Diabetic Ulcers

Practice Essentials

Diabetic foot ulcers, as shown in the images below, occur as a result of various factors, such as mechanical changes in conformation of the bony architecture of the foot, peripheral neuropathy, and atherosclerotic peripheral arterial disease, all of which occur with higher frequency and intensity in the diabetic population.^{[1, 2]}

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Diabetic ulcer of the medial aspect of left first toe before and after appropriate wound care.

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Diabetic ulcer of left fourth toe associated with mild cellulitis.

Nonenzymatic glycation predisposes ligaments to stiffness. Neuropathy causes loss of protective sensation and loss of coordination of muscle groups in the foot and leg, both of which increase mechanical stresses during ambulation.

Diabetic foot lesions are responsible for more hospitalizations than any other complication of diabetes.^[3] Diabetes is the leading cause of nontraumatic lower extremity amputations in the United States, with approximately 5% of diabetics developing foot ulcers each year and 1% requiring amputation.

Physical examination of the extremity having a diabetic ulcer can be divided into examination of the ulcer and the general condition of the extremity, assessment of the possibility of vascular insufficiency,^[4] and assessment for the possibility of peripheral neuropathy.

The staging of diabetic foot wounds is based on the depth of soft tissue and osseous involvement.^{[5, 6, 7]} A complete blood cell count should be done, along with assessment of serum glucose, glycohemoglobin, and creatinine levels.

The management of diabetic foot ulcers requires offloading the wound by using appropriate therapeutic footwear,^{[8, 9]} daily saline or similar dressings to provide a moist wound environment,^[10] debridement when necessary, antibiotic therapy if osteomyelitis or cellulitis is present,^{[11, 12]} optimal control of blood glucose, and evaluation and correction of peripheral arterial insufficiency.

A vascular surgeon and/or podiatric surgeon should evaluate all patients with diabetic foot ulcers so as to determine the need for debridement, revisional surgery on bony architecture, vascular reconstruction, or soft tissue coverage.

The hemorrheologic agent cilostazol is contraindicated in patients with congestive heart failure. See Medication regarding the product's black box warning.

For more information, see Diabetes Mellitus, Type 1 and Diabetes Mellitus, Type 2.

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Pathophysiology

Atherosclerosis and peripheral neuropathy occur with increased frequency in persons with diabetes mellitus (DM).

Diabetes-related atherosclerosis

Overall, people with diabetes mellitus (DM) have a higher incidence of atherosclerosis, thickening of capillary basement membranes, arteriolar hyalinosis, and endothelial proliferation. Calcification and thickening of the arterial media (Mönckeberg sclerosis) are also noted with higher frequency in the diabetic population, although whether these factors have any impact on the circulatory status is unclear.

Diabetic persons, like people who are not diabetic, may develop atherosclerotic disease of large-sized and medium-sized arteries, such as aortoiliac and femoropopliteal atherosclerosis. However, significant atherosclerotic disease of the infrapopliteal segments is particularly common in the diabetic population. Underlying digital artery disease, when compounded by an infected ulcer in close proximity, may result in complete loss of digital collaterals and precipitate gangrene.

The reason for the prevalence of this form of arterial disease in diabetic persons is thought to result from a number of metabolic abnormalities, including high low-density lipoprotein (LDL) and very-low-density lipoprotein (VLDL) levels, elevated plasma von Willebrand factor, inhibition of prostacyclin synthesis, elevated plasma fibrinogen levels, and increased platelet adhesiveness.

Diabetic peripheral neuropathy

The pathophysiology of diabetic peripheral neuropathy is multifactorial and is thought to result from vascular disease occluding the vasa nervorum; endothelial dysfunction; deficiency of myoinositol-altering myelin synthesis and diminishing sodium-potassium adenine triphosphatase (ATPase) activity; chronic hyperosmolarity, causing edema of nerve trunks; and effects of increased sorbitol and fructose.^[13]

The result of loss of sensation in the foot is repetitive stress; unnoticed injuries and fractures; structural foot deformity, such as hammertoes, bunions, metatarsal deformities, or Charcot foot (see the image below); further stress; and eventual tissue breakdown. Unnoticed excessive heat or cold, pressure from a poorly fitting shoe, or damage from a blunt or sharp object inadvertently left in the shoe may cause blistering and ulceration. These factors, combined with poor arterial inflow, confer a high risk of limb loss on the patient with diabetes.

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Charcot deformity with mal perforans ulcer of plantar midfoot.

See Diabetic Neuropathy for more information.

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Etiology

The etiologies of diabetic ulceration include neuropathy,^[14] arterial disease,^[15] pressure,^[8] and foot deformity.^[16] Diabetic peripheral neuropathy, present in 60% of diabetic persons and 80% of diabetic persons with foot ulcers, confers the greatest risk of foot ulceration; microvascular disease and suboptimal glycemic control contribute.

A study by Naemi et al indicated that tissue mechanics may be associated with foot ulceration in patients with diabetic neuropathy, with an evaluation of 39 patients finding that the heel pad in nonulcerated feet tended to be stiffer than in ulcerated feet.^[17] . These results were further elucidated in another study by Naemi et al, which reported that the risk of diabetic foot ulcer is higher in diabetic neuropathy patients who have greater plantar soft tissue thickness and lower stiffness in the area of the first metatarsal head. The investigators found that adding the mechanical properties of plantar soft tissue (stiffness and thickness) to commonly evaluated clinical parameters improved specificity, sensitivity, prediction accuracy, and prognosis strength by 3%, 14%, 5%, and 1%, respectively.^[18]

The anatomy of the foot must be considered in risk calculation. A person with flatfoot is more likely to have disproportionate stress across the foot and may have an increased risk for tissue inflammation in high-stress regions.

Charcot foot

Sensory neuropathy involving the feet may lead to unrecognized episodes of trauma due to ill-fitting shoes. Motor neuropathy, causing intrinsic muscle weakness and splaying of the foot on weight bearing, compounds this trauma. The result is a convex foot with a rocker-bottom appearance. Multiple fractures are unnoticed until bone and joint deformities become marked. This is termed a Charcot foot (neuropathic osteoarthropathy) and most commonly is observed in diabetes mellitus, affecting about 2% of diabetic persons.

If a Charcot foot is neglected, ulceration may occur at pressure points, particularly the medial aspect of the navicular bone and the inferior aspect of the cuboid bone. Sinus tracts progress from the ulcerations into the deeper planes of the foot and into the bone. Charcot change can also affect the ankle, causing displacement of the ankle mortise and ulceration, which can lead to the need for amputation.

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Epidemiology

According to the National Institute of Diabetes and Digestive and Kidney Diseases, an estimated 16 million Americans are known to have diabetes, and millions more are considered to be at risk for developing the disease. Diabetic foot lesions are responsible for more hospitalizations than any other complication of diabetes.^[3] Among patients with diabetes, 15% develop a foot ulcer, and 12-24% of individuals with a foot ulcer require amputation. Indeed, diabetes is the leading cause of nontraumatic lower extremity amputations in the United States. In fact, every year approximately 5% of diabetics develop foot ulcers and 1% require amputation.

Age distribution for diabetic ulcers

Diabetes occurs in 3-6% of Americans. Of these, 10% have type 1 diabetes and are usually diagnosed when they are younger than 40 years. Among Medicare-aged adults, the prevalence of diabetes is about 10% (of these, 90% have type 2 diabetes). Diabetic neuropathy tends to occur about 10 years after the onset of diabetes, and, therefore, diabetic foot deformity and ulceration occur sometime thereafter.

Prevalence of diabetic ulcers by race

The issue of diabetic foot disease is of particular concern in the Latino communities of the Eastern United States, in African Americans,^[19] and in Native Americans, who tend to have the highest prevalence of diabetes in the world.

See Diabetic Foot Infections for more information.

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Prognosis

Mortality in people with diabetes and foot ulcers is often the result of associated large vessel arteriosclerotic disease involving the coronary or renal arteries.

In assessing the health-related quality of life (HRQOL) in adults with diabetic foot ulcers, a literature review by Khunkaew et al found that such patients scored poorly on four of eight scales on the 36-Item Short Form Health Survey (SF-36), specifically, physical functioning, role physical, general health, and vitality. Risk factors for a lower HRQOL included the existence of pain, a C-reactive protein level above 10 mg/L, an ulcer size of over 5 cm², an ankle-brachial index value of less than 0.9, a high glycosylated hemoglobin level, and a body mass index of over 25 kg/m².^[20]

Limb loss is a significant risk in patients with diabetic foot ulcers, particularly if treatment has been delayed.^[21] Diabetes is the predominant etiology for nontraumatic lower extremity amputations in the United States. Half of all nontraumatic amputations are a result of diabetic foot complications, and the 5-year risk of needing a contralateral amputation is 50%.^[22]

In diabetic people with neuropathy,^[23] even if successful management results in healing of the foot ulcer, the recurrence rate is 66% and the amputation rate rises to 12%.

A study by Chammas et al indicated that ischemic heart disease is the primary cause of premature death in patients with diabetic foot ulcer, finding it to be the major source of mortality on postmortem examination in 62.5% of 243 diabetic foot ulcer patients. The study also found that in patients with diabetic foot ulcer, the mean age of death from ischemic heart disease, as derived from postmortem examination, was 5 years below that of controls. Patients with neuropathic foot ulcers were determined to have the highest risk of premature death from ischemic heart disease.^[24]

A study by Chen et al indicated that following hospital treatment for diabetic foot ulcer, invasive systemic infection associated with the ulcer (DFU-ISI) is an important late complication that increases mortality risk. In the study’s patients, methicillin-resistant Staphylococcus aureus (MRSA) gave rise to 57% of the ISIs. Using Cox regression modeling, the investigators found that complicated ulcer healing and the presence of MRSA in the initial ulcer culture predicted the development of DFU-ISIs (hazard ratios of 3.812 and 2.030, respectively), with the hazard ratio for mortality risk in association with DFU-ISIs being 1.987.^[25]

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Patient Education

The risk of foot ulceration and limb amputation in people with diabetes is lessened by patient education stressing the importance of routine preventive podiatric care, appropriate shoes, avoidance of cigarette smoking, control of hyperlipidemia, and adequate glycemic control. For excellent patient education resources, visit eMedicineHealth’s Diabetes Center. Also, see eMedicineHealth’s patient education article Diabetic Foot Care.

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History

The history should focus on symptoms indicative of possible peripheral neuropathy or peripheral arterial insufficiency.

Symptoms of peripheral neuropathy

The symptoms of peripheral neuropathy include the following:

• Hypoesthesia
• Hyperesthesia
• Paresthesia
• Dysesthesia
• Radicular pain
• Anhydrosis

Symptoms of peripheral arterial insufficiency

Most people harboring atherosclerotic disease of the lower extremities are asymptomatic; others develop ischemic symptoms. Some patients attribute ambulatory difficulties to old age and are unaware of the existence of a potentially correctible problem.

Patients who are symptomatic may present with intermittent claudication, ischemic pain at rest, nonhealing ulceration of the foot, or frank ischemia of the foot.

Cramping or fatigue of major muscle groups in one or both lower extremities that is reproducible upon walking a specific distance suggests intermittent claudication. This symptom increases with ambulation until walking is no longer possible, and it is relieved by resting for several minutes. The onset of claudication may occur sooner with more rapid walking or walking uphill or up stairs.

The claudication of infrainguinal occlusive disease typically involves the calf muscles. Discomfort, cramping, or weakness in the calves or feet is particularly common in the diabetic population because they tend to have tibioperoneal atherosclerotic occlusions. Calf muscle atrophy may also occur. Symptoms that occur in the buttocks or thighs suggest aortoiliac occlusive disease.

Rest pain is less common in the diabetic population. In some cases, a fissure, ulcer, or other break in the integrity of the skin envelope is the first sign that loss of perfusion has occurred. When a diabetic patient presents with gangrene, it is often the result of infection.

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Physical Examination

Physical examination of the extremity having a diabetic ulcer can be divided into 3 broad categories:

• Examination of the ulcer and the general condition of the extremity
• Assessment of the possibility of vascular insufficiency^[4]
• Assessment for the possibility of peripheral neuropathy

Remember that diabetes is a systemic disease. Hence, a comprehensive physical examination of the entire patient is also vital.

Examination of extremity

Diabetic ulcers tend to occur in the following areas:

• Areas most subjected to weight bearing, such as the heel, plantar metatarsal head areas, the tips of the most prominent toes (usually the first or second), and the tips of hammer toes (ulcers also occur over the malleoli because these areas commonly are subjected to trauma)
• Areas most subjected to stress, such as the dorsal portion of hammer toes

Other physical findings include the following:

• Hypertrophic calluses
• Brittle nails
• Hammer toes
• Fissures

Assessment of possible peripheral arterial insufficiency

Physical examination discloses absent or diminished peripheral pulses below a certain level.

Although diminished common femoral artery pulsation is characteristic of aortoiliac disease, infrainguinal disease alone is characterized by normal femoral pulses at the level of the inguinal ligament and diminished or absent pulses distally. Specifically, loss of the femoral pulse just below the inguinal ligament occurs with a proximal superficial femoral artery occlusion. Loss of the popliteal artery pulse suggests superficial femoral artery occlusion, typically in the adductor canal.

Loss of pedal pulses is characteristic of disease of the distal popliteal artery or its trifurcation. However, be aware that absence of the dorsalis pedis pulse may be a normal anatomic variant that is noted in about 10% of the pediatric population. On the other hand, the posterior tibial pulse is present in 99.8% of persons aged 0-19 years. Hence, absence of both pedal pulses is a more specific indicator of peripheral arterial disease.

Other findings suggestive of atherosclerotic disease include a bruit heard overlying the iliac or femoral arteries, skin atrophy, loss of pedal hair growth, cyanosis of the toes, ulceration or ischemic necrosis, and pallor of the involved foot followed by dependent rubor after 1-2 minutes of elevation above heart level.

Assessment of possible peripheral neuropathy

Signs of peripheral neuropathy include loss of vibratory and position sense, loss of deep tendon reflexes (especially loss of the ankle jerk), trophic ulceration, foot drop, muscle atrophy, and excessive callous formation, especially overlying pressure points such as the heel.

The nylon monofilament test helps diagnose the presence of sensory neuropathy.^[26] A 10-gauge monofilament nylon is pressed against each specific site of the foot just enough to bend the wire. If the patient does not feel the wire at 4 or more of these 10 sites, the test is positive for neuropathy. General use filaments can be obtained from the National Institute of Diabetes and Digestive and Kidney Diseases, or the clinician can use professional Semmes-Weinstein filaments.

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Approach Considerations

Patient workup for diabetic ulcers includes blood tests, pulse-volume recording, ultrasonography, ankle-brachial index, radiography, computed tomography, magnetic resonance imaging, bone scans, and angiography.

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Blood Tests

A complete blood count should be done. Leukocytosis may signal plantar abscess or other associated infection. Wound healing is impaired by anemia. In the face of underlying arterial insufficiency, anemia may precipitate rest pain.^[27]

Assessment of serum glucose, glycohemoglobin, and creatinine levels helps to determine the adequacy of acute and chronic glycemic control and the status of renal function.

Blood testing should also include hemoglobin A1c (HbA1c) assessment because a normal value is a surrogate marker for wound healing.^[28]

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Pulse-Volume Recording

Pulse-volume recording (PVR), or plethysmography, uses pneumatic cuffs encircling the thighs, calves, ankles, feet, and, occasionally, toes to sense segmental volume changes with each pulse beat. The resulting tracings provide useful information about the hemodynamic effects of the arterial disease at each level. In severe disease, tracings at the transmetatarsal level may become nearly flat. In mild disease, particularly involving the aortoiliac segment, PVR tracings may appear normal at rest and become abnormal only after the patient walks until symptoms occur.

PVR is noninvasive and rapid and, therefore, may be repeated frequently to help assess the overall hemodynamic response to medical or surgical treatment. Ordinarily, if pedal pulses are satisfactory, arterial evaluation PVR provides no useful information.

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Ultrasonography

Duplex ultrasonography can provide images of arterial segments that help localize the extent of disease, and simultaneous Doppler measurement of flow velocity can help estimate the degree of stenosis. Duplex scanning is quite useful in visualizing aneurysms, particularly of the aorta or popliteal segments. Use of this technique probably is best left to the discretion of the vascular specialist.

A handheld Doppler scanner may be used to assess arterial signals, to localize arteries to facilitate palpation of pulses, or to determine the loss of Doppler signal as a proximal blood pressure cuff is inflated (as in measurement of systolic pressure in extremity arteries).

Laser Doppler studies also have been used but may not be reliable.

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Ankle-Brachial Index

The systolic pressure in the dorsalis pedis or posterior artery divided by the upper extremity systolic pressure is called the ankle-brachial index (ABI) and is an indication of severity of arterial compromise. Normal ABI averages 1.0. An ABI less than 0.9 suggests atherosclerotic disease, with a sensitivity of approximately 95%. In general, an ABI below 0.3 suggests a poor chance for healing of distal ischemic ulcerations. Unfortunately, the ABI often is falsely elevated (and thus may be unreliable) if the underlying arteries are heavily calcified, a finding common in diabetic persons.

See recommendations for the workup of patients with atherosclerotic disease of the extremities in the Medscape Reference article Infrainguinal Occlusive Disease.

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Plain Radiography

Plain radiographic studies of the diabetic foot may demonstrate demineralization and Charcot joint and occasionally may suggest the presence of osteomyelitis. Plain radiographs are not routinely obtained in the workup of peripheral arterial occlusive disease. This is because arterial calcification seen on plain radiographs is not a specific indicator of severe atherosclerotic disease. Calcification of the arterial media is not diagnostic of atherosclerosis, and even calcification of the arterial intima, which is diagnostic of atherosclerotic disease, does not necessarily imply hemodynamically significant stenosis.

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Computed Tomography and Magnetic Resonance Imaging

Although an experienced clinician usually can diagnose a plantar abscess by physical examination alone, computed tomography (CT) scanning or magnetic resonance imaging (MRI) is indicated if a plantar abscess is suspected but not clear on physical examination.

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Bone Scans

Bone scans are of questionable use because of a sizable percentage of false-positive and false-negative results. A recent study suggests Technetium-99m-labeled ciprofloxacin is a somewhat useful marker for osteomyelitis.^[29]

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Conventional Angiography

If vascular or endovascular surgical treatment is contemplated, angiography is needed to delineate the extent and significance of atherosclerotic disease. Major risks associated with conventional contrast-injection angiography are related to the puncture and to the use of contrast agents. See also Infrainguinal Occlusive Disease.

Technique

Typically, a catheter is inserted retrograde via a femoral puncture, and contrast is power-injected into the infrarenal aorta. Films are taken as the contrast is followed down to both feet. In certain cases, as with aortic occlusion, a femoral approach to the aorta may not be possible. In this case, the interventionalist (interventional cardiologist, vascular surgeon, or interventional radiologist) may use an alternative entry point, such as via the brachial or axillary artery. The arterial catheter is usually passed through a 5F sheath that is 1.6 mm in diameter. This is a sizable hole in the femoral artery, which may be only 6-10 mm in diameter. After the catheter is removed, gentle pressure must be applied to the puncture site for approximately 30 minutes. In most cases, the physician performing the angiogram may elect to use a small device to aid in closing the puncture site (“closure device”). Successful deployment of these devices eliminates the need for prolonged pressure application.

Puncture-related complications

Risks associated with catheter insertion include hemorrhage, pseudoaneurysm formation, and clotting or dislodgement of an intimal flap, which may acutely occlude the artery at or near the entry site. Use of percutaneous closure devices on the puncture sites has significantly reduced site complication rates.

Contrast-related risks

Angiographic contrast material is nephrotoxic. The risk of precipitating acute renal failure is highest in patients with underlying renal insufficiency and those with diabetes. Patients with both of these risk factors have a 30% rate of acute renal failure following contrast angiography. Hence, an acceptable serum creatinine level must be confirmed prior to elective angiography. Avoid contrast angiography (if possible) for patients with any significant degree of renal impairment. If contrast angiography is absolutely required despite renal impairment, use a minimal volume of contrast material. In addition, providing adequate hydration prior to, during, and after the procedure is essential. Oral administration of the antioxidant acetylcysteine (Mucomyst) the night prior to and then just before angiography may be protective of renal function for patients at risk of contrast-induced nephropathy.^[11]

Metformin warning

To prevent the possibility of fatal lactic acidosis, patients with diabetes who are taking metformin (Glucophage) must not take this medication immediately following contrast angiography. Patients may resume taking the medication when normal renal function is confirmed 1-2 days after contrast exposure.

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Alternatives to Conventional Angiography

Magnetic resonance angiography

Magnetic resonance angiography (MRA) is an alternative for patients who are allergic to iodinated contrast material. MRA is not innocuous. Gadolinium chelates, the contrast agents used in MRA, have been linked recently to 3 potentially serious side effects in patients with renal insufficiency: acute renal injury, pseudohypocalcemia, and nephrogenic systemic fibrosis. MRA is contraindicated in patients with implanted hardware such as a hip prostheses or pacemakers.

The resolution provided by MRA may be inadequate for the vascular surgeon in planning reconstructive procedures, particularly in the smaller infrapopliteal arteries, although MRA technology and contrast agents continue to improve.^[12]

Multidetector CT angiography

Multidetector CT (MDCT) angiography avoids arterial puncture. By using precisely timed intravenous contrast injection, multidetector (16 or 64 channel) CT scanners can generate angiographic images of excellent resolution and at a relatively high acquisition speed. MDCT angiography carries the contrast-related risks described above.^[30]

Carbon dioxide angiography

Carbon dioxide angiography is an alternative for patients with renal insufficiency; however, it is not widely available and requires some iodinated contrast material in addition to the carbon dioxide gas in order to provide useful images.

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Transcutaneous Tissue Oxygen Studies

Transcutaneous tissue oxygen studies are reserved for borderline situations in which the advisability of arterial bypass surgery may be unclear.

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Staging

Stage diabetic foot wounds based on the depth of soft tissue and osseous involvement.^{[5, 6, 7]} Any ulcer that seems to track into or is deep to the subcutaneous tissues should be probed gently, and if bone is encountered, osteomyelitis is likely.

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Laboratory Studies

A multicenter, prospective, cross-sectional study by Nelson et al indicated that the use of tissue samples is superior to that of wound swabs in identifying pathogens in infected diabetic foot ulcers. The investigators found that pathogens were more often identified, and nonpathogens less often identified, using tissue samples than wound swabs, with antibiotic regimen changes more frequently recommended by blinded clinicians in response to the results of tissue samples than to those of swabs.^[31]

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Approach Considerations

The management of diabetic foot ulcers requires offloading the wound by using appropriate therapeutic footwear,^{[8, 9]} daily saline or similar dressings to provide a moist wound environment,^[10] debridement when necessary, antibiotic therapy if osteomyelitis or cellulitis is present,^{[11, 12]} optimal control of blood glucose, and evaluation and correction of peripheral arterial insufficiency.^[32]

Wound coverage by cultured human cells^{[30, 33]} or heterogeneic dressings/grafts, application of recombinant growth factors,^{[34, 35, 36, 37]} and hyperbaric oxygen treatments also may be beneficial at times, but only if arterial insufficiency is not present.

Physicians of diabetic patients with ulcers must decide between the sometimes conflicting options of (1) performing invasive procedures (eg, angiography, bypass surgery) for limb salvage and (2) avoiding the risks of unnecessarily aggressive management in these patients, who may have significant cardiac risk. In general, the greatest legal risks are associated with delay in diagnosis of ischemia associated with diabetic ulceration, failure to aggressively debride and treat infection, and failure to treat the wound carefully.

If a patient presents with a new diabetic foot ulcer, he or she should receive care from physicians, surgeons, podiatrists, and pedorthotists who have an active interest in this complex problem.

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Management of Systemic and Local Factors

Treatment of diabetic foot ulcers requires management of a number of systemic and local factors.^{[38, 39, 40, 41]}

Precise diabetic control is, of course, vital, not only in achieving resolution of the current wound, but also in minimizing the risk of recurrence. Management of contributing systemic factors, such as hypertension, hyperlipidemia, atherosclerotic heart disease, obesity, or renal insufficiency, is crucial.^{[42, 43]} Management of arterial insufficiency, treatment of infection with appropriate antibiotics, offloading the area of the ulcer, and wound care are also essential.

For more information, see Diabetes Mellitus, Type 1 and Diabetes Mellitus, Type 2.

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Wound and Foot Care

The basic principle of topical wound management is to provide a moist, but not wet, wound bed.^{[10, 44]}

For more information, see Diabetic Foot Infections.

Wound coverage

After debridement, apply a moist sodium chloride dressing or isotonic sodium chloride gel (eg, Normlgel, IntraSite gel) or a hydroactive paste (eg, Duoderm). Optimal wound coverage requires wet-to-damp dressings, which support autolytic debridement, absorb exudate, and protect surrounding healthy skin. A polyvinyl film dressing (eg, OpSite, Tegaderm) that is semipermeable to oxygen and moisture and impermeable to bacteria is a good choice for wounds that are neither very dry nor highly exudative. Wound coverage recommendations for some other wound conditions are as follows (see the Table, below)^[45] :

• Dry wounds: Hydrocolloid dressings, such as DuoDERM or IntraSite Hydrocolloid, are impermeable to oxygen, moisture, and bacteria; maintain a moist environment; and support autolytic debridement. They are a good choice for relatively desiccated wounds.
• Exudative wounds: Absorptive dressings, such as calcium alginates (eg, Kaltostat, Curasorb), are highly absorptive and are appropriate for exudative wounds. Alginates are available in a rope form, which is useful for packing deep wounds.
• Very exudative wounds: Impregnated gauze dressings (eg, Mesalt) or hydrofiber dressings (eg, Aquacel, Aquacel-Ag) are useful for extremely exudative wounds. In these cases, twice-daily dressing changes may be needed.
• Infected wounds: For infected superficial wounds, use Silvadene (silver sulfadiazine) if the patient is not allergic to sulfa drugs; if a sulfa allergy exists, either bacitracin-zinc or Neosporin ointment is a good alternative. Where heavy bacterial contamination of deeper wounds exists, irrigation using one-fourth strength Dakin solution and 0.25% acetic acid may be useful for a brief period of time; a hydrofiber-silver dressing (Aquacel-Ag) can help control wounds that are both exudative and potentially colonized.
• Wounds covered by dry eschar: In this case, simply protecting the wound until the eschar dries and separates may be the best management. Occasionally, painting the eschar with povidone iodine (Betadine) is beneficial to maintain sterility while eschar separation occurs; an uninfected dry heel ulcer in a well-perfused foot is perhaps best managed in this fashion.
• Areas that are difficult to bandage: Bandaging a challenging anatomical area, such as around a heel ulcer, requires a highly conformable dressing, such as an extra thin hydrocolloid; securing a dressing in a highly moist challenging site, such as around a sacrococcygeal ulcer, requires a conformable and highly adherent dressing, such as a wafer hydrocolloid.
• Fragile periwound skin: Hydrogel sheets and nonadhesive forms are useful for securing a wound dressing when the surrounding skin is fragile.

Other topical preparations that occasionally may be useful in the management of diabetic foot ulcers are as follows:

• Platelet-derived growth factors (PDGF): Topically applied PDGF has a modestly beneficial effect in promoting wound healing. Becaplermin gel 0.01% (Regranex), a recombinant human PDGF that is produced through genetic engineering is approved by the US Food and Drug Administration (FDA) to promote healing of diabetic foot ulcers.^[35] Regranex is meant for a healthy, granulating wound, not one with a necrotic wound base, and is contraindicated with known skin cancers at the site of application.
• Enzymatic debridement: Collagen comprises a significant fraction of the necrotic soft tissues in chronic wounds; the enzyme collagenase, derived from fermentation of Clostridium histolyticum, helps remove nonviable tissue from the surface of wounds. However, it is not a substitute for an initial surgical excision of a grossly necrotic wound.
• Miscellaneous topical agents: Various other topical agents that have been used for wound management include sugar, antacids, and vitamin A and D ointment.

Cytotoxic agents, such as hydrogen peroxide, povidone iodine, acetic acid, and Dakin solution (sodium hypochlorite), should be avoided, except as noted above under infected wounds.

Table. Characteristics and Uses of Wound Dressing Materials

View Table

See Table

For more information, see Diabetic Foot Infections.

Vacuum-assisted closure

Clean but nonhealing deep cavity wounds may respond to repeated treatments by application of negative pressure under an occlusive wound dressing (vacuum-assisted closure [VAC]).^[46]

Hydrotherapy

Intractable, infected, cavity wounds sometimes improve with hydrotherapy using saline pulse lavage under pressure (PulsEvac).

Extracorporeal shock-wave therapy

Two multicenter, randomized, sham-controlled, double-blinded, phase III clinical trials by Snyder et al indicated that extracorporeal shock-wave therapy (ESWT) can effectively treat neuropathic diabetic foot ulcers that fail to heal with standard therapy alone. At 24 weeks, in patients with diabetic foot ulcers that had not been reduced by 50% or greater over the course of 2 weeks’ standard treatment, complete healing occurred in 37.8% of patients treated with ESWT and standard care, compared with 26.2% of patients treated with sham therapy and standard care.^[47]

Treatment of Charcot foot

Charcot foot is treated initially with immobilization using special shoes or braces but eventually may require podiatric surgery such as ostectomy and arthrodesis.

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Surgical Care

All patients harboring diabetic foot ulcers should be evaluated by a qualified vascular surgeon and/or podiatric surgeon who will consider debridement, revisional surgery on bony architecture, vascular reconstruction, and options for soft tissue coverage.

For more information, see Perioperative Management of the Diabetic Patient.

Debridement

Surgical management is indicated for debridement of nonviable and infected tissue from the ulceration, removal of excess callus, curettage of underlying osteomyelitic bone, skin grafting, and revascularization. The wound usually requires an initial surgical debridement and probing to determine the depth and involvement of bone or joint structures. Visible or palpable bone implies an 85% chance of osteomyelitis.

Revisional surgery

Revisional surgery for bony architecture may be required to remove pressure points.^[48] Such intervention includes resection of metatarsal heads or ostectomy.^[49]

Vascular reconstruction

In general, the indications for vascular surgery in the presence of a reconstructible arterial lesion include intractable pain at rest or at night, intractable foot ulcers, and impending or existing gangrene.^{[15, 50, 51]} Intermittent claudication alone is only infrequently disabling and intractable enough to warrant bypass surgery. Physicians must specifically ask for symptoms suggestive of intermittent claudication, such as pain in the buttocks and thighs while walking and abatement of pain when at rest.

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Options for Soft Tissue Coverage of the Clean but Nonhealing Wound

Once a wound has reached a steady clean state, a decision has to be made about allowing healing by natural processes or expediting healing by a surgical procedure. Clinical experience and observation of the healing progress in each case dictate the appropriate management. Surgical options include skin grafting, application of bioengineered skin substitutes, and flap closures.^[52]

Skin grafts

The autologous skin graft is the criterion standard for viable coverage of the partial thickness wound. The graft can be harvested under local anesthesia as an outpatient procedure. Meshing the graft allows wider coverage and promotes drainage of serum and blood.

A cadaveric skin allograft is a useful covering for relatively deep wounds following surgical excision when the wound bed does not appear appropriate for application of an autologous skin graft. The allograft is, of course, only a temporary solution.

Tissue-cultured skin substitutes

Dermagraft (Smith & Nephew) is a cryopreserved human fibroblast–derived dermal substitute produced by seeding neonatal foreskin fibroblasts onto a bioabsorbable polyglactin mesh scaffold. Dermagraft is useful for managing full-thickness chronic diabetic foot ulcers. It is not appropriate for infected ulcers, those that involve bone or tendon, or those that have sinus tracts.

A multicenter study of 314 patients demonstrated significantly better 12-week healing rates with Dermagraft (30%) versus controls (17%). Allergic reactions to its bovine protein component have been reported.

Apligraf (Organogenesis) is a living, bilayered human skin substitute.^{[53, 33]} It is not appropriate for infected ulcers, those that involve tendon or bone, or those that have sinus tracts. Allergic reactions to the agarose shipping medium or its bovine collagen component have been reported.

A prospective observational study by Hwang et al indicated that treatment with allogeneic keratinocyte dressings is effective in patients with chronic, intractable diabetic foot ulcers. Of the 71 patients in the study, all of whom underwent weekly keratinocyte therapy, 56 (78.9%) experienced complete wound healing, including 46 (64.8%) in whom complete healing occurred within an average of 6.1 weeks.^[54]

The use of bioengineered skin substitutes has been questioned because the mechanism of action is not clear, the efficacy is questionable, and the cost is high.

Xenograft

Oasis (Healthpoint, Ltd) is a xenogeneic, acellular collagen matrix derived from porcine small intestinal submucosa in a way that allows an extracellular matrix and natural growth factors to remain intact. This provides a scaffold for inducing wound healing. Do not use this for patients with allergies to porcine materials.

Surgical wound closure

Delayed primary closure of a chronic wound requires well-vascularized clean tissues and tension-free apposition; it usually requires undermining and mobilization of adjacent tissue planes by creation of skin flaps or myocutaneous flaps.^[55]

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Hyperbaric Oxygen Treatment

Hyperbaric oxygen therapy is used rarely and is certainly not a substitute for revascularization.^[56] In the presence of an intractable wound and associated noncorrectible ischemic arterial disease, hyperbaric oxygen therapy may be beneficial (in selected cases).^[57] Löndahl et al found that 40 hyperbaric oxygen treatments (85 min daily, 5 d/wk for 8 wk) resulted in complete healing of chronic diabetic foot ulcers in 52% of patients in the treatment group. Among patients in the placebo group, 29% had complete healing at 1-year follow-up.^[58] Although data are equivocal on the impact of hyperbaric oxygen therapy in ischemic and pressure ulcers, positive benefits have been documented in diabetic chronic foot ulcers.^{[59, 60]}

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Dietary Chages

The recommended diet is diabetic and low in saturated fat.

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Restriction of Activity

Offloading of the ulcerated area is imperative. This may require bed rest acutely. Custom footwear or custom clamshell orthosis (for severe deformities) or total contact casting (a fiberglass shell with a walking bar on the bottom) are required for patients who are ambulatory.

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Measures for Prevention of Diabetic Ulcers

The risk of ulceration and limb amputation in people with diabetes can be improved by routine preventive podiatric care, appropriate shoes, and patient education.^[61] Diabetic clinics should screen all patients for altered sensation and peripheral vascular disease.^[37] Of diabetic foot ulcers, 85% are estimated to be preventable with appropriate preventive medicine, including the following:

• Daily foot inspection
• Gentle soap and water cleansing
• Application of skin moisturizer
• Inspection of the shoes to ensure good support and fit: Medicare covers custom shoes with appropriate physician documentation confirming that the patient is at risk for ulceration.
• Minor wounds require prompt medical evaluation and treatment.
• Prophylactic podiatric surgery to correct high-risk foot deformities may be indicated.
• Avoid hot soaks, heating pads, and irritating topical agents.

A literature review by Matos et al suggested that exercise and physical activity are effective against the complications of diabetic foot. The investigators found that patients involved in physical activity and exercise had a lower annual incidence of ulcers than other patients in the study (0.02 vs 0.12, respectively). Moreover, nerve velocity conduction, peripheral sensory function, and foot peak pressure distribution significantly improved in the physical activity/exercise group.^[62]

Glycemic control

The Diabetes Control and Complications Trial, performed by the Diabetes Control and Complications Trial ResearchGroup,studiedthe effect of intensive treatment of diabetes on the development and progression of long-term complications in insulin-dependent diabetes mellitus (1993).^[63] This trial found that uncontrolled hyperglycemia correlates with the onset of diabetic microvascular complications and that good glycemic control can reduce or even prevent the complications of diabetes, including nephropathy, neuropathy, and retinopathy.

Cigarette smoking should be stopped, and hypertension and hyperlipidemia should be controlled.

To see complete information on the conditions below, please go to the main article by clicking on the title:

• Diabetic Neuropathy
• Diabetic Nephropathy
• Diabetic Retinopathy

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Consultations

Any of the following evaluations may prove productive:

• Endocrinologist
• Cardiologist
• Nephrologist
• Infectious diseases specialist
• Vascular surgeon
• Podiatrist
• Orthopedic specialist
• Plastic surgeon
• Wound care specialist
• Nutritionist

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Long-Term Monitoring

For the most part, diabetic ulcers are managed in the outpatient setting, with brief hospital stays often occurring for initial evaluation and debridement, subsequent vascular procedures, and, possibly, flap or skin graft wound management.

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Medication Summary

Many medications may have a role in the treatment of diabetes, the complications of diabetes, and the etiologies of diabetic ulcer. For example, hemorheologic agents and antiplatelet agents are sometimes used in the management of underlying atherosclerotic disease. The role of aspirin, however, remains unclear.

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Pentoxifylline (Trental)

• Dosing, Interactions, etc.

Clinical Context:  Pentoxifylline is indicated to treat intermittent claudication. It may alter rheology of red blood cells, which in turn reduces blood viscosity. Two to eight weeks of therapy may be required before symptomatic improvement occurs, and only about 60% of patients respond to this drug.

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Cilostazol (Pletal)

• Dosing, Interactions, etc.

Clinical Context:  Cilostazol is indicated to reduce symptoms of intermittent claudication, as indicated by an increased walking distance. It affects vascular beds and cardiovascular function and produces nonhomogeneous dilation of vascular beds, with greater dilation in femoral beds than in vertebral, carotid, or superior mesenteric arteries. Renal arteries were not found to be responsive to its effects. The mechanism of cilostazol involves inhibition of PDE, especially PDE III, and reversible inhibition of platelet aggregation. Patients may respond as early as 2-4 weeks after initiation of therapy, but treatment for as many as 12 weeks may be needed before a beneficial effect is experienced.

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Class Summary

Hemorrheologic agents such as pentoxifylline (Trental) improve intermittent claudication in approximately 60% of patients after 3 months. Cilostazol (Pletal) is an alternative hemorrheologic agent for patients who cannot tolerate pentoxifylline.^[64] Cilostazol is contraindicated in patients with congestive heart failure. However, there is no conclusive evidence of any direct beneficial effect of either pentoxifylline or cilostazol on the healing of diabetic foot ulcers.

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Clopidogrel (Plavix)

• Dosing, Interactions, etc.

Clinical Context:  Clopidogrel selectively inhibits ADP binding to platelet receptor and subsequent ADP-mediated activation of glycoprotein GPIIb/IIIa complex, thereby inhibiting platelet aggregation. It is indicated as antiplatelet therapy in some patients with atherosclerotic disease.

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Aspirin (Bayer, Anacin, Empirin)

• Dosing, Interactions, etc.

Clinical Context:  Aspirin inhibits prostaglandin synthesis, preventing formation of platelet-aggregating thromboxane A2. It may be used in low dose to inhibit platelet aggregation and to improve complications of venous stases and thrombosis. The recommended dose varies with indication, and, often, the literature is unclear on the optimal dosing.

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Class Summary

Antiplatelet therapy with aspirin or clopidogrel (Plavix) may be warranted in some cases for the prevention of the complications of atherosclerosis, although neither has a direct benefit in healing diabetic foot ulcers. Antiplatelet agents inhibit platelet function by blocking cyclooxygenase and subsequent platelet aggregation.

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Becaplermin (Regranex)

• Dosing, Interactions, etc.

Clinical Context:  Becaplermin gel 0.01% (Regranex), a recombinant human PDGF that is produced through genetic engineering, is approved by the US Food and Drug Administration (FDA) to promote healing of diabetic foot ulcers.^[25] Regranex is meant for a healthy, granulating wound, not one with a necrotic wound base, and it is contraindicated with known skin cancers at the site of application.

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Class Summary

Topically applied platelet-derived growth factors (PDGF) such as becaplermin gel (Regranex) have a modestly beneficial effect in promoting wound healing.

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