Overview of treatment of chronic wounds

INTRODUCTION — 

A chronic wound is one that is physiologically impaired and does not heal in the expected time frame. Examples include nonhealing or infected surgical or traumatic wounds, venous ulcers, pressure-induced skin and soft tissue injury, diabetic foot ulcers, ischemic ulcers, and some malignancy-associated wounds.

Local care of chronic wounds includes serial debridement and wound dressings selected for the specific conditions of the wound to promote healing. Other issues common to chronic wounds (odor, bleeding, itching, exudate, and pain) must also be addressed. Underlying medical condition(s) must be evaluated and addressed prior to surgical intervention, which is often needed to manage factors contributing to the chronic wound state and for definitive wound closure once wound bed preparation is completed.

The management of chronic wounds is reviewed. Risk factors for nonhealing and the management of wounds for which there is no expectation of healing are reviewed separately. (See "Risk factors for impaired wound healing and wound complications", section on 'Impaired wound healing' and "Overview of the care of adult patients with nonhealable wounds".)

CHRONIC WOUND STATE — 

A chronic wound may be defined as one that is physiologically impaired due to a disruption of the wound healing cycle as a result of impaired angiogenesis, innervation, or cellular migration, among other reasons [1].

The precise timeline for epithelialization of a wound varies depending on numerous factors, including comorbidities (eg, diabetes, autoimmune disease, peripheral artery disease, increased body mass index), anatomic location, and medications. Regardless of etiology, wound healing normally progresses at a sustained, measurable rate. However, for some wounds, healing stagnates. While there is no specific time frame that clearly differentiates an acute from a chronic wound, some suggest that the lack of approximately 15 percent reduction weekly or approximately 50 percent reduction of the surface area of the wound over a one-month period indicates a chronic state [2].

Characteristics of chronic wounds that prevent an adequate cellular response to wound-healing stimuli include the accumulation of devitalized tissue, decreased angiogenesis, hyperkeratotic tissue, exudate, and biofilm formation (ie, bacterial overgrowth on the surface of the wound) [3]. (See "Clinical assessment of chronic wounds".)

While acute wound fluid is rich in growth factors and has a balance of metalloproteases that interact with one another and with other cytokines to stimulate wound healing [4,5], the effect of chronic wound fluid on healing may not be as beneficial. (See "Basic principles of wound healing" and "Principles of acute wound management", section on 'Importance of moisture'.)

Chronic wound fluid contains persistently elevated levels of inflammatory cytokines that may inhibit the proliferation of fibroblasts [6-8]. Excessive periwound edema and induration contribute to the development of chronic wound fluid and need to be managed to minimize this effect.

Examples of common chronic wounds include nonhealing or infected surgical or traumatic wounds, venous ulcers, pressure ulcers, diabetic foot ulcers, ischemic ulcers, and malignancy-associated wounds. Skin breakdown can also be associated with chronic medical conditions and hard-to-heal wounds including rheumatoid arthritis, sickle cell disease, pyoderma gangrenosum, calciphylaxis, epidermolysis bullosa, toxic epidermal necrolysis, vasculitis, radiation dermatitis, and infectious diseases (eg, Buruli ulcer).

GENERAL CARE — 

General management of patients with chronic wounds includes local wound care as well as management of any underlying medical conditions contributing to the chronic wound state.

Overall approach — Local care of chronic wounds includes debridement and the use of wound dressings selected to address the specific conditions of the wound to promote wound healing. Necrotic debris or nonviable tissue should be aggressively removed, ideally using sharp surgical debridement. Proper local care is an important element of preparing the wound bed for wound closure or accepting a skin graft or flap when indicated. (See 'Wound bed preparation' below.)

Chronic wounds from cutaneous ulceration that occur in the setting of systemic disease states such as vasoocclusive, autoimmune, and inflammatory disorders (eg, rheumatoid arthritis, sickle cell disease, pyoderma gangrenosum, scleroderma) are difficult to treat and are often colonized with antibiotic-resistant bacteria [9]. Appropriate medical management of the underlying condition must be addressed prior to any planned definitive surgical procedure.

Surgery has inherent risks and medical optimization is important to decrease the risk of intraoperative and postoperative complications. The risks and benefits of surgery should be assessed to determine if the surgical intervention is the best course of treatment. Chronic wounds associated with malignancy can often be approached surgically if there are no prohibitive comorbidities and doing so aligns with the patient's goals for care. Even with advanced systemic disease, surgical debridement and coverage of the wound are possible.

However, some patients may be too sick or unable to undergo repeated procedures, which are often necessary to achieve wound closure. For debilitated patients with chronic lower extremity ischemia or malignancy-related wounds on the lower extremity, palliative care or even primary amputation may be a more appropriate course of action. (See "Overview of the care of adult patients with nonhealable wounds".)

Treatment of infection/cellulitis — Systemic antibiotic therapy should be reserved for only those wounds that appear clinically infected [10]. All chronic wounds are expected to be colonized with microbes; however, this does not assume or indicate the presence of an acute infectious process [11,12]. There is no published evidence to support systemic antibiotic therapy as "prophylaxis" in chronic wounds without clinical evidence of infection or as a means to improve the healing potential of wounds.

Clinical signs of wound infection that might warrant antibiotic therapy may be local (cellulitis, lymphangitic streaking, purulence, malodor, wet gangrene, osteomyelitis) or systemic (fever, chills, nausea, hypotension, hyperglycemia, leukocytosis, change in mental status) [13,14]. (See "Cellulitis and skin abscess: Epidemiology, microbiology, clinical manifestations, and diagnosis".)

In patients with clinical infection, antibiotic therapy should be targeted and determined by wound culture and sensitivity to decrease the development of bacterial resistance [15,16]. Wound cultures should not be taken as a superficial swab in these situations, but rather from the base of the wound after irrigation and debridement. (See 'Wound culture/biopsy' below.)

Glycemic control — Most clinicians make glycemic control a priority when treating wounds, although there is no robust clinical evidence in support of short-term glycemic control as directly affecting wound healing potential [17,18]. (See "Perioperative management of blood glucose in adults with diabetes mellitus" and "Glycemic control in critically ill adult and pediatric patients".)

Patients at risk for the development of chronic wounds often have comorbid conditions associated with immunocompromised states (eg, diabetes) and may not have classic systemic signs of infection such as fever and leukocytosis on initial presentation [19]. In these patients, the presence of hyperglycemia may be a more sensitive measure of infection.

Nutrition support — Patients identified by nutrition screening as being malnourished should be offered supplemental nutrition. While there is no definitive evidence that supplemental nutrition helps the healing of wounds, adequate nutrition is likely still important to assist in wound healing and minimize the potential for wound complications. (See "Clinical assessment of chronic wounds", section on 'Nutrition screening' and "Overview of perioperative nutrition support".)

Managing pain — Pain associated with chronic wounds, and specifically with dressing changes, should not be ignored. The World Health Organization (WHO) analgesic ladder, which was developed for the treatment of cancer-related pain, is applicable to other types of chronic pain. For patients receiving stable doses of a long-acting opioid around the clock, supplemental doses of a short-acting agent should be considered prior to dressing changes if they are painful. Topical or local anesthetics can be used but may have limited effect. (See "Approach to the management of chronic non-cancer pain in adults" and "Overview of cancer pain syndromes".)

WOUND BED PREPARATION — 

Wound bed preparation is defined as the process of removing local barriers to wound healing to maximize the potential for successful healing. This is accomplished primarily through debridement. Wound bed preparation facilitates ordered restoration and regeneration of damaged tissue and may enhance the function of specialized wound care products and advanced biologic tissue substitutes [20,21].

In general, surgical intervention of chronic wounds, which often requires multiple staged surgical procedures, is used to prepare the wound bed first by removing infected or necrotic debris, and subsequently handling any underlying factors contributing to wound chronicity (eg, bony deformities, biomechanical instability, ischemia). If these are successful in converting the chronic wound to an acute state, provisional or definitive wound coverage can be performed. Depending on the size of the wound, it may be left to heal secondarily or undergo wound coverage/closure. (See 'Wound coverage/closure' below.)

Adjunctive methods to aid in preparing the chronic wound bed include negative pressure wound therapy (NPWT) and hyperbaric oxygen therapy (HBOT), which are discussed briefly below and, in more detail, elsewhere. (See 'Adjunctive therapies' below.)

Surgical debridement — The majority of chronic wounds require planned serial debridement to sufficiently prepare the wound bed and restore an optimal wound-healing environment [22]. Sharp surgical debridement is the most appropriate choice for removing large areas of necrotic or infected tissue and is always indicated whenever there is any evidence of infection (cellulitis, sepsis). Surgical debridement also handles undermined wound edges and is used to obtain tissue from the base of the wound for wound culture and pathologic evaluation, as needed [22-24]. Serial surgical debridement appears to be associated with an increased likelihood of healing [22,25-28].

Wounds may require serial debridement in the operating room [29,30]. In some cases, particularly wounds that are larger or more complex, it is more appropriate to debride the wounds in the operating room, even if no definitive closure/coverage is planned, due to the degree of nonviable tissue, degree of contamination, or infection. The operating room is a safer environment for the debridement of such wounds, which often require the management of deeper soft tissue and bone-related issues. Clinic-based debridement often does not allow for sufficiently aggressive removal of nonviable tissue and biofilm due to inadequate pain control and the limited ability to achieve hemostasis [31].

For selected patients for whom serial debridement may not be tolerated or who have barriers that limit frequent clinic visits, enzymatic or biologic (larval) debridement is an alternative. These interventions may be helpful in reducing treatment complexity in the interval between serial debridement. (See 'Other methods' below and "Remote wound care".)

Technique — Sharp excisional debridement uses a scalpel or other sharp instruments (eg, scissors or curette) to remove devitalized tissue and other accumulated debris, pathogens (biofilm), contaminants, and foreign (or other) material. Sharp excisional debridement decreases bacterial load, stimulates wound contraction and epithelialization, and drains areas of infection [32]. It is important that debridement includes the base of the wound as well as the wound perimeter.

Prior to debridement, most chronic wounds benefit from irrigation to decrease bacterial load and remove any loose material [33-35]. Low-pressure irrigation (eg, <15 pounds per square inch) using saline or water with a bulb syringe is usually adequate to remove material from the surface of most chronic wounds. Higher-pressure irrigation may be useful during the initial debridement of highly contaminated wounds. Low- versus high-pressure irrigation and the utility of additives are reviewed separately. (See "Principles of acute wound management", section on 'Irrigation'.)

Bleeding from the surface of the wound commonly occurs during debridement. The propensity for a wound to bleed depends upon the type of wound and the stage of wound healing. Bleeding impairs the ability to see what tissue should be debrided, so if bleeding occurs after a dressing is removed, it should be stopped before commencing debridement. Bleeding can occur from the healing surfaces or from the deep layers of the skin at the wound edge. Diffuse bleeding from healing surfaces is managed with gentle pressure. Bleeding from the skin from a subdermal vessel can be coagulated using an electrocautery or a silver nitrate stick depending on the clinical setting. Once the bleeding stops, debridement can continue.

Wound culture/biopsy — If there is suspicion of infection (purulence, heavy drainage, clinical signs of infection in the surrounding tissue), wound/tissue cultures should be obtained during operative debridement to help direct antimicrobial therapy. Cultures should be obtained from the deepest margins of the wound and, if possible, include tissue from the wound base. The bacterial flora may evolve to a more resistant bacterial phenotype over time. Thus, cultures should be obtained serially, if clinically indicated

A random culture will most likely yield a positive result in a chronic wound environment, even though it may not be pathogenic [36]. This may lead to unnecessary antibiotic treatment. In addition, biofilm cannot be detected through traditional agar culture methods. Other methods are necessary for biofilm detection, such as 16S rDNA pyrosequencing [37]. The degree of impact of biofilm on chronic wounds has not been fully elucidated.

If the etiology of the wound is unknown or the wound displays atypical characteristics, an excisional biopsy of the wound and/or wound perimeter should also be obtained for histology.

Other methods — Alternative methods of debridement (enzymatic, biologic) may be helpful when a clinician with expertise in surgical debridement is not available, frequent surgical debridement may not be tolerated, or there are barriers to wound care.

Enzymatic — Enzymatic debridement involves applying exogenous enzymatic agents to the wound. Many products are commercially available (table 1), but the results of clinical studies are mixed and their specific effect remains unclear [38]. Ulcer healing rates are not improved with the use of most topical agents, including debriding enzymes [39]. However, collagenase may promote endothelial cell and keratinocyte migration, thereby stimulating angiogenesis and epithelialization as its mechanism of action, rather than functioning as a strict debridement agent [40]. Enzymatic debridement also remains a good option in patients who require debridement but are not surgical candidates.

Biologic — Another method of wound debridement uses the larvae of the Australian sheep blowfly (Lucilia [Phaenicia] cuprina) or green bottle fly (Lucilia [Phaenicia] sericata, medical maggots) [41,42]. Biologic debridement or "maggot therapy" can be used as a bridge between debridement procedures, or for debridement of chronic wounds when surgical debridement is not available or cannot be performed [43]. Maggot therapy has been used in the treatment of pressure ulcers [44,45], chronic venous ulceration [46-49], diabetic foot ulcers [41,50], and other chronic wounds [51].

The larvae secrete proteolytic enzymes that liquefy necrotic tissue, which is subsequently ingested while leaving healthy tissue intact. Basic and clinical research suggests that maggot therapy has additional benefits, including antimicrobial action and stimulation of wound healing [42,46,52,53]. Maggot therapy may also reduce the duration of antibiotic therapy in some patients [54]. However, randomized trials have not found consistent reductions in the time to wound healing compared with standard wound therapy (eg, debridement, hydrogel, moist dressings) [55,56].

Dressing changes include the application of a perimeter dressing and a cover dressing of mesh (chiffon) that helps direct the larvae into the wound and limits their migration (movie 1). Larvae are generally changed every 48 to 72 hours. One study that evaluated maggot therapy in chronic venous wounds found no advantage to continuing maggot therapy beyond one week [47]. Patients were randomly assigned to maggot therapy (n = 58) or conventional treatment (n = 61). The difference in the slough percentage was significantly increased in the maggot therapy group compared with the control groups at day 8 (67 versus 55 percent), but not at 15 or 30 days.

The larvae can also be applied within a prefabricated "biobag" (picture 1), commercially available outside the United States, that facilitates application and dressing change [57-60]. Randomized trials comparing "free-range" with "biobag"-contained larvae in the debridement of wounds have not been performed.

A main disadvantage of maggot therapy relates to negative perceptions about its use by patients and staff. One concern among patients is the possibility that the larvae can escape the dressing, but this rarely occurs. Although one study identified that approximately 50 percent of patients indicated they would prefer conventional wound therapy over maggot therapy, 89 percent of the patients randomly assigned to maggot therapy said they would undergo larval treatment again [61]. Perceived pain or discomfort with the dressings associated with maggot therapy may limit its use in approximately 20 percent of patients [62].

Adjunctive therapies

Negative pressure wound therapy — NPWT refers to wound dressing systems that continuously or intermittently apply subatmospheric pressure to the surface of a wound. NPWT promotes the development of granulation tissue to cover deeper exposed tissues [63]. Information regarding the mechanism of action and use of this device and contraindications (eg, malignancy in the wound) is reviewed elsewhere. (See "Negative pressure wound therapy".)

NPWT is primarily used in situations where healing is expected; however, NPWT may improve the healing of some types of chronic wounds/ulceration, provided they are well vascularized [64-68]. Patients with extremity wounds and inadequate peripheral pulses should undergo noninvasive vascular testing to confirm adequate perfusion prior to instituting NPWT, especially patients with diabetes or other risk factors for peripheral artery disease. (See "Noninvasive diagnosis of upper and lower extremity arterial disease".)

●Compared with conventional dressing changes, NPWT reduces the time to closure of diabetic foot ulcers and wounds resulting from diabetic foot surgery. In this population of patients, NPWT is also associated with shorter lengths of hospitalization, decreased complication rates, and reduced costs. The use of NPWT in the management of diabetic foot lesions is discussed in detail separately. (See "Local care of diabetic foot ulcers", section on 'Role of negative pressure wound therapy'.)

●Trials have evaluated the use of NPWT as an adjunctive therapy for the management of pressure-induced skin and soft tissue. While no significant differences have been identified with respect to quantitative wound healing measures (eg, wound surface area reduction), NPWT improved patient comfort and was less labor intensive. (See "Local care of pressure-induced skin and soft tissue injury".)

Hyperbaric oxygen therapy/topical oxygen therapy — HBOT has been used as an adjunct to wound care in the treatment of chronic wounds [69-75]. HBOT has been shown to have in vitro effects on wound healing [76]. HBOT may also aid wound bed preparation by increasing local tissue oxygen perfusion prior to the definitive surgical procedure, which may be particularly important for some wounds such as those that develop as a late effect of radiation therapy for the treatment of cancer [69,77-79]. (See "Hyperbaric oxygen therapy" and "Management of late complications of head and neck cancer and its treatment", section on 'Hyperbaric oxygen'.)

Most studies of HBOT in chronic wounds are observational, and the few available trials are limited by small sample size and low quality [80-82]. Systematic reviews have concluded that, although hyperbaric oxygen may benefit some types of wounds (eg, post-radiation therapy), there is insufficient evidence to support routine use [83,84].

There is some evidence to support the use of topical oxygen therapy [85], but no studies directly compare the outcomes of HBOT with topical oxygen therapy. Topical oxygen therapy provides localized oxygen delivery directly to the wound bed and periwound surfaces. This option may be more acceptable to patients who find the frequency of HBOT cumbersome or for those who are not candidates for HBOT.

WOUND DRESSINGS — 

Following debridement, a suitable dressing is applied to the wound and changed appropriately to maintain an optimal healing environment. In addition, wounds must be continually monitored as their characteristics and dressing requirements change over time [86].

No single dressing is perfect for all wounds; rather, a clinician should evaluate the wounds and choose the best dressing on a case-by-case basis. A detailed description of common, differing types of wounds and potential dressings is provided in the tables (table 2 and table 3). Some dressings may have additional benefits in terms of local antimicrobial effects, reduced pain on change, odor control, and anti-inflammatory or mild debridement ability. These benefits are secondary to the primary function of the dressing in maintaining a moist but not excessively moist environment and protecting the wound [87]. (See "Principles of acute wound management".)

Selection and frequency — The moisture content of a wound bed must be kept in balance. A dressing should keep the wound moist enough to promote healing, but excess exudate must be absorbed away from the wound to prevent maceration of the healthy tissue.

There is little clinical evidence to aid in the choice between the different types of wound dressings in the management of chronic wounds. Consensus opinion supports the following general principles for chronic wound management [88].

●Hydrogels for the debridement stage (see 'Hydrogels' below)

●Low-adherent dressings that maintain moisture balance for the granulation stage

●Low-adherent dressings for the epithelialization stage

The advantages and disadvantages of the various dressing types are discussed below. (See 'Common dressings' below.)

Some dressings impede some aspects of wound healing, they should be used with caution. As examples, alginate dressings with high calcium content may impede epithelialization by triggering premature terminal differentiation of keratinocytes (see 'Alginates' below) [88], and highly silver-containing dressings (see 'Silver-based' below) are potentially cytotoxic and should not be used in the absence of significant infection.

Dressings are typically changed once a day or every other day to avoid disturbing the wound-healing environment. The degree of drainage/moisture should help guide the clinician in terms of dressing selection and frequency. Some chronic wounds (eg, chronic venous ulcers) can have copious amounts of drainage and require more frequent dressing changes. Excessive moisture is detrimental leading to maceration of the wound and surrounding skin.

Common dressings — Dressings can be categorized by their water-retaining abilities as open, semi-open, or semi-occlusive. (See "Principles of acute wound management", section on 'Dressing types'.)

●Open – Open dressings include primarily gauze, which is typically moistened with saline before placing it into the wound. Gauze dressings are inexpensive but often require frequent dressing changes. Wet-to-moist gauze dressings are useful for packing large soft-tissue defects until wound closure or coverage can be performed (eg, pressure-induced injury). (See "Principles of acute wound management", section on 'Open'.)

●Semi-open – Semi-open dressings generally do not maintain a moisture-rich environment or provide good exudate control. These dressings may have specific uses, often in postoperative wounds (eg, Xeroform over burn wound harvest area). (See "Principles of acute wound management", section on 'Semi-open'.)

●Semi-occlusive – Semi-occlusive dressings are often used in the management of chronic wounds and come in a wide variety of occlusive properties, absorptive capacities, conformability, and bacteriostatic activity (table 2). Semi-occlusive dressings such as films, foams, alginates, hydrocolloids, and hydrogels, are frequently used to manage chronic wounds and are discussed in detail below.

Films — Polymer films are transparent sheets of synthetic self-adhesive dressing that are permeable to gases such as water vapor and oxygen but impermeable to larger molecules, including proteins and bacteria. This property enables insensible water loss to evaporate, traps wound fluid enzymes within the dressing, and prevents bacterial invasion.

●Advantages include their ability to maintain moisture, encourage rapid re-epithelization, transparency, and self-adhesive properties.

●Disadvantages include limited absorptive capacity. They are not appropriate for moderate to heavily exudative wounds. If they are allowed to remain in place over a wound with heavy exudates, the surrounding skin is likely to become macerated. In addition, if the wound dries out, film dressings may adhere to the wound and be painful and damaging to remove.

Foams — Foam dressings can be thought of as film dressings with the addition of absorbency. They consist of two layers, a hydrophilic silicone or polyurethane-based foam that lies against the wound surface, and a hydrophobic, gas-permeable backing to prevent leakage and bacterial contamination. Some foams require a secondary adhesive dressing. Foams are marketed under names such as Allevyn, Adhesive, Lyofoam, and Spyrosorb.

●Advantages include their high absorptive capacity and the fact that they conform to the shape of the wound and can be used to pack cavities.

●Disadvantages include the opacity of the dressings and the fact that they may need to be changed each day. Foam dressings may not be appropriate on minimally exudative wounds, as they may cause desiccation.

Alginates — Natural complex polysaccharides from various types of algae form the basis of alginate dressings. Their activity as dressings is unique because they are insoluble in water, but in the sodium-rich wound fluid environment these complexes exchange calcium ions for sodium ions and form an amorphous gel that packs and covers the wound. Alginates come in various forms including ribbons, beads, and pads. Their absorptive capacity ranges depending upon the type of polysaccharide used. In general, these dressings are more appropriate for moderately to heavily exudative wounds.

●Advantages include augmentation of hemostasis [89,90], they can be used for wound packing, most can be washed away with normal saline to minimize pain during dressing changes, and they can stay in place for several days.

●Disadvantages are that they require a secondary dressing that must be removed to monitor the wound, they can be too drying on a minimally exudative wound, and they have an unpleasant odor.

In a trial of 77 patients, patients with diabetic foot wounds were randomly assigned to alginate or petroleum gauze dressings [91]. Patients treated with alginates had significantly superior granulation tissue coverage at four weeks of treatment, significantly less pain, and fewer dressing changes than the petroleum gauze group.

Hydrocolloids — Hydrocolloid dressings usually consist of a gel or foam on a carrier of self-adhesive polyurethane film. The colloid composition of this dressing traps exudate and creates a moist environment. Hydrocolloid products include DuoDERM, Tegasorb, Johnson and Johnson Ulcer Dressing, and Comfeel.

●Advantages are that bacteria and debris are trapped and washed away with dressing changes in a gentle, painless form of mechanical debridement. Another advantage of hydrocolloids is the ability to use them for packing wounds.

●Disadvantages include malodor, the potential need for daily dressing changes, and possible allergic contact dermatitis [92]. Iodine-induced hyperthyroidism has been documented with use of cadexomer iodine for leg ulcers [93].

Cadexomer iodine is a type of hydrocolloid in which iodine is dispersed and slowly released after it comes in contact with wound fluid. The concentration of iodine released is low and does not cause tissue damage [94]. (See 'Iodine-based' below.)

Hydrogels — Hydrogels are a matrix of various types of synthetic polymers with >95 percent water formed into sheets, gels, or foams that are usually sandwiched between two sheets of removable film. The inner layer is placed against the wound, and the outer layer can be removed to make the dressing permeable to fluid. Sometimes a secondary adhesive dressing is needed. These unique matrices can absorb or donate water depending upon the hydration state of the tissue that surrounds them. Hydrogels are most useful for dry wounds. Hydrogel products include Intrasite Gel, Vigilon, Carrington Gel, and Elastogel.

●An advantage is that they initially lower the temperature of the wound environment they cover, which provides cooling pain relief for some patients [95].

●A potential disadvantage, although there have been no reports of increased wound infection, is that hydrogels have been found to selectively permit gram-negative bacteria to proliferate [96].

Hydroactive — Hydroactive is a polyurethane matrix that combines the properties of a gel and a foam. Hydroactive selectively absorbs excess water while leaving growth factors and other proteins behind [97].

A randomized trial compared hydroactive dressings with two different hydrocolloids and found the hydroactive dressing to be equally effective at promoting ulcer healing and alleviating ulcer-associated pain after 12 weeks of treatment [98]. Another study reported that hydroactive dressings combined with enzymatic debridement were more cost-effective than gauze alone in dressing pressure ulcers and venous stasis ulcers [99].

Topical therapies — After appropriately addressing debridement of necrotic tissue, pressure offloading, infection, and ischemia, there are several adjunctive therapies that may be helpful to augment wound healing.

Antiseptics and antimicrobial agents — Some topical antimicrobials may be associated with potential benefits in selected patient populations. The properties of some broadly used agents are reviewed briefly below; others are reviewed separately (table 2). (See "Topical agents and dressings for local burn wound care".)

Iodine-based — Cadexomer iodine (eg, Iodosorb) is an antimicrobial that reduces bacterial load within the wound and may support healing by providing a moist wound environment [100]. Cadexomer iodine is bacteriocidal to all gram-positive and gram-negative bacteria. For topical preparations, there is some evidence to suggest that cadexomer iodine generates higher healing rates than standard care but should likely only be considered for use on a short-term basis.

A multicenter trial reported that over a 12-week period, cadexomer iodine paste was more cost-effective than non-iodinated hydrocolloid dressing or paraffin gauze dressing in patients with exudating venous ulcers [101]. A systematic review found some evidence that topical application of cadexomer iodine enhanced venous ulcer healing rates compared with standard care (with and without compression) [39]. The treatment regimen was complex, and it is unclear if the results are generalizable to most clinical settings.

Silver-based — Silver is toxic to bacteria and silver-containing dressings are used by many clinicians to decrease heavy bacterial surface contamination [102]. Silver-containing dressings have not demonstrated consistent benefits in comparison with other topical wound dressings [103-107].

However, a systematic review and meta-analysis of four randomized trials reported a significantly higher relative reduction in wound area after six weeks of treatment with a silver ion-releasing foam dressing compared with controls [104]. Other observed benefits included a reduction in the time to disappearance of odor, a relative reduction of exudate, a reduced proportion of patients with periwound erythema, and less pain at dressing removal.

Honey — Honey has been used since ancient times for the management of wounds. Honey has broad-spectrum antimicrobial activity due to its high osmolarity and high concentration of hydrogen peroxide [108]. Medical-grade honey products are now available as a gel, paste, and impregnated into adhesive, alginate, and colloid dressings [109,110]. Based upon the results of systematic reviews evaluating honey to aid healing in a variety of wounds, there are insufficient data to provide any recommendations for the routine use of honey for all wound types; specific wound types, such as burns, may benefit, whereas others, such as chronic venous ulcers, may not [111-120].

Beta blockers — Keratinocytes have beta-adrenergic receptors, and beta blockers may influence their activity and increase the rate of maturation and migration. The use of systemic beta blockers has been studied in burn patients [121], and several case studies have presented the use of topical esmolol or timolol in chronic wounds [122-125].

Timolol is a topically applied beta blocker with some limited evidence that it promotes keratinocyte migration and epithelialization of chronic wounds, which have been unresponsive to standard wound interventions.

In a trial that randomized 176 participants with diabetic foot ulcers, the proportion of participants receiving esmolol who achieved target ulcer closure within 12 weeks was increased compared with routine care (60.3 versus 41.7 percent; odds ratio 2.13; 95% CI 1.08-4.17).

Growth factors — Growth factors important for wound healing include platelet-derived growth factor (PDGF), fibroblast growth factor, and granulocyte-macrophage colony-stimulating factor (GM-CSF), amongst others. (See "Basic principles of wound healing".)

Recombinant human growth factors have been developed and are being actively investigated for the treatment of chronic ulcers, mostly those affecting the lower extremities. As with other therapies, isolated growth factors applied in the absence of good-quality debridement, infection control, and offloading when indicated are likely to be ineffective in promoting healing [23,126].

●PDGF – Becaplermin is a PDGF gel preparation that promotes cellular proliferation and angiogenesis and thereby improves wound healing [127]. It is approved for use in the United States as an adjuvant therapy for the treatment of diabetic foot ulcers and is the only pharmacologic agent approved for the treatment of chronic wounds. The growth factor is delivered in a topical aqueous-based sodium carboxymethylcellulose gel. It is indicated for noninfected diabetic foot ulcers that extend into the subcutaneous tissue and have an adequate vascular supply [128]. A boxed warning mentions a concern for malignancy; however, the overall malignancy risk is believed to be low. Malignancy complications of this therapy may reflect usage of the agent in multiple courses of treatment, and possible selective transformation of wounds already at risk [129]. A post-marketing study found an increased rate of mortality secondary to malignancy in patients treated with three or more tubes of becaplermin (3.9 versus 0.9 per 1000 person-years) compared with controls [130,131].

●Epidermal growth factor – In a study of chronic venous ulcers, topical application of human recombinant epidermal growth factor was associated with a greater reduction in ulcer size (7 versus 3 percent reduction) and higher ulcer healing rate (35 versus 11 percent) compared with placebo, but these differences were not statistically significant [132]. Epithelialization was not significantly affected.

●GM-CSF – Intradermal injections of GM-CSF promote the healing of chronic leg ulcers, including venous ulcers [133,134]. A trial that randomly assigned 60 patients with venous ulcers to four weekly injections with GM-CSF 200 mcg, 400 mcg, or placebo found significantly higher rates of healing at 13 weeks in the GM-CSF group (57, 61, and 19 percent, respectively) [134]. GM-CSF has been used in various types of chronic wounds to promote healing [135]. (See "Evaluation and management of chronic venous insufficiency including venous leg ulcer", section on 'Ulcer care'.)

Wound packing — Packing chronic wounds associated with significant dead space, tunneling, or undermining is important to reduce physiological dead space, absorb exudate/seroma collection, and reduce the potential for infection. Wound packing and materials are discussed separately. (See "Principles of acute wound management", section on 'Wound packing'.)

Specific chronic wound issues — Local wound care of chronic wounds is also directed toward dealing with the troublesome chronic wound problems that affect the patient physically and emotionally, such as excess exudate that can lead to unpleasant odors, pain and itching, and bleeding from the wound.

Odor — Wound odor can be controlled with interval mechanical debridement to decrease the microbial bioburden on the wound surface, with topical antimicrobial therapy (eg, metronidazole) [136-138] and/or with odor-absorbing dressings such as those that have absorptive charcoal within the dressing (eg, Actisorb, Carboflex). Soaks of dilute acetic acid, hypochlorous acid, or Dakin solution can also help to minimize odor. Long-term frequent use of potentially locally cytotoxic agents such as Dakin solution is not recommended.

Bleeding — A nonadherent dressing can be placed directly on the friable wound to reduce bleeding and reduce pain associated with dressing changes. A second layer of alginate dressings that contain coagulants can also help to minimize bleeding (table 3).

Chronic wounds that are prone to oozing from the ulcer bed (eg, malignant wounds that cannot be excised) can be controlled with topical hemostatic agents or sucralfate [139] and gentle pressure in the form of elastic bandages, with focal points of bleeding managed with silver nitrate, handheld cautery, or local anesthetic with epinephrine. (See "Overview of topical hemostatic agents and tissue adhesives" and "Subcutaneous infiltration of local anesthetics".)

Pruritus — Itching can be a complaint with chronic wounds. Itching and irritation are usually due to dry or wet skin or contact dermatitis. Keeping a proper moisture balance and protecting the skin will help reduce itching and skin irritation, and, if necessary, topical corticosteroid creams can be applied. (See "Irritant contact dermatitis in adults", section on 'Management'.)

Exudate — An absorptive dressing should be placed over the nonadherent dressing to control drainage, reduce periwound maceration, and control the amount of exudate in the wound, and should be tailored to the specific anatomic location and wound depth (table 3).

Alternatively, wound drainage can be drawn away using a collecting device (eg, ostomy appliance, negative pressure wound therapy device), provided there are no contraindications. Exudate-absorbing topicals, including cadexomer iodine and medicinal honey formulations, may be helpful in removing scant to moderate exudate from the wound surface.

WOUND COVERAGE/CLOSURE — 

Surgical procedures that provide wound coverage/closure are briefly described below. It is important to address the underlying etiology of the wound prior to performing the definitive procedure to minimize the risk of recurrence. Recurrence of the wound at the same site or development of wounds at another location can occur after initial healing, especially in high-risk patients. As an example, patients with diabetes with peripheral neuropathy must be adequately protected with specialized accommodative inserts, shoes, and braces. Thus, careful follow-up is needed. (See 'General care' above.)

If the wound is relatively small, it can be completely excised and closed primarily (sutures/staples), provided there is no to minimal skin tension. An understanding of appropriate tension and blood supply is paramount to allow for healing. In a previously infected wound, we avoid placing absorbable sutures deeply within the wound. In this situation, vertical mattress sutures may help bring the deep and superficial spaces together.

Larger or more complicated wounds may require graft or flap coverage. These can be done once a layer of healthy granulation tissue has developed at the base of the wound. Procedures that provide coverage for chronic wounds are listed below and discussed in more detail in the linked topics.

●Split-thickness skin graft – Split-thickness skin grafts (STSGs), also called partial-thickness grafts, are autologous epidermal/dermal grafts. Chronic wounds with a good bed of granulation tissue and without exposed tendons or bone are good candidates for skin grafting. STSGs may be complicated by secondary contracture and should be avoided in areas around joint surfaces. (See "Skin autografting", section on 'Split-thickness skin grafting'.)

●Full-thickness skin grafts – Full-thickness skin grafts (FTSGs) are autologous epidermal and full-thickness dermal grafts. These grafts have a decreased incidence of secondary contracture. FTSG is appropriate when a thicker autograft is necessary, such as for deeper wounds or in areas that require more durable tissue (eg, foot). (See "Skin autografting", section on 'Full-thickness skin grafting'.)

●Xenografts/allografts – If an autologous graft is not possible, a xenograft or allograft can be used. One strategy is to use a xenograft or allograft to build up a dermal tissue layer prior to STSG application. The xenograft or allograft will be replaced by the host tissue over time. There are a variety of xenografts/allografts that serve different purposes. Porcine epidermis can be applied to the wound surface as a test to ensure that adequate debridement was performed prior to the definitive closure/coverage procedure, or it can be used as a biologic dressing when there is low confidence in patient compliance. Other xenografts, including bovine collagen, can be used to cover deeper soft tissue defects to form a neodermis in preparation for receiving a split-thickness skin graft. (See "Skin substitutes", section on 'Xenografts'.)

Allografts can be used for the same purpose. The various types of skin substitutes, their classification, and their uses are reviewed separately. (See "Skin substitutes".)

●Local tissue flaps – Local tissue rearrangement is useful in many circumstances when primary closure is not possible. These techniques involve the recruitment of skin from surrounding areas and transposing it into the defect to allow for closure. Blood supply to the flap must be preserved. Common local tissue flaps include V-to-Y advancement, rotation flaps, and advancement flaps. (See "Z-plasty" and "Overview of flaps for soft tissue reconstruction", section on 'Skin'.)

●Pedicled flaps – Pedicled flaps are useful when muscle or fascia is needed to cover a large wound or deep wound that has an exposed tendon or bone. The blood supply to the harvested muscle must be preserved, and the flap is rotated to cover the wound defect. Pedicled flaps include expendable muscles, such as the abductor hallucis muscle flap for coverage of medial foot or ankle defects or the hemi-gastrocnemius muscle flap to cover knee defects. Another common flap is the soleus flap for coverage of mid-tibial defects. (See "Surgical reconstruction of the lower extremity" and "Overview of flaps for soft tissue reconstruction", section on 'Pedicled'.)

●Free tissue transfers – Free tissue transfer is an important technique for the closure of larger soft tissue defects that may not be amenable to pedicled or local advancement flaps. The muscle or fascia is harvested, with or without the overlying skin, along its vascular pedicle. The free flap is placed into the defect, and the arterial and venous blood supply is sutured to a local artery and vein nearby. (See "Overview of flaps for soft tissue reconstruction", section on 'Skin'.)

SPECIFIC TYPES OF CHRONIC WOUNDS — 

The management of specific chronic wounds is briefly discussed below.

Diabetic foot ulcers — Diabetic foot ulcers are a unique category of chronic wounds that require multiple considerations (algorithm 1). The treatment diabetic foot ulcers is discussed separately. (See "Local care of diabetic foot ulcers".)

Ischemic ulcers and gangrene — The presence of ischemia influences the timing of revascularization, debridement, and definitive coverage/closure. For patients with chronic limb-threatening ischemia, revascularization will be necessary before there can be any expectation of wound healing [140]. (See "Management of chronic limb-threatening ischemia".)

●For patients with wet gangrene or abscess (picture 2), the wound should be debrided immediately regardless of the need for revascularization. The dressing choice depends upon the level of anticipated drainage and the size of the wound. Dead space is usually managed with gauze packing. The extremity should be revascularized as soon as safely possible, if needed, after drainage/debridement and control of the infection.

●For patients with dry gangrene without cellulitis (picture 3), the limb should be revascularized first. The wound dressing is protective, reducing the risk of trauma or infection. The wound should be lightly wrapped with a bulky dry gauze bandage, avoiding excess pressure that could aggravate ischemia. Following revascularization, the wound should be monitored closely for signs of healing or for tissue necrosis/drainage that may indicate a need for further debridement.

Chronic orthopedic wounds — Large soft tissue defects of the extremities are often the result of trauma and are frequently accompanied by bony fractures. When traumatic wounds become chronic, wound coverage options are dictated by the severity of the initial injury and the anatomic location. (See "Severe lower extremity injury in the adult patient" and "Surgical reconstruction of the lower extremity".)

For traumatic wounds that require internal fixation, the chronicity of the wound may be due to an underlying bone infection (osteomyelitis) or biofilm on a screw, plate, anchor, or heavy suture. Thus, the removal of affected materials will be necessary for definitive closure. Bone infection requires resection of the infected segment, long-term antibiotics, or the use of antibiotic-impregnated cement. The skeletal framework must be addressed to provide stability of the overlying soft tissue envelope. Treatment of chronic or subacute osteomyelitis can occur over many months, with standard antibiotic treatment regimens lasting typically six weeks, following a period of time off antibiotics, at which time bone culture is repeated. If the repeat culture or aspirate is negative, definitive soft tissue closure/coverage can proceed. (See "Osteomyelitis in the absence of hardware: Approach to diagnosis in adults".)

Total joint implants pose a difficult problem. Expeditious soft tissue coverage or closure over noninfected joint implants or internal fixation is important. Infected internal fixation constructs and joint implants may require removal with subsequent reimplantation once the infection is resolved. Typically, these problems require pedicled flaps or free tissue transfers for definitive coverage. (See 'Wound coverage/closure' above and "Skin autografting" and "Surgical reconstruction of the lower extremity".)

The following case examples illustrate different types of chronic orthopedic wounds.

●The pictures in the figure show the management of a patient with an infected total knee arthroplasty (picture 4). Four weeks after the procedure, the incision site evidenced drainage and was opened. Following the debridement of necrotic tissue, a rotation flap was used to close the open knee defect, over which a skin graft was placed to provide coverage of the muscle.

●The pictures in the figure show the management of a patient with a chronic draining sinus three years after open reduction and internal fixation for a fibular fracture (picture 5). After debridement and removal of the previously placed fibular plate, a location rotation flap was used to cover the exposed bone, over which a skin graft was placed to provide coverage of the residual exposed subcutaneous tissue.

●The pictures in the figure show the management of a patient with a chronic draining sinus related to the repair of a prior calcaneal fracture one year previously (picture 6). Following incision, drainage, debridement, and removal of infected hardware, a free flap was placed.

●The pictures in the figure show the management of a patient with chronic draining sinus emanating from osteomyelitis in a bone sequestrum following a prior traumatic injury (picture 7). Following bone debridement and removal of the sequestrum, the bone was packed with an antibiotic spacer, and a free muscle flap was used to provide coverage, over which a skin graft was used to cover the muscle.

Abdominal wounds — A chronic open abdominal wound can occur following local skin separation, partial fascial dehiscence, or complete fascial dehiscence, leading to evisceration from an abdominal incision. More often, open abdominal wounds result from intentionally leaving an abdominal incision open at the completion of an abdominal procedure to prevent abdominal compartment syndrome. Rarely, large defects are the result of traumatic injury (eg, shotgun blast).

If the wound is small and the fascia is intact, local wound care with bedside incision and drainage may be all that is needed. Negative pressure wound therapy (NPWT) can aid the closure of clean abdominal wounds. For wounds that are larger, those that have drainage, and those with abdominal wall necrosis, surgical debridement, and sequential second-look procedures are more optimal for achieving definitive closure. (See "Surgical management of necrotizing soft tissue infections" and "Management of the open abdomen in adults".)

The following case examples illustrate different types of chronic abdominal wounds.

●The pictures in the figure show the management of a patient with a necrotizing abdominal wall infection related to a surgical site infection. Following debridement of infected and necrotic material (picture 8), including the fascial edges, the wound was able to be closed primarily.

●The pictures in the figure show the management of a child with a nonhealing abdominal wall wound that was present for five months (picture 9). The wound was treated with open dressings until a bed of granulation tissue was present, after which a xenograft was initially placed to ensure that a skin graft would be taken. NPWT was used to secure the xenograft. A skin graft was placed five days later with a good result.

Pressure-induced skin and soft tissue injury — Pressure-induced injury is due to chronic pressure in susceptible areas that leads to ischemia and skin loss. The treatment of pressure ulcers depends upon the stage of the ulcer. (See "Local care of pressure-induced skin and soft tissue injury" and "Surgical management of pressure-induced skin and soft tissue injuries".)

Ulcerated and fungating malignancy-related wounds — The palliative treatment of malignancy-related (eg, post radiation therapy) or ulcerating or fungating malignant wounds represents a clinical challenge without evidence-based guidelines or established protocols. The clinician should establish goals for wound management with the patient.

Chronic wounds related to malignancy require appropriate treatment of the malignancy. Although symptom management strategies for comfort may work in tandem with healing interventions with the goal of eventual wound closure, it is important to recognize when efforts toward wound closure may become unrealistic or burdensome for the patient. In some cases, palliation may be all that can be offered [141-143] (See "Overview of the care of adult patients with nonhealable wounds".)

Venous stasis ulcers — The mainstay of treatment for venous ulceration is local wound care and compression therapy. Skin grafting may improve ulcer healing and is indicated for those who do not exhibit appropriate wound healing after 12 months of medical care. (See "Evaluation and management of chronic venous insufficiency including venous leg ulcer", section on 'Ulcer care'.)

SOCIETY GUIDELINE LINKS — 

Links to society and government-sponsored guidelines from selected countries and regions around the world are provided separately. (See "Society guideline links: Open wound management".)

SUMMARY AND RECOMMENDATIONS

●Chronic wounds – A chronic wound may be defined as one that is physiologically impaired due to a disruption of the wound healing cycle. A chronic state is defined by some as a less than 15 percent reduction of the surface area of the wound over one week or less than 50 percent reduction over one month. Examples of chronic wounds include nonhealing or infected surgical or traumatic wounds, venous ulcers, pressure ulcers, diabetic foot ulcers, ischemic ulcers, and some malignancy-associated wounds. (See 'Introduction' above and 'Chronic wound state' above.)

●General care – General care of patients with chronic wounds includes local wound care as well as management of any underlying medical conditions contributing to the chronic wound state. In general, surgical intervention is necessary to manage infection and prepare the wound bed for subsequent coverage/closure, which may require repeated procedures, and to handle any underlying factors that are contributing to the chronic wound state (eg, bony deformities, foreign body, biomechanical instability), and sometimes to restore adequate perfusion through revascularization. Underlying medical condition(s) contributing to the chronic wound must be evaluated and addressed prior to any planned definitive surgical procedure. (See 'General care' above.)

●Wound bed preparation – Local care of chronic wounds includes debridement and proper wound dressings.

•Debridement – For optimal wound healing, the wound bed should be well vascularized, free of devitalized tissue, clear of infection, and moist. For most patients with chronic wounds or ulcers, we suggest sharp surgical debridement over nonsurgical methods for the debridement of devitalized tissue (Grade 2C). When surgical expertise is not available or for selected patients for whom serial debridement may not be tolerated or who have barriers that limit frequent clinic visits, alternative methods include enzymatic or biologic debridement. These may also be used between surgical debridement, as needed. (See 'Surgical debridement' above and 'Other methods' above.)

•Adjunctive therapies – Negative pressure wound therapy (NPWT) is frequently used to manage complex wounds and reduce the complexity of definitive closure. Other therapies have been used with the aim of enhancing wound healing. Some of these therapies have shown a marginal benefit and may be useful as adjuncts for managing chronic wounds. (See 'Adjunctive therapies' above.)

●Wound dressings – Wound dressings should be chosen based on their ability to manage dead space, control exudate, reduce pain during dressing changes (as applicable), prevent bacterial overgrowth, ensure proper fluid balance, be cost-efficient, and be manageable for the patient or nursing staff. Adjuncts to wound healing may include NPWT and hyperbaric oxygen therapy (HBOT), provided there are no contraindications for their use. (See 'Wound dressings' above.)

•Topical therapy – Topical agents such as antiseptics and antimicrobial agents can be used to control locally heavy contamination. Significant improvements in rates of wound healing have not been reported, and toxicity to the tissues might be a significant disadvantage. (See 'Topical therapies' above.)

•Specific chronic wound issues – Wound care should also be directed toward dealing with the most troublesome chronic wound problems that affect the patient physically and emotionally, such as odor, bleeding, itching, excess exudate, pain, and minimizing infection. (See 'Specific chronic wound issues' above.)

●Wound coverage/closure – Following wound bed preparation, chronic wounds that demonstrate progressive healing as evidenced by granulation tissue and epithelialization along the wound edges can undergo delayed closure or coverage with skin grafts or bioengineered tissues. (See 'Wound coverage/closure' above.)

•Limited chronic wounds may be amenable to complete excision and primary closure (sutures/staples), provided there is no to minimal skin tension.

•Larger or more complicated chronic wounds may require coverage using a skin graft or skin/muscle flap.

●Follow-up care – Once a chronic wound has been closed or covered, clinical follow-up and wound surveillance are necessary. Wounds can recur after initial healing, particularly in high-risk populations, such as in patients with diabetic foot wounds. To prevent recurrence, it is important to address the factors that were responsible for the development of the wound.

●Specific chronic wounds – The management of specific chronic wounds, diabetic foot wounds, chronic orthopedic wounds, chronic abdominal wounds, pressure ulcers, ulcerated and fungating malignancy-related wounds, and venous ulcers is briefly reviewed in this topic. (See 'Specific types of chronic wounds' above.)