Venous Ulcers

Jason Reichenberg, MD, and Mark Davis, MD

Veneous ulcers are extremely common, accounting for a large proportin of all lower extremity ulcers. Due to their chronicity and relatively high prevalence, their impact on the cost of healthcare and the lives of the patients affected is quite signicant. There has been progress in understanding the pathophysiology, clinical features, and diagnosis of these ulcers, but the basic principles of care have remained consistent for almost a half century. To allow for optimal healing, it is important to maintain a clean moist wound bed, treat any clinically signicant infection, and decrease surrounding edema. Semin Cutan Med Surg 24:216-226 2005 Elsevier Inc. All rights reserved. KEYWORDS venous, leg, ulcer, wound, insufciency, compression

enous ulcers are extremely common, accounting for a large proportion of all lower-extremity ulcers, and affect every socioeconomic class.1,2 They frequently become chronic.2 Worldwide, the cost of treating venous ulcers exceeds several billion dollars.3-5 Despite these expenditures, venous ulcers are viewed by many as a minor inconvenience on the basis they usually are not very painful and infrequently lead to amputation.6 For centuries, the treatment of leg ulcers has been anecdotally based. Different societies have developed diverse ways of treating these ulcerations. In recent years, there has been renewed interest in the eld as awareness increases about the profound impact that venous ulcers have on the cost of health care and the lives of millions of patients. This article aims to summarize ndings concerning the epidemiology, diagnosis, pathogenesis, and treatment of venous ulcers. There have been several excellent reviews of this subject by Abbade7 and Nelson.8

younger than 65 years at 0.08, those between 65 and 74 years at a rate of 2.11, and those older than 85 years with a prevalence of 8.29 per 1000. The rate in women increased with age in a similar fashion.10 Another study in patients older than 45 found a prevalence of 0.19%, with an annual incidence 0.35%. Recurrent ulcers compromised 47% of all of the ulcers studied.11 A questionnaire and follow-up examination in Sweden showed an estimate of ulcerations caused by vascular insufciency and/or diabetes to be 1.02% in those older than 65.12 Chronic leg ulcers often are dened as those ulcers lasting longer than 6 weeks.10 The causes of chronic leg ulcerations include primary arterial or venous insufciency, diabetes, trauma, sickle cell disease, infection, malignancy, and inammatory disorders such as rheumatoid arthritis. Venous leg ulcerations (chronic leg ulcers in which venous insufciency is thought to play a role) have been estimated to account for 58%10 to 70%13of all leg ulcerations.

Epidemiology
Leg ulcers, dened by a break in the epidermis extending to the dermis by any cause on the lower extremities, are common, although the exact prevalence and incidence has varied between different studies. Fowkes et al 9 found that 1% of the general population report a history of a healed or unhealed ulcer. The prevalence of ulcers lasting longer than 4 weeks was reported to be 0.45 per 1000 in England. In this study, the prevalence increased with age, with prevalence in men
Department of Dermatology, Mayo Clinic, Rochester, MN. Address reprints requests to Mark D. P. Davis, MD, Department of Dermatology, Mayo Clinic, Rochester, MN 55905. E-mail: davis.mark2@mayo. edu

Venous Insufciency
Venous disease is widespread in the general population, and is associated with ulceration (venous ulceration) in 2% to 4%.14 A 1991 study in France estimated that 11 million patients in the country have chronic venous insufciency (CVI), of which 7 million are symptomatic.15 Callam16 reviewed epidemiologic studies from the United States, Japan, Brazil, and countries in Europe and Africa and estimated that half of all adults worldwide have minor signs of CVI, with women slightly more commonly affected than men. Less than half of this group, however, will have visible varicose veins, with 20% to 25% of women affected and 10% to 15% of all men. Recently, another review was performed on the past half-

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1085-5629/05/$-see front matter 2005 Elsevier Inc. All rights reserved. doi:10.1016/j.sder.2005.10.002

Venous ulcers
century of literature regarding the epidemiology of CVI. This study found that estimates of the prevalence of CVI ranging from less than 1% of women to as much as 40%, and between 1% and 17% in men. The prevalence of visible varicose veins ranges from 1% to 73% in women and from 2% to 56% in men.17 Age14-18 and number of pregnancies14,17 are positively correlated with CVI. Venous insufciency is more prevalent in women than men although, with age, this ratio begins to equalize.19 Recent epidemiologic studies have suggested that CVI may be more common than previously estimated in men, although it was noted that men were more likely to have mild disease than women.18 Evans postulated that the changing face of the workplace may have modied the epidemiology of venous disease, with more men and women exchanging their work standing in an assembly line for a desk job.18 Many authors agree that occupations in which workers stand place them at higher risk for venous disease.17 Despite this assertion, some studies have upheld that venous disease is not related to social class18 or the occupation of the patient.16 In a study of the population of a country town in Brazil, the prevalence of varicose veins was similar to those of industrialized populations, with 37.9% of men and 50.9% of nonpregnant women demonstrating stigmata of disease. Along the same lines, the defecation habits of patients do not seem to have a correlation to the presence of varicose veins.14 Previous studies have shown race to serve as a risk factor for CVI,16 and this Brazilian study conrmed the previous data. They found varicose veins more commonly in white population than in other races.14 Conicting evidence exists regarding the role of obesity and family history, with some authors pointing to a paucity of evidence,16 and with other more recent studies asserting that both are signicantly correlated.17 Other factors that are currently under scrutiny include diet and exogenous hormone use, but further research is needed before a denitive correlation can be made.17

217 80 years of age.21 Venous ulcers often are persistent: 34% of patients with venous ulcers had their ulcers for more than 5 years,21 and a recurrence rate has been estimated to be as high as 72%.2

Social and Economic Impact

Venous ulcerations tend to be a chronic or recurrent problem and, therefore, it is not surprising that they are associated with signicant economic cost and psychological impact. Although venous ulcerations have been reported to be associated with very little pain2,6 and to be a relatively minor medical problem, more recent literature details that as many as three-quarters of patients with venous ulcers report pain and a decreased quality of life associated with the disease.22,23 Patients often have a sense that they have lost control of their disease and nd themselves losing faith in their health care providers.24 Active treatment of these ulcers (even if the ulcer does not entirely resolve) may allow for a dramatic reversal of their bodily pain and health transition. After completing a treatment program, their scores for bodily pain, general health, and mental health were comparable with agematched controls in the population.25 Taken together, the majority of costs involved in the treatment of chronic venous ulcers have been reported to result from hospitalizations, home health care, and dressing changes.26 Cost estimates in Europe range from approximately 1% to 2% of the national health care budgets,27 and estimates in Belgium were equivalent to approximately almost 300 million US dollars28 in 1995, or more than 2% of the total health care budget.5 In 1991, the French estimated their expenditures on CVI to exceed 2% of their total health expenditures. The major components of their costs were drugs (41%), hospital care (34%), and medical fees (13%).15 They report approximately 200,000 hospitalizations per year, making CVI the eighth-leading cause of hospitalization in France.15 In the United States, expenses may be between 1.9 and 2.5 billion3,4 The cost of treatment per Medicare patient runs at a mean of $9685 and a median of $3036 per year (calculated in a report in 1999).26 The cost for weekly treatments in a wound care center was $400 for 6 weeks in 1996.29 Six million days of work are lost in the US as a result of the complications of CVI. 30 Very similar results are reported from a French study by Lafuma and colleagues.15

Venous Ulcers
CVI can vary from being mild to severe and can be associated with ulceration and its attendant morbidity and mortality. Slightly more than 2% of men and 4% of women with CVI will develop ulceration.14 Epidemiologic estimates as to the prevalence of venous ulcers in the general population vary greatly, ranging from 0.39 to 2%2,6 The incidence of venous ulcerations also varies greatly. An incidence of venous leg ulcers of 0.16% in the Swedish population has been reported.2 In patients older than 65 seen by general practitioners in the United Kingdom, the incidence of venous ulcers was between 1.13 and 1.2 per 100 person-years, with a prevalence of 1.69%. Venous ulcers have been estimated to be up to twice as common in women than men (1.42:0.76).20 The proportions in men increases with age and, in subjects older than the age of 85, more men than women have been reported to be affected.20 Much like all ulcers, venous ulcers seem to have an increased rate in older age groups, with a peak between 60 to

Pathogenesis
To understand the appropriate evaluation and treatment of venous leg ulcers, one must have a basic understanding of the pathophysiology of venous ulceration, which is thought to be the end stage of venous insufciency. For a more comprehensive discussion, the reader is referred to a review of this topic by Abbade and Lastoria.7 The occurrence of venous ulcerations appears to be directly related to the presence of CVI.31 One study of a cross section of patients found that in patients with an ambulatory venous pressure of less than 30 mm Hg, no ulceration oc-

218 curred, whereas there was a 100% incidence in patients with an ambulatory venous pressure greater than 90 mm Hg.32 In healthy venous circulation, the contraction of the leg muscles, primarily the calf muscle, causes an increase in venous pressure, allowing for blood to ow toward the heart (termed systole), guided by one-way ow valves in these veins. During relaxation of the calf muscles, pressure in the veins decreases, allowing them to ll with blood once again (termed diastole). There are 2 main networks of veins in the lower legs, the supercial and deep venous systems, connected by the perforating venous system. Calf pump dysfunction31 is the term applied to any defect in the return of blood from the distal extremity to the trunk. It can be caused by an inability of the calf muscle to pump blood because of neuromuscular paralysis or trauma, an obstruction in the blood ow by deep or supercial vein thrombosis, or an anatomic or pathologic stula between the arterial and venous system. In the majority of cases, calf pump dysfunction is caused, at least in part, by venous insufciency.33 Venous insufciency is a dysfunction of the valves of the supercial, deep, or perforator veins, resulting in the reversal of blood ow during diastole. A recent study has conrmed that the severity of venous disease is directly related to the degree of valve incompetence. Minor forms of venous disease are associated with supercial venous incompetence alone, whereas severe venous disease was seen in patients with perforator and deep venous insufciency.34 In venous ulcers, there is usually incompetence in multiple levels of the venous system.35 Regardless of the etiology of the calf pump dysfunction, without an efcient method of returning blood to the heart, the blood will pool in the venous system of the legs. This increased blood volume will put added pressure onto the vasculature, often referred to as venous hypertension. For more than 2 decades, it has been widely accepted that a direct causative relation exists between venous hypertension and venous ulceration33,36,37 although the exact pathway by which hypertension causes the ulceration is unknown. Originally, it was thought that the increased venous pressure would directly distend the endothelial cells in capillary walls, allowing for the extravasation of brinogen into the extravascular space. This would, in turn, form a pericapillary brin cuff around the vessels that would prevent the diffusion of nutrients to the surrounding tissues and lead to ischemia.38 Although brin cuffs have proven to be a distinct histopathologic feature of venous disease,39 their presence has not been shown to be universally present, nor unique to CVI, and they have not been proven to act as an oxygenimpermeable barrier.40 To this effect, Coleridge and coworkers suggested that a prolonged increase in the pressure in the venous system would result in the shunting of the circulation away from the affected capillary bed. This would lead to the pooling of leukocytes in these capillaries. They originally proposed that the leukocytes would directly occlude the vessels, causing tissue ischemia.41 Although the cause for the leukocytes presence in the microcirculation has been debated, many studies have borne out that they are, in fact, present.42,43 They

J. Reichenberg and M. Davis

have been shown to release multiple inammatory factors such as tumor necrosis factor-alpha,44 proteolytic enzymes such as metalloproteinases, and free radicals.40 They also can be seen associated with platelets, which irreversibly sequester in the vasculature.45 More recently, it has been proposed once again that distension between the endothelial cells caused by the increased hydrostatic pressure can allow for the extravasation of various macromolecules into the extravascular space that trap endogenous factors.40 This trap hypothesis has gained support from studies that demonstrate the presence of proteins, including alpha 2-macroglobulin, within perivascular cuffs.46 The alpha 2-macroglobulin can bind to transforming growth factor-beta and other growth factors, which may account for broblast dysfunction and the impairment of wound healing. This argument is supported by experiments in which chronic wound uid was found to impair newborn broblast growth by preventing their entry into the S-phase of the cell cycle.47 Likely, all of the above mechanisms, including brin cuffs, leukocyte-platelet sequestration, and growth-factor trapping will be found to contribute to venous disease. The integration of these theories into the pathogenesis of venous ulceration is not yet complete. Once an ulcer has formed, various contributing factors can lead to its perpetuation. These factors include increased age, nutritional deciency, chronic illness, chronic immunosuppression, hypoxia, vasculopathy, and infection. The concept of a biolm, although relatively new to clinical medicine, is the focus of increased interest among researchers and clinicians.48 A biolm is composed of communities of microorganisms adhering to environmental surfaces. These communities often are surrounded by a polysaccharide capsule that renders them resistant to topical or systemic antibiotics.49 They have important implications into wound care because physical or enzymatic dbridment would be necessary to eliminate the organisms. Some propose that asymptomatic or subclinical infection with bacteria may hinder wound healing by the release of inammatory mediators. However, a recent clinical trial in France showed that the presence of Staphylococcus aureus was not predictive of wound progression.50 The role of deep vein thrombosis in the etiology or in relation to venous ulcers is controversial.7 In one study, 96% of patients with venous ulcers had a either history of deep venous thrombosis or a condition that would predispose to developing them.51 A possible exacerbating factor that is just starting to become recognized is contact dermatitis. In the past 3 decades52 work has been done to demonstrate an increased incidence of allergic contact dermatitis in patients with venous ulcers. More than 50% of venous ulcer patients have been shown to have a sensitivity to one of the commonly used topical treatments for leg ulcers,53 including neomycin and benzocaine.52 In addition, the longer the duration of the ulcer, the greater the number of sensitivities detected.53. This phenomenon is important to treatment, and will be addressed further in the following sections.

Venous ulcers
This increased rate of sensitization is likely the result of local perturbations in the skin barrier and in the inammatory cascade. It may be that the thickened epidermis may act as a reservoir for potential allergens. As the result of chronic inammation, the number of antigen-presenting cells may be increased in the epidermis and dermis.54

219 Vascular Studies The initial evaluation of a venous leg ulcer should rule out concurrent arterial disease. Using a standard sphygmomanometer, the clinician can determine an ankle to brachial pressure index (ABPI). If the patient has an ABPI between 0.5 and 0.8, it indicates that there may be concurrent arterial and venous disease. If the ABPI is less than 0.5, the ulcer is more likely to be arterial in origin.10 Color duplex ultrasound often is the initial technique of choice for patient evaluation because it is widely available and easy to use. With this technique, a clinician can delineate the patients vascular architecture and determine the presence or absence of venous reux. It is important that the clinician assesses the greater and lesser saphenous veins, the perforating veins, the femoral vein, the popliteal vein, as well as the deep veins of the calf.33 For a venous evaluation, the patient is examined in the standing position because previous techniques examining the patient in the supine position have been shown to be less accurate. Compression of the calf by manual pressure on the bulk of the muscle produces a systolic ow of blood in the anterograde direction. After the diastolic release of the calf muscle, a patient with valvular incompetence will demonstrate retrograde ow in the vein being evaluated.57 In the supercial veins, deep femoral and deep calf veins, greater than 500 ms of reux indicates clinically signicant disease, in the perforators, more than 350 ms, and in the common femoral, femoral, and popliteal veins the best cut-off is 1000 ms.58 Despite the widespread use of this technique, considerable skill is necessary for a thorough evaluation of the deep veins. In fact, in a recent trial by Mantoni et al,59 which compared 5 methods of venous evaluation, continuous wave Doppler was found to yield many false positive and negatives in the evaluation of deep venous incompetence. This nding is important because deep system or multisystem reux is thought to be more directly correlated to the later stages of venous disease and ulceration.60,61 Mantonis group suggests, instead, a comprehensive triple ultrasound evaluation. Functional testing such as plethysmography can be a complementary method alongside ultrasound for the evaluate of calf muscle dysfunction62,63 by observing the changing volumes of the lower legs before and after exercise. In a wellfunctioning system of venous return, the volume of the calf should decrease during exercise and increase with rest. The change in the volume is graphed and analyzed against normal values. By applying pressure with a tourniquet, one can limit the ow through the supercial vessels therefore testing the deep venous system in isolation. Radiological Studies Computed tomography of the venous system may be used and requires less contrast dye than venography (discussed below). Magnetic resonance imaging is becoming more popular for imaging the soft tissue surrounding the vessels, and magnetic resonance venography can show occluded vessels and alteration of ow. In end-stage CVI, the patient will often

Differential Diagnosis and Evaluation

The complete workup of a venous ulcer requires a comprehensive history and physical examination, with the appropriate use of supplementary investigative modalities such as vascular studies and biopsy. Often serial studies are necessary to make a denitive diagnosis.55 It is essential for the clinician to rule out other causes of (or secondary factors contributing to) ulceration, such as arterial insufciency, trauma, diabetes, sickle cell disease, infection, malignancy, and inammatory disorders. The physician must inquire into when and how the ulcer began, how it has progressed with time, and whether the patient has signicant pain. It is important to take a comprehensive history including past medical and surgical history, family and social history, and extensive review of systems. A list of the patients medications should be obtained, especially in regards to agents such as hydroxyurea that are a known cause of leg ulceration.56 A history of previous and current topical treatments is important to decide on the need for patch testing. Although these ulcers are not typically symptomatic, pain, discomfort or burning may be present.

The Physical Examination

Venous ulcers often are diagnosed clinically based on a constellation of signs and symptoms. The ulcer may begin as an erosion or shallow wound, frequently precipitated by minor trauma, and gradually progress. The borders usually are sloping. Many patients will show signs of venous disease in the skin surrounding the ulcer, with dermatitis, erythema, or edema. The skin may be thickened or hyperpigmented, indicating lipodermatosclerosis. Varicose veins and ankle swelling frequently are observed.31 Venous ulcers can occur anywhere on the leg or foot but are characteristically located between the lower third of the calf and one inch below the malleolus6 This location has been termed the gaiter area, referring to a region on the boots of British soldiers. During a thorough physical examination, the patient should be examined for inammation, which may be consistent with a contact dermatitis. If he or she has undergone treatment with various topical agents or has erythema that is not easily explained by infection or edema, the patient may require testing with a patch test panel that is specically created to test for the agents under suspicion.

Diagnostic Testing
The clinical diagnosis may be supported by further diagnostic testing as indicated, especially if other diagnoses are being considered in the differential.

220 display subcutaneous brosis and inltration of the extrafascial spaces.64 Invasive Techniques The gold standard for dening the patients venous anatomy and demonstrating reux is venography. In ascending venography, the patient is upright while a tourniquet is applied above or below the knee. Contrast dye is introduced, and if the dye is seen distal to the tourniquet, the patient is assumed to have venous reux. In descending venography, the patient placed in the supine position and the contrast is injected into the common femoral vein. The patient is then tilted downward, and the level to which the contrast dye leaks is observed. A leak below the level of the knee considered significant for reux. A recent comparison between various invasive and noninvasive techniques were performed by Mantonis group. They found continuous wave Doppler and ambulatory strain gauge plethysmography of little value in the workup of patients with deep venous insufciency. Descending phlebography was technically possible in less than one third of patients. They suggested triple ultrasound should be used as a rst line diagnostic tool, with ascending phlebography used only when the triple ultrasound is inconclusive.59 Biopsy is rarely warranted in the case of classic venous disease. If there is any doubt as to the diagnosis, or if the physician is concerned about the presence of another diagnosis such as infection or malignancy, a skin biopsy with preservative-free saline can performed, with half sent in formalin to pathology and the other half for culture. Although tissue culture has been hailed as the gold standard in the assessment of wound infection, recent studies have shown a culture swab to be equivalent in the initial evaluation of bacterial wound infection.65 However, if there is a concern for antimicrobial resistance or the ulcer is refractory to treatment, a deep tissue biopsy has been shown to be more sensitive for resistant organisms66 In these cases, bacterial, fungal and atypical mycobacterial organisms should be ruled out.

J. Reichenberg and M. Davis

Table 1 Classication of Chronic Venous Disease in the Lower Limbs C Clinical signs Grades 06, 0 no visible venous disease, 6 active ulceration Asymptomatic or Symptomatic Congenital, Primary, Secondary Supercial, Perforating, Deep different segments noted by numerals 118 Reux or Obstruction different segments noted by numerals 118

E A

Etiology Anatomic distribution

Pathophysiology

Adapted from the Classication and grading of chronic venous disease in the lower limbs. A consensus statement by Beebe et al68

bone. Although rare, this complication has signicant morbidity and mortality, therefore clinical suspicion must remain high. In any chronic venous ulcer that demonstrates palpable bone or tendon at the time of evaluation, the clinician should consider radiological evaluation or a consultation with orthopedic surgery for possible dbridment and tissue culture.6 There is great controversy regarding the radiological evaluation for osteomyelitis, the details of which are beyond the scope of this review. Plain x-rays, magnetic resonance imaging scans, and 3-phase bone scans all can be considered.

Squamous Cell Carcinoma (SCC)

In patients with chronic venous ulcers, the risk of SCC is increased within the wound. Given the rarity of this phenomenon, an epidemiologic study can be very difcult. Baldursson and coworkers71 were able to nd 17 cases of SCC that appeared directly related to venous ulcers. By comparing these patients to the general population, they determined a relative risk of 5.8. Of note, these ulcers had been present for a median of 25 years, stressing the importance of the chronicity of the ulcer. This same group has continued to investigate this rare phenomenon, with a total of 25 patients in their series. They were able to determine their average age to be 78.5 years,72 which is very close to the average age of 75 for all patients with leg ulcers.10. The tumors were more aggressive than other SCCs, with a median survival time of 1 year. More than 50% of the tumors were either moderately or poorly differentiated, and metastases were proven in almost one-third of the cases. The authors stress the importance of thorough evaluation of patients with suspected SCC in association with a venous ulcer, and suggest aggressive treatment to minimize mortality.72 The cause of SCC is thought to be chronic inammation, but the exact mechanism is unknown. Recent studies conrm that the carcinomas found in venous ulcers express different proto-oncogenes than those thought to be induced by ultraviolet light.73 Increased levels of both c-fos and c-ras mRNA have been found in the basal layer of epidermis in chronic wounds.74 The exact carcinogen, however, has yet to be elu-

Classication and Grading Schemes

In 1994, the American Venous Forum formed a consensus for the classication of venous disease. This classication system has been adopted by several vascular associations and the details were published in vascular, surgical, and dermatologic journals in several countries (Table 1).67-70 This classication system has allowed for the standardization of diagnosis and treatment of venous disease. Of note, the CEAP classication is not a permanent label, and the patient should be reclassied at intervals throughout their treatment.

Complications
Osteomyelitis
Although most venous ulcers begin as supercial lesions, the ulcerations can progress deeply to involve the underlying

Venous ulcers
cidated. Work has also found that despite the presence of HPV in some chronic venous ulcers, none of the SCCs found in association with a venous ulcer were HPV positive.75
Table 2 Dressing Classes Available

221

Therapy
General Principles
The core principles for management of venous ulcerations are (1) clean wound base and (2) compression. It has been said that if these methods fail to work within 3 months, a patient should be referred to a specialist.55 The management of leg ulcers was well summarized by Kantor and Margolis.76

Gauze (May be impregnated; petrolatum, etc) Hydrocolloids Transparent lms Hydrogels Foams Alginates Antimicrobials: iodine, silver, alcohols, biguanides, chlorine Collagen

The Clean Ulcer

The aim of wound care is to provide an optimum environment for healing. A clean ulcer with healthy-appearing beefyred granulation tissue at its base is considered the best environment. Dbridment It generally is agreed that ulcers should be dbrided of any dead tissue. Numerous reasons for performing dbridment have been proposed. Necrotic material on an ulcer bed may enhance bacterial colonization, leading to infection. Necrotic material may stimulate inammation leading to destruction of surrounding healthy tissue. It may also act as a physical barrier to reepithelialization. There is a variety of methods of dbridment, including surgical, mechanical, autolytic, and enzymatic. Treating Infection When clear evidence of an infection is present, such as a cellulitis surrounding the wound, empiric therapy should be initiated. Appropriate regimens may include cephalexin, clindamycin, amoxicillin/clavulanate, or a uoroquinolone.77 The use of oral antibiotics for asymptomatic infection is controversial. Wounds are almost always colonized with bacteria, even when a patient is on antibiotics. In a study of 656 chronic wounds of various etiologies, almost all ulcers (95.1%) were colonized with at least one bacterial species despite more than one quarter being treated with antibiotics.78 Eradication of Staphylococcus aureus from a wound may not speed healing.50 Oral antibiotics may not penetrate in sufcient concentration in a wound to be effective. It has been recently considered that biolms (colonies of bacteria surrounded by a polysaccharide capsule) may act as a barrier to the diffusion of antibiotics into the wound. Ongoing studies are examining the possibility of disrupting this barrier with enzymatic therapy or other agents.79 In the meantime, physical removal of these biolms may be achievable using methods of debridement already outlined. Biolms are likely barriers to healing in a wound and may physically block the action of topical therapies. Use of specic topical antibiotics also is very controversial. Although considered ineffective in improving wound healing in the past couple of decades,80 there has been a recent surge

of interest in the use of topical antimicrobials in literature and anecdotal common usage. Slow-release iodine and silver have been added into numerous wound care dressings, and reports have begun to validate their use. Silver sulfadiazine 1% cream has been shown to be superior to placebo in reducing the size of ulcers that were not thought to be infected. It is thought that silver sulfadiazine may permit keratinocyte replication and have an anti-inammatory affect.81 Additionally, low concentrations of silver ions exhibit antibacterial properties.82 Because of the increased risk of contact allergy in patients with venous insufciency, it generally is recommended to avoid specic topical antibiotics, particularly Bacitracin and Neosporin because they are common sensitizers.55,83

Wound Care: Topical Agents

A plethora of topical preparations are now on the market under the rubric of wound care materials. The choice of agents can be bewildering. An excellent summary of currently available topical preparations has been published in book form,84 but it is important to note that there are many new products on the market every year. One of the most important principals of wound care, one that is often misunderstood by patients and practitioners alike, is the recognition that a moist environment will best promote wound healing.8586 Before these publications in the 1960s, it had been considered that a dry environment was optimal for wound healing. There are many classications of wound dressings, including that outlined in the next sections. Different classes are now being combined so that new dressings can be a synergistic combination of an alginate with an antimicrobial and hydrogel, silver with alginate, or collagen with a hydrocolloid. Different wound dressings are appropriate for different ulcerations and even different phases of healing of ulcerations. For example, for dry wounds, hydrogels, hydrocolloids and impregnated gauze work well, and for exudative wounds it is best to use alginates, foams, or dry gauze. Classes of dressings are shown in Table 2.

Compression
Compression is undoubtedly one of the most important factors in the healing of venous ulcers.87 Compression not only supplements the pumping action of the calf muscle but also increases tissue pressure to reverse the gradient between the capillaries and the intravascular space, allowing for the reab-

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Table 3 Types of Skin Grafts 1) 2) 3) 4) Full thickness Partial thickness Allogeneic (cultured) Articial (tissue-engineered skin) a) Dermagraft b) Apligraf

J. Reichenberg and M. Davis

cure after surgery, no longer requiring the use of compression stockings. In the well-selected patient with CVI, vascular surgery or sclerotherapy can treat insufciency in the supercial and perforator veins. This can speed up healing time and improve long-term prognosis.33,95 By eliminating or repairing venous incompetence, one can reduce the risk of recurrent venous ulceration, but it is important to use vascular imaging to distinguish this problem from that of postthrombotic syndrome. Such conditions are treated much differently.96 Subfascial endoscopic perforator vein surgery has been described for treatment of venous ulceration with proven incompetent perforators.97 Although this technique is associated with a risk of nerve damage,98 recent advances and modications of the technique promise decreased pain and recovery time from the procedure.99

sorption of tissue edema.3388 It is important to rule out concomitant arterial disease55 before initiating compression therapy, or risk compromising the patients arterial supply and tissue anoxia.89 Several values for the ABPI have been used as a cut-off, ranging from 0.7 to 0.9.90 Below these values, it is recommended to avoid compression. Many methods are available, including nonelastic wraps, elastic wraps, and orthotic intermittent compression devices. Generally, even minimal compression is better than no compression, and the higher the compression, the more effective it is. Most clinicians use graduated compression of 30 to 40 mm Hg at the ankle.55 Intermittent pneumatic compression, which uses an air pump to inate and deate an airtight bag wrapped around the leg, may be as effective as other compression devices.8,92 However they are expensive and must be placed on the ulcer for at least 6 hours per day.93 In situations in which a patient will not comply with other methods used for leg compression, intermittent pneumatic compression may be a consideration.

Prevention of Recurrence
The cornerstone of prevention of recurrence of venous ulcerations is compression55 Interestingly, although this is the conventional view, there are no trials that have compared compression with no compression for the prevention of recurrence. A Cochrane review cited circumstantial evidence for the benet of compression as a whole, and referred to evidence that high compression is superior to moderate compression for the prevention of recurrence.91 Patient education is important in the prevention of recurrence as well.55

Skin Grafts and Flaps

Skin grafts and aps have been used for the management of chronic ulcerations (Table 3). They should only be applied to a clean, uninfected ulceration with an adequate vascular supply. It has been suggested that the benet of skin grafts are the transplanted cells, which can secrete growth factors and other products that might enhance healing. Full-thickness or split-thickness grafts can be used. Allogeneic (cultured) keratinocytes also may be used but can be expensive. There is increasing interest in tissue-engineered skin. Graftskin (Apligraf) is a bilayered skin equivalent that includes dermal and epidermal components and is manufactured by harvesting neonatal foreskins and extracting both keratinocytes and broblasts that are then cultured separately to create the epidermal and dermal components. Graftskin has been approved by the Food and Drug Administration (FDA) for use in diabetic neuropathic ulcerations and venous ulcerations. Dermagraft is comprised of human broblasts on a bioabsorbable scaffold; studies indicate that this product also may be useful for venous ulcerations.

Oral Agents for the Treatment of Venous Ulcers

Pentoxifylline is a xanthine derivative that is thought to help treat occlusive disease by decreasing blood viscosity with approval by the FDA for the treatment of claudication.100 In a systemic review of clinical trials, it has been found to be helpful in treating venous ulcers and has been recommended as an adjunctive treatment in treatment regimens.101 Although some argue that it may only provide marginal benet, it has an excellent risk prole with adverse effects similar to placebo (rare gastrointestinal upset).101 Zinc was popularized as a topical treatment for leg ulcers during the past century, and one study found it helpful for arterial and venous ulcers.102 Although it may have a mild antimicrobial effect, there is no evidence that zinc can improve wound healing.102 It is argued that although Unna boots (made with zinc paste) are used in the treatment of venous ulcers, they may be effective because of a compressive effect and not because of the composition of the plaster.103 A metaanalysis did not nd sufcient evidence that oral zinc sulfate could improve the healing of venous ulcers.104 Diuretic treatment of peripheral edema caused by CVI is a temporizing measure that does not address the true physiologic problem.105 In the treatment of venous ulcers, however, they may occasionally be found useful to acutely decrease the volume of leg edema and allow for better wound care and compression to begin. Oral micronized puried avonoid fraction modulates

Surgical Intervention/Procedures
One study of venous ulcers showed that no more than 15% of patients had isolated deep venous reux, whereas in 53% of patients there was supercial reux only.94 Patients with reux on in the supercial and perforating veins may be more amenable to treatment, and may actually have a clinical

Venous ulcers
leukocyte adhesion and prevents endothelial damage, and there is evidence that it promotes venous leg ulcer healing.106

223 When pain cannot be managed with topical agents, it is important to provide the patient with oral agents.125

Adjunctive Management/Advanced Techniques/Investigational Techniques

Several supplemental techniques have been tried or are under investigation. The topical application of Simulium vittatum erythema protein extracted from black ies may locally increase blood ow to aid in wound healing107 Topical autologous platelets have no signicant adjuvant effect on healing of chronic venous leg ulcers 108,109 Plateletderived growth factors, however, have become commonplace in wound care centers, and have been shown to be helpful in diabetic110, neuropathic,111 and decubitus112 ulcers. In the laboratory, they show promise for the promotion of wound healing in venous ulcers,113 and a clinical trial is now underway.114 Overall, clinical trials using growth factors to accelerate wound healing have been disappointing. Recombinant PDGF-BB (becaplermin) has been approved by the FDA for use in diabetic foot ulcers.110, and a recombinant GCSF product (Filgrastim) is proven to be effective as a subcutaneous injection for the treatment of infected diabetic foot ulcers.115 Cymetra, a collagen ller often used in cosmetic applications, was found to be helpful in healing sinus tracts116, and was recently tried for chronic ulcers, including pyoderma gangrenosum. At this time, none of these treatments have been comprehensively studied for the treatment of venous ulcers.

Wound Care Center

If a venous ulceration does not improve with standard compression and optimum wound care in the primary care setting, consideration should be given to sending the patient for care at a specialized wound healing center if accessible. Some studies have shown a signicant increase in cure rate among patients receiving more specialized care. A study in England showed that after 12 weeks, patients attending the existing hospital-based venous ulcer care clinics had a cure rate of 22%, while those attending a specialized community leg ulcer clinic were completely healed 80%. Of note, the hospitalbased clinic was 2.5 times more expensive for the same treatment period.126

Prognostic Indices
Patient treatment may be guided, in part, by the patients prognosis. This is particularly poignant for venous ulcers, which tend to be chronic in nature. One study investigating chronic venous ulcers showed a 24-week healing rate of 76% with a 1-year recurrence rate of 17%.127 Men and diabetic patients have a lower chance of complete resolution of their chronic lower extremity ulcers.128 Margolis has found that size and duration of the venous ulcer are the best predictors of wound healing. In ulcerations that are less than 10 cm2 and less than 12 months old at their initial evaluation, more than 70% will heal by 24 weeks, whereas in those ulcers greater than 10 cm2 and greater than 12 months old, only 22% will heal during the same period of time.129 With a cut-off values of less than 5 cm2 and less than 12 months duration, ulcers had a 93% chance of healing, whereas those patients with an ulcer larger than 5 cm2 and greater than 12 months duration have only 13% chance of resolution over the same treatment interval.114 A multicenter study by Phillips and coworkers showed similar results. In those venous ulcers less than 5 cm2, 72% healed at 12 weeks, whereas those ulcers larger than 5 cm2 had only 40% rate of healing. Out of ulcers less than a year old, 64% had complete healing in 4 weeks, whereas those ulcers greater than 3 years duration had an only 24% rate of healing.130 The size and duration of the ulcer also affected the rate of healing; those ulcers less than 5 cm2 took an average of 7.5 weeks to heal, while those larger than 5 cm2 took an average of 9.8 weeks.130 Not surprisingly, ulcers that began to show signs of healing early on had an increased chance of full resolution in the long term. If an ulcer showed 44% healing at week three of compression and wound care, it could be predicted to completely heal over 12 weeks in 77% of the cases studied.130 Another study showed a 30% healing by week 2 to be similarly predictive of a positive outcome.128 There is some evidence that the age of the patient is also correlative with the ulcer duration.127 In addition, those patients who did not treat their supercial venous reux with surgery had a higher risk of ulcer recurrence.127

Medical Devices
Medical devices may play a role in the healing of venous ulcers. Hyperbaric oxygen therapy is a treatment designed to increase the supply of oxygen to wounds by placing patients in a specially designed chamber. A Cochrane review found that hyperbaric oxygen therapy was helpful in people with diabetic ulcers but did not have enough evidence to suggest its use in ulcers of other etiologies.117 Therapeutic ultrasound was not shown to be helpful in the treatment of venous ulcers in a recent review,118 nor has laser therapy.119 Electromagnetic therapy (also called PEMF pulsed electromagnetic eld) has been promoted by the Agency for Health Care Research and Quality for pressure ulcers120; however, there is no reliable evidence to show whether electromagnetic therapy can help heal venous leg ulcers.121

Management of Ulceration Pain

Although venous ulcers classically are associated with a minimum of pain, recent work has shown that patients can still suffer from physical or emotional discomfort.22,23 The patients may have pain at rest or during dressing changes and wound dbridment. There is a paucity of published trials concerning the appropriate management of ulcer pain.122,123 EMLA, a mixture of lidocaine and prilocaine (AstraZenica, Wilmington, DE) provides good pain relief for dbridment, although its effect on wound healing is of yet unknown.124

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leg: extent of the problem and provision of care. Br Med J Clin Res Ed 290:1855-1856, 1985 Krasner D: Painful venous ulcers: themes and stories about their impact on quality of life. Ostomy Wound Manage 44:38-42, 1998 Phillips T, Stanton B, Provan A, et al: A study of the impact of leg ulcers on quality of life: nancial, social, and psychologic implications. J Am Acad Dermatol 31:49-53, 1994 Charles H: The impact of leg ulcers on patients quality of life. Professional Nurse 10:571-572, 1995 Charles H: Does leg ulcer treatment improve patients quality of life? [comment]. J Wound Care 13:209-213, 2004 Olin JW, Beusterien KM, Childs MB, et al: Medical costs of treating venous stasis ulcers: evidence from a retrospective cohort study. Vasc Med 4:1-7, 1999 Ruckley CV: Socioeconomic impact of chronic venous insufciency and leg ulcers. Angiology 48:67-69, 1997 XE:com. XE:com Universal Currency Converter DePalma RG, Kowallek DL: Venous ulceration: a cross-over study from nonoperative to operative treatment. J Vasc Surg 24:788-792, 1996 Weiss RA, Heagle CR, Raymond-Martimbeau P: The Bulletin of the North American Society of Phlebology. Insurance Advisory Committee Report. J Dermatol Surg Oncol 18:609-616, 1992 Gross EA, Wood CR, Lazarus GS, et al: Venous leg ulcers: an analysis of underlying venous disease. Br J Dermatol 129:270-274, 1993 Nicolaides AN, Hussein MK, Szendro G, et al: The relation of venous ulceration with ambulatory venous pressure measurements. J Vasc Surg 17:414-419, 1993 Zimmet SE: Venous leg ulcers: modern evaluation and management. Dermatol Surg 25:236-241, 1999 Delis KT: Leg perforator vein incompetence: functional anatomy. Radiology 235:327-334, 2005 Hanrahan LM, Araki CT, Rodriguez AA, et al: Distribution of valvular incompetence in patients with venous stasis ulceration [see comment]. J Vasc Surg 1991;13:805-811; discussion 811-812 Browse NL, Burnand KG: The cause of venous ulceration. Lancet 2:243-245, 1982 Zimmet SE: Leg ulcers. J Am Acad Dermatol 27:487-8, 1992; author reply 488-489 Browse NL, Burnand KG: The cause of venous ulceration. Lancet 2:243-245, 1982 Van de Scheur M, Falanga V: Pericapillary brin cuffs in venous disease. A reappraisal. Dermatol Surg 23:955-959, 1997 Falanga V, Eaglstein WH: The trap hypothesis of venous ulceration [see comment]. Lancet 341:1006-1008, 1993 Coleridge Smith PD, Thomas P, Scurr JH, et al: Causes of venous ulceration: a new hypothesis. Br Med J Clin Res Ed 296:1726-1727, 1988 Peyton BD, Rohrer MJ, Furman MI, et al: Patients with venous stasis ulceration have increased monocyte-platelet aggregation. J Vasc Surg 27:1109-1115, 1998; discussion 1115-1116 Powell CC, Rohrer MJ, Barnard MR, et al: Chronic venous insufciency is associated with increased platelet and monocyte activation and aggregation. J Vasc Surg 30:844-851, 1999 Claudy AL, Mirshahi M, Soria C, et al: Detection of undegraded brin and tumor necrosis factor-alpha in venous leg ulcers. J Am Acad Dermatol 25:623-627, 1991 Dormandy JA: Microcirculation in venous disorders: the role of the white blood cells. Int J Microcirculation 15:3-8, 1995 (suppl 1) Higley HR, Ksander GA, Gerhardt CO, et al: Extravasation of macromolecules and possible trapping of transforming growth factor-beta in venous ulceration. Br J Dermatol 132:79-85, 1995 Phillips TJ, al-Amoudi HO, Leverkus M, et al: Effect of chronic wound uid on broblasts. J Wound Care 7:527-532, 1998 Stewart P: Theoretical aspects of antibiotic diffusion into microbial biolms. Antimicrob Agents Chemother 40:2517-2522, 1996 Costerton, Cheng K-J, Geesey GG et al: Bacterial biolms in nature and disease. Ann Rev Microbiol 41:435-464, 1987 Trividic-Rumeau M, Bouyssou-Gauthier ML, Mounier M, et al: Etude

Conclusion
Venous ulcers are a common problem and have a profound impact on the health care budget of every nation. Signicant advances have been made in understanding the pathophysiology, clinical features, and diagnosis. Although the arsenal of currently available therapeutic interventions continues to expand, the basic principles remain: a clean moist wound with elimination of surrounding edema will provide the optimum healing conditions for a venous ulcer.70,75
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