**6. Management**

It is essential to treat the patients with multidisciplinary approach. The complete assessment of the chronic venous insufficiency should be evaluated together with vascular surgeons. The decision of the surgical treatment in appropriate cases should be considered with plastic surgeons. Knowledge of pathogenesis of venous ulcers and avoiding from its risk factors will be provided to choose the optimal treatment for patients with venous leg ulcers, which cause both impairment of life quality and socioeconomic burden. A multidisciplinary team of specialists will be helpful in the evaluation of venous leg ulcers and providing the most appropriate treatment.

Several treatment options are available for the management of venous ulcers. Pain reduction, closure of the ulcers, and prevention of the recurrences are the main goals of the treatment [56]. Reversing the effects of venous hypertension is the primary purpose of the treatment of venous leg ulcers. The easiest method is leg elevation [57]. Although it seems to be impractical to most of the patients, elevation of the legs above the heart level for 30 minutes, 3–4 times a day, provides the dissolution of the swelling and improves the microcirculation [58]. Leg elevation can also be performed at night by raising the foot 15–20 cm high [59]. Moreover, good nutrition and assessment with each dressing change are necessary to support the therapy. Initially and at each dressing change, the depth, width, and height of the wound bed should be measured to evaluate the improvement. Appropriate therapy of the wound must be selected patient centered. Infection control, debridement, antibiotics, dressings, compression, and adjuvant therapies will be described in this section.

### **6.1. Wound cleansers**

Cleansers are the first and main step in preparing the wound bed. Wound cleansing with a neutral, nonirritating solution with a minimum chemical and mechanical trauma should be performed at each dressing change. Wound exudate and other debris around the wound area in venous leg ulcers must be cleansed with an appropriate solution. Although several cleansing solutions are in the market, the choice of the cleanser should have the purpose of avoiding toxicity to the viable tissue in the wound bed [31].

### **6.2. Debridement**

Debridement during the initial evaluation is recommended to remove the necrotic tissue, excessive bacterial burden, and nonviable cells [31]. Although debridement of the wound is commonly performed to allow the formation of good granulation tissue and proper epitheli‐ alization by creating an appropriate environment to keratinocyte migration, there is a lack of evidence that routine wound debridement accelerates wound healing [31]. There are several ways of wound debridement, including autolytic, chemical, and mechanical [60].

### *6.2.1. Autolytic debridement*

boring regions [42, 54]. The coumarin derivatives, nifedipine, diltiazem, barbiturates, and

It is essential to treat the patients with multidisciplinary approach. The complete assessment of the chronic venous insufficiency should be evaluated together with vascular surgeons. The decision of the surgical treatment in appropriate cases should be considered with plastic surgeons. Knowledge of pathogenesis of venous ulcers and avoiding from its risk factors will be provided to choose the optimal treatment for patients with venous leg ulcers, which cause both impairment of life quality and socioeconomic burden. A multidisciplinary team of specialists will be helpful in the evaluation of venous leg ulcers and providing the most

Several treatment options are available for the management of venous ulcers. Pain reduction, closure of the ulcers, and prevention of the recurrences are the main goals of the treatment [56]. Reversing the effects of venous hypertension is the primary purpose of the treatment of venous leg ulcers. The easiest method is leg elevation [57]. Although it seems to be impractical to most of the patients, elevation of the legs above the heart level for 30 minutes, 3–4 times a day, provides the dissolution of the swelling and improves the microcirculation [58]. Leg elevation can also be performed at night by raising the foot 15–20 cm high [59]. Moreover, good nutrition and assessment with each dressing change are necessary to support the therapy. Initially and at each dressing change, the depth, width, and height of the wound bed should be measured to evaluate the improvement. Appropriate therapy of the wound must be selected patient centered. Infection control, debridement, antibiotics, dressings, compression, and adjuvant

Cleansers are the first and main step in preparing the wound bed. Wound cleansing with a neutral, nonirritating solution with a minimum chemical and mechanical trauma should be performed at each dressing change. Wound exudate and other debris around the wound area in venous leg ulcers must be cleansed with an appropriate solution. Although several cleansing solutions are in the market, the choice of the cleanser should have the purpose of avoiding

Debridement during the initial evaluation is recommended to remove the necrotic tissue, excessive bacterial burden, and nonviable cells [31]. Although debridement of the wound is commonly performed to allow the formation of good granulation tissue and proper epitheli‐ alization by creating an appropriate environment to keratinocyte migration, there is a lack of evidence that routine wound debridement accelerates wound healing [31]. There are several

ways of wound debridement, including autolytic, chemical, and mechanical [60].

erythropoietin in very rare cases, may trigger ulcer development [42].

**6. Management**

292 Wound Healing - New insights into Ancient Challenges

appropriate treatment.

**6.1. Wound cleansers**

**6.2. Debridement**

therapies will be described in this section.

toxicity to the viable tissue in the wound bed [31].

In venous ulcers, it is possible that wound occlusion itself promotes re‐epithelialization, reduces associated pain, enhances autolytic debridement, and provides an additional barrier to bacteria [61, 62]. Hydrogels, alginates, hydrocolloids, foams, and films are the basic occlusive dressings. Wound features, exudate amount and cost of the material, and patient and physician preference affect the choice of dressing [63].

### *6.2.2. Chemical debridement*

Several enzyme‐debriding agents have been developed to promote the removal of the necrotic tissue and the formation of proper granulation tissue [64, 65]. Specific proteolytic enzyme therapies to the venous ulcers may accelerate the removal of fibrin cuffs [66]. Various enzyme‐ debriding agents are available, including collagenase, papain, trypsin, and tissue plasminogen activator [60, 67, 68]. Frequency of the application of the dressing may vary up to the manu‐ facturer's recommendations. Enzymatic debridement, which does not require a trained clinician for application, has been found in several studies to remove nonviable tissue from the wound beds of venous leg ulcers, but there is no evidence that this method provides a benefit over surgical debridement [69, 70].

### *6.2.3. Mechanical debridement*

Application of wet‐to‐dry dressings, hydrotherapy, irrigation, and dextranomers are some of the methods of mechanical debridement [71]. The removal of the viable tissue along with the necrotic material is the major disadvantage of mechanical debridement [72]. Hydrosurgical debridement was showed to have a shorter procedure time but requires additional cost and a trained clinician [73, 74]. Furthermore, it may be associated with a significant periprocedural pain [69]. Dextranomer's hydrophilic structure that provides a high absorptive capacity makes it useful for wounds with heavy exudate. The possibility of dehydration of the wound bed demands caution [4]. Surgical debridement, which may be performed with a curette, forceps, scalpel, or sharp scissors, is another way to remove necrotic tissue. As venous ulcers do not comprise frank necrosis or eschar tissue, this method is rarely used in venous ulcers [75]. During surgical debridement, local infiltrative, regional block, or general anesthesia may be required according to the extensity of the wound [31].

### **6.3. Antibiotics**

Antimicrobial therapy is suggested in venous ulcers with >1 × 106 colony‐forming unit (CFU)/g of bacteria on quantitative culture and clinical evidence of infection. Systemic antibiotic therapy, guided by sensitivities performed on wound culture, is recommended. Oral antibiotics are preferred in the beginning of the therapy duration and should be limited to 2  weeks [31]. Combination of mechanical debridement and antibiotic therapy is thought to be successful in eradicating infection in venous leg ulcer. In case of cellulitis, beta‐lactam and non beta‐lactam antibiotics may be treatment options. Trimethoprim‐sulfamethoxazole and clindamycin are recommended as initial empiric therapy if methicillin‐resistant Staphylococ‐ cus aureus is the suspected reason of cellulitis [76]. The use of topical silver for infected venous ulcers is controversial [31]. Recently, cadexomer iodine is reported to shorten the healing time of venous ulcers [77].

It is likely to be an increased risk of contact dermatitis in patients with chronic venous insufficiency, so in these patients any topical preparation must be used carefully [4]. There is a lack of evidence of the positive effects of topical antimicrobials in the healing of venous ulcers [31].

### **6.4. Periulcer skin management**

It is important to keep the periulcer skin healthy to provide improvement in venous ulcers. Management of dermatitis and other abnormalities in periulcer skin accomplishes other therapy strategies in venous ulcers [31]. As mentioned above, contact dermatitis related to topical agents and dressings used in the treatment of venous ulcers are very common. In severe contact dermatitis, a short term of systemic steroids may be needed [4, 31]. Skin lubricants will be helpful in the terms of dermatitis in the calf and ankle due to venous hypertension [31]. Care of the periulcer skin will improve the venous wound healing; therefore, it is necessary to recognize the abnormalities in this area and start the appropriate treatment.

### **6.5. Dressing**

Several types of wound dressings including gauzes, films, gels, foams, hydrocolloids, algi‐ nates, hydrogels, and other polymers are being used beneath compression bandages. Some of the dressings show biological activity on its own, while some provide the release of bioactive constituents. Different types of wound dressings such as hydrogels, hydrocolloids, foams, films, and wafers may comprise of antimicrobials, anti‐inflammatory agents, analgesics, growth factors, and proteins, which would be useful in different problems of wound healing [78, 79]. During the choice of the wound dressing type, features of the ulcer should be consid‐ ered and the mostly desired function of the dressing (such as cleaning, absorbing, regulating, creating a moist environment, and the possibility of adding medication, protecting the periulcer skin) should be decided [80]. Of course, the patient's needs and cost‐effectiveness are other factors affecting the dressing choice [81]. The optimal wound dressing should absorb the exudate and also maintain a moist, warm wound bed and protect the periulcer skin [31, 76]. Routine use of topical antimicrobial dressings is not recommended [31]. While using wound dressings, risk of allergy should be kept in mind in venous ulcers. In conclusion, topical wound dressings are recommended as a part of the standard therapy in venous ulcers [31].

### **6.6. Compression**

Compression therapy remains the mainstay treatment of venous leg ulcers [76]. Compression is a kind of mechanical therapy, which is simply based on applying pressure to the limb [31]. There is a significant improvement in ulcer healing and reduction in recurrence rates with an appropriate compression therapy [4, 82]. Compression therapy corrects the venous hyperten‐ sion by improving venous pumping function and lymphatic drainage [83]. And as a result of compression, local hydrostatic pressure increases and superficial venous pressure decreases; thus, the edema dissolves resulting in cutaneous blood flow increase [83]. Other effects of compression therapy are clinical improvement in lipodermatosclerotic skin through lymph propulsion along with the increase in lymph transport and fibrinolysis [4]. Besides the mechanical effect, compression reduces the release of macromolecules into the extravascular space, some of which play role in wound healing [84].

Various types of devices have been used for compression therapy, such as different types of bandages, bandage systems, ready‐to‐use garments, and several pneumatic devices [31]. It is thought that an external pressure of 35–40 mm Hg at the ankle is necessary to overcome venous hypertension [85]. For acute disease, reducing edema and improving the healing process, inelastic or rigid bandages as well as elastic and multilayered bandages are suggested. The bandage system should have high pressures when the patient walks (working pressure) and low pressure when the patient is on rest (resting pressure). Traditional Unna boot, a moist zinc‐ impregnated paste bandage, is a prototype of this system [83, 86]. Modified Unna boots (short‐ stretch bandages) have the same properties. Their stable shape despite the volume changes in leg secondary to edema reduction, unpleasant odor due to wound exudate, and potential development of contact dermatitis are the limiting factors of Unna boots' use [76, 77]. After edema reduces, long‐stretch bandages are beneficial as they provide appropriate working pressure and higher resting pressure. Its easy use and providing of frequent dressing changes make the elastic compression bandages practical. Covering the leg by overlapping the bandage between turns will produce a multilayer bandage. Different components of bandages may be applied at each layer. While this application increases the pressure and also makes the final multilayer bandage less elastic and more stiff due to the friction between the surfaces of each bandage [31], intermittent pneumatic compression (IPC) pumps are also used. These devices consist of plastic air chambers, encircling the lower leg. As the air chamber fills to a preset pressure then deflated. With this system, compression of the leg is provided periodically [87].

Although compression therapy is known to be effective in both healing of venous ulcers and prevention of recurrent ulcers, there is still no optimized compression method [31, 88].

### **6.7. Adjuvant therapies**

cus aureus is the suspected reason of cellulitis [76]. The use of topical silver for infected venous ulcers is controversial [31]. Recently, cadexomer iodine is reported to shorten the healing time

It is likely to be an increased risk of contact dermatitis in patients with chronic venous insufficiency, so in these patients any topical preparation must be used carefully [4]. There is a lack of evidence of the positive effects of topical antimicrobials in the healing of venous

It is important to keep the periulcer skin healthy to provide improvement in venous ulcers. Management of dermatitis and other abnormalities in periulcer skin accomplishes other therapy strategies in venous ulcers [31]. As mentioned above, contact dermatitis related to topical agents and dressings used in the treatment of venous ulcers are very common. In severe contact dermatitis, a short term of systemic steroids may be needed [4, 31]. Skin lubricants will be helpful in the terms of dermatitis in the calf and ankle due to venous hypertension [31]. Care of the periulcer skin will improve the venous wound healing; therefore, it is necessary to

Several types of wound dressings including gauzes, films, gels, foams, hydrocolloids, algi‐ nates, hydrogels, and other polymers are being used beneath compression bandages. Some of the dressings show biological activity on its own, while some provide the release of bioactive constituents. Different types of wound dressings such as hydrogels, hydrocolloids, foams, films, and wafers may comprise of antimicrobials, anti‐inflammatory agents, analgesics, growth factors, and proteins, which would be useful in different problems of wound healing [78, 79]. During the choice of the wound dressing type, features of the ulcer should be consid‐ ered and the mostly desired function of the dressing (such as cleaning, absorbing, regulating, creating a moist environment, and the possibility of adding medication, protecting the periulcer skin) should be decided [80]. Of course, the patient's needs and cost‐effectiveness are other factors affecting the dressing choice [81]. The optimal wound dressing should absorb the exudate and also maintain a moist, warm wound bed and protect the periulcer skin [31, 76]. Routine use of topical antimicrobial dressings is not recommended [31]. While using wound dressings, risk of allergy should be kept in mind in venous ulcers. In conclusion, topical wound

dressings are recommended as a part of the standard therapy in venous ulcers [31].

Compression therapy remains the mainstay treatment of venous leg ulcers [76]. Compression is a kind of mechanical therapy, which is simply based on applying pressure to the limb [31]. There is a significant improvement in ulcer healing and reduction in recurrence rates with an appropriate compression therapy [4, 82]. Compression therapy corrects the venous hyperten‐ sion by improving venous pumping function and lymphatic drainage [83]. And as a result of

recognize the abnormalities in this area and start the appropriate treatment.

of venous ulcers [77].

**6.4. Periulcer skin management**

294 Wound Healing - New insights into Ancient Challenges

ulcers [31].

**6.5. Dressing**

**6.6. Compression**

Systemic pharmacotherapy may be useful as an adjuvant therapy in venous ulcers. Most of the systemic agents used as adjuvant therapy acts in mechanism of one or more points in the pathophysiology of venous leg ulceration.

### *6.7.1. Pentoxifylline*

Pentoxifylline, an antifibrinolytic agent, is thought to promote wound healing as an adjunctive therapy. Pentoxifylline has been shown to play role in microcirculation by promoting leukocyte migration, reducing platelet aggregation and fibrinogen levels, decreasing plasma viscosity, stimulating collagenase production, and blocking the effects of tumor necrosis factor‐alpha on fibroblasts [89, 90]. Pentoxifylline may act in venous ulcer healing through the effects of cytokine production [91]. The conventional dose of pentoxifylline in venous leg ulcers is 400  mg three times a day. But recently, it has been proposed that the use of pentoxifylline 800 mg three times a day is more effective in venous ulcer healing. The main side effects reported were gastrointestinal disturbances such as nausea, indigestion, and diarrhea [89, 92, 93]. In studies, pentoxifylline has shown to be an effective adjuvant to compression therapy in venous leg ulcers. According to a Cochrane review, pentoxifylline plus bandaging is more effective than compression plus placebo and pentoxifylline may even be effective in the absence of com‐ pression [93].
