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 medicine Piorry commented, "It is rather difficult to understand why the investigation of veins has been
passed over almost in silence, while such a great diagnostic value has been attached to the investigation
of arteries. ''1 Little has changed since. Our understanding of venous diseases remains inadequate.
Today, chronic venous insufficiency (CVI) afflicts
millions of Americans and causes substantial morbidity and medical expenditure. Many patients with
leg ulcerations due to CVI have reduced work capacity and restricted leisure activity. Occasionally, CVI
leads to loss of employment. 2
The prevalence of this disease varies with the population 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 (lipodermosclerosis) and chronic nonhealing leg ulcerations. The
diagnosis is usually clear from the history and physical examination, but various noninvasive and invasive testing modalities are available to assist in the
evaluation. Although compression therapy is the
mainstay of medical treatment of CVI, operative
management is an option for the rare case that does
not respond to medical treatment. This article reviews the epidemiologic characteristics, pathophysiologic 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 Vascular Medicine (HL 02663) from the National Heart, Lung and Blood Institute.
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

856

EPIDEMIOLOGIC CHARACTERISTICS

The United States National Health Survey of 1935

was the first major epidemiologic study of varicose
veins, which predisposes to CVI. 3 This questionnaire-based survey did not yield a specific prevalence
for varicose veins but ranked it seventh among the
conditions surveyed. Since then, numerous epidemiologic studies have demonstrated that the prevalence 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 varicose 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. Parity was associated with varicose 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 proximally in the deep veins. The backflow of blood is prevented by the valves in the veins. Proximal propulsion of the blood allows the communicating or perfo-

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American Heart Journal

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 decreases 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 valvular incompetence. Because of poor valve function,
reflux of the unopposed venous blood occurs and
causes venous hypertension. In patients with secondary 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 primary 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 levels 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 deprive the skin of oxygen; however, further research
into this theory showed no increased numbers of arteriovenous fistulas in CVI patients. 1, 11
In 1930, Landis 12 demonstrated that venous hypertension in the lower extremities leads to increased 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 tissues 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 barrier to oxygen diffusion.
The "white-cell trapping" hypothesis advanced by

lbrah~rn, MacFherson, and Goldhaber 857

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 capillary perfusion pressure that in turn decreases the
blood flow and traps white cells in the capillaries.
Activation of the white cells releases proteolytic enzymes, oxygen metabolites, and lipid products. This
process, these investigators suggest, damages the
capillary endothelium and leads to increased capillary 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 patients 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 hypertension leads to lipodermosclerosis and ulceration remains unclear. However, it 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, particularly 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

858

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--lbrahim, --

AmericanHeartJournal

and Goldhaber

---Macl-'herson,

Table II. Differential diagnosis of chronic leg ulcers

I Decreased 1
perfusion pressure

!
Plugging of
capillaries by
whitecells
Rheological

deterioration

, i ,.c.om,a-1

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

nes

Protelytic!nzymes
Oxygen metabolites
Lipid products

I1

I Endothelial[

dan, age... 1
I

Increased permeability

1
Deposition of

fibdnogen
and fibrin

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 r a u m a to this area may
cause an ulcer. Venous disease is not the only cause
of chronic leg ulcers. 22 Whether the patient has concomitant illnesses such as peripheral arterial occlusive disease, vasculitis, or diabetes should be considered before it is assumed that CVI is the cause of an
ulcer on the medial malleolus (Table II).
Although evaluation of CVI is accomplished principally with the history and physical examination,
invasive and noninvasive testing modalities may
complement these examinations. The invasive tests,
venography and direct venous pressure measurement, 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-

tute the noninvasive tests currently in use for evaluation 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 measurements that approximate those made by direct venous
pressure measurement. 23 Venous ultrasound is the
best initial laboratory test for evaluating CVI. Duplex ultrasound combines B-mode ultrasound with
pulsed Doppler examination and provides information 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 render invasive tests unnecessary. 24
MANAGEMENT

Leg elevation and vascular compression therapy

are the mainstay of medical treatment 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 severe 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 therapy 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 oldfashioned design and uncomfortable fit of the stockings. Consequently, the design has improved significantly during the past decade. Today, stockings of

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Ibrahim, MacPherson, and GoIdhaber 859

American Heart Journal

Table III. Costs of graduated-compression stockings

Length

Pressure (ram Hg)

Ready-made

Custom-made

Knee-high
Knee-high
Knee-high
Thigh-high
Pantyhose

20-30
30-40
40-50
30-40
30-40

$55-$68/pair
$55-$68/pair
$78/pair
$97-$112/pair
$90-$140

Not available
$58/leg
Marked variability
$72/1eg
$200-$218

Table IV. Compression gradient and indications for use

Gradient pressure (ram Hg)

Indications

14-18
20-30

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

30-30

40-50
50-60

DVT, Deep-vein thrombosis.

various colors, styles, length, and fit are available

(Tables III and IV).
Vascular compression therapy simulates calf-muscle pump function by enhancing the venous blood
flow in the legs. 27 Physiologically, it promotes fibrinolysis and increases local interstitial pressure, thus
preventing fibrin-cuff formation and white-cell accumulation.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 proximal portion of the leg, appear to be the most effective. In 1854, Unna described the use of a medicated
compression bandage to treat ulcers caused by CVI.
Contemporary "Unna boots" are roll bandages impregnated with a uniformly spread paste of zinc oxide, 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 intermittent 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, double-blind trial demonstrated that enteric-coated aspirin, 300 mg daily, reduces ulcer size and accelerates ulcer healing compared with placebo. 29a
Other adjunctive treatments 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 ultrasound 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, ligation, and valvular reconstruction are the major surgical techniques used in CVI treatment. In patients with
isolated superficial venous insufficiency, stripping of the
incompetent superficial varicose veins may be curative. 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 procedure 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 morbidity that results from venous hypertension of the extremities. Increased perfusion pressure probably
traps excessive numbers of white blood cells in the
capillaries. Activated leukocytes subsequently damage capillary endothelium, increase capillary permeability, 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. Vascular compression therapy remains the foundation of
medical management for CVI. Refractory cases may
require a combined medical and operative approach.
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