Di

Richard M Stillman, MD, FACS, Honorary Medical Staff, Northwest Medical Center; Former Chief of
Staff and Medical Director, Wound Healing Center, Department of Surgery, Northwest Medical Center

Updated: Jun 7, 2010

Introduction

Background

Diabetic foot ulcers, as shown in the image below, occur as a result of various factors. Such factors
include 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. Nonenzymatic glycosylation 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 ulcer of the medial aspect of left first toe before and after appropriate wound care.

Pathophysiology

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.

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

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.
[1 ]
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, as depicted in 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.

Frequency

United States

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. 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." 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.

Even after successful management resulting in ulcer healing, the recurrence rate in that patient
population is 66% and the amputation rate rises to 12%. Half of all nontraumatic amputations are a
result of diabetic foot complications, and the 5-year risk of needing a contralateral amputation is 50%.
[2 ]

Mortality/Morbidity

Limb loss: Unfortunately, limb loss is a significant risk in patients with diabetic foot ulcers, particularly
if treatment has been delayed.[3 ]

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

Race

The issue of diabetic foot disease is of particular concern in the Latino communities of the Eastern
United States, African Americans[4 ], and in Native Americans, who tend to have the highest
prevalence of diabetes in the world.

Age

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.

Clinical

History

Peripheral neuropathy: The symptoms of peripheral neuropathy include the following:

Hypesthesia

Hyperesthesia

Paresthesia

Dysesthesia

Radicular pain

Anhydrosis

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, while symptoms that occur in the
buttocks or thighs suggest aortoiliac occlusive disease.

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. 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

Physical examination of the extremity having a diabetic ulcer can be divided into 3 broad categories:
(1) examination of the ulcer and general condition of the extremity, (2) assessment of the possibility of
vascular insufficiency,[5 ]and (3) 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.

Extremity examination

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

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.

For further details, see Infrainguinal Arterial Occlusive Disease.

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.[6 ]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 (NIDDK), or the clinician can use the professional Semmes-Weinstein filaments described
here.

Causes

The etiologies of diabetic ulceration include neuropathy,[7 ]arterial disease,[8 ]pressure,[9 ]and foot
deformity.[10 ]

Differential Diagnoses

Atherosclerosis
Chronic Venous Insufficiency
Diabetic Foot Infections

Other Problems to Be Considered

The classic diabetic trophic ulcer must be distinguished from various other problems that tend to occur
in persons with diabetes, such as diabetic dermopathy, bullosis diabeticorum, eruptive xanthoma,
necrobiosis lipoidica, and granuloma annulare.

The leg pain of peripheral arterial disease must be distinguished from other causes of leg pain, such as
arthritis, muscle pain, radicular pain, spinal cord compression, thrombophlebitis, anemia, and
myxedema.

Diabetic neuropathy should be distinguished from other forms of neuropathy, including vasculitic
neuropathies, metabolic neuropathies, autonomic neuropathy, radiculopathy, and many others.
Workup

Laboratory 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.
[11 ]

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 the
eMedicine article 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 radiograph studies of the diabetic foot may demonstrate demineralization and Charcot joint and
occasionally may suggest the presence of osteomyelitis. Note that plain radiograph studies have no role
in the evaluation of arterial disease. This is because arterial calcification observed 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.

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 use because of a sizable percentage of false-positive and false-negative
results. A recent study suggests 99mTc-labeled ciprofloxacin is a somewhat useful marker for
osteomyelitis.[12 ]
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 radiologist may use an alternate entry such as via an axillary artery or even directly into the
infrarenal aorta via a translumbar approach.

Puncture-related complications: 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, and the radiologist must balance the need for hemostasis against the possibility of arterial
occlusion. Risks include hemorrhage, pseudoaneurysm formation, and clotting or dislodgement of an
intimal flap, which may acutely occlude the artery at or near the entry site. Currently, newer methods of
percutaneous closure of the puncture sites have significantly reduced the 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.
[13 ]

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.

Alternatives to conventional angiography

Magnetic resonance angiography: Magnetic resonance angiography (MRA) is an alternative both for
patients 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 (see this article on Medscape). MRA is contraindicated in patients with implanted
hardware such as a hip prostheses or pacemakers. The resolution 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.[14 ]

Multidetector computed tomographic angiography (MDCT): MDCT 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
carries the contrast-related risks described above.[15 ]

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.

Plain radiography: 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.

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.

Staging

Stage diabetic foot wounds based on the depth of soft tissue and osseous involvement.[16,17,18 ]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.

Treatment

Medical Care

Treatment of diabetic foot ulcers requires management of to a number of systemic and local factors,
including:[19,20,21,22 ]

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.[23,24 ]
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).[9 ]Lndahl 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.[25 ]

The management of diabetic foot ulcers requires offloading the wound by using appropriate therapeutic
footwear,[26,9 ]daily saline or similar dressings to provide a moist wound environment,[27 ]
debridement when necessary, antibiotic therapy if osteomyelitis or cellulitis is present,[13,14 ]optimal
control of blood glucose, and evaluation and correction of peripheral arterial insufficiency.

Wound coverage by cultured human cells[15,28 ]or heterogeneic dressings/grafts, application of

recombinant growth factors,[29,30,31,32 ]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]).[33 ]

Hyperbaric oxygen therapy is used rarely and is certainly not a substitute for revascularization.[34 ]

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.

Characteristics and Uses of Wound Dressing Materials

Category

Examples

Description

Applications

Alginate

AlgiSite
Comfeel
Curasorb
Kaltogel
Kaltostat
Sorbsan
Tegagel

This seaweed extract contains guluronic and mannuronic acids that provide tensile strength and
calcium and sodium alginates, which confer an absorptive capacity. Some of these can leave fibers in
the wound if they are not thoroughly irrigated. These are secured with secondary coverage.

These are highly absorbent and useful for wounds having copious exudate. Alginate rope is particularly
useful to pack exudative wound cavities or sinus tracts.

Hydrofiber

Aquacel
Aquacel-Ag
Versiva

An absorptive textile fiber pad, also available as a ribbon for packing of deep wounds. This material is
covered with a secondary dressing. The hydrofiber combines with wound exudate to produce a
hydrophilic gel. Aquacel-Ag contains 1.2% ionic silver that has strong antimicrobial properties against
many organisms, including methicillin-resistant Staphylococcus aureus and vancomycin-resistant
Enterococcus.

These are absorbent dressings used for exudative wounds.

Debriding agents

Hypergel (hypertonic saline gel)

Santyl (collagenase)
Accuzyme (papain urea)

Various products provide some degree of chemical or enzymatic debridement.

These are useful for necrotic wounds as an adjunct to surgical debridement.

Foam

LYOfoam
Spyrosorb
Allevyn

Polyurethane foam has some absorptive capacity.

These are useful for cleaning granulating wounds having minimal exudate.

Hydrocolloid

Aquacel
CombiDERM
Comfeel
Duoderm CGF Extra Thin
Granuflex
Tegasorb

These are made of microgranular suspension of natural or synthetic polymers, such as gelatin or pectin,
in an adhesive matrix. The granules change from a semihydrated state to a gel as the wound exudate is
absorbed.

They are useful for dry necrotic wounds, wounds having minimal exudate, and clean granulating
wounds.

Hydrogel

Aquasorb
Duoderm
IntraSite Gel
Granugel
Normlgel
Nu-Gel
Purilon Gel
(KY jelly)

These are water-based or glycerin-based semipermeable hydrophilic polymers; cooling properties may
decrease wound pain. These gels can lose or absorb water depending upon the state of hydration of the
wound. They are secured with secondary covering.

These are useful for dry, sloughy, necrotic wounds (eschar).

Low-adherence dressing

Mepore
Skintact
Release

These are various materials designed to remove easily without damaging underlying skin.

These are useful for acute minor wounds, such as skin tears, or as a final dressing for chronic wounds
that have nearly healed.

Transparent film

OpSite
Skintact
Release
Tegaderm
Bioclusive

These are highly conformable acrylic adhesive film having no absorptive capacity and little hydrating
ability, and they may be vapor permeable or perforated.
These are useful for clean dry wounds having minimal exudate, and they also are used to secure an
underlying absorptive material. They are used for protection of high-friction areas and areas that are
difficult to bandage such as heels (also used to secure IV catheters).

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.

Debridement: Surgical management is indicated for debridement of nonviable and infected tissue from
the ulceration, removal of excess callous, 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.[35 ]Such intervention includes resection of metatarsal heads or ostectomy.[36 ]

Vascular surgery: 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.[37,8,38 ]Intermittent claudication alone is only infrequently disabling and
intractable enough to warrant bypass surgery.

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.[39 ]

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 fibroblastderived 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.[40,28 ]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.[41 ]

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

The recommended 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

The basic principle of topical wound management is to provide a moist, but not wet, wound bed.
[27,42 ]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 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.[30 ]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.

Hemorrheologic Agents

Many medications may have a role in the treatment of diabetes, the complications of diabetes, and the
etiologies of diabetic ulcer (see Diabetes Mellitus, Type 2). For example, hemorheologic agents and
antiplatelet agents are sometimes used in the management of underlying atherosclerotic disease. See
also Infrainguinal Occlusive Disease.

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[43 ]. Cilostazol is contraindicated in patients with congestive heart failure. The
product's black box warning reads as follows:

Cilostazol and several of its metabolites are inhibitors of phosphodiesterase III. Several drugs with this
pharmacologic effect have caused decreased survival compared to placebo in patients with class III-IV
congestive heart failure. Pletal is contraindicated in patients with congestive heart failure of any
severity.

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)
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.

Dosing

Adult

400 mg PO tid with meals; if digestive or CNS adverse effects develop, decrease dose to 400 mg PO
bid or discontinue

Pediatric

Not established

Interactions

Coadministration with cimetidine or theophylline increases effect/toxic potential; pentoxifylline

increases effect of antihypertensives

Contraindications

Documented hypersensitivity; cerebral and/or retinal hemorrhage

Precautions

Pregnancy

C - Fetal risk revealed in studies in animals but not established or not studied in humans; may use if
benefits outweigh risk to fetus

Precautions

Caution in renal impairment; do not administer this drug without thoroughly reading complete
prescribing information

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.
Dosing

Adult

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

Not established

Interactions

Diltiazem, erythromycin, grapefruit juice, itraconazole, ketoconazole, macrolide antibiotics, and

omeprazole may increase levels

Contraindications

Documented hypersensitivity; CHF; coadministration with grapefruit juice

Cilostazol and several of its metabolites are inhibitors of phosphodiesterase III. Several drugs with this
pharmacologic effect have caused decreased survival compared to placebo in patients with class III-IV
congestive heart failure. Pletal is contraindicated in patients with congestive heart failure of any
severity.

Precautions

Pregnancy

C - Fetal risk revealed in studies in animals but not established or not studied in humans; may use if
benefits outweigh risk to fetus

Precautions

Caution in renal impairment; do not prescribe or administer without thoroughly reading complete
prescribing information

Antiplatelet agents

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)

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.

Dosing

Adult

75 mg PO qd

Pediatric

Not established

Interactions

Coadministration with naproxen is associated with increased occult GI blood loss; clopidogrel prolongs
bleeding time; safety of coadministration with warfarin not established

Contraindications

Documented hypersensitivity; active pathological bleeding, such as peptic ulcer or intracranial

hemorrhage

Precautions

Pregnancy

C - Fetal risk revealed in studies in animals but not established or not studied in humans; may use if
benefits outweigh risk to fetus

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

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.
Dosing

Adult

75-325 mg PO qd

Pediatric

Not established

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

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

Precautions

Pregnancy

D - Fetal risk shown in humans; use only if benefits outweigh risk to fetus

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

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.[44 ]

Inpatient & Outpatient Medications

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.[45 ]Diabetic clinics should screen
all patients for altered sensation and peripheral vascular disease.[32 ]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).[46 ]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 neuropathywhich occurs in 60% of people with diabetesconfers the greatest risk of foot
ulceration; microvascular arterial disease and suboptimal glycemic control also contribute. In diabetic
people with neuropathy,[47 ]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

Medicolegal 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 dbride 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.

Multimedia

Media file 1: Diabetic ulcer of the medial aspect of left first toe before and after appropriate wound
care.

Media file 2: Diabetic ulcer of left fourth toe associated with mild cellulitis.

Media file 3: Charcot deformity with mal perforans ulcer of plantar midfoot.