I I

Chronic venous insufficiency: Mechanisms and management

Said Ibrahim, MD, a Donna R. MacPherson, RN, b and Samuel Z. Goldhaber, MD a Boston, Mass.

In 1837, the distinguished French professor of med- icine Piorry commented, "It is rather difficult to un- derstand why the investigation of veins has been passed over almost in silence, while such a great di- agnostic value has been attached to the investigation of arteries. ''1 Little has changed since. Our under- standing of venous diseases remains inadequate. Today, chronic venous insufficiency (CVI) afflicts millions of Americans and causes substantial mor- bidity and medical expenditure. Many patients with leg ulcerations due to CVI have reduced work capac- ity and restricted leisure activity. Occasionally, CVI leads to loss of employment. 2

The prevalence of this disease varies with the pop- ulation studied. It is more prevalent in industrialized nations. ~ The pathophysiologic basis of CVI is venous hypertension in the lower extremities that occurs as a consequence of incompetent valves in the deep veins of the leg. The clinical presentation ranges from mild varicosities of only cosmetic importance to induration and fibrosis of the skin (lipodermosclero- sis) and chronic nonhealing leg ulcerations. The diagnosis is usually clear from the history and phys- ical examination, but various noninvasive and inva- sive testing modalities are available to assist in the evaluation. Although compression therapy is the mainstay of medical t reatment of CVI, operative management is an option for the rare case that does not respond to medical treatment. This article re- views the epidemiologic characteristics, pathophys- iologic basis, clinical presentation, diagnosis, and management of CVI.

From the aDepartments of Medicine and bNnrsing, Brigham and Women's Hospital, Harvard Medical School.

Dr. Goldhaber is a recipient of an Academic Award in Systemic and Vas- cular Medicine (HL 02663) from the National Heart, Lung and Blood Insti- tute.

Received for publication Nov. 27, 1995; accepted Jan. 4, 1996.

Reprint requests: Samuel Z. Goldhaber, MD, Cardiovascular Division, Brigham and Women's Hospital, 75 Francis St., Boston, MA 02115.

Am Heart J 1996;132:856-60.

Copyright © 1996 by Mosby-Year Book, Inc. 0002-8703/96/$5.00 + 0 411/73675

EPIDEMIOLOGIC CHARACTERISTICS

The United States National Heal th Survey of 1935 was the first major epidemiologic study of varicose veins, which predisposes to CVI. 3 This question- naire-based survey did not yield a specific prevalence for varicose veins but ranked it seventh among the conditions surveyed. Since then, numerous epidemi- ologic studies have demonstrated that the preva- lence of varicose veins varies according to the group of people studied and according to the definition of varicose veins adopted in a particular study. 3 Coon et al. 4 estimated that 24 million Americans have varicose veins; 6 million have chronic venous stasis skin changes; and about 400,000 to 500,000 of these patients have chronic leg ulcers.

Various risk factors have been associated with CVI (Table I). The Framingham Study reported that var- icose veins are more prevalent in women than in men. 5 The highest rates were seen in the age range of 40 to 49 years for women and the age range of 70 to 79 years for men. Pari ty was associated with var- icose veins, even though women in nonindustrialized countries who have higher parity rates were found to have a lower incidence of varicose veins. The Framingham Study also found that obesity and a sedentary lifestyle are risk factors for CVI, in women more than men. In men, cigarette smoking increases the likelihood of CVI. 5

PATHOPHYSIOLOGIC BASIS

CVI and its clinical manifestations result from venous hypertension in the lower extremities. The natural safeguards against venous hypertension in the legs rely on proper functioning of the calf-muscle pump and the valves in the veins. Failure of either of these mechanisms usually leads to high venous pressure in the legs. Venous pressure is a product of the hydrostatic pressure exerted by the column of blood between the legs and the right atrium. The contraction of the calf muscles propels blood proxi- mally in the deep veins. The backflow of blood is pre- vented by the valves in the veins. Proximal propul- sion of the blood allows the communicating or perfo-

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American Heart Journal lbrah~rn, MacFherson, and Goldhaber 857

rating veins to empty into the deep veins, thus lowering the pressure in the superficial veins. 6 It is estimated that the calf-muscle pump action de- creases foot vein pressure from 90 to 30 mm Hg and increases the femoral vein blood flow significantly in normal subjects. 7

In patients with primary varicosities, a congenital defect in the vein walls in the superficial and the communicating or perforating Veins results in val- vular incompetence. Because of poor valve function, reflux of the unopposed venous blood occurs and causes venous hypertension. In patients with sec- ondary varicosities, the deep venous system usually is affected. Commonly, a thrombus in a deep vein damages the valve directly or indirectly by causing vein-wall injury and dilatation. This phenomenon is most commonly observed in postphlebitic syndrome. The result is the same as that in patients with pri- mary varicosities, although lipodermosclerosis and ulcerations are more frequently seen in patients with secondary varicosities, s

The association of venous disease and chronic leg ulcerations has been known for a long time, but the mechanism by which high venous pressures cause edema and progress to skin changes and ulcerations remains uncertain. In 1914, Homans 9 proposed that low oxygen levels in the stagnant venous blood caused hypoxia of the skin. Later studies failed to substantiate this theory. Paradoxically, oxygen lev- els were higher in the veins of patients with venous disease. This finding led to the theory that patients with CVI have arteriovenous fistulas that may de- prive the skin of oxygen; however, further research into this theory showed no increased numbers of ar- teriovenous fistulas in CVI patients. 1°, 11

In 1930, Landis 12 demonstrated that venous hy- pertension in the lower extremities leads to in- creased intraluminal pressure of the capillary bed. This finding was followed by the work of Burnand et a1.,13, 14 who proposed the "fibrin cuff' hypothesis in 1982. They suggested that the increased venous pressure in the lower extremities leads to damage of the vessel wall that in turn allows the leakage of plasma proteins and fibrinogen. The leaked plasma products form a fibrin cuff in the pericapillary area and cause restriction of oxygen diffusion into the tis- sues of the skin. This process leads to skin damage and possible ulcer formation. That patients with venous disease have reduced fibrinolytic activity in the blood and veins 15, 16 gives some support to this hypothesis; however, no studies to date convincingly demonstrate that fibrin cuffing presents a true bar- rier to oxygen diffusion.

The "white-cell trapping" hypothesis advanced by

Table I. Risk factors associated with CVI

Gender (female) Age (old) Family history History of deepwein thrombosis Sedentary lifestyle Obesity Occupation (many hours of standing) Cigarette smoking Varicose veins

Coleridge-Smith et al. 17 and Cheatle et al. is proposes that an accumulation of white cells in the peripheral circulation in patients with venous hypertension is the cause of ulceration. According to this hypothesis, the raised venous pressure results in increased cap- illary perfusion pressure that in turn decreases the blood flow and traps white cells in the capillaries. Activation of the white cells releases proteolytic en- zymes, oxygen metabolites, and lipid products. This process, these investigators suggest, damages the capillary endothelium and leads to increased capil- lary permeability. Fibrinogen then leaks and leads to the formation of a fibrin cuff that causes ischemia and decreases the supply of nutritive substances to the skin (Fig. 1). Support for this hypothesis comes from the work of Thomas et al., 19 who investigated white-cell accumulation in the dependent legs of pa- tients with venous hypertension and found that fewer white cells circulated out of the dependent foot than did in normal patients. This trapping of white cells was reversed when the leg was elevated.

The true mechanism by which venous hyperten- sion leads to lipodermosclerosis and ulceration re- mains unclear. However, i t is apparent that venous hypertension sets the stage for a myriad of adverse conditions that eventually lead to skin damage and impaired healing.

CLINICAL PRESENTATION AND DIAGNOSIS

Clinical evaluation of CVI should begin with a thorough history to assess symptoms and reveal any family history of varicosities and any history of deep-vein thrombosis. The most common complaint among patients with varicose veins is the altered appearance of the legs. Typically, patients with a family history ofvaricosities notice a small cluster of leg veins that become increasingly evident over time. A dull ache, heaviness, or pressure in the legs, par- ticularly the calves, occurs after prolonged standing and usually can be relieved with leg elevation. About half of patients with these symptoms have a history of deep-vein thrombosis. 2°, 21

As CVI progresses, patients observe burning and

October 1996 858 - - --lbrahim, - - - - -Macl- 'herson, and Goldhaber American Heart Journal

Rheological deterioration

I Decreased 1 perfusion pressure

! Plugging of I

capillaries by white cells

! nes

Protelytic !nzymes Oxygen metabolites

Lipid products

I1 I Endothelial [

dan, age... 1 I

Increased permeability 1

Deposition of • fibdnogen

and fibrin

, i ,.c.om,a-1

Fig. 1. Proposed mechanism by which trapping of white blood cells in peripheral circulation results in formation of ulcers. (Adapted from Coleridge-Smith et al. BMJ 1988; 296:1693-5.)

itching of their skin over the medial malleolus. A red or brown discoloration due to hemosiderin deposition in the skin, with eczemalike dermatitis, may be seen. This condition may worsen and lead to induration and fibrosis of the skin. Mild t rauma to this area may cause an ulcer. Venous disease is not the only cause of chronic leg ulcers. 22 Whether the patient has con- comitant illnesses such as peripheral arterial occlu- sive disease, vasculitis, or diabetes should be consid- ered before it is assumed that CVI is the cause of an ulcer on the medial malleolus (Table II).

Although evaluation of CVI is accomplished prin- cipally with the history and physical examination, invasive and noninvasive testing modalities may complement these examinations. The invasive tests, venography and direct venous pressure measure- ment, were introduced with the advent of surgical techniques for treating CVI. Together they provide a means for objectively evaluating, anatomically and hemodynamically, the severity of CVI before surgical options are pursued.

Plethysmography and venous ultrasound consti-

Table II. Differential diagnosis of chronic leg ulcers

cvI Arterial disease Vasculitis Lymphatic obstruction Neuropathy Metabolic disorder Sickle cell disease or other hematologic disorder Neoplasm: squamous cell cancer Panniculitis

tute the noninvasive tests currently in use for eval- uation of CVI. Photoplethysmography and air plethysmography involve the use of light and air to estimate the blood flow and volume changes in the veins of the lower extremities. These tests, when done skillfully, can provide hemodynamic measure- ments that approximate those made by direct venous pressure measurement. 23 Venous ultrasound is the best initial laboratory test for evaluating CVI. Du- plex ultrasound combines B-mode ultrasound with pulsed Doppler examination and provides informa- tion on the direction and flow velocity of blood. Today, plethysmography and ultrasound, and especially duplex ultrasound, can provide accurate anatomic and hemodynamic measurements that usually ren- der invasive tests unnecessary. 24

M A N A G E M E N T

Leg elevation and vascular compression therapy are the mainstay of medical t reatment for CVI. Proper leg elevation requires raising the feet above the thighs when in the sitting position and above the heart when in the supine position. Leg elevation alone, although sufficient therapy for some forms of mild CVI, usually is not adequate in moderate to se- vere cases of CVI. It also may be unwieldy or simply not practical for many employed people.

Wright, 25 in 1931, documented the first successful use of elastic wraps in venous ulcer healing. Since then, numerous types of vascular compression ther- apy have been introduced. These range from simple wraps that provide only uniform compression to elastic stockings that provide graduated pressure from the distal to the proximal portion of the leg. In 1940, Jobst, a mechanical engineer who had CVI, designed elastic stockings that provided an upward pressure gradient. 26 However, vascular compression stockings have been associated with poor patient compliance: patients often complain about the old- fashioned design and uncomfortable fit of the stock- ings. Consequently, the design has improved signif- icantly during the past decade. Today, stockings of

Volume 132, Number 4 American Heart Journal Ibrahim, MacPherson, and GoIdhaber 859

Table III. Costs of graduated-compression stockings

Length Pressure (ram Hg) Ready-made Custom-made

Knee-high 20-30 $55-$68/pair Not available Knee-high 30-40 $55-$68/pair $58/leg Knee-high 40-50 $78/pair Marked variability Thigh-high 30-40 $97-$112/pair $72/1eg Pantyhose 30-40 $90-$140 $200-$218

Table IV. Compression gradient and indications for use

Gradient pressure (ram Hg) Indications

14-18 20-30

30-30

40-50 50-60

Primary prevention of DVT Mild venous insufficiency; mild

varicosities Varicose veins; CVI; peripheral

edema; postphlebitic syndrome; varices in pregnancy; secondary prevention of DVT; stasis ulcers

Severe CVI Very severe CVI

DVT, Deep-vein thrombosis.

various colors, styles, length, and fit are available (Tables III and IV).

Vascular compression therapy simulates calf-mus- cle pump function by enhancing the venous blood flow in the legs. 27 Physiologically, it promotes fibrin- olysis and increases local interstitial pressure, thus preventing fibrin-cuff formation and white-cell ac- cumulation.2S, 29 Stockings that provide a pressure gradient, with most pressure at the bottom of foot and a gradual reduction of the pressure in the prox- imal portion of the leg, appear to be the most effec- tive. In 1854, Unna described the use of a medicated compression bandage to treat ulcers caused by CVI. Contemporary "Unna boots" are roll bandages im- pregnated with a uniformly spread paste of zinc ox- ide, calamine lotion, glycerine, and gelatin. Unna boots, now commonly used for ulcer healing, have the disadvantage of pressure variability that depends on the person who applies them. 22 Although intermit- tent pneumatic devices are effective, the elastic stockings are the most convenient type of vascular compression therapy. Stockings can be fitted, are easy to use, and provide a pressure gradient that can be adjusted to the severity of a patient's disease.

Recently a randomized, placebo-controlled, dou- ble-blind trial demonstrated that enteric-coated as- pirin, 300 mg daily, reduces ulcer size and acceler- ates ulcer healing compared with placebo. 29a

Other adjunctive t reatments for CVI that may be promising include ultrasound therapy and some oral agents such as oxpentifyl]ine. In combination with

standard compression therapy, application of ultra- sound to the tissues surrounding the leg ulcers in patients with CVI has been reported to accelerate ulcer healing compared with that in a control group.J° Similarly, oxpentifylline, a cytokine antagonist with profibrinolytic activity, has been found effective in ulcer healing in one small study. 31 However, adverse effects from the drug may include edema, depression, vomiting, dyspepsia, and diarrhea.

Surgical management is most often reserved for severe or medically refractory CVI. Venous stripping, li- gation, and valvular reconstruction are the major surgi- cal techniques used in CVI treatment. In patients with isolated superficial venous insufficiency, stripping of the incompetent superficial varicose veins may be cura- tive. 32 In contrast, patients with valvular incompetence due to deep-vein obstruction may not benefit from this procedure. For these patients, ligation of the perforating or communicating veins was a popular surgical proce- dure in the 1940s and 1950s but fell out of favor by the mid 1980s because of a high recurrence rate (50%) at 5 years)Y, 34 Today, valvular reconstruction and venous valve transplantation from the upper extremities to the lower extremities are surgical options currently under investigation for patients with deep-vein disease.

SUMMARY

CVI is a common disease with significant morbid- ity that results from venous hypertension of the ex- tremities. Increased perfusion pressure probably traps excessive numbers of white blood cells in the capillaries. Activated leukocytes subsequently dam- age capillary endothelium, increase capillary perme- ability, and cause ischemia of the overlying skin as a result of leakage of fibrinogen and formation of a fibrin cuff. Diagnosis of CVI is not difficult because its clinical manifestations are usually evident. Vas- cular compression therapy remains the foundation of medical management for CVI. Refractory cases may require a combined medical and operative approach.

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October 1996 8 6 0 Ibrahim, MacPherson, and Goldhaber American Heart Journal

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