Review

Treatment for diabetic foot ulcers

Peter R Cavanagh, Benjamin A Lipsky, Andrew W Bradbury, Georgeanne Botek

People with diabetes develop foot ulcers because of neuropathy (sensory, motor, and autonomic decits), ischaemia, or both. The initiating injury may be from acute mechanical or thermal trauma or from repetitively or continuously applied mechanical stress. Patients with clinically signicant limb ischaemia should be assessed by a vascular surgeon to determine the need for angioplasty, stenting, or femorodistal bypass. When infection complicates a foot ulcer, the combination can be limb or life-threatening. Infection is dened clinically, but wound cultures reveal the causative pathogens. Tissue specimens are strongly preferred to wound swabs for wound cultures. Antimicrobial therapy should be guided by culture results, and should aim to cure the infection, not to heal the wound. Alleviation of the mechanical load on ulcers (off-loading) should always be a part of treatment. Neuropathic ulcers typically heal in 6 weeks with total contact casting, because it effectively relieves pressure at the ulcer site and enforces patient compliance. The success of other approaches to off-loading similarly depends on the patients adherence to the effectiveness of pressure relief. Surgery to heal ulcers and prevent recurrence can include tenotomy, tendon lengthening, reconstruction, or removal of bony prominences. However, these procedures may result in secondary ulceration and other complications. Ulcer recurrence rates are high, but appropriate education for patients, the provision of posthealing footwear, and regular foot care can reduce rates of re-ulceration. People with diabetes have a 1225% lifetime risk of developing a foot ulcer.1,2 The high rates of diabetes in many parts of the world make foot ulcers a major and increasing public-health problem. Foot ulcers cause substantial morbidity, impair quality of life, engender high treatment costs (about US$17 50027 987 [UK953315 246])3,4 and are the most important risk factor for lower-extremity amputation.5,6 Unfortunately, treatment provided for foot ulcers is often inadequate,7,8 resulting in avoidable complications and unnecessarily extended healing times. In the hope of improving outcomes, we present an overview of the state of the art in medical and surgical treatment for diabetic foot ulcers. developing countries, also occur.14 Restricted joint mobility,15 poor foot care,16 and foot deformity resulting in bony prominences17 also contribute to risk of ulceration.

Lancet 2005; 366: 172535 See Articles pages 1695 and 1704 See Review page 1736 Diabetic Foot Care Program, Departments of Biomedical Engineering and Orthopaedic Surgery, and the Orthopaedic Research Center, Cleveland Clinic Foundation, Cleveland, OH, USA (Prof P R Cavanagh DSc); Cleveland Clinic Lerner College of Medicine of Case Western Reserve University, Cleveland, OH, USA (Prof P R Cavanagh); General Internal Medicine Clinic, VA Puget Sound Health Care System, University of Washington School of Medicine, Seattle, WA, USA (Prof B A Lipsky MD); Department of Vascular Surgery, University of Birmingham, Birmingham, UK (Prof A W Bradbury FRCS); Heart of England NHS Foundation Trust, Birmingham, UK (Prof A W Bradbury); and Diabetic Foot Care Programme, Department of Orthopaedic Surgery, The Cleveland Clinic Foundation, Cleveland, OH, USA (G Botek DPM) Correspondence to: Dr Peter R Cavanagh, Diabetic Foot Care Program, Department of Biomedical Engineering, ND20, The Cleveland Clinic Foundation, 9500 Euclid Avenue, Cleveland, OH 44195, USA cavanap@ccf.org

Classication
Several foot-ulcer classication schemes have been proposed, but none is universally accepted. The sixgrade Wagner-Meggitt classication, which has been used for decades,18 classies wounds by the depth of ulceration and extent of gangrene. The University of Texas system18 grades wound by depth and then stages them by the presence or absence of infection and ischaemia, but it does not include measures of neuropathy or ulcer area. The S(AD) SAD classication19 grades ve categories (size [area, depth], sepsis, arteriopathy, and denervation) on a four-point scale (03). Similarly, the International Working Group on the Diabetic Foot has proposed the PEDIS classication,20 which grades the wound on the basis of ve features: perfusion (arterial supply), extent (area), depth, infection, and sensation. The Infectious Diseases Society of America published guidelines in 200421 that subclassify infected diabetic foot wounds into the categories of mild (restricted involvement of only skin
Search strategy and selection criteria In the preparation of this review, we used search strings that included: diabetic foot in combination with ulcers, healing, infection, surgery, biomechanics, and cost in a PubMed search, emphasising papers (in any language) published since 1995. We also searched for references in other databases, including EMBASE and the Cochrane Library. Because there were only a few comparative randomised controlled trials on this topic, we selected articles for reference based on an attempt to be comprehensive rather than on a formal assessment of study quality.

Cause
Assessment of the cause of an ulcer helps clinicians in determining the most appropriate treatment. Many clinicians classify foot ulcers in people with diabetes as neuropathic, ischaemic, or neuroischaemic, depending on the relative contributions of the late diabetic complications of peripheral neuropathy and arterial disease to the ulcers cause.9 Motor10 and autonomic11 decits could also contribute to the risk of ulceration. Neuropathic ulcers, the most common type, result from tissue-damaging mechanical loads applied to an insensate foot. Reduced sensation can substantially impair the patients perception of touch, deep pressure, temperature, and joint position. Peripheral vascular disease in diabetes characteristically affects vessels between the knee and the ankle12 (see later). Mechanical damage to poorly perfused (and often friable) tissues typically causes ischaemic ulcers. The foot injury that initiates ulcers could result either from trauma (stepping on a skin-penetrating object) or from mechanical stress that is repetitive (walking barefoot or in improper footwear) or continuously applied (extended unperceived pressure). Thermal injury13 and bites from animals and vermin, especially in
www.thelancet.com Vol 366 November 12, 2005

1725

Review

and subcutaneous tissues), moderate (more extensive or affecting deeper tissues), and severe (accompanied by systemic signs of infection or metabolic instability).

Perfusion
Nearly all patients with lower-limb ulcers can benet from evidence-based therapy aimed at reducing the risk of atherosclerotic vascular disease.22,23 This treatment includes help on smoking cessation,24,25 diet improvement, and medication prescription when needed to reach target concentrations of total and LDL cholesterol;26,27 potential antiplatelet drug treatment;28 and the achieving of optimum blood pressure29,30 and glycaemic control.31 Medical and surgical specialists should work with the patients primary care provider to achieve these goals.32,33 Any diabetic patient with a skin break below the knee that has not healed with appropriate care in 2 weeks should be referred urgently to a suitable specialist for an assessment.3437 Because treatment for neuropathic ulcers is mainly non-surgical (see later), the initial assessment must differentiate patients with a predominantly ischaemic versus neuropathic cause. The provider must also establish the extent of any neuropathy or vascular disease,38 which includes testing for sensation, palpating for foot pulses, measuring the ankle-brachial pressure index (ABPI) and toe pressures,39 and often undertaking colour-ow duplex ultrasonography.35,40 Patients with lower-limb tissue loss from ischaemia should be assessed by a vascular surgeon. Magnetic resonance angiography (MRA) or conventional intra-arterial digital subtraction angiography could be needed to help plan the reconstruction.41 Surgeons (general, vascular, orthopaedic, plastic, podiatric) generally become involved in treating severe tissue infection,42,43 especially when gangrene or underlying osteomyelitis remain despite antibiotic treatment.4447 MRI may help distinguish neuropathic osteoarthropathy (Charcot foot) from osteomyelitis48 and reveal the extent of the underlying necrosis and investigate whether a functional foot can be salvaged.4951 The main purpose of surgery is to remove infected and necrotic soft and bony tissue back to a healthy base that will support granulation tissue and allow healing by secondary intention. Advanced surgical techniques, such as free tissue transfers, could provide excellent results in skilled hands in selected patients.5257 Reconstructive and corrective surgery may also be indicated in patients with an unstable Charcot foot.5861 In some instances, it is reasonable to attempt healing of ischaemic and neuroischaemic ulcers before revascularisation.32,62,63 However, many diabetic patients will need revascularisation to achieve timely and durable healing. How this healing is achieved depends on whether the patient has supra-inguinal (aorto-iliac) disease, infra-inguinal (femoro-popliteal-crural) disease, or both.64 Angiography, preferably MRA, will determine
1726

whether patients with aorto-iliac disease are suitable for endovascular surgery.65 The long-term results of angioplasty (with or without stenting) in these large, high-ow vessels tend to be good and the risks generally low.12 Open surgeryeither anatomic (aorto-[bi]-femoral bypass) or extra-anatomic (femoro-femoral crossover or axillo-[bi]-femoral bypass)is reserved for patients who do not have an endovascular option.65 Because no satisfactory evidence base exists,66,67 treatment of infrainguinal disease is more difcult67 and controversial. The debate centres on whether rst-line treatment should be surgical or endovascular.68,69 The standard treatment for patients with ischaemic (or neuroischaemic) ulceration is still femorodistal bypass with autogenous tissue, which is usually the long saphenous vein.37,65,70,71 If such tissue is unavailable, prosthetic grafts can be used,72 although they are associated with reduced patency rates73 and less resistance to infection. Specialised centres report few complications and high patency and limb salvage rates after lower-limb bypass surgery.37 However, these are long, technically demanding operations in high-risk patients74 and, even in the wealthiest countries, not all patients have access to heath-care services that can deliver such favourable outcomes.75 Many vascular surgeons and interventional radiologists believe that the multi-level (often distal and heavily calcied) disease typically seen in diabetic patients with ischaemic (or neuroischaemic) ulceration is not amenable to conventional (transluminal) angioplasty.12,68,69 The use of stents,76,77 remote endarterectomy devices,78 and various other novel recanalising techniques, such as subintimal angioplasty,79,80 all show promise. The results of an ongoing 5-year prospective study (BASIL; bypass versus angioplasty in severe ischaemia of the leg)68,69 are expected in late 2005. These will, for the rst time, provide level I evidence regarding the most clinically and cost-effective treatment of lower-limb ulceration and tissue loss secondary to infra-inguinal disease in patients with diabetes. Sometimes, especially in smokers or individuals with other comorbidities, and even in countries with sophisticated health-care systems, the foot is non-viable and needs urgent amputation.81,82 In poorer countries,83 and in disadvantaged groups in wealthy countries, the risk of lower-extremity amputation can be very high and the outcome poor outside a few specialised centres.82,8487 Amputees represent a high-risk group with a generally poor prognosis.8893 In addition to the direct surgical morbidity and mortality, inadequate and delayed rehabilitation and limb tting94 increases the risk of complications, such as infection with antibiotic-resistant organisms95 and thromboembolic disease.96 By contrast, if such patients receive timely, evidence-based care97 from a multidisciplinary team (consisting of, among others, diabetologists, surgeons, podiatrists, specialist nurses, footwear experts, rehabilitation specialists, and
www.thelancet.com Vol 366 November 12, 2005

Review

prosthetists),84,98,99 morbidity and mortality can be kept at a minimum,100 physical and psychological outcomes can be improved,90,101 and health and social-care costs reduced.102104 More research and evidence is needed to dene the best preoperative and postoperative care pathways for amputees.90,105

Presentation

Presentation after debridement

Day 4

Extent and depth

Serial measurement of the wound area can help measure the rate of healing, and therefore the efcacy of treatment.106 Wound areas can be directly measured in several ways, for example, by tracings inked on clear acetate, calibrated digital photographs (gure 1), or direct measurement of maximum length and width, among other techniques. Wound volume is difcult to measure, but ultrasonography could prove useful.107 The criterion most accepted for healing studies is complete closure or epithelialisation after 20 weeks of treatment,108,109 but reduction in the wound area at 10 and 20 weeks is also used. Wound areas that are 2 cm2 or less, have been present for 2 months or less, are relatively shallow, and are non-infected have the highest probability of healing.110

Day 7

Day 14

Day 21

Infection
Not all diabetic foot wounds become infected, but when infection does take place, the patients limb, and sometimes life, can be at risk. All open wounds are colonised with microorganisms, and even virulent pathogens (eg, Staphylococcus aureus) can sometimes be colonisers or contaminants. Because of this, infection cannot usually be dened microbiologically.111,112 The generally accepted clinical denition of infection is the presence of purulent secretions or at least two signs or symptoms of inammation (erythema, warmth, tenderness, pain, induration).21 Since the presence of ischaemia or neuropathy can both mimic and obscure these cardinal manifestations, it has been suggested that signs such as friable tissue, wound undermining, and foul odour imply infection.47,113 Most diabetic foot infections do not produce systemic manifestations, such as fever or leucocytosis,86,114 but when these signs are present, they typically suggest that any accompanying infection is severe.114 A diabetic patient presenting with a foot infection must be assessed promptly and systematically. The assessment must include attention to the foot, limb, and entire body of patient.21 Initial management consists of cleansing of the wound, debriding of any necrotic or gangrenous material, and the probing (preferably with a blunt sterile metal instrument) for foreign bodies or exposed bone.115 With infected ulcers, clinicians should obtain material for a wound culture (gure 2). Tissue specimens are strongly preferred to wound swabs, because they provide more sensitive and specic results.21 Tissue can be obtained by scraping of the base of the ulcer with a scalpel or dermal curette (curettage) or by wound biopsy
www.thelancet.com Vol 366 November 12, 2005 Figure 1: Rapid healing of an uncomplicated neuropathic ulcer The ulcer had been present for 8 weeks and was treated by weekly applications of total contact casting. Scale in cm.

(obtained at the bedside, clinic, or operating theatre). Aseptically obtained aspirates of pus (purulent secretions) or tissue uid can also provide good specimens for culture. The specimen should be processed for both aerobic and anaerobic cultures and a gram-stained smear, if possible. Blood obtained for a complete blood count (and leucocyte differential), basic serum chemistry panels, and inammatory markers
Swab A B Curettage C Aspiration

Figure 2: Methods used to obtain specimens for wound culture The wound should be debrided before the specimen is obtained. Specimens obtained by a wound swab (A) are less accurate than tissue obtained by curettage (B) or biopsy (not shown). Aspiration of purulent secretions (C) also provides good specimens.

1727

Review

(erythrocyte sedimentation rate [ESR] or C-reactive protein) can help dene the severity of the infection.45 In most instances, plain radiographs of the foot will help to identify foreign bodies, gas in the tissues, or evidence of osteomyelitis. More sophisticated imaging tests (the best of which is MRI) might be needed to better dene the presence or absence of bone or deep soft-tissue infection.116118 Clinicians should use available data to decide whether infections are safe to treat on an outpatient basis, or whether hospital care is needed for medical, diagnostic, surgical, or psychosocial reasons. The most important pathogens causing diabetic foot infections are aerobic gram-positive cocci (GPC), especially S aureus, but also -haemolytic streptococci (especially group B) and coagulase-negative staphylococci. These GPCs often cause monomicrobial infections, but patients with chronic ulcers, or those who have recently received antibiotic treatment, often have a polymicrobial mix of aerobic gram-negative bacilli with GPCs.119125 Obligate anaerobes are rarely the only pathogens in these infections, but they could contribute to mixed infections, especially in patients with foot ischaemia or gangrene.126,127 Some organisms, such as Pseudomonas aeruginosa and Enterococcus species, often represent colonisers that do not need specically directed antibiotic therapy.128,129 Although clinically uninfected lesions do not need antimicrobial treatment, all infected wounds do. The initial regimen should usually be selected empirically, and then be modied on the basis of both the patients clinical response and the results of culture and sensitivity testing.128,130,131 The clinician should base the selected antibiotic drugs largely on the probable causative organisms, taking into account any known local antibiotic resistance patterns (especially the presence of meticillin-resistant S aureus [MRSA]).91,132134 Factors such as renal or hepatic dysfunction or a history of drug allergy (especially to penicillin) could constrain antibiotic choices. Patients with severe infections need parenteral treatment, at least initially; oral therapy is often adequate for those with mild or moderate infections. Topical antimicrobials are often effective for mildly infected ulcers, but few studies of this approach exist.135137 Some topical antiseptics can impair wound healing, but dressings containing silver or iodine seem to be safe, and possibly useful.138140 Several antibiotic regimens have shown efcacy (often in case series or non-comparative studies) in treating diabetic foot infections, but none has emerged as the preferred choice.21 Recent trials of antibiotic therapy have used a more robust randomised controlled design.141143 The largest and latest study144 with a double-blind protocol showed similar efcacy for ertapenem and piperacillin/ tazobactam. For mild infections, 7 or 10 days of treatment are usually sufcient, whereas most moderate and severe soft-tissue infections need up to 2 to 3 weeks
1728

of treatment.21 The aim of antimicrobial therapy is to cure the infection, not to heal the wound; extended treatment increases the risk of drug-related toxic effects and development of antibiotic resistance. Antibiotic treatment without off-loading a plantar wound (ie, the relieving of a mechanical load) is unlikely to result in ulcer healing (see later). Although antibiotic therapy is crucial for treating diabetic foot infections, most patients also need adequate wound care.31,145,146 With moderate or severe infections, an experienced surgeon may need to determine if more extensive surgery,147150 including arterial revascularisation for patients with an ischaemic foot, is needed.35,71,151,152 The clinician must also select an adequate wound-care regimen, attempt to improve glycaemic control, and ensure that the patient puts no pressure on the wound (see later). If the clinician elects ambulatory treatment, the patient should return for a follow-up assessment a few days after the initial encounter to check on clinical progress and culture and sensitivity results. Infection of bone underlying a foot ulcer is an especially difcult diagnostic and therapeutic problem.153 Osteomyelitis is probably present if the bone is visible or palpable by probing. A substantially raised ESR ( 70 mm/h) also suggests bone infection, but the sensitivity of this nding could be low.154,155 Bone infection must usually be present for at least 2 weeks before it can be regarded as the cause of abnormalities seen on plain radiographs. Where present, bony lesions could also represent non-infectious Charcot foot. Most nuclear medicine tests (eg, technetium bone scans or labelled leucocyte scans) are more sensitive than plain radiography, but are relatively non-specic and less accurate than MRI.116,156 The gold standard test for osteomyelitis is a bone biopsy sample processed for culture and histology.153,157 Because results of wound cultures do not reliably indicate those of bone, the use of a specimen from either surgical debridement of bone or percutaneous biopsy is preferred.158,159 Bone infection almost always occurs by direct extension from the soft tissue and represents chronic osteomyelitis. We believe that this condition is best treated by surgical resection of all infected and necrotic bone,160,161 but retrospective studies suggest that long-term treatment (at least for 46 weeks) with drugs that penetrate well into bone (eg, uoroquinolones) can often produce a remission of infection.157

Wound treatments
Another Review109 in this issue looks at the biology of wound healing and novel therapies. New treatments for diabetic foot ulcers continue to be introduced,162 yet few are subjected to controlled or comparative studies of their efcacy.135,163 Recent developments include the use of bone-marrow-derived stem cells,164 negative pressure dressings,165,166 bioengineered skin equivalents,167 and
www.thelancet.com Vol 366 November 12, 2005

Review

growth-factor therapy.168 Hyperbaric oxygen treatment seems to reduce the risk of major amputation, but not the time to ulcer healing or the rate of minor amputation.169 Routine debridement of devitalised tissue at follow-up visits is widely recommended, but evidence showing that it accelerates healing is scarce.170 Maggot (larval) biotherapy seems to be effective for debridement171 and acceleration of healing,172,173 and perhaps also in reducing antibiotic use and risk of amputation.174

Mechanical load relief

Patients should be counselled never to walk in the same shoes that could have contributed to a foot ulcer.175,176 Pressure relief on ulcers, commonly referred to as offloading, should always be a part of the treatment plan. The most compelling evidence that off-loading accelerates ulcer healing comes from studies using a total contact cast for healing non-infected neuropathic ulcers.177,178 Neuropathic ulcers that have resisted healing for many months or years typically heal in about 6 weeks in a total contact cast.177 Bony deformity or displacement of soft tissues can lead to high plantar pressure, which is associated with ulceration179,180 and failure to heal.181 The measurement of pressure between the foot and ground and between the foot and shoe (gure 3),182 although not yet widely available in clinical practice, shows whether the patient has adequate load relief during and after ulcer healing. Pressure between the foot and ground at a plantar prominence can exceed 1000 kPa, whereas pressure between a correctly applied total contact cast and a potential ulcer site is less than 100 kPa.183 Plantar shear forces are probably pathophysiologically important, but cannot be easily measured at present.184 Total contact casts are successful when properly applied and changed at least weekly,185 partly because patients cannot remove them easily. Patients with an ulcer are frequently non-compliant with a removable off-loading device.186 Alternative approaches to nonremovable healing footwear are also efcacious, including the so-called instant total contact cast.187 However, all such devices could restrict the patients ability to engage in typical daily activities, such as bathing or driving. Often the only treatment available or acceptable to the patient is a removable device. Crutches, bedrest, wheelchairs, and assistive ambulatory devices are probably not effective for offloading without direct intervention at the foot, because of poor patient compliance. Various ambulatory braces,188190 splints,191,192 modied shoes,178 and sandals193 can off-load the plantar surface or immobilise the foot and ankle (or both).194,195 Many of these devices have rigid, rockered outsoles that are very effective in relieving pressure in the forefoot.196 Certain modied half-shoes can off-load a forefoot ulcer area entirely,197 but the value of the other devices depends on how
www.thelancet.com Vol 366 November 12, 2005

Figure 3: Plantar pressure distribution under the foot during (A) barefoot walking and (B) walking in appropriate therapeutic shoes and custom insoles181 Peak pressures are more than 1000 kPa in (A) and less than 200 kPa in (B). This patient had previous ulcers at the site of raised pressure under the hallux.

successfully they reduce weight-bearing pressure on the ulcer. For example, unmodied postsurgical shoes are not effective in relieving load.198 Approaches to load relief in ambulatory devices include felted-foam and other special dressings,199 soft polymeric (sometimes molded) insoles, and orthoses with load-isolation regions.200 In felted-foam 199 dressings, which do not usually need to be applied by a skilled footwear technician, the wound is isolated by the application of layers of felt-backed foam to the skin in areas surrounding, but not on top of, the ulcer. Frequent replacement of all soft insole and dressing materials under the foot might be needed if the material compresses. Relief of mechanical load is also important for nonplantar ulcers, such as those on the posterior aspect of the heel, and the lateral aspect of the midfoot or forefoot. Such ulcers often arise in neuropathic patients during bedrest for a comorbid illness, but are preventable with appropriate precautions.201,202 The prognosis for non-plantar heel ulcers can be predicted from ulcer size and vascular status.203 Ulcers can also be caused by contact between the dorsal surface of deformed toes and footwear that does not provide adequate toe room.204 Pressure on ulcers that occur on
1729

Review

the tips of clawed toes can be unloaded in half shoes, which lack a forefoot weight-bearing area, or in rigid shoes with molded insoles and a deep cut-out for the ulcer. However, if such ulcers recur, practitioners should consider surgical treatment of the toes (see later). For interdigital lesions, the close or overlapping toes must be separated. Ulcers on the plantar aspect of the heel take longer to heal than those on the forefoot in total contact casts185 and could benet from special shoes without a rear-foot platform. Irrespective of the off-loading technique used, patients with an ulcer should be encouraged to reduce their activity levels temporarily. Patients are typically less active in total contact casts than in healing shoes,178 presumably because of the bulk and weight of the irremovable device. Increased activity, with the consequent high cumulative load, can delay or prevent ulcer healing.205,206

reduce ulcer recurrence. Guidelines for the prescription of footwear are not well standardised, and few practitioners measure plantar pressure at previous ulcer sites to ensure that high pressures are reduced by the footwear (gure 3). Available evidence suggests that, in addition to appropriate footwear, provision of patient education224 and regular footcare (including debridement of calluses)225 can help prevent recurrent ulcers.226

Cost-benet analysis
The treatment cost of diabetic foot ulcers must be seen in the context of amputation prevention.4,227 Also, a healed ulcer greatly improves the low quality of life caused by a foot ulcer, whereas failure to heal reduces the quality of life for both patients and their caregivers.228,229 Utility values have been developed230 to calculate quality-adjusted life years (QALY) that might result from differential ulcer treatment. Markov models have predicted a cost per QALY gained of less than $25 000 (13 619) for even relatively low levels of preventive foot care.231 Findings from a simulation study suggest that an intensive prevention strategy could be cost effective if the risk of foot ulcers and amputations are reduced by 25%.232 The cost-effectiveness of ulcer treatment with bioengineered skin substitutes,233 hyperbaric oxygen,234 and growth factor therapy235,236 have been estimated, and modest cost savings over standard wound care have been postulated. However, a systematic review of wound healing treatments has described comparative studies of ulcer healing as being too few to make any denitive conclusions that can guide treatment.237

Surgery to heal foot ulcers

Surgical interventions can both help heal foot ulcers and prevent their recurrence,207,208 but few randomised controlled studies have compared surgical with nonsurgical treatments. Complications of surgery in diabetic patients59 include ulcers at other sites,209 infection,208 and Charcot foot.210 Percutaneous lengthening of the Achilles tendon temporarily reduces pressure under the metatarsal heads,211,212 but carries an additional risk of secondary heel ulcers resulting from an altered gait.209 Percutaneous tenotomy of the toe extensors reduces toe deformity and can hasten ulcer healing and prevent recurrence.213 Some surgeons advocate metatarsal osteotomy210 and resection of prominent214 or all215 metatarsal heads, either prophylactically208 or at the time of ulceration,214 but this procedure poses a risk of secondary ulceration216 or other complications.210,217 If an ulcer occurs at a midfoot prominence, surgical removal of the prominence or creation61 of a more plantigrade (anatomical) foot can lower focal pressures. Occasionally, ulcerectomy and surgical closure of plantar wounds might also be appropriate.218 Currently, no controlled trials exist that compare surgery with medical therapy for foot ulcers. A retrospective analysis of ulcers under the fth metatarsal head showed a reduction in re-ulceration for patients treated surgically.214

Conclusions
We have described the components of assessment and treatment that can help ensure successful and rapid healing of foot ulcers in diabetic patients. These approaches should be used whenever feasible to reduce the high morbidity and risk of serious complications resulting from foot ulcers. There is still much room for improvement in both the types of techniques used and in the assurance that clinicians provide the highest current standard of care.8 Multidisciplinary specialty foot clinics, which combine the expertise of many types of health-care providers, almost certainly will improve the outcome for diabetic persons with foot ulcers.99
Contributors All authors read and approved the nal version. P R Cavanagh was responsible for overall editing and coordination and for all sections apart from those mentioned below. B A Lipsky made substantial contributions to editing and was responsible for the infection section. A W Bradbury was responsible for the perfusion section. G Botek made contributions to the off-loading and surgery sections. Conict of interest statement P R Cavanagh is an investor in DIApedia LLC, State College, PA, USA. B A Lipsky has been a consultant to, received research funds from, and been a speaker for Pzer, Merck, and Cubist Pharmaceuticals. A W Bradbury and G Botek declare that they have no conict of interest.

Prevention of ulcer recurrence

Prevention of ulcer recurrence is a major clinical challenge,219 as shown by recurrence rates ranging from 28% at 12 months220 to 100% at 40 months.221 After complete healing, patients should slowly change to full activity and weightbearing, using appropriate therapeutic footwear with custom insoles that have been prepared in advance.175 Rigid rocker shoes effectively reduce forefoot plantar pressure. Several221,222 but not all223 studies of therapeutic shoes have shown them to
1730

www.thelancet.com Vol 366 November 12, 2005

Review

Acknowledgments P R Cavanagh is funded by the US National Institutes of Health. A W Bradbury is funded by the UK National Health Service (NHS) Research and Development Health Technology Assessment Programme, the British Heart Foundation, the Stroke Association, the European Union, the UK Government Department of Health, Engineering and Physical Science Research Council (EPSRC), the Royal College of Surgeons, the UK Medical Research Council, the Higher Education Council for England, the Heart of England NHS Foundation Trust, and the University of Birmingham School of Medicine. These funding sources had no role in the preparation of this review. We appreciate the editorial assistance of Christine Kassuba and Tammy Owings. References 1 Singh N, Armstrong DG, Lipsky BA. Preventing foot ulcers in patients with diabetes. JAMA 2005; 293: 21728. 2 Abbott CA, Garrow AP, Carrington AL, Morris J, Van Ross ER, Boulton AJ. Foot ulcer risk is lower in South-Asian and AfricanCaribbean compared with European diabetic patients in the UK: the north-west diabetes foot care study. Diabetes Care 2005; 28: 186975. 3 Ramsey SD, Newton K, Blough D, et al. Incidence, outcomes, and cost of foot ulcers in patients with diabetes. Diabetes Care 1999; 22: 38287. 4 Ragnarson Tennvall G, Apelqvist J. Health-economic consequences of diabetic foot lesions. Clin Infect Dis 2004; 39 (suppl 2): S13239. 5 Pecoraro RE, Reiber GE, Burgess EM. Pathways to diabetic limb amputation. Basis for prevention. Diabetes Care 1990; 13: 51321. 6 Margolis DJ, Allen-Taylor L, Hoffstad O, Berlin JA. Diabetic neuropathic foot ulcers and amputation. Wound Repair Regen 2005; 13: 23036. 7 Margolis DJ, Kantor J, Berlin JA. Healing of diabetic neuropathic foot ulcers receiving standard treatment. A meta-analysis. Diabetes Care 1999; 22: 69295. 8 Margolis DJ, Allen-Taylor L, Hoffstad O, Berlin JA. Healing diabetic neuropathic foot ulcers: are we getting better? Diabet Med 2005; 22: 17276. 9 Edmonds ME. Progress in care of the diabetic foot. Lancet 1999; 354: 27072. 10 Bus SA, Yang QX, Wang JH, Smith MB, Wunderlich R, Cavanagh PR. Intrinsic muscle atrophy and toe deformity in the diabetic neuropathic foot: a magnetic resonance imaging study. Diabetes Care 2002; 25: 144450. 11 Aye M, Masson EA. Dermatological care of the diabetic foot. Am J Clin Dermatol 2002; 3: 46374. 12 Bates MC, Aburahma AF. An update on endovascular therapy of the lower extremities. J Endovasc Ther 2004; 11 (suppl 2): II10727. 13 Dijkstra S, vd Bent MJ, vd Brand HJ, et al. Diabetic patients with foot burns. Diabet Med 1997; 14: 108083. 14 Abbas ZG, Lutale J, Archibald LK. Rodent bites on the feet of diabetes patients in Tanzania. Diabet Med 2005; 22: 63133. 15 Zimny S, Schatz H, Pfohl M. The role of limited joint mobility in diabetic patients with an at-risk foot. Diabetes Care 2004; 27: 94246. 16 Connor H, Mahdi OZ. Repetitive ulceration in neuropathic patients. Diabetes Metab Res Rev 2004; 20 (suppl 1): S2328. 17 Robertson DD, Mueller MJ, Smith KE, Commean PK, Pilgram T, Johnson JE. Structural changes in the forefoot of individuals with diabetes and a prior plantar ulcer. J Bone Joint Surg Am 2002; 84A: 1395404. 18 Oyibo SO, Jude EB, Tarawneh I, Nguyen HC, Harkless LB, Boulton AJ. A comparison of two diabetic foot ulcer classication systems: the Wagner and the University of Texas wound classication systems. Diabetes Care 2001; 24: 8488. 19 Treece KA, Macfarlane RM, Pound N, Game FL, Jeffcoate WJ. Validation of a system of foot ulcer classication in diabetes mellitus. Diabet Med 2004; 21: 98791. 20 Schaper NC. Diabetic foot ulcer classication system for research purposes: a progress report on criteria for including patients in research studies. Diabetes Metab Res Rev 2004; 20 (suppl 1): S9095. 21 Lipsky BA, Berendt AR, Deery HG, et al. Diagnosis and treatment of diabetic foot infections. Clin Infect Dis 2004; 39: 885910.

22

23 24

25

26

27 28

29

30

31

32 33

34

35

36

37

38

39

40

41

42

43 44 45

46 47

Burns P, Lima E, Bradbury AW. What constitutes best medical therapy for peripheral arterial disease? Eur J Vasc Endovasc Surg 2002; 24: 612. Burns P, Gough S, Bradbury AW. Management of peripheral arterial disease in primary care. BMJ 2003; 326: 584-88. Hobbs SD, Bradbury AW. Smoking cessation strategies in patients with peripheral arterial disease: an evidence-based approach. Eur J Vasc Endovasc Surg 2003; 26: 341-47. Hobbs SD, Wilmink AB, Adam DJ, Bradbury AW. Assessment of smoking status in patients with peripheral arterial disease. J Vasc Surg 2005; 41: 45156. Hobbs SD, Jones A, Wilmink AB, Bradbury AW. Near patient cholesterol testing in patients with peripheral arterial disease. Eur J Vasc Endovasc Surg 2003; 26: 26771. Prisant LM. Clinical trials and lipid guidelines for type II diabetes. J Clin Pharmacol 2004; 44: 42330. Hirsh J, Bhatt DL. Comparative benets of clopidogrel and aspirin in high-risk patient populations: lessons from the CAPRIE and CURE studies. Arch Intern Med 2004; 164: 210610. Whaley-Connell A, Sowers JR. Hypertension management in type 2 diabetes mellitus: recommendations of the Joint National Committee VII. Endocrinol Metab Clin North Am 2005; 34: 6375. Hobbs SD, Thomas ME, Bradbury AW. Manipulation of the renin angiotensin system in peripheral arterial disease. Eur J Vasc Endovasc Surg 2004; 28: 57382. Jeffcoate WJ, Price P, Harding KG. Wound healing and treatments for people with diabetic foot ulcers. Diabetes Metab Res Rev 2004; 20 (suppl 1): S7889. Sumpio BE. Foot ulcers. N Engl J Med 2000; 343: 78793. Aronow WS. Management of peripheral arterial disease of the lower extremities in elderly patients. J Gerontol A Biol Sci Med Sci 2004; 59: 17277. Dyet JF, Nicholson AA, Ettles DF. Vascular imaging and intervention in peripheral arteries in the diabetic patient. Diabetes Metab Res Rev 2000; 16 (suppl 1): S16-22. Lepantalo M, Biancari F, Tukiainen E. Never amputate without consultation of a vascular surgeon. Diabetes Metab Res Rev 2000; 16 (suppl 1): S2732. Bailey CM, Saha S, Magee TR, Galland RB. A 1 year prospective study of management and outcome of patients presenting with critical lower limb ischaemia. Eur J Vasc Endovasc Surg 2003; 25: 13134. Andros G. Diagnostic and therapeutic arterial interventions in the ulcerated diabetic foot. Diabetes Metab Res Rev 2004; 20 (suppl 1): S2933. Adam DJ, Raptis S, Fitridge RA. Trends in the presentation and surgical management of the acute diabetic foot. Eur J Vasc Endovasc Surg 2005; published online July 14. DOI:10.1016/j.ejvs.2005.05.039. Caruana MF, Bradbury AW, Adam DJ. The validity, reliability, reproducibility and extended utility of ankle to brachial pressure index in current vascular surgical practice. Eur J Vasc Endovasc Surg 2005; 29: 44351. Faries PL, Teodorescu VJ, Morrissey NJ, Hollier LH, Marin ML. The role of surgical revascularization in the management of diabetic foot wounds. Am J Surg 2004; 187: 34S7S. Teodorescu VJ, Chen C, Morrissey N, Faries PL, Marin ML, Hollier LH. Detailed protocol of ischemia and the use of noninvasive vascular laboratory testing in diabetic foot ulcers. Am J Surg 2004; 187: 75S80S. Balbierz JM, Ellis K. Streptococcal infection and necrotizing fasciitisimplications for rehabilitation: a report of 5 cases and review of the literature. Arch Phys Med Rehabil 2004; 85: 120509. Lew DP, Waldvogel FA. Osteomyelitis. Lancet 2004; 364: 36979. Armstrong DG, Lipsky BA. Advances in the treatment of diabetic foot infections. Diabetes Technol Ther 2004; 6: 16777. Lipsky BA. A report from the international consensus on diagnosing and treating the infected diabetic foot. Diabetes Metab Res Rev 2004; 20 (suppl 1): S6877. Jude EB, Unsworth PF. Optimal treatment of infected diabetic foot ulcers. Drugs Aging 2004; 21: 83350. Edmonds ME, Foster A. The use of antibiotics in the diabetic foot. Am J Surg 2004; 187: 25S8S.

www.thelancet.com Vol 366 November 12, 2005

1731

Review

48

49 50

51

52

53

54

55

56

57 58 59 60 61 62 63 64

65

66 67 68

69

70

71 72

73

74

Berendt AR, Lipsky B. Is this bone infected or not? Differentiating neuro-osteoarthropathy from osteomyelitis in the diabetic foot. Curr Diab Rep 2004; 4: 42429. Schweitzer ME, Morrison WB. MR imaging of the diabetic foot. Radiol Clin North Am 2004; 42: 6171. Al-Khawari HA, Al-Saeed OM, Jumaa TH, Chishti F. Evaluating diabetic foot infection with magnetic resonance imaging: Kuwait experience. Med Princ Pract 2005; 14: 16572. Chatha DS, Cunningham PM, Schweitzer ME. MR imaging of the diabetic foot: diagnostic challenges. Radiol Clin North Am 2005; 43: 74759. Illig KA, Moran S, Serletti J, et al. Combined free tissue transfer and infrainguinal bypass graft: an alternative to major amputation in selected patients. J Vasc Surg 2001; 33: 1723. Attinger CE, Ducic I, Cooper P, Zelen CM. The role of intrinsic muscle aps of the foot for bone coverage in foot and ankle defects in diabetic and nondiabetic patients. Plast Reconstr Surg 2002; 110: 104754. Yildirim S, Akan M, Akoz T. Soft-tissue reconstruction of the foot with distally based neurocutaneous aps in diabetic patients. Ann Plast Surg 2002; 48: 25864. Chen SL, Chen TM, Chou TD, Chang SC, Wang HJ. Distally based sural fasciomusculocutaneous ap for chronic calcaneal osteomyelitis in diabetic patients. Ann Plast Surg 2005; 54: 4448. Czerny M, Trubel W, Zimpfer D, et al. Limb-salvage by femorodistal bypass and free muscle ap transfer. Eur J Vasc Endovasc Surg 2004; 27: 63539. Ozkan O, Coskunrat OK, Ozgentas HE. Reliability of free-ap coverage in diabetic foot ulcers. Microsurgery 2005; 25: 10712. Garapati R, Weinfeld SB. Complex reconstruction of the diabetic foot and ankle. Am J Surg 2004; 187: 81S6S. Resch S. Corrective surgery in diabetic foot deformity. Diabetes Metab Res Rev 2004; 20 (suppl 1): S3436. Baravarian B, Van Gils CC. Arthrodesis of the Charcot foot and ankle. Clin Podiatr Med Surg 2004; 21: 27189. Pinzur MS. Surgical versus accommodative treatment for Charcot arthropathy of the midfoot. Foot Ankle Int 2004; 25: 545-49. Lioupis C. The role of distal arterial reconstruction in patients with diabetic foot ischemia. Int J Low Extrem Wounds 2005; 4: 4549. Aronow WS. Management of peripheral arterial disease. Cardiol Rev 2005; 13: 6168. Ruef J, Hofmann M, Haase J. Endovascular interventions in iliac and infrainguinal occlusive artery disease. J Interv Cardiol 2004; 17: 42735. Dormandy JA, Rutherford RB. Management of peripheral arterial disease (PAD). TASC Working Group. TransAtlantic Inter-Society Concensus (TASC). J Vasc Surg 2000; 31: S1S296. Bradbury AW, Ruckley CV. Angioplasty for lower-limb ischaemia: time for randomised controlled trials. Lancet 1996; 347: 27778. Dorrucci V. Treatment of supercial femoral artery occlusive disease. J Cardiovasc Surg (Torino) 2004; 45: 193201. Bradbury AW, Bell J, Lee AJ, et al. Bypass or angioplasty for severe limb ischaemia? A Delphi consensus study. Eur J Vasc Endovasc Surg 2002; 24: 41116. Bradbury AW, Wilmink T, Lee AJ, et al. Bypass versus angioplasty to treat severe limb ischemia: factors that affect treatment preferences of UK surgeons and interventional radiologists. J Vasc Surg 2004; 39: 102632. Akbari CM, Pomposelli FB Jr, Gibbons GW, et al. Lower extremity revascularization in diabetes: late observations. Arch Surg 2000; 135: 45256. Gibbons GW. Lower extremity bypass in patients with diabetic foot ulcers. Surg Clin North Am 2003; 83: 65969. Lauterbach SR, Torres GA, Andros G, Oblath RW. Infragenicular polytetrauoroethylene bypass with distal vein cuffs for limb salvage: a contemporary series. Arch Surg 2005; 140: 48793. Berglund J, Bjorck M, Elfstrom J. Long-term results of above knee femoro-popliteal bypass depend on indication for surgery and graftmaterial. Eur J Vasc Endovasc Surg 2005; 29: 41218. Hobbs SD, Yapanis M, Burns PJ, Wilmink AB, Bradbury AW, Adam DJ. Peri-operative myocardial injury in patients undergoing surgery for critical limb ischaemia. Eur J Vasc Endovasc Surg 2005; 29: 30104.

75

76 77

78

79 80

81 82

83

84

85 86

87

88

89

90

91

92

93

94

95

96

97

98

Ho V, Wirthlin D, Yun H, Allison J. Physician supply, treatment, and amputation rates for peripheral arterial disease. J Vasc Surg 2005; 42: 8187. Machan L. Drug eluting stents in the infrainguinal circulation. Tech Vasc Interv Radiol 2004; 7: 2832. Bockler D, Blaurock P, Mansmann U, et al. Early surgical outcome after failed primary stenting for lower limb occlusive disease. J Endovasc Ther 2005; 12: 1321. Rosenthal D, Martin JD, Schubart PJ, Wellons ED. Remote supercial femoral artery endarterectomy. J Cardiovasc Surg (Torino) 2004; 45: 18592. Bolia A. Subintimial angioplasty, the way forward. Acta Chir Belg 2004; 104: 54754. Lazaris AM, Tsiamis AC, Fishwick G, Bolia A, Bell PR. Clinical outcome of primary infrainguinal subintimal angioplasty in diabetic patients with critical lower limb ischemia. J Endovasc Ther 2004; 11: 44753. Jeffcoate WJ, van Houtum WH. Amputation as a marker of the quality of foot care in diabetes. Diabetologia 2004; 47: 205158. Feinglass J, Rucker-Whitaker C, Lindquist L, McCarthy WJ, Pearce WH. Racial differences in primary and repeat lower extremity amputation: results from a multihospital study. J Vasc Surg 2005; 41: 82329. Ramachandran A. Specic problems of the diabetic foot in developing countries. Diabetes Metab Res Rev 2004; 20 (suppl 1): S1922. Aksoy DY, Gurlek A, Cetinkaya Y, et al. Change in the amputation prole in diabetic foot in a tertiary reference center: efcacy of team working. Exp Clin Endocrinol Diabetes 2004; 112: 52630. Kidmas AT, Nwadiaro CH, Igun GO. Lower limb amputation in Jos, Nigeria. East Afr Med J 2004; 81: 42729. Armstrong DG, Lavery LA, Sariaya M, Ashry H. Leukocytosis is a poor indicator of acute osteomyelitis of the foot in diabetes mellitus. J Foot Ankle Surg 1996; 35: 28083. Resnick HE, Carter EA, Lindsay R, et al. Relation of lowerextremity amputation to all-cause and cardiovascular disease mortality in American Indians: the Strong Heart Study. Diabetes Care 2004; 27: 128693. Inderbitzi R, Buettiker M, Enzler M. The long-term mobility and mortality of patients with peripheral arterial disease following bilateral amputation. Eur J Vasc Endovasc Surg 2003; 26: 5964. Aulivola B, Hile CN, Hamdan AD, et al. Major lower extremity amputation: outcome of a modern series. Arch Surg 2004; 139: 39599. Davis BL, Kuznicki J, Praveen SS, Sferra JJ. Lower-extremity amputations in patients with diabetes: pre- and post-surgical decisions related to successful rehabilitation. Diabetes Metab Res Rev 2004; 20 (suppl 1): S4550. Tentolouris N, Jude EB, Smirnof I, Knowles EA, Boulton AJ. Methicillin-resistant Staphylococcus aureus: an increasing problem in a diabetic foot clinic. Diabet Med 1999; 16: 76771. Ploeg AJ, Lardenoye JW, Vrancken Peeters MP, Breslau PJ. Contemporary series of morbidity and mortality after lower limb amputation. Eur J Vasc Endovasc Surg 2005; 29: 63337. Subramaniam B, Pomposelli F, Talmor D, Park KW. Perioperative and long-term morbidity and mortality after above-knee and belowknee amputations in diabetics and nondiabetics. Anesth Analg 2005; 100: 124147. de Noordhout BM, Pirnay L, de Brogniez A. Early tting of articial limbs to amputated lower limbs. Acta Chir Belg 2004; 104: 39395. Coello R, Charlett A, Wilson J, Ward V, Pearson A, Borriello P. Adverse impact of surgical site infections in English hospitals. J Hosp Infect 2005; 60: 93103. Huang ME, Johns JS, White J, Sanford K. Venous thromboembolism in a rehabilitation setting after major lowerextremity amputation. Arch Phys Med Rehabil 2005; 86: 7378. Wraight PR, Lawrence SM, Campbell DA, Colman PG. Creation of a multidisciplinary, evidence based, clinical guideline for the assessment, investigation and management of acute diabetes related foot complications. Diabet Med 2005; 22: 12736. Stanley S, Turner L. A collaborative care approach to complex diabetic foot ulceration. Br J Nurs 2004; 13: 78893.

1732

www.thelancet.com Vol 366 November 12, 2005

Review

99 100 101 102 103

104 105

106

107

108

109 110

111

112 113 114

115

116 117 118 119 120 121

122

123 124

125

126

Van Damme H, Limet R. [The diabetic foot]. Rev Med Liege 2005; 60: 51625. Sandnes DK, Sobel M, Flum DR. Survival after lower-extremity amputation . J Am Coll Surg 2004; 199: 394402. Horgan O, MacLachlan M. Psychosocial adjustment to lower-limb amputation: a review. Disabil Rehabil 2004; 26: 83750. Saar WE, Lee TH, Berlet GC. The economic burden of diabetic foot and ankle disorders. Foot Ankle Int 2005; 26: 2731. Cruz CP, Eidt JF, Capps C, Kirtley L, Moursi MM. Major lower extremity amputations at a Veterans Affairs hospital. Am J Surg 2003; 186: 44954. Brem H, Sheehan P, Boulton AJ . Protocol for treatment of diabetic foot ulcers. Am J Surg 2004; 187: 1S10S. Dillingham TR, Pezzin LE. Postacute care services use for dysvascular amputees: a population-based study of Massachusetts. Am J Phys Med Rehabil 2005; 84: 14752. Zimny S, Schatz H, Pfohl M. The effects of ulcer size on the wound radius reductions and healing times in neuropathic diabetic foot ulcers. Exp Clin Endocrinol Diabetes 2004; 112: 19194. Wendelken ME, Markowitz L, Patel M, Alvarez OM. Objective, noninvasive wound assessment using B-mode ultrasonography. Wounds 2005; 15: 35160. Margolis DJ, Gelfand JM, Hoffstad O, Berlin JA. Surrogate end points for the treatment of diabetic neuropathic foot ulcers. Diabetes Care 2003; 26: 1696700. Falanga V. Wound healing and its impairment in the diabetic foot. Lancet 2005; 366: 173643. Margolis DJ, Allen-Taylor L, Hoffstad O, Berlin JA. Diabetic neuropathic foot ulcers: predicting which ones will not heal. Am J Med 2003; 115: 62731. Bowler PG, Duerden BI, Armstrong DG. Wound microbiology and associated approaches to wound management. Clin Microbiol Rev 2001; 14: 24469. Bowler PG, Davies BJ. The microbiology of infected and noninfected leg ulcers. Int J Dermatol 1999; 38: 57378. Heggers JP. Dening infection in chronic wounds: methodology. J Wound Care 1998; 7: 45256. Pittet D, Wyssa B, Herter-Clavel C, Kursteiner K, Vaucher J, Lew PD. Outcome of diabetic foot infections treated conservatively: a retrospective cohort study with long-term follow-up. Arch Intern Med 1999; 159: 85156. Grayson ML, Gibbons GW, Balogh K, Levin E, Karchmer AW. Probing to bone in infected pedal ulcers: a clinical sign of underlying osteomyelitis in diabetic patients. JAMA 1995; 273: 72123. Gil HC, Morrison WB. MR imaging of diabetic foot infection. Semin Musculoskelet Radiol 2004; 8: 18998. Morrison WB, Ledermann HP. Work-up of the diabetic foot. Radiol Clin North Am 2002; 40: 117192. Becker W. Imaging osteomyelitis and the diabetic foot. Q J Nucl Med 1999; 43: 920. Lipsky BA, Pecoraro RE, Wheat LJ. The diabetic foot. Soft tissue and bone infection. Infect Dis Clin North Am 1990; 4: 40932. El-Tahawy AT. Bacteriology of diabetic foot. Saudi Med J 2000; 21: 34447. Goldstein EJ, Citron DM, Nesbit CA. Diabetic foot infections. Bacteriology and activity of 10 oral antimicrobial agents against bacteria isolated from consecutive cases. Diabetes Care 1996; 19: 63841. Pathare NA, Bal A, Talvalkar GV, Antani DU. Diabetic foot infections: a study of microorganisms associated with the different Wagner grades. Indian J Pathol Microbiol 1998; 41: 43741. Urbancic-Rovan V, Gubina M. Bacteria in supercial diabetic foot ulcers. Diabet Med 2000; 17: 81415. Viswanathan V, Jasmine JJ, Snehalatha C, Ramachandran A. Prevalence of pathogens in diabetic foot infection in South Indian type 2 diabetic patients. J Assoc Physicians India 2002; 50: 101316. Abdulrazak A, Ibrahim Bitar Z, Ayesh Al-Shamali A, Ahmed Mobasher L. Bacteriological study of diabetic foot infections. J Diabetes Complications 2005; 19: 13841. Johnson S, Lebahn F, Peterson LR, Gerding DN. Use of an anaerobic collection and transport swab device to recover anaerobic bacteria from infected foot ulcers in diabetics. Clin Infect Dis 1995; 20 (suppl 2): S28990.

127 Gerding DN. Foot infections in diabetic patients: the role of anaerobes. Clin Infect Dis 1995; 20 (suppl 2): S28388. 128 Cunha BA. Antibiotic selection for diabetic foot infections: a review. J Foot Ankle Surg 2000; 39: 25357. 129 Teppler H, McCarroll K, Gesser RM, Woods GL. Surgical infections with enterococcus: outcome in patients treated with ertapenem versus piperacillin-tazobactam. Surg Infect (Larchmt) 2002; 3: 33749. 130 Lipsky BA. Evidence-based antibiotic therapy of diabetic foot infections. FEMS Immunol Med Microbiol 1999; 26: 26776. 131 Temple ME, Nahata MC. Pharmacotherapy of lower limb diabetic ulcers. J Am Geriatr Soc 2000; 48: 82228. 132 Roghmann MC, Siddiqui A, Plaisance K, Standiford H. MRSA colonization and the risk of MRSA bacteraemia in hospitalized patients with chronic ulcers. J Hosp Infect 2001; 47: 98103. 133 Game F, Jeffcoate W. MRSA and osteomyelitis of the foot in diabetes. Diabet Med 2004; 21 (suppl 4): 1619. 134 Dang C, Prasad Y, Bouton A, Jude EB. Methicillin-resistant Staphylococcus aureus in the diabetic foot clinic: a worsening problem. Diabet Med 2003; 20: 15961. 135 OMeara SM, Cullum NA, Majid M, Sheldon TA. Systematic review of antimicrobial agents used for chronic wounds. Br J Surg 2001; 88: 421. 136 Sibbald RG. Topical antimicrobials. Ostomy Wound Manage 2003; 49: 1418. 137 Kaye ET. Topical antibacterial agents: role in prophylaxis and treatment of bacterial infections. Curr Clin Top Infect Dis 2000; 20: 4362. 138 Flynn J. Povidone-iodine as a topical antiseptic for treating and preventing wound infection: a literature review. Br J Community Nurs 2003; 8: S3642. 139 Sibbald RG, Orsted H, Schultz GS, Coutts P, Keast D. Preparing the wound bed 2003: focus on infection and inammation. Ostomy Wound Manage 2003; 49: 2351. 140 Rayman G, Rayman A, Baker NR, et al. Sustained silver-releasing dressing in the treatment of diabetic foot ulcers. Br J Nurs 2005; 14: 10914. 141 Lipsky BA, Itani K, Norden C. Treating foot infections in diabetic patients: a randomized, multicenter, open-label trial of linezolid versus ampicillin-sulbactam/amoxicillin-clavulanate. Clin Infect Dis 2004; 38: 1724. 142 Harkless L, Boghossian J, Pollak R, et al. An open-label, randomized study comparing efcacy and safety of intravenous piperacillin/tazobactam and ampicillin/sulbactam for infected diabetic foot ulcers. Surg Infect (Larchmt) 2005; 6: 2740. 143 Lipsky BA, Stoutenburgh U. Daptomycin for treating infected diabetic foot ulcers: evidence from a randomized, controlled trial comparing daptomycin with vancomycin or semi-synthetic penicillins for complicated skin and skin-structure infections. J Antimicrob Chemother 2005; 55: 24045. 144 Lipsky BA, Armstrong DG, Citron DM, Tice AD, Morgenstern DE, Abramson MA. Ertapenem versus piperacillin/tazobactam for diabetic foot infections (SIDESTEP): a prospective, randomised, controlled, double-blinded, multicentre trial. Lancet 2005; 366: 1695703. 145 American Diabetes Association. Consensus development conference on diabetic foot wound care: 78 April 1999, Boston, Massachusetts. Diabetes Care 1999; 22: 3541360. 146 Frykberg RG. Diabetic foot infections: evaluation and management. Adv Wound Care 1998; 11: 32931. 147 Taylor LM Jr, Porter JM. The clinical course of diabetics who require emergent foot surgery because of infection or ischemia. J Vasc Surg 1987; 6: 45459. 148 Van Damme H, Rorive M, Martens De Noorthout BM, Quaniers J, Scheen A, Limet R. Amputations in diabetic patients: a plea for footsparing surgery. Acta Chir Belg 2001; 101: 12329. 149 Ruth Chaytor E. Surgical treatment of the diabetic foot. Diabetes Metab Res Rev 2000; 16 (suppl 1): S6669. 150 Tan JS, Friedman NM, Hazelton-Miller C, Flanagan JP, File TM Jr. Can aggressive treatment of diabetic foot infections reduce the need for above-ankle amputation? Clin Infect Dis 1996; 23: 28691. 151 LoGerfo FW, Misare BD. Current management of the diabetic foot. Adv Surg 1997; 30: 41726.

www.thelancet.com Vol 366 November 12, 2005

1733

Review

152 Chang BB, Darling RC 3rd, Paty PS, Lloyd WE, Shah DM, Leather RP. Expeditious management of ischemic invasive foot infections. Cardiovasc Surg 1996; 4: 79295. 153 Lipsky BA. Osteomyelitis of the foot in diabetic patients. Clin Infect Dis 1997; 25: 131826. 154 Kaleta JL, Fleischli JW, Reilly CH. The diagnosis of osteomyelitis in diabetes using erythrocyte sedimentation rate: a pilot study. J Am Podiatr Med Assoc 2001; 91: 44550. 155 Karr JC. The diagnosis of osteomyelitis in diabetes using erythrocyte sedimentation rate. J Am Podiatr Med Assoc 2002; 92: 314. 156 Greenspan A, Stadalnik RC. A musculoskeletal radiologists view of nuclear medicine. Semin Nucl Med 1997; 27: 37285. 157 Jeffcoate WJ, Lipsky BA. Controversies in diagnosing and managing osteomyelitis of the foot in diabetes. Clin Infect Dis 2004; 39 (suppl 2): S11522. 158 Zuluaga AF, Galvis W, Jaimes F, Vesga O. Lack of microbiological concordance between bone and non-bone specimens in chronic osteomyelitis: an observational study. BMC Infect Dis 2002; 2: 8. 159 Khatri G, Wagner DK, Sohnle PG. Effect of bone biopsy in guiding antimicrobial therapy for osteomyelitis complicating open wounds. Am J Med Sci 2001; 321: 36771. 160 Ha Van G, Siney H, Danan JP, Sachon C, Grimaldi A. Treatment of osteomyelitis in the diabetic foot. Contribution of conservative surgery. Diabetes Care 1996; 19: 125760. 161 Mader JT, Ortiz M, Calhoun JH. Update on the diagnosis and management of osteomyelitis. Clin Podiatr Med Surg 1996; 13: 70124. 162 Eldor R, Raz I, Ben Yehuda A, Boulton AJ. New and experimental approaches to treatment of diabetic foot ulcers: a comprehensive review of emerging treatment strategies. Diabet Med 2004; 21: 116173. 163 Sibbald RG, Mahoney J. A consensus report on the use of vacuumassisted closure in chronic, difcult-to-heal wounds. Ostomy Wound Manage 2003; 49: 5266. 164 Badiavas EV, Abedi M, Butmarc J, Falanga V, Quesenberry P. Participation of bone marrow derived cells in cutaneous wound healing. J Cell Physiol 2003; 196: 24550. 165 Venturi ML, Attinger CE, Mesbahi AN, Hess CL, Graw KS. Mechanisms and clinical applications of the vacuum-assisted closure (VAC) device: a review. Am J Clin Dermatol 2005; 6: 18594. 166 Armstrong DG, Lavery LA, for the Diabetic Foot Study Consortium. Negative pressure wound therapy after partial diabetic foot amputation: a multicentre, randomised controlled trial. Lancet 2005; 366: 170410. 167 Saap LJ, Donohue K, Falanga V. Clinical classication of bioengineered skin use and its correlation with healing of diabetic and venous ulcers. Dermatol Surg 2004; 30: 1095100. 168 Smiell JM, Wieman TJ, Steed DL, Perry BH, Sampson AR, Schwab BH. Efcacy and safety of becaplermin (recombinant human platelet-derived growth factor-BB) in patients with nonhealing, lower extremity diabetic ulcers: a combined analysis of four randomized studies. Wound Repair Regen 1999; 7: 33546. 169 Roeckl-Wiedmann I, Bennett M, Kranke P. Systematic review of hyperbaric oxygen in the management of chronic wounds. Br J Surg 2005; 92: 2432. 170 Steed DL, Donohoe D, Webster MW, Lindsley L. Effect of extensive debridement and treatment on the healing of diabetic foot ulcers. Diabetic Ulcer Study Group. J Am Coll Surg 1996; 183: 6164. 171 Wolff H, Hansson C. Larval therapyan effective method of ulcer debridement. Clin Exp Dermatol 2003; 28: 13437. 172 Horobin AJ, Shakesheff KM, Woodrow S, Robinson C, Pritchard DI. Maggots and wound healing: an investigation of the effects of secretions from Lucilia sericata larvae upon interactions between human dermal broblasts and extracellular matrix components. Br J Dermatol 2003; 148: 92333. 173 Rosales A, Vazquez JR, Short B, et al. Use of a maggot motility index to evaluate survival of therapeutic larvae. J Am Podiatr Med Assoc 2004; 94: 35355. 174 Armstrong DG, Salas P, Short B, et al. Maggot therapy in lowerextremity hospice wound care: fewer amputations and more antibiotic-free days. J Am Podiatr Med Assoc 2005; 95: 25457. 175 Cavanagh PR. Therapeutic footwear for people with diabetes. Diabetes Metab Res Rev 2004; 20 (suppl 1): S5155.

176 Macfarlane RM, Jeffcoate WJ. Factors contributing to the presentation of diabetic foot ulcers. Diabet Med 1997; 14: 86770. 177 Mueller MJ, Diamond JE, Sinacore DR, et al. Total contact casting in treatment of diabetic plantar ulcers. Controlled clinical trial. Diabetes Care 1989; 12: 38488. 178 Armstrong DG, Nguyen HC, Lavery LA, van Schie CH, Boulton AJ, Harkless LB. Off-loading the diabetic foot wound: a randomized clinical trial. Diabetes Care 2001; 24: 101922. 179 Caselli A, Pham H, Giurini JM, Armstrong DG, Veves A. The forefoot-to-rearfoot plantar pressure ratio is increased in severe diabetic neuropathy and can predict foot ulceration. Diabetes Care 2002; 25: 106671. 180 Veves A, Murray HJ, Young MJ, Boulton AJ. The risk of foot ulceration in diabetic patients with high foot pressure: a prospective study. Diabetologia 1992; 35: 66063. 181 Armstrong DG, Lavery LA. Decreasing foot pressures while implementing topical negative pressure (vacuum-assisted closure) therapy. Int J Low Extrem Wounds 2004; 3: 1215. 182 Bus SA, Ulbrecht JS, Cavanagh PR. Pressure relief and load redistribution by custom-made insoles in diabetic patients with neuropathy and foot deformity. Clin Biomech (Bristol, Avon) 2004; 19: 62938. 183 Petre M, Tokar P, Kostar D, Cavanagh PR. Revisiting the total contact cast: maximizing off-loading by wound isolation. Diabetes Care 2005; 28: 92930. 184 Perry JE, Hall JO, Davis BL. Simultaneous measurement of plantar pressure and shear forces in diabetic individuals. Gait Posture 2002; 15: 10107. 185 Nabuurs-Franssen MH, Sleegers R, Huijberts MS, et al. Total contact casting of the diabetic foot in daily practice: a prospective follow-up study. Diabetes Care 2005; 28: 24347. 186 Armstrong DG, Lavery LA, Kimbriel HR, Nixon BP, Boulton AJ. Activity patterns of patients with diabetic foot ulceration: patients with active ulceration may not adhere to a standard pressure offloading regimen. Diabetes Care 2003; 26: 259597. 187 Katz IA, Harlan A, Miranda-Palma B, et al. A randomized trial of two irremovable off-loading devices in the management of plantar neuropathic diabetic foot ulcers. Diabetes Care 2005; 28: 55559. 188 Baumhauer JF, Wervey R, McWilliams J, Harris GF, Shereff MJ. A comparison study of plantar foot pressure in a standardized shoe, total contact cast, and prefabricated pneumatic walking brace. Foot Ankle Int 1997; 18: 2633. 189 Crenshaw SJ, Pollo FE, Brodsky JW. The effect of ankle position on plantar pressure in a short leg walking boot. Foot Ankle Int 2004; 25: 6972. 190 Lavery LA, Vela SA, Lavery DC, Quebedeaux TL. Reducing dynamic foot pressures in high-risk diabetic subjects with foot ulcerations. A comparison of treatments. Diabetes Care 1996; 19: 81821. 191 Hissink RJ, Manning HA, van Baal JG. The MABAL shoe, an alternative method in contact casting for the treatment of neuropathic diabetic foot ulcers. Foot Ankle Int 2000; 21: 32023. 192 Knowles EA, Armstrong DG, Hayat SA, Khawaja KI, Malik RA, Boulton AJ. Ofoading diabetic foot wounds using the scotchcast boot: a retrospective study. Ostomy Wound Manage 2002; 48: 5053. 193 Birke JA, Novick A, Graham SL, Coleman WC, Brasseaux DM. Methods of treating plantar ulcers. Phys Ther 1991; 71: 11622. 194 Snyder RJ, Lanier KK. Ofoading difcult wounds and conditions in diabetic patient. Ostomy Wound Manage 2002; 48: 2228, 30, 3235. 195 van Deursen R. Mechanical loading and off-loading of the plantar surface of the diabetic foot. Clin Infect Dis 2004; 39 (suppl 2): S8791. 196 Brown D, Wertsch JJ, Harris GF, Klein J, Janisse D. Effect of rocker soles on plantar pressures. Arch Phys Med Rehabil 2004; 85: 8186. 197 Chantelau E. Half-shoes for off-loading diabetic plantar ulcers. Diabetes Care 2001; 24: 2016. 198 Giacalone VF, Armstrong DG, Ashry HR, Lavery DC, Harkless LB, Lavery LA. A quantitative assessment of healing sandals and postoperative shoes in ofoading the neuropathic diabetic foot. J Foot Ankle Surg 1997; 36: 2830. 199 Zimny S, Schatz H, Pfohl U. The effects of applied felted foam on wound healing and healing times in the therapy of neuropathic diabetic foot ulcers. Diabet Med 2003; 20: 62225.

1734

www.thelancet.com Vol 366 November 12, 2005

Review

200 Caravaggi C, Faglia E, De Giglio R, et al. Effectiveness and safety of a nonremovable berglass off-bearing cast versus a therapeutic shoe in the treatment of neuropathic foot ulcers: a randomized study. Diabetes Care 2000; 23: 174651. 201 Gilcreast DM, Warren JB, Yoder LH, Clark JJ, Wilson JA, Mays MZ. Research comparing three heel ulcer-prevention devices. J Wound Ostomy Continence Nurs 2005; 32: 11220. 202 Bots TC, Apotheker BF. The prevention of heel pressure ulcers using a hydropolymer dressing in surgical patients. J Wound Care 2004; 13: 37578. 203 Chipchase SY, Treece KA, Pound N, Game FL, Jeffcoate WJ. Heel ulcers dont heal in diabetes. Or do they? Diabet Med 2005; 22: 125862. 204 Henke PK, Blackburn SA, Wainess RW, et al. Osteomyelitis of the foot and toe in adults is a surgical disease: conservative management worsens lower extremity salvage. Ann Surg 2005; 241: 88592. 205 Maluf KS, Mueller MJ. Novel Award 2002. Comparison of physical activity and cumulative plantar tissue stress among subjects with and without diabetes mellitus and a history of recurrent plantar ulcers. Clin Biomech (Bristol, Avon) 2003; 18: 56775. 206 Armstrong DG, Lavery LA, Holtz-Neiderer K, et al. Variability in activity may precede diabetic foot ulceration. Diabetes Care 2004; 27: 198084. 207 Armstrong DG, Frykberg RG. Classifying diabetic foot surgery: toward a rational denition. Diabet Med 2003; 20: 32931. 208 Armstrong DG, Lavery LA, Stern S, Harkless LB. Is prophylactic diabetic foot surgery dangerous? J Foot Ankle Surg 1996; 35: 58589. 209 Holstein P, Lohmann M, Bitsch M, Jorgensen B. Achilles tendon lengthening, the panacea for plantar forefoot ulceration? Diabetes Metab Res Rev 2004; 20 (suppl 1): S3740. 210 Fleischli JE, Anderson RB, Davis WH. Dorsiexion metatarsal osteotomy for treatment of recalcitrant diabetic neuropathic ulcers. Foot Ankle Int 1999; 20: 8085. 211 Mueller MJ, Sinacore DR, Hastings MK, Strube MJ, Johnson JE. Effect of Achilles tendon lengthening on neuropathic plantar ulcers: a randomized clinical trial. J Bone Joint Surg Am 2003; 85A: 143645. 212 Maluf KS, Mueller MJ, Strube MJ, Engsberg JR, Johnson JE. Tendon Achilles lengthening for the treatment of neuropathic ulcers causes a temporary reduction in forefoot pressure associated with changes in plantar exor power rather than ankle motion during gait. J Biomech 2004; 37: 897906. 213 Coughlin MJ. Lesser toe abnormalities. Instr Course Lect 2003; 52: 42144. 214 Armstrong DG, Rosales MA, Gashi A. Efcacy of fth metatarsal head resection for treatment of chronic diabetic foot ulceration. J Am Podiatr Med Assoc 2005; 95: 35356. 215 Giurini JM, Habershaw GM, Chrzan JS. Panmetatarsal head resection in chronic neuropathic ulceration. J Foot Surg 1987; 26: 24952. 216 Petrov O, Pfeifer M, Flood M, Chagares W, Daniele C. Recurrent plantar ulceration following pan metatarsal head resection. J Foot Ankle Surg 1996; 35: 57377. 217 Tillo TH, Giurini JM, Habershaw GM, Chrzan JS, Rowbotham JL. Review of metatarsal osteotomies for the treatment of neuropathic ulcerations. J Am Podiatr Med Assoc 1990; 80: 21117. 218 Piaggesi A, Schipani E, Campi F, et al. Conservative surgical approach versus non-surgical management for diabetic neuropathic foot ulcers: a randomized trial. Diabet Med 1998; 15: 41217.

219 Mantey I, Foster AV, Spencer S, Edmonds ME. Why do foot ulcers recur in diabetic patients? Diabet Med 1999; 16: 24549. 220 Chantelau E, Kushner T, Spraul M. How effective is cushioned therapeutic footwear in protecting diabetic feet? A clinical study. Diabet Med 1990; 7: 35559. 221 Uccioli L, Faglia E, Monticone G, et al. Manufactured shoes in the prevention of diabetic foot ulcers. Diabetes Care 1995; 18: 137677. 222 Busch K, Chantelau E. Effectiveness of a new brand of stock diabetic shoes to protect against diabetic foot ulcer relapse. A prospective cohort study. Diabet Med 2003; 20: 66569. 223 Reiber GE, Smith DG, Wallace C, et al. Effect of therapeutic footwear on foot reulceration in patients with diabetes: a randomized controlled trial. JAMA 2002; 287: 255258. 224 Valk GD, Kriegsman DM, Assendelft WJ. Patient education for preventing diabetic foot ulceration. Cochrane Database Syst Rev 2001; 4: CD001488. 225 Murray HJ, Young MJ, Hollis S, Boulton AJ. The association between callus formation, high pressures and neuropathy in diabetic foot ulceration. Diabet Med 1996; 13: 97982. 226 Pinzur MS, Slovenkai MP, Trepman E, Shields NN. Guidelines for diabetic foot care: recommendations endorsed by the Diabetes Committee of the American Orthopaedic Foot and Ankle Society. Foot Ankle Int 2005; 26: 11319. 227 Apelqvist J. Wound healing in diabetes. Outcome and costs. Clin Podiatr Med Surg 1998; 15: 2139. 228 Nabuurs-Franssen MH, Huijberts MS, Nieuwenhuijzen Kruseman AC, Willems J, Schaper NC. Healthrelated quality of life of diabetic foot ulcer patients and their caregivers. Diabetologia 2005; 48: 190610. 229 Vileikyte L. Diabetic foot ulcers: a quality of life issue. Diabetes Metab Res Rev 2001; 17: 24649. 230 Redekop WK, Stolk EA, Kok E, Lovas K, Kalo Z, Busschbach JJ. Diabetic foot ulcers and amputations: estimates of health utility for use in cost-effectiveness analyses of new treatments. Diabetes Metab 2004; 30: 54956. 231 Ortegon MM, Redekop WK, Niessen LW. Cost-effectiveness of prevention and treatment of the diabetic foot: a Markov analysis. Diabetes Care 2004; 27: 90107. 232 Ragnarson Tennvall G, Apelqvist J. Prevention of diabetes-related foot ulcers and amputations: a cost-utility analysis based on Markov model simulations. Diabetologia 2001; 44: 207787. 233 Redekop WK, McDonnell J, Verboom P, Lovas K, Kalo Z. The cost effectiveness of Apligraf treatment of diabetic foot ulcers. Pharmacoeconomics 2003; 21: 117183. 234 Abidia A, Laden G, Kuhan G, et al. The role of hyperbaric oxygen therapy in ischaemic diabetic lower extremity ulcers: a double-blind randomised-controlled trial. Eur J Vasc Endovasc Surg 2003; 25: 51318. 235 Sibbald RG, Torrance G, Hux M, Attard C, Milkovich N. Costeffectiveness of becaplermin for nonhealing neuropathic diabetic foot ulcers. Ostomy Wound Manage 2003; 49: 7684. 236 Kantor J, Margolis DJ. Treatment options for diabetic neuropathic foot ulcers: a cost-effectiveness analysis. Dermatol Surg 2001; 27: 34751. 237 OMeara SM, Cullum NA, Majid M, Sheldon TA. Systematic reviews of wound care management: (3) antimicrobial agents for chronic wounds; (4) diabetic foot ulceration. Health Technol Assess 2000; 4: 1237.

www.thelancet.com Vol 366 November 12, 2005

1735