WORKUP	Section 5 of 11
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Lab Studies:

• CBC count: 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.

• Metabolic profile and glycohemoglobin: 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.

• Noninvasive vascular laboratory study: 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.

• The ankle-brachial blood pressure index is potentially unreliable because of arterial calcification.

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

Imaging Studies:

• Duplex scanning 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.

• Plain x-ray studies of the diabetic foot may demonstrate demineralization and Charcot joint and occasionally may suggest the presence of osteomyelitis. Note that plain x-ray studies have no role in the evaluation of arterial disease. This is because arterial calcification observed on plain x-rays 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.

• CT scan and MRI: Although an experienced clinician usually can diagnose a plantar abscess by physical examination alone, CT scan or MRI is indicated if a plantar abscess is suspected but not clear on physical examination.

• Bone scans are of questionable utility because of a sizable percentage of false-positive and false-negative results. A recent study suggests 99mTc-labeled ciprofloxacin as a somewhat useful marker for osteomyelitis (Dutta, 2006).

• Contrast angiography is indicated if hemodynamically significant vascular disease precludes healing of the ulcer or is causing intractable pain at rest. Angiography is best ordered by the vascular or endovascular surgeon (not the generalist) to ensure that the study performed actually visualizes the entire segment of the arterial tree apropos to the potential vascular procedure.

• Alternatives to contrast angiography

• For patients with renal insufficiency, carbon dioxide angiography is an alternative. However, it is not widely available and requires some iodinated contrast material in addition to the carbon dioxide gas to provide meaningful films.

• Magnetic resonance angiography (MRA) is an alternative for patients with renal compromise and patients who are allergic to contrast materials. MRA requires no iodinated contrast material but is contraindicated by hardware such as a hip prosthesis or a pacemaker, and the resolution often is inadequate for the vascular surgeon in planning reconstructive procedures, particularly in the smaller infrapopliteal arteries.

Other Tests:

• A hand-held 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. The latter pressure 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, ABI often is falsely elevated if the underlying arteries are heavily calcified, a finding common in diabetic persons.

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

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

	TREATMENT	Section 6 of 11
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Medical Care:

• Treatment of foot ulcers includes treatment of the diabetes itself.

• Management of contributing systemic factors, such as hypertension, hyperlipidemia, atherosclerotic heart disease, obesity, or renal insufficiency, is crucial.

• Management of arterial insufficiency, treatment of infection with appropriate antibiotics, offloading the area of the ulcer, and wound care are also essential.

• In the presence of an intractable wound and associated noncorrectible ischemic arterial disease, hyperbaric oxygen therapy may be beneficial (in selected cases).

• The management of diabetic foot ulcers requires appropriate therapeutic footwear, daily saline or similar dressings to provide a moist wound environment, debridement when necessary, antibiotic therapy if osteomyelitis or cellulitis is present, optimal control of blood glucose, and evaluation and correction of peripheral arterial insufficiency.

• Wound coverage by cultured human cells or heterogeneic dressings/grafts, application of recombinant growth factors, and hyperbaric oxygen treatments also may be beneficial at times.

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

• 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]).

• Hyperbaric oxygen therapy is used rarely and certainly is not a substitute for revascularization.

• Charcot foot is treated initially with immobilization using special shoes or braces but eventually may require podiatric surgery such as ostectomy and arthrodesis. If neglected, ulceration may occur at pressure points, particularly the medial aspect of the navicular bone and the inferior aspect of the cuboid bone.

• 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. 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.

  • 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.

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

Diet: Diet is diabetic and low in saturated fat.

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.

	MEDICATION	Section 7 of 11
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The basic principle of topical wound management is to provide a moist, but not wet, wound bed. 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):

• 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 Food and Drug Administration (FDA) to promote healing of diabetic foot ulcers. Regranex is meant for a healthy, granulating wound, not one with a necrotic wound base. Regranex 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.

Topical agents to avoid: Avoid cytotoxic agents, such as hydrogen peroxide, povidone iodine, acetic acid, and Dakin solution (sodium hypochlorite), except as noted above under infected wounds.

Drug Category: Hemorheologic agents -- Many medications may have a role in the treatment of diabetes and the complications of diabetes. Pentoxifylline (Trental) improves intermittent claudication in approximately 60% of patients after 3 months. Cilostazol (Pletal) is an alternative hemorheologic agent for patients who cannot tolerate pentoxifylline. However, no conclusive evidence of any direct beneficial effect of either pentoxifylline or cilostazol on the healing of diabetic foot ulcers exists. 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.

Drug Name	Pentoxifylline (Trental) -- Indicated to treat intermittent claudication. May alter rheology of red blood cells, which in turn reduces blood viscosity. From 2-8 wk of therapy may be required before symptomatic improvement occurs, and only about 60% of patients respond to this drug.
Adult Dose	400 mg PO tid with meals; if digestive or CNS adverse effects develop, decrease dose to 400 mg PO bid or discontinue
Pediatric Dose	Not established
Contraindications	Documented hypersensitivity; cerebral and/or retinal hemorrhage
Interactions	Coadministration with cimetidine or theophylline increases effect/toxic potential; pentoxifylline increases effect of antihypertensives
Pregnancy	C - Safety for use during pregnancy has not been established.
Precautions	Caution in renal impairment; do not administer this drug without thoroughly reading complete prescribing information

Drug Name	Cilostazol (Pletal) -- Indicated for the reduction of symptoms of intermittent claudication, as indicated by an increased walking distance. Affects vascular beds and cardiovascular function. Produces nonhomogenous dilation of vascular beds, with greater dilation in femoral beds than in vertebral, carotid, or superior mesenteric arteries. Renal arteries were not responsive to its effects. Mechanism involves inhibition of PDE, especially PDE III, and reversible inhibition of platelet aggregation. Patients may respond as early as 2-4 wk after initiation of therapy, but treatment for as many as 12 wk may be needed before a beneficial effect is experienced.
Adult Dose	100 mg PO bid taken at least 0.5 h before or 2 h after breakfast and dinner; consider 50 mg bid if coadministering with inhibitors of CYP3A4, such as ketoconazole, itraconazole, erythromycin, and diltiazem, or with inhibitors of CYP2C19 such as omeprazole
Pediatric Dose	Not established
Contraindications	Documented hypersensitivity; CHF; coadministration with grapefruit juice
Interactions	Diltiazem, erythromycin, grapefruit juice, itraconazole, ketoconazole, macrolide antibiotics, and omeprazole may increase levels
Pregnancy	C - Safety for use during pregnancy has not been established.
Precautions	Caution in renal impairment; do not prescribe or administer without thoroughly reading complete prescribing information

Drug Category: Antiplatelet agents -- Inhibit platelet function by blocking cyclooxygenase and subsequent platelet aggregation.

Drug Name	Clopidogrel (Plavix) -- Selectively inhibits ADP binding to platelet receptor and subsequent ADP-mediated activation of glycoprotein GPIIb/IIIa complex, thereby inhibiting platelet aggregation. Indicated as antiplatelet therapy in some patients with atherosclerotic disease.
Adult Dose	75 mg PO qd
Pediatric Dose	Not established
Contraindications	Documented hypersensitivity; active pathological bleeding, such as peptic ulcer or intracranial hemorrhage
Interactions	Coadministration with naproxen is associated with increased occult GI blood loss; clopidogrel prolongs bleeding time; safety of coadministration with warfarin not established
Pregnancy	C - Safety for use during pregnancy has not been established.
Precautions	Caution in patients at increased risk of bleeding from trauma, surgery, or other pathological conditions; caution in patients with lesions with propensity to bleed (eg, ulcers); do not administer this drug without thoroughly reading complete prescribing information

Drug Name	Aspirin (Bayer, Anacin, Empirin) -- Inhibits prostaglandin synthesis, preventing formation of platelet-aggregating thromboxane A2. May be used in low dose to inhibit platelet aggregation and improve complications of venous stases and thrombosis. The recommended dose varies with indication, and, often, the literature is unclear on the optimal dosing.
Adult Dose	75-325 mg PO qd
Pediatric Dose	Not established
Contraindications	Documented hypersensitivity; liver damage; hypoprothrombinemia; vitamin K deficiency; bleeding disorders; asthma; due to association of aspirin with Reye syndrome, do not use in children (<16 y) with flu
Interactions	Effects may decrease with antacids and urinary alkalinizers; corticosteroids decrease salicylate serum levels; additive hypoprothrombinemic effects and increased bleeding time may occur with coadministration of anticoagulants; may antagonize uricosuric effects of probenecid and increase toxicity of phenytoin and valproic acid; doses >2 g/d may potentiate glucose-lowering effect of sulfonylurea drugs
Pregnancy	D - Unsafe in pregnancy
Precautions	May cause transient decrease in renal function and aggravate chronic kidney disease; caution in patients with severe anemia, with history of blood coagulation defects, or taking anticoagulants; do not administer this drug without thoroughly reading complete prescribing information

	FOLLOW-UP	Section 8 of 11
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Further Inpatient Care:

• Hospital admission is indicated for acutely infected ulcers, infected gangrene, penetration of digital infections into the forefoot, septic involvement deep to the plantar fascia, and uncontrolled diabetes.

Further Outpatient Care:

• 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.

• Hyperbaric oxygen therapy may be beneficial in certain cases of intractable foot ulcers accompanied by uncorrectable arterial insufficiency.

In/Out Patient Meds:

• Antibiotics

• Hemorheologic agents

• Antiplatelet agents

• Hypoglycemic medications

• ACE inhibitors

Deterrence/Prevention:

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

• 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.

• 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). 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.

Prognosis:

• Among people with diabetes, 1 in 20 will develop a foot ulcer and 1 in 100 will require amputation annually. Hence, diabetes is the predominant etiology for nontraumatic lower extremity amputations in the United States, accounting for half of all nontraumatic leg amputations. Contralateral amputation will be required in 50% of these patients during the subsequent 5-year interval.

• Peripheral neuropathy—which occurs in 60% of people with diabetes—confers the greatest risk of foot ulceration; microvascular arterial disease and suboptimal glycemic control also contribute. In diabetic people with neuropathy, even if successful management results in healing of the foot ulcer, the recurrence rate is 66% and the amputation rate rises to 12%.

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 eMedicine's Diabetes Center. Also, see eMedicine's patient education article Diabetic Foot Care.

	MISCELLANEOUS	Section 9 of 11
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Medical/Legal Pitfalls:

• 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.

	PICTURES	Section 10 of 11
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Caption: Picture 1. Diabetic ulcer of the medial aspect of left first toe before and after appropriate wound care.
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Caption: Picture 2. Diabetic ulcer of left fourth toe associated with mild cellulitis.
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	BIBLIOGRAPHY	Section 11 of 11
Author Information Introduction Clinical Differentials Workup Treatment Medication Follow-up Miscellaneous Pictures Bibliography

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Diabetic Ulcers excerpt