Risk factors for impaired wound healing and wound complications

INTRODUCTION — Acute wounds in normal, healthy individuals heal through an orderly sequence of physiologic events. Some individuals have one or more factors that contribute to impaired wound healing, which can lead to chronic ulcerations or nonhealing wounds, or can complicate the surgical course.

The risk factors associated with impaired wound healing due to patient factors, underlying disease, and disease treatments are reviewed here. Wound mechanisms, normal phases of wound healing, and wound classification, as well as the clinical evaluation and management of wounds, are discussed elsewhere. (See "Basic principles of wound healing" and "Clinical assessment of chronic wounds" and "Basic principles of wound management" and "Overview of treatment of chronic wounds".)

GENERAL PRINCIPLES

Impaired wound healing — A wound is a disruption of the normal structure and function of the skin and underlying soft tissue [1]. Acute wounds in normal, healthy individuals heal through an orderly sequence of physiologic events. (See "Basic principles of wound healing".)

The overlapping intricacy of the wound healing pathway serves to prevent a single primary factor from disrupting the process. As examples, local tissue ischemia and neuropathy can impair chemotaxis during the hemostasis and inflammatory stages, tissue necrosis and infection alter the balance of inflammation and compete for oxygen, and uncontrolled periwound edema and wound instability disrupt myofibroblast activity, collagen deposition, and cross-linking. Impaired wound healing often occurs in the setting of multiple, smaller contributing issues to stall the healing process; however, infection or ischemia alone can substantially impair wound healing.

When the healing process is stalled, a chronic wound may develop, and this is more likely to occur in patients with underlying medical disorders. Chronic ulceration commonly affects the lower extremities with a prevalence that ranges between 0.18 and 1.3 percent in the adult population (figure 1) [2-5]. The most common nonhealing wounds affecting the lower extremities are associated with chronic venous insufficiency, peripheral artery disease, and diabetes mellitus [1,2,6-8].

Risk factors — Risk factors associated with impaired wound healing leading to wound healing complications or chronic nonhealing wounds are listed and discussed in more detail in the following sections [1,2,6,7]. The discussion of the more common factors assumes that nothing else is specifically contributing to acute local inflammation, such as a retained foreign body.

●Infection – (See 'Infection' below.)

●Smoking – (See 'Smoking and nicotine replacement therapy' below.)

●Aging – (See 'Aging' below.)

●Malnutrition – (See 'Malnutrition' below.)

●Immobilization – (See 'Immobilization' below.)

●Diabetes – (See 'Diabetes' below.)

●Vascular disease – (See 'Vascular disease' below.)

●Immunosuppressive therapy – (See 'Immunosuppressive therapy' below.)

●Others – (See 'Less common factors' below.)

INFECTION — The presence of infection impairs several steps of the wound healing process [9]. Bacteria produce inflammatory mediators that inhibit the inflammatory phase of wound healing and prevent epithelialization [10,11]. Infection also results in cellular death, which will increase the local inflammatory environment. New tissue growth also cannot occur in the presence of necrotic tissue. This might also result in a pathologic cycle as the presence of necrotic tissue additionally serves as a nidus for bacterial proliferation.

Surgical site infection — Surgical site infection (SSI) is defined by the United States Centers for Disease Control and Prevention as infection related to an operative procedure that occurs at or near the surgical incision within 30 days of the procedure or within 90 days if prosthetic material is implanted at surgery (table 1) [12]. SSIs are often superficial and localized to the incision site but can also extend into deeper adjacent structures. (See "Overview of the evaluation and management of surgical site infection" and "Complications of abdominal surgical incisions", section on 'Surgical site infection'.)

The degree of contamination of a surgical wound at the time of the operation is an important risk factor for infection. Wounds are classified as clean (uninfected), clean-contaminated (entry into the respiratory, alimentary, urinary or genital tracts), contaminated (traumatic wounds, break in sterile technique), or dirty/infected using the National Healthcare Safety Network (NHSN) wound class [13], which is based upon an adaptation of the American College of Surgeons surgical wound classification [13-15]. (See "Overview of the evaluation and management of surgical site infection", section on 'Surgical wound classification'.)

Cellulitis — Cellulitis is both a descriptive term used to describe a clinical finding and a pathophysiologic process accompanying infection. Cellulitis refers to a non-necrotizing inflammation of the skin and subcutaneous tissue. Infectious changes causing cellulitis typically involve direct inoculation through the skin. However, the source is frequently not obvious and may involve microscopic breaches in the integument. (See "Acute cellulitis and erysipelas in adults: Treatment".)

Burn wound infection — Thermal injury with tissue loss is often accompanied by concomitant immunosuppression, which can place the injured person at greater risk for infection [16]. (See "Burn wound infection and sepsis".)

SMOKING AND NICOTINE REPLACEMENT THERAPY — Smoking is associated with adverse outcomes following surgery, including surgical site infection and pulmonary complications [17]. Pulmonary complications and recommendations on smoking cessation and nicotine replacement therapy are discussed in detail elsewhere. (See "Strategies to reduce postoperative pulmonary complications in adults", section on 'Smoking cessation' and "Overview of smoking cessation management in adults".)

The constituents of tobacco smoke and mechanisms responsible for the vasoactive and other effects of smoking have not been fully elucidated; for many years nicotine was presumed to be responsible, but other constituents of tobacco smoke may have a greater impact. Tobacco smoke is a complex mixture of compounds (eg, nicotine, carbon monoxide, tar, hydrogen cyanide, nitrogen oxides, N-nitrosamines, formaldehyde, benzene), several of which have a physiologic impact [18-20]. The detrimental effect of smoking on wound healing is multifactorial, with mechanisms that include vasoconstriction causing a relative ischemia of operated tissues, a reduced inflammatory response, impaired bacteriocidal mechanisms, and alterations of collagen metabolism [18]. These are postulated to impair wound healing and cause wound dehiscence and incisional hernia. (See "Basic principles of wound healing", section on 'Wound healing'.)

Smoking is associated with postoperative wound healing complications, which occur more often in smokers compared with nonsmokers as well as in former smokers compared with those who never smoked. A systematic review identified four randomized trials that evaluated the impact of preoperative smoking cessation (four- to eight-week intervals of abstinence) on postoperative wound healing. Preoperative smoking cessation significantly reduced the incidence of surgical site infection (odds ratio [OR] 0.40, 95% CI 0.20-0.83), but did not impact the incidence of other postoperative wound complications (OR 0.48, 95% CI 0.19-1.25) [21]. In a separate study, current or past smoking was associated with an increased risk for postoperative infection (OR 1.9, CI 1.0-3.5) [22].

Although smoking-induced vasoconstriction, mediated by nicotine, can reduce blood flow by up to 40 percent, the effect appears to be temporary, with tissue blood flow and oxygen levels restored to normal levels within 45 minutes [23-26]. Most tissues with an adequate blood supply probably tolerate these transient alterations; however, tissue flaps, which have a fragile blood supply, and other ischemic tissues (eg, moderate-to-severe peripheral artery disease) might be vulnerable to smoking-induced reductions in blood flow. With respect to other effects of nicotine, both impaired and stimulated wound healing have been identified in experimental studies; however, no clinically significant detrimental or beneficial effects on wound healing have been demonstrated with the use of nicotine replacement therapies [27-34].

AGING — Skin is not excluded from the complex processes of aging. The supply of cutaneous nerves and blood vessels decreases with age, in addition to a general thinning of tissue, including the dermis and basement membrane. There is a progressive loss of collagen and diminished ability to produce more collagen. These physiologic changes associated with aging contribute to slowed or impaired wound healing in older adults [35,36].

In several studies, the extremes of age (infants and older individuals) were identified as a risk factor for surgical site infection (SSI) [37]. One cohort study of more than 144,000 adult surgical patients found that increasing age independently predicted an increased risk of SSI only until age 65 years (risk increasing 1.1 percent per year between 17 and 65 years) [38]. At age ≥65 years, increasing age independently predicted a decreased risk of SSI (risk decreased 1.2 percent for each additional year). However, the observed decreased risk of SSI in patients ≥65 years may reflect selection bias (frail older adult patients are more likely to forego surgery).

MALNUTRITION — Although there is insufficient evidence to definitively conclude that nutritional supplementation helps wound healing [39-41], adequate nutrition is important for the prevention of infection, which has deleterious effects on wound healing [42]. (See 'Infection' above and "Overview of perioperative nutrition support", section on 'Consequences of malnutrition in surgical patients' and "Overview of the evaluation and management of surgical site infection".)

Thus, we generally prefer to screen for malnourishment by obtaining preoperative serum prealbumin and albumin levels in potentially high-risk patients and monitoring them to optimize nutritional status. Prealbumin and albumin are not perfect markers of nutritional status; however, these should be obtained on patients with nonhealing wounds [43]. In addition, measures of frailty and functional status may be linearly related to malnutrition and might also be incorporated into an assessment [44,45].

IMMOBILIZATION — Patients undergoing periods of prolonged immobilization, particularly those with spinal cord disease, are at an increased risk for the development of chronic wounds. These are typically pressure wounds, similar in pathogenesis and appearance to neuropathic wounds occurring in areas of bony prominence such as the sacrum, knees, ankle malleoli, and heels. The sacrum may be particularly at risk when the presence of incontinence in spinal cord patients leads to a moist environment [46]. (See "Epidemiology, pathogenesis, and risk assessment of pressure-induced skin and soft tissue injury".)

Immobilization in the absence of pressure is probably not a risk factor for wound development or chronicity. In fact, complete immobilization with total contact casting is an effective treatment for plantar diabetic foot ulceration [47].

IMMUNOSUPPRESSIVE THERAPY — Any patient on immunosuppressive therapy is at an increased risk for delayed wound healing and the development of chronic wounds and wound infection, particularly in the clinical situations of organ transplantation and malignancy [48-51].

The inflammatory phase of wound healing may be blunted in patients on long-term immune suppression such as is used in treating transplant patients and HIV patients, among others.

Chemotherapy — The administration of chemotherapy may have a detrimental effect on wound healing, specifically through its direct or indirect effects on vascular endothelial growth factor (VEGF). VEGF is an important factor contributing to angiogenesis during the early stages of wound healing but may also be an important regulator in malignancy and thus is a target of cancer therapy [52]. (See "Non-cardiovascular toxicities of molecularly targeted antiangiogenic agents", section on 'Delayed wound healing' and "Non-cardiovascular toxicities of molecularly targeted antiangiogenic agents", section on 'Cutaneous toxicity'.)

Furthermore, neuropathy secondary to chemotherapy can produce loss of protective sensation and instability in a similar manner to diabetes.

Glucocorticoids — Glucocorticoids may not have the same degree of negative effect as other immunosuppressive therapies, and locally applied topical steroids are often used in the treatment of chronic wounds [53]. While some degree of anti-inflammation may prevent wounds from becoming arrested in the inflammatory stage, significant suppression of inflammation can prevent wounds from progressing into the next stages of wound healing. This is a subjective and currently unquantifiable inflammatory balance [54,55].

Several studies have demonstrated the potential beneficial effects of topical steroid application in the treatment of chronic wounds, particularly when an abnormal and uncontrolled inflammatory stage is suspected within the stages of wound healing.

Radiation — Radiation therapy has evolved as a powerful tool for tumor control as a sole therapy or administered adjunctively. More than 50 percent of cancer patients receive some form of radiation treatment, and, despite improvements in radiation technique, radiation-induced injury still contributes to poor wound healing.

The term "radiation injury" refers to the morphologic and functional changes that can occur in noncancerous tissue as a direct result of ionizing radiation and may include apoptosis (cell death) with low doses of radiation or outright tissue necrosis with higher doses of radiation. Irradiated skin in the chronic stage is thin, hypovascular, extremely painful, and easily injured by slight trauma or infection [56]. (See "Clinical manifestations, evaluation, and diagnosis of acute radiation exposure", section on 'Cutaneous'.)

Skin ulcers due to radiation injury are more commonly delayed in presentation and are due to ischemic tissue changes. Characteristic features of delayed radiation injury include telangiectasia and eccentric myointimal proliferation in the small arteries and arterioles. The proliferative changes may progress to obstruction, or the lumen may thrombose. These ulcers heal very slowly and may persist for several years.

Given the changes that are known to occur with respect to the perfusion of irradiated tissue and the phases of wound healing, surgical incisions in these locations are more likely to develop a wound complication. If an incision is planned in an area of radiation exposure, the optimal timing for surgery remains unclear. While some have recommended waiting three to six weeks after radiation therapy to perform an incision or conversely to delay radiation therapy three to four weeks after an incision, surgery in the immediate perioperative period has been reported [57,58]. It is likely that the dosing and duration of radiation therapy affects this decision making, preventing the ability to make generalized recommendations; each case needs to be individualized.

DIABETES — Numerous cytologic factors contribute to impaired wound healing in patients with diabetes [59]. These include decreased or impaired growth factor production, angiogenic response, macrophage function, collagen accumulation, epidermal barrier function, quantity of granulation tissue, keratinocyte and fibroblast migration and proliferation, number of epidermal nerves, bone healing, and abnormal balance between the accumulation of extracellular matrix components and their remodeling by matrix metalloproteinases.

Diabetes is a particularly important risk factor for the development of chronic wounds from neuropathy and vasculopathy, which increase the risk of infection and delay healing [8,60]. Diabetes is frequently associated with peripheral artery disease (PAD) with atherosclerosis developing at a younger age and affecting more distal arteries below the knee (eg, popliteal, tibial arteries). PAD in combination with diabetic neuropathy contributes to higher rates of nonhealing wounds and limb loss in diabetic patients compared with those without diabetes [61,62]. Up to one-third of people with diabetes in the United States will develop a foot ulcer [60,63,64]. Peripheral artery obstruction is present in approximately 20 percent of these patients and diabetic neuropathy in up to 50 percent of these patients [56,60].

Neuropathy alone can be responsible for the development of diabetic foot ulcers. Neuropathy associated with diabetes affects sensory, motor, and autonomic nerves. Sensory neuropathy diminishes the perception of pain that is protective when tissue injury has occurred [65]. Patients with diabetes may not be aware of the injury, particularly if the injured region cannot be seen or if the patient has a visual impairment. The motor nerves to the intrinsic muscles of the foot are affected in approximately 50 percent of patients with diabetes, resulting in claw deformities in the digits that transfer pressure to the plantar metatarsal heads. Increased local tissue pressure on the plantar surface or in other regions where bony deformities contact the shoe may lead to skin erosion and ulceration that may go unnoticed in patients with sensory deficits. In addition, autonomic neuropathy causes the skin to become dry and susceptible to skin fissures, tearing, and infection due to a loss of sweat and oil gland function. Loss of vascular tone may lead to foot edema [66].

VASCULAR DISEASE

Peripheral artery disease — Peripheral artery disease (PAD) with multilevel arterial obstruction decreases arterial blood flow, diminishes the delivery of oxygen and nutrients to the tissues, and impairs removal of metabolic waste products. Limb-threatening ischemia develops when blood flow is insufficient to meet the metabolic demands of tissue at rest and manifests clinically with extremity pain, nonhealing wounds (picture 1), or tissue loss [1,2].

There is no single cutoff or perfusion threshold for limb-threatening ischemia, as the condition is a spectrum. The presence of concomitant factors such as diabetes, renal failure, nutritional status, the complexity and extent of the wound, and recent or concomitant wound infection may require greater perfusion than expected to heal a given wound, particularly for foot wounds in patients with diabetes. For this reason, blood flow should be assessed in all such wounds and graded as part of a spectrum of ischemia that may require revascularization to expedite wound healing [8]. The ankle-brachial index is widely considered to be an appropriate baseline test for this assessment. (See "Clinical features and diagnosis of lower extremity peripheral artery disease" and "Upper extremity atherosclerotic disease".)

Chronic venous insufficiency — Venous leg ulcers account for approximately 40 percent of wounds of the lower extremity [59]. An understanding of the normal anatomy and physiology of the venous return to the heart is essential for understanding the defects present in patients with chronic venous disease and ulceration. (See "Pathophysiology of chronic venous disease".)

Faulty vein valves, venous obstruction, or failure of the "venous pump" leads to abnormally directed flow from the deep to superficial venous systems via the perforating veins. The most common site of incompetent perforators is 5 to 10 cm above the medial malleolus [63]. Congestion and pooling of blood in the superficial veins leads to venous hypertension, which, if sustained, is associated with histologic changes in the vein wall. (See "Pathophysiology of chronic venous disease", section on 'Histologic changes'.)

EDEMA — Peripheral edema can be caused by a variety of conditions, but regardless of the etiology, the accumulation of interstitial fluid reduces the integrity of the skin and subcutaneous tissue, making it prone to injury. The increased interstitial pressure also impairs the capillary diffusion and cellular function required as part of the normal tissue healing process, contributing to impaired healing when wounds do occur. (See "Pathophysiology and etiology of edema in adults".)

OBESITY — Obese individuals have a higher incidence of wound complications, including seroma, hematoma, wound infection, and wound dehiscence, as well as a higher incidence of pressure ulcers and venous ulcers.

The etiology of wound complications in obese individuals is multifactorial, involving both local and systemic factors. Locally, factors contributing to poor wound healing include relative hypovascularity of the subcutaneous adipose tissue, which may also reduce antibiotic delivery and increase wound tension. Poor skin perfusion also makes obese individuals susceptible to pressure injury, which can be aggravated by difficulties in repositioning and increased shear forces during movement.

LESS COMMON FACTORS — Other etiologies that can impair wound healing or lead to skin breakdown and chronic ulceration include conditions that cause vascular inflammation, obstruction, or thrombosis at the microvascular level. The final common pathway that produces ulceration or poor wound healing in these disorders is tissue ischemia. (See 'Impaired wound healing' above and "Approach to the differential diagnosis of leg ulcers".)

Sickle cell disease — Sickle cell disease represents a form of local tissue ischemia occurring at the specific location of the wound. It is also obstructive in nature, similar to peripheral artery disease, but is caused by dysmorphic red blood cells physically occluding small vessels, usually of the lower extremities. The location and appearance of sickle cell wounds may be similar to ischemic and venous ulcerations. A peripheral blood smear may be helpful in making the diagnosis. Treatment of these wounds is similar to the treatment of other chronic wounds, but sickle cell wounds are known to progress much more slowly through wound healing and carry an increased risk of reoccurrence [67]. (See "Overview of the clinical manifestations of sickle cell disease", section on 'Leg ulcers'.)

Others — Other conditions associated with impaired wound healing include cholesterol embolism, vasculitis, pyoderma gangrenosum, polyarteritis nodosum, scleroderma, cryoglobulinemia, granulomatosis with polyangiitis, thromboangiitis obliterans, warfarin-associated necrosis, heparin-induced thrombocytopenia, protein C deficiency, protein S deficiency, and antiphospholipid antibody syndrome. The cutaneous manifestations of these diseases can be found in separate topic reviews.

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: Chronic wound management".)

SUMMARY AND RECOMMENDATIONS

●Acute and chronic wounds – A wound is a disruption of the normal structure and function of the epidermis. Wounds may be caused by a variety of mechanisms, including acute injury (abrasion, puncture, crush), surgery, or other factors that cause breakdown of previously intact skin (eg, ischemia, pressure). There is no specific time frame that distinguishes between acute and chronic wounds. Impaired wound healing and the development of chronic wounds are associated with physiologic derangements that alter the normal wound healing process. (See 'General principles' above.)

●Risk factors for impaired wound healing – Many disease states alter the process of wound healing, the most common of which are diabetes, peripheral artery disease, and chronic venous disease. Small vessel arterial diseases are also associated with the development of skin ulcers and poor wound healing due to vascular obstruction or vascular thrombosis. Other factors that contribute to skin or surgical wound breakdown and nonhealing ulcers include smoking, aging, malnutrition, immobilization, and immunosuppressive therapies, including radiation therapy, edema, and obesity. (See 'Risk factors' above.)

●Surgical site infection – Among surgical patients, surgical site infections (SSIs) are the most common type of nosocomial infection and are associated with impaired wound healing and surgical site breakdown, leading to substantial morbidity and mortality. Other types of infections associated with open wounds (eg, cellulitis, burn wound infection) also impair the progress of wound healing. (See 'Infection' above and "Overview of the evaluation and management of surgical site infection".)