Chronic venous
insufficiency
Leg ulcer
A
cutaneous ulcer is a wound that is associated with loss of both epidermal and
dermal tissues. Chronic ulcers, which are due to a variety of systemic and/or
local factors, can represent both a diagnostic and therapeutic challenge. The majority
of ulcers occur on the lower extremities, and most are related to venous
insufficiency/venous hypertension, peripheral artery disease, or peripheral
neuropathy.
|
COMPARISON OF CLINICAL
FINDINGS IN THE THREE MAJOR TYPES OF LEG ULCERS |
|||
|
Venous |
Arterial |
Neuropathic/mal perforans* |
|
|
Location |
Medial malleolar and supramalleolar region |
1. Pressure
sites 2. Distal
points (toes) |
Pressure sites |
|
Morphology |
1. Usually
shallow 2. Irregular
borders 3. Yellow
fibrinous base |
1. Dry,
necrotic base 2. Well-demarcated
(“punched out”) |
“Punched out” |
|
Surrounding skin |
1. Yellow–brown
to brown discoloration due to hemosiderin deposits 2. Pinpoint
petechiae (“stasis purpura”) 3. Lipodermatosclerosis |
Shiny atrophic skin with hair loss |
Thick callus |
|
Other physical examination findings |
1. Varicosities 2. Leg/ankle edema 3. ± Stasis
dermatitis 4. ±
Lymphedema |
1. Weak/absent
peripheral pulses 2. Cool
feet 3. Prolonged
capillary refill time (>3–4 seconds) 4. Pallor
on leg elevation (45° for 1 min) 5. Dependent
rubor |
1. Peripheral
neuropathy with decreased sensation 2. ± Foot
deformities |
* Most commonly due to
diabetes mellitus.
Chronic venous insufficiency
results from failure of centripetal return of venous blood and increased
capillary pressure.
• The resultant
changes include edema, stasis dermatitis, hyper pigmentation, fibrosis of the
skin and subcutaneous tissue (lipodermatosclerosis) of the leg, and ulceration.
• Venous ulcers are
the most common chronic wounds in humans.
Venous ulcer
Introduction
Venous leg ulcers (VLU) are chronic skin ulcers at the gaiter area
that result from chronic venous
insufficiency (CVI). CVI is a complex disease of symptoms
and signs based on an inadequate venous return, which leads to a decompensation
of the venous and the microcirculatory function.
They represent the most advanced grade and severest manifestation
of this
disorder. A venous ulcer with no tendency to heal within 6 weeks to 3 months or
that has not healed within a year after optimum phlebological therapy is
designated as therapy resistant. About three-quarters of all leg ulcers are
generally considered to be mainly of venous origin.
CVI
results from chronic peripheral venous hypertension caused by venous reflux
and/or obstruction, or by neuromusculoskeletal dysfunction of the leg. Venous
pathologies involve the deep vein system and/or the superficial vein system and
perforator veins. Venous reflux can occur at the deep venous system – primarily
or secondarily after deep venous thrombosis – or at the superficial venous
system (long and/or short saphenous vein). Perforator vein insufficiency rarely
occurs in an isolated fashion and contributes less to CVI and VLU than
previously suspected. All forms of neuromuscular diseases and/or ankle and knee
joint dysfunction can induce CVI and VLUs. The ‘C’ grading of the CEAP
classification system of venous disease describes the insidious development of
chronic venous insufficiency leading from ankle edema (C3) and reversible
morphological skin changes in the early stages of CVI, such as stasis eczema and early lipodermatosclerosis (grade C4a),
over irreversible morphological changes
in late stages such as severe forms of lipodermatosclerosis (with a leg shape
of an inverted champagne bottle) and atrophie blanche (grade C4b), to active
(C6) or healed (C5) VLUs. Chronic and recurrent protein‐rich edema and aseptic inflammation induce fibrosis and
tissue hypoxia. VLU represents the highest grade of CVI. It can occur spontaneously
as a result from dermal and epidermal hypoxia or after minor trauma to the
trophically predamaged gaiter area.
Predisposing
factors
Venous leg ulceration
has a lifetime prevalence of 1%. The prevalence of venous leg ulceration
increases with age. Chronic ulceration in those younger than 60 years is
unusual and often related to severe deep venous insufficiency.
Risk factors for chronic venous disease include
family history, age, female gender, obesity, pregnancy, occupations requiring prolonged
standing, greater
height, venous thromboembolism, varicose veins, ankle joint
ankyloses and neuromuscular diseases with an impact on venous calf pump
ejection.
Obesity is certainly a risk factor for venous leg ulcers.
Obesity may cause venous hypertension and later venous ulcers, even without
valve incompetence or permanent obstruction of the venous system. Dependency is
another negative co-factor. The muscle pumps will not function due to
immobility and consequently venous hypertension will occur. In both cases, the
venous valves can be patent. This is also one of the important reasons to
combine the classical physical examination with the technical investigations,
especially duplex ultrasound techniques. The duplex examination is for this
reasons best performed by the physician and a technician.
Factors causing
venous leg ulceration
Pathways from vein to ulcer
Pathogenesis
The venous system of the lower extremities consists
of an interconnected network of superficial veins, deep veins, and perforator
or communicating veins which connect the superficial and deep systems.
Throughout the superficial, communicating and deep veins, one-way bicuspid
valves ensure unidirectional flow toward the deep system, thus allowing blood
to flow in a cephalad direction and preventing reflux. It is primarily the
contraction of calf muscles that drives blood from the leg toward the heart.
A.
Under normal circumstances, blood is pumped
against gravity towards the heart by the calf muscles. Blood flows from the superficial
veins to the deep venous system via the perforating veins. Bicuspid valves
ensure the unidirectionality (one-way) of the blood flow.
B.
B When the valves are incompetent and/or
hydrostatic pressure is elevated, blood flows back into the superficial venous
system, leading to the formation of varicose veins.
During
standing, as leg muscles relax, venous pressure in the legs may reach up to 80
to 90 mmHg. Calf muscle contractions, as during ambulation, transiently
increase pressure within the deep leg veins, propelling blood towards the
heart. When pressure rises within the deep system, the valves closes,
preventing retrograde flow and transmission of high pressure to the superficial
system. When the deep system empties, the deep vein pressure abruptly falls to
<30 mmHg i.e. the venous pressure drops when the person is walking and the
valves open, enabling flow from the superficial into the deep system. In all
patients with venous disease there is failure of these one-way valves and this
can result in varicose veins.
Once
valves fail, high pressures generated in the deep veins by calf muscle
contraction (in upright position) are transmitted to the superficial venous
system and distally as far as the capillary system of the skin, causing
capillary hypertension, and eventually leading to destruction of the nutritive
capillaries. A sustained elevation in venous pressure is responsible for the
typical clinical picture seen in chronic venous disease and is termed increased ambulatory venous pressure or venous
hypertension or venous insufficiency.
The
most common cause of valvular failure is thrombosis. The nidus for venous
thrombosis is typically the valve cusp, and when the thrombus is lysed by
plasmin, valve function is often lost as well. Calf muscle pump failure after
deep venous thrombosis (DVT) is often referred to as the postphlebitic
syndrome. In a large number of cases, long-term complications of deep venous
thrombosis, the so-called post-thrombotic syndrome, may lead to venous ulcers.
The post-thrombotic syndrome is a special part of CVI in which the underlining etiological event is a venous thrombosis. Estimates vary, but on the average,
one in three patients who suffers from a deep venous thrombosis develops
post-thrombotic complications in the subsequent 5 years. The chance of
developing CVI after a thrombotic leg, thus a post thrombotic syndrome, is
about 50% lower when medical elastic compression hosiery (MECH) is worn.
Additional
causes of venous hypertension include venous outflow obstruction and failure of
the calf muscle pump due to obesity or leg immobility.
The theories include the presence of
pericapillary cuffs due to leakage of fibrinogen, binding of growth factors by
leaked molecules, and the trapping of leukocytes with subsequent chronic
inflammation, dermal changes and ulcer formation. TGF, transforming growth
factor; VEGF, vascular endothelial growth factor.
Although
venous hypertension appears to be central to the skin changes seen in chronic
venous disease, the exact pathogenic cascade from valvular incompetence to
frank ulceration remains obscure. A few pathomechanisms have been suggested,
but it is still unclear whether they represent causative factors or
epiphenomena. For example, Browse and Burnand proposed that cuffs of fibrin
around dermal capillaries (due to leakage of fibrinogen) could impede the
diffusion of oxygen and nutrients to surrounding tissues and lead to
degenerative skin changes. Falanga and Eaglstein postulated that venous pooling
induced inter-endothelial space widening and deposition of fibrin and other
macromolecules that then “trapped” growth factors, rendering them unavailable
for wound repair.
The
current predominant theory is that chronic inflammation plays a key role in
chronic venous ulcers. In the setting of elevated venous pressure, there is
entrapment of leukocytes within small blood vessels and the skin of the lower
extremity (referred to as the micro vascular leukocyte-trapping hypothesis).
These trapped leukocytes become activated and they initiate an inflammatory
response that leads to cellular and tissue dysfunction, resulting in the dermal
changes often observed in patients with chronic venous insufficiency.
Expression
of specific adhesion molecules on endothelial cells attracts various leukocytes
(e.g. macrophages, T lymphocytes, mast cells) into the dermis via diapedesis,
where they further promote inflammatory responses via the release of cytokines
and activated proteinases. Specifically, increased expression and activity of
matrix metalloproteinase (MMPs) contribute to the breakdown of the
extracellular matrix, which promotes the formation of ulcers and impairs
healing. Elevated levels of cytokines such as transforming growth factor-beta
(TGF-β) and vascular endothelial growth factor
(VEGF) translate into increased dermal fibrosis and proliferation of dermal
capillaries, respectively. Capillary hyper permeability and extravasation of
red blood cells lead to deposition of ferric iron within affected skin,
resulting in brown discoloration. A persistent inflammatory response can
eventually give rise to ulcer formation, as continued production of MMPs and
cytokines (e.g. interleukin-1 and tumor necrosis factor-alpha [TNF-α]) leads to impaired fibroblast function and increased
degradation of growth factors necessary for wound healing. In addition,
oxidative stress-induced premature aging and dysfunction of wound fibroblasts
contribute to the chronicity of venous ulcers.
The Rotterdam model explains the pathways from venous
hypertension to venous leg ulcer (clinical symptoms are in purple).
Clinical Features
History
The events preceding ulceration happen insidiously over
many years and may be ignored by the patient. A history of thrombosis may be
missing because most episodes of lower extremity venous thrombosis are
clinically silent. Relevant inquiry related to thrombosis risk should include a
family history of similar problems (suggesting perhaps a familial thrombotic
tendency), any episode of leg immobilization including knee or hip surgery and
fractures, and any head injury associated with loss of consciousness.
Most patients complain of leg swelling, and many have
been given diuretics, though the edema of venous disease, unlike the edema in
salt-retaining states, like heart failure, cirrhosis, and nephrotic syndrome,
does not respond to diuretics. An edematous leg not responsive to diuretic
therapy is a strong clue to the diagnosis.
Cutaneous Lesions
Very
Early: Tenderness to palpation
Early
signs: edema,
hyperpigmentation, and varicose veins.
Late
signs: atrophie blanche, lipodermatosclerosis, and venous
ulcers.
Once
there is venous valvular failure, a rather predictable series of changes occur
in the skin. The earliest (though not universal) physical finding is soft
tissue tenderness, even of normal appearing skin, discovered when checking for
the presence of edema by palpation. The
early sign of chronic venous insufficiency is usually a cushion-like pitting
edema (especially around the ankle). Edema is more pronounced in the evening
and resolves overnight. Frequently
one notes the appearance of pinpoint petechiae superimposed on a yellow–brown
discoloration due to extravasation of red blood cells and deposition of hemosiderin
within macrophages, which is sometimes accompanied by hyperpigmentation.
Varicose
veins, dilated and tortuous veins, especially noticeable
when the patient is standing, and smaller varicosities appear about the dorsum
of the foot and ankle. Although they are usually asymptomatic, patients may
complain of symptoms of aching, cramping, itching, fatigue, and swelling that
are worse with prolonged standing.
Stasis
dermatitis, characterized by relatively
sharply demarcated erythema,
scaling, pruritus, erosions, oozing, crusting, and occasional vesicles may
occur during any stage of chronic venous insufficiency. It typically occurs in
the medial supramalleolar region where microangiopathy is most intense. Over
time, lesions may lichenify; can be
complicated by secondary infection.
As 58% to 86% of patients with venous leg
ulcers develop contact sensitization to topical therapies, it is important to
evaluate for coexisting allergic contact dermatitis. Contact sensitization often leads to secondary
dissemination. Patches of eczema arise in a strikingly symmetric distribution
pattern, particularly on the anterior aspect of the contralateral leg, the
anterior thighs and the extensor surface of the upper extremities; lesions may
generalize to involve the trunk and face. Other pattern is asteatotic
dermatitis (synonym: eczema craquelé). Frequent washing may cause extreme
dehydration of the skin and a morphologically similar to eczema with a ‘crazy
paving’ pattern appears.
Over a period of years, the skin, subcutaneous adipose
tissue and deep fascia become mutually adherent and the skin begins to
feel progressively indurated (chronic
“lipodermatosclerosis”) due to fibrosis of the dermis and subcutaneous fat. This is a fibrosing
panniculitis characterized by a bound-down, indurated plaque that begins at the
medial ankle above the malleolus and extends circumferentially around the lower
leg. As the fibrosis increases, a firm circular cuff is formed which may constrict and
strangle the lower third of the leg further, impeding venous and lymphatic flow
and leading to brawny edema above and below the fibrosis. These late changes
resemble an inverted champagne bottle or "piano leg. Chronic lipodermatosclerosis may be preceded by an acute
inflammation of the subcutaneous fat, and histologically there is acute septal panniculitis.
Acute lipodermatosclerosis is characterized by warm, erythematous, mildly indurated plaques that are tender and painful and are
often misdiagnosed as cellulitis (“pseudo
erysipelas”).
Atrophie
blanche is the result of decreased capillary
density caused by microthrombi and matrix degradation causing hypoxia. There is
an atrophic epidermis and a thickened, scleroderma‐like dermis with proliferative dilated capillaries. Fully established
lesions of atrophie blanche consist of irregular, smooth, ivory‐white depressed atrophic scared plaques with surrounding hyper
pigmentation and punctate telangiectasias,
often located on the lower legs. Usually multiple lesions (diameter
0.5–15 cm) are present. It is observed in up to 40% of patients with
chronic venous insufficiency.
Acroangiodermatitis (pseudo-Kaposi sarcoma) has purple
macules, nodules, or verrucous plaques on the dorsal feet and toes of patients
with long-standing venous insufficiency and mimics Kaposi sarcoma clinically
and histologically.
The venous leg ulcer arises either
‘spontaneously’ or often after a minor trauma. Venous leg ulcers can be
painful. The complaints of pain are particularly prominent in the ulcerative
phase of atrophie blanche or if accompanied by other factors such as an infection.
Though venous ulcers are classically located above the medial malleolus, they
are always found anywhere below the knee. VLUs
are less commonly located in the lateral retromalleolar area (related to deep
and short saphenous vein reflux).
Predilection
sites of the venous ulcers are primarily the region above the medial malleolus
(usually along
the line of the long saphenous
vein) or above the lateral malleolus (usually along the line of the small saphenous vein. The ulcers are sharply
defined, irregularly shaped, relatively shallow with a sloping border, and are
usually tender; the ulcer bed is often covered by a yellow, fibrinous necrotic exudates
and there is always secondary bacterial colonization. If it is appropriately
debrided, a red-base of healthy, non-ischemic granulation tissue is usually
seen. When untreated, venous ulcers tend to become larger and can even become
circumferential on the lower extremity. Venous ulcers do not usually develop beyond the fascias. If
deeper structures (tendons, muscles, bones) are involved, additional or
alternative causes must be considered (such as PAOD, diabetes mellitus, or
vasculitis). Pedal
pulses are usually palpable. If they are not palpable because of induration or
edema, an ankle–brachial index should be obtained to exclude concomitant
peripheral artery disease.
The changes in the skin in venous insufficiency are a
result of changes in the macro- and microcirculation. It is unclear why an
extensive lipodermatosclerosis is
formed in one patient, whereas a atrophie blanche is prominent in another
patient. Local factors possibly play a role in this and should be investigated
further.
Laboratory Evaluation
Standardized
evaluation of patients with chronic venous disease is based on the CEAP
classification system which generates scores derived from objective clinical
signs (C), etiology (E), anatomic (A) location of the affected veins, and
pathophysiology (P) (reflux, obstruction or both).
CEAP
(Clinical, Etiologic, Anatomic, Pathophysiologic) classification of chronic
venous disorders
|
CEAP CLASSIFICATION OF
CHRONIC VENOUS DISORDERS |
|
Clinical classification (C) |
|
1.
C0: no
visible or palpable signs of venous disease 2.
C1:
telangiectasias or reticular veins 3.
C2: varicose
veins 4.
C3: edema 5.
C4a:
hemosiderin pigmentation, eczematous dermatitis (stasis dermatitis) 6.
C4b:
lipodermatosclerosis, livedoid vasculopathy (atrophie blanche) 7.
C5: healed
venous ulcer 8.
C6: active
venous ulcer 9.
S: symptoms
including aches, pains, tightness, skin irritation, heaviness, muscle cramps,
and other complaints attributable to venous dysfunction 10.
A:
asymptomatic |
|
Etiologic classification (E) |
|
1.
Ec:
congenital 2.
Ep: primary 3.
Es: secondary
(post-thrombotic) 4.
En: no venous
etiology identified |
|
Anatomic classification (A) |
|
1.
As:
superficial veins 2.
Ap:
perforator veins 3.
Ad: deep
veins 4.
An: no venous
location identified |
|
Pathophysiologic classification (P) |
|
1.
Pr: reflux 2.
Po:
obstruction 3.
Pr,o: reflux and
obstruction 4.
Pn: no venous
pathophysiology identified |
1. Vascular investigations
· Assessment of
peripheral arterial disease: It is crucial to
evaluate arterial blood flow. A useful bedside screening test is to calculate
the ratio of the systolic blood pressure in the ankle (as measured by Doppler)
to the systolic pressure in the brachial artery (also measured by Doppler).
This “ankle/brachial pressure index”
(ABPI)
is greater than or equal to one in normal individuals. Anything less than one
is an indication of peripheral arterial disease. The lower the ratio, the more
severe the arterial obstruction.
· Assessment of
venous pathologies: Duplex ultrasonography, preferably
performed with the patient in a standing position, is useful for assessing both
reflux and obstruction within the deep, superficial and perforating veins, from
the inferior vena cava to the calf veins. It provides
information that is necessary for determining the CEAP score. In general,
venography is performed if an intervention is planned. Venography gives good morphological information. Ascending venography is
recommended for patients with post-thrombotic disease as it gives a detailed
anatomic map of the venous return of the lower extremity, whereas descending
venography is helpful in assessing valvular disease and estimating reflux
severity.
2. Microbiology
In the presence of clinical signs of critical colonization
and/or bacterial cellulitis and/or sepsis, wound microbiology must be analyzed.
A swab from the wound base (after the removal of fibrin layers and biofilms) or
a small tissue biopsy from the wound base – if feasible – yields more
representative microbiology results than superficial swabs from necrotic
material.
3. Wound histology
If there is a suspicion of vasculitis, pyoderma gangrenosum,
hypertensive ischemic leg ulcer, ulcerating malignant skin tumour or in any
refractory chronic leg ulcer showing no trend to heal after 3 months treatment,
a biopsy should be performed. A deep and narrow (3–4 mm wide) ellipse
biopsy, usually 3–5 cm long and including the vital wound border and ulcer
base, should be taken and sent for routine histology (H&E), direct
immunofluorescence and cryoconservation for eventual further examinations. The
body of the ellipse biopsy that is sent in for H&E histology should be left
intact and sectioned lengthwise, in order to get a histological profile from
vital skin to the ulceration, extending from the epidermis to the deep
subcutis.
4. Assessment of malnutrition
Total protein, albumin and lymphocyte count are sufficient
to indicate malnutrition in the vast majority of cases. More costly vitamin
and/or zinc measurements should be restricted to specific questions.
5. Pain assessment
Pain should be assessed at regular (e.g. 4 weeks) intervals,
with reproducible methods such as the visual analogue scale (VAS).
Pathology
In the skin surrounding the ulceration, there is sclerosing panniculitis.
The epidermis is acanthotic, while the dermis is thickened and fibrotic with
an apparent increase of vessels (venules) at the level of the subpapillary
plexus. The apparent increase in vessels is caused by multiple cross‐sections through tortuous subpapillary
venules. The venules are elongated and have thick walls, changes caused by
chronic venous hypertension. There is extravasation of red blood cells and hemosiderin
deposits within macrophages. The chronically inflamed and fibrotic dermis
expands and extends into the subcutis. The fascia is thickened and fibrotic;
the leg muscles may show fatty degeneration. The ulceration itself is non‐specific, exposing fibrin and/or
biofilm layers, granulation tissue and a mixed inflammatory infiltrate.
Complications
Recurrent ulceration is frequent. Any open wound provides
a portal of entry for bacteria, and cellulitis, though infrequent, may develop
at any time. Given that venous dermatitis may be extremely pruritic, and that
these patients are easily sensitized to the topical agents they apply, contact
dermatitis, especially due to topical antibiotics, is common. The skin is
easily excoriated and may become infected. Many of these individuals are
predisposed to thrombi, and recurrent episodes of venous thrombosis may occur.
All patients with advanced venous disease have some
degree of lymphatic impairment. Loss of lymphatic drainage from the lower leg
may lead to verrucous changes and cutaneous hypertrophy, elephantiasis nostras.
Prognosis and Clinical
Course
The prognosis for healing areas of ulceration and
inflammation is excellent in the absence of comorbid illness that interferes
with healing. The vast majority of uncomplicated patients respond well to
ambulatory outpatient therapy. Permanent changes include hemosiderosis and
fibrosis that develop before the initiation of therapy. Loss of valvular
function is irreversible. In the absence of continual lifelong cutaneous
support in the form of inelastic wraps or elastic stockings, skin and soft
tissue injury continues.
Treatment
Treatment for all
clinical manifestations of chronic venous insufficiency includes therapies that
lower venous pressure and improve venous and lymphatic flow by mechanical
means, dressings, drugs, and surgery. The initial
step in the approach to an ulcer should be to address all systemic and local
factors that may impair healing.
Moisture and
occlusion
In
the past, the mainstay of wound management was to dry the wound bed with
absorptive gauzes. A major breakthrough in the management of chronic wounds was
the realization that a moist environment is critical for wound healing and
occlusive dressings do not increase the risk of infection. Moist retentive
wound dressings stimulate collagen synthesis, promote angiogenesis by creating
a hypoxic environment, encourage re-epithelialization, and decrease pain. By serving
as a barrier against external contamination and by lowering wound pH, occlusive
dressings actually decrease wound infection rates.
Dressings
should be changed based on their potential for absorbency and the amount of
exudate, with attention to the delicate balance between over hydration and
excessive dryness. For example, occlusive dressings applied to highly exudative
wounds may cause maceration and erosion of the surrounding skin, possibly
leading to further deterioration of the wound. In addition, chronic wound fluid
can perpetuate cytokine and MMP production, thereby affecting the function of
fibroblasts and growth factors and contributing to chronicity. It is therefore
important to protect the skin surrounding the wound bed with an ointment in
order to preserve barrier integrity.
Debridement
Debridement
consists of the removal of necrotic, non-viable, or infected tissue from the
wound bed in order to promote healing. In a sense, debridement is an attempt to
shift the wound from a chronic state (with a milieu characterized by an
abnormal extracellular matrix, an excess of proteolytic enzymes, and senescent
cells) into an acute state. Debridement can be surgical (sharp debridement),
mechanical (wet-to-dry), autolytic, chemical (enzymatic), and biologic (maggot
therapy).
Sharp
debridement with surgical instruments represents
the most rapid method for debriding a wound and is most appropriate for large
necrotic and/or infected wounds. It also enables the clinician to estimate the
extent and severity of a wound. Although damage to viable tissue is possible,
sharp debridement performed by a skilled physician is usually highly selective.
Caution is advised in the case of arterial ulcers because of the potential risk
for tissue desiccation and ulcer enlargement. Sharp debridement may be
associated with bleeding and pain and may necessitate analgesia.
Wet-to-dry
(mechanical) debridement consists of placing gauze
moistened with saline over the wound, allowing the gauze to dry, and then
removing the dry gauze along with adherent non-viable tissue. It is relatively
fast and easy to perform, but is painful and does not discriminate between
viable and non-viable tissue. It is indicated for wounds with large amounts of
necrotic tissue.
Autolytic
debridement is the process by which the body uses
its own proteolytic enzymes and phagocytic cells to clear necrotic debris. The
process is enhanced by moist retentive wound dressings and may require weeks to
accomplish. Autolytic debridement is selective, painless, and suited primarily
for wounds with minimal debris. It is contraindicated if the wound is infected.
Enzymatic
(chemical) debridement utilizes topically applied
proteolytic enzyme preparations such as papain–urea or collagenase to digest
necrotic tissue, collagen, fibrin, and wound exudate. Chemical debridement is a
gradual process. The papain–urea preparation contains papain, which is derived
from the plant Carica papaya and is a
non-selective cysteine protease. It is active over a broad pH range and is
associated with an intense inflammatory response and digestion of viable
tissue; local pain or a burning sensation is often described. Therefore, the
product should be applied only to the wound bed and not to the surrounding
intact skin. Collagenase preparations are derived from Clostridium histolyticum; they specifically target
native collagen and are active within a narrow pH range of 6 to 8. These
preparations are highly selective and do not harm viable cells. Prior to
application, it is advisable to cross-hatch the eschar, if present, in order to
increase penetration.
For
therapy-resistant, chronic ulcers with marked necrosis and slough, maggot debridement therapy can be considered.
Essentially, it exploits the ability of maggots to decompose necrotic tissue
(benign myasis), but the debridement is done in a controlled manner so as to
avoid undesirable effects on healthy tissues. Degradation via proteinases that
are in larval excretory/secretory products is thought to contribute to wound
debridement. It is important to select larval strains that feed preferentially
on necrotic tissue and to avoid applying too many larvae to a wound. The flies
most often employed are facultative calliphorids, in particular the green
bottle blowfly, Luciliasericata.
Maggots
are used to treat various types of chronic ulcers, including pressure ulcers,
venous ulcers, and neurovascular diabetic ulcers, as well as traumatic and
postsurgical wounds. In a multicenter, randomized, open study that compared the
clinical effectiveness of larval therapy to a standard debridement technique (hydrogel)
for “sloughy” or necrotic leg ulcers, larval therapy did not improve the rate
of healing or reduce bacterial load, but it did significantly reduce the time
to debridement and increase ulcer pain.
Novel
approaches to wound debridement are currently under investigation, including
both hydrosurgery and ultrasound- and radiofrequency-based techniques.
Wound
dressings
The ideal
wound dressing should: (1) provide a moist retentive environment; (2) absorb
excess exudate without causing maceration of surrounding skin; (3) protect
against bacteria; (4) leave no residual debris but cause no trauma when
removed; (5) decrease odour; and (6) relieve pain. In addition, the ideal wound
dressing should be cost-effective, easy to handle, and be neither irritating
nor allergenic. Obviously, there is no single dressing that can fulfil all
these criteria throughout the entire healing process. A vast array of dressings
exists and the choice of a dressing depends upon the wound type and its
characteristics at a given time
MMPs, matrix metalloproteinases.
|
TYPES OF WOUND
DRESSINGS |
|||
|
Dressing type |
Properties |
Disadvantages |
Indications |
|
Gauzes |
Good
absorption Can
be impregnated with: -
NaCl
to become highly absorbent, discourage bacterial overgrowth, and prevent
formation of excess granulation tissue -
petrolatum
so less drying and adherent, but then less absorbent -
iodine
or silver as an antiseptic |
Adhere
to wound bed and promote desiccation Can
cause pain and trauma, including removal of epithelium, upon removal |
Wet
wounds with heavy exudate May
serve as a secondary dressing |
|
Films |
Semi-occlusive,
thin polyurethane membranes Maintain
moisture Permeable
only to vapors, not to liquids Transparency
enables wound visualization |
Non-absorbent Can
cause maceration if applied to wounds with heavy exudate |
Wounds
with minimal exudate As
a secondary dressing |
|
Hydrogels |
Maintain
a moist environment Promote
autolytic debridement Non-adhesive Relieve
pain |
Can
lead to maceration of skin surrounding wound if used in exudative wounds |
Dry
wound Wound
with minimal exudate |
|
Hydrocolloids |
Adhesive,
occlusive dressings that absorb exudates with the formation of hydrophilic
gel Provide
a moist environment |
Not
suitable for wounds with heavy exudate or infected wounds May
produce a brown, malodorous exudate May
be traumatic on removal |
Wounds
with a mild to moderate exudate |
|
Alginates |
Fibrous
dressings derived from brown seaweed Highly
absorbent and require moisture to function Ion
exchange between calcium in the alginate and sodium in the wound fluid leads
to the formation of a moist retentive gel Hemostatic |
May
adhere to dry wounds May
leave fibrous debris in the wound Can
lead to maceration around the wound unless cut to the size of the wound bed |
Wounds
with a moderate to heavy exudate Undermined
or tunneling wounds |
|
Foams (polyurethane) |
Good
absorbance capacity Non-traumatic
upon removal Provide
thermal and shear protection |
May
produce malodorous drainage Maceration
around wound possible |
Wounds
with a moderate to heavy exudate |
|
Collagens |
Collagen
matrix that physically entraps MMPs and facilitates growth factor activity |
Nonspecific
inhibition of MMPs |
Clean,
non-infected, recalcitrant chronic wounds |
Management of wound infection
The presence of a microbial infection is always
detrimental to wound healing. However, all chronic open wounds are colonized
with bacteria and it is important, although often difficult, to distinguish
true infection from bacterial colonization. Of note, colonization is defined by
the presence of replicating bacteria and adherent microorganisms, but without
evidence of tissue damage.
Critical
colonization is a relatively
new concept in which the bacterial burden within a chronic wound does not
elicit the typical symptoms or signs of an infection, but does delay healing.
The presence of ≥106 colony-forming units of
bacteria/gram of tissue predicts delayed wound healing and a high risk for
developing an infection. More recent studies have demonstrated that in many
chronic wounds, bacteria persist in the form of biofilms. The latter represent
communities of bacteria, protected by an adhesive polymeric matrix cover, that
communicate with each other via water channels. Through these communication
channels, bacteria are able to regulate the transcription of genes and protein
products in a manner that is beneficial to them, but which can delay healing
(quorum sensing). Biofilms are particularly resistant to antimicrobial therapy.
Wounds become clinically
infected when host defenses are overwhelmed. Signs and symptoms of infection
include an increased exudate, purulent discharge, pain, and surrounding
erythema and swelling. However, sometimes an increase in ulcer size and
malodorous or friable granulation tissue are the only clues to the presence of
an active infection within a chronic wound. Systemic signs of infection such as
fever, chills, tachycardia, and leukocytosis may suggest that the infection has
progressed to a bacteremia or septicemia, although the former may be subtle in
elderly patients, necessitating a high index of suspicion.
Most chronic wounds have
a polymicrobial flora. Bacterial cultures usually grow aerobic Gram-positive
cocci, which are often mixed with Gram-negative bacilli and sometimes
anaerobes. Clinically infected wounds should be cultured and treated initially
with broad-spectrum systemic antibiotics. The antibiotic regimen is then
adjusted based on the results of sensitivity testing.
In
properly treated, non-healing wounds that demonstrate critical colonization,
topical antimicrobials should be considered. Topical antimicrobial agents are
divided into two major categories: antiseptics and antibiotics. Antiseptics
have a broad antimicrobial spectrum as well as multiple microbial targets, but
they are often toxic to host tissues. Topical antibiotics have specific
cellular targets and a narrower spectrum of activity; they are not toxic to
human cells but are more likely to induce bacterial resistance. Commonly used
topical antibiotics include bacitracin, neomycin, mupirocin, retapamulin,
gentamicin, and fusidic acid. However, topical antibiotics can cause allergic
contact dermatitis, in particular neomycin and bacitracin. It is also
preferable to avoid topical antimicrobials that have a systemic counterpart.
Commonly
used antiseptics include hydrogen peroxide, chlorhexidine, iodine-based
preparations (e.g. povidone-iodine, cadexomer iodine), and silver-releasing
agents. Hydrogen peroxide and povidone-iodine have a broad antimicrobial
spectrum with minimal resistance but may be cytotoxic. Cadexomer iodine is a
complex of 0.9% elemental iodine plus cadexomer microbeads which are composed
of a modified starch-based polymer. Upon absorption of exudate, the cadexomer
beads swell and slowly release iodine into the wound bed, thus maintaining
non-toxic iodine concentrations.
Silver
is an effective antiseptic agent with broad-spectrum activity, including
against methicillin-resistant Staphylococcus aureus (MRSA),
vancomycin-resistant enterococci (VRE), and extended-spectrum β-lactamase producers. Resistance
has rarely been reported, primarily with Gram-negative species. Only the
ionized form of silver (Ag+) has
antimicrobial properties, so exposure to wound fluid or exudate is required if
the source is metallic silver. Silver ions kill bacteria by damaging bacterial
cell walls and intracellular and nuclear membranes as well as denaturing
bacterial DNA, RNA, and key enzymes (e.g. respiratory enzymes). Silver may also
promote cellular proliferation and re-epithelialization by inducing the
production of metallothionein by epidermal cells. Metallothionein increases
zinc- and copper-dependent enzymes required for cellular proliferation and
matrix remodeling. Silver has been incorporated into various dressing products
(e.g. gauzes, hydrocolloids, alginates, foams) in addition to creams, gels, and
barrier protectants which differ in their solubility and the rate at which
silver ions are released into the wound bed. Disadvantages of silver products
include potential irritation, permanent blue–gray discoloration (localized
argyria), and cost. Topical silver sulfadiazine can cause neutropenia in
children which is reversible once the cream is discontinued.
Lastly,
as chronic wounds may serve as a portal of entry for Clostridium tetani, it is recommended that the tetanus
immune status of patients with chronic leg ulcers be assessed.
Adjuncts to
wound care
Compression
Compression
therapy is a mainstay in the treatment of venous insufficiency. Compression
stockings improve venous return, reduce edema, stimulate healthier granulation
tissue within venous ulcers, and improve quality of life. A Cochrane
meta-analysis of 39 randomized controlled trials concluded that compression
therapy increased ulcer healing rates when compared to no compression.
Elastic
stockings, preferably with graduated compression, are available in a wide range
of compressive pressures (15 to 60 mmHg), lengths, and materials. Lower levels
of compression (20 to 30 mmHg) are sufficient for preventing mild edema,
whereas higher levels of compression (30 to 40 mmHg) are required to control
stasis dermatitis or lead to the healing of ulcers. Compression stockings also
prevent the recurrence of venous ulcers once healed. Therefore, lifelong use of
compression is recommended for patients with a history of venous ulcers. In
addition to stockings, there are other forms of compression such as bandages
and wraps. Of note, surgical correction of superficial venous reflux (plus
compression) does not improve ulcer healing but does reduce the recurrence of
ulcers.
It is important to remember that compression
therapy in patients with undiagnosed arterial insufficiency can lead to ulcer
worsening, gangrene or even limb amputation. As many patients with venous
disease have concomitant arterial insufficiency, clinically significant
arterial disease must be excluded before prescribing compression therapy. The
latter is also relatively contraindicated in patients with uncompensated
congestive heart failure.
|
CLASSES OF
COMPRESSION STOCKINGS |
||
|
Class |
Pressure at the ankle |
Indication |
|
I |
20–30 mmHg |
Simple varicose veins |
|
Mild edema |
||
|
Leg fatigue |
||
|
II |
30–40 mmHg |
Moderate edema |
|
Severe varicosities |
||
|
Moderate venous
insufficiency |
||
|
III |
40–50 mmHg |
Severe edema |
|
Severe venous
insufficiency |
||
|
Post-thrombotic
lymphedema |
||
|
IV |
50–60 mmHg |
Elephantiasis |
|
TYPES OF
COMPRESSION THERAPY |
||
|
Bandage |
Advantages |
Disadvantages |
|
Elastic wraps |
1.
Inexpensive 2.
Can
be reused |
1.
Often
applied incorrectly by the patient 2.
Tend
to unravel 3.
Do
not maintain sustained compression 4.
Lose
elasticity after washing |
|
Self-adherent wraps |
1.
Self-adherent 2.
Maintain
compression |
1.
Expensive 2.
Cannot
be reused |
|
Unna boot |
1.
Comfortable 2.
Protects
against trauma 3.
Full
maintenance of ambulatory outpatient status 4.
Minimal
interference with regular activities 5.
Substitutes
for a failing pump |
1.
Pressure
changes over time 2.
Needs
to be applied by well-trained physicians and nurses 3.
Does
not accommodate highly exudative wounds |
|
Four-layer bandage |
1.
Comfortable 2.
Can
be left in place for 7 days 3.
Protects
against trauma 4.
Maintains
a constant pressure for 7 days because of the overlap and elasticity of the
bandages 5.
Useful
for highly exudative wounds |
1.
Needs
to be applied by well-trained physicians and nurses 2.
Expensive |
|
Graduated compression
stockings |
1.
Reduce
the ambulatory venous pressure 2.
Increase
venous refilling time 3.
Improve
calf pump function 4.
Different
types of stockings accommodate different types of leg disorders 5.
Dressings
underneath can be changed frequently |
1.
Often
cannot monitor patient compliance 2.
Difficult
to put on, unless have zipper or Velcro straps |
|
Orthotic device |
1.
Adjustable
compression 2.
Sustained
pressure 3.
Easily
put on and removed 4.
Comfortable |
1.
Expensive 2.
Bulky
appearance |
|
Compression pump |
1.
Augments
venous return 2.
Improves
hemodynamics and microvascular functions 3.
Enhances
fibrinolytic activity 4.
Prevents
postoperative thromboembolic complications in high-risk patients |
1.
Expensive 2.
Requires
immobility for a few hours per day |
|
CLASSES OF
COMPRESSION BANDAGES |
|
|
Class |
Properties |
|
Class I |
Lightweight and
conforming |
|
Stretch and simple
dressing retention properties |
|
|
Class II |
Also known as short
stretch bandages |
|
Act like rigid,
non-elastic bandages |
|
|
Used for light support |
|
|
Class III |
|
|
-
Class
IIIA |
Light compression
bandages |
|
-
Class
IIIB |
Moderate compression
bandages |
|
-
Class
IIIC |
Extra-high performance |
|
Achieve 40 mmHg at the
ankle |
|
|
Useful for severe
varicosities, severe edema, post-phlebitic syndrome |
|
Manual lymph drainage
Edema is
a significant cause of delayed healing of venous ulcers. Identifying the cause
of the edema is instrumental in choosing the appropriate therapy, which in
turn is critical for ulcer resolution. However, even with identification and
treatment of contributing factors (e.g. after load reduction, diuretics), edema
may be persistent.
Manual lymph drainage is a massage technique
in which lymph conduits are contracted more frequently and lymphatic fluid is
moved away from affected lymph edematous regions toward more centrally located,
functioning lymph basins, and thereby reducing edema volume. This manual
drainage is employed during the early, intensive phase of lymphedema therapy
and is combined with short-stretch compression bandaging applied immediately after
treatment. The regimen also includes a series of exercises to increase
lymphatic flow through functioning collateral pathways, skin care, and
sometimes the use of intermittent pneumatic compression. This intensive,
short-term therapy is referred to as “complete decongestive physiotherapy” and
is followed by a maintenance phase that consists of skin care, elastic
compression, and exercise.
Topical negative pressure therapy
In
topical negative pressure therapy, ideally performed using a vacuum-assisted
closure (VAC) system, negative pressure is applied to hasten wound healing. It
is used primarily for ulcers that are due to venous disease or diabetes. The
system includes an open pore foam conduit (cut to the wound size) sealed with a
semi-occlusive drape which is then attached to a vacuum source via a tube. When
sub atmospheric pressure (100–125 mm Hg) is applied to the foam–wound interface
(continuously or intermittently), accumulated fluid is transferred to a
canister. Topical negative pressure therapy promotes wound healing by creating
mechanical forces that stimulate a biological response while maintaining a
moist environment. It also removes exudate, reduces edema, increases local
perfusion, decreases the bacterial count, and enhances granulation tissue
formation.
Before application, the wound must be
debrided of necrotic tissue in order to prevent infection. Topical negative
pressure therapy is contraindicated for ischemic wounds and ulcerated
malignancies because it may cause necrosis of the wound edges and tumor growth,
respectively. The foam should be changed every 48 to 72 hours. Sometimes, new
granulation tissue grows into the foam, which can result in pain during foam
changing. If this occurs, then the foam should be changed more frequently or a denser
foam employed. In up to 25% of patients, there are complications such as pain,
odor, peri wound irritation or maceration, infection, bleeding, and necrosis;
most of these problems can be avoided with careful patient selection and
skilled management.
Skin substitutes
Patients
with recalcitrant chronic ulcers can sometimes benefit from autologous skin
grafting, especially when the ulcers are due to venous disease. However, there
has been an increase in the use of biologic dressings and synthetic skin
substitutes in such patients. Living skin substitutes are tissue-engineered
products that contain a cellular component of autologous or allogeneic origin
plus a biodegradable scaffold, and they serve as a replacement for the
epidermis, dermis or both. These skin mimetics provide temporary wound
coverage, serving primarily as a source for growth factors and extracellular
matrix. Although effective in wound repair, their clinical use is still limited
due to their high cost and complex technology. In general, these living skin substitutes
are indicated for venous and diabetic ulcers.
There are also biologic dressings that
consist of just an extracellular matrix (i.e. they have no cellular component).
Structural extracellular matrix components, such as collagen, fibronectin and proteoglycans,
provide a temporary scaffold that supports cellular proliferation and
migration. In addition, they contain cytokines, e.g. TGF-β, bFGF, which promote wound healing. These dressings
are also used for diabetic and venous ulcers.
Another approach is a bio-inspired artificial
hydrogelmatrix that utilizes natural enzymatic reactions to become bioactive. It
is able to incorporate and then deliver biomolecules (e.g. MMPs, growth
factors) and at the same time be degraded and remodeled by them, ultimately
being replaced by newly formed tissue. Emerging therapies include application
of bone marrow-derived mesenchymal cells and spraying of allogeneic fibroblasts
and keratinocytes onto the wound.
Topical and oral medications
Daily, short-contact application of topical
tretinoin solution (0.05%; currently requires compounding) is reported to
stimulate granulation tissue formation and healing of chronic leg ulcers.
Application of small amounts of 0.025% tretinoin cream is also observed to
induce neovascularization in ischemic wound beds.
Pentoxifylline,
a drug that targets inflammatory cytokine release, leukocyte activation and
platelet aggregation at the microcirculatory level, is occasionally a component
of the treatment regimen for chronic venous insufficiency. Although evidence of
a beneficial effect when the drug is used as monotherapy is largely lacking,
pentoxifylline has been shown (at a dose of 1200 mg/day), in conjunction with
compression therapy, to modestly improve ulcer healing as compared to compression
plus placebo. This effect has been attributed to the drug’s fibrinolytic
properties, antithrombotic effects, and/or ability to inhibit the production of
proinflammatory cytokines.
Ulcers
secondary to livedoid vasculopathy may benefit from antiplatelet and
anticoagulant agents including aspirin, low-molecular-weight heparin, and
direct oral anticoagulants (DOACs), as well as fibrinolytics, vasodilators, and
immunosuppressants or immunomodulators (e.g. IVIg).
Approximately
half of patients with VLU suffer from superficial venous reflux which can be
abolished by a variety of methods (flush ligation and stripping, endovenous
thermo ablation, foam sclerotherapy), whereas patients with predominantly deep
venous reflux have no benefit from superficial vein surgery. Refractory VLUs
can be treated with skin equivalents or shave operation and split‐skin grafts of VLU. VLU recurrence
is common (30% in 12 months). Consistent compression therapy and the
elimination of superficial venous reflux is the key to VLU prevention.
EMG=Electromyography
Summary of treatment
of venous ulcer
