 1.5% to 2.0% of the total healthcare budget annually.⁶ In addition to a staggering monetary drain, nonfinancial costs, such as decreased quality of life of CVU patients, are also great. Patients suffer from severe discomfort, inconvenience, embarrassment, decreased mobility, and loss of independence.⁶ Appropriate treatment may improve the quality of life of these patients.

Pathogenesis

    Venous hypertension, a sustained elevation of ambulatory venous pressure, is the hallmark of venous disease and may be caused by an abnormal calf muscle pump. An abnormal calf muscle pump may, at times, be due to incompetent veins or valves of the lower extremities, muscular dysfunction, limited mobility, or any combination of the three.¹⁵ Vein incompetence may be acquired or congenital and often is due to valvular dysfunction or their absence, leading to venous reflux.¹⁶ In approximately two-thirds of patients with CVU, damage involves both superficial and deep venous systems.¹⁶

    Contraction of the calf muscles, specifically the gastrocnemius and the soleus muscles, serves as a pump to empty the intramuscular deep veins and decrease the volume of venous blood present in the lower extremities.¹⁷ The pressure of the column of blood in the deep veins must be less than the pressure exerted by the calf muscles in order to force blood against gravity and back to the heart for re-oxygenation and distribution through the arterial system. Thus, muscular weakness may allow venous blood to pool in the extremities.¹⁸ Anatomically, the plantar venous plexus of the foot has a wider vessel diameter than does the outflow tract of the posterior tibial deep veins, thus aiding the cephalad flow of venous blood.¹⁷ Compression of the plantar plexus is assisted by ambulation, increasing the performance of and decreasing the strain on the calf muscle pump. Venous ulcers may occur in selected bedridden patients who lack the benefit of the calf muscle pump and the plantar plexus that facilitate the ascension of blood back to the heart.

    For people who experience short periods of recumbency, this lack of mobility is no problem. In fact, lying down relieves the increased pressure caused by standing. Erect, ambulatory patients who lack proper compensation of the venous system will suffer from venous pooling near the ankle. Increased venous pressure with concomitant reduced differential between the arteriolar and venular side of the capillary bed^12,19,20 may trap leukocytes in the post-capillary venules.¹² These leukocytes may activate and release proteolytic enzymes, which leads to the formation of free radicals that ultimately may cause tissue damage.^12,21 Activated leukocytes also can release cytokines such as tumor necrosis factor (TNF), interleukin 1 (IL-1), and various leukotrienes.²² In addition to leukocyte activation, margination of white cells leads to oxygen deprivation of nearby tissues²³ and may result in ischemia.¹² The marginated white cells can act as a diffusion barrier to oxygen and nutrients necessary for tissue survival.²⁴

    Concomitantly, venous blood pooling leads to dilatation and subsequent venous tortuosity,²² accompanied by a decrease in the number of capillaries, an increase in capillary intraluminal pressure,^23,25 and stretching of the interendothelial pores^23,26 due to increased pressure. Pore widening causes an increase in capillary permeability and edema formation.²³ Additionally, macromolecules such as fibrinogen and alpha-macroglobulin leak into the dermis through the dilated capillary pores.^23,27-29 Alpha-macroglobulin may bind growth factors (GF) such as TNF and transforming growth factor beta (TGFb),^28,29 which are needed for wound repair.²⁹ Trapping these growth factors may make them unavailable for tissue repair.

    Fibrinogen leaking into the dermis leads to the formation and deposition of a “fibrin cuff” around dermal blood vessels.²³ Systemic abnormalities in fibrinolysis, seen in patients with venous disease, contribute to the “pericapillary fibrin cuff,” which also may act as an additional diffusion barrier to oxygen and nutrients.^12,23

    Recently, it also has been proposed that arterio-venous (AV) shunting may play a role in the pathogenesis of venous ulcers.³⁰ This theory is supported by the presence of elevated oxygen content of venous blood, premature venous filling, increased blood flow in the skin of the legs on angiography, and decreased capillary density in leg skin in patients with venous insufficiency — possibly representing hypoperfusion of the nutritive capillaries.

Classification

    Clinical severity of chronic venous insufficiency (CVI) was divided into four classes in 1988 by the Ad Hoc Committee for Reporting Standards of the Society of Vascular Surgery and the North American Chapter of the International Cardiovascular Society (see Table 1).³¹ Class 0 is asymptomatic, with no signs or symptoms of disease. Class 1 is mild disease, presenting with limited swelling and local dilatation of subcutaneous veins. Class 2 is moderate disease characterized by hyperpigmentation, moderate edema, and subcutaneous fibrosis. Class 3 is severe disease, in which patients have chronic leg pain, ulcers or pre-ulcerative changes, dermatitic changes, and severe edema. With increasing severity, the deep venous system becomes progressively more involved. In one study, 90.3% of patients with class 1 disease have solely superficial reflux, while conversely, 60% of patients with class 3 disease have deep venous reflux.^16,32 Additionally, valve closure times of the superficial veins were significantly shorter in class 0 than the other classes, indicating superficial reflux increases with worsening clinical changes.¹⁶ The number of incompetent perforator veins (veins that connect the superficial to the deep system) is also highest in class 3.³¹ Rarely are patients with isolated deep or perforating vein incompetence encountered. These changes may be measured by a variety of methods, including photoplethysmography, air plethysmography, and duplex ultrasonography.¹⁶

    In 1996, the classification of venous ulcers was redefined based on clinical manifestations (C), etiologic factors (E), anatomic distribution of involvement (A), and underlying pathophysiologic findings (P) (see Table 2).³³ This new CEAP classification system provides additional information to compare limbs accurately.

Prognostic Indicators

    A number of recent studies have reported several prognostic factors important in stratifying patients based on venous ulcer healing potential. Phillips et al³⁴ found large baseline venous ulcer size (mean 15.9 cm²) and long duration of leg ulcer (mean 27 months) were poor prognostic signs. Margolis et al³⁵ also found size and duration to be important, along with a history of venous surgery, hip or knee replacement, ankle brachial index (ABI) <0.8, and presence of fibrin in >50% of the wound — all of which heralded a poor prognosis. On the other hand, Skene et al³⁶ reported that young age and absence of deep venous insufficiency were good prognostic indicators. Not surprisingly, patient noncompliance with compression therapy also has been reported as indicative of decreased venous ulcer healing.³⁷

    Patient symptoms. Patients with venous ulcers commonly complain of swelling and aching of the legs, often worse at the end of the day, which may be exacerbated by dependency and improved by leg elevation.³⁸ A history of ulcer recurrence, particularly at the same location, is characteristic. Up to three-quarters of patients with venous ulcers report pain that adversely impacts their quality of life.^39,40 Several risk factors for the development of venous ulcers have been identified. Nearly half of patients with CVI have a history of leg injury.¹³ Obesity, phlebitis, family history of varicose veins, type of employment and lifestyle (activities that require long hours of standing or sitting), deep vein thrombosis, and previous surgery for varicose veins also are considered important risk factors for the development of venous ulcerations.^41,42

Clinical Characteristics

    Venous ulcers are characteristically located over the medial malleolus, also called gaiter area. They may be single or multiple and if untreated can involve the entire circumference of the leg. Venous ulcers usually have irregular, flat, or only slightly steep borders. The ulcer bed tends to be shallow with granulation tissue and exhibits some fibrinous material. The wound surface rarely if ever shows necrosis or exposed tendons; if present, another etiology should be considered.⁴³

    Commonly associated findings include dependent edema, varicose veins (ranging from a submalleolar venous flare to various degrees of vessel dilatation), and reddish-brown pigmentation and purpura due to extravasation of red blood cells and subsequent hemosiderin deposition. Eczematous changes with redness, scaling, and pruritus — often referred to as venous dermatitis — are also commonly present. This eczematous dermatitis is caused or aggravated by sensitization to applied topical medications to which patients with venous disease are particularly susceptible.^44,45 Atrophie blanche — smooth, ivory-white atrophic plaques of sclerosis speckled with telangiectases — is described in up to one-third of patients with CVI; when present in the gaiter area, this may point to a venous etiology of a lower extremity ulcer.⁴⁶

    In long-standing venous disease, the skin develops an induration and sclerosis of the dermis and subcutaneous tissue with a dramatic loss of subcutaneous tissue sharply demarcated from proximal normal leg skin, resulting in the appearance of an inverted bottle. Lipodermatosclerosis (LDS), a term used to describe these clinical findings, suggests a greater impairment of the fibrinolytic system and is highly associated with and usually restricted to the legs of patients with venous insufficiency.^44,47

Diagnostic Tests

    In most cases of venous ulcers, diagnosis is based solely on clinical criteria.^48-50 However, 25% of patients will have ulcers with mixed characteristics; therefore, noninvasive methods may help ascertain an accurate diagnosis and enhance the anatomical and functional evaluation of the venous system.^51,52

    Obtaining an ABI is key in detecting peripheral vascular disease. The systolic blood pressure is measured by placing an appropriately sized cuff around the calf and inflating it to occlude the pedal arteries. The sounds heard with the Doppler after deflation of the cuff represent the ankle systolic pressure. This number is divided by the brachial systolic pressure to determine the ABI (normal >1). Values less than 0.97 identify patients with peripheral arterial disease with a sensitivity of 96% to 97% and a specificity of 94% to 100%.⁵⁰ Although false normal results may be observed in elderly and/or diabetic patients, this simple noninvasive method can be useful to detect arterial disease. In elderly patients and patients with diabetes, a transcutaneous oxygen measurement may be preferred to evaluate the patient’s arterial flow. This is important to determine because compression therapy, the mainstay of therapy for venous ulcers, can lead to worsening of an arterial ulcer and, at times, gangrene.⁵³

    Color duplex ultrasound scanning is currently the gold standard in evaluating venous disease. It is accurate, reproducible, noninvasive, and provides anatomic and functional information about both the arterial and venous systems.^54,55 Using color duplex ultrasound scanning, veins can be identified and their dimensions, velocity, and the direction of flow can be measured. Other exams, such as photo and air plethysmography, allow the clinician to assess whole limb venous hemodynamics at rest and after exercise and are adjuncts to duplex scanning. Invasive venography is usually reserved for investigation before surgery, if indicated.
If osteomyelitis is suspected, radiographs, bone scans, and bone biopsy should be considered. The incidence of osteomyelitis in chronic venous ulcers is unknown. In persons with diabetic foot ulcers, a prospective trial⁵⁶ found that probing of sinuses and deep ulcers was a highly sensitive method of detecting bone infection. Therefore, if bone is palpable at the base of an ulcer, with no intervening soft tissue, the likelihood that osteomyelitis is present is high and further investigation is warranted.

    Independent of the suspected cause, if a wound is present for more than 3 months, a biopsy is recommended to exclude the presence of malignancy.^57,58 Some clinicians recommend biopsying all wounds; others suggest biopsying only atypical or recalcitrant (nonhealing) wounds. Atypical wounds may be characterized by features that include, but are not limited to, increased size, malodor, and pain; excess granulation tissue/bleeding/drainage; and exophytic or irregular margins or base. Also, if the clinical diagnosis is not evident, a biopsy should be performed. At that time, an atypical infection can be detected by microscopic examination as well as tissue culture.

Compression Therapy

    Compression dressings (bandages) are the mainstay treatment for CVU. The goal of compression is to increase healing of the venous ulcer by improving venous return and reducing edema of the lower extremities.^59,60 Compression treatment may work by either compressing the legs during sedentary periods or by increasing the calf muscle pump activity during active periods. Compression is useful for ulcer healing and preventing ulcer recurrence.⁶¹

    During initial treatment, patients may benefit from inelastic (short stretch) bandages; during the maintenance phase, elastic compression dressings (long stretch) can maintain the previously achieved reduction in edema. In addition to elastic or inelastic bandages, a number of different types of compression dressings are available for CVU treatment, including single- or multilayer systems and compression stockings (see Table 3).⁶²

    Inelastic. Short stretch bandages are inelastic or rigid.⁶³ They promote a lower resting pressure than elastic bandages and offer a high working pressure that decreases edema and improves venous flow. The lower resting pressure of inelastic bandages makes them safer for patients with arterial occlusive disease. Unfortunately, compression rapidly diminishes because a large loss in pressure occurs immediately after application.⁶⁵ Brands of inelastic dressings include Circaid® (Coloplast Corp., Marietta, Ga.), which features Velcro strips⁶⁵; Comprilan® (Beiersdorf Medical, Charlotte, NC), which can be re-wrapped daily as edema decreases⁶³; and Tenderwrap® Unna boot (Tyco Health Care/Kendall, Mansfield, Mass.), a zinc-impregnated inelastic dressing that is usually not changed daily. Although compression levels diminish somewhat as edema decreases, the Unna boot still keeps a high working pressure due to the leg “pressing” or “bouncing” against the boot, rendering it more effective for ambulatory patients. Often, an elastic compression dressing such as Coban® (3M Health Care, St. Paul, Minn.) is placed over the Unna boot to sustain compression when the patient is not ambulating.⁶⁶

    Elastic. Elastic compression dressings maintain pressure during working and resting phases⁶¹; little pressure is lost over time. However, maintaining sustained compression can be dangerous for patients with arterial occlusive disease.⁶⁷ Elastic bandages are available in high compression and light compression.⁶² Examples of high compression bandages are Setopress® and Surepress® (both from ConvaTec, a Bristol-Myers Squibb Company, Princeton, NJ). Both of these high-compression, washable, re-usable bandages consist of an elastic layer with printed rectangles that become squares when stretched to the appropriate tension. Setopress® has one elastic layer; Surepress® has two layers — an elastic layer and a padding layer. Elastocrepe® (Smith & Nephew, Largo, Fla.) is an example of a light compression bandage. In a study comparing Setopress® and Elastocrepe®,⁶⁸ the former healed 58% of ulcers after 15 weeks of use while the latter healed 35% of ulcers, suggesting that high compression is superior to lower compression bandages. High compression bandages retain a higher pressure for up to 1 week before a bandage change is needed. Although the light compression bandages obtain lower pressures, their ability to be washed and re-used may make them an attractive and cost-effective alternative.

    Single- and multilayer compression. Compression systems are available in single- or multilayer forms.⁶² Single-layer dressings work by delivering constant compression pressure to decrease edema of the lower extremities and increase venous return to speed healing of the ulcer. Examples include Setopress® and Comprilan®. Multilayer bandages deliver graded pressure of 40 mm Hg at the ankle, which gradually decreases to 17 mm Hg at the knee. Although the exact mechanism of action of the multilayer systems, like all compression systems, is still unknown, studies have shown a reduction in edema and distension of the lower extremity veins, reversal of venous hypertension, and an increased healing rate. For example, Profore® (Smith & Nephew, Largo, Fla.), a four-layered bandage plus a wound contact layer, has been shown to improve healing compared to a single layer of compression.⁶⁹ This bandage consists of a low-adherent wound contact layer, Tricotex® (allows wound exudates to escape), and four compression layers: a natural orthopedic wool layer to absorb exudate and protect bony prominences applied in a spiral fashion with 50% overlap, a second absorptive layer that holds the previous layer in place and is also applied in a spiral fashion with 50% overlap; a third layer applied in a figure-eight pattern to prevent slippage of the dressing; and a self-adherent, cohesive flexible layer applied with a 50% overlap. A similar bandage is used in the UK.⁶² Several other companies have developed their own multilayered compression bandages.

    Often, the ulcer site may not be receiving sufficient compression to affect healing. In these cases, localized supplemental pressure (LSP) can be used between the ulcer and the compression wraps^70-72 by adding several gauze pads directly to the wound site before placing the compression dressings (see Figure 1). According to Laplace’s Law, by decreasing the radius of the leg at the wound site, increased pressure is delivered specifically to the ulcer.⁷² These gauze pads enhance local compression to improve healing rates of venous ulcers.^70-72

    Pneumatic compression. In controlled studies sequential pneumatic compression has been shown to be a beneficial adjunct in healing venous ulcers.⁶² This type of compression system consists of high pressure delivered for a short duration, which prevents significant pain to the patient.⁷³ Pressures as high as 180 mm Hg can be delivered in short cycles.

    Based on these studies and others, a recent meta-analysis performed by the Cochrane Group concluded that compression therapy significantly increased ulcer healing rates when compared to not using compression.^62,74 Multilayered dressings appear to be more effective than single-layer dressings for healing ulcers, high compression is superior to low compression, and pneumatic compression is a useful adjunct to standard compression.

    Recurrence. Once healing is achieved, patients are at risk for recurrence. Compression stockings prevent recurrence. Patients should be encouraged to use stockings consistently and forever. As with compression dressings, stockings are designed to have the highest pressure at the ankle and the lowest pressure at the calf or thigh to enable increased venous return^75-78 and prevent venous thrombosis.^75,79-82 Three classes of stockings³⁶ help avoid recurrence: Class 1 stockings deliver light support and are used primarily for varicose veins (see Figure 2); Class 2 stockings give medium support for the treatment of more severe varicose veins and the prevention of venous ulcers (see Figure 3); and Class 3 stockings provide strong support needed to treat severe varicose veins and severe venous hypertension and to prevent venous ulcers (see Figure 4).

    Compression stockings must be worn consistently to be of benefit. Mayberry et al^4,83 found that 100% of the ulcers in their study recurred without the use of stockings, compared to 16% recurrence if the stocking were worn faithfully. One study evaluating recurrence found that 78% of patients who had recurrent ulcers did not wear their stockings.⁴ Other studies also reported compliance with stocking usage as a factor in recurrence. Nielsen et al^4,37 reports a 22% recurrence rate for patients who did not comply with stocking use.

Dressings

    Occlusive dressings have been used as adjuvants to compression in various venous ulcer management regimens.^49,84,85 Controlled and non-controlled studies have shown that occlusive dressings may speed healing, aid in debridement, and absorb exudate.⁸⁶ Occlusive dressings also can be used in conjunction with compression dressings to relieve pain.⁹ This combination of an occlusive and compression dressing may be optimal for venous ulcers.⁹

    While the use of moist wound healing principles and absorption/control of excess exudate is conventional wisdom and routinely practiced, unequivocal data are lacking to support this approach. The authors agree with conventional wisdom; however, adjuvant modalities to compression therapy with or without occlusive dressings should be considered.

Systemic Therapy

    Pentoxifylline. For venous ulcers, several systemic adjunctive treatments may be used in conjunction with compression therapy. Pentoxifylline has been shown to decrease white blood cell adhesion and activity,^7,87,88 blood viscosity, platelet aggregation, and pro-coagulation,^89,90 as well as to increase fibrinolytic activity.^70,88,90,91 Pentoxifylline is metabolized in the liver and red blood cells to seven active metabolites.⁹¹ Studies suggest that it may be effective in treating venous ulcers but at doses higher than used for treating claudication. When pentoxifylline plus compression was compared to placebo plus compression, the healing rates were 64% and 34%, respectively.⁷ Belcaro et al,⁹² in a 6-month randomized placebo-controlled trial comparing pentoxifylline 400 mg three times daily with compression to placebo with compression in 172 patients, found that patients treated with pentoxifylline showed significantly greater healing (67% versus 30.7%, P <0.05). Treatment with pentoxifylline also was determined to be more cost effective. Falanga et al⁹³ reported the effects of compression bandaging plus pentoxifylline 800 mg, pentoxifylline 400 mg, and placebo three times a day for 6 months. Pentoxifylline was well tolerated at both doses but patients healed faster with the 800-mg dose. DeSanctis et al,⁹⁴ in a 12-month randomized, placebo-controlled trial comparing pentoxifylline 400 g three times daily with compression versus placebo with compression in 85 patients, found significantly higher healing in the pentoxifylline group (88% versus 44%, P <0.05). No significant side effects from using pentoxifylline were reported. Recently, Jull et al⁹⁵ published their results of a systematic review of all randomized controlled trials using pentoxifylline for venous ulcers, including the studies previously referenced. Pentoxifylline was shown to give added benefit when used in conjunction with compression therapy and may possibly be efficacious as monotherapy.

    Aspirin. Aspirin also has been reported to aid healing of venous ulcers when used in conjunction with compression therapy. Aspirin is both an antithrombotic and an anti-inflammatory but its precise mechanism of action in healing venous ulcers is unknown.⁸⁷ One study⁸⁷ found 38% of patients healed with 300 mg of aspirin daily plus compression, while none of the patients healed with daily placebo and compression. In addition, a 50% reduction in ulcer size occurred with aspirin use as opposed to 26% reduction with placebo use. Limitations of this study include small sample size, an end point of reduction in size of the ulcer rather than the complete healing of the ulcers, and the use of laser Doppler flowmetry to diagnose venous ulcers. Also, the healing rates were unusually low, given the use of compression in both groups. Ibbotson et al,⁹⁶ in 4-month, randomized, double-blind placebo-controlled trial comparing the daily use of 300 mg of aspirin with compression therapy versus placebo with compression therapy, found healing increased significantly (as assessed by percent decrease in wound size) by 69% in aspirin group and 47% in the placebo group (P <0.05). This study also was limited by a small sample size and lower rates of healing than expected with the use of compression therapy.

    Micronized purified flavonoid fraction. Recently, micronized purified flavonoid fraction (MPFF) (Daflon®, Servier, Neuilly-Sur-Seine Cedex, France), an oral phlebotropic drug consisting of 90% micronized diosmin and 10% flavonoids expressed as hesperidin, has shown efficacy in the treatment of venous ulcers.^97-99 This drug increases venous tone, improves lymphatic drainage and edema, and protects the microcirculatory system by inhibiting the synthesis of prostaglandins and free radicals, decreasing leukocyte activation and trapping, decreasing bradykinin-induced vascular leakage, and decreasing neutrophil chemotaxis. Guilhou et al¹⁰⁰ reported the results of a 2-month, randomized, double-blind, placebo-controlled trial comparing MPFF 500 mg twice daily plus compression to placebo plus compression. Patients treated with MPFF showed complete healing in 32% of ulcers versus 13% with placebo. Glinski et al¹⁰¹ published similar results with their 6-month, open, multicenter, placebo-controlled trial comparing MPFF 500 mg twice daily plus compression to placebo plus compression. The MPFF-treated group showed improved healing (46.5% versus 27.5%) and was found to be cost-effective.

(Continued in Part 2)