INVITED ARTICLE CLINICAL PRACTICE

Ellie J. C. Goldstein, Section Editor

(D
State-of-the-Art Treatment of Chronic Venous Disease
Michael S. Weingarten
Departrrient of Surgery, and Division of Vascular Surgery, Crozer-Chester Medical Center, Upland, Pennsylvania

The article summarizes the epidemiology, classification and differential diagnosis of venous disease and its complications.
Theories of venous ulceration and diagnostic and treatment modalities are reviewed.

PREVALENCE
Chronic venous disease and its complications, which includes
chronic venous insufficiency (CVI) and venous ulceration, are
major health issues in developed countries. CVI is estimated
to be present in 0.1%-0.2% of the population at risk in Western
countries [1]. In the United States, ~7 million people have CVI,
which is thought to be the underlying cause of 70%-90% of
all leg ulcers [2], The American Venous Forum estimates that
at any given time, 1 person in every 1000 in the United States
has an unhealed venous ulcer [3]. Population studies in Aus-
tralia and the United Kingdom suggest that venous ulcers occur
with similar prevalence in these countries [4, 5].
Accurate data about the exact incidence of CVI and venous
ulceration are difficult to obtain, because most patients are
treated by a variety of specialists in different clinics. For ex-
ample, patients may be seen by internists, vascular surgeons,
plastic surgeons, or dermatologists, depending on their settings
for treatment. This fragmentation of care interferes with data
collection. CVI and its complications also can begin in younger
persons, who may delay seeking medical attention.
ECONOMIC FACTORS
The cost of treating CVI has been estimated to be $750 million
to $1 billion per year in the United States. The average cost of
Received 28 September 2000: revised 13 November 2000: eiectronically pubiished 7 March
2001.
Reprints or correspondence: Dr. IVIichael S. Weingarten, Division of Vascular Surgery,
Medical Coliege of Pennsylvania Hospital, 300 Henry Ave., Phiiadelphia, PA 19013
|MSWS6@aol.connl.
Clinical Infectious Diseases 2001;32:949-54
© 2001 by the Infectious Diseases Society of America. All rights reserved.
1058-4838/2001/3206-0012$03.00
care for a single patient with CVI over a lifetime can exceed
$40,000 [6]. Because this condition often affects people of
working age, reduction in ability to work adds to the cost. An
estimated 2 million workdays are lost annually in the United
States because of leg ulcers [7].
EPIDEMIOLOGY
Epidemiological studies have found that the incidence of ve-
nous ulcers increases with age and that such ulcers are asso-
ciated with obesity, diabetes, heart failure, hypertension, renal
disease, and rheumatoid arthritis [4, 8]. In a study in the United
States, Scott et al. [9] found no racial differences in the inci-
dence of CVI. These authors also.found that up to 50% of
patients with CVI had had some form of serious leg injury in
the past, including fractures, burns, crush injuries, or pene-
trating trauma. A history of trauma increased the risk of de-
veloping CVI years later by 2.4%. As many as 45% of patients
with CVI in the study of Scott et al. [9] had a history of
phlebitis. The authors estimated that a history of phlebitis in-
creased the chances of developing CVI by 25.7 %. Finally, a
family history of varicose veins or CVI was also associated with
an increased incidence of CVI, suggesting a genetic component
to the disease.
Venous ulceration and its sequelae also have a negative psy-
chological impact on patients and families and therefore affect
their quality of life. In a study by Phillips et al. [7], pain was
a major problem for 65% of patients with venous ulceration.
This has been observed by others as well [10]. Anger, depres-
sion, and fear were also commonly seen in these patients, but
these conditions tended to resolve as the ulcer healed [7].

CLINICAL PRACTICE • CID 2001:32 (15 March) • 949

SIGNS AND SYMPTOMS
The clinical symptoms of CVI include heaviness and pain in
the affected limb, especially at the end of the day. Physical
findings include swelling, varicose veins, and areas of hyper-
pigmentation [6]. Hyperpigmentation is due to the deposits of
hemosiderin in the skin—byproducts of melanin and eryth-
rocyte breakdown [11]. Over time, patients with CVI develop
lipodermatosclerosis of the limb. This term describes the pro-
gressive replacement of the skin and subcutaneous tissue by
fibrous scarring. This dermal change may be mistaken for cel-
lulitis and often precedes the development of a venous ulcer
[12]. Ulcerations classically occur along the medial malleolar
area of the lower leg—the gaiter area. Venous ulcers may occur
in other areas, such as the lateral malleolar area and the dorsum
of the foot. Patients with CVI, with or without ulceration, also
have a higher incidence of stasis and contact dermatitis [13].
REPORTING STANDARDS
The American Venous Forum and the major vascular societies
in the United States have recommended reporting standards
for describing patients with CVI and venous ulceration [14,
15]. These standards are referred to as the "CEAP classification
scheme," and they are based on a clinical classification of the
disease, as well as etiologic, anatomic, and pathophysiological
factors.
Clinical classification starts with no signs of CVI and then
considers the presence of varicosities, edema, lipodermatoscle-
rosis, and active ulceration. This can be determined by physical
assessment. The etiologic classification distinguishes between
primary and secondary CVI, Patients with a history of phlebitis
or trauma would be classified as having secondary CVI. Patients
with no known cause for the CVI would be classified as having
primary CVI, The anatomic classification attempts to define
the contribution of individual venous segments in the deep,
superficial, and perforator systems. The individual venous seg-
ments can be readily evaluated by duplex scanning (see below).
The pathophysiological criteria assess the presence of venous
obstruction, reflux, or both, which can be determined by color-
flow duplex scanning (see below). Clinical trials judging the
efficacy of treatments for CVI and venous ulceration are urged
to classify their patients by this standard,
DIFFERENTIAL DIAGNOSIS
In assessing a patient with a leg ulcer, a differential diagnosis
should be kept in mind. The "typical" venous ulcer presents
as a painful lower leg lesion, associated with hyperpigmentation
and lipodermatosclerosis. However, an estimated 21% of pa-
tients with a venous ulcer have associated arterial insufficiency
[2]. Palpation of the dorsalis pedis or posterior tibial pulses
950 • CID 2001:32 (15 March) • CLINICAL PRACTICE
may be difficult in these patients because of the presence of
edema. The presence of arterial disease can be determined non-
invasively by placing a blood pressure cuff around the ankle
and inflating it so as to occlude the pedal arteries. A systolic
pressure can be obtained by deflating the cuff and listening to
the return of blood flow in the dorsalis pedis or posterior tibial
arteries by means of a hand-held Doppler transducer. The sys-
tolic pressure obtained is then compared with the arm systolic
pressure, to determine the ankle/brachial index (normal, 1).
Determination of pressure at the ankle and ankle/brachial index
may not be possible if the ulcer is in the area where the blood
pressure cuff has to be applied. Arterial assessment in these
cases may be done by determining pressure at the toe by using
a small cuff placed around the toe and inflating it so as to
occlude the digital arteries. The digital pressure is determined
by deflating the cuff while listening to the digital artery flow
with a Doppler apparatus. The pressure at the toe must be
compared with the brachial pressure to determine the toe/bra-
chial index (normal, 0.6-0.7) [16], The recognition of an ar-
terial component to a venous ulcer is essential. Compression
therapy, critical in treating CVI, can have disastrous results if
compression pressures exceed arterial pressures.
Chronic leg ulcers, often mistakenly classified and treated as
venous ulcers, may have undergone malignant degeneration.
The presence of squamous cell or basal cell carcinoma in a
classic "venous ulcer" has been described many times [17], For
ulcers of long-standing duration (>6 months) or ulcers that do
not respond promptly to therapy, a biopsy specimen should be
examined to confirm the diagnosis, Vasculitic ulcers associated
with underlying connective tissue or immune system disorders
may be misdiagnosed as venous ulcers. Biopsy specimens from
the edge of the ulcer may reveal the presence of vasculitis [15],
PATHOPHYSIOLOGY
The appearance of venous ulcers in patients with CVI has been
attributed to elevated venous pressures as a result of venous
valvular incompetence, venous obstruction, or a combination
of both [15], In my earlier study of patients with CVI and
ulceration [18], which used duplex scanning to evaluate the
venous system, only 4 of 403 limbs were found to have venous
obstruction of the deep system as a cause of CVI and ulcera-
tion. Venous reflux in multiple segments of both the deep and
superficial venous systems was associated with CVI and
ulceration.
Venous reflux in the deep and superficial systems below the
knee leads to calf pump failure. Venous pressures remain high
in the lower leg during ambulation, when normally these pres-
sures should fall. The tissue below the knee is therefore exposed
to elevated venous pressures continually when the legs are de-
pendent. It is unclear, however, why elevated venous pressures
 Table 1. Management of venous ulcer disease.

Class and type of treatment Comments

Local wound care
Moist wound dressings
Debridement of necrotic tissue
Control of invasive infection
Pain management
Compression therapy
Elastic wraps Inexpensive; easy to apply; useful in initial management of
massive edema
Stockings Effective; difficult to put on, so compliance is an issue; ex-
pensive and often not covered by third party payers
Compression pumps Adjunct to stockings or wraps; expensive; covered by
Medicare only after failure of trial of stockings or wraps
Venous surgery Must be combined with aggressive compression therapy
Ablative surgery For perforator and/or superficial vein ligation in patients
with recalcitrant ulcers
Valve repair, transplant, Indications uncertain
or transposition
Skin grafting
Autologous Creates donor site wound; must be followed with aggres-
sive compression therapy
Human skin equivalents May be useful for patients with failure of autologous
grafts; must be combined with compression therapy;
expensive

lead to venous ulcers. Edema secondary to venous hypertension
may be a factor. However, patients with congestive heart failure
or hepatic congestion and associated limh edema do not de-
velop the skin changes and ulcerations typical of venous stasis
disease.
Two theories try to explain the changes in the limh exposed
to elevated venous pressures. The fihrin cuff theory holds that
elevated venous pressures in the lower limh lead to an increase
in the size of the capillary hed and widening of the interstitial
pores. This allows leakage through the capillary pores of fi-
hrinogen, which polymerizes to fihrin. Fihrin then forms a cuff
around the capillaries. The deposition of pericapillary fihrin
deposits may interfere with the diffusion of oxygen and nu-
trients to the skin. Fibrin cuffs may also trap growth factors
necessary for wound healing [6, 19], The skin therefore be-
comes hypoxic and lacking in nutrients. Minor trauma may
lead to a venous ulcer. Recent studies of patients at higher risk
for venous disease but without the signs of lipodermatosclerosis
support the theory that pericapillary fibrin deposits precede the
development of skin changes [20].
Another theory of venous ulceration is that WBCs are en-
trapped in the capillary endothelial wall in capillary beds that
are exposed to high venous pressures. WBCs attach to intra-
cellular adhesion molecules, such as intercellular adhesion mol-
ecule-1, in the capillary wall. The cells are then activated, and
cytokines and free radicals are released into the venous bed.
This may set up an inflammatory reaction, leading to injury
to the venous valves and/or the surrounding tissue and pre-
disposing to ulceration [21-23],
NONINVASIVE VASCULAR ASSESSMENT
Noninvasive vascular assessment of patients with CVI is most
reliably done hy use of color-flow-assisted duplex scanning.
Individual venous segments in the deep and superficial systems
can be visualized. The presence of obstruction, reflux, or a
combination of both can be determined. Reflux times can be
measured and have been found to correlate with the duration
and size of the venous ulcer [18]. Air plethysmography allows
the clinician to assess whole limb venous hemodynamics at rest
and after exercise and is an adjunct to duplex scanning [24],
Both of these modalities have been useful in research studies
involving patients with CVI. Practically speaking, the main role
of these tests may be in assessing CVI patients for venous
surgery.
TREATMENT OF VENOUS ULCERS
Table 1 summarizes recommendations for the management of
venous ulcer disease.

CLINICAL PRACTICE • CID 2001:32 (15 March) • 951

Pharmacologic Treatment
Diuretics. Diuretics are probably the most commonly used
drugs in the treatment of CVI and the edema associated with
venous ulceration. Diuretics may help mobilize fluid in con-
junction with aggressive compression therapy, but they are in-
effective if given alone for edema control.
Antibiotics. Chronic venous ulcers open for weeks to years
are usually colonized by many different organisms. Systemic
antibiotics should be used in the treatment of chronic venous
ulcers only if there is evidence of invasive infection; their use
should be based on results of culture of tissues and determi-
nation of bacterial sensitivities [25],
Hemorheologic and venotonic agents. Pentoxifylline has
heen used in various trials in the treatment of venous ulceration
in attempts to alter the microcirculation in patients with CVI,
Pentoxifylline may prevent inappropriate WBC activation and
improve oxygen delivery to ischemic tissue [26], In a multi-
center study of standard compression therapy and high dosages
of pentoxifylline (=S800 mg t,i,d. for 24 weeks), healing was
accelerated in the pentoxifylline-treated group over that in pa-
tients receiving compression therapy alone [27], Many authors
have advocated the use of venotonic drugs, such as Daflon
(Servier), in the treatment of CVI. The drugs are thought to
increase venous tone in patients with abnormal venous elasticity
and thereby decrease capillary leakage, thus altering the mi-
crocirculation [28, 29],
Compression Therapy
The most effective treatment of CVI and venous ulceration
is aggressive compression therapy. This concept was known to
Hippocrates (460-377 B.C) in ancient Creece and to Roman
physicians centuries later [30], In 1885, the Unna boot, a zinc
paste bandage, was introduced by Dr. Paul Unna and is still in
use today. The goal of compression therapy is to provide a
gradient of pressure from the ankle to the knee or thigh, de-
pending on the type of device ordered. Maximum pressure is
exerted at the ankle and minimum pressure is exerted at the
top of the device. Aggressive compression coapts damaged valve
leaflets, lowers capillary pressure, and therefore improves the
efficiency of the calf pump.
Compression stockings are classified into 4 grades on the
basis of the compression exerted at the ankle. Stockings graded
at 20-30 mm Hg are recommended for patients with varicose
veins, mild edema, or leg fatigue. Stockings graded at 30-40
mm Hg are useful for treating patients with severe varicosities
or moderate CVI. Stockings graded at 40-50 mm Hg and &60
mm Hg may be used for patients with severe CVI and its
complications. Knee-high stockings are better tolerated by most
patients than thigh-high stockings and should be ordered pref-
erentially [31], The disadvantages associated with stockings in-
clude the patient's difficulty in putting them on, especially over
952 • CID 2001:32 (15 March) • CLINICAL PRACTICE
bandages. This is a major problem for patients with severe
arthritis, for elderly patients, or for the obese. Continued use
of compression stockings after ulcer healing has been found to
lower the incidence of recurrent venous ulceration [32], Un-
fortunately, compression stockings are often not covered by
insurance plans.
Elastic wraps are available for patients who are unable to
wear stockings. These wraps have printed indicators in the
fabric that tell how much pressure is being applied (Setopress;
ACME United) [31]. Unna boots work primarily by providing
graded compression to the leg and offer no statistical advantage
over standard compression stockings [33], Unna boots are un-
suited for patients with a large amount of exudate from the
ulcer or those with poor hygiene.
Intermittent pneumatic compression pumps may be used as
an adjunct to compression wraps or stockings. The pumps
improve venous return and may improve fibrinolytic activity
within the capillary beds, thus reducing the size of the fibrin
cuff around the capillary bed [34], Multicompartment pumps
have been shown to mobilize more edema fluid in patients with
lymphedema than do single compartment pumps [35], In a
study of patients who were being treated for venous ulcers,
healing times decreased for those treated with compression
stockings and intermittent pneumatic compression pumps
compared with patients treated only with compression stock-
ings [36],
Compression therapy in any form should not be used for
patients with invasive infection at the ulcer site until the in-
fection is controlled. Compression therapy must be used cau-
tiously for patients with a history of congestive heart failure.
Patients suspected of having associated arterial disease must
have noninvasive arterial testing done before a compression
stocking or wrap is applied. Compression devices may be con-
traindicated for certain patients who have had arterial revas-
cularization procedures in the affected limb.
Wound Care
Care of the wound itself is critical to healing a venous ulcer,
Necrotic infected tissue should he debrided. The wound should
be kept moist to promote healing. Saline dressings provide a
cost-effective way of keeping the wound moist but need to be
changed at least twice per day to maintain the moist environ-
ment, Hydrogel dressings are also effective in maintaining a
moist environment in situations in which the dressings cannot
be changed more than once per day. Moist wound dressings
often provide pain relief for these wounds. Prolonged use of
agents toxic to wound healing, such as povidone-iodine, hy-
drogen peroxide, acetic acid, and Dakin's solution, should be
avoided [17], A moist, occlusive dressing promotes wound
healing and often decreases wound pain.
Surgery
Venous surgery. Surgery for treatment of venous ulcera-
tion is aimed at iiealing the ulcer itself or correcting the un-
derlying venous insufficiency. Venous valve repair, transposi-
tion, and transplantation are techniques described by several
authors [37]. These techniques have proved of limited value in
most patients who have CVI. Ablative surgery for the treatment
of CVI and venous ulceration is probably the most common
venous surgery for these patients. In patients with primary CVI
with reflux in the deep, superficial, and perforating systems,
ligation of the superficial veins and perforating veins improves
the hemodynamics of the limb and should be done before
considering deep venous reconstruction [38]. Subfascial liga-
tion of perforating veins, by use of minimally invasive tech-
niques, is a new treatment modality; however, prospective stud-
ies are needed to determine which patients might benefit [39].
Techniques of wound coverage. Ulcer excision with split-
thickness skin grafting is an effective way to deal with recal-
citrant venous ulcers. Skin grafting must be followed by the
application of compression stockings once the graft has taken,
or the incidence of graft failure and ulcer recurrence is high.
In severely diseased limbs, excision of the ulcer area and the
surrounding region of lipodermatosclerosis and placement of
a free flap of muscle and skin or omentum have been used [40,
41].
New Technologies
New technologies in wound healing, such as growth factors
and skin substitutes, focus on providing an active stimulus to
the wound. Previous treatment protocols, including debride-
ment, compression therapy, and venous surgery, optimized the
wound healing environment but did not stimulate healing di-
rectly. Crowth factors applied directly to the wound may be
helpful in actively stimulating the wound to heal. Recombinant
human platelet-derived growth factor, becaplermin, actively
stimulates fibroblast proliferation and collagen synthesis. The
US Food and Drug Administration has approved the use of
this topical agent for the treatnient of diabetic foot ulcers [42].
The efficacy of becaplermin in the treatment of venous ulcers
has not been determined. Topically applied recombinant tissue
plasminogen activator has also been used to actively remove
the fibrin cuff around capillary beds and promote healing [43].
Viable living human skin equivalents have been used in the
treatment of venous ulcers. Graftskin (Apligraf; Novartis) is a
viable human skin equivalent that contains an epidermal layer
with live keratinocytes and a dermal layer that delivers growth
factors and cytokines to the wound base [44]. Graftskin has
been approved by the US Food and Drug Administration for
the treatment of venous ulcers and may be a cost-effective way
to heal recalcitrant wounds [45]. Such technologies as vacuum-
assisted therapy and warming therapy have been advocated for
the treatment of these wounds, but controlled trials have not
yet been published [46].
CONCLUSION
CVI and venous ulceration have been recognized since ancient
times. These disease entities continue to defy understanding.
Compression therapy, first practiced by Greek physicians, re-
mains the most effective intervention to date. New technologies
hold hope for the future, but their cost effectiveness still needs
to be determined.
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