JOURNAL

of the

AmeRICaN ACaDemy OF

DerMaTOLOGY VOLUME 25

Continuing

NUMBER 6

PART I

DECEMBER 1991

medical education

Leg ulcers Tania J. Phillips, MD, MRCP, FRcpC,a and Jeffrey S. Dover, MD, FRCPCb Boston, Massachusetts The treatment of leg ulcers is a common and sometimes difficult problem. They can be costly to treat and are associated with loss of working capacity and sometimes significant morbidity. In the western world, leg ulcers are most frequently caused by venous insufficiency, arterial insufficiency, neuropathy (usually diabetic), or a combination of these factors. The pathogenesis, clinical features, and management of these types of leg ulcers are emphasized in this review. (J AM ACAD DERMATOL 1991;25:965-87.)

The prevalence of leg ulcers in Europe is well documented, varying between 0.18% and 1%in different countries. 1-7 No recent or accurate estimate is available for the United States; the true prevalence is likely higher8, 9 than the frequently quoted figures of 500,000 10 and 600,000 11 patients. Leg ulcers occur more commonly in the elderly, and their prevalence is likely to increase as the average age of the population increases,6, 12 In Sweden, 4% to 5% of the population older than 80 years sought medical advice for ulcers. 3 However, the elderly are not the only population at risk; in one study ulceration began before the age of 40 years in 22% of the population studied. 12 COST AND MORBIDITY

The cost of chronic nonhealing wounds is enormous, but estimates ofthe costs of treating leg ulcers vary widely. A study in England analyzing the cost of dressing material used in venous leg ulcers The CME articles are made possible through an educational grant from the Dermatological Division, Ortho Pharmaceutical Corporation. From the Department of Dermatology, Boston University School of Medicine,a and the Departments of Medicine, New England Deaconess Hospital, and Dermatology, Harvard Medical School.b Reprint requests: Tania J. Phillips, Department of Dermatology, Boston University Medical Center, K-103, 80 E. Concord St., Boston, MA 02118.

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estimated that the cost for 4 months of outpatient treatment varied between $250 and $2500. 13 Estimated annual costs ofulcer treatment in Sweden are $25 million. 14 Projecting these figures to the U.S. population, costs would vary between $775 million and $1 billion. The morbidity ofleg ulcers, added to the cost of health care, significantly affects patients' lifestyles. 15 There is an estimated loss of 2,000,000 work days annually in the United States because ofleg ulcers. 16 In addition, working capacity may be permanently affected. I. 17, 18 ETIOLOGY

In the western world leg ulcers are most frequently caused by venous insufficiency, arterial insufficiency, neuropathy, diabetes, or a combination of these factors. Venous ulcers are the most common type of leg ulcer, accounting for approximately 80% to 90% of cases. Arterial disease accounts for another 5% to 10%; most of the others are due to neuropathy (usually diabetic) or combinations of those diseases. 19, 20 These disorders are emphasized in this review. A classification for leg ulcers is presented in Table I. VENOUS ULCERS

Pathogenesis

The association between ulceration at the ankle and venous disorders of the lower limb has been 965

Journal of the

American Academy of Derma tology

966 Phillips and Dover Table I. Causes of leg ulcers I. Vascular diseases A. Venous B. Arterial Atherosclerosis Thromboangiitis obliterans Arteriovenous malformation Cholesterol embolism C. Vasculitis

Small vessel

Hypersensitivity vasculitis Rheumatoid arthritis Lupus erythematosus Scleroderma Sjogren's syndrome Beh~et's disease Atrophie blanche

Medium and large vessel

Polyarteritis nodosa Nodular vasculitis Wegener's granulomatosis

D. Lymphatics Lymphedema II. Neuropathic Diabetes Tabes dorsalis Syringomyelia III. Metabolic Diabetes Gout Prolidase deficiency Gaucher's disease IV. Hematologic diseases A. Red blood cell disorders Sickle cell anemia Hereditary spherocytosis Thalassemia Polycythemia rubra vera B. White blood cell disorders Leukemia C. Dysproteinemias Cryoglobulinemia Cold agglutinin disease Macroglobulinemia

known for more than 2000 years. 21 ,22 The term varicose ulcer is misleading as venous ulcers are usually associated with deep venous insufficiency. This connection between deep vein damage and ulceration was noted by G ay23 and later by Homans,24

Table I. Cont'd V. Trauma Pressure Cold injury (frostbite, pernio) Radiation dermatitis Burns (thermal, chemical) Factitia VI. Neoplastic A. Epitheliomas Squamous cell carcinoma Basal cell carcinoma B. Sarcoma (e.g., Kaposi's sarcoma) C. Lymphoproliferative Lymphoma Cutaneous T cell lymphoma D. Metastatic tumors VII. Infection A. Bacterial Furuncle Ecthyma Ecthyma gangrenosum Septic emboli Gram-negative infections Anaerobic infections Mycobacterial (typical and atypical) Spirochetal B. Fungal Majocchi's granuloma Deep fungal infections C. Protozoal Leishmania D. Infestations and bites VIII. Panniculitis Weber-Christian disease Pancreatic fat necrosis Necrobiosis lipoidica IX. Pyoderma gangrenosum

who also noticed that venous ulcers often had few visible varicose veins. The concept of venous stasis suggested that stagnant blood lying within tortuous and dilated veins close to the skin might cause tissue anoxia and cell death. Later studies, however, showed that limbs with venous ulcers have a faster circulation time than normal with a higher oxygen content in the veins of limbs with venous ulcers. 24-28 Thus the popular term stasis ulceration is a misnomer. In patients with venous disease, there is incompetence of the valves within the perforating veins connecting the superficial to the deep venous systems in the leg. In normal subjects, venous pressure de-

Volume 25 Number 6, Part I December 1991

Leg ulcers 967

,{i 5",,,tlo;., V/

J-( venous system

(low pressure)

Competent valves

Perforating vein

Incompetent valves

Fig. 1. The low-pressure superficial venous system is protected by valves from the high-pressure deep venous system. In venous insufficiency, there is valvular dysfunction. High pressure is thus transmitted throughout the superficial and deep venous systems. creases during exercise. In patients with venous incompetence, pressure remains high during exertion. 29 High venous pressure is associated with capillary proliferation and increased permeability of large molecules into the skin. 29, 30 In 1982, Browse and Burnand22 proposed that the high ambulatory venous pressure within the calf muscle pump is transmitted to the capillary circulation in the skin and subcutaneous tissues of the calf (Fig. I). They hypothesized that the distended local capillary bed widened the endothelial pores, allowing fibrinogen molecules to escape into the extracellular fluid, where they form fibrin complexes around the capillaries. 31 It was postulated that this layer of fibrin forms a pericapillary barrier to the diffusion of oxygen and other nutrients that are essential for the normal vitality of the skin (Fig. 2). Burnand et al. demonstrated a pericapillary fibrin layer in patients with venous disease, a finding which has been subsequently confirmed by others. 32 Pericapillary fibrin has been shown to impede oxygen diffusion in patients with venous disease. 33 In patients with ulcers of other origins, pericapillary fibrin deposition is not found. In addition, patients with venous disease have been found to have faulty fibrinolysis with prolonged euglobulin lysis time and an elevated plasma fibrinogen level,34 but it is uncertain whether these findings are primary or secondary to the fibrin

deposition. A more recent hypothesis proposes that in venous ulceration, trapped leukocytes occlude capillaries, thereby resulting in cutaneous ischemia. 35 Clinical features History. Not all patients with venous insufficiency will give a history of deep vein thrombosis; indeed, the majority of patients have silent thromboses. 2o The patient may complain of aching and swelling in the legs that are exacerbated by dependency and relieved by elevation of the limb. Examination. Edema of the lower limbs is common in venous insufficiency. It becomes persistent unless treated with compression. Brown or brownred pigmentation and purpura occur because of extravasation of red blood cells into the dermis, collections of hemosiderin within macrophages, and melanin deposition. Eczematous changes are common, with erythema, scaling, pruritus, and sometimes weeping. Lipodermatosclerosis is the term used to describe induration and fibrosis of the dermis and subcutaneous tissue that develops in venous insufficiency. Eventually the entire lower third ofthe leg may become sclerotic and woody, resulting in an "inverted champagne bottle" appearance. 36 Lipodermatosclerosis often precedes venous ulceration, 16 Venous ulcers usually develop over the malleoli,

Journal of the American Academy of Dermatology

968 Phillips and Dover

Endothelial cells

Normal Capillary Bed

Capill ary proliferation

Pericapillary fibrin deposition

Fig. 2. In venous insufficiency, high venous pressure is transmitted to the capillary circulation. The endothelia! pores widen, allowing escape of fibrinogen into the extracellular fluid, with deposition around capillaries. Capillary proliferation also occurs.

particularly on the medial aspect of the leg, and characteristically have an irregular "shaggy" border. Once ulceration is well established, repeated episodes of infection and cellulitis can contribute to damage ofthe lymphatic system, resulting in chronic lymphedema. Ultimately, patients may have fibrous or bony ankylosis at the ankle because of immobility. A typical venous ulcer is shown in Fig. 3. ARTERIAL ULCERS Pathogenesis Atherosclerosis is a degenerative disease characterized by the accumulation of cells, matrix fibers, lipids, and tissue debris in the vessel intima, which result in narrowing of the lumen and obstruction of blood flow. The arteries of the lower limbs are frequently affected by atherosclerotic plaque and are subject to variation in hydrostatic pressure and flow rate, depending on the level of physical activity. A sedentary lifestyle is associated with low arterial flow rate in lower limbs and increased plaque formation. 3? Ulceration often arises after minor trauma to an atherosclerotic limb. History Patients with peripheral arterial disease are characteristically older than 45 years. Symptomatically

they have intermittent claudication, characterized by pain in the calves or buttocks that occurs on exertion but is relieved by rest. With more severe occlusive disease, the patient may experience pain at rest. The pain from ulceration is usually severe and difficult to control, often worsening when the legs are elevated and improving on dependency. Patients sometimes sleep in a chair at night to relieve the pain. Cigarette smoking and diabetes mellitus are the risk factors most closely associated with atherosclerosis of the lower limbs. Examination Ischemic ulcers appear typically "punched out" with a sharply demarcated border and frequently occur over sites of pressure or trauma, such as bony prominences, or at distal points, such as the toes. They usually appear dry with a gray or black base that may be covered with necrotic debris (Fig. 4). Granulation tissue is often scant or absent. Associated findings include loss of hair and shiny, atrophiclooking skin. Peripheral pulses may be diminished or absent, and a palpable or audible bruit over the femoral artery is usually associated with proximal atherosclerotic lesions in the iliac Or common femoral arteries. Capillary refilling time is measured by manual compression of the tip of the great toe for a

Volume 25 Number 6, Part 1 December 1991

Fig. 3. Typical venous ulcer located above the medial malleolus with surrounding hemosiderin hyperpigmentation.

few seconds until it blanches and then release of the toe. The time taken for the toe to return to its normal color is 3 to 4 seconds in normal subjects but is prolonged in the patient with arterial disease. The legs should be elevated slightly when performing the test to exclude capillary venous congestion. If peripheral pulses cannot be palpated, Doppler ultrasonography is helpful (see "Vascular Studies" section). The change in color of the limbs with alteration in position is another simple index of ischemia. Mter elevation of the limb at a 45-degree angle for 1 minute, the ischemic limb will become pale. On subsequent dependency there is delay in filling of the veins beyond the normal 10- to IS-second period. When the color does return, the limb becomes pink or bright red. In general, the greater the arterial insufficiency, the longer the venous filling time and the greater the intensity and extent of rubor.

Leg ulcers 969

Fig. 4. Arterial ulcer over the medial aspect of the foot. Note sharply demarcated borders, absence of granulation tissue, and presence of a dry, black base. There is also an ischemic bulla under the first metatarsal head. The patient had previously had a forefoot amputation.

is most common in the diabetic patient. The patient with a neuropathic ulcer may have pain, paresthesia, or anesthesia of the legs and feet, although occasionally the ulcer is completely asymptomatic. The character of the pain is often described as burning, tingling, numbing, or needlelike. At times it is almost constant and frequently is most severe at night. 4o In contrast, ischemic pain that is often localized to the foot is WOrse on reclining and relieved by dependency. Neuropathic pain may be relieved by exertion, whereas ischemic pain is exacerbated by exercise.

Examination

Neuropathic ulcers usually arise from frequent trauma to tissue, which results in inflammation and eventual ulceration. In a foot or limb with normal sensation, this degree of trauma would not be tolerated because of pain. 38 Neuropathic ulcers have been reproduced experimentally in animal models and appear to result not from a single injury, but from repetitive trauma. 39

The first sensation to be lost is light touch in the great toe, then in the foot. Vibration sense is subsequently lost, foHowed by loss of the ankle jerk, and finally joint position sense. 40, 41 Patients are usually unaware of trauma, which commonly leads to ulceration of the heel, the plantar metatarsal area, or the great toe42 (Fig. 5). The neuropathic ulcer is often surrounded by thick callus. Prolonged purulent drainage of these ulcers may be associated with underlying osteomyelitis. 43 Some patients have hyperesthesia of their feet, which may be so great that the patient cannot stand even the lightest touch. Conversely, the ulcer may be completely anesthetic to pinprick and deep tendon reflexes, and vibration sense to low frequencies (128 cycles/sec) may be impaired. 40, 41

History

THE DIABETIC PATIENT

Neuropathy should be excluded in any patient who comes for treatment of a leg or foot ulcer. This

Diabetic patients are predisposed to peripheral vascular disease, neuropathy, infection, and im-

NEUROPATHIC ULCERS

Pathogenesis

970

Journal of the American Academy of Dermatology

Phillips and Dover

Fig. 5. Neuropathic ulcer on right sole of 30-year-old diabetic patient. The ulcer developed within 12 hours of wearing a shoe with crumpled label on insole. The patient had previously undergone amputation of four toes of the left foot because of chronic ischemia.

paired healing. 44 Forty-five to seventy percent of all lower limb amputations are performed on diabetic patients40, 45-48 and 41 %to 70% of these patients do not survive more than 5 years after the surgical procedure. 49-52 Early detection of neuropathy or angiopathy in the patient with diabetes may prevent acceleration of complications or even reverse the process.53

Pathogenesis of diabetic ulcers Foot ulcers commonly arise in the diabetic patient with neuropathy, usually at sites of repeated trauma, such as over the toes, heel, and metatarsal heads on the plantar surface of the foot. Motor neuropathy can alter the patient's gait, thereby resulting in pressure over unusual sites. Autonomic neuropathy, with the loss of perspiration, can cause fissuring of skin, which acts as a nidus for ulceration. Arterial ulcers occur more frequently in diabetic patients and at an earlier age than in the nondiabetic population. Vascular involvement tends to be multisegmental, above and below the knee, in contrast to the nondiabetic patient in whom involvement generally occurs above the knee only. In diabetic patients there is involvement of the femoropopliteal segment, as in nondiabetic patients, but also a high propensity towards atherosclerotic occlusion of the tibial and peroneal arteries. 42 Thus it is not unusual to see a diabetic patient with an ischemic foot but with a strong popliteal pulse. In these patients distal arterial reconstruction can produce excellent results. 54 The

systolic blood pressure at the ankle studied with a Doppler flowmeter can be sometimes misleadingly high in the diabetic patient, because of medial calcification of the arteries. In these patients, measurement of pulse amplitude with an oscillometer or plethysmograph is helpfu1. 42 The diabetic patient should be given every opportunity for limb salvage. When modern techniques of arterial reconstruction are used, long-term prognosis in diabetic patients is nearly identical to that in nondiabetic patients.55 In the diabetic patient with ulceration of the limb, and decreased ankle/brachial systolic pressure index (AB!) measurements or limb pulsation, arteriography should be performed. The term small-vessel disease or microvascular occlusive disease has often been ascribed to diabetic patients. However, some light microscopic, vascular, and physiologic studies have demonstrated as much microvascular occlusive disease in nondiabetic as in diabetic patients.56, 57 Prospective studies of small arterial or capillary branches of diabetic patients have shown no evidence of intimal hyperplasia56 -59 although there does appear to be thickening of the basement membrane of muscle capillaries. Recent studies have also shown widened endothelial spaces in diabetic postcapillary venules and capillaries, possibly accounting for the increased vascular permeability of diabetic vessels. 60 The exact mechanism by which diabetes mellitus causes angiopathy and neuropathy is unknown,40,53 although factors such as impaired autoregulation, a reduced hyperemic response to injury, and impaired neurogenic vasodilation may reduce the healing potential of the skin after minor injury.61 TREATMENT

The following pertinent questions should be asked of patients with leg ulcers 19 :

1. How did the ulcer develop? In many patients, trauma is an initiating factor, but it may be important in neuropathic or factitious ulcers. [9 2. Did it develop rapidly or slowly? Arterial ulcers tend to develop slowly, whereas other types (venous, pyoderma gangrenosum) may progress rapidly.19 3. Is it painful? Ulcers caused by arterial disease, hypertension, or vasculitis are usually extremely painful. 19 Venous ulcers are less exquisitely painful but may be associated

Volume 25 Number 6, Part I December 1991

4.

5.

6.

7.

8.

9.

10.

11.

with an aching sensation. Neuropathic ulcers may be associated with paresthesia, burning sensations, or may be painless. Exacerbating or relieving factors: Pain from arterial ulcers is usually exacerbated by elevation ofthe limb or exertion, and relieved by dependency or rest. Discomfort from venous ulcers usually diminishes with leg elevation. 19 Associated features: A history of intermittent claudication is suggestive of arterial disease, whereas ankle swelling suggests venous insufficiency. Current treatment: Topical and systemic medications can impair wound healing. A variety of topical medications may cause contact dermatitis. Common sensitizers include ethylene diamine, lanolin, neomycin, nitrofurazone, parabens, and vitamin E creams. 62-65 A variety of systemic medications, such as corticosteroids, may impair wound healing. 65 -7o Habits: Cigarette smoking can severely impair wound healing. High alcohol intake is often associated with poor nutritional status, which can impede wound healing. Medical history: Although a large percentage of patients are unaware of previous deep vein thrombosis, a previous history of unilateral leg swelling is suggestive, particularly during or after pregnancy or surgery. General health: Diabetes and connective tissue disorders such as lupus erythematosus, rheumatoid arthritis, and polyarteritis nodosa may predispose patients to ulceration. Family history: Certain hematologic disorders may predispose patients to leg ulcers, including sickle cell anemia, thalassemia, and hereditary spherocytosis. A family history of diabetes mellitus, rheumatoid arthritis, or other connective tissue disorders could be significant. Social history: Does the patient live alone? Does he or she need visiting nurse services? Is he or she capable of changing dressings?

In the patient with leg ulcers a general physical examination should be performed to exclude cardiac failure and other medical conditions. Although other causes of leg ulceration are less common (Table 1), they should be considered in any patient whose ul-

Leg ulcers 971 cer has an unusual morphology, appears in an atypicallocation, or fails to respond to treatment. INVESTIGAnONS

A routine blood cell count and blood glucose level are helpful to exClUde signmcant hematologiC disorders or diabetes mellitus. A high erythrOCyte sedimentation rate (ESR) may indicate osteomyelitis or a connective tissue disorder. Low serum albumin or transferrin levels may suggest nutritional deficiencies. 71,72 Vitamins, particularly vitamins A and C, and trace elements, especially iron and zinc, are important in wound healing 73 ,74 and deficiencies should be corrected. Bacterial cultures of the wound bed usually reveal Staphylococcus aureus and var~ lOUS aerobic gram-negative bacilli, alone or in combination. 75 Some authors suggest that bacterial cultures of venous or diabetic ulcers are not warranted unless cellulitis or other complications are present. 76 We prefer to have a "baseline" bacterial culture and sensitivity result available, in case future complications such as cellulitis or sepsis develop. This will provide useful guidelines for initial antibiotic therapy pending further culture results. Other investigations, such as testing for antinuclear antibody and rapid plasma reagin, should be performed when appropriate. Vascular studies Simple vascular studies are important in excluding arterial disease in the patient with a leg ulcer. The measurement of systolic blood pressure in the ankle is the most sensitive method for detecting large-vessel disease. 42 In patients whose peripheral pulses are impalpable, a Doppler flowmeter should be used to hear the arterial pulsations over the dorsalis pedis and posterior tibial arteries. A comparison of systolic pressure in the ankle with that in the arm is made and the ABI is calculated. Patients with moderate to severe arterial disease will have an ABI of less than 0.7. 42 Any patients whose Doppler studies suggest arterial disease should have arteriography and surgical assessment for the feasibility of arterial reconstruction. Venous insufficiency can be assessed with a variety of techniques. Doppler ultrasonography is one of the cheapest and simplest tests to perform, but it is sometimes difficult to differentiate between superficial and deep venous insufficency with this technique. Photoplethysmography (PPG) assesses variation in light absorption of the skin by hemoglobin

Journal of the

American Academy of Dermatology

972 Phillips and Dover in dermai venous plexuses. When venous pressure is high and the dermal venous plexuses are full, the light is absorbed. As venous pressure decreases, and the venous plexuses empty, light transmission increases.77 This is a useful screening test to identify venous disease and to differentiate between superficial and deep vein incompetence. Light reflex rheography (a variant ofPPG), strain-gauge plethysmography, foot volumetry, and phlebography are other techniques enabling determination of venous insufficiency. Duplex ultrasound imaging is rapidly replacing phlebography in the assessment of venous reflux and phlebography in the assessment ofvenous reflux and thrombosis, although it is not yet widely available.77

Biopsy Biopsies should be done for chronic nonhealing ulcers, but various authors differ as to the optimal biopsy time. Some advocate biopsy of all patients at presentation,15 others recommend biopsy after 4 months, t2 and still others at a year. to Biopsy ofthe ulcer edge certainly seems to be a procedure that can be performed at no risk to the patient. We recommend biopsy of all ulcers that have not improved after 3 months of treatment, either by us or by the referring physician. This will help to exclude squamous cell carcinoma, basal cell carcinoma, or vasculitis. If a biopsy is being done to exclude squamous cell carcinoma, a wedge rather than a standard punch biopsy should be performed.

X·ray X-ray film of the ulcerated area may reveal evidence of osteomyelitis. In consultation with an orthopedic surgeon further investigations such as bone scan, computed tomographic scan, gallium scan, and bone biopsy may be necessary to confirm a diagnosis of osteomyelitis.

Patch tests Patch tests should ideally be performed in all patients with chronic leg ulcers, particularly if there is any suspicion of contact dermatitis. I5 The common allergens causing problems in these patients include neomycin, lanolin, bacitracin, formaldehyde, and parabens. 62-65 , 78 A typical "leg ulcer patch testtray" includes components of ointment bases and preservatives (wood alcohols, balsam of Peru, formaldehyde, parabens, propylene glycol, ethylene diamine);

antibacterial agents (neomycin/soframycin /framycetin, bacitracin, chinoform, gentamicin, quinoline mix): additives in bandages (MBT, thiuram, colophony) and any other agents the patient may have been applying topically.62-65, 78

MANAGEMENT OF VENOUS ULCERS

Control of edema The primary role of treatment is to reverse the effects of venous hypertension. The simplest method is to get the patient off his or her feet and into bed. This reduces venous pressure and allows swelling and pain to subside rapidly. Unfortunately, this may not be practical either because the patient has no help at home or because the current cost of prolonged hospitalization is prohibitive. The longest diagnosisrelated group time allowed for leg ulcer admission in the United States is 12.1 days.79 Because it usually takes much longer than this to heal a leg ulcer with bed rest, this form of therapy is impractical for most patients. However, putting the patient to bed for a few days can be helpful if the edema is severe. Leg elevation should beencouraged in all patients with venous insufficiency.

Compressive dressings Elastic support stockings are of proven value in overcoming the effects of prolonged venous hypertension. 80-83 Elastic compression applied to the calf raises the local hydrostatic pressure and decreases the superficial venous pressure, thereby reducing the leak of solutes and fluid into the interstitial space. 80 Compression also improves venous return, as seen in an increase in flow velocity through unoccluded deep and superficial veins. 84 Compression enhances the local release of plasminogen activator,85 which is of potential benefit in restoring defective fibrinolysis and stimulating the breakdown of pericapillary fibrin deposits. 86 The optimal amount of compression at the ankle and calf necessary to heal and prevent venous ulcers is not known. Stemmer et al. 82 calculated that external pressure of 35 to 40 mm Hg was necessary to prevent capillary exudation in legs severely affected by venous disease. Hendricks and Swallow87 found that graded compression from 24 mm Hg at the ankle to 16 mm Hg at the calf promoted healing of venous ulcers, whereas Sigel et al. 88 found that optimal blood flow could be achieved in the deep veins of healthy people with the use of compression

Volume 25

Number 6, Part 1 December 1991

between 18 mm Hg at the ankle and 8 mm Hg at the thigh. We usually recommend 30 to 40 nun Hg of compression in patients with venous ulcers. The major advantage of elastic compression therapy is patient comfort because elastic support stockings or support bandages may be removed at night for bathing or sleeping. The major disadvantage is that patients with arthritis find it difficult to apply and to remove the stockings. However, some new varieties of stockings are now available with a zipper insertion to facilitate stocking application and removal. Before compression is considered, arterial pulses should be carefully palpated. Doppler pressure should be measured at the ankle ifthere is any suspicion of arterial disease because skin necrosis or even gangrene can result from compression of arterially compromised limbs. 89 Unna's paste boots are semirigid flexible bandages that protect the ulcer from the environment and help to control edema. They have been used for many decades for the treatment of leg ulcers. 90, 91 Although they require less patient time and cooperation than elastic support stocking therapy, they can cause localized purpura, cyanosis, ulceration, or necrosis of the skin. 89 The ankle/calf compression ratio is variable depending on who applies the dressing. 92, 93 They are useful in areas where it is difficult to maintain adequate external pressure, such as the sides of the foot, and are especially helpful in protecting the limb from external trauma. They need to be replaced every 7 to 10 days and the ulcer can only be cleaned as often as the boot is changed. When correctly applied, however, Unna's paste boots are helpful in the elderly patient, especially those with physical disabilities that make it difficult for them to apply their own wound dressings. Ifsecondary infection is a problem, infectious exudate and debris will accumulate around the ulcer, and the boot should be changed more frequently (every 3 to 4 days).

Intermittent pneumatic compression Pneumatic compression devices may be used for the relief of edema 15, 94 and may promote healing in patients with venous ulcers. 95 , 96 They also are useful in the treatment of lymphedema. 97 , 98 They consist of a sleeve that fits over the leg, attached to a pump device. A variety of pneumatic pumps with different specifications are available. 94, 97, 98 The response to treatment usually depends on the absolute

Leg ulcers 973 pressure generated, the compression cycle, and the sequence and duration of compression,94 Wegenerally use the compression pump in patient~ with venous ulcers that have not responded to compressive dressings.

Acute dermatitis Dermatitis associated with venous ulcers is common. In cases of acute dermatitis associated with oozing and erosions ofthe skin, frequent applications of nonirritating wet dressings (such as saline-soaked gauze), bed rest, and application of a moderate p0tency corticosteroid cream for a few days may be necessary. Antibiotic coverage may be required for secondary infection of the skin. In cases of chronic dermatitis, in which pruritus and lichenification of the skin may be severe, liberal use of emollients such as petroleum jelly should be recommended. Topical corticosteroids should be limited, where possible, to hydrocortisone or class VI· preparations because more potent corticosteroids will impair wound healing. 99 Corticosteroid ointments are less liable to cause contact dermatitis than creams.

Ulcer cleaning and debridement Various agents that have been traditionally used to clean ulcers are detrimental to wound healing, as discussed later in this article. Frequent moist saline dressings are safe, keep the wound surface moist, remove surface bacteria, and help debride ulcer surfaces. 78 Frequent wet to dry saline dressings are often used to debride necrotic tissue and can be effective. A saline-soaked gauze is placed over the ulcer and covered with dry dressings. After 4 to 6 hours, the now dry gauze is removed from the ulcer, together with dry necrotic debris adherent to it. This technique can be painful for the patient and should not be used on wounds that are clean because it can strip away newly formed epithelium. Surgical debridement, with a curette or scissors and forceps, can be performed in the outpatient setting by the dermatologist. Again, this can be painful for the patient but 2% lidocaine gel applied to the wound 20 minutes before debridement provides significant anesthesia. Extensive surgical debridement is usually an inpatient procedure requiring local or general anesthesia. Another disadvantage of this technique is the possibility of removing viable tissue during debridement. Occlusive dressings are probably the gentlest

Journal of the

974

Phillips and Dover

Table II. Instructions for the diabetic or neuropathic patient • Stop smoking. • Inspect feet daily for blisters, scratches, red areas. If your vision is impaired, get someone to do this for you. • Wash your feet daily in warm water. Dry carefully between toes. • Apply petroleum jelly to dry areas of skin but not between the toes. • Always test water temperature before bathing. • Inspect inside your shoes before putting them on. • Do not remove corns or apply strong chemicals to your feet. • Cut nails straight across. • See your podiatrist regularly. -Wear properly fitting shoes. New shoes should be worn for 1 to 2 hours daily only. Check your feet for red spots afterwards. • Avoid open-toed sandals and pointed shoes. • Never walk barefoot. • Ifyou develop any breaks in the skin or blisters, inform your doctor. • See your doctor regularly. Modified from Levin M, O'Neal ME. The diabetic foot. 8t. Louis: CV I?88.

Mosby,

method to debride ulcers and are discussed later in this article.

MANAGEMENT OF ARTERIAL ULCERS The most important objective in treatment of arterial ulcers is to increase the blood supply to the affected area. Certain simple measures are helpful in this regard. The patient should stop smoking, and diabetes or hypertension should be well controlled. ExerCise should be encouraged to promote development of a collateral circulation. The head of the patient's bed should be elevated 4 to 6 inches, to encourage gravity-dependent arterial flow, and the limbs should be kept warm. Direct heat should not be applied, however, because of the risk of thermal injury: If the patient spends much time in bed, a sheepskin should be placed under the feet to protect bony prominences from pressure. A foot cradle should be used, when possible, to protect the toes. Many ischemic ulcers are precipitated by trauma. Therefore, the patient should be given detailed instructions regarding care of the lower limb (see instructions for diabetics, Table II). Regular use of analgesics may be required for the relief of ischemic pain. The use of systemic agents to promote healing of arterial ulcers remains controversial 1OO and is discussed later in this article. If rest pain or acute

American Academy of

Dermatology

infection is present, the patient should be hospitalized and treated in close collaboration with a vascular surgeon. Cellulitis or lymphangitis should be treated with systemic antibiotics. Moist saline dressings applied 3 to 4 times daily are helpful in infected ulcers but debridement of dry eschar is not generally recommended in ulcers caused by arterial insufficiency because it may promote further tissue ischemia. lOi Arterial reconstruction should be considered in patients with arterial ulcers, especially if rest pain or rubor is present. After arteriographic studies, endarterectomy to remove localized atheromatous plaques and/or reconstruction to bypass occluded areas is performed. 101

MANAGEMENT OF DIABETIC AND NEUROPATIDC ULCERS Neuropathic ulcers are most commonly seen in diabetic patients. In all patients, but especially in the diabetic patient, prevention is better than cure. Education and preventive measures can decrease the risk of limb ulceration and amputation by 68%.102 Patients with diabetic neuropathy should inspect their feet daily for skin breaks or blisters and see their doctor immediately should these develop. They should not smoke, remove corns, or apply strong chemicals to the skin. They should avoid sandals or cut-out shoes, adhesive tape, hot water or heating pads, and should never go barefoot. 4o Shoes should be made of leather; socks should be cotton and nonconstricting. New shoes should only be worn for 1 to 2 hours daily, and the feet should be checked for red spots over sites of pressure. Before shoes are put on, footwear should always be checked for foreign bodies that might otherwise go undetected because of neuropathy 40 (Table II). Something as seemingly insignificant as a slightly crumpled label on the insole of a shoe is sufficient to induce ulceration in a neuropathic diabetic foot within 12 hours (Fig. 3). The feet should be examined regularly for tinea, pes cavus deformities, and onychogryphosis. Once ulceration has developed in a diabetic limb, the severity of tissue destruction and sepsis may not be immediately apparent from just looking at the ulcer. It is important to unroof all crusted areas and inspect and probe the wound to determine its depth and the extent of tissue destruction.103-105 In early infection with minimal cellulitis, the wound should be cultured and debrided. A broadspectrum oral antibiotic should be started and changed according to sensitivity results and treat-

Volume 25

Number 6, Part 1 December 1991

ment response. l06 The wound can be cleaned with application of saline-wetted gauze to the wound twice daily. The ulcerated area should be completely relieved of any pressure, by a build-up bandage with a cut-out over the affected area or complete bed rest. 107 Ifthere is no significant improvement within 48 hours, the patient should be admitted to the hospital. Patients who are immunocompromised, who have significant ischemia, or who have limb-threatening infection, should be hospitalized. Non-weight bearing is essential until healing is in progress. Insulin is usually required to ensure good diabetic control, and broad-spectrum intravenous antibiotics are indicated.l°7 In consultation with a vascular surgeon, debridement of all necrotic tissue should be performed, conserving all healt~y areas as far as possible. Changes of osteomyelitis may not become obvious on x-ray for at least 2 weeks, but air within soft tissues is helpful in confirming the presence of gas-producing anaerobes. Bacteroides, coliforms, and Peptostreptococcus are frequently cultured. 4o, 103, 107 Simple dressings, such as gauze pads moistened with saline solution, applied to the wound three times daily are helpful. Indiscriminate use of antiseptics or other chemicals may complicate the situation by impairing wound healing. l03 , 108 Once infection has been controlled, a decision can be made as to whether the patient requires further surgical intervention. TOPICAL TREATMENTS FOR LEG ULCERS Once the underlying cause for a leg ulcer has been diagnosed and treated, can topical agents be used to promote healing? Since 1600 Be, when hot oils and waxes were used to promote wound repair,109 a wide variety of treatments, from mundane to exotic, have been promoted as wound-healing agents. It is beyond the scope of this article to discuss every available topical treatment for cutaneous wounds. It is well known that infection retards wound repair llO, III and that systemic antibiotics have greatly diminished the frequency and severity of wound infections. 112 Only more recently have we become more aware that antimicrobial agents that have been traditionally used topically on wounds for many years may in fact inhibit wound healing and retard epithelialization. As early as 1919, Alexander Fleming l13 cautioned his colleagues against excessive use of topical antiseptics, when he stated that the antiseptic should play no part in the primary treatment of a wound. More recently, we have become

Leg ulcers 975 aware that some topical antimicrobial agents can be cytotoxic in vitro and retard epithelialization in vivo. l08 ,112,114 Topical povidone iodine can cause microcirculatory damage when applied undiluted to living animal tissue. 115, 116 High concentrations of povidone iodine are toxic to fibroblasts in vitro 115 and can inhibit wound contraction in animal models. los A concentration of 0.001 % povidone iodine maintains bactericidal activity while being noncytotoxic. 114 Thus a 10% applicator solution, which contains 1% povidone iodine, should be diluted 1:100 ifbeing used on open wounds. 1l7 Iodine can cause contact sensitization and should be used cautiously, if at all. 118 Hexachlorophene should be avoided on open wounds because it is known to be tissue toxic 119 and systemic toxicity can occur. 120 Benzalkonium chloride and other quaternary ammonium compounds as well as chlorhexidine and alcohol should probably also be avoided on open wounds. 112 Hydrogen peroxide is rapidly catalyzed by tissues to produce molecular oxygen and water. Its antimicrobial activity is transient, but the effervescence may cause some physical debridement of the wound surface. Its fibroblast toxicity exceeds its bacterial toxicity, but it did not impair wound healing in an animal model. 114 Sodium hypochlorite (Dakin's solution) is toxic to fibroblasts and adversely affects wound healing in an animal model. However, at low concentrations (0.005%) it retains bactericidal activity but is not cytotoxic. I 14 Acetic acid is commonly used in the treatment of wounds infected with Pseudomonas aeruginosa. In concentrations of 0.25%, wound healing is impaired compared with a normal saline control. 114 Nevertheless, it is useful clinically in wounds that are heavily infected with Pseudomonas. 121 Silver compounds have been used extensively in burn care. One percent silver sulfadiazine appears to reduce populations of S. aureusand P. aeruginosa in wound beds. lOS Some authors 122 report enhanced epithelialization in wounds treated with 1% silver sulfadiazine, whereas others lO8 have reported that 1% silver sulfadiazine caused a mild delay in contraction of full-thickness wounds. Silver nitrate 0.5% soaks are sometimes useful temporarily to clean chronic wounds 73 but should not be used long term because they impair granulation tissue formation. Benzoyl peroxide has antimicrobial properties, and the 20% lotion has been found to enhance wound

Journal of the

American Academy of Dermatology

976 Phillips and Dover Table III. Effect of topical antibiotics on wound healing

......

.-...,..~~.-...,..-:--

I

Epithelialization

Contact dermatitis

Neomycin Polymyxin B Neosporin

Promotes

Silver sulfadiazine Bacitracin

Promotes

Gentamicin

Delayed (in solution)

Pseudomonic acid (mupirocin) Erythromycin

Unknown

Reports of anaphylaxis when applied to leg ulcers Occasional (crossreacts with neomycin) Rare

Unknown

Not documented

No decrease

Frequent (neomycin) Cross-reacts with gentamicin Occasional Yes

Adapted with permission from Reed BR, Clarke RAF. J AM ACAD DERMATOL 1985;13:919-41.

healing when applied to chronic wounds under occlusion. 123, 124 Wound contraction is, however, inhibited by 20% benzoyl peroxide lotion. 108 Topical antibiotics can cause contact dermatitis, especially in patients with leg ulcers. Anaphylaxis has rarely been reported. l25 Topical erythromycin and mupirocin rarely cause sensitization. The effects of these two latter agents on wound healing have not been documented; however, their use in the treatment of chronic leg ulcers has been suggested 125 (Table III). Wound dressings A bewildering variety of wound dressings is currently available. Most dressings aid wound healing by acting as a barrier between the wound and the environment, preventing drying of the tissues. More recently, it has been recognized that occlusive dressings can modify the wound environment to enhance the healing process. Actions of occlusive dressings Since Odland1.26 first demonstrated that a blister healed faster if left intact, and Winter l27 showed that occluded wounds in pigs epithelialized twice as quickly as nonoccluded wounds, a wide variety of synthetic occlusive dressings have become available.

Many investigators have confirmed the beneficial effects of occlusive dressings on wound healing in both animals and humans. 94, 128-132 In acute wound models, occlusive dressings appear to promote healing through a variety of mechanisms. One attractive hypothesis is that a multitude of growth factors are present in wound fluid that can modulate tissue repair. 133 Wound fluid from occluded acute wounds has been found to stimulate fibroblast growth and epidermal growth in vitro,134, l35 and this activity could be inhibited by antibodies to platelet-derived growth factor (PDGF).134 This suggests that biologically active PDGF is present under occluded wounds and that growth factor accumulation may be significant in promoting healing under occlusive dressings. Occluded wounds are known to have increased bacterial colonization compared with air-exposed wounds. 136 Surprisingly, this does not appear to impede healing and may actually stimulate epidermal migration. 137 Maintenance of a voltage gradient lateral to the wound, maintaining endogenous current flow, may also be important in wound epithelialization.D8. 139 Occlusive dressings may affect the dermis of acute wounds, promoting early regeneration of connective tissue. l27, 140 One hydrocolloid dressing has been shown to enhance fibrinolysis and angiogenesis, 141, 142 with reduction of pericapillary fibrin cuffs in venous ulcers. * This is the first suggestion that a topical dressing can actually modify the pathologic characteristics associated with venous ulcers. In chronic wounds, the mechanism of action of occlusive dressings is less well understood because of the lack of a good animal model. In clinical studies, however, occlusive dressings appear to be of great benefit in wound debridement,l43 promotion of healthy granulation tissue,129, 144 and epithelialization in some, but not all, cases. 129 Favorable responses have been reported with chronic wounds caused by epidermolysis bullosa, l45 chronic leg wounds,146 neuropathy,147 and pressure. 148 Because chronic wounds are invariably colonized with bacteria, infective complications associated with occlusion seem likely to be more prevalent. However, a recent review of 69 studies evaluating *Mulder G, Bolton LL, Lydon ML. Resolution of pericapillary fibrin in venous ulcers treated with hydrocolloid dressing. Poster presented at the 49th Annual Meeting of the American Academy of Dermatology, Atlanta, Ga., Dec. l-6, 1990.

Volume 25 Number 6, Part 1 December 1991

clinical infection under occlusive or conventional dressings was reassuring; a low figure of 2.6% of wounds were infected under occlusion compared with 7.6% with conventional dressings. 149 Some authors have found occlusion to be safe even in chronic wounds with heavy bacterial colonization. 129 Nevertheless, we do not use occlusive dressings in wounds that appear to be infected. Types of dressings

Films are thin, transparent adhesives, usually made of polyurethane. They vary slightly in their vapor permeability, strength, flexibility, and delivery systems. Several include OpSite, Bioc1usive, Tegaderm, and Thin Film Dressing. Omniderm is a combination polymer film that adheres to moist wounds without adhesives. Most films, because of their adherence, may strip away newly formed epithelium on removal. Hydrogels are gel-like sheets that are nonadhesive, semitransparent, comfortable, and absorbent. They include Vigilon, Geliperm, and Spenco 2nd Skin. They are helpful in desloughing wounds and could act as potential drug vehicles. They may cause maceration of skin around the wound and tend to be expensive. Hydrocolloids such as DuoDERM, Comfeel, and Restore are opaque, gas-impermeable, absorbent dressings composed of a hydrocolloid with a polyurethane outer coating. They adhere to skin surrounding the wound. They are easy to use, cost effective, and effective in debriding wounds. Yellowbrown wound fluid gradually accumulates under the dressing and can give rise to an unpleasant odor that some patients find offensive. These dressings can be difficult to use in cavities and can sometimes stimulate excess granulation tissue. Premature dressing removal can injure newly formed epidermis. Granules of dextranomer (Debrisan), copolymer starch (Bard Absorption dressing), or hydroactive materials (DuoDERM) are absorbent granules that are helpful in desloughing wounds and in the treatment of draining fistulas and ulcers with undermined edges. Some, such as Iodosorb may have antiseptic qualities. They can sometimes be difficult to handle and can dry out the wound bed (K Harding, MD, personal communication, March 1990). Occasionally there can be difficulties in removing the granules from the wound bed. Alginates such as Sorbsan and Kaltostat are biodegradable dressings derived from seaweed. They

Leg ulcers 977 are highly absorbent and form a hydrophilic gel over the wound surface. They also have hemostatic properties. There have been encouraging results with alginates to treat chronic skin ulcers in pilot studies. 150-152 However, large quantities ofsaline are necessary to remove the fibers on large wounds and ifthe wound is moist, frequent dressing changes are required. In our experiynce, they can dry out nonexuding wounds, making them painful. Foam dressings such as Lyofoam and Allevyn are microporous dressings manufactured from polyurethane foam. One side has a hydrophilic, soft surface that absorbs wound exudate. The other side is hydrophobic and inhibits leakage ofexudate through the dressing. Foam dressings provide a moist healing environment and are nonadherent, provided the exudate does not dry out. Ifthe dressing is changed after the exudate dries, however, it adheres to the wound, which causes pain on removal and possibly strips a way newly formed epithelium. Laminates such as Biobrane consist of a laminate of silicone rubber with nylon, linked with porcine collagen peptides. The dressing absorbs exudate, and its flexibility makes it useful for areas such as elbows, knees, and shoulders. It is mainly used on clean superficial wounds. WHICH DRESSINGS WHEN?

Clinical judgment is necessary in deciding which type of occlusive dressing should be used in the chronic wound (Table IV). In general, hydrocolloid dressings are effective in the treatment of chronic wounds,128-132 are easy to use, and patient compliance is generally good. One problem of fluid leakage from the edge of the dressings has been addressed in some biocc1usive dressings with the introduction of a more absorptive controlled gel formula (e.g., in DuoDERM CGF). Alginate dressings may be helpful in exudative wounds, although experience with these dressings is limited. Extreme caution should be exercised if a wound appears heavily infected, and we would not recommend the use of occlusive dressings in any wound associated with cellulitis. Ifthere is dermatitis surrounding the wound, it is preferable not to use adherent dressings, which can sometimes worsen the condition. 129 A nonadherent dressing such as a hydrogel or alginate would be preferable. We have found that application of a layer of zinc oxide paste to the wound margins can prevent maceration, which sometimes otherwise occurs with hydrocolloids.

Journal of the American Academy of Dermatology

978 Phillips and Dover Table IV. Advantages and disadvantages of various occlusive dressings _ _ _ _ _ _1

Films Hydrogels Hydrocolloids

Advantages

Adherent Transparent Form a bacterial barrier Comfortable Absorbent Desloughing agents Easy to use Cost-effective Promote granulation tissue

Granules

Absorbent Antiseptic Debriding action Alginates Absorbent Useful in sinuses Hemostatic properties Foam dressings Absorbent Conforms to body contours Laminates Absorbent Conforms to body contours

Disadvantages

1

Fluid colIection Can be difficult to apply Possibility of stripping away newly formed epithelium on removal Nonadherent Maceration of skin around wound Cost Unpleasant odor Yellow-brown, gel-like fluid drainage Difficult to use in cavities Can stimulate excess granulation tissue Difficult to handle Difficult to remove from wound Large quantities of saline to remove fibers on wound Frequency of dressing change, if wound is moist Not useful for dry wounds Can adhere to wounds if exudate dries Recommended for superficial wounds

Occasionally, ulcers treated with hydrocolloid dressings will granulate extremely well, sometimes with exuberant granulation tissue, but will fail to epithelialize. At this point, it is advisable to change the type of dressing to a nonadherent type or to consider other procedures to promote rapid epithelialization, such as pinch grafting or split-thickness skin grafting. SYSTEMIC TREATMENT

Antibiotics In patients with venous ulcers, cultures from wound swabs seem to correlate well with cultures from biopsy specimens. 153 Bacteria from the ~ound can be variable, but S. aureus is a common pathogen, together with gram-negative bacilli and other organisms. 75 , 153 The patients' individual flora tend to remain constant irrespective of local therapy. The species and concentration of bacteria do not correlate with the presence or absence of purulence or the rate of healing. 75 , 76 The administration of systemic antibiotics in patients with uncomplicated venous ulcers does not significantly affect the rate of healing or influence the bacteriology of the ulcers. 154 We recommend that systemic antibiotics be reserved for patients who have evidence of cellulitis or systemic evidence of infection, according to results of bacterial culture and sensitivity.

Fibrinolytics Browse et al. 34 have demonstrated that the blood of patients with lipodermatosc1erosis has depressed fibrinolytic activity. Theoretically, enhancement of these patients' blood fibrinolytic activity might help in removing the extravascular fibrin that cuffs the vessels and may be the cause of venous ulceration. Stanozo101, an anabolic steroid and fibrinolytic enhancing agent, was found to improve liposc1erosis but not venous ulceration in 14 patients treated in a preliminary open trial. 155 However, in a subsequent double-blind cross-over trial in 23 patients, no significant difference could be detected between the group who used only elastic compression stockings and the group who also received stanozolol. 156 To date there are no convincing published data that suggest any benefit from the use of stanozolol in patients with lipodermatosclerosis or established ulceration. 157 Hemorrheologics Pentoxifylline (Trenta1), a substituted xanthine derivative, also increases fibrinolytic activity. It reduces risk of thrombus formation by decreasing blood viscosity, increasing red blood cell deformability, and inhibiting platelet aggregation. Its effectiveness in the treatment of peripheral arterial and venous disease is controversial. In some con-

Volume 25 Number 6, Part I December 1991

Leg ulcers 979

Fig.·t;. Pinch grafting. A, Appearance of the donor site 1 week after pinch graft haTYesting. B, The pinch grafts are placed dermal side down on the ulcer bed. (Courtesy Dr. I. M. Leigh.)

C, Healing wound; 2 weeks after pinch grafting. D, Final result 3 months later.

trolled studies improvement of venous ulcers l58 and of the symptoms of arterial disease l59, 160 has been demonstrated in patients taking 400 mg of pentoxifylline three times daily compared with controls. However, the limited amount and quality of reported data preclude a reliable estimate of pentoxifylline's efficacy.160 Side effects, including gastrointestinal upset and dizziness, are most frequent in elderly patients and are dose dependent. Vasodilators Prostaglandin E 1 and Prostaglandin 12• Prostaglandin E 1 (PGEd and prostaglandin 12 (PGh, prostacyclin) are potent peripheral vasodilators that also inhibit platelet aggregation. Early uncontrolled reports of successes of intravenous infusions ofPGEl or PGI2 in patients with severe peripheral vascular disease with ulceration were met with enthusiasm. 161 However, two controlled trials,162, 163 including a large multicenter trial, 164 demonstrated no difference between placebo- and drug-treated groups. Calcium channel blockers. Nifedipine is a vasodilator. Its mode of action in angina is probably related to a decrease in total peripheral resistance. Increased blood flow in the calf and foot in healthy subjects af-

ter sublingual nifedipine l65 has prompted study of calcium channel blockers in patients with peripheral arterial insufficiency. Results are conflicting. 166, 167 At least at present the available information suggests that there is probably no value in the long-term treatrhent of peripheral ischemic disease with calcium channel blockers. Serotonin antagonists. Ketanserin, a serotonin antagonist, is widely used as an antihypertensive agent. It reduces peripheral vascular resistance and may improve peripheral hemodynamics in patients with intermittent claudication. 168 Preliminary results of ketanserin in treating patients with impending gangrene and peripheral ulceration appear promising,169 but further data are needed. Topical 2% ketanserin ointment appears to improve granulation tissue formation in skin ulcers. 170 SKIN GRAFTING Pinch grafts (Fig. 6)

These are the simplest type of split-thickness skin graft and are safe and easy to perform. They are particularly useful in patients who have medical problems, or who are taking medications that might interfere with normal wound healing. The procedure can be performed on an outpatient basis.

Journal of the American Academy of Dermatology

980 Phillips and Dover Before pinch grafting, the ulcer bed should be clean with healthy granulation tissue at its base. A donor site (usually the anterior thigh) is selected and preparedfor surgery. Localanesthetic(1%lidocaine) is either injected into the whole area to be harvested, or can be injected at multiple sites intradermally to raise a small bleb. The grafts are taken by shaving the top of each wheal with a Parker No. 11 blade, or with a bent No. 25 needle to raise small "pinches" of skin in the donor area, which can then be shaved with a blade. 171 These grafts are then placed, dermal side down, on the ulcer bed, 2 to 3 mm apart (Fig. 4). The grafted ulcer and donor site are covered with a dressing, either transparent adherent, transparent nonadherent, or xeroform gauze, according to preference. In both wounds, the dressing should overlap onto normal skin by about 3 em. A gauze pad is then applied firmly to the grafted area, and an elastic wrap applied. The area should remain immobilized for at least 1 week. Exercise should be kept to a minimum to avoid dislodging the grafts. If any exudate collects under the donor or graft sites, it can be aspirated with an 18-gauge needle. l71 The disadvantage of this procedure is that it can be time-consuming and tedious and is thus not very practical for large wounds. The recipient area, when healed, usually retains a "cobblestone" appearance, that may not be cosmetically appealing. Nevertheless, this time-tested, simple technique can often be used for nonhealing chronic ulcers.

Split-thickness skin grafting This technique is used for larger wounds. It usually requires extensive local anesthesia, spinal anesthesia, or occasionally general anesthesia. Because of contraction of the graft after harvesting, the tissue to cover the defect has to be approximately 25% larger. This usually results in a large donor site, which may be slow to heal, and a source of postoperative pain. The graft site may not recover normal sensation. 171 In grafting chronic ulcers, graft failure may occur because of a build-up of exudate underneath the graft. This can be avoided by use of a meshed graft. 172 Slits are made in the graft by a mechanical mesher, which allows the graft to expand and allows drainage of exudate. With this technique, a smaller donor site can be used. The interstices of the mesh graft heal by secondary intention, which results in a slightly more irregular surface. The healing time is

not significantly different from that of a traditional split-thickness skin graft, providing the interstices are not too large. 172

Monitoring progress Once therapy has been initiated, it is important to document wound size. This can be done simply by measuring the widest and longest diameters of the ulcer. We prefer to trace the ulcer outline onto transparent sheets; a plastic sandwich bag is placed over the ulcer, the outline traced with an indelible marker pen, the outer layer of the bag that has been in contact with the wound is discarded and the traced layer of the bag stapled into the patient's chart. Regular photography of the ulcer is also helpful. Failure to heal In ulcers that fail to heal, the diagnosis should be reviewed and a biopsy should be performed. A schematic for leg ulcer management is shown in Fig. 7. Biopsy sites at the edges of ulcers usually heal rapidly, with epithelialization ceasing at the ulcer margin. Care should be exercised in the biopsy of nonulcerated areas of lipodermatosclerosis. This can result in new ulcers. 15 In cases of slow epithelialization with nonsurgical measures, skin grafting should be considered.

FUTURE DIRECTIONS IN LEG ULCER TREATMENT Cultured epidermal grafting Autografts. One approach in the treatment of venous stasis ulceration is use of cultured epidermal cells (keratinocytes) as a skin graft. Keratinocyte sheets cultured from the patient's own skin (autografts) have been successfully used for several years in many centers in the United States and Europe to cover large burn wounds. 173 Other investigators have applied cultured autografts to chronic nonhealing wounds such as leg ulcers. One group reported healing of four of six chronic ulcers within 35 days of application of cultured epithelial autografts with three of the four remaining healed for up to 2 years. 174 Others have reported less successful results~175 Allografts. A recent development has been the use of epithelium derived not from the patient's own skin but from an unrelated or allogeneic donor. Our own experience,176-178 in more than 100 chronic ulcers caused by venous stasis, paraplegia, rheumatoid arthritis, scleroderma, and surgical trauma, suggest

Volume 25 Number 6, Part 1 December 1991

Leg ulcers 981 HISTORY

Symptoms of vascular disease or neuropathy General heafih Topical and

sy~emlc

medications

Diabetes, cardiac disorders Connective tissue disorder Habits: smoking, alcohol

IPHYSICALEXAMI

Venous Arterial NeuropethlO Mixed other

I

!INVESTGATION

I

I

I I I I

I

Blood

I

Hb,WBC, ESR Albumin, Glucose

I

Wound

I

Culture BiOpsy if persisting > 3 months

IVascular studies

I

Ankle-Brachial Pressure Index Doppler, Photoplethysmography Venogram/arteriogram

I

Radiologic tests

I

X-ray, Bone scan, CT scan

I

Special

I

ANA, Rheumatoid factor RPR, Vitamins, Trace elements

-_.._-----"--.---------------_. I ARTERIAL

I

Stop smoking Encourage exercise Keep limbs warm Control of pain and infection Vascular surgery opinion

DIABETIC/ NEUROPATHIC

I

Stop smoking Lose weight Good foot care Control glucose Debridement Infection control Early vascular opinion

Fig. 7. Ulcer management and evaluation,

Journal of the American Academy of Dermatology

982 Phillips and Dover that cultured newborn epidermal allografts provide a potent stimulus to wound healing in difficult leg ulcers. More than two thirds of ulcers healed completely within 8 weeks with a mean healing time of 3.3 weeks. In the remaining ulcers there was marked reduction in size within 8. weeks after grafting. The mechanism of action of cultured epidermal allografts is unknown, but strong evidence from chromosome analysis in sex-mismatched grafts and DNA analysis indicates that grafted allogeneic keratinocytes are rapidly replaced by host keratinocytes.179-182 Thus it appears that allografts act as temporary wound coverings and are eventually replaced by host epithelium. Growth factor release by allografted keratinocytes may be a significant factor in the promotion of wound healing. 183-189 Cultured epidermal allografts can be grown in advance, cryopreserved, and stored in skin banks. 190 They are simple to apply, and the grafting procedure is painless. They often provide pain relief and appear to accelerate healing. However, the cultivation procedure for keratinocytes is complex and labor intensive, which makes these grafts expensive and timeconsumingto produce. Cultured allografts shouldbe reserved, therefore, for the treatment ofwounds that have failed to heal by conservative measures. EI~trical stimulation. Direct current surface electropotentials in wounds are thought to have a role in regulation of the healing process. 139 Electrical stimulation has been demonstrated to enhance wound healing without demonstrable side effects in many studies. 139, 191-193 The mechanisms by which healing occurs remains unknown. They may include inhibition of bacterial growth, 194, 195 effects on fibroblast motility,I96, 197 orincreasedexpression oftransforming growth factor-fj on fibroblasts. 198 The ideal parameters for clinical use of the therapy have not yet been fully determined.

GROWTH FACfORS In the past few years, there has been an exponential rise in research on growth factors. Manyof these growth factors have effects on skin and potential effects on wound healing. They have recently been reviewed in an excellent article. 199 In animal models, epidermal growth factor (EGF), promotes granulation tissue formation and wound healing. 2o G-203 A variety ofgrowth factors have angiogenic properties. These include tumor necrosis factor-a, fibroblast growth factor, transforming growth factors (TGF) 0