Foot complications are a major cause of morbidity and mortality in persons with diabetes and contribute to increased healthcare utilization and costs (1–3). In populations with diabetes, individuals with peripheral neuropathy and peripheral arterial disease (PAD) are predisposed to foot ulceration and infection, which ultimately may lead to lower-extremity amputation (4–6). Although amputation rates for people with diabetes have decreased in the past decade, they remain exceedingly high compared to nondiabetic populations (7,8). Therefore, it is essential that every effort possible be made to prevent foot problems, and, if they do occur, that early and aggressive treatment be undertaken.
Characteristics that have been shown to confer a risk of foot ulceration in persons with diabetes include peripheral neuropathy, previous ulceration or amputation, structural deformity, limited joint mobility, PAD, microvascular complications, high glycated hemoglobin (A1C) levels and onychomycosis (9–11). Loss of sensation over the distal plantar surface to the 10-g Semmes Weinstein monofilament is a significant and independent predictor of future foot ulceration and the possibility of lower-extremity amputation (12).
In those persons with diabetes with foot ulcers, a number of wound classification systems have been developed to provide objective assessment of severity. Of these, the University of Texas Diabetic Wound Classification System has been validated as a predictor of serious outcomes in patients with diabetes with foot ulcers ( Table 1 ) (13,14).
In persons with diabetes with underlying ischemia, the distribution of PAD is greater in the arterial tree below the knee than is seen in those without diabetes (15). Noninvasive assessments for PAD in diabetes include the use of the ankle-brachial blood pressure index (ABI), determination of systolic toe pressure by photoplethysmography (PPG) (PPG assesses the intensity of light reflected from the skin surface and the red cells below, which is indicative of arterial pulse flow in the arterioles of the respective area), transcutaneous oximetry (tcPO 2 ) and Doppler arterial flow studies (16,17). Although the ABI is a readily available and easy-to-perform technique, it may underestimate the degree of peripheral arterial obstruction in some individuals with diabetes partly due to medial arterial wall calcification in lower-extremity arteries (18). Measurement of systolic toe pressure by PPG may be more accurate in determining the presence of arterial disease in this population (19).
For those persons in whom lower-limb ischemia is suspected, intra-arterial digital subtraction contrast arteriography has provided the most definitive assessment of PAD but may precipitate renal failure in individuals with higher degrees of renal insufficiency. Advanced magnetic resonance angiography (MRA) and computed tomographic angiography (CTA) do not require arterial access and, therefore, have gained popularity as reliable alternatives to iodinated contrast studies due to their less invasive approaches (20–22). However, caution is still necessary with MRA and CTA in persons with renal dysfunction. The injection of intravenous radiocontrast dye also must be used in CTA; therefore, caution should be exercised (as with the use of intra-arterial iodinated contrast) in persons with renal insufficiency so as to avoid precipitating acute renal failure. Gadolinium-based contrast agents used in MRA have been associated with the development of nephrogenic systemic fibrosis in individuals with poor renal function (23,24).
University of Texas Diabetic Wound Classification System (13)
The foot examination should include the assessment of skin temperature since increased warmth is the first indicator of inflammation in an insensate foot and also may be the first sign of acute Charcot neuroarthropathy resulting from the loss of protective sensation in the foot (25–27). In addition, an acute Charcot foot may be associated with erythema and swelling, with overall clinical characteristics very similar to cellulitis (28,29). The clinical and radiological differentiation between an acute Charcot foot and a foot infection can be very challenging (30). Plain radiographs have low sensitivity and specificity in differentiating osteomyelitis from Charcot changes. Magnetic resonance imaging (MRI) of the foot may help clarify this differential diagnosis, although no single radiological investigation to date has proven to be completely definitive (31).
Management and Preventative Care
The prevention of amputations has involved the use of various preventative measures, including regular foot examination and evaluation of amputation risk, regular callus debridement, patient education, professionally fitted therapeutic footwear to reduce plantar pressure and accommodate foot deformities, and early detection and treatment of diabetic foot ulcers (32). Many of the studies conducted to assess interventions designed to reduce the occurrence of and heal diabetic foot ulcers have, unfortunately, suffered from methodological problems, thereby reducing the quality of the evidence to support their use (33,34).
Generally, the management of foot ulceration should address glycemic control, pressure relief/offloading, infection, lower-extremity vascular status and local wound care (35). This is best achieved with an interdisciplinary approach (36,37).
Specific recommendations about dressing types cannot be made as there is insufficient evidence to support the use of one variety versus another; however, the concepts that are generally accepted as the essentials of good wound care include the provision of an optimal wound environment, pressure offloading from the ulcer site and, in nonischemic wounds, regular debridement of nonviable tissue (38,39). In general, wound dressings that maintain a moist wound environment should be selected. There are insufficient data to support the use of specific dressing types or antimicrobial dressings in the routine management of diabetic foot wounds (40–48). There is also insufficient evidence to make any recommendation about the role of negative pressure wound therapy (NPWT) in the routine management of neuropathic wounds. There is, however, some evidence to support NPWT as a postoperative intervention after extensive debridement (49–52). Other adjunctive measures for wound healing, such as topical growth factors and dermal substitutes, have been studied in diabetic foot ulcer management, but these studies have been limited in sample size, duration and follow-up. These therapies may be considered if other conventional options already have been explored (53).
Pressure offloading may be achieved with temporary footwear until the ulcer heals and the character of the foot stabilizes. Removable and irremovable cast walkers and total contact casting have demonstrated efficacy as pressure-reducing devices in plantar surface ulcers (54–56). Although very effective in healing noninfected, nonischemic plantar surface neuropathic ulcers, total contact casting requires careful individual selection and personnel trained specifically in its application due to its potential for complications (57). Where bony foot deformities prevent the fitting of appropriate footwear and/or offloading of pressure-related ulcers, consultation with a surgeon skilled in foot surgery may be considered to address the deformity (58–60).
Treatment of the acute Charcot foot requires immobilization of the foot, typically for several months, in a total contact cast or removable walker device until excessive foot temperatures return to normal (61). Although bisphosphonate therapy has been considered for the management of Charcot arthropathy, further studies are necessary to fully evaluate the use of these agents and other medical therapies in the routine treatment of Charcot arthropathy (62–64).
Infection may complicate foot ulcers and may progress rapidly to become limb and/or life threatening (65). When infections first begin, the most frequently encountered pathogens include Staphylococcus aureus, Streptococcus pyogenes (group A streptococcus) and Streptococcus agalactiae (group B streptococcus). With time and the presence of devitalized tissue, gram-negative and anaerobic pathogens also can play a role in the process, leading to polymicrobial infections (66,67). Specimens for culture from the surface of wounds, as opposed to deeper tissues obtained by debridement, are unreliable in determining the bacterial pathogens involved (68–70). Initial antibiotic therapy is typically empiric and may be broad spectrum, with subsequent antibiotic selection tailored to the sensitivity results of cultured specimens. With the exception of only a small number of antimicrobial agents that do have a specific indication for the treatment of diabetic foot infections, the majority of the agents available for use are selected for their antibacterial spectrum (66,71). Table 2 summarizes the different antimicrobial choices for the empiric management of foot infections in persons with diabetes. Uncontrolled diabetes can result in immunopathy with a blunted cellular response to infection. Up to 50% of patients with diabetes who have a significant limb infection may not have systemic signs of fever or leukocytosis at presentation (72). Deep infections require prompt surgical debridement in addition to appropriate antibiotic therapy (73). Granulocyte colony-stimulating factors have been used as adjunctive therapy in infected diabetic wounds and, in some studies, were found to reduce the need for surgical intervention. Data are limited and caution is advised in interpreting these findings (74).
In medically suitable individuals with PAD, distal limb revascularization has potential benefit in long-term limb salvage. Certain subpopulations with diabetes on insulin therapy have poorer outcomes after revascularization than those on oral anithyperglycemic therapy, perhaps reflecting a greater association of comorbidities (75,76). Endovascular techniques with angioplasty and stenting in infrainguinal arteries are also effective in limb salvage, although the long-term results are inferior in the population with diabetes compared to those without diabetes (77,78).
Empiric antimicrobial therapy for infection in the diabetic foot
Hyperbaric oxygen therapy (HBOT) is not considered part of the routine management of persons with neuropathic/neuroischemic foot ulcerations with or without underlying infection. In carefully selected persons with nonhealing foot ulcerations for whom all possible interventions have been attempted, HBOT may be considered as an adjunctive therapy (79–81). Currently, evidence-based criteria for the selection of persons with diabetes who have foot problems and who may benefit from HBOT do not exist.