Venous Ulcer

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Journal of General - Procedural Dermatology & Venereology Journal of General - Procedural Dermatology & Venereology Indonesia

Indonesia

Volume 2

Number 2 Vol. 2, No. 2 (Dec 2017) Article 5

12-31-2017

Venous Ulcer Venous Ulcer

Irene Dorthy Santoso

Department of Dermatology & Venereology, Faculty of Medicine Universitas Indonesia, Dr. Cipto Mangunkusumo National Hospital, Jakarta, Indonesia

Hanny Nilasari

Shannaz Nadia Yusharyahya

Follow this and additional works at: https://scholarhub.ui.ac.id/jdvi

Part of the Dermatology Commons, Integumentary System Commons, and the Skin and Connective Tissue Diseases Commons

Recommended Citation Recommended Citation

Santoso, Irene Dorthy; Nilasari, Hanny; and Yusharyahya, Shannaz Nadia (2017) "Venous Ulcer," Journal of General - Procedural Dermatology & Venereology Indonesia: Vol. 2: No. 2, Article 5.

DOI: 10.19100/jdvi.v2i2.65

Available at: https://scholarhub.ui.ac.id/jdvi/vol2/iss2/5

This Article is brought to you for free and open access by UI Scholars Hub. It has been accepted for inclusion in Journal of General - Procedural Dermatology & Venereology Indonesia by an authorized editor of UI Scholars Hub.

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Review article

Irene Dorthy Santoso, Hanny Nilasari, Shannaz Nadia Yusharyahya

Department of Dermatology & Venereology, Faculty of Medicine Universitas Indonesia, Dr. Cipto Mangunkusumo National Hospital,

Jakarta, Indonesia E-mail: irene.dorthy@yahoo.co.id

Abstract

Leg ulcers are common problems in the adult and geriatric population with approximately 1-2% prevalence.

Sedentary lifestyle and obesity increase the incidence of leg ulcers. Deterioriation of quality of life in patients with venous ulcers happens due to slow healing and high rate of occurrence. Diagnosis, latest treatments, and preventive measures are essential to discuss.

Keywords: venous ulcer, geriatric, diagnosis, management, prevention

Background

Indonesia is the fourth most populous country in the world with 237 million people.¹ In the next 25 years, this number is expected to continually rising. The number of people aged above 65 years old will also increase from 5% to 10.6% with the improvement of life expectancy, which increased from 67.89 years in 2010 to 68.87 years in 2014. This number is also predicted to rise to 72.9 years in 2035.³ This aging population will come with various health problems.⁴ Ulcers of the lower extremities is a common problem, found in 1-2% of the adult and geriatric population.

Sedentary lifestyle including long hours sitting, lack of physical activity, and obesity, contributes to the growing number of patients with leg ulcers.⁵

Leg ulcers are defined as ulcers located in the lower extremities that are difficult to heal within 4-6 weeks.⁶ The most common form of leg ulcers is venous ulcers, which account for 45-85% of all leg ulcers.^7-9 Venous ulcers are leg ulcers (located between the lower knee until above the medial ankle) caused by venous insufficiency. Venous ulcers can be classified as acute and chronic, with a cut-off of 6 weeks.^6,10,11 Chronic venous insufficiency causes high venous pressure in the lower extremities.¹² The global

prevalence of venous ulcers vary between 0.6-2%⁸, and happens more in females than males.⁹

The decline in quality of life is generally caused by sleep disturbance due to pain,¹³ limited limb movement,¹⁴ psychiatric problems such as depression and social evasion (happens in 91.66%

of patients),¹⁵ disturbances in the workplace, and the high cost of treatment.^11,16,17 Slow healing rate, varying around 4-72 weeks (with an average of 24 weeks), and the level of recurrence happening in 26- 72% of patients within the first year further contribute to the patients’ low quality of life.¹⁸ Therefore, appropriate diagnosis, latest treatments, and preventive measures are fundamental to discuss.

Risk Factors

The main risk factors found in most of the available literature are old age and the female sex. Venous ulcers are mostly found in people aged 60-80 years old, and the number of cases increases with age.¹⁹ Around 72% of patients present with their first ulcer at age 60, 22% of patients were in their 40s, and 13%

were younger than 30 years old.^8,20The influencing factors include the increasing venous rigidity causing hypertension followed by the decreasing endothelial relaxation which contributes to vascular problems.

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Most of the collagen and smooth muscles are accumulated in the subendothelial layer, causing the skin to appear thinner, increasing susceptibility to ulceration and disturbed tissue perfusion.¹² Venous ulcers are found to be 1.42% more prevalent in females than males (0.76%).^5,12 Hormonal factors and esthetics cause women to seek treatment three times more often than men.²¹

Other influencing factors for venous ulcers include obesity, non-Hispanic racial background, history of physical trauma and family history of ulcers. History of deep vein thrombosis, chronic edema of the lower extremities or presence of congestive heart disease also increase the risk of developing venous ulcer.

Sedentary lifestyle, number of pregnancies, and patients who works in a standing position for long hours also have higher risk in developing venous ulcer.^5,11

Anatomy and Physiology

The lower extremity venous system consists of the superficial veins, the deep veins, and the perforating veins. The main superficial veins are the great saphenous vein (v. saphena magna) and the short saphenous vein (v. saphena parva). When calf muscles contract, blood will flow from the superficial vein to the deep veins, towards the heart. The normal calf muscle pumps will pump 85-90% of the venous blood in the legs, and the superficial component will carry 10-15% of the blood. During relaxation, The deep veins will dilate, causing negative pressure, which will pull blood from the superficial venous system to the deep veins through the perforating veins. In venous insufficiency, blood flows back to the superficial veins from the deep veins. In healthy people, optimum function of the perforating veins’

valves prevent this from happening.⁸

Patophysiology

Venous ulcers occur due to failure of the calf muscle pump, which causes an increase in venous pressure (venous hypertension).^19,20Several theories try to explain the pathophysiology of venous ulcers, such as the pericapillary fibrin cuff theory, the fibrinolytic abnormalities theory, the growth factor trap hypothesis, and the white cell trapping hypothesis.⁸ The pericapillary fibrin cuffs and fibrinolytic abnormalities theory was first postulated in 1982 by Browse and Burnand based on histological examination of lipodermatosclerosis. Venous hypertension will affect capillary circulation, causing

capillary wall dilatation, and macromolecule leakage of fibrinogens from the capillaries to the dermis and subcutaneous tissue. The fibrinogen will form pericapillary cuffs that obstruct oxygen and nutrition diffusion, causing tissue necrosis and ulceration.

Fibrin and fibrinogen also have direct effects on type 1 procollagen synthesis by fibroblasts, which will impede the healing process.^11,22

Falanga and Eaglstein proposed a theory on how the leakage of fibrinogen, α2-macroglobulin and other macromolecules into the dermis is caused by venous hypertension or capillary damage, and will cause failure in the maintenance of tissue integrity and wound repair, causing ulceration.⁸

Arterial and venous pressure differences in venous hypertension causes erythrocyte aggregation and leukocyte plugging in the capillaries, causing local tissue ischemia. The release of mediators such as collagenase, elastase, cytokines, free radicals, and chemotactic factors will lead to fibrinogen release to the pericapillary tissue. These acute changes are reversible when the leg is elevated.²⁰ But none of the hypotheses has been able to precisely explain venous ulcers’ pathophysiology.²³

Diagnosis

Risk factors for venous ulcers are important to investigate during history-taking, including lower extremity swelling which worsens at night and improves with leg elevation; legs that felt heavy, itchy, tender; pins and needles sensation; history of previous thromboembolism; and usage of oral contraception.^24,25

Physical Examination

Venous ulcers are usually found in the gaiter area (Figure 2), which is the area from the mid-calf to the ankle, and are generally located around the medial malleolus compared to the lateral malleolus or other more proximal areas (Figure 3). Ulcers located above the mid-calf or on the foot are rarely of venous origin. Venous ulcers can present as single or multiple ulcers, can be of various sizes, with irregular shape. They are usually shallow, rarely extending to the muscles, fascia, or bone. The ulcer bed may contain granulation tissue or yellow fibrinous exudates, while black necrotic tissue is rarely seen.

The region around the ulcer is surrounded by hyperpigmentation due to hemosiderin deposits.¹¹

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Patients with venous disorders can present with various degrees of skin manifestations, ranging from edema, lipodermatosclerosis, to venous ulcers.

Lipodermatosclerosis is a chronic process of dermal and subcutaneous fibrosis caused by venous insufficiency, where the skin seems hardened and indurated (Figure 4). In acute lipodermatosclerosis, the skin is indurated, erythematous, and tender. In the chronic stages, the skin is hardened and the legs have an upside-down bottle appearance, where the proximal leg is swollen while the distal leg is constricted due to fibrosis and loss of subcutaneous tissue.⁵

Physical examination is fundamental in diagnosing venous ulcers, and in 1994 the American Venous Forum published a classification for chronic venous diseases, the CEAP (Clinical, Etiology, Anatomy, and Physiology) classification.²⁴ CEAP is recommended in many of the current literature over other less used classification systems, including the Venous Clinical Severity Score (VCSS), Venous Segmental Disease Score (VSDS), and Venous Disability Score (VDS).^24-26The CEAP classification utilizes the description of objective clinical findings (C), etiology (E), anatomy (A) in the form of reflux or obstruction distribution in the superficial, deep, or perforating veins, and the underlying pathophysiology (P) (reflux or obstruction).²⁷ (Table 1)

In identifying the ulcer, description includes the ulcer’s location and its size (length, width, and depth). Taking a photograph of the ulcer with a ruler will assist ulcer measurement.^28,29 The ulcer’s characteristics, the amount and type of exudate, appearance of the ulcer bed, signs of infection, smell, and tenderness should be documented in each visit.²⁵

Moreover, there are several factors that can impair venous ulcers healing, which are the ulcers’ size, duration, ABPI (Ankle Brachial Pressure Index) <0.8, history of venous surgery, history of hip or knee replacement surgery, and >50% fibrin content in ulcers.¹¹

Workup

After taking the patient’s history and a comprehensive physical examination, further workup can be performed to make the diagnosis and determine treatment approach. Examination of the

arterial system is also needed to rule out the presence of concomitant arterial and venous disorder; almost 25% of patients with venous ulcers also have arterial disorders.⁵ Generally, the workup can be divided into non-invasive and invasive procedures. The types of ancillary examinations for detection of chronic venous insufficiency that underlie venous ulcers include:

1. ABPI (Ankle Brachial Pressure Index) and TBPI (Toe Brachial Pressure Index)

ABPI is a non-invasive procedure that can be performed for screening purposes, with a sensitivity of 85% and specificity of 97% in detecting arterial occlusion. The ABPI value is obtained from dividing the doppler pressure of the ankles with the highest value of brachial pressure. The normal value for ABPI is 0.9 to 1.3.

Toe Brachial Pressure Index (TBPI) is a non- invasive procedure to measure the arterial perfusion of the thumb and soles. The device is put on the hallux, and the result is divided by the highest value of brachial systolic pressure. TBPI is able to identify arterial calcification in patients with diabetes mellitus and kidney diseases.^5,28 2. Handheld continuous wave doppler (CW

doppler)

CW doppler is a non-invasive procedure using ultrasound technology to measure venous flow.

The reliability of CW doppler is considered low in detecting obstruction or reflux in the deep veins.

This device is not capable of providing information on venous morphology, thus it is not appropriate for investigating anatomical abnormalities of the vein.²⁵

3. Duplex ultrasound examination (DUS) DUS is a combination of ultrasound and pulsed wave Doppler used to investigate the anatomy and hemodynamics of the venous system. DUS can show blood flow with color to improve accuracy. With the availability of DUS, invasive procedures such as phlebography is rarely performed. DUS can be considered to be a gold standard to diagnose chronic venous diseases, and it can also be used for therapy evaluation.^25,29

4. Plethysmography

Plethysmography provides information on venous reflux, obstruction, and functions of the calf muscle pump. The use of plethysmography is limited due to the scarcity of the device. This

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procedure includes strain gauge plethysmography, photoplethysmograph, air plethysmography (APG).^25,29

5. Phlebography

Radiological examination with contrast can be classified into ascending phlebography and descending central phlebography. The use of phlebography have decreased significantly since the availability of DUS, due to its similar reliability to phlebography. Phlebography can provide additional information on the thrombus’ age, valve damage, and further information on the venous system for surgery preparation.⁵ In cases of obstruction of pelvic vein insufficiency and vascular malformation, and the problem of device availability, phlebography is a preferable solution.²⁶

6. Other imaging methods

Several other imaging methods include CTV (Computed Tomography Venography) and MRV (Magnetic Resonance Venography), which can provide detailed three-dimensional images of the venous vessels. This method can be used in cases of post-thrombotic obstruction and venous compression or stenosis.²⁵

7. Ulcer biopsy

Biopsy must be obtained from several sides, including the border and the center of the wound.

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8. Ulcer microbiology examination

Contamination or colonization of bacteria and fungi is found in the majority of leg ulcers, but 10- 15% is negative upon examination. The microorganisms often found in cultures are Staphylococcus, Streptococci (excluding group A beta-hemolytic), and Pseudomonas aeruginosa. Anaerobic bacteria are found in 30%

of cultures, and Candida albicans and other fungal species are found in 15-30% of specimens.³⁰ Several studies recommend against routine microbial culture unless an indication is present. Indications include signs of infection such as erysipelas, increasing pain, increasing ulcer size, redness around the ulcer, and purulent exudate.³¹

9. Blood workup

Blood workup commonly performed are blood glucose to rule out diabetes mellitus, hemoglobin level to rule out hematological disorders, albumin

and transferrin to rule out nutritional deficiency, and reactive C protein. Reactive C protein can be detected in 25% of patients with venous ulcers and in 50% of patients with recurrent venous thrombosis. Patients with chronic and recurrent venous ulcers can often be associated with thrombophilia.²⁹

10. Ultrasonography (USG) to detect cutaneous changes in chronic venous diseases USG is not only used to determine the location and form of venous disorders, but also to identify acute and chronic disturbances that are not clearly visible. Cutaneous USG can contribute to the determination of venous disorders’ degree of severity. The disadvantage of this examination is that it is operator-dependent.³²

Differential Diagnosis

Several differential diagnosis that can be considered when a patient presents with leg ulcers include:⁷ 1. Arterial ulcers (Figure 5)

Arterial insufficiency is caused by atherosclerosis and is worsened by smoking and hypertension, which can cause tissue necrosis.

Arterial ulcers are mainly found on the hallux and heel. On examination, whitish or blueish, shiny punched out lesions are observed. Patients usually complain of pain at night when lying on the bed or at rest and when the legs are elevated.

The pain decreases when the patients’ feet steps on the ground, due to increasing blood flow.

2. Diabetic ulcers (Figure 6)

Diabetic ulcers are found in diabetic patients with uncontrolled blood glucose levels, due to a combination of arterial disorders, neural damage, commonly found on pressure points such as the halux and heels. Early lesions can present as callous as a response to repeated trauma, which will progress to ulceration. The characteristic form is a punched-out lesion, similar to arterial ulcers. Charcot joints, which are swollen joints due to repeated trauma in areas with neuropathy, are often found at the same time as diabetic ulcers.

3. Neuropathic ulcers (Figure 7)

Neuropathic ulcers that are unrelated to diabetes can happen due to infections of the nervous system such as leprosy and Bechet disease. If a non-diabetic patient presents with ulcers similar

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to diabetic ulcers in appearance, the underlying process must be investigated.

4. Pyoderma gangrenosum (PG) (Figure 12) PG is rare, with an incidence of 1:100,000. The patient’s chief complaint is chronic, painful wound. There are four clinical variants:

ulcerative, bullous, pustular, and superficial granulomatous. The cause of PG is generally unknown, but 45-75% of the cases are related to systemic diseases including bowel diseases, myeloproliferative disorders, and rheumatoid arthritis. PG ulcers usually have purulent ulcer beds, centrifugal with irregular border, dark blue to greyish brown in color. The healed ulcer usually leaves a cribriform, atrophic, and pigmented scar. Ulceration in PG can happen after cutaneous trauma or damage, and this phenomenon is known as pathergy.

Other differential diagnoses include vasculitis, panniculitis with ulceration, calciphylaxis, marjolin

ulcer, bacterial infections, martorell ulcers, or Hypertensive Ischemic Leg Ulcer (HYIL), and malignant wound (Figure 8-11).³³ In ulcers with slow healing rate, allergic contact dermatitis should be considered.²⁶

Treatment

1. Wound cleansing

Ulcer treatment is initiated with wound cleansing.¹⁹ Wound cleansing has three components, which are technique, solution, and equipment. Cleansing techniques consist of swabbing, irrigation, and bathing. Swabbing is rubbing with wet gauze to discard dead tissue and contaminants. Irrigation includes spraying the wound with 0.9% normal saline using 18 or 19G needle with a 30-35 ml syringe or a spraying device, with 4-15 psi pressure. Bathing is bathing the wounded leg, included in hydrotherapy.

Other than normal saline, water and antiseptic solutions can be used as cleansing solutions.¹⁶

Table 1. CEAP (Clinical, Etiology, Anatomy, and Physiology) classification in chronic venous disease⁵ Clinical classification (C) Etiologic

classification (E)

Anatomic classification (A)

Pathophysiology (P) C0: No visible or palpable

signs of venous disease

Ec: Congenital As: Superficial veins

Pr: Reflux C1: Teleangiectasis or reticular

veins

Ep: Primary Ap: Perforating veins

Po: Obstruction

C2: Varicose veins Es: Secondary Ad: Deep veins Pr, o: Reflux and obstruction

C3: Edema En: No venous cause

identified

An: No venous location identified

Pn: No venous

pathophysiology identified C4a: Pigmentation or eczema

C4b: Lipodermatosclerosis or atrophie blanche C5: Healed venous ulcer

C6: Active venous ulcer

S: Symptomatic, including ache, pain, tightness, skin irritation, heaviness, and muscle cramps, and other complaints attributable to venous dysfunction.

A: Asymptomatic

2. Wound dressing

There are no single dressing that can be used in all stages of the ulcer, because each dressing has its own specification for different stages of wound healing.³⁴ Novel dressings have different mode of action from traditional ones. They provide wound protection, whilst traditional dressings maintain wound dryness.³⁵ Novel dressings for venous ulcers

do not only ensure a moist wound environment, but also avoid maceration, because excessive moisture will facilitate production of toxic mediators.

Traditional dressings using gauze dampened with normal saline or ringer solution usually cause problems when the gauze has dried up, because the gauze will stick to the wound.³⁶

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Table 2. Recommendation and clinical evaluation of venous ulcer work-up²⁴

No. Recommendation Clinical

evaluation 1. ABPI (Ankle Brachial Pressure Index) dan TBPI (Toe Brachial Pressure Index)

Arterial examination and ABPI measurement are recommended to be performed on all venous ulcers patients

1B 2. Duplex ultrasound examination (DUS)

Comprehensive DUS examination of the lower extremity is recommended for all patients with suspected venous leg ulcers.

1B 3. Plethysmography

Selective use of venous plethysmography is suggested in the evaluation of patients with suspected venous leg ulcer if venous DUS does not provide definitive diagnostic information.

2B

4. Other venous imaging

Other types of venous imaging can be suggested for operative planning before open or endovenous interventions such as computed tomography venography, magnetic resonance venography, contrast venography and intravascular ultrasound

2C

5. Ulcer biopsy

Ulcer biopsy is recommended for leg ulcers that do not improve with standard therapy and post-therapeutic compression for 4-6 weeks, and atypical ulcers

1C 6. Ulcer microbiology work-up

Routine venous ulcer culture is not recommended. Culture is only performed after clinical evidence of infection.

2C 7. Blood work-up

Perform blood laboratory work-up investigating thrombophilia in patients with history of recurrent venous thrombosis and chronic venous ulcers

2C

The factors considered in choosing the appropriate dressing include wound depth, amount of exudate, wound characteristics, cost, dressing change frequency, and the need for secondary dressing. The ideal dressing is a dressing that can maintain moisture, discard excessive exudate, facilitate debridement, enable gas exchange, minimize scar formation, impermeable to bacteria, non-toxic, and comfortable for the patient.³⁷

The types of dressing available on the markets are semi-permeable film, foams, alginates, hydrocolloids, hydrogels, and hydroactive. Semi- permeable film is used for ulcers with epithelialization, foams are used for exudative wounds, alginates are used for bleeding wounds, hydrocolloids are used for wounds with hypogranulation, hydrogels are used for necrotic wounds, and hydroactive functions similarly to foams for exudative wounds. Hydrophobic dressings can be used for trapping bacteria in infectious wounds.^38-42

3. Compression therapy

Compression therapy is a preferred therapeutic approach in venous ulcers, which aims to accelerate venous ulcer healing by improving blood flow and reducing edema and distension.⁴³ Types of compression can be divided into static and dynamic compression.²⁶ Compression techniques include bandage, stocking or socks, and using intermittent compression devices.

Bandages can be classified as elastic (long stretch) and inelastic (short stretch). The elastic bandage can be stretched out to 100-200% of its original size, while the inelastic type can only be stretched 40-99%. Elastic bandages can conform to the leg’s size and shape, while inelastic bandage is more rigid and can hold the expansion of calf muscles during contraction, but does not press down on the calf when the limbs are in supine position.⁴⁴ The Unna boot is a type of bandage with a zinc oxide lining, a type of inelastic bandage.⁴⁵ Inelastic bandages are recommended for ulcers of mixed arterial- venous origins.⁴⁴

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Table 3. Stocking classification⁴⁴

Class

Ankle pressure

(mmHg)

Indication I 20-30 Mild edema, varicose

veins, and venous ulcers

II 30-40 Moderate edema,

moderate venous disorders, varicose veins, and venous ulcers III 40-50 Severe edema, severe

venous disorders, venous ulcers, and lymphedema IV 50-60 Lymphedema

Based on the number of bandage layers, bandage usage can be divided into 1 layer, 2 layers, 3 layers, and 4 layers, then simplified into simple component and multi component; the 4- layers bandage is known as 4LB.²⁷ 4LB provides consistent pressure of 40 mmHg even at rest.⁴³ 4LB is proven to be safe and effective in ulcer recovery with minimal complications, while also reducing symptoms and accelerating healing, so the patient can go back to their daily activities.⁴⁶ Compression is proven to significantly increase healing rate and improve psychosocial complaints, compared to no compression.⁴⁷ Stocking or socks, also including leggings, are also part of compression therapy. Stocking is mostly used as maintenance therapy after the venous ulcers have healed. Stocking use improves QALys (Quality Adjusted Life-years) because some patients choose stockings due to more affordable cost and better comfort compared to bandages. Stockings consist of knee-high stockings, calf-high stockings, and waist-high stockings; knee-high stockings are most commonly used due to the comfort.²⁷ Incorrect compression can cause disorders such as distal gangrenes and predominant arterial diseases.⁴⁴ Adequate movement of the ankles must be preserved. Patients need to be informed to monitor signs of poor perfusion such as numbness, pins and needles, changes in skin color, worsening pain, or paresthesia.³³

Intermittent Pneumatic Compression (IPC) produces sequential pressure to the limbs, so it can be used simultaneously with bandages and

stockings. IPC is usually used for immobilized patients to prevent edema of the lower extremities.⁴⁴ IPC is proven to speed up the healing process compared to no compression.⁴⁸ 4. Medications

a. Pentoxifylline improves healing of venous ulcers, especially ulcers older than one year old. Pentoxifylline is a methylxanthin derivate with good oral absorption rate, metabolized in the liver before being excreted through the urine.⁴⁵ Pentoxifylline is an inhibitor of prostaglandin E, and can reduce elastase levels.³³ The recommended dose is 400 mg three times a day, with dose adjustments for patients with kidney failure.

Several studies reported 800 mg three times a day is more effective compared to 400 mg.

The maximum effect can be observed after 2-4 months. A few of pentoxifylline’s mechanisms of action include increasing erythrocite deformability and inhibition of neutophil adhesion and activation. Side effects of pentoxifylline are nausea, abdominal discomfort, dizziness, and prolonged bleeding time.⁴⁴ Pentoxifylline is an effective adjuvant ineiodinfor compression therapy in venous ulcers.⁵⁰ b. Sulodexide is an antithrombotic and

fibrinolytic agent, used for vascular disorders including venous ulcers. Sulodexide acts as a vascular protective and anti-inflammatory agent, making it appropriate as an adjuvant therapy for venous ulcers⁴⁴, although the body of evidence supporting this is still weak and further studies are needed.⁵¹

c. Simvastatin, aside from being used to reduce cholesterol levels, have pleiotropic effects which can assist wound healing. A 40 mg dose once a day is proven to significantly accelerate wound healing.⁵²

d. Aspirin is used to reduce pain, fever, and inflammatory processes, and preventing blood clot formation. Aspirin cuts wound healing duration and lower the recurrence rate of venous ulcers.⁵³ A once daily dose of 300 mg aspirin combined with compression therapy show clinical improvement and reduction of ulcer size. Aspirin therapy is administered if no contraindications are present.⁴⁵

e. Flavonoid can be synthesized and is found in cocoa, tea, and red grape plants.³³ Flavonoids accelerate venous ulcers healing

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by reducing edema thus improving venous pressure, assisting lymphatic drainage, and protecting microcirculation. But, flavonoid therapy’s efficacy needs further investigation.⁵⁴ Inflammation response and symptoms of chronic venous disorders will be diminished after consumption of 500 mg of flavonoid taken twice a day for 6 months.⁴⁴ f. Systemic antibiotic is not given routinely in

patients with venous ulcers.⁵⁵ Antibiotics are administered if there are signs of infection in clinical or laboratory examinations.

Antibiotics are given if >10⁶ bacteria per gram of tissue are found, because the toxin from the bacteria can cause tissue damage and impede wound healing in superficial wounds. Several topical antimicrobial alternatives are available, such as ionized silversulfadiazine (SSD) and cadexomer iodine.⁴⁴Evidence of SSD use in venous ulcers is limited.⁵⁶ Cadexomer iodine is a topical antiseptic with anti-microbial properties, which is safe and effective for wound debridement and for stimulating granulation tissue.^8,55 Iodine is proven to be as effective as other antiseptics and does not disturb the wound healing process.⁵⁷

g. Honey has been used for years to speed up the wound healing process.⁵⁸ Honey has antimicrobial effects and it stimulates cell growth. Studies report that honey can decrease wound size, pain, and foul smell after 12 weeks of use.⁵⁹ In venous ulcer management, the use of honey is still controversial, due to the wide variety of honey used in studies.⁵⁸

5. Surgical therapy a. Debridement

Debridement is recommended to be performed during the initial assessment to discard of necrotic tissue. Most of the patients receiving debridement procedure experience improvement in wound healing compared to patients who were not debrided.²⁴ The evidence is not conclusive on whether the frequency of debridement

significantly affects wound healing.⁶⁰ Local, usually topical, anesthesia can be administered to reduce discomfort during the debridement process. Use of EMLA 5%

cream (lidocaine-prilocaine) is proven to significantly reduce pain score compared to no topical anesthetic agents.⁶¹ Infiltrative anesthesia, regional block, or general anesthesia should be used for extensive debridement. Several types of debridement can be used, such as sharp debridement, enzimatic debridement, mechanical debridement, biological debridement, and autolytic debridement.⁶²

b. Skin grafting

Skin grafting is a procedure of taking skin of various thickness to be relocated, in order to induce new blood circulation in the new location.⁶³ Skin grafting is proven to reduce pain intensity compared to conservative therapy.⁶⁴ Skin grafting can be classified as punch graft and split thickness graft, and both are proven effective for treating venous ulcers.⁴⁴Skin grafts can be divided into autograft or allograft, according to the donor.

Based on the type of the synthesized skin, it can be divided into single layer or bilayer.¹⁹ When used with compression therapy, bilayer artificial skin is more effective than single layer.⁶³

c. Surgery for venous insufficiency

Invasive procedures such as venous stripping have been replaced by less invasive percutaneous surgery procedures, such as ultrasound guided foam sclerotherapy, endovascular laser ablation (EVA), and radiofrequency therapy.

Recalcitrant venous ulcers can be managed through compression of the iliac vein or the vena cava.⁴⁴ Venous stripping is a procedure done under local or general anesthesia to remove the whole length of the vein.⁶⁵ EVA is a minimally-invasive procedure, with similar efficacy and safety to venous stripping.⁴⁴

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Table 4. Treatment recommendation and clinical evaluation ²⁴

No. Recommendation Clinical

evaluation 1. Wound cleaning

Venous ulcers are recommended to be cleansed initially and at each dressing change with a neutral, nonirritating, nontoxic solution, with minimal chemical or mechanical trauma.

2C 2. Wound dressing

 The recommended dressings are dressings that will manage exudate and maintain moisture.

 Topical antimicrobial-containing dressings are not recommended for treating non-infected venous leg ulcers.

2C 2A 3. Compression therapy

 Compression therapy is recommended to increase the healing rate of venous leg ulcers.

 Multicomponent compression bandage is recommended over single component bandages for the treatment of venous leg ulcers.

 In venous leg ulcers with underlying arterial disease, compression therapy is not recommended if the ABPI is 0.5 or less, or if the absolute ankle pressure is less than 60 mmHg.

 Intermittent pneumatic compression is recommended if other compression therapy is unavailable, cannot be used, or have failed in treating venous ulcers after prolonged compression therapy.

1A 2B 2C

2C

4. Mechanical therapy – negative pressure

Negative pressure therapy is not recommended for routine treatment of venous ulcers. 2C 5. Debridement

 Debridement is recommended during initial evaluation to remove necrotic tissue, excessive bacterial burden, and cellular burden of dead and senescent cells.

 Additional debridement can be performed to maintain optimal skin condition for healing.

 Enzymatic debridement is preferred if no trained clinician is available to perform surgical debridement.

Skin grafting

 Split-thickness skin grafting is not recommended as a main therapy for venous ulcers.

 Split-thickness skin grafting with compression is recommended for extensive venous ulcers that do not improve after 4-6 weeks of standard therapy.

1B 2C 2C

2B 2B 7. Larval therapy

Larval therapy can be performed as an alternative to surgical debridement. 2B 8. Physiotherapy and extremity elevation

 Electrical stimulation therapy is not recommended in venous ulcers.

 Active exercise under supervision is recommended to improve muscle pump function and to reduce pain and edema in patients with venous leg ulcers.

2C 2B 9. Nutrition management

Nutririon management is recommended for malnourished patients with venous ulcers.

Best practice 10. Prevention

 Compression therapy is recommended to prevent recurrency of venous ulcers.

 Patients with clinical CEAP (Clinical, Etiology, Anatomy, and Physiology) C3-4 disease due to primary valvular reflux are recommended to receive 20-30 mmHg knee or thigh high compression.

2B 2C

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6. Larval therapy

With the rise of microbial resistance, MDT (Maggot Debridement Therapy) is starting to be considered as an alternative therapy for chronic wounds and ulcers. MDT is indicated for open wounds and ulcerations with or without signs of infection. MDT usually utilizes live and sterile larvae, such as the green bottle fly (Phaenicia (Lucilia) sericata).⁶⁶Meta-analysis have reported MDT to be more effective and efficient for wound healing, granulation tissue formation, and chronic ulcers debridement compared to conventional therapy.⁶⁷ MDT works through induction and enhancement of IL-6, carboxypeptidase, leucine aminopeptidase, collagenase, serine protease, and epidermal growth factors.^68-69 Optimal duration for MDT is 2-3 larvae cycles or 3-5 days, and there is no benefits of prolonging therapy for more than a week.⁷⁰ Severao reported complications of MDT include pain, mild fecer, and larvaes getting loose from the dressing.⁷¹

7. Physiotherapy and limb elevation

Physiotherapy aims to reduce venous pressure and edema, resulting in venous ulcers improvement.^72-73 Symptoms experienced by patients with venous ulcers include limited range of motion (ROM) of the ankles, and reduction of walking speed and endurance, mobility, and activity level.⁷⁴ Vascular physiotherapy for chronic venous disorders is called vascular kinesiotherapy, consisting of three phases: warm up, training, and relaxation. This exercise is performed three times a week for one hour.

Evaluation of wound diameter, venous functions, and gait is performed in various periods, ranging from 6 weeks to 6 months.²¹ In addition to physical therapy, other techniques are available such as HVS (High Voltage Stimulation), LLLT (Low Level Laser Therapy) and ultrasound therapy.⁷HVS and ultrasound can be used as an adjuvant therapy for small venous ulcers, but are not effective for recurrent cases.^75-76 LLLT is not efficient for venous ulcer management.⁷⁷

Limb elevation is performed by raising the limb above the heart, to reduce swelling, improve microcirculation and oxygen distribution, and accelerate ulcer healing.²⁷ Elevation should be done 3-4 times a day for 30 minutes or 1-2 hours twice a day.⁴⁵ Limb elevation is not beneficial in severe venous disorders.²⁷

8. Nutritional management

Patients with venous ulcers have higher metabolism rate due to the systemic inflammation and increased cellular activity on the wound, thus needing larger nutritional intake to assist wound healing. Vitamin C, zinc, protein, and amino acids are important nutrients for wound healing. Vitamin C is important for synthesizing connective tissue; inadequate vitamin C intake causes weakness of the fibrous tissue and increases risk of wound dehiscence.

Zinc plays a role in tissue regeneration and collagen formation, because zinc facilitates synthesis of DNA and RNA. Amino acids are important for tissue regeneration and systemic immunity. Polyunsaturated Fatty Acids (PUFA) manipulation through diet is an effective method to reduce inflammation and accelerate healing of venous ulcers.⁷⁸

9. Prevention

Venous ulcer prevention can be done by using stockings, superficial or perforating vein surgery, sclerotherapy, aside from exercise, limb elevation, and lifestyle changes.⁷⁹ High compression hosiery is more effective in reducing recurrence compared to no compression.⁸⁰ Stocking is recommended to be worn throughout the day, everyday, for maximum efficacy. The use of moisturizers, diet, supplements, smoking cessation, weight loss are important in patients with a history of venous ulcers.⁷⁹ Furthermore, the patient and their family members need to be informed on the disease, recurrence rate, factors that help and disrupt wound healing, and the efficacy and side effects of the current treatment choice. Education can be given through various media, such as leaflets, TV, computer, or person-to-person education.⁸¹

Conclusion

Several therapeutic choices are available for patients with venous ulcers. Choice of therapy can depend on various factors, such as the patients’ unique clinical conditions, socioeconomic factors, family support, and patients’ choices. Collaboration between the physician and the patient is an important key to therapeutic success and long-term recurrency prevention.

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