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Diabe
etic U
Ulcerss
In
ntrod
duction
Bac
ckground
Diab betic foot ulc
cers occur ass a result of various facttors. Such faactors includ
de mechanical
chan nges in confformation of the bony arc chitecture off the foot, pe
eripheral neuuropathy, an
nd
athe erosclerotic peripheral arterial diseasse, all of which occur with higher freequency and d
intensity in the diabetic
d poppulation. Non n-enzymatic glycosylatio on predisposses ligamentss to
stifffness. Neuroopathy cause es loss of prootective senssation and lo oss of coord
dination of
mus scle groups ini the foot annd leg, both of which inc crease mech hanical stress
ses during
amb bulation.

Patthophysio
ology
Diabbetic persons, like peoplle who are no ot diabetic, may
m develop p atherosclerrotic disease e of
large-sized and medium-size ed arteries, such
s as aorttoiliac and fe
emoropoplite eal
atheerosclerosis.. However, significant
s attherosclerotiic disease off the infrapop pliteal segments
is paarticularly co
ommon in th he diabetic population. Underlying
U diigital artery d
disease, whe en
commpounded by y an infectedd ulcer in close proximity y, may resultt in complete e loss of digital
collaaterals and precipitate
p g
gangrene. Thhe reason forr the prevalence of this fform of arterial
diseease in diabe etic persons is thought to result from m a number of o metabolic c abnormalities,
incluuding high loow-density lipoprotein (L LDL) and verry-low-densiity lipoprotein (VLDL) lev vels,
elev
vated plasma a von Willebrrand factor, inhibition off prostacyclin n synthesis, elevated
plassma fibrinoge en levels, an
nd increased d platelet adh hesiveness.

Ove
erall, people with
w diabete
es have a hig
gher incidenc
ce of atheros
sclerosis, thickening of
capiillary basement membranes, arteriolar hyalinosis
s, and endotthelial prolife
eration.
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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.

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 fructose1

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 Image 3); 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.

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
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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 Americans4 , 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:

o Hypoesthesia
o Hyperesthesia
o Paresthesia
o Dysesthesia
o Radicular pain
o Anhydrosis
• Peripheral arterial insufficiency
o 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.
o Patients who are symptomatic may present with intermittent claudication,
ischemic pain at rest, nonhealing ulceration of the foot, or frank ischemia of the
foot.
o 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
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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.
o 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 insufficiency5 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:
o Hypertrophic calluses
o Brittle nails
o Hammer toes
o 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
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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 neuropathy6
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.

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
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• 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.

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 osteomyelitis12
• 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.
• Technique: Typically, a catheter is inserted retrograde via a femoral
puncture, and contrast is power-injected into the infrarenal aorta. Films are
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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
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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 factors19,20,21,22
o Precise diabetic control is, of course, vital, not only in achieving resolution
of the current wound, but also in minimizing the risk of recurrence.
o Management of contributing systemic factors, such as hypertension,
hyperlipidemia, atherosclerotic heart disease, obesity, or renal
insufficiency, is crucial23,24
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o Management of arterial insufficiency, treatment of infection with

appropriate antibiotics, offloading the area of the ulcer, and wound care are
also essential.
o In the presence of an intractable wound and associated noncorrectible
ischemic arterial disease, hyperbaric oxygen therapy may be beneficial (in
selected cases).9
• The management of diabetic foot ulcers requires offloading the wound by using
appropriate therapeutic footwear25,9 daily saline or similar dressings to provide a
moist wound environment,26 debridement when necessary, antibiotic therapy if
osteomyelitis or cellulitis is present13,14 optimal control of blood glucose, and
evaluation and correction of peripheral arterial insufficiency.
• Wound coverage by cultured human cells15,27 or heterogeneic dressings/grafts,
application of recombinant growth factors28,29,30,31 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])32
• Hyperbaric oxygen therapy is used rarely33
• 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 This seaweed extract contains guluronic and These are highly absorbent and
Comfeel mannuronic acids that provide tensile strength useful for wounds having copious
Curasorb and calcium and sodium alginates, which confer exudate.
Kaltogel an absorptive capacity. Some of these can leave Alginate rope is particularly useful
Kaltostat fibers in the wound if they are not thoroughly to pack exudative wound cavities or
Sorbsan irrigated. These are secured with secondary sinus tracts.
Tegagel coverage.
Hydrofiber Aquacel An absorptive textile fiber pad, also available as These are absorbent dressings
Aquacel-Ag a ribbon for packing of deep wounds. This used for exudative wounds.
Versiva 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.
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Debriding Hypergel Various products provide some degree of These are useful for necrotic
agents (hypertonic chemical or enzymatic debridement. wounds as an adjunct to surgical
saline gel) debridement.
Santyl
(collagenase)
Accuzyme
(papain
urea)
Foam LYOfoam Polyurethane foam has some absorptive These are useful for cleaning
Spyrosorb capacity. granulating wounds having minimal
Allevyn exudate.
Hydrocolloid Aquacel These are made of microgranular suspension of They are useful for dry necrotic
CombiDERM natural or synthetic polymers, such as gelatin or wounds, wounds having minimal
Comfeel pectin, in an adhesive matrix. The granules exudate, and clean granulating
Duoderm change from a semihydrated state to a gel as the wounds.
CGF Extra wound exudate is absorbed.
Thin
Granuflex
Tegasorb
Hydrogel Aquasorb These are water-based or glycerin-based These are useful for dry, sloughy,
Duoderm semipermeable hydrophilic polymers; cooling necrotic wounds (eschar).
IntraSite Gel properties may decrease wound pain. These gels
Granugel can lose or absorb water depending upon the
Normlgel state of hydration of the wound. They are
Nu-Gel secured with secondary covering.
Purilon Gel
(KY jelly)
Low- Mepore These are various materials designed to remove These are useful for acute minor
adherence Skintact easily without damaging underlying skin. wounds, such as skin tears, or as a
Release final dressing for chronic wounds
dressing
that have nearly healed.
Transparent OpSite These are highly conformable acrylic adhesive These are useful for clean dry
film Skintact film having no absorptive capacity and little wounds having minimal exudate, and
Release hydrating ability, and they may be vapor they also are used to secure an
Tegaderm permeable or perforated. underlying absorptive material.
Bioclusive 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).
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Surgical Care
All patients harboring diabetic foot ulcers should be evaluated by a qualified vascular
surgeon and/or podiatric surgeon who will consider debridement, revisional surgery on
bony architecture, vascular reconstruction, and options for soft tissue coverage.

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 points34 Such intervention includes resection of metatarsal heads or
ostectomy35
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 gangrene36,8,37 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
substitutes38

The autologous skin graft is the criterion standard for viable coverage of the partial
thickness wound. The graft can be harvested under local anesthesia as an
outpatient procedure. Meshing the graft allows wider coverage and promotes
drainage of serum and blood.
A cadaveric skin allograft is a useful covering for relatively deep wounds following
surgical excision when the wound bed does not appear appropriate for application
of an autologous skin graft. The allograft is, of course, only a temporary solution.
Tissue-cultured skin substitutes

™ Dermagraft (Smith & Nephew) is a cryopreserved human fibroblast–

derived dermal substitute produced by seeding neonatal foreskin
fibroblasts onto a bioabsorbable polyglactin mesh scaffold. Dermagraft
is useful for managing full-thickness chronic diabetic foot ulcers. It is
not appropriate for infected ulcers, those that involve bone or tendon,
or those that have sinus tracts. A multicenter study of 314 patients
demonstrated significantly better 12-week healing rates with
Dermagraft (30%) versus controls (17%). Allergic reactions to its bovine
protein component have been reported.
™ Apligraf (Organogenesis) is a living, bilayered human skin
substitute39,27 It is not appropriate for infected ulcers, those that
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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.40

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.26,41 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,
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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.29 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
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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. For example, hemorheologic agents and
antiplatelet agents are sometimes used in the management of underlying atherosclerotic
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
pentoxifylline42 . 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
• Interactions
• Contraindications
• Precautions
Adult

400 mg PO tid with meals; if digestive or CNS adverse effects develop, decrease dose to
400 mg PO bid or discontinue
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Pediatric
Not established

• DosingInteractionsContraindicationsPrecautionsDosingInteractionsContraindicationsPrecautionsDosingInteraction
sContraindicationsPrecautions

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
• Interactions
• Contraindications
• Precautions
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

• DosingInteractionsContraindicationsPrecautionsDosingInteractionsContraindicationsPrecautionsDosingInteraction
sContraindicationsPrecautions

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
• Interactions
• Contraindications
• Precautions
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Adult
75 mg PO qd

Pediatric
Not established

• DosingInteractionsContraindicationsPrecautionsDosingInteractionsContraindicationsPrecautionsDosingInteraction
sContraindicationsPrecautions

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
• Interactions
• Contraindications
• Precautions
Adult
75-325 mg PO qd

Pediatric
Not established

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.43

Inpatient & Outpatient Medications

• Antibiotics
• Hemorheologic agents
• Antiplatelet agents
• Hypoglycemic medications
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• 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.44
Diabetic clinics should screen all patients for altered sensation and peripheral
vascular disease.31 Of diabetic foot ulcers, 85% are estimated to be preventable with
appropriate preventive medicine.
o Daily foot inspection
o Gentle soap and water cleansing
o Application of skin moisturizer
o 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.
o Minor wounds require prompt medical evaluation and treatment.
o Prophylactic podiatric surgery to correct high-risk foot deformities may be
indicated.
o Avoid hot soaks, heating pads, and irritating topical agents.
• Glycemic control
o 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).45
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.
o 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,46 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
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• The risk
k of foot ulce
eration and liimb amputattion in peoplle with diabe
etes is lessen
ned
by patie
ent education n stressing the
t importan nce of routine
e preventive
e podiatric ca
are,
approprriate shoes, avoidance
a off cigarette sm
moking, conntrol of hyperlipidemia, and
a
adequatte glycemic control.
c
• For exceellent patient education resources, visit
v eMedicine's Diabetees Center. Also,
see eMeedicine's patient educatio on article Dia
abetic Foot Care.
C

Mis
scellaneo
ous

Med
dicolegal Pitfalls
Physicians of diiabetic patients with ulceers must dec cide between n the sometimes conflictting
options of (1) pe
erforming invvasive proce edures (eg, angiography
a y, bypass surrgery) for limmb
salv
vage and (2) avoiding thee risks of unn necessarily aggressive managemen
m t in these
patie
ents, who may have sign nificant card
diac risk. In general,
g the greatest
g lega
al risks are
assoociated with delay in diagnosis of isc chemia asso ociated with diabetic ulce eration, failu
ure
to ag
ggressively débride and d treat infectiion, and failu
ure to treat th
he wound ca arefully. If a
patie
ent presentss with a new diabetic fooot ulcer, he or
o she should d receive carre from
physsicians, surg
geons, podia atrists, and pedorthotists
p s who have an a active interest in this
commplex problemm.

Mu
ultimedia
a

Media file 1: Dia

abetic ulcer of the medial
asp
pect of left fiirst toe befo
ore and after
approprriate wound care.

(Enlarge Image))

Media fille 2: Diabetic ulcer of le

eft fourth toe
e
asssociated with
w mild celllulitis.

(Enlarge Image)
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(Enlarge Image)

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