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Diabetic angiopathy

Angiopathy is the generic term for a disease of the blood vessels (arteries, veins, and capillaries). The best known and most prevalent angiopathy is the diabetic angiopathy, a complication that may occur in chronic diabetes. more...

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There are two types of angiopathy: macroangiopathy and microangiopathy. In macroangiopathy, fat and blood clots build up in the large blood vessels, stick to the vessel walls, and block the flow of blood. In microangiopathy, the walls of the smaller blood vessels become so thick and weak that they bleed, leak protein, and slow the flow of blood through the body. The decrease of blood flow through stenosis or clot formation impair the flow of oxygen to cells and biological tissues (called ischemia) and lead to their death (necrosis and gangrene, which in turn may require amputation). Thus, tissues which are very sensitive to oxygen levels, such as the retina, develop microangiopathy and may cause blindness (so-called proliferative diabetic retinopathy). Damage to nerve cells may cause peripheral neuropathy, and to kidney cells, diabetic nephropathy (Kimmelstiel-Wilson syndrome).

Macroangiopathy, on the other hand, may cause other complications, such as ischemic heart disease, stroke and peripheral vascular disease which contributes to the diabetic foot ulcers and the risk of amputation.

Diabetes mellitus is the most common cause of adult kidney failure worldwide. It also the most common cause of amputation in the US, usually toes and feet, often as a result of gangrene, and almost always as a result of peripheral vascular disease. Retinal damage (from microangiopathy) makes it the most common cause of blindness among non-elderly adults in the US.

"Diabetic dermopathy" is a manifestation of diabetic angiopathy. It is often found on the shin.


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Diabetic foot ulcers and infections: Current concepts
From Advances in Skin & Wound Care, 1/1/02 by Calhoun, Jason H


To offer an educational experience that will help improve the participant's understanding of diabetic foot ulcers and infections.


This CME/CE activity is intended for physicians and nurses with an interest in the prevention and treatment of diabetic foot ulcers and infections.


1. Describe the factors that put a diabetic patient's foot at risk for ulceration.

2. Identify the components of optimal treatment of diabetic foot ulcers.

3. Explain the roles of vascular and orthopaedic surgery in the treatment of diabetic foot ulcers and infections.

ADV SKIN WOUND CARE 2002;15:31-45.

Submitted August 23,2000; accepted in revised form May 29,2001.

Diabetic foot ulcers and infections are complicated and difficult to treat.

They occur in individuals with a systemic illness that has compromising effects on multiple areas of the body, including the nervous, vascular, musculoskeletal, and immunologic systems. Each of these compromised systems plays a variably weighted role in the occurrence, chronic nature, and eventual recovery or loss of limb in this patient population. The pathogenesis of diabetic foot ulcers and subsequent infections is complex and involves 3 interactive processes: angiopathy, neuropathy, and immunopathy. An understanding of these processes is essential for the treatment and prevention of diabetic foot ulcers.

Standard wound care for diabetic foot ulcers consists of thorough debridement, application of adequate wound dressings, frequent dressing changes, and use of off-loading devices. Adjunctive therapy such as hyperbaric oxygen, should be considered for nonhealing diabetic foot ulcers. Newer technologies brought about by tissue engineering and growth factor research offer further treatment options for some difficult-to-heal wounds.

Infection complicates treatment of a diabetic foot wound, requiring the use of antibiotic therapy and a more aggressive wound care strategy. The systemic nature of diabetes requires a team approach to the care of diabetic foot ulcers and infections, with wound care provided at a specialized facility. Ultimately, prevention of ulcers is the best form of care for the diabetic foot.


A diabetic foot wound is the most common cause for hospitalization of patients with diabetes.1-4 Pecoraro et als showed that ischemia was singularly responsible for lower limb amputation. McNeely et alb found 3 tests to be significant and independent predictors of foot ulceration: absence of the Achilles' tendon reflex, a foot insensate to the 5.07 SemmesWeinstein monofilament7 (North Coast Medical, Inc, San Jose, CA), and a transcutaneous oxygen tension (TcPO2) of less than 30 mm Hg. Of these, impaired cutaneous oxygenation was found to be the strongest risk factor for foot ulceration. These characteristics indicate a significant alteration of the wound healing process in the diabetic patient. The pathogenesis is complex and involves the interactive processes of angiopathy, neuropathy, and immunopathy.


Diabetic angiopathy is perhaps the most frequent cause of morbidity and mortality in a patient with diabetes.8 Angiopathy can be divided into 2 categories: macroangiopathy and microangiopathy.

Macroangiopathy in a diabetic patient presents as a more diffuse disease than in a nondiabetic patient, with more multisegmental involvement and compromised collateral circulation. It is more often seen bilaterally in the lower extremities; the infrapopliteal vessels are more frequently involved9 than in nondiabetic patients. Vascular impairment, evaluated by resting Doppler ankle pressure, was found to correlate with the development of diabetic foot ulcers.11 Large vessel disease predisposes a patient with diabetes to foot lesions secondary to ischemic skin changes that, in turn, lead to ulceration and possible infection.

The subject of microangiopathy is a debated topic, with some researchers showing that it is a factor in diabetic foot ulceration and others showing that it is not. Tooke and Brash" discussed the hemodynamic hypothesis of the pathogenesis of diabetic microangiopathy. This hypothesis states that in the early stages, vessel capillaries of diabetic patients have increased microvascular pressure and flow. The increased capillary pressure results in an injury response within the microvascular endothelium. Injury causes release of extravascular matrix proteins, resulting in microvascular sclerosis. Sclerosis is manifested in the arteriole as hyalinosis and in the capillary as basement membrane thickening,12,is the ultrastructural hallmark of diabetic microangiopathy. With increasing duration of diabetes, the sclerotic process results in limitation of vasodilatation with reduced maximal hyperemia and in loss of autoregulatory capacity. A key observation has been that nailfold capillary pressure is elevated in the early stages of type 1 diabetes. This has been positively correlated with glycemic control, judged by the glycosylated hemoglobin value at the time of pressure measurement. In addition, pressure appears to be particularly high in those individuals at high risk for microangiopathy, yet relatively normal in patients who have avoided the clinical complications of diabetes over many years.

Tooke and Brashll also suggested a role for intrinsic capillary fragility leading to microhemorrhage and hypothesized that this may, in part, explain the potential for rapid advancement of infection through tissue planes. Ferguson et a114 evaluated the histologic appearance of diabetic wounds and found that the majority of wounds were well vascularized. However, narrowing or occlusion of some large blood vessels due to vessel wall thickening was often observed in diabetic ulcers and occasionally in the surrounding skin samples.14 In addition, Raskin et a115 observed a significant reduction in the width of skeletal-muscle capillary basement membrane with improved control of blood glucose in patients with type 1 diabetes.

Other investigators believe that the management of diabetic foot problems has been impeded by the misconception that occlusive lesions in the microvasculature preclude restoration of perfusion.16-18 LoGerfo noted that prospective studies that evaluated arterial casting19 and histologic changes,20 measured vascular resistance, and made use of plethysmography2 have not confirmed the existence of an arteriolar or microcirculatory occlusive process. If an occlusive lesion existed in the microcirculation, it would be a contraindication for arterial reconstruction because both runoff and tissue perfusion would be limited. However, arterial reconstruction has been shown to be beneficial2l when an occlusion is present in large vessels.

LoGerfo16,17 suggests that there are nonocclusive anatomic and physiologic abnormalities in the microcirculation associated with diabetes. Most notable is the thickening of the capillary basement membrane.12,13 This is not associated with a reduction in luminal diameter. In fact, the capillary luminal diameter has been increased in the skin and nerves of patients with diabetes, even in the presence of neuropathy. Increased glycation of basement membrane proteins occurs with displacement of highly charged sulfur groups.22 This is one explanation for the frequently noted increase in leakage of albumin from the capillaries in diabetic patients. Although not proven, it is logical to assume that capillary basement membrane thickening impairs the flux of nutrients and possibly the migration of white blood cells. There is no evidence, however, of impairment of oxygen diffusion. The TcPO2 of diabetic patients with foot ulcers is often higher than that of nondiabetic patients with foot ulcers.23 Peripheral vascular disease is more often related to ulcers in nondiabetic patients; neuropathy is usually the underlying cause of foot ulceration in diabetic patients.


Neuropathy occurs early in the pathogenesis of diabetic foot problems and is the most prominent risk factor for diabetic foot ulcers. All components of nerve function are compromised. The progress of polyneuropathy is variable, but, in general, the longest, finest fibers are affected first. This includes the motor fibers to the intrinsic muscles of the foot. With the loss of lumbrical function, the toes become drawn up into the clawfoot position. As a result, there are points of increased susceptibility to pressure or friction beneath the metatarsophalangeal joints, over the dorsum of the toes, or at the tips of the toes. In some patients, this process leads to Charcot foot.24

Autonomic dysfunction also occurs early in the course of neuropathy. In the foot, autonomic dysfunction results in shunting of blood through direct arteriolevenule communications, diminishing the effectiveness of perfusion.25,26 There is loss of hair, sweat, and oil gland function, leading to dry, scaly skin that cracks and fissures easily.27,28

Vibration, pain, and temperature sensations are affected more than touch or proprioception. The most common method of diagnosing neuropathy involves the use of the Semmes-Weinstein monofilament. The inability to feel a 5.07 thickness monofilament indicates the absence of protective sensation, resulting in decreased awareness of pressure injury or trauma. Decreased sensation in combination with motor nerve-induced deformity sets the stage for ulceration. When skin injury occurs in the absence of the neuroinflammatory response, infection may develop without the usual accompaniment of pain, swelling, and erythema. This may explain why infections in the diabetic foot are often more extensive than anticipated based on the physical signs and symptoms.17


The contribution of immunopathy to the development of infection in a patient with diabetes is controversial. Most investigators believe that poor glucose control predisposes patients to infection.29 However, humoral immunity in the patient with diabetes appears to be normal. Normal to elevated levels of circulating immunoglobulins and normal numbers of B lymphocytes are found.30 In the mouse model, there appears to be no defect in antibody response or complement fixation.31

The impaired host defense mechanism in the diabetic patient appears to occur at the cellular level where impaired leukocyte function and impaired intracellular killing have been observed. A defect in the in vitro chemotaxis of polymorphonuclear leukoyctes from 31 diabetic patients has been described by Mowat and Baum.32 This defect was corrected by the incubation of these cells with insulin, an observation that has been reproduced by another investigator.33 Phagocytosis and the intracellular killing function of the leukocyte appear to be significantly altered in the presence of hyperglycemia.29,31,35 These defects have been partly or completely reversed by improved diabetic control.

Cell-mediated immune responses are also significantly impaired by elevated glucose concentrations. MacCuish et a136 demonstrated a decrease in phytohemagglutinin-induced lymphocyte transformation in poorly controlled diabetic patients, but not in well controlled patients or in healthy subjects. In another study, a poor response of lymphocytes to staphylococcal antigen has been demonstrated in diabetic patients, regardless of the degree of glycemic control.37 In addition, work in a diabetic rat model has detected T lymphocyte immunodeficiency in type 1 diabetes.38,39


Diabetic foot ulcers can be prevented in many patients. Tight glycemic control and patient education are the most important components of a prevention program. Medical management of glucose levels can help reduce the development of diabetic foot pathology. Maintaining glycemic control involves dietary management, home glucose monitoring, proper use of medications, and effective treatment of hyperglycemia. In addition, patients should be educated about the potential for foot problems and taught basic foot care techniques. The most significant risk factor for ulceration of a diabetic foot is the presence of neuropathy; therefore, basic care of the neuropathic diabetic foot is essential. Pinzer et a140 published a comprehensive guide to diabetic foot care based on recommendations of the American Orthopaedic Foot and Ankle Society. When discussing foot care with diabetic patients, practitioners should consider these points:

* Daily inspection of the toes and feet should be emphasized.

* Patients should be advised to wear well-fitting socks and shoes and to inspect their shoes daily for foreign objects or irregularities that can cause wounds.

* Toenails should be trimmed and rough edges should be filed with an emery board.

* Patients should be reminded to wash their feet daily and dry them well and to keep their feet warm and dry.

* Lotion should be used to avoid dryness and cracking of the skin.

* Exercise, proper nutrition, and smoking cessation are important components of a diabetic ulcer prevention program.

Many patients are not aware that they have diabetes. Almost half (43%) of all diabetic patients have their first hospital admission or diagnosis of diabetes associated with a foot ulcer or infection.41,42 After a patient has developed an ulcer, prevention techniques are useful during the wound healing process to prevent further or recurrent ulceration.

Wound Care Techniques

Management of diabetic foot ulcers is becoming more challenging and controversial with the increasing number of wound care products, protocols, and algorithms available. This difficulty is especially pronounced for health care professionals without specialized training in wound care.43 The evolution of wound management and wound care products has created the need for standardized clinical pathways for wound management in the treatment of diabetic ulcerations.

Numerous classification systems have been developed to aid in the treatment of diabetic foot ulcers and infections.42,44,45 One of the best known is the Wagner classification system.46 A useful modification of this system with the addition of treatment guidelines is presented in Table 144

Optimal treatment of diabetic foot ulcers includes a program of ongoing debridement, adequate application of dressings and frequent dressing changes, efforts to reduce pressure points on a patient's feet, and the use of adjunctive therapies and newer technologies for nonhealing wounds.


The first step in treating a diabetic foot ulcer is to perform debridement of the wound. Debridement should be ongoing throughout the healing process. In a retrospective study by Steed et al,47 higher healing rates were seen in patients who received more frequent debridement.

Proper debridement removes all necrotic and infected tissue, leaving a clean, open wound; this is essential for healing to occur. In addition, debridement reduces the bacterial load of the wound, which can impede wound healing and lead to infection. Debridement also allows for better visualization of the wound, which helps in making an accurate assessment. Superficial debridement around the ulcer site can be performed on a neuropathic diabetic foot without the use of an anesthetic. For some wounds, however, deeper surgical debridement may be necessary.

Wound dressings

The primary function of a wound dressing is to promote a moist healing environment, which is necessary for tissue repair.48 The parameters of a particular wound dressing are often overlooked when the features of a specific dressing category are considered. Dressings are often categorized by their ability to provide protection and conformability to the wound and comfort to the patient Functional parameters of dressings include (1) exudate absorptive capacity,49 (2) the ability to debride nonviable tissue and reduce microbial contaminants, (3) promotion of wound rehydration,50 and (4) the potential for use as a vehicle for antibiotic delivery to the wound bed. Table 2 outlines the functions and indications of commonly used types of dressing materials.

To aid in the proper selection of dressing material, an accurate description of the wound characteristics should be obtained.51 Several aspects of a wound that should be given particular attention include the color of the wound bed, the size and location of the wound, the wound margins (to identify sinus tracts and undermining), and the characteristics of the exudate (type, amount, color, consistency, odor, and adherence to the wound base). The wound should be observed on an ongoing basis so that dressing selection is based on the wound stage. One particular dressing should not be used for all wound healing stages and situations. The overall goal is to select the appropriate dressing for restoring and maintaining normal wound physiology.52


Pressure reduction, or off-loading, is a key element in the proper treatment of diabetic foot ulcers. The excessive and prolonged abnormal pressures that occur in a neuropathic diabetic foot must be corrected before wound healing can occur. Off-loading is any measure to eliminate these abnormal pressure points to promote healing or prevent recurrence of diabetic foot ulcers. Several methods have been used to protect the foot from abnormal pressures, such as bed rest, non-weight bearing crutches, walkers, and a myriad of orthotic devices. Many of these methods are impractical; patients are often noncompliant and their wounds are unable to heal.

The goal of off-loading therapy, therefore, should be to reduce the pressure at the ulcer site while maintaining ambulation. Total contact casts (TCCs) have been shown to be effective in the treatment of plantar foot ulceration while allowing the patient to be ambulatory.53,54 TCCs are minimally padded, well-molded plaster casts that allow for even distribution of pressure across the plantar surface of the foot,55 thereby eliminating the excessive concentration of pressure responsible for the ulceration. Patients are unable to remove the casts, forcing compliance. Most studies using TCCs to treat plantar ulcers have found typical mean healing times of approximately 8 weeks.54 TCCs are not indicated for infected wounds. They also require a high degree of skill on the practitioner's part to ensure proper fitting.

Other devices such as the Charcot's restraint orthotic walker (CROW walker), removable walking casts, or half shoes are alternatives that can be removed for local wound care. Patient compliance while using removable devices is essential or healing will not occur. Pressure reduction must be maintained following healing to prevent recurrent ulceration.

Hyperbaric oxygen therapy

Wound healing is a dynamic process and adequate oxygen tensions are needed for healing to occur. Hyperbaric oxygen (HBO) therapy has been used for many years as an adjunctive therapy in the treatment of diabetic foot wounds. In 1969, Silver56 demonstrated the oxygen gradient in wounds. Since that time, both hypoxia and lactic acid production have been found to be stimulants for fibroblast replication,57 collagen production,58 and angiogenesis.59 Fibroblasts are stimulated to divide by low oxygen tensions, yet require higher (>30 mm Hg) oxygen tension for collagen synthesis. Tissue, especially healing tissue, requires oxygen for viability. HBO therapy increases tissue oxygen levels, combating the local ischemic effect at the perimeter of the wound where much of the collagen is laid down by the fibroblasts. The increased tissue oxygen levels at the wound perimeter also increase the oxygen gradient between the viable wound edge and the wound's dead space, thereby stimulating fibroblast division at the wound edge and the wound healing process.

Infection can cause pedal ischemia and decrease oxygen levels. The decrease in the partial pressure of oxygen at the periphery of the wound will impede the growth of new tissue into the wound space. Diabetic wound infections are polymicrobial with a high incidence of anaerobes. Elevated tissue oxygen levels improve leukocyte killing of bacteria6,61 and are toxic to anaerobic organisms.

Although HBO therapy causes local vasoconstriction, the overall increase in blood oxygen levels results in a net gain that increases the oxygen concentration at the wound level. If the patient has adequate arterial circulation, HBO therapy may significantly assist the wound healing process. A common method for evaluating patients for HBO therapy is through the use of transcutaneous oximetery. Normal TcP02 values in the lower extremities are at least 40 mm Hg. If the value is lower in a diabetic patient with a nonhealing foot ulcer, he or she may be a good candidate for HBO therapy.

Several anecdotal and retrospective studies support HBO therapy as effective adjunctive therapy in the medical and surgical management of diabetic wounds.62-66 Hammarlund and Sundberg67 published the only double-blind clinical trial that showed a significant benefit on ulcer healing however, this study did not include diabetic patients. Stone and Scott68 showed a greater limb-salvage rate in the HBO therapy-treated group (72% versus 53%), despite the HBO therapy-treated group having more serious wounds. Stone and Cianci are reportedly conducting a prospective, controlled, randomized, double-blind trial of HBO therapy for the treatment of diabetic foot wounds.69

Advanced technologies

Recent developments in wound care have made advanced technologies available for the treatment of diabetic foot ulcers. These include the Food and Drug Administration (FDA) approval of the tissue-engineered skin substitutes Graftskin (Apligraf; Organogenesis Inc, Canton, MA, and Novartis Pharmaceuticals Corporation, East Hanover, ND, and Interactive Wound Dressing (Dermagraft Advanced Tissue Science, La Jolla, CA, and Smith & Nephew, Largo, FL), as well as becaplermin (Regranex; Ortho-McNeil, Raritan, ND, a topical gel containing recombinant human platelet-derived growth factor. When used in conjunction with standard wound care techniques (including ongoing debridement, frequent dressing changes, pressure relief, and treatment of infection),70 these products have shown promise in treating diabetic foot ulcers. In addition, they may be helpful in managing diabetic ulcers that are unresponsive to standard therapy.

Apligraf gained FDA approval on June 20, 2000, for use in the treatment of noninfected diabetic foot ulcers (it had been previously approved for venous ulcers). A bilayered skin substitute, Apligraf is made from bovine collagen and cells derived from human infant foreskins. Apligraf contains living fibroblasts and keratinocytes that allow it to produce cytokines, growth factors, and matrix proteins associated with wound healing.71 Apligraf provides wound protection and fosters the growth of new skin. In a 4week study, Pham et alt used a regimen of standard wound care and weekly applications of Apligraf. Complete wound closure was obtained in 80% of the patients treated with Apligraf, compared with 42% of patients in the control group. Furthermore, the median time to complete closure in the patients receiving Apligraf was 42.5 days, compared with 91 days in the control group. Apligraf produced a higher healing rate in their patient population.

Dermagraft is a cryopreserved human fibroblast-derived dermal substitute. It is composed of fibroblasts, extracellular matrix, and a bioabsorbable scaffold. The product is manufactured from human fibroblast cells derived from neonatal foreskin tissue. The FDA approved Dermagraft for marketing on September 28, 2001. In the pivotal clinical trial submitted to the FDA,73 patients in the treatment group received up to 8 applications of Dermagraft over the course of the 12-week study. All patients received pressure-reducing footwear and were encouraged to stay off their study foot as much as possible. Analysis of the data from the study concluded that there was a 98.4% probability that Dermagraft plus conventional therapy increased the chance of achieving wound closure with ulcers greater than 6 weeks' duration over and above that of conventional therapy alone. By week 12, the median percentage of wound closure was 91% for the Dermagraft group compared with 78% for the control group (P=0.44). Time to complete wound closure was also significantly faster in ulcers treated wth Dermagraft (P = .040). In addition, wounds treated with Dermagraft were 1.7 times more likely to close than those of control patients at any given time during the study. (P = .044.)

Regranex is a topical growth factor that stimulates the migration of cells to the wound site and promotes healing. It received FDA approval for treatment of diabetic foot ulcers on December 17,1997, and it is indicated for the treatment of deep diabetic neuropathic foot ulcers that have adequate circulation. Its efficacy in superficial diabetic ulcers or ischemic diabetic ulcers has not been evaluated. In a phase 3 study, 50% of the patients treated with Regranex 100 jig/gram in conjunction with standard wound care achieved wound closure, compared with 35% of patients treated with placebo gel and standard wound care.70 In addition, the mean time to achieve complete healing decreased by 32%: 86 days in the Regranex group versus 127 days in patients who received a placebo gel.

Infections Foot infections in diabetic patients can be classified as non-limb-threatening or limb-threatening. Non-limb-threatening infections include superficial infections without systemic toxicity, minimal cellulitis extending less than 2 cm from the portal of entry, and ulceration not extending fully through the skin and lacking significant ischemia. Limb-threatening infections include more extensive cellulitis, lymphangitis, ulcers penetrating through skin into subcutaneous tissues, and prominent ischemia.

Staphylococcus aureus is the most common pathogen isolated in nonlimb-threatening infections. Facultative streptococci are isolated in about one third of patients. Facultative Gramnegative bacilli and anaerobes are uncommon. In contrast, limb-threatening infections are most commonly polymicrobial. S aureus, group B streptococci, Enterococcus, and facultative Gram-negative bacilli are the major pathogens; anaerobic Gram-positive cocci, Peptostreptococcus, and Bacteroides species may also be present. The frequency of the different organisms cultured from diabetic wounds in various studies is presented in Table 3.74

Deep tissue cultures provide the most reliable bacteriologic information in diabetic foot infections. When these are not available, cultures and Grams stain smears of material obtained from curettage of the base of the ulcer or from purulent exudate may provide useful information to guide antimicrobial therapy. When gas is present in surrounding tissues on radiologic examination, it may represent air introduced through the ulcer or gas generated in the soft tissues by infecting aerobic or anaerobic organisms.

If possible, antibiotic treatment of infected diabetic foot ulcers should be based on culture data. Initial antimicrobial treatment in a previously untreated patient with a non-limb-threatening infection is focused primarily on staphylococcus and streptococcus species. For mild infections that can be treated at home, oral clindamycin, cephalexin, amoxicillin/clavulanate, or dicloxacillin for 2 weeks has proved satisfactory. When superficial diabetic ulcers are complicated by cellulitis requiring parenteral antibiotics, intravenous cefazolin or nafcillin are effective. Initial antimicrobial treatment of limb-threatening infections requires broad-spectrum antibiotics because these infections are frequently polymicrobial (S aureus, group B streptococci, other streptococcus species, Enterobacteriaceae, anaerobic Gram-positive cocci, and Bacteroides species including B fragilis). The combination of dindamycin and cefepime or a fluoroquinolone has often been used, as well as cefoxitin or ampicillin/sulbactam. Although ciprofloxacin has been used successfully as monotherapy, potential problems exist. In these infections, ciprofloxacin has very poor coverage for some of the primary pathogens, including stcus species and Bactero/des species, and resistance is emerging among S aureus strains. The combination therapy of clindamycin and levofloxacin offers broad coverage and is a common empiric therapy for diabetic foot infections. A variety of antibiotic regimens are advocated for initial empiric therapy of diabetic foot infections.74,75 Initial antibiotics are modified, if necessary, after culture and sensitivity results are obtained.

Role of Surgery When a nonhealing infected diabetic foot ulcer is worsening despite adequate wound care and culture-directed antibiotics, surgery is needed. Achieving a healed wound and restoring the functional status of the limb are the goals of surgical procedures in this situation. Stabilizing the vascular and orthopaedic components of diabetic foot ulcers is necessary to impede the cycle of ulcer-infection-amputation.

Vascular surgery Because adequate tissue perfusion is required for healing and the delivery of antibiotics, the presence of ischemia should be suspected in diabetic patients with nonhealing ulcers, warranting referral to a vascular surgeon.

The diagnosis of peripheral ischemia in the diabetic patient can be difficult. Claudication is usually the first manifestation of an ischemic lower extremity.76However, the presence of neuropathy often obscures the symptoms associated with claudication in diabetic patients. Other clinical indications of ischemia include nonhealing ulcers, the lack of palpable foot pulses, loss of hair, atrophy of the skin, or cornification of the nails.76 Noninvasive procedures such as Doppler systolic pressure measurements, Doppler ankle pressure measurements and the ankle-brachial index, Doppler waveform analysis, TcPO2 monitoring, pulse volume recordings, and an evaluation of toe pressures may help to confirm the diagnosis of ischemia.76

If intervention is warranted, the arterial system of the lower extremity is visualized before making therapeutic decisions concerning surgery. Contrast angiography is considered the standard technique for imaging by many clinicians. However, newer, less-invasive techniques provide a lower risk to diabetic patients. Duplex ultrasound and magnetic resonance angiography are noninvasive techniques that may be used. In some cases, these methods may be superior to angiography.77,18 Options for treatment of vascular disease include percutaneous transluminal angioplasty with or without stenting, revascularization by a bypass graft, or amputation at a level that will provide function, healing, and protective sensation.

A vascular surgeon should determine the extent of ischemia and whether the patient is a candidate for vascular interventions. Gibbons76 recommends evaluating the patient's associated risk factors and state of well-being when determining the type of vascular intervention. A patient's general medical condition, functional status, motivation, compliance, vascular status, and wound characteristics (infection and necrosis) are variables that influence the decision-making process. In addition, the cost, time, and effort involved should be weighed in relation to the procedures that will result in the greatest long-term functional benefit to a patient. These considerations are appropriate for any aggressive surgical approach to limb salvage and should be addressed in the decision-making process by the medical team, the patient, and the patient's family. A flowchart of the surgical decision-making process is presented in Figure 1.

Orthopaedic surgery The role of orthopaedic surgery in the treatment of diabetic ulcers and infections is varied. An orthopaedic surgeon may debride the area to remove nonviable tissue from an ulcer site or an osteomyelitic bone; perform a variety of procedures to correct deformities, relieve pressure areas, and restore the biomechanical integrity of the lower extremity; or, in the presence of an infected nonhealing ulcer, perform a partial or full amputation. The goals of orthopaedic surgical treatment are wound healing and restoration of efficient functioning of the lower extremity.

The amount of tissue or bone removed during debridement is determined by the amount of nonviable tissue and the extent of infection. Enough tissue must be resected to ensure removal of all necrotic and infected material. Because the most accurate culture data is obtained from deep cultures, a biopsy should be performed and analyzed. The results may help guide the most effective course of antibiotic therapy.

Surgical procedures performed to correct deformities include tenotomy, exostectomy, and, although rare, hammer-toe or clawtoe corrections and arthrodesis.79 Reconstructive surgery in a diabetic patient is difficult and has a high risk for complications. The best long-term functional outcome for the patient may be provided through either partial or full amputation, especially in the presence of an infected, nonhealing wound.

Diabetes is the leading cause of amputation in the United States. In 1996, 86,000 lower-extremity amputations were performed on diabetic patients.80 Diabetic patients are 40 times more likely to have an amputation than nondiabetic patients. The most common indications for amputation are gangrene or infection in a nonhealing ulcer.81 Because ischemia is usually present in this situation, consultation with a vascular surgeon is prudent when determining the necessity and the level of amputation. It may be possible to improve the circulation with vascular intervention. Although this may not eliminate the need for amputation, it may reduce the level of the amputation. However, amputations at a more distal level are associated with higher reamputation rates and, consequently, longer healing times.82,83 Amputations at higher levels, on the other hand, are associated with lower reamputation rates and shorter healing times.82

The decision to amputate is difficult for patients and emotional factors often impede their ability to make a decision that will provide the best long-term functional outcome. A sensitive approach is required during the decision-making process. Counseling and time to consider the procedure may help the patient. Also, the patient can be encouraged to seek a second opinion. In addition, physical factors such as the patients general health, nutrition, and immunocompetence should be evaluated. The patient's ability to follow through with rehabilitation should be taken into consideration as well.

Morbidity and mortality rates are high following amputation and an accurate decision making process is essential. Those who undergo a lower-extremity amputation have up to a 30% chance of undergoing a similar amputation on the contralateral limb within 3 years or up to a 50% chance in 5 years.41,42 Additionally, in an evaluation of selected studies, the National Institutes of Health reported that the mortality rate 1 year after amputation is between 11% and 41%, the 3year postamputation mortality rate is 20% to 50%, and the 5-year rate is 39% to 68%.84 Serious comorbid conditions are common in the diabetic population and mortality in diabetic amputees has been attributed to cardiac or renal complications.85

Conclusion Robson has said, "Infection in a wound, like infection elsewhere in the body, is a manifestation of a disturbed hostbacteria equilibrium in favor of the bacteria... to be able to prevent and manage wound infections requires an understanding of how each prophylactic or therapeutic maneuver works to maintain or reestablish the bacteria-host balance. Only when this equilibrium is in balance can the normal processes of wound healing proceed to give a satisfactory healing trajectory."86

The treatment of diabetic foot ulcers and infections is complicated by the systemic nature of diabetes. Treatment is best rendered by a medical team consisting of endocrinologists, internists, diabetic educators, wound care specialists, orthotics specialists, podiatrists, vascular and orthopaedic surgeons, and infectious disease specialists. The application of optimal wound care techniques and the use of new technologies provide the best outcome for patients with diabetic foot ulcers and infections. Prevention of diabetic foot ulcers is possible and offers the best first-line approach to the care of the diabetic foot. #


1. Gibbons GW, Eliopoulos GM. Infections of the diabetic foot. In: Kozak GP, Campbell DR, Frykberg RG. Management of Diabetic Foot Problems, 2nd ed. Philadelphia, PA: WB Saunders; 1995.

2. Frykberg RG. Diabetic foot ulcerations. In: Frykberg RG. The High Risk Foot in Diabetes Mellitus. New York, NY: Churchill Livingstone; 1991.

3. Thomson FJ, Veves A, Ashe H, et al. A team approach to diabetic foot care: the Manchester

experience. Foot 1995;2:75.

4. Edmonds ME, Blundell MP, Morris ME, et al. Improved survival of the diabetic foot.the role of a specialised foot clinic. Q J Med 1986;232:763.

5. Pecoraro RE, Reiber GE, Burgess EM. Pathways to diabetic limb amputation. Basis for prevention. Diabetes Care 1990;13:513-21.

6. McNeely MJ, Boyko EJ, Ahroni JH, et al.The independent contributions of diabetic neuropathy and vasculopathy in foot ulceration. How great are the risks? Diabetes Care 1995;18:216-9.

7. Rith-Najarian SJ, Stolusky T, Gohdes DM, Identifying diabetic patients at high risk for lower-extremity amputation in a primary health care setting. A prospective evaluation of simple screening criteria. Diabetes Care 1992;15:1386-9.

8. Joseph WS, LeFrock JL.The pathogenesis of diabetic foot infections-immunopathy, angiopathy, and neuropathy. J Foot Surg 1987;26 (1 Suppl):S7-511.

9. Dinerstein C, Mason R, Giron F. Lower extremity complications of diabetes mellitus. Surgical Rounds 1984;7:26-41.

10. Delbridge L, Appleberg M, Reeve TS. Factors associated with development of foot lesions in the diabetic. Surgery 1983;93(1 Pt 1):78-82.

11. Tooke JE, Brash PD. Microvascular aspects of diabetic foot disease. Diabet Med 1996;13:526-529. 12. Goldenberg SG, Alex M, Joshi RA, et al.

Nonatheromatous peripheral vascular disease of the lower extremity in diabetes mellitus. Diabetes 1959;8:261-73.

13. Aagenaes 0, Moe H. Light- and electronmicroscope study of skin capillaries of diabetics. Diabetes 1961;10:253-8.

14. Ferguson MW, Herrick SE, Spencer MJ, Shaw JE, Boulton AJ, Sloan, R The histology of diabetic foot ulcers. Diabet Med 1996;13:530-533.

15. Raskin P, Pietri AO, Under R, Shannon WA, The effect of diabetic control on the width of skeletal-muscle capillary basement membrane in patients with type I diabetes mellitus. N Engl J Med 1983;309:1546-50.

16. LoGerfo FW, Coffman JD. Current concepts. Vascular and microvascular disease of the foot in diabetes. Implications for foot care. N Engl J Med 1984;311:1615-9.

17. LoGerfo FW, Misare FD. Current management of the diabetic foot. Adv Surg 1997;30:417-26.

18. Pham HT, Economides PA, Veves A. The role of endothelial function on the foot. Microcirculation and wound healing in patients with diabetes. Clin Podiatr Med Surg 1998;15(1):85-93.

19. Conrad MC. Large and small artery occlusion in diabetics and nondiabetics with severe vascular disease. Circulation 1967;36:83-91.

20, Strandness DEJ, Priest RE, Gibbons GE. Combined clinical and pathologic study of diabetic and nondiabetic peripheral arterial dis

ease. Diabetes 1964;13:366-72.

21. LoGerfo FW, Gibbons GW, Pomposelli FB Jr, et al. Trends in the care of the diabetic foot expanded role of arterial reconstruction. Arch Surg 1992;127:617-21.

22. Brownlee M, Cerami A,Vlassara H. Advanced glycosylation end products in tissue and the biochemical basis of diabetic complications. N Engl J Med 1988;318:1315-21.

23. Wyss CR, Matsen FA, Simmons CW, et al. Transcutaneous oxygen tension measurements on limbs of diabetics and nondiabetics with peripheral vascular disease. Diabetes 1964;13:366-72.

24. Klenerman L. The Charcot joint in diabetes. Diabet Med 1995;13:552-554.

25. Partsh H. Neuropathies of the ulcero-mutilating types: clinical aspects, classification, circulation measurements. Vasa 1977:1-48.

26. Boulton AJ, Scarpello JH, Ward JD. Venous oxygenation in the diabetic neuropathic foot: evidence for arteriovenous shunting? Diabetologia 1982;22:6-8.

27. Deanfield JE, Daggett PR, Harrison MJ. The role of autonomic neuropathy in diabetic foot ulceration. Neurol Sci 1980;47:203-10.

28. Edmonds ME, Nicolaides KH, Watkins PJ. Autonomic neuropathy and diabetic foot ulcerations. Diabet Med 1986;3:56-9.

29. Rayfield EJ, Ault MJ, Keusch GT, Brothers MJ, Nechemias C, Smith H. Infection and diabetes: the case for glucose control. Am J Med 1982;72:439-50.

30. Ellenberg M, Bifkin H, eds. Diabetes Mellitus: Theory and Practice. New York, NY: McGraw-Hill; 1970: p 734-58.

31. Dolkart RE, Halpern B, Perlman J. Comparison of antibody response in normal and alloxan diabetic mice. Diabetes 1971;20:162-7.

32. Mowat AG, Baum J. Chemotaxis of polymorphonuclear leukocytes from patients with diabetes mellitus. N Engl J Med 1971;284:621-7.

33. Molenaar DM, Palumbo PJ, Wilson WR, Ritt RE Jr. Leukocyte chemotaxis in diabetic patients and their nondiabetic first degree relatives. Diabetes 1976;25(2 Suppl):880-3.

34. Bybee JD, Rodgers DE.The phagocytic activity of polymorphonuclear leukocytes obtained from patients with diabetes mellitus, J Lab Clin Med 1964;64:1-13.

35. Bagdade JD, Root RK Bulger RD. Impaired leukocyte function in patients with poorly controlled diabetes. Diabetes 1974;23:9-15.

36. MacCuish AC, Urbaniak SJ, Campbell CJ, Duncan U, Irvine WJ. Phytohemagglutinin transformation and circulating lymphocyte subpopulations in insulin-dependent diabetic patients. Diabetes 1974;23:708-12.

37. Casey JI, Heeter BJ, Klyshevich KA. Impaired responses of lymphocytes of diabetic subjects

to antigen of Staphylococcus aureus.J Infect Dis 1983;136:495-501.

38. Elder ME, MacLaren NK. Identification of profound peripheral T lymphocyte immunodeficiencies in the spontaneously diabetic BB rat. J Immunol 1983;130:1723-31.

39. Naji A, Silvers WK, Kimura H, Bellgrau D, Markmann JF, Barker CF. Analytical and functional studies on the T cells of untreated and immunologically tolerant diabetes-prone BB rats. J Immunol 1983;130:2168-72.

40. Pinzur MS, Slovenkai MP, Trepman E. Guidelines for diabetic foot care. Foot Ankle Int 1999;20(11):695-702.

41. Jacobs RL. Salvage of a functional lower limb in diabetic patients after amputation. Instr Course Lect 1993;42:159-67.

42. Brodsky JW. Outpatient diagnosis and care of the diabetic foot. Instr Course Lect 1993;42:121-39. 43. van Rijswijk L, Beitz J.The traditions and termino

gy of wound dressings: food for thought.J Wound Ostomy Continence Nurs 1998;25:116-22.

44. Calhoun JH, Cantrell J, Cobos J, et al. Treatment of diabetic foot infections:Wagner classification, therapy, and outcome. Foot Ankle 1988;9:101-6.

45. Calhoun JH, Keogh P, Koen S, Mader JT. Diabetic foot infections: 902 cases. A prospective study of protocol versus non-protocol treatment. Presented at: American Orthopaedic Foot and Ankle Society Winter Meeting; 1998; New Orleans, LA.

46. Wagner FW Jr.The dysvascular foot: a system for diagnosis and treatment. Foot Ankle 1981;2(2):64-122.

47. Steed DL, Donohoe D, Webster MW, Lindsley L. Effect of extensive debridement and treatment on the healing of diabetic foot ulcers. J Am Coll Surg 1996;183:61-4.

48. Sussman G. Management of the wound environment In: Sussman C, Bates-Jensen BM, eds.Wound Care: A Collaborative Practice Manual for Physical Therapists and Nurses. Gaithersburg MD, Aspen Publishers, Inc; 1998: p 201-13.

49. Bryant RA. Acute and Chronic Wounds, Nursing Management. St. Louis, MO: Mosby-Yearbook, Inc; 1994.

50. Gibbons GW, Habershaw GM. Diabetic foot infections. Anatomy and surgery. Infect Dis Clin North Am 1995,9:131-42.

51. Day MR, Fish SE, Day RD.The use and abuse of wound care materials in the treatment of diabetic ulcerations. Clin Podiatr Med Surg 1998;15:139-50.

52. Dunn JM. Local wound care in the diabetic. Clin Podiatr Med Surg 1987;4:413-8.

53. Helm PA, Walker SC, Pullium G. Total contact casting in diabetic patients with neuropathic foot ulcerations. Arch Phys Med Rehabil 1984;65:691-3.

54. Sinacore DR.Total contact casting for diabetic neuropathic ulcers. Phys Ther 1996; 76(3):296-301.

55. Bauman JH, Girling, JP, Brand PW. Plantar pressures and trophic ulceration. J Bone Joint Surg 1963;45A:652-73.

56. Silver IA.The measurement of oxygen tension in healing tissue. Progress Respir Res 1969;3:124. 57. Hunt TK.The physiology of wound healing. Ann Emerg Med 1988;17:1265-73.

58. Hunt TK, Pai MR The effect of varying ambient oxygen tensions on wound metabolism and collagen synthesis. Surg Gynecol Obstet 1972;135:561-7.

59. Knighton DR, Silver IA, Hunt TK. Regulation of wound-healing angiogenesis-effect of oxygen gradients and inspired oxygen concentration. Surgery 1981;90(2):262-70.

60. Mandell GL. Bactericidal activity of aerobic and anaerobic polymorphonuclear neutrophils. Infect Immun 1974,9:337-41.

61. Mader JT, Brown GL, Guckian JC, Wells CH, Reinarz JA.A mechanism for the amelioration by hyperbaric oxygen of experimental staphylococcal osteomyelitis in rabbits. J Infect Dis 1980;142:915-22.

62. Davis JC.The use of adjuvant hyperbaric oxygen in treatment of the diabetic foot. Clin Podiatr Med Surg 1987;4:429-37.

63. Oriani G, Meazza D, Favales F, et al. Hyperbaric oxygen therapy in diabetic gangrene. J Hyperb Med 1990;5:171-5,

64. Hart GB, Strauss MD. Responses of ischemic ulcerative condition to OHR In: Sixth International Congress on Hyperbaric Medicine. Aberdeen,TX: Aberdeen University Press; 1979.

65. Wattel E, Mathieu DM, Fassati P, et al. Hyperbaric oxygen in the treatment of diabetic foot lesions. J Hyperb Med 1991;6:263-8.

66. Baroni G, Porro T, Faglia E, et al. Hyperbaric oxygen in diabetic gangrene treatment. Diabetes Care 1987;10:81-6.

67. Hammarlund C, Sundberg T. Hyperbaric oxygen reduced size of chronic leg ulcers: a randomized double-blind study. Plast Reconstr Surg 1994;93(4):829-33.

68. Stone JA, Scott RG. The role of hyperbaric oxygen and platelet derived growth factors in the treatment of the diabetic foot. Abstract. Undersea Biomed Res 1995;22:78.

69. Stone JA, Cianci R The adjunctive role of hyperbaric oxygen therapy in the treatment of lower extremity wounds in patients with diabetes. Diabetes Spectrum 1997;10:1.

70. Wieman TJ, Smiell JM, Su Y. Efficacy and safety of a topical gel formulation of recombinant human platelet-derived growth factor-BB (becaplermin) in patients with chronic neuropathic diabetic ulcers. A phase III randomized placebo-controlled double blind study. Diabetes Care 1998;21(5)-822-7.

71. Falanga VJ.Tissue engineering in wound repair. Adv Skin Wound Care 2000;13(2 Suppl):15-9.

72. Pham HT, Rosenblum BI, Lyons TE, et al. Evaluation of Graftskin (Apligraf), a human skin equivalent, for the treatment of diabetic foot ulcers. Abstract. Diabetes 1999;48(1 Suppl):18A.

73. Summary of safety and effectiveness data. [November 5,2001].

74. Frykberg RG, Veves A. Diabetic foot infections. Diabetes Metab Rev 1996;12(3):255-70.

75. Grayson ML Diabetic foot infections.Antimicrobial therapy. Infect Dis Clin North Am 1995,9:143-61. 76. Gibbons GW. Vascular evaluation and long-term

results of distal bypass surgery in patients with diabetes. Clin Podiatr Med Surg 1995;12(1):129-40. 77. Carpenter JP, Owen RS, Baum RA, et al. Magnetic

resonance angiography of peripheral runoff vessels.J Vasc Surg 1992;16:807-15.

78. Larch E, Minar E, Ahmadi R, et al. Value of color duplex sonography for evaluation of tibioperoneal arteries in patients with femoropopliteal obstruction: a prospective comparison with anterograde intraarterial digital subtraction angiography. J Vasc Surg 1997;25:629-36.

79. Chayton ER Surgical treatment of the diabetic foot Diabetes Metab Res Rev 2000,16(1 Suppl)566-569. 80. Centers for Disease Control and Prevention.

Diabetes Surveillance Report. 1999. Available at: tm. Accessed April 30,2001.

81. Mayfield JA, Reiber GE, Sanders U, Janisse D, Pogach LM. Preventive foot care in people with diabetes. Diabetes Care 1998;21:2161-77.

82. Larsson J, Apelqvist J.Towards less amputations in diabetic patients. Incidence, causes, cost, treatment, and prevention-a review. Acta Orthop Scand 1995,66:181-92.

83. Larsson J, Agardh CD, Apelqvist J, Stenstrom A. Long-term prognosis after healed amputation in patients with diabetes. Clin Orthop 1998;350:149-58.

84. Reiber GE, Boyko EJ, Smith DG. Lower extremity foot ulcers and amputations in diabetics. In: National Institute of Diabetes and Digestive and Kidney Diseases. Diabetes in America, 2nd edition. NIH Publication No. 95-1468. Rockville, MD: National Institutes of Health; 1995.

85. Lee JS, Lu M, Lee VS, Russell D, Bahr C, Lee Er. Lower extremity amputation. Incidence, risk factors, and mortality in the Oklahoma Indian Diabetes Study. Diabetes 1993.42:876-82.

86. Robson MC.Wound infection. A failure ofwound healing caused by an imbalance of bacteria. Surg Clin North Am 1997;77(3):637-50.

From the University of Texas Medical Branch, Galveston, TX

Jason H. Calhoun, MD e Professor and Chairman . Department of Orthopaedics and Rehabilitation

Kristi A. Overgaard, BS o Medical Editor e Department of Orthopaedics and Rehabilitation

C. Melinda Stevens, BS e Research Director e Department of Orthopaedics and Rehabilitation e Division of Hyperbaric Medicine and Wound Care

James P. F. bowling, BS . Research Assistant * Department of Orthopaedics and Rehabilitation

Jon T. Mader, MD o Professor 9 Department of Orthopaedics and Rehabilitation Division of Hyperbaric Medicine and Wound Care e Division of Surgical Infectious Diseases

The authors have disclosed that they do not have any significant relationships with or financial interests in any commercial companies that pertain to this educational activity.

Copyright Springhouse Corporation Jan/Feb 2002
Provided by ProQuest Information and Learning Company. All rights Reserved

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