Diabetic Foot Ulcers

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

Trophic changes

Non-enzymatic glycosylation of skin and connective tissue, along with decreased collagen production in people with diabetes, result in alterations in the biomechanics in the diabetic foot. This is frequently seen in the Achilles tendon, where increased stiffness results in a contracture that limits ankle dorsiflexion, a condition known as equinus. Equinus has been associated with diabetic foot ulcers, as it increases plantar pressures in the forefoot and midfoot.

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.[12]

Motor dysfunction of peripheral nerves in diabetic neuropathy leads to muscular imbalances in the diabetic foot. Muscle wasting of the intrinsic pedal muscles leads to overpowering of the spared extrinsic muscles, which results in significant forefoot deformities such as claw toes or hammer toes.[13, 14] Autonomic dysfunction of the peripheral nervous system may lead to sudomotor dysfunction. This will result in dry, cracked skin, which is more prone to injury and breakdown.[15]

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.

Charcot deformity with mal perforans ulcer of plantar midfoot.

See Diabetic Neuropathy for more information.

The etiologies of diabetic ulceration include neuropathy,[16] arterial disease,[17] pressure,[6] and foot deformity.[18] 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.[19] . 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.[20]

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.

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, there is a 25% likelihood that they will develop a foot ulcer.[21] Nearly half of them will become infected, and about 20% of those with moderate to severe infection will require some degree of amputation.[22, 23] Indeed, diabetes is the leading cause of nontraumatic lower extremity amputations, as it accounts for 85% of these procedures.[21]

Mortality

People with diabetes who have ulcerations are at 2.5 times higher risk of death at 5 years, versus those without ulcerations.[24] While patients who have had a diabetes-related amputation have a 70% risk of mortality at 5 years, those on dialysis have an even greater risk, at 74%.[25]

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,[26] and in Native Americans, who tend to have the highest prevalence of diabetes in the world.

See Diabetic Foot Infections for more information.

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.[27]

Limb loss is a significant risk in patients with diabetic foot ulcers, particularly if treatment has been delayed.[28] 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%.[29]

In diabetic people with neuropathy,[30] 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.[31]

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.[32]

The risk of foot ulceration and limb amputation in people with diabetes is lessened by patient education stressing the importance of routine preventive foot care, daily self inspection of feet, appropriate shoes, avoidance of barefoot walking, avoidance of cigarette smoking, control of hyperlipidemia, and adequate glycemic control.

The history should focus on the signs and symptoms of a diabetic foot ulcer or pre-ulcerative lesion. Symptoms indicative of possible peripheral neuropathy or peripheral arterial insufficiency should also be investigated.

In the diagnosis of diabetic foot ulcers or pre-ulcerative lesions, the following should be taken into account:

• History of trauma
• History of puncture wound (with or without shoe gear)
• History of change in shoe gear
• History of deformity, either acquired or congenital
• History of callus or blister
• History of wound care management
• History of offloading
• Local signs of infection
• Systemic signs of infection

Symptoms of peripheral neuropathy

The symptoms of peripheral neuropathy include the following:

• Hypoesthesia

• Hyperesthesia

• Paresthesia

• Dysesthesia

• Radicular pain

• Anhidrosis

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.

Physical examination of the extremity that has a diabetic ulcer can be divided into different categories:

• Examination of ulceration

• Examination of the feet

• 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 ulceration

Accomplish the following in examination of ulceration

• Determine the location of the ulceration, as ulcers are typically located around bony prominences and weight-bearing surfaces; typical locations include the dorsal interphalangeal joints of hammertoes and distal tips of digits, below metatarsal heads in claw toes, the medial and lateral forefoot in patients with bunions and bunionettes, plantar lateral wounds in Charcot foot, and the lateral foot and lateral malleoli in varus deformities
• Measure the size, including the depth of the wound
• Describe the wound base (granular, fibrotic, necrotic, eschar)
• Inspect for probing to bone
• Inspect for any undermining or tunneling of the wound
• Describe any drainage
• Describe the periwound area (maceration, hyperkeratotic tissue)

Examination of feet 

Carry out the following in foot examination[33] :

• Inspect the static posture of the feet on the examination table, as well as when weight-bearing.
• ​Assess for gross deformities and determine if they are reducible or rigid
• Assess ankle range of motion using the Silfverskiöld test - If there is limited ankle dorsiflexion (cannot pass neutral) with the knee both flexed and extended, it is considered gastrocsoleal tightness; if there is increased dorsiflexion with the knee flexed, however limited with the knee in extension, it is considered gastrocnemius equinus 
• Assess range of motion at the interphalangeal joints, metatarsophalangeal joints, midtarsal joints, and subtalar joints
• Evaluate muscle power of dorsiflexors, plantar flexors, invertors, and evertors to identify any muscular imbalances
• Examine the skin for dryness and fissures, as well as for discrete calluses; hemorrhagic calluses in particular are a sign of impending foot ulceration.

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.[34] 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.

Patient workup for diabetic ulcers includes blood tests, radiography, ankle-brachial index and toe pressure, pulse-volume recording, ultrasonography, computed tomography (CT) scanning or magnetic resonance imaging (MRI), bone scans, and angiography.

IWGDF guidelines

In 2019, the International Working Group on the Diabetic Foot (IWGDF) published an update to its evidence-based guidelines on diabetic foot disease prevention and management. These included the following practical guidelines with regard to assessment of ulcers[35] :

• An individual with diabetes who is at very low risk for foot ulceration (IWGDF risk 0) should, to assess the subsequent risk for ulcers, be examined annually for signs or symptoms of protective sensation loss and peripheral artery disease
• A patient with diabetes who has protective sensation loss or peripheral artery disease (IWGDF risk 1-3) should undergo a more comprehensive examination, with the following taken into account: history, vascular status, skin, bone/joint, protective sensation loss, footwear, poor foot hygiene, physical limitations that may hinder self care of the feet (eg, problems with visual acuity, obesity), and foot care knowledge

A complete blood count (CBC) should be performed. Leukocytosis may signal an associated diabetic foot infection. Wound healing is impaired by anemia. In the face of underlying arterial insufficiency, anemia may precipitate rest pain.[36]

A comprehensive metabolic panel should also be obtained. Random glucose levels will demonstrate the adequacy of glycemic control and may be elevated in the setting of infection. Creatinine levels will assess renal function. Low albumin levels are associated with a poorer prognosis for wound healing.[37]

Blood testing should also include an HbA1c assessment, since a normal value is a surrogate marker for wound healing.[38]

Erythrocyte sedimentation rate (ESR) and C-reactive protein (CRP) are inflammatory markers which are elevated in the setting of infection and osteomyelitis. They can be measured serially to determine the efficacy of treatment.

In the setting of infection with systemic inflammatory responses, obtainment of blood cultures and lactic acid assessment are appropriate.

Plain radiographs should be obtained in the setting of diabetic foot ulcers, as well as pre-ulcerative lesions. Weight-bearing radiographs of the foot are preferred, and three views are typically ordered. Radiography allows clinicians to assess for deformities that may be the driving force for ulcerations. Osteomyelitis can often be detected on plain radiographs; however, the images may appear normal in the first 2 weeks of the disease process. Soft tissue gas may be present in the setting of gas gangrene and necrotizing soft tissue infections, which require prompt surgical intervention.

Radiographs may demonstrate calcifications of extremity vasculature. However, 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.

In the setting of osteomyelitis, MRI is said to be both specific and sensitive. MRI is also useful for evaluating deep space infections, infectious tenosynovitis, myositis, and septic arthritis. However, in the setting of Charcot arthropathy, it is difficult to distinguish that condition from osteomyelitis.

CT scanning can be used to identify osseous changes such as cortical erosions, pathologic fracture, and periosteal reactions. Because of resolution limitations, however, this modality may not be as useful in evaluating soft tissue infection, although injection of intravenous contrast may provide better visualization of deep space abscess formation.

Bone scans can be beneficial when the use of MRI and CT scanning is contraindicated for evaluating osteomyelitis. However, although bone scans have high sensitivity for osteomyelitis, they have low specificity, resulting in an increased number of false-positive scans. Labeling with gallium and indium radionuclides may lead to more specificity for suspected osteomyelitis.[39]

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.

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.

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.

Transcutaneous oxygen levels of 40 mmHg or greater in people with diabetes demonstrate the ability to heal from a perfusion standpoint. Transcutaneous tissue oxygen studies are often reserved for borderline situations in which the advisability of arterial bypass surgery may be unclear.

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.[9]

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.

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.[10]

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.[40]

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.

Diabetic foot ulcers can be staged using the WIfi threatened-limb system. This system allows communication between providers and provides risk stratification for major amputation[5]

Wound classification is as follows:

• Grade 0 – Rest pain; no wound, no ulcer, no gangrene.
• Grade 1 – Small shallow ulcer(s) on distal leg or foot; any exposed bone is only limited to distal phalanx; no gangrene (ie, minor tissue loss: limb salvage possible with simple digital amputation [1 or 2 digits] or skin coverage)
• Grade 2 – Deeper ulcer on distal leg or foot with exposed bone, joint, or tendon, or shallow heel ulcer without involvement of the calcaneus; gangrenous changes confined to the digits (ie, major tissue loss: salvageable with ≥3 digital amputations or standard transmetatarsal amputation [TMA] plus skin coverage)
• Grade 3 – Extensive deep ulcer of the forefoot and/or midfoot or full-thickness heel ulcer with or without involvement of the calcaneus (ie, extensive tissue loss: salvageable only with complex foot reconstruction or nontraditional TMA [eg, Chopart or Lisfranc amputation])

Classification of Ischemia is as follows:

• Grade 0 – ABI ≥0.8, ankle systolic pressure >100 mmHg, toe pressure (TP)/transcutaneous oxygen (TcPO2) ≥60
• Grade 1 – ABI 0.6-0.79, ankle systolic pressure 70-100 mmHg, TP/TcPO2 40-59
• Grade 2 – ABI 0.4-0.59, ankle systolic pressure 50-70 mmHg, TP/TcPO2 30-39
• Grade 3 – ABI ≤0.39, ankle systolic pressure < 50 mmHg, TP/TcPO2 < 30

Classification of foot infection is as follows:

• Grade 0 – No symptoms or signs of infection
• Grade 1 – Infection is present, and at least two of the following are present: local swelling or induration, erythema >0.5 to ≤2 cm around ulcer, local tenderness or pain, local warmth, or purulent discharge; other causes of an inflammatory response of the skin have been excluded (eg, gout, fracture)
• Grade 2 – Local infection is present as defined for grade 1 but extends >2 cm around ulcer or involves structures deeper than the skin and subcutaneous tissues (eg, abscess, osteomyelitis, septic arthritis, fasciitis); no clinical signs of systemic inflammatory response
• Grade 3 – Local infection is present as defined for grade 2, but clinical signs of systemic inflammatory response are present as manifested by two or more of the following: temperature >38°C or < 36°C; heart rate >90 beats per minute, respiratory rate >20 breaths per minute or partial pressure of carbon dioxide (PaCO ₂) < 32 mmHg; white blood cell count >12,000 or < 4000 (cu/mm) or 10% immature band forms present

Wound cultures

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.[41]

Probe to bone test

Using a sterile, solid instrument, the wound should be probed deeply without using force. If there is a rough, coarse feel, this establishes a clinical diagnosis of osteomyelitis. Specificity and sensitivity for the probe to bone test for confirmed osteomyelitis are as high as 0.83 and 0.87, respectively.[42]

Bone biopsy

If osteomyelitis is suspected, a bone biopsy is the gold standard for confirming the diagnosis. Bone biopsies are performed either through open technique or percutaneously, with or without the assistance of fluoroscopy. Osseous specimens are sent for histologic and microbiologic evaluation.

Skin biopsy

In the setting of a nonhealing, chronic wound, it is advisable to send a skin biopsy for histopathologic examination to rule out malignancy. Skin biopsies may also be beneficial to rule out other differential diagnoses such as calciphylaxis, vasculitis, and venous stasis. The wound biopsy can be incisional, excisional, or performed via punch biopsy.

The management of diabetic foot ulcers requires offloading the wound,[6, 7] daily saline or similar dressings to provide a moist wound environment,[8] débridement when necessary, antibiotic therapy with or without surgical intervention if osteomyelitis or soft tissue infection is present,[9, 10] optimal control of blood glucose, and evaluation and correction of peripheral arterial insufficiency.[11]

To promote ulcer healing in a person with diabetes and a neuropathic plantar ulcer, consider, if nonsurgical offloading therapy is unsuccessful, Achilles tendon lengthening, metatarsal head resection(s), or joint arthroplasty.

Wound coverage by cultured human cells[40, 43] or biologic skin substitutes, application of recombinant growth factors,[44, 45, 46, 47] 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, soft tissue and musculoskeletal reconstruction, 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 a multidisciplinary team of physicians, surgeons, podiatrists, and pedorthotists who have an active interest in this complex problem.

IWGDF guidelines

The aforementioned IWGDF practical guidelines state the following with regard to pressure offloading in ulcer treatment[35] :

• For patients with a neuropathic plantar ulcer, a nonremovable knee-high offloading device—ie, either a total contact cast (TCC) or a removable walker that is rendered irremovable by the provider who fits the device—is the preferred offloading treatment
• In patients who cannot tolerate a nonremovable, knee-high offloading device, or if such a device is contraindicated, a removable version can be considered; should a removable device be contraindicated or if it cannot be tolerated, an ankle-high offloading device can be considered; patients must be educated with regard to the benefits of adherence to removable device use
• In the absence of other forms of biomechanical relief, felted foam, in combination with appropriate footwear, can be considered
• While offloading remains important in the presence of infection or ischemia, greater caution is necessary
• Nonplantar foot ulcers, depending on their type and location, should be addressed with a removable, ankle-high offloading device, footwear modifications, toe spacers, or orthoses

With regard to restoration of tissue perfusion, the practical guidelines state the following[35] :

• When ankle pressure is below 50 mmHg or the ankle brachial index (ABI) is less than 0.5, urgent vascular imaging and, in the presence of appropriate findings, revascularization, should be considered; revascularization should also be considered if the toe pressure is below 30 mmHg or the transcutaneous pressure of oxygen (TcpO ₂) is less than 25 mmHg; however, revascularization may be considered at higher pressures should extensive tissue loss or infection occur
• If optimal treatment does not result in ulcerative healing signs within 6 weeks, revascularization should be considered, regardless of the outcomes of the above-mentioned vascular tests
• If an above-the-ankle amputation is being contemplated, revascularization should first be considered as an option
• Revascularization should be avoided in patients with an unfavorable risk-benefit ratio
• Individual factors (eg, morphologic distribution of peripheral artery disease, autogenous vein availability, patient comorbidities) and local operator expertise should be considered when selecting a revascularization technique
• Following revascularization, perfusion should be objectively measured to assess the procedure’s effectiveness
• Pharmacologic treatments have not been proven to benefit perfusion
• Smoking cessation, hypertension and dyslipidemia control, and antiplatelet drug use, as the means to reduce cardiovascular risk, should be emphasized

With regard to treatment of infection, the practical guidelines state the following[35] :

• For a superficial ulcer with limited soft tissue (mild) infection - The ulcer should be cleansed and all necrotic tissue and surrounding callus should be debrided; start empiric oral antibiotic therapy directed against Staphylococcus aureus and streptococci (unless there are indications that alternative or additional likely pathogens exist)
• For deep or extensive (potentially limb-threatening) infection (moderate or severe infection) - The need for surgical intervention to remove necrotic tissue, including infected bone, should be urgently evaluated, and compartment pressure should be released or abscesses drained; assess for peripheral artery disease (with urgent treatment, including revascularization, to be considered if such disease is present); empiric, parenteral, broad-spectrum antibiotic therapy aimed at common gram-positive and gram-negative bacteria, including obligate anaerobes, should be initiated; the clinical response to empirical therapy, along with culture and sensitivity results, should be used to adjust (constrain and target, if possible) the antibiotic regimen

With regard to local ulcer care, the practical guidelines recommend the following[35] :

• The ulcer must be inspected regularly by a trained health-care provider, with the severity of the ulcer, the underlying pathology, the presence of infection, the amount of exudation, and wound treatment provided determining the frequency of examination
• Ulcer débridement and removal of the surrounding callus (preferably with sharp surgical instruments) should be carried out, with the procedure repeated as necessary
• Selected dressings should control excess exudation and keep the environment moist
• Foot soaking may cause skin maceration and so should not be employed in treatment
• Negative pressure should be considered as an aid to healing postoperative wounds
• If noninfected ulcers do not heal after 4-6 weeks of optimal clinical care, one of the following adjunctive treatments should be considered - If severe ischemia is not present in a neuro-ischemic ulcer, a sucrose octasulfate–impregnated dressing; if moderate ischemia is either present or absent, a multi-layered patch of autologous leucocytes, platelets, and fibrin; also in the presence of absence of moderate ischemia, placental membrane allografts; in ischemic ulcers in which revascularization has not led to healing, adjunctive treatment with systemic oxygen therapy

Treatment of diabetic foot ulcers requires management of a number of systemic and local factors.[48, 49, 50, 51]

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.[52, 53] 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.

The basic principle of topical wound management is to provide a moist, but not wet, wound bed.[8, 54]

It is prudent to address the underlying etiologies in diabetic foot ulcers for any of the following wound care modalities to be successful. Without addressing the osseous deformities and muscular imbalances, infections, and vascular insufficiency, there will be minimal benefit in employing advanced wound care dressings.

Wound coverage

After débridement, 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 débridement, 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)[55] :

• Dry wounds: Hydrocolloid dressings, such as DuoDERM or IntraSite Hydrocolloid, are impermeable to oxygen, moisture, and bacteria; maintain a moist environment; and support autolytic  débridement. 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.[45] 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 débridement: Collagen makes up 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 (Open Table in a new window)

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]).[56]

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.[57]

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.

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

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

Débridement

 Débridement is indicated for preventing ulceration of nonviable and/or infected tissue. Hyperkeratotic tissue, fibrin, eschar, biofilm, and necrotic tissue need to be removed from the wound and periwound to facilitate wound healing. It is not uncommon for the wound to be larger in size following debridment, especially after the initial débridement. Chronic wounds such as diabetic foot ulcers are often arrested in the healing cascade, and with débridement there is the creation of a reservoir of growth factors to assist the wound in moving forward in healing. These include platelet-derived growth factor, which is excreted by small vessels in the fresh, bleeding edges of a debrided wound.[58]

Reconstructive foot and ankle surgery

Reconstructive surgery can be considered when nonremovable knee-high offloading devices are failing to achieve wound healing, when the patient is unable to transition from knee-high offloading devices to custom diabetic orthopedic shoes/insoles due to recurring pressure, or in the setting or pre-ulcerative lesions/calluses in the neuropathic patient. Prior to surgical intervention, a thorough musculoskeletal exam must be performed, and appropriate imaging such as plain radiographs, CT scans, and MRI scans must be reviewed to determine the surgical plan. Surgical options include arthroplasties, osteotomies, resection, arthrodesis, tenotomies, tendon transfers, and tendon lengthening. The goal is to rebalance the foot and create a plantigrade foot that distributes pressure appropriately. These procedures can be considered a type of internal, surgical offloading.[59]

Revisional surgery for bony architecture may be required to remove pressure points.[60] Such intervention includes resection of metatarsal heads or ostectomy.[61]

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.[17, 62, 63] 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.

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.[64]

Clinicians have to treat the underlying etiology of these wounds for these modalities to work appropriately. This includes addressing osseous deformities and muscular imbalances, treating infection, and addressing any vascular compromise.

Skin grafts

The autologous split-thickness skin graft is the criterion standard for viable coverage of a full-thickness granular wound. The graft can be harvested under local anesthesia as an outpatient surgery. Meshing the graft allows wider coverage and promotes drainage of serum and blood. The surgery does create a secondary partial-thickness wound, which can be a site of pain and morbidity.

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.[65, 43] 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.[66]

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 (Smith & Nephew) is a xenogeneic, acellular collagen matrix derived from porcine small intestinal submucosa that allows an extracellular matrix and natural growth factors to remain intact. 

Integra (Integra LifeSciences) is a bilayered skin substitute that is composed of bovine collagen and chondroitin 6-sulfate for dermal regeneration. The silicone top layer mimics epidermis, providing protection and preventing moisture loss. 

Primatrix (Integra LifeSciences) is a collagen-based dermal repair scaffold that is derived from fetal bovine dermis. There is an option of obtaining this graft with ionic silver impregnation, which provides antimicrobial coverage for contaminated wounds.

ACell (ACell) is an acellular wound scaffold derived from porcine urinary bladder matrix that can be obtained in either fenestrated sheet form or in a particulate form that is useful for deep and tunneling wounds.

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, local muscle flaps, or myocutaneous flaps.[67]

Hyperbaric oxygen therapy is used rarely and is certainly not a substitute for revascularization.[68] In the presence of an intractable wound and associated noncorrectible ischemic arterial disease, hyperbaric oxygen therapy may be beneficial (in selected cases).[69] 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.[70] 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.[71, 72]

The recommended diet is diabetic and low in saturated fat.

Offloading of the ulcerated area is imperative. This may require non–weight-bearing or weight-bearing, as tolerated in appropriate offloading devices. Custom footwear, a 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.

The risk of ulceration and limb amputation in people with diabetes can be improved by routine preventive podiatric care, appropriate shoes, and patient education.[21] Diabetic clinics should screen all patients for altered sensation and peripheral vascular disease.[47] 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.[73]

Glycemic control

The Diabetes Control and Complications Trial, performed by the Diabetes Control and Complications Trial Research Group, studied the effect of intensive treatment of diabetes on the development and progression of long-term complications in insulin-dependent diabetes mellitus (1993).[74] 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

Any of the following evaluations may prove productive:

• Endocrinologist

• Podiatrist

• Orthopedist

• Vascular surgeon

• Interventional cardiologist/interventional radiologist

• Infectious disease specialist

• Plastic surgeon

• Pedorthist

• Wound care specialist

• Physical therapist

• Dietitian

For the most part, diabetic ulcers are managed in the outpatient setting, with brief hospital stays often occurring for initial evaluation and débridement; management of infection, including via intravenous antibiotics and amputations; and vascular evaluation and interventions.

Risk classification and follow-up based on the comprehensive foot examination ^[75] (Open Table in a new window)

LOPS = Loss of protective sensation

PAD = Peripheral arterial disease

In 2019, the International Working Group on the Diabetic Foot (IWGDF) published an update to its evidence-based guidelines on diabetic foot disease prevention and management. These included the following practical guidelines with regard to assessment of ulcers[35] :

• An individual with diabetes who is at very low risk for foot ulceration (IWGDF risk 0) should, to assess the subsequent risk for ulcers, be examined annually for signs or symptoms of protective sensation loss and peripheral artery disease
• A patient with diabetes who has protective sensation loss or peripheral artery disease (IWGDF risk 1-3) should undergo a more comprehensive examination, with the following taken into account: history, vascular status, skin, bone/joint, protective sensation loss, footwear, poor foot hygiene, physical limitations that may hinder self care of the feet (eg, problems with visual acuity, obesity), and foot care knowledge

In terms of ulcer treatment, the practical guidelines state the following with regard to pressure offloading[35] :

• For patients with a neuropathic plantar ulcer, a nonremovable knee-high offloading device—ie, either a total contact cast (TCC) or a removable walker that is rendered irremovable by the provider who fits the device—is the preferred offloading treatment
• In patients who cannot tolerate a nonremovable, knee-high offloading device, or if such a device is contraindicated, a removable version can be considered; should a removable device be contraindicated or if it cannot be tolerated, an ankle-high offloading device can be considered; patients must be educated with regard to the benefits of adherence to removable device use
• In the absence of other forms of biomechanical relief, felted foam, in combination with appropriate footwear, can be considered
• While offloading remains important in the presence of infection or ischemia, greater caution is necessary
• Nonplantar foot ulcers, depending on their type and location, should be addressed with a removable, ankle-high offloading device, footwear modifications, toe spacers, or orthoses

With regard to restoration of tissue perfusion, the practical guidelines state the following[35] :

• When ankle pressure is below 50 mmHg or the ankle brachial index (ABI) is less than 0.5, urgent vascular imaging and, in the presence of appropriate findings, revascularization, should be considered; revascularization should also be considered if the toe pressure is below 30 mmHg or the transcutaneous pressure of oxygen (TcpO ₂) is less than 25 mmHg; however, revascularization may be considered at higher pressures should extensive tissue loss or infection occur
• If optimal treatment does not result in ulcerative healing signs within 6 weeks, revascularization should be considered, regardless of the outcomes of the above-mentioned vascular tests
• If an above-the-ankle amputation is being contemplated, revascularization should first be considered as an option
• Revascularization should be avoided in patients with an unfavorable risk-benefit ratio
• Individual factors (eg, morphologic distribution of peripheral artery disease, autogenous vein availability, patient comorbidities) and local operator expertise should be considered when selecting a revascularization technique
• Following revascularization, perfusion should be objectively measured to assess the procedure’s effectiveness
• Pharmacologic treatments have not been proven to benefit perfusion
• Smoking cessation, hypertension and dyslipidemia control, and antiplatelet drug use, as the means to reduce cardiovascular risk, should be emphasized

With regard to treatment of infection, the practical guidelines state the following[35] :

• For a superficial ulcer with limited soft tissue (mild) infection - The ulcer should be cleansed and all necrotic tissue and surrounding callus should be debrided; start empiric oral antibiotic therapy directed against Staphylococcus aureus and streptococci (unless there are indications that alternative or additional likely pathogens exist)
• For deep or extensive (potentially limb-threatening) infection (moderate or severe infection) - The need for surgical intervention to remove necrotic tissue, including infected bone, should be urgently evaluated, and compartment pressure should be released or abscesses drained; assess for peripheral artery disease (with urgent treatment, including revascularization, to be considered if such disease is present); empiric, parenteral, broad-spectrum antibiotic therapy aimed at common gram-positive and gram-negative bacteria, including obligate anaerobes, should be initiated; the clinical response to empirical therapy, along with culture and sensitivity results, should be used to adjust (constrain and target, if possible) the antibiotic regimen

With regard to local ulcer care, the practical guidelines recommend the following[35] :

• The ulcer must be inspected regularly by a trained health-care provider, with the severity of the ulcer, the underlying pathology, the presence of infection, the amount of exudation, and wound treatment provided determining the frequency of examination
• Ulcer débridement and removal of the surrounding callus (preferably with sharp surgical instruments) should be carried out, with the procedure repeated as necessary
• Selected dressings should control excess exudation and keep the environment moist
• Foot soaking may cause skin maceration and so should not be employed in treatment
• Negative pressure should be considered as an aid to healing postoperative wounds
• If noninfected ulcers do not heal after 4-6 weeks of optimal clinical care, one of the following adjunctive treatments should be considered - If severe ischemia is not present in a neuro-ischemic ulcer, a sucrose octasulfate–impregnated dressing; if moderate ischemia is either present or absent, a multi-layered patch of autologous leucocytes, platelets, and fibrin; also in the presence of absence of moderate ischemia, placental membrane allografts; in ischemic ulcers in which revascularization has not led to healing, adjunctive treatment with systemic oxygen therapy

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

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.[76] 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.

Pentoxifylline (Trental)

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.

Cilostazol (Pletal)

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.

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.

Clopidogrel (Plavix)

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.

Aspirin (Bayer, Anacin, Empirin)

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.

Class Summary

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

Becaplermin (Regranex)

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.